Application of asymmetric catalysis for the synthesis and medicinal chemistry study …... ·...

Application of Asymmetric Catalysis for the Synthesis and Medicinal

Chemistry Study of Polyketide Natural Products

by Yanping Wang

B. Eng. in Polymer, Shandong Institute of Light Industry

M.S. in Chemistry, Wuhan University

M.S. in Chemistry, University of Pittsburgh

A dissertation submitted to

The Faculty of

the College of Science of

Northeastern University

in partial fulfillment of the requirements

for the degree of Doctor of Philosophy

June 24, 2014

Dissertation directed by

George A. O’Doherty

Professor of Chemistry and Chemical Biology

ii

ACKNOWLEDGEMENTS

I would like to thank my research advisor, Professor George O’Doherty for the opportunities

to work in his group, for the broad knowledge and sharp insight for chemistry he had taught me

patiently. I also gave my great appreciation to Prof. Geoffrey Coates and Brandon Tiegs, who

helped me to finish and discuss the carbonylation of epoxides for tetrahydrolipstatin project. I

would like to give my thanks to my committee, Professors Graham Jones, Michael Pollastri and

Zhaohui Sunny Zhou for their advice and guidance. Without their help, I could not complete my

dissertation.

I would also like to show my appreciation to my group colleagues, especially Dr. Qian Chen

for his discussion of chemistry with me, and Drs. Huayu Leo Wang and Mike Cuccarese for their

teaching me biological assays. I would like to give my great gratitude to Dr. Roger Kautz, who

taught most knowledge about NMR I had learned.

iii

ABSTRACT

Most polyketide natural products are chiral and exist in enantiomerically pure form, often

containing more than one stereogenic centers. During synthesis of the polyketide natural

products, these centers can be either derived from nature’s chiral pools or from resolution of

racemic mixtures. Alternatively, the chiral center can be installed using asymmetric catalysis.

The asymmetric catalysis approach has the potential to be the most efficient strategy for the

construction of libraries of stereochemical polyketide natural products by the installation

stereochemistry into the achiral starting materials.

Asymmetric catalysis was used to synthesize two categories of polyketide natural products,

cryptocaryols and tetrahydrolipstatin, in 25 and 10 longest linear steps, respectively. In addition,

five cryptocaryol and eight tetrahydrolipstatin stereochemical analogues were also accessed,

which demonstrated the versatility of the catalytic asymmetric approach. The asymmetric

catalysis strategy is also applied to an ongoing project the total synthesis of EBC-23.

These stereochemical analogues were used to develop structure activity relationship profiles

for cryptocaryols and tetrahydrolipstatin cytotoxicity against cancer cell lines (e.g. MCF-7 and

H460).

iv

Table of Contents

Acknowledgements ii

Abstract iii

Table of Contents iv

List of Figures vi

List of Schemes vii

List of Tables viii

List of Abbreviations x

Chapter 1. Cryptocaryol A and B: Total Syntheses, Stereochemical Revision, Structure

Elucidation, Structure-Activity Relationship and Ability to Stabilize PDCD4

1

1.1 Introduction of PDCD4 and cryptocaryols 1

1.2 Restrosynthetic analysis 4

1.3 Synthesis of pseudo-Cs symmetric intermediate 4

1.4 Synthesis of 6-epi-ent-cryptocaryol B 5

1.5 Synthesis of ent-cryptocaryol A and B 8

1.6 Synthesis of cryptocaryol A and B 10

1.7 Synthesis of cryptocaryol analogues 11

1.8 Biological evaluation of cryptocaryol analogues 12

Chapter 2. Total Synthesis of Tetrahydrolipstatin and Stereoisomers via a Highly Regio-

and Diastereoselective Carbonylation of Epoxyhomoallylic Alcohols

20

2.1 Introduction of tetrahydrolipstatin 20

2.2 Retrosynthetic analysis 22

2.3 Formal synthesis of tetrahydrolipstatin 23

2.4 Asymmetric synthesis of cis-epoxyhomoallylic alcohol 24

v

2.5 Total synthesis of tetrahydrolipstatin 25

2.6 Alternative approach to THL 26

2.7 Examination of late stage of carbonylation of epoxides 29

2.8 Syntheis of other THL stereoisomers 35

Chapter 3. Total Synthesis of EBC-23 37

3.1 Introduction of EBC-23 37

3.2 Restrosynthetic analysis of EBC-23 39

3.3 Synthesis of protected diol methyl ketone 40

3.4 Synthesis of acyl chloride 40

3.5 End game of synthesis of EBC-23 41

Experimental Section 43

References 184

vi

Lists of Figures

Figure 1. Tumor-suppressive effects of PDCD4/inhibition of eIF4A 2

Figure 2. Purported structures of cryptocaryols A–H (I-1–I-8) and revised structures of

cryptocaryol A (I-9) and B (I-10)

3

Figure 3. 1H NMR of reported cryptocaryol B and synthesized I-2 7

Figure 4. 13

C NMR comparison of reported cryptocaryol B and synthesized I-2 8

Figure 5. 1H NMR of reported cryptocaryol A and synthesized I-42 9

Figure 6. 13

C NMR comparison of reported cryptocaryol A and synthesized I-42 10

Figure 7. PDCD4 stabilization by cryptocaryol analogues 14

Figure 8. Effect of cryptocaryol A and cryptocaryol B on the cytotoxicity of

camptothecin and digitoxin against MCF-7 cells

15

Figure 9. Changes in CTC/anticancer drug profiles depending on the presence of 20

nM of TPA

17

Figure 10. HT-29 cells were pretreated with PDCD4 stabilizers CTCA, CTCB (1 µM)

and rapamycin (10 nM) followed by DIG or CPT

18

Figure 11. Tetrahydrolipstatin (THL, II-1), lipstatin (II-2) and analogues (II-3) 20

Figure 12. Rationale for loss of regiocontrol for epoxides II-33 and II-35 34

Figure 13. Structures of EBC family members 37

vii

Lists of Schemes

Scheme 1. Retrosynthetic analysis of cryptocaryol A and B 4

Scheme 2. Synthesis of pseudo-Cs symmetric intermediate I-13 5

Scheme 3. Synthesis of 6-epi-ent-cryptocaryol B (I-2) 6

Scheme 4. Synthesis of ent-cryptocaryol A and B (I-42 and I-46) 9

Scheme 5. Synthesis of cryptocaryol A and B (I-9 and I-10) 11

Scheme 6. Synthesis of cryptocaryol analogues for SAR 12

Scheme 7. Regioselective carbonylation of protected cis-epoxyhomoallylic alcohols 21

Scheme 8. Retrosynthetic analysis of THL (II-1) 23

Scheme 9. Formal synthesis of THL (II-1) 24

Scheme 10. Synthesis of cis-epoxyhomoallylic alcohol II-23 25

Scheme 11. Synthesis of THL (II-1): carbonylation of MOM-protected epoxide II-6b 26

Scheme 12. Synthesis of THL (II-1): a late-stage carbonylation of epoxide 29

Scheme 13. Synthesis of diastereomer II-31 30

Scheme 14. Synthesis of stereoisomeric epoxides from II-23 31

Scheme 15. Synthesis of stereoisomeric epoxides from ent-II-23 31

Scheme 16. Synthesis of β-lactones II-40 and II-41 from known β-lactone II-4b 34

Scheme 17. Evidence for minor regioisomer II-40a by thermolysis 35

Scheme 18. Synthesis of THL stereoisomers 36

Scheme 19. Williams’ restrosynthetic analysis of EBC-23 38

Scheme 20. Restrosynthetic analysis of EBC-23 by Yamamoto 39

Scheme 21. Our de novo retrosynthetic analysis of EBC-23 39

Scheme 22. Synthesis of protected diol ketone III-16 40

Scheme 23. Synthesis of acyl chloride III-17 41

Scheme 24. End game of synthesis of EBC-23 41

viii

Lists of Tables

Table 1. Cryptocaryols cytotoxicity data 13

Table 2. Co-dosing effects of the cryptocaryols in MCF-7 cells 16

Table 3. Co-dosing effect of cryptocaryol B and CPT in the presence of TPA in

MCF-7

17

Table 4. Perturbation in IC50 for CPT and DIG in the presence of CTCA, CTCB or

rapamycin against HT-29 cells.

18

Table 5. 1H NMR assignments of THL. 27

Table 6. 1H NMR assignments of THL. 28

Table 7. Stereochemical scope of regioselective carbonylation 33

ix

List of Abbreviations

5FU 5-fluorouracil

[] specific rotation

Ac acetyl

br broad

Boc tert-butoxycarbonyl

calc calculated

CI chemical ionization

CPT camptothecin

CTC cryptocaryol

δ chemical shift

d doublet

DBU 1,8-Diazabicyclo[5.4.0]

DCC Dicyclohexyl Carbodiimide

DIBALH diisobutylaluminium hydride

DIG digitoxin

DIPEA N,N-diisopropylethylamine

DMAP 4-(dimethylamino)pyridine

DMF dimethylformamide

DMSO dimethylsulfoxide

dr diastereomeric ratio

ee enantiomeric excess

equiv equivalent

ESI electrospray ionization

Et ethyl

x

ETO etoposide

FBS fetal bovine serum

g gram

IC50 half maximal inhibitory concentration

h hour(s)

HRMS high resolution mass spectrometry

Hz Hertz

IR infra red

J coupling constant

k kilo-

L liter

LAH lithium aluminum hydride

m milli; multiplet

M molar

Me methyl

Mes 2,4,6-trimethylphenyl (mesityl)

MHz megahertz

min minute(s)

mol mole

MOM methoxymethyl

mp melting point

MW molecular weight

MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NBS N-iodosuccinimide

NMR nuclear magnetic resonance

xi

OXA oxaliplatin

Ph phenyl

PKC protein kinase C

PMB para-methoxybenzyl

Pr propyl

PVDF polyvinylidene fluoride

q quartet

rt room temperature

Rf retention factor

s second; singlet

SiO2 silica gel

sp species

t ,t tert, triplet

TBAF tetrabutylammonium fluoride

TBS t-butyldimethylsilyl

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TPA 12-O-tetradecanoylphorbol-13-acetate

TsOH para-toluenesulfonic acid

1

Chapter 1

Cryptocaryol A and B: Total Syntheses, Stereochemical Revision, Structure

Elucidation, Structure-Activity Relationship and Ability to Stabilize PDCD4*

1.1 Introduction of PDCD4 and cryptocaryols

The early success and subsequent limitation found with the development of protein kinase C

(PKC) as a target for cancer and other diseases, have led to the search for alternative downstream

kinase targets for development (e.g., mTOR, Akt).1 It is believed that the regulation of these

new targets will selectively produce all the desired outcomes (e.g., tumor suppression) without

side effects (e.g., non-cancer cell toxicity).2 Programmed cell death 4 (PDCD4), a downstream

target of Akt, is a novel tumor suppressor protein (Figure 1).3 PDCD4 interaction with eukaryotic

initiation factor 4A (eIF4A) inhibits protein synthesis.4 In addition, PDCD4 suppresses the

activation of activator protein-1 (AP-1) through c-Jun.5 Not surprisingly, the stabilization of

PDCD4 is linked to the induction of apoptosis.6 Also, expression of PDCD4 has been shown to

confer increased sensitivity to some anti-cancer drugs and reduce the malignancy of ovarian

cancer cells.7 Conversely, its low expression levels are linked with the progression of several

cancers (e.g., lung, liver, ovary and brain).8 Loss of PDCD4 is observed in lung, breast, colon

and prostate cancers.4d

Similarly, in a panel of 124 lung cancer patients, expression of PDCD4 in

tumor cells was inversely related to poor prognosis.9 Thus, PDCD4 is a target for the

development of novel antineoplastic agents.10

* Wang, Y.; O’Doherty, G. A. J. Am. Chem. Soc. 2013, 135, 9334-9337. Cuccarese, M. F.; Wang, Y.; Beuning, P.

J.; O’Doherty, G. A. ACS Med. Chem. Lett. 2014, 5, 522-526. (The synthetic work and cytotoxicity assays were

carried out by YW; and the immunoblot experiment by MFC). Reproduced by permission of American Chemical

Society.

2

PDCD4 is degraded within the cell via a discrete pathway. Phosphorylation of PDCD4 by

PI3K/Akt leads to ubiquitination and proteasomal degradation.11

This degradation (aka,

destabilization) appears to be increased in some tumors.3 Given the benefits of PDCD4

expression, stabilization of PDCD4 is an attractive way to elevate PDCD4 levels, and holds the

potential to increase cancer cell sensitivity to chemotherapy. Rapamycin (RAP) is known to both

stabilize PDCD4 and synergize with anticancer drugs;12

unfortunately, the use of rapamycin in

cancer treatment is hindered by its immunosuppressive effects.13

Figure 1. Tumor-suppressive effects of PDCD4/inhibition of eIF4A.a

a PDCD4 is an inhibitor of protein synthesis via inhibition of initiation factor eIF4A. The E3 ubiquitin ligase -TrCP

binds to phosphorylated PDCD4, targeting it for ubiquitination and degradation via the 26S proteasome. TPA

activates PKC, which initiates phosphorylation and degradation of PDCD4 via PI3K, Akt or mTOR. Stabilizers of

PDCD4 interfere with the degradation of PDCD4 (i.e., rapamycin inhibits mTOR, reducing PDCD4

phosphorylation).

In an effort to find natural products that stabilize levels of PDCD4, Gustafson et al.

developed a high-throughput in vivo cell-based assay that identified cryptocaryols A–H (I-1–I-8)

(Figure 2).14

This class of natural products isolated from Cryptocarya spp. shares a 5,6-dihydro-

α-pyranone and a 1,3-polyol segment. In addition, the eight cryptocaryols stablized PDCD4 in

3

12-O-tetradecanoylphorbol-13-acetate (TPA) challenged cells with EC50 ranging from 1.3 to 4.9

µM. The structures of these compounds were elucidated by a combination of NMR, HRMS and

CD analyses. The all syn-tetraol relative configuration was assigned using Kishi's 13

C NMR

database,15

and the absolute configuration of pyranone at C-6 was assigned as R from its Cotton

effect.16

Unfortunately, the development and interpretation of structure-activity relationship

(SAR) data was limited by the ambiguities associated with the absolute and relative

stereochemistry of these structures.17

Figure 2. Purported structures of cryptocaryols A–H (I-1–I-8) and revised structures of cryptocaryol A

(I-9) and B (I-10).

aEC50 = µM concentration for recovery of 50% PDCD4 concentration from TPA-induced degradation in

HEK293 cell lines. bIC50 = µM concentration for cytotoxicity activity against MCF-7 cell lines.

1.2 Restrosynthetic analysis

Thus, we devised a plan for the synthesis of cryptocaryol A and B with the aims of

establishing the 3D structure and providing material for SAR studies (Scheme 1). In particular,

we envisioned an approach that would take advantage of the pseudo-Cs symmetry of a tetraol

fragment in I-13,18

which would be amenable for the synthesis of the purported structures of

these natural products (I-1 and I-2), along with their enantiomers (I-12) and C-6/16-

diastereomers (e.g., I-9, I-10 and I-11). Recently, we developed an iterative hydration of polyene

4

strategy to build 1,3-polyols,19

which has proved to be extremely successful for the syntheses of

related 1,3-polyol natural products20

as well as more complicated variants.21

Scheme 1. Retrosynthetic analysis of cryptocaryol A and B

1.3 Synthesis of pseudo-Cs symmetric intermediate

Towards this end, we began with the synthesis of orthogonally protected pentaol I-13 from

commercially available 5-hexyn-1-ol (I-16) (Scheme 2). The primary alcohol was protected as a

PMB ether I-17, and the terminal alkyne in I-17 was homologated (n-BuLi/methyl

chloroformate, I-17 to I-18) and then subsequently isomerized (PPh3/PhOH)22

to give dienoate I-

19 in an excellent overall yield for three steps (88%). The distal double bond of dienoate I-19

was asymmetrically oxidized under the Sharpless conditions ((DHQ)2PHAL) to give a 2-enoate-

4,5-diol I-20,23

which upon treatment with triphosgene and pyridine gave carbonate I-21. A Pd-

catalyzed regioselective reduction of I-21 with (Et3N/HCO2H, catalytic Pd/PPh3) produced δ-

hydroxy enoate I-22. Acetal formation using the Evans’ conditions (benzaldehyde/KOt-Bu)

diastereoselectively transformed I-22 into benzylidene protected syn-1,3-diol I-23.24

Thus in

four steps, the initial protected diol fragment of I-13 was installed in I-23 from I-19.

The installation of the second protected diol fragment of I-13 began with an ester to aldehyde

reduction of I-23 (DIBALH) followed by Leighton allylation to give homoallylic alcohol I-25.25

5

The homoallylic alcohol stereochemistry of I-25 was used to stereospecifically install the final

benzylidene protected diol fragment. This was accomplished with a two-step cross metathesis

(ethyl acrylate/Grubbs II) and Evans’ acetal formation sequence to furnish the pentaol I-13 via δ-

hydroxy enoate I-26.26

Scheme 2. Synthesis of pseudo-Cs symmetric intermediate I-13

1.4 Synthesis of 6-epi-ent-cryptocaryol B

With the key pentaol I-13 in hand, our efforts were turned to the synthesis of the purported

cryptocaryol A (I-1) and B (I-2). The PMB group in I-13 was deprotected with DDQ to release

the primary alcohol I-27, which then was oxidized with DMP to afford aldehyde I-28 (Scheme

3). Nucleophilic alkyne addition (1-pentadecyne/n-BuLi, –78 °C) to aldehyde I-28 gave a

propargyl alcohol, which upon oxidation (Dess–Martin) and asymmetric reduction (Noyori)

diastereoselectively gave propargyl alcohol I-30 via ynone I-29.27

The alkyne in I-30 was

reduced to alkane I-31 with excess diimide (NBSH/Et3N). A two-step DIBALH reduction and

alcohol acylation procedure on ester I-31 produced aldehyde I-33 via alcohol I-32. The final

stereocenter in I-2 was installed to afford homoallylic alcohol I-34 with the use of a second

6

Leighton allylation, which after acylation (acrylic acid/DCC) was then converted into diene I-35.

A ring closing metathesis (Grubbs I) installed the desired pyranone to give I-36, which after

benzylidene deprotection (AcOH/H2O) furnished the structure purported to be cryptocaryol B (I-

2).17

Scheme 3. Synthesis of 6-epi-ent-cryptocaryol B (I-2)

Although great similarities existed between the 1H and

13C NMR spectra of I-2 and the data

reported for cryptocaryol B,14

our analysis led us to conclude that they did not match (Figure 3

and Figure 4).17

This included discrepancies in the 1H NMR (e.g., H-5a/H-5b, H-7a/H-7b, and H-

8) and the 13

C NMR (C-6, C-7 and C-8), with the variances (0.6 to 0.9 ppm) in the 13

C NMR

values being the hardest to reconcile. In order to gain a locus for further comparison, we

attempted to convert I-2 into the structure reported for cryptocaryol A (I-1). Unfortunately, we

were unable to find conditions to selectively hydrolyze the C-16 acetate without concomitant

hydrolysis of the pyranone ring. Next, we targeted the C-6 diastereomers of I-1 and I-2 (I-42 and

7

I-46, respectively), as the stereochemical relationship between the C-6 and C-8 positions was

ambiguously assigned by Gustafson.14

Moreover, we found the greatest variance in the C-5 to C-

9 positions in our comparison of the 1H and

13C NMR.

Figure 3. 1H NMR of reported cryptocaryol B and synthesized I-2

1H NMR of reported cryptocaryol B

1H NMR of synthesized I-2

8 5 7

8 5

7

8

Figure 4. 13

C NMR comparison of reported cryptocaryol B and synthesized I-2

Difference of chemical shift between reportedcryptocaryol B (I) and synthesized I-2 (II)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

-2

-1

0

1

2II-I

Carbon Number

1.5 Synthesis of ent-cryptocaryol A and B

These revised efforts returned to alcohol I-31 and involved the use of the enantiomeric (R,R)-

Leighton reagent (Scheme 4). In practice, we protected the secondary alcohol in I-31 as a TBS

ether I-37 and reduced the ester to aldehyde I-38. Application of the diasteromeric Leighton

allylation, acylation (acrylic acid/DCC) gave diene I-40 via homoallylic alcohol I-39, which in

two steps (Grubbs I; AcOH/H2O) was converted into I-42. The 1H NMR and

13C NMR spectral

data (Figure 5 and Figure 6) for synthetic I-42 were found to be identical to the data reported for

cryptocaryol A, with the exception of optical rotation (reported: [α]D = +12 (c = 0.1, MeOH);

synthetic: [α]D21

= –13.4 (c = 0.1, MeOH)). Replacing the TBS group in I-40 with an acetate

group (TBAF; Ac2O/Et3N) gave I-44 via alcohol I-43, the precursor for ent-cryptocaryol B,

which in two steps (Grubbs I; AcOH/H2O) was converted into I-46. Once again, the spectral data

for synthetic I-46 was identical to the data reported for cryptocaryol B.14

Thus the structures for

cryptocaryol A and B should be reassigned to I-9 and I-10, respectively.

9

Scheme 4. Synthesis of ent-cryptocaryol A and B (I-42 and I-46)

Figure 5. 1H NMR of reported cryptocaryol A and synthesized I-42

1H NMR of reported cryptocaryol A

1H NMR of synthesized of I-42

10

Figure 6. 13

C NMR comparison of reported cryptocaryol A and synthesized I-42

Difference of chemical shift between reportedcryptocaryol A (I) and synthesized I-42 (II)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

-1.0

-0.5

0.0

0.5

1.0 II-I

Carbon Number

1.6 Synthesis of cryptocaryol A and B

With the elucidation of the structures for the cryptocaryol A and B, we set out to undertake

their enantioselective synthesis and biological evaluation as anticancer agents. This effort began

with pseudo-Cs symmetric protected pentaol I-13, and requires the reversal in the order of

pyranone and side chain installation (Scheme 5). The revised route begins with the conversion of

ester I-13 into ynone I-48 (DIBALH; 1-pentadecyne; Dess–Martin). The C-16 stereochemistry

was installed in alcohol I-50 by a two-step Noyori asymmetric and diimide reduction procedure.

Adjustments of the protecting groups involved the protection of the C-16 alcohol of I-50 as a

TBS group (TBSCl) followed by PMB deprotection (DDQ) to give I-52. Oxidation of the

primary alcohol in I-52 (Dess–Martin) followed by Leighton allylation and acrylate acylation

(acrylic acid/DCC) provided diene I-55, from which I-58 was prepared with the required C-16

acetate group. Using the same ring closing metathesis/deprotection sequence, the dienes I-55 and

I-58 were uneventfully converted into cryptocaryol A (I-9) and B (I-10). The 1H and

13C NMR

data for the synthetic material were identical to the data reported for the isolated material.

11

Scheme 5. Synthesis of cryptocaryol A and B (I-9 and I-10)

1.7 Synthesis of cryptocaryol analogues

In addition to providing ample material (>5 mg/each) for structural elucidation, the route also

provided enough material for the cancer cell cytotoxicity studies. As part of these SAR studies,

additional analogues (hexaol I-60, hexaol acetate I-63 and saturated pyranone compound I-64)

were required for evaluation. These analogues were readily prepared from intermediates I-50 and

I-52, and cryptocaryol B (I-10) by deprotection of benzylidene and hydrogenation of alkene,

respectively (Scheme 6).

12

Scheme 6. Synthesis of cryptocaryol analogues for SAR

1.8 Biological evaluation of cryptocaryol analogues

While other PDCD4 stabilizers are known to be cytotoxic, there is very little data to correlate

their cytotoxicity to PDCD4 stabilization.28

We chose three cancer cell lines to evaluate

cytotoxicity for the eight polyols. Three cell lines selected for study were chosen based on their

basal PDCD4 contents as measured by RNA microarray and protein content analysis by

immunoblot. The first cell line studied was MCF-7, which has been shown to have high

expression levels of PDCD4. The second cell line chosen was HT-29, which has a medium

expression level of PDCD4. The third cell line studied was H460, which has very low expression

levels of PDCD4.7

Both cryptocaryols A and B possessed growth inhibitory activity against the three cell lines

in the micromolar range (Table 1). The relative cytotoxicity of the cryptocaryols was consistent

with their PDCD4 stabilizing activity (i.e., I-10 slightly more active than I-9) for each cell line;

however, the cell line sensitivity to a given compound did not correlate with the cell line’s

PDCD4 expression levels. That is to say, HT-29 cell lines, with the medium level of PDCD4

13

expression, were the most sensitive (e.g., 4.2 µM for I-9); whereas, MCF-7 cells, with the

highest level of PDCD4 expression were the least sensitive (e.g., 8.1 µM for I-9). This trend held

true for cryptocaryols A and B (I-9/I-10) as well as the diastereomers I-2, I-42 and I-46. The

pyranone functionality was identified to be an important pharmacophore, as the two analogues,

I-53 and I-56, without a pyranone ring and the one without the double bond I-57 were least

active. The stereochemistry of the pyranone ring has some importance for cytotoxicity, as the

diastereomer I-2 (with only the C-6 pyrano-stereocenter retained) had a small loss in cytotoxicity

(~2 fold). The effect of C-16 acylation could be seen in the comparison between cryptocaryols A

and B (I-9/I-10), as well as, I-60/I-63, which lacked the pyranone ring. Surprisingly, the

stereochemistry of natural products did not have a significant effect on cytotoxicity as ent-

cryptocaryol B (I-46) and ent-cryptocaryol A (I-42) had only a 2- to 3- fold loss in cytotoxicity.

Table 1. Cryptocaryols cytotoxicity data

Compound (1 µM) Cell Line, IC50 (µM)

a [rel.]

MCF-7 HT-29 H460 PDCD4b

cryptocaryol A (I-9) 8.1 4.2 5.4 3.6

cryptocaryol B (I-10) 5.8 2.9 3.8 4.5

ent-cryptocaryol A (I-42) 25.8 4.1 7.9 3.8

ent-cryptocaryol B (I-46) 9.0 2.4 4.0 3.6

6-epi-ent-cryptocaryol B (I-2) 13.3 4.9 7.8 1.9

hexaol (I-60) 162 1278 >1000 1.8

hexaol Ac (I-63) 133 108 >1000 2.8

2H-cryptocaryol B (I-64) >500 >1500 >1500 N/A aIC50 was determined via MTT colorimetric analysis and curve fitting in Graphpad

® Prism.

bPDCD4 stabilization is

presented as a relative value over cells treated only with TPA (see Figure 7).

In addition, seven compounds were evaluated for their ability to stabilize PDCD4 (The

experiment was carried out by Dr. Mike Cuccarese). This analysis by immunoblot followed the

protocol described by Tobias Schmid,28

which useed the TPA to initiate PDCD4 degradation,

with the known PDCD4 stabilizer, rapamycin, as the positive control. The high expression level

of MCF-79 made it the ideal cell line for PDCD4 stabilization studies. These results are outlined

in Table 1 and Figure 7. Cryptocaryols A and B both showed significant ability to stabilize

14

PDCD4 levels, with cryptocaryol B being a slightly better stabilizer than A, which was in line

with the results found by Gustafson’s high throughput screen.14

To our surprise, the cryptocaryol

diastereomers also showed the ability to stabilize PDCD4 levels. It is also noteworthy that both

hexaol I-60 and hexaol acetate I-63, which lack of the pyranone ring retained significant PDCD4

stabilizing ability, while essentially losing all cytotoxicity (>10 fold). As with the cytotoxicity,

the polyol with the C-16 acetate was a better stabilizer than the one without the acetate.

Figure 7. PDCD4 stabilization by cryptocaryol analogues

Pdcd4 L

evel

NT

TPARAP

CTC

A

CTC

B

ent-C

TCA

ent-C

TCB

6-epi-ent

-CTC

B

Hex

aol

Hex

aol-A

c0

2

4

6

8

MCF-7 cells were seeded at 100,000 cells per well in 12-well plates. After 24 h, cells were treated with RAP

(10 nM) or cryptocaryol analogues (1 µM). After 30 min, cells were treated with TPA (20 nM). After an additional 6

h, cells were harvested by scraping and lysed with RIPA buffer. Gel electrophoresis was carried out with 16 µL of

cell lysate on a 12% polyacrylamide gel and transferred to a PVDF membrane. Western analysis was performed

with antibodies for PDCD4 (Abcam ab87678) and β-actin (Abcam ab8226), and visualized with

chemiluminescence. Contrast was adjusted uniformly over the image for clarity. Band density measurements

(Imagestudio) were made prior to contrast-adjustment. Bars are band density relative to TPA only, which was set to

1. (CTC = cryptocaryol. The experiment was carried out by Dr. Mike Cuccarese)

Encouraged by the significant PDCD4 stabilization, we further explored the potential use of

cryptocaryols in combination with other anticancer drugs to determine if PDCD4 stabilization

could result in an enhanced anticancer effect. These studies were carried out in both MCF-7

(Figures 8 and 9) and HT-29 (Figure 10) cell lines. The co-dosing studies were performed first

with just the combination of cryptocaryol and cancer drug and later with the addition of TPA,

which might better mimic the tumor environment where PDCD4 is more rapidly degraded.

15

Figure 8. Effect of cryptocaryol A and cryptocaryol B on the cytotoxicity of camptothecin and digitoxin

against MCF-7 cells.a

Cryptocaryol A with CPT against MCF-7

-2 0 2 4 60

20

40

60

80

100

log(nM)

%v

iab

ility

1 nM

10 nM

100 nM

1 µM

CPT

Cryptocaryol A with DIG against MCF-7

-2 0 2 4 60

20

40

60

80

100

log(nM)

%v

iab

ility

1 nM

10 nM

100 nM

1 µM

DIG

Cryptocaryol B with CPT against MCF-7

-2 0 2 4 60

20

40

60

80

100

log(nM)

%v

iab

ility

1 nM

10 nM

100 nM

1 µM

CPT

-2 0 2 4 60

20

40

60

80

100

Cryptocaryol B with DIG against MCF-7

log(nM)

%v

iab

ility

DIG

1 µM

100 nM

10 nM

1 nM

aCells were pre-treated with 1 nM to 1 µM of CTCA or CTCB followed by CPT or DIG and cytotoxicity was

measured by MTT after 72 h. No enhancement of anticancer activity was observed following treatment with

cryptocaryols.

We initially studied whether simple co-dosing of cryptocaryols A and B would reveal a

synergistic effect in MCF-7 cells. Adopting a drug combination strategy from our gentamicin-

induced sensitization studies,29

our results are outlined in Figure 8 and Table 2. MCF-7 cells

were treated with several concentrations of cryptocaryol A and cryptocaryol B followed by

camptothecin and digitoxin. Similar results were observed with HT-29 cells (Figure 10). No

enhancement of cytotoxicity for either anticancer drug was observed. Chou-Talalay analysis of

this data gave CI @ ED75 values in the range of 1.3 to 0.8, which are consistent with no

synergistic relationship between the two drugs.14

Table 2. Co-dosing effects of the cryptocaryols in MCF-7 cells

IC50 (102 nM)

a

Co-Drug cryptocaryol A cryptocaryol B

16

Drug CPT DIG CPT DIG

0 nM 1.39 3.27 0.99 2.04

1 nM 1.24 4.35 0.86 3.46

10 nM 1.33 3.06 1.05 2.75

100 nM 1.08 4.74 1.38 2.86

1 µM 0.81 4.86 1.13 2.99 bCI @ ED75 0.78 1.34 1.12 1.04

cRel. PDCD4 3.6 4.5

aIC50 for CPT and DIG in combination with cryptocaryols.

bCI @ ED75 was calculated via Chou-Talalay

(Calcusyn). No synergistic relationship was observed. cCryptocaryols with the highest PDCD4 stabilization activity

were chosen. PDCD4 stabilization activity does not enhance the cytotoxicity of CPT or DIG in MCF-7.

To further probe for a sensitization for the PDCD4 stabilizers we decided to perform the co-

dosing studies in the presence of TPA, which reduces PDCD4 levels by interaction with PKC.

This experiment was performed for four cancer drugs (CPT, ETO, 5FU, OXA), but only clean

dose-response curves could be obtained for camptothecin (Figure 9). Thus, MCF-7 cells were

exposed to a range of camptothecin doses in the presence of TPA (20 nM) and cryptocaryol B (1

µM). Using similar conditions to our Western blot studies (i.e., where PDCD4 stabilization was

observed), the cells were dosed with cryptocaryol B 30 minutes prior to addition of TPA. After

an additional 8 h, cells were treated with a range of CPT concentrations. Under these conditions,

no sensitization effect could be seen. In fact, TPA had a larger protective effect than cryptocaryol

B.

Figure 9. Changes in CTC/anticancer drug profiles depending on the presence of 20 nM of TPA.a

17

-2 0 2 4 60

20

40

60

80

100

log(nM)

% v

iab

ility

CTCB/TPA/CPT

TPA/CPT

aWhen MCF-7 cells were treated with 1 µM CTCA or CTCB and anticancer drugs, the presence of TPA had no

effect, indicating that the degradation of PDCD4 with TPA and recovery with CTCB did not play a role in

cytotoxicity.

Table 3. Co-dosing effect of cryptocaryol B and CPT in the presence of TPA in MCF-7

Treatment CPT IC50 (102 nM)

a

No combination 1.41

20 nM TPA 2.14

1 µM CTCB+TPA 2.02

aAn increase in cell viability was observed in the presence of TPA, whereas pretreatment with CTCB had no further

effect on cytotoxicity of CPT. Drugs with lower cytotoxicity (ETO, 5FU, OXA, see SI) were also tested but accurate

IC50 measurements could not be calculated.

Using the optimized conditions we found for MCF-7 (Table 1, entry 5), we also screened for

a sensitizing effect in HT-29 cells. With 12 h pretreatment with PDCD4 stabilizers, sensitivity of

HT-29 cells to 5FU and CPT was unchanged and appeared to have an antagonistic effect with

DIG. The HT-29 cell line was the most sensitive to the cryptocaryols (Figure 10 and Table 4)

and expressed a moderate level of PDCD4. These studies were conducted with 1 µM

cryptocaryols A or B and at a range of cancer drug doses (camptothecin and digitoxin) without

the use of TPA. As was observed for MCF-7, no enhancement in cytotoxicity between

cryptocaryols (CTCA and CTCB) and anticancer drugs (CPT and DIG) could be observed. This

dose-response assay was also performed for CPT with CTCB in the presence of TPA, once again

no significant enhancement in cytotoxicity was observed (see SI). Similar studies were also

carried out with 5FU, but these gave inconclusive dose-response curves without observable

18

IC50s.30

Interestingly, rapamycin, a well-known PDCD4 stabilizer,31

also showed no significant

enhancement in this co-dosing cytotoxicity assay. This result indicated that the PDCD4 levels in

these cells tested did not necessarily function as the apoptosis factor as expected, or the low level

of PDCD4 did not sensiticize the cancer cells to the cancer drugs.

Figure 10. HT-29 cells were pretreated with PDCD4 stabilizers CTCA, CTCB (1 µM) and rapamycin (10

nM) followed by DIG or CPT.

-2 0 2 4 6

0

50

100

CTCA/DIG

DIG

CTCB/DIG

Rapamycin/DIG

log(nM)

% v

iab

ility

-2 0 2 4 6

0

50

100

CTCA/CPT

CPT

CTCB/CPT

Rapamycin/CPT

log(nM)

% v

iab

ility

Table 4. Perturbation in IC50 for CPT and DIG in the presence of CTCA, CTCB or rapamycin against

HT-29 cells. Drug, IC50 (10

2 nM)

a

Co-Drug PDCD4

Stabil. CPT DIG

no co-drug 0 2.07 1.52

1 µM CTCA (1) 3.6 1.87 2.04

1 µM CTCB (2) 4.5 2.14 2.24

10 nM rapamycin 6.6 1.84 2.00 aNo significant change in IC50 was observed.

In conclusion, the first total synthesis, structural elucidation/correction and SAR of

cryptocaryol A and B have been achieved. The enantioselective synthesis was accomplished in

23 and 25-step linear sequence, respectively, from commercially available 5-hexyn-1-ol. The

stereochemically divergent synthesis concisely enabled the exact stereochemical assignment. It is

worth noting that the difficulties in distinguishing between the two diastereomers (e.g., I-2 and I-

10) demonstrate the need for stereochemically divergent approaches for structural determination.

19

We have determined the cytotoxicity of both cryptocaryols A and B in three cell lines as well as

for several analogues. In addition, the ability to stabilize the tumor suppressor PDCD4 was also

determined for these compounds. Rudimentary structure activity relationships could be drawn as

structures with the best PDCD4 stabilizing ability tending to be the most cytotoxic. However,

changes to the structures that removed cytotoxicity (e.g., I-60 and I-63) did not completely

remove the PDCD4 stabilizing activity. To our surprise, both the cytotoxicity and PDCD4

stabilizing ability were tolerant to changes in stereochemistry, as enantiomers (e.g., I-42 and I-

46) and diastereomers (e.g., I-2) retained significant activity in both assays. For the two most

potent PDCD4 stabilizers, cryptocaryols A and B, no sensitization effects could be seen in co-

dosing studies with several cancer drugs (CPT, DIG, 5FU) in two different cancer cell lines

(MCF-7 and HT-29). Further efforts to elucidate the mechanism of action for this class of natural

products are ongoing.

20

Chapter 2

Total Synthesis of Tetrahydrolipstatin and Stereoisomers via a Highly Regio-

and Diastereoselective Carbonylation of Epoxyhomoallylic Alcohols†

2.1 Introduction of tetrahydrolipstatin

Tetrahydrolipstatin (THL, II-1) is an over-the-counter anti-obesity drug that acts by

inhibiting the absorption of dietary fats. THL is the saturated form of lipstatin (II-2), a natural

product isolated from Streptomyces toxytricini in 1987.32

Due to its greater stability, THL was

chosen over lipstatin for pharmaceutical development. Both THL and lipstatin contain an α-

alkylated β,δ-dihydroxy acid which exists in the β-lactone form (Figure 11). The β-lactone in

THL and lipstatin is believed to ring-open and covalently bind to pancreatic lipase, which results

in irreversible inhibition.32a,33

In addition, THL and related β-lactones have been found to inhibit

the thioesterase domain of fatty acid synthase (FAS),34

the inhibition of which has been linked to

anticancer activity.35

More recently, THL has been shown to inhibit the in vitro growth of G.

duodenalis, the causative parasite of the gastrointestinal disease giardiasis.36

Figure 11. Tetrahydrolipstatin (THL, II-1), lipstatin (II-2) and analogues (II-3)

Since the first synthesis of THL by Schneider,37a

there have been numerous total37–43

and

† Portion of the chapter will appear in a manuscript that was submitted for publication. This manuscript was initially

written by Yanping Wang, and further revised and edited by all the coauthors (Michael Mulzer, Brandon J. Tiegs,

Prof. Geoffrey W. Coates, and Prof. George A. O'Doherty). The synthetic work was carried out by YW, and

carbonylation reaction by MM and BJT.

21

formal syntheses of THL,44

which have involved a diverse range of approaches. In terms of how

they derive absolute stereochemistry, these approaches can be classified into the following

categories: 1) chiral auxiliary,37

2) asymmetric aldol,38

3) asymmetric allylation/crotylation,39

4)

asymmetric reductions,40

5) asymmetric resolutions,41

6) asymmetric oxidations,42

and 7) chiron

approach.43

These routes include the elegant use of a chiral phosphate-template,40c

a tandem

Mukaiyama aldol-lactonization,38e,7i

an anti-aldol segment via a non-aldol route,38h

and a Prins

cyclization for stereocontrol.41b

Scheme 7. Regioselective carbonylation of protected cis-epoxyhomoallylic alcohols

As part of a larger effort aimed at the use of catalysis for the asymmetric synthesis and

structure-activity relationship studies of biologically active natural products,45

we became

interested in the synthesis of THL (II-1) and related analogues II-3 (Figure 11). We were

particularly interested in the carbonylation of epoxides using bimetallic [Lewis acid]+[Co(CO)4]

–

catalysts which has recently emerged as a reliable, direct route to β-lactones.46

The O’Doherty

and Coates groups have had success using this type of carbonylation catalyst for the synthesis of

terminal β-lactones en route to natural products.47

However, unsymmetrically disubstituted

22

epoxides are prone to give a mixture of regioisomeric β-lactones. Presumably this is because of

an unselective SN2-ring opening reaction in the case of electronically or sterically unbiased

substrates (Scheme 7).

This problem has recently been addressed by the introduction of catalysts that can carbonylate

racemic and enantioenriched trans-disubstituted epoxides to the corresponding cis-β-lactones

with high and opposing regioselectivities.48

We hypothesized that it would be possible to obtain

the desired β-lactone isomer 3b of THL and its analogues via regioselective carbonylation of

protected cis-epoxyhomoallylic alcohols (Scheme 7). Herein, I disclose a new route for the

synthesis of THL and seven stereoisomers using regioselective carbonylation of an epoxide to

form the β-lactone moiety. The fatty acid lipid portion of THL ( 4b) was prepared from

protected cis-epoxyhomoallylic alcohol 6b with all the lipid stereogenic centers in place via a

de novo asymmetric route (Scheme 8).

2.2 Retrosynthetic analysis

Retrosynthetically, we envisioned preparing THL from its lipid core II-4b and N-formyl-L-

leucine (Scheme 8). Using a regioselective carbonylation reaction, the lipid portion of THL (II-

4b) could be prepared either directly from cis-epoxyalcohol II-6b, or from II-6a after alkylation

of the terminal β-lactone II-4a. Epoxides II-6a/b could be prepared from a highly diastereo-

selective epoxidation of homoallylic alcohol II-7a/b, which in turn could be prepared from II-

8a/b via asymmetric synthesis. Key to the success of this approach is the need for high

regioselectivity in the carbonylation (II-6 to II-4). Presumably, this could be accomplished with

a high degree of confidence using terminal epoxide II-6a.46a

However, the subsequent alkylation

of terminal β-lactones such as II-4a is highly problematic.41a,49

Consequently, a greater degree of

synthetic efficiency would result from a regioselective carbonylation of a 2,3-disubstituted

23

epoxide with all the requisite lipid carbons in place, i.e. II-4b to II-6b. Regioselective

carbonylation of epoxides had very little precedence in the synthesis of complex molecules prior

to our endeavors.50

Scheme 8. Retrosynthetic analysis of THL (II-1)

We anticipated that the precise choice of hydroxyl protecting group in II-6b could be critical

for the control of the carbonylation regioselectivity. At the outset, we chose a methoxymethyl

group (MOM) for its potential to participate in chelated transition states. However, we were also

interested in investigating the use of N-formyl-L-leucine, thus avoiding the need for a protecting

group at this stage. This had the added advantage of testing the compatibility of the [Lewis

acid]+[Co(CO)4]

– carbonylation catalyst with the Lewis basic and Brønsted acidic formamide

functional group as well as the epimerizable α-amino ester group.

2.3 Formal synthesis of tetrahydrolipstatin

To ensure success with this approach, we began our efforts with the synthesis of the

diastereomeric terminal epoxides II-11/ II-14 (Scheme 9). The approach began with a Leighton

allylation25

of dodecanal II-8a to give homoallylic alcohol II-7a. After Boc-protection of alcohol

II-7a the resulting t-butylcarbonate II-9 was treated with iodine to form cyclic carbonate II-10.

Hydrolysis of carbonate II-10 led to in situ epoxidation to form II-11, which was then protected

as a MOM ether II-6a (MOMCl/DIPEA). Alternatively, the stereochemistry at C5 in II-11 was

24

inverted using Mitsunobu conditions to give II-14 after hydrolysis (PNBA/PPh3/DIAD,

K2CO3/MeOH), which was also protected as a MOM ether II-15. Epoxides II-6a/II-15

underwent regioselective carbonylation to give β-hydroxy esters II-12/II-16 when exposed to

carbonylation conditions (CO, 10 mol % Co2(CO)8, 20 mol % 3-hydroxypyridine).51

The

synthesis of β-hydroxy ester II-16 constitutes a formal synthesis of THL (II-1) as II-16 has been

previously transformed into THL via the n-hexyl α-alkylation of a dianion generated from II-

16.43

Scheme 9. Formal synthesis of THL (II-1)

2.4 Asymmetric synthesis of cis-epoxyhomoallylic alcohol II-23

With access to a formal synthesis of THL, we turned our focus to potentially more efficient

approaches to THL, which involved carbonylation of the more challenging 2,3-disubstituted cis-

epoxide II-6b. The synthesis of epoxide II-6b required a practical asymmetric synthesis of

epoxyhomoallylic alcohol II-23 (Scheme 10). Our approach involved the novel construction of

the Z-homoallylic alcohol functionality via a Noyori reduction/alkyne zipper/Lindlar reduction

sequence.52

To establish the absolute stereochemistry for this route, we used a highly

25

enantioselective (95% ee) Noyori asymmetric reduction53

of achiral ynone II-8b, which could be

prepared in one step from a known Weinreb amide II-8c. Using the alkyne zipper reaction,54

the

internal 2-alkyne in II-17 was isomerized into a terminal alkyne and then TBS protected to give

II-19. Alkylation of terminal alkyne II-19 (n-BuLi then n-Hex-I, 88%) and TBAF-promoted

deprotection of the TBS-ether provided the homopropargyl alcohol II-21. Partial hydrogenation

of alkyne II-21 using Lindlar conditions55

(1 atm H2, Pd/CaCO3, quinoline, 96%) cleanly gave

(Z)-olefin II-7b. Finally, a highly diastereoselective hydroxy-directed epoxidation of II-7b

furnished II-23 (t-BuOOH, 2 mol % VO(acac)2, 94%, 92% dr) via putative intermediate II-22.56

Scheme 10. Synthesis of cis-epoxyhomoallylic alcohol II-23

2.5 Total synthesis of tetrahydrolipstatin

With the establishment of a practical and stereocontrolled synthesis of epoxide II-23, we

began our investigation of the regioselectivity of the carbonylation reaction (Scheme 11). This

study began with the protection of the alcohol as a MOM ether II-6b (MOMCl, 85%). To our

delight, when the MOM-protected epoxide II-6b was subjected to carbonylation (1 mol %

[ClTPPAl][Co(CO)4], CO (900 psi)),46f

a single regioisomer β-lactone II-24 was formed which

was obtained in an 81% isolated yield.

26

Scheme 11. Synthesis of THL (II-1): carbonylation of MOM-protected epoxide II-6b

The synthesis of THL was easily finished via a four-step deprotection/acylation/deprotection/

formylation procedure. Thus, the MOM group was removed with BF3 etherate to give II-4b

(83%). A DCC coupling of II-4b with N-Cbz-L-leucine installed the amino acid side chain in II-

25. Finally, a one-pot hydrogenolysis/formylation procedure both removed the Cbz group (1 atm

H2, Pd/C in AcOCHO) and installed the N-formyl group to give THL (II-1) without any

epimerization (vide infra).37f,38h

The synthetic THL produced had spectral (1H,

13C NMR, IR) and

optical properties (reported: [α]D20

= –33 (c = 0.36, CHCl3),37b

synthetic: [α]D23

= –33.7 (c =

0.48, CHCl3)) consistent with what has been reported in the literature. 1H NMR completely

matches the reported in the existing literature, although the coupling constants are slightly

different for several peaks (Table 5). The matching situation also happens to 13

C NMR, except

that two publications reported extra peaks, which might be from unremoved impurities (Table 6).

2.6 Alternative approach to THL

To test the functional group compatibility of the carbonylation catalyst, we explored

alternatives to the MOM protecting group. In this vein, we looked at the use of the N-formyl-L-

leucine ester group (i.e., II-26) (Scheme 12) as a replacement for the MOM ether. Along with

testing the functional group compatibility of the carbonylation conditions, this substitution also

had the advantage of reducing steps.

Table 5. 1H NMR assignments of THL (

1H NMR comparision with existed publications).

27

Position J. Antibiot.

1987, 1086 This Work

J. Org. Chem.

2012, 4885

Org. Lett. 2010,

1556

J. Org. Chem.

2009, 4508

Synthesis

2006, 3888

CHO

(1H) 8.21 (s)

a 8.22 (s) 8.22 (s) 8.22 (s) 8.22 (s) 8.23 (s)

2''-NH

(1H) 6.43 (d, 9) 5.91 (d, 8.5) 5.90 (d, 8.5) 5.96 (d, 8.4) 5.91 (d, 8.1) 6.05 (d, 8.5)

5

(1H) 5.03 (m) 5.03–5.00 (m)

5.03 (dddd, 7.0,

6.5, 5.5, 4.0)

5.06–4.99 (m,

1H) 5.05–5.00 (m) 5.02 (m, 1H)

2''

(1H)

4.68 (ddd, 9, 9,

5)

4.69 (ddd, 9.0, 9.0,

5.0)

4.69 (ddd, 13.0,

8.5, 4.0)

4.68 (td, 8.7,

4.1) 4.71–4.66 (m) 4.68 (m,1H)

3

(1H)

4.32 (ddd, 9, 5,

4)

4.29 (ddd, 7.5, 5.0,

5.0)

4.29 (ddd, 8.0,

4.5, 4.5)

4.32–4.27 (m,

1H)

4.29(dt, 7.3,

4.7) 4.28 (m, 1H)

2

(1H)

3.24 (ddd, 7.5,

7.5, 4)

3.22 (ddd, 7.5, 7.5,

4.0)

3.21 (ddd, 11.5,

4.5, 4.0 )

3.22 (ddd, 7.9,

7.2, 4.1)

3.22 (dt, 7.1,

3.2)

3.22 (dt, 7.6,

3.9)

4, 4a

(2H)

1.9–2.25 (m,

2H)

2.17 (ddd, 15.0,

7.5, 7.5)

2.16 (dt, 15.0,

8.0, 7.0)

2.21–2.12 (m,

1H)

2.15–2.10 (m,

1H)

2.25–2.11 (m,

1H)

2.00 (ddd, 15.0,

4.5, 4.5)

2.01 (dt, 15.0,

4.5, 4.0)

1.99 (ddd, 14.9,

4.7, 4.1)

2.08–2.00 (m,

1H) 2.02 (m, 1H)

CH2

(33H) 1.15–1.85 (m) 1.84–1.78 (m, 1H)

1.85–1.50 (m,

6H)

1.86–1.49 (m,

7H)

1.85–1.51 (m,

7H)

1.80–1.15 (m,

33H)

1.77–1.63 (m, 4H)

1.61–1.53 (m, 2H)

1.47–1.41 (m, 1H) 1.50–1.15 (m,

27H)

1.49–1.03 (m,

26H)

1.41–1.15 (m,

26H)

1.32–1.24 (m,

25H)

5'', 5'''

(6H)

0.97 (d, 6, 6H) 0.972 (d, 6.5, 3H) 1.05–0.82 (m,

12H)

0.97 (dd, 6.1,

2.5, 6H) 0.96 (t, 6.3, 6H)

0.95 (d, 5.2,

6H)

0.967 (d, 6.5, 3H)

16, 6'

(6H) 0.89 (t, 7, 6H) 0.885 (t, 6.5, 3H) 0.89 (t, 6.9, 3H) 0.89 (t, 6.5, 6H)

0.87 (distorted

t, 6H)

0.878 (t, 7.0, 3H) 0.88 (t, 6.9, 3H) a (multiplicity, coupling constant (J) in Hz)

Table 6. 13

C NMR assignments of THL (13

C NMR comparision with existed publications).

28


1987, 1086

This

Work

J. Org. Chem.

2012, 4885

Org. Lett.

2010, 1556

J. Org. Chem.

2009, 4508

Synthesis

2006, 3888

1, 1'' 171.93 171.92 171.9 171.9 171.9 171.9

170.73 170.75 170.7 170.7 170.7 170.8

1''' 160.83 160.60 160.6 160.6 160.5 160.7

3, 5 74.74 74.76 74.7 74.7 74.7 74.8

72.63 72.76 72.7 72.7 72.7 72.6

2, 2'' 57.07 57.03 57.0 57.0 57.0 56.9

49.76 49.60 49.6 49.6 49.6 49.7

4, 6, 9

12, 13,

14, 1', 2',

3' 4', 3'',

41.44 41.56 41.5 41.5 41.5 41.4

38.73 38.70 38.7 38.7 38.7 38.7

34.07 34.05 34.0 34.0 34.0 34.0

31.93 31.89 31.9 31.9 31.8 31.9

31.51 31.47 31.4 31.4 31.4 31.2

29.63 29.60 29.6 29.6 29.6 29.6

29.63 29.60

29.57 29.53 29.5 29.5 29.5

29.46 29.42 29.4 29.4 29.4 29.4

29.35 29.33 29.3 29.3 29.3 29.3

29.35 29.29 29.3 29.2 29.2

7, 8, 10,

11

28.99 28.96 28.9 28.9 28.9 28.8

27.67 27.61 27.6 27.6 27.6 27.7

26.73 26.70 26.7 26.7 26.6 26.8

25.12 25.09 25.1 25.0 25.0 25.2

4'' 24.93 24.88 24.9 24.8 24.8 24.9

5'' or 5''' 22.87 22.87 22.8 22.8 22.8 22.8

15, 5' 22.69 22.68 22.7 22.6 22.6 22.7

22.53 22.51 22.5 22.5 22.5 22.5

5'' or 5''' 21.78 21.73 21.7 21.7 21.7 21.7

16, 6' 14.10 14.12 14.1 14.1 14.1 14.1

14.00 14.01 14.0 14.0 14.0 14.0

unknown 21.9 25.8

Notes: 1) Residual solvent signal was used as reference: CDCl3 δc 77.0 ppm. (77.23 ppm for Org. Lett. 2006,

4497)

2) The paper (J. Org. Chem. 2012, 4885) reported one extra peak at 21.9 ppm. The paper (J. Org. Chem.

2009, 4508) reported one extra peak at 25.8 ppm.

We initially investigated the synthesis of epoxide II-26 via the direct DCC coupling of N-

29

formyl-L-leucine with II-23. Unfortunately, we were not able to find conditions under which the

coupling occurred without appreciable amounts of epimerization (i.e., II-26 and II-27 were

isolated as a 6:4 mixture of epimers).37f,38h

To circumvent the epimerization problem, we

returned to the less epimerizable N-Cbz-protected L-leucine (less electron withdrawing property).

Under the same DCC coupling procedure, N-Cbz-L-leucine coupled with II-23 to afford ester II-

28 in 99% yield without any sign of epimerization.37f

Exposure of II-28 to the two-step/one-pot

hydrogenolysis/formylation conditions (1 atm H2, Pd/C then HCO2H/DCC) provided the desired

epoxide II-26 in 79% yield. Gratifyingly, under carbonylation conditions (2 mol %

[ClTPPAl][Co(CO)4], CO (900 psi)), epoxide II-26 with an N-formyl-L-leucine side chain was

cleanly transformed into THL (II-1) as the single regioisomer which was obtained in excellent

yield (80%) without any sign of epimerization.

Scheme 12. Synthesis of THL (II-1): a late-stage carbonylation of epoxide

2.7 Examination of late stage of carbonylation of epoxides

The successful synthesis of THL via late-stage regioselective carbonylation of epoxide II-26

prompted us to explore the scope of this approach. In particular, we were interested in exploring

its utility for the synthesis of various stereoisomers of THL.57

To do this, we required access to a

30

series of stereoisomeric epoxides with various groups at the C5 position. This was carried out

from epoxyalcohol II-23 and its enantiomer ent-II-23, which was synthesized for ynone II-8b

using the same strategy as that for II-23 (Scheme 13). Thus, the C5 diastereomer II-31 with a

MOM-protecting group was easily prepared from ent-II-23 by means of a three-step

Mitsunobu/hydrolysis/protection sequence in a 74% overall yield.

Scheme 13. Synthesis of diastereomer II-31

Using both invertive and retentive acylation chemistry, the three epoxides with an N-formyl

leucine side chain (II-27, II-33, and II-35) were prepared from epoxide II-23 (Scheme 14). To

circumvent the problem associated with epimerization during the DCC coupling with N-formyl

leucine, we resorted to the use of N-Cbz-L-leucine in the coupling to form II-32, which could be

readily converted into N-formyl amide II-27 by hydrogenolysis followed by a DCC coupling

with formic acid. In contrast to the DCC coupling of with N-formyl leucine, the invertive

Mitsunobu acylation of epoxide II-23 with N-formyl leucine occurred with complete

stereocontrol to give II-33. Epoxide II-35 was also made from II-23 via ester II-34 by means of

a two-step Mitsunobu acylation and hydrogenolysis N-Cbz to N-formyl group exchange (1 atm

H2, Pd/C then HCO2H/DCC).

Scheme 14. Synthesis of stereoisomeric epoxides from II-23

31

Using related invertive and retentive acylation chemistry, three stereoisomeric epoxides (ent-

II-28, ent-II-34, and II-37) and their enantiomers were made with N-Cbz leucine side chain from

epoxide ent-II-23 (Scheme 15). To serve as a control group for the amide substitution, epoxide

II-36 with no amino-substitution was prepared by a Mitsunobu acylation with isohexanoic acid.

Scheme 15. Synthesis of stereoisomeric epoxides from ent-23

We next investigated the regioselectivity of the carbonylation with the various epoxide

stereoisomers (Table 7). Exposure of the MOM-protected diastereomeric epoxide II-31 to typical

carbonylation conditions cleanly converted it into β-lactone II-38 (Entry 1, 88%) with complete

32

regioselectivity. Similarly, clean conversion was found for the C2” stereoisomeric epoxide II-27,

which reacted to give β-lactone II-39 as a single regio- and stereoisomer (Entry 2, 77%). In

contrast to changes in stereochemistry at C2”, the inversion of the stereochemistry at C5 had a

significant effect on the regioselectivity of the reaction (Entries 3 and 4). Epoxide II-33 with an

N-formyl amide carbonylated to give β-lactones II-40 in good yields of a 6:1 mixture of

regioisomers. The C2” epimeric epoxide II-35 also carbonylated with lower regioselectivity to

give β-lactones II-41 in good yields of a 5:1 mixture of regioisomers. In addition to poor

regioselectivities, epoxides II-33 and II-35 also required higher catalyst loadings.

We hypothesized that the loss in regioselectivity for substrates II-33 and II-35 could be the

result of hydrogen bonding interactions (Figure 12). This hydrogen bonding interaction in turn

could lower the barrier for pathway a to the regioisomeric β-lactone. To test this hypothesis, we

investigated the carbonylation of epoxides (II-36, ent-II-28, ent-II-34, and II-37). When the N-

formyl group was removed as in epoxide II-36 (Entry 5), the carbonylation occurred to give β-

lactone II-42 with complete control of regioselectivity. Interestingly, when the N-formyl group

was replaced with the less acidic N-Cbz-group the high regioselectivity returned. Thus, epoxides

ent-II-28, ent-II-34, and II-37 carbonylated to form β-lactones ent-II-25, ent-II-43, and ent-II-

44 as single regioisomers (Entries 6–8; 75%, 80%, 74%; respectively).

Table 7. Stereochemical scope of regioselective carbonylationa

33

Entry Epoxide major regioisomer

b

Ratiob

b:a

Isolated

Yield (%)

1

>99:1 88

2

>99:1 77

3

6:1 72

4

5:1 77

5

>99:1 53

6

>99:1 75

7

>99:1 80

8

>99:1 74

aSee Supporting Information for detailed reaction conditions for each entry.

bRatio determined by

1H NMR

spectroscopy; for entries 1–2, 5–8 regioisomer a was not observed.

`

Figure 12. Rationale for loss of regiocontrol for epoxides II-33 and II-35

34

In order to confirm the connectivity of unknown β-lactones II-40, II-41, II-43, and II-44, we

prepared them independently from known β-lactone II-4b (Scheme 16). The β-lactone II-4b was

converted into Cbz-protected leucine esters II-43 and II-44 via a Mitsunobu esterification. A

hydrogenolysis/formylation reaction converted II-43 and II-44 into II-41 and II-40, respectively,

which had identical 1H NMR spectra to the products prepared from the carbonylation reactions.

Scheme 16. Synthesis of β-lactones II-40 and II-41 from known β-lactone II-4b

In support of the structure of the minor isomers formed from the carbonylation of epoxides

II-33 and II-35 (entries 3 and 4; II-40 and II-41), we carried out a thermolytic decarboxylation

reaction on the product mixture II-40 and presumed regioisomer II-40a (Scheme 17).

35

Specifically, a 2:1 mixture of II-40 and hypothesized II-40a was heated to 230 °C in a sealed

tube under argon for 1 hour producing trans-olefin II-45 as the sole product. The identity of

olefin II-45 was confirmed by its synthesis from homoallylic alcohol II-46, which in turn was

made from terminal olefin II-7a using cross metathesis.26

For comparison, cis-olefin II-47 was

prepared from II-7b, which was readily distinguishable from its trans-isomer II-45 by 13

C NMR

spectra.

Scheme 17. Evidence for minor regioisomer II-40a by thermolysis

2.8 Syntheis of other THL stereoisomers

With the route established above, we were able to accomplished the synthesis of the other

THL stereisomers trans-β-lactones ent-II-1, ent-II-39, ent-II-40, and ent-II-41 (Scheme 18).

Taking advantage of the epimerization of DCC coupling of epoxide ent-II-23 and N-formyl-L-

leucine, a mixture of ent-II-26 and ent-II-27 was afforded, which upon carbonylation conditions

was converted into a mixture of two β-lactone ent-II-1 and ent-II-39 smoothly. With preparative

HPLC, ent-II-1 and ent-II-39 were successfully separated with high purity. In this manner, ent-

II-1 and ent-II-39 could be accomplished in two steps and one HPLC purification, which was

slightly more effiecient than synthesizing them independently. The two β-lactone ent-II-43 and

36

ent-II-44 were transformed into THL stereoisomers ent-II-41 and ent-II-40, respectively, by

replacing the Cbz group with formyl group.

Scheme 18. Synthesis of THL stereoisomers

2.9 Conclusions

A concise enantioselective synthesis of THL has been achieved in 10 steps and 31% overall

yield from achiral ynone II-8b. The route is amenable for the production of eight stereoisomers

(only one set of enantiomers were shown). In addition, the route demonstrated the versatility and

regioselectivity of the bimetallic [Lewis acid]+[Co(CO)4]

– catalyzed carbonylation of

enantiomerically pure cis-epoxides to trans-β-lactones. Further application of bimetallic

carbonylation catalysts for the synthesis and medicinal chemistry studies of natural products will

be reported in due course.

37

Chapter 3

Total Synthesis of EBC-23

3.1 Introduction of EBC-23

Nature contains a rich source of chemical compounds, which have the potential to be used to

treat human diseases (e.g., cancers, fungal infection).58

Tremendous efforts have been focused on

the isolation natural product from nature sources (e.g., plants, bacteria) using liquid-solid

chromatographic techniques.59

In an effort to discover new bioactive compounds, Williams et al.

isolated eight novel spiroketal products from the fruit of Cinnamomum laubatii (family

Lauraceae) (Figure 13).60

This family of compounds showed anticancer activity against several

cancer cell lines MM96L, MCF7 and DU145. More importantly, EBC-23 was found to inhibit

the growth of prostate tumor in immunodeficient mice.60

Figure 13. Structures of EBC family members

After elucidation of the structure of this family compounds by a combination of analyses of

NMR and HRMS, the Williams group also completed the first total synthesis of the EBC-23 by

using a linchpin strategy (Scheme 19). In this retrosynthetic analysis, EBC-23 (III-1) was

derived from polyketide III-2 by ring opening of the spiroketal. The protected precursor of III-2,

38

polyol III-3, could be constructed from three fragments epoxide III-4, 1,3-dithianes III-5 and

epoxide III-6 via a Tietze-Smith61

type dithiane linchpin methodology. In turn, the left-hand

fragment III-4 was also assembled using a linchpin strategy again via III-7 form three partners

dithiane III-5, epoxide III-8 and epoxide III-9. In the synthesis, four of the six stereogenic

centers were introduced from enantiopure starting materials.

Scheme 19. Williams’ retrosynthetic analysis of EBC-23

A second EBC-23 total synthesis was accomplished by Yamamoto et al. utilizing their

“supersilyl” chemistry (Scheme 20).62

Similar to Williams’ retrosynthetic analysis, EBC-23 was

envisioned from polyketide III-10, which was constructed from polyhydroxy ketone (±)-III-11

and chiral aldehyde III-12 using an aldol reaction. The racemic intermediate (±)-III-11 was

generated from tetradecanal III-13 and silyl enol ether III-14 applying an iterative

supersilyldirected aldol method. Although the total synthesis was only seven steps in the longest

linear sequence, the absolute stereochemistry of EBC-23 was introduced at late stage by using a

chiral fragment III-12 for differentiation, leading to an inefficient access to the synthetic material

due to the need of separated diasteroisomers.

Scheme 20. Restrosynthetic analysis of EBC-23 by Yamamoto

39

3.2 Restrosynthetic analysis of EBC-23

Intrigued by the unique structure and biological activity of this family products, we decided

to synthesize EBC-23 using an asymmetric synthetic strategy developed in our group (Scheme

21). Retrosynthetically, ring opening of the spiroketal in EBC-23 revealed a diketone

intermediate III-15, which could be derived from protected diol ketone III-16 and acyl chloride

III-17 using lithium mediated coupling.63

The stereochemistry in III-16 was envisioned to be

elucidated from tetradecanal III-13 via III-18 using asymmetric Leighton allylation,25

cross

metathesis26

and Evans’ acetal formation.24

Meanwhile, the chirality of pyranone III-17 could be

introduced utilizing Noyori reduction27

and stereoselective NaBH4 mediated asymmetric

reduction from 2-acetyl furan III-20 via β-hydroxy ester III-19.64

Herein, I will present the

efforts to the total synthesis of EBC-23.

Scheme 21. Our de novo retrosynthetic analysis of EBC-23

3.3 Synthesis of protected diol methyl ketone

40

The efforts to EBC-23 began with the synthesis of protected diol ketone III-16 from

tetradecanal III-13 (Scheme 22). Leighton allylation25

of III-13 gave homoallylic alcohol III-18,

which was converted into δ-hydroxy enoate III-21 using metathesis reaction (Grubbs II) with

ethyl acrylate. Then, III-21 was exposed to Evans’ acetal formation conditions (PhCHO, KOt-

Bu)24

to form benzylidene protected diol III-22. The ester moiety in III-22 was transformed into

methyl ketone III-16 via Weinreb amide III-23 in two steps.

Scheme 22. Synthesis of protected diol ketone III-16

3.4 Synthesis of acyl chloride

With access to the ketone III-16, efforts were turned to the synthesis of acyl chloride III-17

(Scheme 23). The effort started from commercially available 2-acetyl furan III-20, which was

homologated to β-keto ester III-24 using a known procedure (CO(OMe)2, NaH).65

Asymmetric

Noyori reduction condition was used to converted β-keto ester III-24 into β-hydroxy ester III-

19. Then a three-step procedure (Achmatowicz reaction/Jones oxidation/reduction) was applied

on III-19 to result in pyranone III-27 in an high yield (61%). The stereochemistry of C-5 was

inverted under Mitsunobu conditions (p-nitrobenzoic acid, DIAD). The resulting ester III-28 was

hydrolyzed with Et3N in MeOH to give an alcohol III-29, which was then protected as a TBS

ether III-30 (TBSOTf, 2,6-lutidine). Hydrolysis of methyl ester in III-30 with LiOH led to an

acid III-31, which was converted into acyl chloride III-17 with Ghosez reagent III-32 (1-choro-

1-(dimethylamino)-2-methyl-2-propene).66

41

Scheme 23. Synthesis of acyl chloride III-17

3.5 End game of synthesis of EBC-23

With the available ketone III-16 and acyl chloride III-17 in hand, lithium mediated

reaction63

will be used to couple these two fragment to arrive at diketone III-15 (Scheme 24).

Exposure of III-15 to acetic acid in water should supply a global deprotection product, which

can subsequently form spiroketal III-33. The ketone in III-33 is then asymmetrically reduced to

the natural product EBC-23.

Scheme 24. End game of synthesis of EBC-23

In summary, a de novo synthesis of EBC-23 has been investigated. Two key fragments

(methyl ketone III-16 and acyl chloride III-17) have been accessed from achiral starting

materials tetradecanal and 2-acetyl furan, respectively. The syntheses of III-16 and III-17

42

feature asymmetric Leighton allylation, diastereoselective Evans’ acetal formation and

asymmetric Noyori reduction. The end game of synthesis of EBC-23 is ongoing in our group.

43

Experimental section

Section A: General Information

1H and

13C NMR spectra were recorded on a Varian 400 or 500 MHz spectrometer. Chemical

shifts were reported relative to internal tetramethylsilane (δ 0.00 ppm) or CDCl3 (δ 7.26 ppm) or

CD3OD (δ 3.30 ppm) for 1H NMR and CDCl3 (δ 77.2 ppm) or CD3OD (δ 49.05 ppm) for

13C

NMR. Infrared (IR) spectra were obtained on a FT-IR spectrometer. Optical rotations were

measured with a digital polarimeter in the solvent specified. Melting points were determined

with a standard melting point apparatus. Flash column chromatography was performed on 60-

200 or 230-400 mesh silica gel. Analytical thin-layer chromatography was performed with

precoated glass-backed plates and visualized by quenching of fluorescence and by charring after

treatment with p-anisaldehyde or potassium permanganate stain. Rf values were obtained by

elution in the stated solvent ratios. Diethyl ether, tetrahydrofuran, methylene dichloride and

triethylamine were dried by passing through activated alumina column with argon gas pressure.

Commercial reagents were used without purification unless otherwise noted. Air- and/or

moisture-sensitive reactions were carried out under an atmosphere of argon/nitrogen using oven-

or flame-dried glassware and standard syringe/septa techniques.

44

Section B: Experiment Procedures

Chapter 1 Cryptocaryol A and B: Total Syntheses, Stereochemical Revision, Structure

Elucidation, Structure-Activity Relationship and Ability to Stabilize PDCD4

(2S,4S,6R,8R,10R)-2,4,6,8-Tetrahydroxy-1-((R)-6-oxo-3,6-dihydro-2H-pyran-2-yl)pentaco

san-10-yl acetate (I-2):

To a flask with I-36 (17.0 mg, 22.8 µmol) was added a solution of acetic acid (2 mL, 80%) in

water. The resulting mixture was heated to 80 °C and stirred for 1 h. The solvent was removed

under reduced pressure. The crude residue was purified by flash chromatography (2 to 8%

MeOH in EtOAc) on silica gel (10 mL) to afford 2 (29.3 mg, 75%) as a colorless oil.

Data for I-2: Rf = 0.23 (5% MeOH in CH2Cl2); [α]D22

= +10.1 (MeOH, c = 0.72); IR (neat):

3367, 2924, 2854, 1721, 1461, 1377, 1260, 1098, 1028 cm-1

; 1H NMR (400 MHz, CD3OD) δ

7.05 (ddd, J = 9.6, 6.0, 2.4 Hz, 1H), 5.98 (dd, J = 9.6, 2.4 Hz, 1H), 5.08 (dddd, J = 9.6, 6.4, 6.4,

2.8 Hz, 1H), 4.68 (dddd, J = 10.4, 6.8, 6.8, 3.6 Hz, 1H), 4.02–3.92 (m, 3H), 3.81–3.74 (m, 1H),

2.54 (dddd, J = 18.8, 5.6, 4.0, 0.8 Hz, 1H), 2.39 (dddd, J = 18.8, 11.6, 2.4, 2.4 Hz, 1H), 2.04 (s,

3H), 1.97 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 1.86 (ddd, J = 14.0, 6.4, 5.2 Hz, 1H), 1.75–1.68 (m,

4H), 1.67–1.56 (m, 6H), 1.29–1.27 (m, 26H), 0.90 (t, J = 6.8 Hz, 3H); 13

C NMR (125 MHz,

CD3OD) δ 173.1, 167.0, 148.4, 121.4, 77.4, 72.9, 69.84, 69.77, 67.6, 67.5, 45.9, 45.4, 45.0, 43.3,

43.1, 36.0, 33.1, 30.8, 30.73, 30.69, 30.6, 30.5, 30.2, 26.3, 23.8, 21.2, 14.5; HRMS (ESI) calcd

for C32H58O8Na [M Na]+: 593.4029 Found: 593.4036.

45

(R)-6-((2R,4R,6R,8R,10S)-2,4,6,8,10-pentahydroxypentacosyl)-5,6-dihydro-2H-pyran-2-one

(I-9):




MeOH in EtOAc) on silica gel (10 mL) to afford I-9 (7.5 mg, 70%) as a white amorphous solid.


= +14.0 (MeOH, c = 0.20); IR (neat):

3304, 2918, 2849, 1719, 1553, 1458, 1378, 1260, 1136, 1096 cm-1

; 1H NMR (400 MHz,

CD3OD) δ 7.04 (ddd, J = 9.6, 6.0, 2.8 Hz, 1H), 5.97 (dd, J = 9.6, 2.5 Hz, 1H), 4.74–4.67 (m,

1H), 4.09 (dddd, J = 8.8, 6.4, 6.4, 2.4 Hz, 1H), 4.04–3.96 (m, 3H), 3.82–3.77 (m, 1H), 2.45 (ddd,

J = 19.2, 5.2, 5.2 Hz, 1H), 2.36 (dddd, J = 19.2, 11.6, 2.8, 2.8 Hz, 1H), 1.94 (ddd, J = 14.8, 9.6,

2.8 Hz, 1H), 1.71–1.55 (m, 7H), 1.52–1.49 (m, 2H), 1.46–1.40 (m, 2H), 1.28–1.25 (m, 26H),

0.89 (t, J = 7.0 Hz, 3H); 13

C NMR (100 MHz, CD3OD) δ 167.0, 148.6, 121.4, 76.6, 70.2, 69.9,

69.1, 68.2, 66.6, 46.0, 45.9, 45.8, 45.3, 43.9, 39.3, 33.1, 31.0, 30.9, 30.85, 30.82, 30.5, 26.8, 23.8,

14.5.14

(2R,4R,6S,8S,10S)-2,4,6,8-tetrahydroxy-1-((R)-6-oxo-3,6-dihydro-2H-pyran-2-

yl)pentacosan-10-yl acetate (I-10):



46



Data for I-10: Rf = 0.36 (5% MeOH in EtOAc); [α]D20

= +22.6 (MeOH, c = 0.25); IR (neat):

3391, 2918, 2850, 1709, 1467, 1377, 1324, 1255, 1111, 1049 cm-1

; 1H NMR (400 MHz,

CD3OD) δ 7.04 (ddd, J = 9.6, 5.6, 2.8 Hz, 1H), 5.97 (dd, J = 9.6, 1.6 Hz, 1H), 5.07 (dddd, J =

9.2, 6.4, 6.4, 2.8 Hz, 1H), 4.74–4.67 (m, 1H), 4.08 (dddd, J = 9.2, 6.4, 6.4, 2.4 Hz, 1H), 4.01–

3.92 (m, 2H), 3.81–3.75 (m, 1H), 2.45 (ddd, J = 18.4, 5.2, 5.2 Hz, 1H), 2.36 (dddd, J = 18.4,

11.2, 2.8, 2.8 Hz, 1H), 2.03 (s, 3H), 1.94 (ddd, J = 14.4, 9.6, 2.8 Hz, 1H), 1.72 (ddd, J = 14.4,

9.2, 2.8 Hz, 1H), 1.67–1.54 (m, 10 H), 1.28–1.25 (m, 26H), 0.89 (t, J = 6.8 Hz, 3H); 13

C NMR

(100 MHz, CD3OD) δ 173.1, 167.0, 148.6, 121.4, 76.6, 72.9, 69.91, 69.84, 67.5, 66.6, 45.9, 45.8,

45.3, 43.9, 43.3, 36.0, 33.1, 31.0, 30.8, 30.73, 30.69, 30.62, 30.5, 26.3, 23.8, 21.2, 14.5.14

Ethyl 2-((2S,4S,6S)-6-(((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-

4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetate (I-13):

To a stirred solution of I-26 (3.43 g, 7.08 mmol) in tetrahydrofuran (20 mL) at 0 °C was added

benzaldehyde (0.72 mL, 7.08 mmol), followed by potassium tert-butoxide (86.5 mg, 0.708

mmol) under N2. The resulting mixture was stirred for 15 min. Then the addition of

benzaldehyde/potassium tert-butoxide was repeated three more times. The mixture was passed

through a pad of silica gel, and the silica gel was washed with EtOAc (50 mL). The filtrate was

concentrated, and the crude residue was purified by flash chromatography (10 to 30% EtOAc in

hexanes) on silica gel (100 mL) to afford I-13 (3.23 g, 77%) as a colorless oil.

47

Data for I-13: Rf = 0.41 (30% EtOAc in hexanes); [α]D23

= –18.0 (CH2Cl2, c = 1.72); IR (neat):

2918, 2859, 1732, 1512, 1247, 1107, 1010 cm-1

; 1H NMR (400 MHz, CDCl3) δ 7.50–7.45 (m,

4H), 7.39–7.33 (m, 6H), 7.26 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.58 (s, 1H), 5.53 (s,

1H), 4.48 (d, J = 11.2 Hz, 1H), 4.43 (d, J = 11.2 Hz, 1H), 4.34 (dddd, J = 13.2, 6.8, 6.8, 2.0 Hz,

1H), 4.17 (q, J = 7.2 Hz, 2H), 4.15–4.02 (m, 3H), 3.78 (s, 3H), 3.68 (ddd, J = 8.8, 8.8, 5.2 Hz,

1H), 3.58 (ddd, J = 10.8, 5.4, 5.4 Hz, 1H), 2.74 (dd, J = 15.2, 7.6 Hz, 1H), 2.53 (dd, J = 15.4, 6.0

Hz, 1H), 2.15 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 1.93 (dddd, J = 14.0, 8.4, 5.2, 5.2 Hz, 1H), 1.86

(dddd, J = 14.0, 8.4, 5.2, 5.2 Hz, 1H), 1.83–1.67 (m, 3H), 1.61–1.46 (m, 2H), 1.27 (t, J = 7.2,

3H); 13

C NMR (100 MHz, CDCl3) δ 171.0, 159.4, 138.9, 138.6, 130.7, 129.6, 129.0, 128.9,

128.5, 128.4, 126.31, 126.28, 114.0, 100.8, 100.7, 74.0, 73.5, 73.26, 73.20, 72.9, 65.9, 60.9, 55.5,

41.9, 41.2, 37.1, 36.6, 36.3, 14.5; HRMS (ESI) calcd for C35H42O8Na [M Na]+: 613.2777

Found: 613.2785.

1-((Hex-5-yn-1-yloxy)methyl)-4-methoxybenzene (I-17):

To a stirred solution of 5-hexyn-1-ol I-16 (45.0 g, 0.459 mol) and 4-methoxybenzyl chloride

(73.2 g, 0.468 mol) in dimethylformamide (500 mL) at 0 °C was added sodium hydride (60%

wt/wt in mineral oil, 36.7 g, 0.917 mol) portionwise, followed by tetra-n-butylammonium

bromide (14.8 g, 45.9 mmol) under N2. The resulting mixture was stirred at 0 °C for 2 h, and

slowly warmed to room temperature. After 16 h, the reaction was quenched by pouring onto ice

slowly, and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with

brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude

48

residue was purified by flash chromatography (2.5 to 5% EtOAc in hexanes) on silica gel (1000

mL) to afford I-17 (100 g, 99%) as a colorless oil.

Data for I-17: Rf = 0.28 (10% EtOAc in hexanes); IR (neat): 3294, 2938, 2861, 1613, 1586,

1514, 1464, 1361, 1302, 1248, 1173, 1101, 1036 cm-1

; 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J

= 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.43 (s, 2H), 3.81 (s, 3H), 3.47 (t, J = 5.6 Hz, 2H), 2.21

(td, J = 7.2, 2.8 Hz, 2H), 1.94 (t, J = 2.8 Hz, 1H), 1.76–1.69 (m, 2H), 1.65–1.56 (m, 2H); 13

C

NMR (100 MHz, CDCl3) δ 159.4, 130.9, 129.4, 114.0, 84.6, 72.8, 69.7, 68.6, 55.5, 29.0, 25.5,

18.4.67

Methyl 7-((4-methoxybenzyl)oxy)hept-2-ynoate (I-18):

To a stirred solution of I-17 (100 g, 0.458 mol) in tetrahydrofuran (600 mL) at –78 °C was added

n-butyl lithium (250 mL, 2.20 M, 0.550 mol) slowly via syringe under N2. After 1 h at the same

temperature, methyl chloroformate (46.1 mL, 0.596 mol) was added via syringe. The resulting

mixture was stirred at –78 °C for 1 h and then allowed to warm to 0 °C for 1 h. The reaction was

quenched by pouring into ice-cold saturated aqueous ammonium chloride and extracted with

EtOAc (3 × 200 mL). The combined organic layers were washed with brine, dried over

anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was

purified by flash chromatography (2.5 to 20% EtOAc in hexanes) on silica gel (1000 mL) to

afford I-18 (127 g, 99%) as a colorless oil.


1586, 1513, 1435, 1361, 1251, 1173, 1080, 1035 cm-1

; 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J

= 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.42 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 3.46 (t, J = 5.6

49

Hz, 2H), 2.35 (t, J = 6.4 Hz, 2H), 1.73–1.66 (m, 4H); 13

C NMR (100 MHz, CDCl3) δ 159.4,

154.4, 130.8, 129.5, 114.0, 89.8, 73.3, 72.8, 69.4, 55.5, 52.8, 29.0, 24.6, 18.7; HRMS (ESI)

calcd for C16H20O4Na [M Na]+: 299.1259, found 299.1254.

(2E,4E)-Methyl 7-((4-methoxybenzyl)oxy)hepta-2,4-dienoate (I-19):

To a stirred solution of I-18 (126 g, 0.456 mol) in benzene (500 mL) at room temperature was

added triphenylphosphine (120 g, 0.456 mol), followed by phenol (42.6 g, 0.456 mol) under N2.

The resulting mixture was heated to 50 °C and stirred at the same temperature for 4 h. The

mixture was diluted with EtOAc (700 mL), washed with NaOH (1 M, 3 × 330 mL) and brine,

dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude

residue was purified by flash chromatography (1 to 20% EtOAc in hexanes) on silica gel (1000

mL) to afford I-19 (114 g, 90%) as a colorless oil.


1613, 1512, 1435, 1244, 1172, 1140, 1087 cm-1

; 1H NMR (400 MHz, CDCl3) δ 7.26 (dd, J =

15.6, 10.4 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.23 (dd, J = 15.2, 10.4

Hz, 1H), 6.13 (ddd, J = 15.2, 6.4, 6.4 Hz, 1H), 5.79 (d, J = 15.2 Hz, 1H), 4.44 (s, 2H), 3.80 (s,

3H), 3.74 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.47 (q, J = 6.8 Hz, 2H); 13

C NMR (100 MHz,

CDCl3) δ 167.9, 159.5, 145.2, 141.0, 130.5, 130.1, 129.6, 119.6, 114.0, 72.9, 68.8, 55.5, 51.7,

33.7; HRMS (ESI) calcd for C16H20O4Na [M Na]+: 299.1259 Found: 299.1265.

50

(4S,5S,E)-Methyl 4,5-dihydroxy-7-((4-methoxybenzyl)oxy)hept-2-enoate (I-20):

To a mechanically stirred mixture of tert-butyl alcohol (270 mL) and water (270 mL) at room

temperature was added potassium hexacyanoferrate (265 g, 0.803 mol), potassium carbonate

(111 g, 0.803 mol), methanesulfonamide (25.5 g, 0.258 mol), osmium tetroxide (490 mg, 1.93

mmol) and (DHQ)2PHAL subsequently. The resulting mixture was stirred at the same

temperature for 1 h and cooled to 0 °C. A solution of I-19 (74.0 g, 0.268 mol) in

dichloromethane (20 mL) was added to the mixture. After 6 h, the reaction was diluted with

water (500 mL) and quenched by adding sodium sulfite (101 g, 0.803 mol). The mixture was

stirred at 0 °C for 30 min and filtered through a pad of Celite. The solid residue was washed with

EtOAc (400 mL). The filtrate was separated, and the aqueous layer was extracted with EtOAc (4

× 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4,

filtered and concentrated under reduced pressure. The crude residue was purified by flash

chromatography (30 to 50% EtOAc in hexanes) on silica gel (500 mL) to afford I-20 (70.5 g,

85%) as a colorless oil.


= –40.9 (MeOH, c = 1.75 ); IR (neat):

3423, 2952, 2865, 1721, 1613, 1514, 1438, 1249, 1174, 1089, 1034 cm-1

; 1H NMR (400 MHz,

1% CD3OD in CDCl3) δ 7.22 (d, J = 8.8 Hz, 2H), 6.94 (dd, J = 15.6, 4.4 Hz, 1H), 6.86 (d, J = 8.8

Hz, 2H), 6.12 (dd, J = 15.6, 1.6 Hz, 1H), 4.43 (s, 2H), 4.13 (ddd, J = 4.4, 4.4, 1.6 Hz, 1H), 3.79

(s, 3H), 3.77–3.74 (m, 1H), 3.72 (s, 3H), 3.70–3.60 (m, 2H), 1.86–1.79 (m, 2H); 13

C NMR (100

MHz, CDCl3) δ 167.0, 159.6, 147.3, 129.72, 129.66, 122.1, 114.2, 74.0, 73.8, 73.4, 68.3, 55.5,

51.9, 32.8; HRMS (ESI) calcd for C16H22O6Na [M Na]+: 333.1314 Found: 333.1321.

51

(E)-Methyl 3-((4S,5S)-5-(2-((4-methoxybenzyl)oxy)ethyl)-2-oxo-1,3-dioxolan-4-yl)acrylate

(I-21):

To a stirred solution of I-20 (65.4 g, 0.211 mol) in dichloromethane (500 mL) at –78 °C was

added pyridine (84.9 mL, 1.05 mol), followed by 4-dimethylaminopyridine (0.515 g, 4.22 mmol)

under N2. Then a solution of triphosgene (43.8 g, 0.148 mol) in dichloromethane (200 mL) was

added to the mixture. After 50 min at the same temperature, the reaction was quenched with

saturated aqueous ammonium chloride (200 mL), and extracted with EtOAc (3 × 300 mL). The

combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and

concentrated under reduced pressure. The crude residue was purified by flash chromatography

(20 to 40% EtOAc in hexanes) on silica gel (400 mL) to afford I-21 (63.3 g, 89%) as a colorless

oil.


= –40.0 (CH2Cl2, c =1.32); IR (neat):

2954, 2866, 1801, 1723, 1612, 1513, 1437, 1245, 1168, 1028 cm-1

; 1H NMR (400 MHz, CDCl3)

δ 7.22 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.84 (dd, J = 16.0, 5.2 Hz, 1H), 6.14 (dd, J =

16.0, 1.6 Hz, 1H), 5.01 (ddd, J = 6.8, 5.2, 1.6 Hz, 1H), 4.53 (q, J = 6.8, Hz, 1H), 4.42 (d, J = 2.4

Hz, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.65–3.55 (m, 2H), 2.09–2.04 (m, 2H); 13

C NMR (100 MHz,

CDCl3) δ 165.7, 159.7, 153.8, 140.1, 129.8, 129.7, 124.3, 114.2, 80.1, 79.7, 73.4, 65.0, 55.5,

52.3, 33.6; HRMS (ESI) calcd for C17H20O7Na [M Na]+: 359.1107 Found: 359.1102.

52

(R,E)-Methyl 5-hydroxy-7-((4-methoxybenzyl)oxy)hept-2-enoate (I-22):

To a stirred solution of I-21 (33.7 g, 0.100 mol) in tetrahydrofuran (200 mL) at 0 °C was added

triethylamine (69.5 mL, 0.500 mol), followed by formic acid (37.8 mL, 1.00 mol) slowly via

syringe under N2. After the white smoke subsided, tris(dibenzylideneacetone)dipalladium(0)

chloroform complex (0.104 g, 0.100 mmol) was added, followed by triphenylphosphine (26.3

mg, 0.100 mmol). The resulting mixture was heated to reflux and became clear. At the moment a

black color was observed, the reaction was cooled to 0 °C immediately, quenched by adding

water (150 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were

washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced

pressure. The crude residue was purified by flash chromatography (20 to 40% EtOAc in



= +11.4 (CH2Cl2, c = 1.39); IR (neat):

3474, 2948, 2860, 1718, 1657, 1612, 1512, 1436, 1245, 1170, 1084, 1030 cm-1

; 1H NMR (400

MHz, CDCl3) δ 7.24 (d, J = 8.8 Hz, 2H), 6.99 (ddd, J = 15.2, 7.6, 7.6 Hz, 1H), 6.88 (d, J = 8.8

Hz, 2H), 5.88 (ddd, J = 15.2, 1.6, 1.6 Hz, 1H), 4.45 (s, 2H), 3.96 (m, 1H), 3.81 (s, 3H), 3.72 (s,

3H), 3.70 (ddd, J = 8.0, 8.0, 3.2 Hz, 1H), 3.62 (ddd, J = 9.2, 8.4, 4.4 Hz, 1H), 2.44–2.31 (m, 2H),

1.82–1.69 (m, 2H); 13

C NMR (100 MHz, CDCl3) δ 167.0, 159.5, 145.8, 130.0, 129.6, 123.4,

114.1, 73.3, 70.7, 69.0, 55.5, 51.8, 40.3, 36.0; HRMS (ESI) calcd for C16H22O5Na [M Na]+:

317.1365 Found: 317.1368.

53

Methyl 2-((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-yl)acetate

(I-23):

To a stirred solution of I-22 (9.26 g, 31.5 mmol) in tetrahydrofuran (60 mL) at 0 °C was added

benzaldehyde (3.20 mL, 31.5 mmol), followed by potassium tert-butoxide (0.353 g, 3.15 mmol)

under N2. The resulting mixture was stirred for 15 min. Then the addition of benzaldehyde/

potassium tert-butoxide was repeated three more times. The mixture was passed through a pad of

silica gel, and the silica gel was washed with EtOAc (300 mL). The filtrate was concentrated,

and the crude residue was purified by flash chromatography (5 to 40% EtOAc in hexanes) on

silica gel (170 mL) to afford I-23 (8.40 g, 67%) as a colorless oil.

Data for I-23: mp 53-55 °C; Rf = 0.45 (40% EtOAc in hexanes); [α]D23

= –28.2 (CH2Cl2, c =

1.62); IR (neat): 2949, 2862, 1737, 1612, 1512, 1442, 1349, 1245, 1088, 1016 cm-1

; 1H NMR

(400 MHz, CDCl3) δ 7.44 (dd, J = 8.0, 2.4 Hz, 2H), 7.37–7.32 (m, 3H), 7.27 (d, J = 8.8 Hz, 2H),

6.87 (d, J = 8.8 Hz, 2H), 5.55 (s, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.43 (d, J = 12.0 Hz, 1H), 4.32

(dddd, J = 13.2, 7.2, 7.2, 2.4 Hz, 1H), 4.07 (dddd, J = 10.8, 7.2, 4.4, 2.4 Hz, 1H), 3.79 (s, 3H),

3.71 (s, 3H), 3.69–3.64 (m, 1H), 3.57 (ddd, J = 9.6, 5.2, 5.2 Hz, 1H), 2.74 (dd, J = 15.6, 7.2 Hz,

1H), 2.52 (dd, J = 15.6, 6.0 Hz, 1H), 1.93 (dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.84 (dddd, J =

14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.72 (ddd, J = 12.8, 2.4, 2.4 Hz, 1H), 1.46 (ddd, J = 12.8, 11.2, 11.2

Hz, 1H); 13

C NMR (100 MHz, CDCl3) δ 171.4, 159.4, 138.7, 130.7, 129.6, 128.9, 128.4, 126.3,

114.0, 100.7, 73.8, 73.4, 72.9, 65.8, 55.5, 52.0, 41.0, 36.8, 36.3; HRMS (ESI) calcd for

C23H28O6Na [M Na]+: 423.1784 Found: 423.1769.

54

2-((2S,4S,6S)-6-(2-((4-Methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-yl)acetaldehyde (I-

24):

To a stirred solution of I-23 (15.2 g, 38.0 mmol) in dichloromethane (110 mL) at –78 °C was

added a solution of diisobutylaluminium hydride (1 M, 38.0 mL, 38.0 mmol) in hexane slowly

via syringe under N2. After the starting material was consumed, the reaction mixture was

quenched by adding 1 N hydrochloric acid (100 mL), and stirred at room temperature for 1 h.

The mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed

with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The

crude residue was purified by flash chromatography (5 to 20% EtOAc in hexanes) on silica gel

(200 mL) to afford I-24 (11.7 g, 83%) as a colorless oil.


= –30.1 (CH2Cl2, c = 1.07); IR (neat):

2923, 2857, 1724, 1612, 1512, 1245, 1097, 1026 cm-1

; 1H NMR (400 MHz, CDCl3) δ 9.86 (t, J =

2.0 Hz, 1H), 7.44 (dd, J = 8.0, 2.0 Hz, 2H), 7.38–7.32 (m, 3H), 7.27 (d, J = 8.8 Hz, 2H), 6.87 (d,

J = 8.8 Hz, 2H), 5.57 (s, 1H), 4.45 (d, J = 6.0 Hz, 2H), 4.43–4.37 (m, 1H), 4.08 (dddd, J = 13.2,

7.6, 4.4, 3.2 Hz, 1H), 3.79 (s, 3H), 3.67 (ddd, J = 9.6, 9.6, 5.2 Hz, 1H), 3.57 (ddd, J = 9.2, 5.2,

5.2 Hz, 1H), 2.80 (ddd, J = 16.8, 8.4, 2.0 Hz, 1H), 2.61 (ddd, J = 16.8, 4.4, 2.0 Hz, 1H), 1.93

(dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.84 (dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.69 (ddd, J =

13.2, 2.4, 2.4 Hz, 1H), 1.49 (ddd, J = 13.2, 11.6, 11.6 Hz, 1H); 13

C NMR (100 MHz, CDCl3) δ

200.6, 159.4, 138.5, 130.7, 129.6, 129.0, 128.4, 126.2, 114.0, 100.8, 73.9, 72.9, 72.1, 65.7, 55.5,

49.6, 36.9, 36.2; HRMS (ESI) calcd for C23H30O6Na [M Na + MeOH]+: 425.1940 Found:

425.1952.

55

(R)-1-((2S,4R,6S)-6-(2-((4-Methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-

ol (I-25):


added a solution of (S,S)-Leighton reagent (5.01 g, 9.03 mmol) in dichloromethane (10 mL)

slowly via syringe, followed by scandium triflate (74.1 mg, 0.151 mmol) under N2. Then the

resulting mixture was transferred to freezer at –10 °C. After 12 h, the reaction was quenched by

adding 1 N hydrochloric acid (20 mL). The formed solid was filtered through a fritted funnel,

and the filtrate was extracted with EtOAc (3 × 50 mL). The combined organic layers were



hexanes) on silica gel (50 mL) to afford I-25 (1.79 g, 72%, dr = 8.7:1.0) as a colorless oil.


= –19.2 (CH2Cl2, c = 0.92); IR (neat):

3518, 3069, 2940, 2915, 2861, 1733, 1611, 1512, 1345, 1244, 1092, 1018 cm-1

; 1H NMR (400

MHz, CDCl3) δ 7.42 (dd, J = 7.2, 2.4 Hz, 2H), 7.36–7.32 (m, 3H), 7.26 (d, J = 8.8 Hz, 2H), 6.86

(d, J = 8.8 Hz, 2H), 5.85 (dddd, J = 16.8, 10.0, 6.8, 6.8 Hz, 1H), 5.56 (s, 1H), 5.16–5.10 (m, 2H),

4.47 (d, J = 12.0 Hz, 1H), 4.43 (d, J = 12.0 Hz, 1H), 4.15–4.02 (m, 2H), 3.97 (dddd, J = 9.2, 6.4,

6.4, 2.8 Hz, 1H), 3.78 (s, 3H), 3.66 (ddd, J = 9.6, 9.6, 5.2 Hz, 1H), 3.56 (ddd, J = 9.6, 5.2, 5.2

Hz, 1H), 2.32–2.21 (m, 2H), 1.92 (dddd, J = 13.6, 8.0, 5.2, 5.2 Hz, 1H), 1.82 (dddd, J = 13.6,

8.0, 5.2, 5.2 Hz, 1H) 1.77–1.75 (m, 1H), 1.69 (ddd, J = 14.8, 2.8, 2.8 Hz, 1H), 1.61 (ddd, J =

13.2, 2.8, 2.8 Hz, 1H), 1.49 (ddd, J = 13.2, 10.8, 10.8 Hz, 1H); 13


159.4, 138.5, 135.0, 130.7, 129.6, 129.0, 128.5, 126.2, 117.9, 114.0, 100.8, 77.6, 74.0, 72.9, 70.6,

56

65.7, 55.5, 42.21, 42.19, 37.4, 36.2; HRMS (ESI) calcd for C25H33O5 [M H]+: 413.2328 Found:

413.2327.

(R,E)-Ethyl 5-hydroxy-6-((2S,4R,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-

dioxan-4-yl)hex-2-enoate (I-26):

To a stirred solution of I-25 (2.95 g, 7.15 mmol) in dichloromethane (10 mL) at room

temperature was added ethyl acrylate (30.4 mL, 0.286 mol), followed by the Grubbs second-

generation catalyst (146 mg, 0.179 mmol) under N2. The resulting mixture was degassed by two

freeze−pump−thaw cycles, then warmed to room temperature and stirred at the same

temperature. After 3 h, the mixture was diluted with hexanes (100 mL), and purified by flash




= –10.9 (CH2Cl2, c = 1.26); IR (neat):

3514, 2941, 2914, 2862, 1713, 1654, 1611, 1511, 1244, 1171, 1094, 1021 cm-1

; 1H NMR (400

MHz, CDCl3) δ 7.41 (dd, J = 7.2, 2.4 Hz, 2H), 7.37–7.33 (m, 3H), 7.26 (d, J = 8.8 Hz, 2H), 6.98

(ddd, J = 14.8, 7.2, 7.2 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 5.91 (d, J = 14.8 Hz, 1H), 5.55 (s, 1H),

4.46 (d, J = 11.6 Hz, 1H), 4.42 (d, J = 11.6 Hz, 1H), 4.18 (q, J = 7.6 Hz, 2H), 4.14–4.02 (m, 3H),

3.78 (s, 3H), 3.65 (ddd, J = 8.8, 8.8, 5.2 Hz, 1H), 3.54 (ddd, J = 10.4, 5.2, 5.2 Hz, 1H), 2.45–2.33

(m, 2H), 1.91 (dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.80 ( dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H),

1.77–1.75 (m, 1H), 1.67 (ddd, J = 14.0, 2.8, 2.8 Hz, 1H), 1.59 (ddd, J = 13.2, 2.4, 2.4 Hz, 1H),

1.50 (ddd, J = 13.2, 10.8, 10.8 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H); 13


166.6, 159.4, 145.2, 138.3, 130.7, 129.6, 129.1, 128.5, 126.2, 124.0, 114.0, 100.9, 77.8, 74.0,

57

72.9, 70.5, 65.6, 60.5, 55.5, 42.3, 40.4, 37.3, 36.2, 14.5; HRMS (ESI) calcd for C28H36O7Na [M

Na]+: 507.2359 Found: 507.2329.

Ethyl 2-((2S,4S,6S)-6-(((2S,4S,6S)-6-(2-hydroxyethyl)-2-phenyl-1,3-dioxan-4-yl)methyl)-2-

phenyl-1,3-dioxan-4-yl)acetate (I-27):

To a stirred solution of I-13 (2.17 g, 3.67 mmol) in dichloromethane (10 mL) at 0 °C was added

water (0.5 mL), followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.50 g, 11.0 mmol)

under N2. The resulting mixture was stirred at the same temperature for 2 h. The reaction was

quenched by adding saturated aqueous sodium bicarbonate (30 mL), and filtered through a pad

of Celite. The filtrate was extracted with EtOAc (3 × 50 mL). The combined organic layers were





= –2.8 (CH2Cl2, c = 1.68); IR (neat):

3493, 3038, 2946, 2872, 1731, 1452, 1377, 1343, 1214, 1106, 1007 cm-1

; 1H NMR (400 MHz,

CDCl3) δ 7.49–7.47 (m, 4H), 7.39–7.33 (m, 6H), 5.58 (s, 1H), 5.57 (s, 1H), 4.34 (dddd, J = 13.2,

6.4, 6.4, 2.0 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 4.18–4.10 (m, 3H), 3.90–3.80 (m, 2H), 2.73 (dd, J

= 15.6, 6.8 Hz, 1H), 2.52 (dd, J = 15.6, 6.0 Hz, 1H), 2.15 (ddd, J = 14.0, 7.2, 7.2 Hz, 1H), 1.97–

1.90 (m, 1H), 1.88–1.83 (m, 1H), 1.82–1.77 (m, 2H), 1.72–1.50 (m, 3H), 1.26 (t, J = 7.2, 3H);

13C NMR (100 MHz, CDCl3) δ 171.0, 138.63, 138.57, 129.1, 129.0, 128.5, 128.4, 126.30,

126.27, 101.0, 100.8, 76.3, 73.5, 73.3, 73.1, 60.9, 60.5, 41.8, 41.2, 38.3, 36.9, 36.6, 14.5; HRMS

(EI) calcd for C27H34O7 [M]+: 470.2305 Found: 470.2297.

58

Ethyl 2-((2S,4S,6S)-6-(((2R,4R,6R)-6-(2-oxoethyl)-2-phenyl-1,3-dioxan-4-yl)methyl)-2-

phenyl-1,3-dioxan-4-yl)acetate (I-28):


Dess–Martin periodinane (1.61 g, 3.80 mmol). After 2 h at the same temperature, the reaction

was quenched by adding saturated aqueous sodium bicarbonate (50 mL) and sodium sulfite

(0.958 g, 7.60 mmol). The mixture was stirred at room temperature for 30 min, and extracted

with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over


purified by flash chromatography (20 to 30% EtOAc in hexanes) on silica gel (50 mL) to afford

I-28 (1.20 g, 81%) as a colorless oil.


= +2.08 (CH2Cl2, c = 1.21); IR (neat):

3064, 2981, 2948, 2917, 2869, 2733, 1725, 1453, 1390, 1343, 1267, 1214, 1107, 1009 cm-1

; 1H

NMR (400 MHz, CDCl3) δ 9.86 (t, J = 2.0 Hz, 1H), 7.50–7.47 (m, 4H), 7.40–7.34 (m, 6H), 5.60

(s, 1H), 5.59 (s, 1H), 4.43 (dddd, J = 11.6, 7.6, 5.2, 2.4 Hz, 1H), 4.34 (dddd, J = 13.2, 6.4, 6.4,

2.4 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.17–4.10 (m, 2H), 2.83 (ddd, J = 16.8, 7.6, 2.0 Hz, 1H),

2.74 (dd, J = 15.6, 7.6 Hz, 1H), 2.63 (ddd, J = 16.8, 4.8, 1.2 Hz, 1H), 2.53 (dd, J = 15.6, 6.0 Hz,

1H), 2.16 (ddd, J = 14.0, 7.2, 7.2 Hz, 1H), 1.83–1.75 (m, 3H), 1.62–1.51 (m, 2H), 1.27 (t, J = 7.2

Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 200.6, 171.0, 138.5, 138.4, 129.1, 129.0, 128.52,

128.48, 126.30, 126.29, 101.0, 100.9, 73.5, 73.2, 73.1, 72.1, 60.9, 49.6, 41.8, 41.2, 36.6, 36.5,

14.5; HRMS (EI) calcd for C27H32O7 [M]+: 468.2148 Found: 468.2146.

59

Ethyl 2-((2S,4S,6S)-6-(((2R,4R,6R)-6-(2-oxoheptadec-3-yn-1-yl)-2-phenyl-1,3-dioxan-4-

yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetate (I-29):

To a stirred solution of 1-pentadecyne (0.409 g, 1.96 mmol) in tetrahydrofuran (5 mL) at –78 °C

was added a solution of n-butyllithium (1.82 M, 0.97 mL, 1.77 mmol) in hexane slowly via

syringe under N2. The resulting mixture was stirred at the same temperature for 30 min, and then

transferred to a stirred solution of I-28 (0.460 g, 0.982 mmol) in tetrahydrofuran (5 mL) at –78

°C via syringe under N2. After the addition, the flask was taken out of the dry ice-acetone bath,

kept in the ambient environment for 4 min with stirring, and immersed in the bath again. The

reaction was quenched by adding saturated aqueous ammonium chloride (10 mL), and extracted


anhydrous Na2SO4, filtered and concentrated under reduced pressure.

The crude residue was dissolved in dichloromethane (6 mL). The resulting solution was cooled

to 0 °C, and Dess–Martin periodinane (0.583 g, 1.38 mmol) was added. After 2 h at the same

temperature, the reaction was quenched by adding saturated aqueous sodium bicarbonate (20

mL) and sodium sulfite (0.348 g, 2.76 mmol). The mixture was stirred at room temperature for

30 min, and extracted with Et2O (3 × 40 mL). The combined organic layers were washed with



mL) to afford I-29 (0.443 g, 67%) as a colorless oil.


= –0.53 (CH2Cl2, c = 1.24); IR (neat):

2925, 2854, 2211, 1737, 1674, 1453, 1391, 1346, 1172, 1115, 1027 cm-1

; 1H NMR (400 MHz,

60

CDCl3) δ 7.50–7.48 (m, 4H), 7.39–7.33 (m, 6H), 5.58 (s, 2H), 4.46 (dddd, J = 13.2, 6.8, 6.8, 2.0

Hz, 1H), 4.34 (dddd, J = 13.2, 6.8, 6.8, 2.0 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.17–4.12 (m, 2H),

3.01 (dd, J = 16.0, 7.2 Hz, 1H), 2.77–2.70 (m, 2H), 2.53 (dd, J = 16.4, 6.8 Hz, 1H), 2.36 (t, J =

7.2 Hz, 2H), 2.16 (ddd, J = 15.2, 7.6, 7.6 Hz, 1H), 1.83–1.75 (m, 3H), 1.61–1.49 (m, 4H), 1.40–

1.36 (m, 2H), 1.33–1.21 (m, 21H), 0.89 (t, J = 6.8 Hz, 3H); 13


185.0, 170.9, 138.6, 138.5, 129.0, 128.43, 128.42, 126.31, 126.27, 100.85, 100.82, 95.7, 81.3,

73.5, 73.1, 72.8, 60.9, 51.5, 41.9, 41.2, 36.6, 32.2, 29.92, 29.88, 29.85, 29.69, 29.60, 29.27,

29.13, 27.9, 22.9, 19.2, 14.5, 14.4; HRMS (ESI) calcd for C42H59O7 [M H]+: 675.4261 Found:

675.4246.

Ethyl 2-((2S,4S,6S)-6-(((2S,4S,6S)-6-((S)-2-hydroxyheptadec-3-yn-1-yl)-2-phenyl-1,3-

dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetate (I-30):

To a stirred solution of I-29 (0.930 g, 1.38 mmol) in triethylamine (7.4 mL, 53.1 mmol) at 0 °C

was added formic acid (2.0 mL, 53.0 mmol) under N2. After the white smoke subsided, (S)-

RuCl[(1S,2S)-p-TsNCH(C6H5)CH(C6H5)NH2](6-mesitylene) (42.9 mg, 69.0 µmol) was added.

The resulting mixture was stirred at room temperature for 7 h. The reaction was quenched by

adding water (10 mL), and extracted with Et2O (3 × 40 mL). The combined organic layers were




61


= –17.8 (CH2Cl2, c = 1.60); IR (neat):

3499, 2924, 2854, 2230, 1737, 1454, 1393, 1346, 1215, 1115, 1027 cm-1

; 1H NMR (400 MHz,

CDCl3) δ 7.50–7.47 (m, 4H), 7.39–7.33 (m, 6H), 5.59 (s, 1H), 5.58 (s, 1H), 4.68–4.63 (m, 1H),

4.37–4.31 (m, 2H), 4.17 (q, J = 6.8 Hz, 2H), 4.17–4.10 (m, 2H), 2.73 (dd, J = 15.2, 7.2 Hz, 1H),

2.53 (dd, J = 15.2, 6.0 Hz, 1H), 2.22 (td, J = 7.6, 1.6 Hz, 2H), 2.15 (ddd, J =14.4, 7.2, 7.2 Hz,


2H), 1.68 (ddd, J = 13.2, 2.8, 2.8 Hz, 1H), 1.65–1.56 (m, 1H), 1.54–1.48 (m, 2H), 1.40–1.36 (m,

1H), 1.28–1.21 (m, 23H), 0.89 (t, J = 6.8 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 170.9, 138.6,

129.03, 128.96, 128.5, 128.4, 126.30, 126.25, 100.85, 100.83, 86.0, 81.0, 74.5, 73.5, 73.4, 73.2,

60.9, 60.3, 43.3, 41.9, 41.2, 36.8, 36.6, 32.2, 29.93, 29.89, 29.80, 29.6, 29.4, 29.1, 28.9, 22.9,

19.0, 14.5, 14.4; HRMS (ESI) calcd for C42H61O7 [M H]+: 677.4417 Found: 677.4410.

Ethyl 2-((2S,4S,6S)-6-(((2S,4S,6S)-6-((R)-2-hydroxyheptadecyl)-2-phenyl-1,3-dioxan-4-

yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetate (I-31):


temperature was added triethylamine (3.59 mL, 25.7 mmol), followed by o-

nitrobenzenesulfonylhydrazide (2.79 g, 12.9 mmol). The resulting mixture was stirred at the

same temperature for 20 h. The reaction was quenched by adding saturated aqueous sodium

bicarbonate, and extracted with Et2O (3 × 40 mL). The combined organic layers were washed


62



Data for I-31:Rf = 0.44 (30% EtOAc in hexanes); [α]D19

= –1.30 (CH2Cl2, c = 2.91); IR (neat):

3517, 2924, 2853, 1737, 1454, 1391, 1345, 1215, 1113, 1027 cm-1


δ 7.49–7.47 (m, 4H), 7.38–7.33 (m, 6H), 5.57 (s, 1H), 5.55 (s, 1H), 4.34 (dddd, J = 13.2, 6.4, 6.4,

2.4 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 4.18–4.10 (m, 3H), 3.99–3.94 (m, 1H), 2.73 (dd, J = 15.6,

7.2 Hz, 1H), 2.52 (dd, J = 15.6, 6.8 Hz, 1H), 2.15 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 1.82–1.74 (m,

3H), 1.71–1.61 (m, 3H), 1.59–1.50 (m, 2H), 1.47–1.43 (m, 1H), 1.28–1.21 (m, 29H), 0.88 (t, J =

6.8 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 170.9, 138.7, 138.6, 128.95, 128.93, 128.5, 128.4,

126.29, 126.25, 100.9, 100.8, 74.6, 73.5, 73.4, 73.2, 68.5, 60.9, 42.7, 41.9, 41.2, 38.0, 36.8, 36.6,

32.2, 29.93, 29.86, 29.85, 29.59, 25.9, 22.9, 14.45, 14.36; HRMS (ESI) calcd for C47H65O7 [M

H]+: 681.4730 Found: 681.4720.

2-((2S,4S,6S)-6-(((2S,4S,6S)-6-((R)-2-Hydroxyheptadecyl)-2-phenyl-1,3-dioxan-4-

yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetaldehyde (I-32):


added a solution of diisobutylaluminum hydride (1 M, 1.1 mL, 1.1 mmol) in hexane slowly via

syringe under N2. After the starting material was consumed, the reaction mixture was quenched

by adding 1 N hydrochloric acid (10 mL), and stirred at room temperature for 1 h. The mixture

was extracted with Et2O (3 × 30 mL). The combined organic layers were washed with brine,


63




= –8.15 (CH2Cl2, c = 1.41); IR (neat):

3426, 2924, 2853, 1725, 1641, 1454, 1390, 1343, 1113, 1026 cm-1


δ 9.86 (t, J = 1.6 Hz, 1H), 7.49–7.47 (m, 4H), 7.39–7.34 (m, 6H), 5.59 (s, 1H), 5.55 (s, 1H), 4.43

(dddd, J = 11.2, 7.6, 5.2, 2.4 Hz, 1H), 4.22–4.09 (m, 3H), 3.98–3.94 (m, 1H), 2.83 (ddd, J = 16.8,

7.2, 2.0 Hz, 1H), 2.64 (ddd, J = 16.8, 4.8, 1.2 Hz, 1H), 2.16 (ddd, J = 14.0, 6.8, 6.8 Hz, 1H),

1.81–1.75 (m, 3H), 1.71–1.53 (m, 4H), 1.50–1.43 (m, 2H), 1.30–1.20 (m, 26H), 0.88 (t, J = 6.8

Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 200.6, 138.7, 138.4, 129.1, 129.0, 128.5, 126.28,

126.26, 100.98, 100.95, 74.6, 73.3, 73.2, 72.1, 68.4, 49.6, 42.7, 41.8, 38.0, 36.8, 36.7, 32.2,

29.94, 29.91, 29.88, 29.86, 29.6, 25.9, 22.9, 14.4; HRMS (ESI) calcd for C40H61O6 [M H]+:

637.4468 Found: 637.4470.

(R)-1-((2R,4R,6S)-6-(((2S,4S,6S)-6-(2-Oxoethyl)-2-phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-

1,3-dioxan-4-yl)heptadecan-2-yl acetate (I-33):


triethylamine (0.33 mL, 2.36 mmol), followed by 4-dimethylaminopyridine (2.8 mg, 24 µmol)

and acetic anhydride (89 µL, 2.36 mmol). The resulting mixture was stirred at the same

temperature for 20 min. The reaction was quenched by adding methanol (0.1 mL), and diluted

with Et2O (60 mL). The mixture was washed with brine, dried over anhydrous Na2SO4, filtered

and concentrated under reduced pressure. The crude residue was purified by flash

64




= –16.9 (CH2Cl2, c = 0.73); IR (neat):

2924, 2853, 1734, 1453, 1373, 1342, 1242, 1112, 1025 cm-1

; 1H NMR (400 MHz, CDCl3) δ 9.86

(s, 1H), 7.52–7.48 (m, 4H), 7.40–7.32 (m, 6H), 5.60 (s, 1H), 5.50 (s, 1H), 5.21 (dddd, J = 9.2,

6.4, 6.4, 3.6 Hz, 1H), 4.43 (dddd, J = 10.0, 7.2, 4.8, 2.0 Hz, 1H), 4.20–4.14 (m, 1H), 4.12–4.05

(m, 1H), 3.90–3.83 (m, 1H), 2.83 (ddd, J = 16.8, 7.2, 1.6 Hz, 1H), 2.63 (ddd, J = 16.8, 4.8, 1.2

Hz, 1H), 2.17 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 2.05 (s, 3H), 1.88–1.76 (m, 3 H), 1.75–1.69 (m,

1H), 1.64–1.50 (m, 5H), 1.25–1.24 (m, 26H), 0.88 (t, J = 6.8 Hz, 3H); 13

C NMR (100 MHz,

CDCl3) δ 200.6, 170.9, 138.7, 138.4, 129.1, 128.8, 128.5, 128.4, 126.3, 126.2, 101.0, 100.5, 73.7,

73.3, 73.1, 72.1, 71.2, 49.6, 41.8, 40.9, 37.2, 36.6, 35.1, 32.2, 29.95, 29.91, 29.83, 29.78, 29.6,

25.4, 23.0, 21.6, 14.4; HRMS (ESI) calcd for C42H62O7Na [M Na]+: 701.4393 Found:

701.4440.

(R)-1-((2R,4R,6S)-6-(((2R,4R,6R)-6-((R)-2-hydroxypent-4-en-1-yl)-2-phenyl-1,3-dioxan-4-

yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadecan-2-yl acetate (I-34):



slowly via syringe, followed by scandium triflate (7.8 mg, 15.8 µmol) under N2. Then the



65

and the filtrate was extracted with Et2O (3 × 40 mL). The combined organic layers were washed





= –10.5 (CH2Cl2, c = 0.49); IR (neat):

3460, 2329, 2853, 1737, 1453, 1373, 1341, 1240, 1113, 1020 cm-1


δ 7.51–7.45 (m, 4H), 7.38–7.32 (m, 6H), 5.84 (dddd, J = 17.6, 10.4, 7.2, 7.2 Hz, 1H), 5.59 (s,

1H), 5.49 (s, 1H), 5.24–5.18 (m, 1H), 5.14–5.09 (m, 2H), 4.17–4.10 (m, 2H), 4.10–4.04 (m, 1H),

3.98 (dddd, J = 8.4, 6.4, 6.4, 2.4 Hz, 1H), 3.89–3.83 (m, 1H), 2.28–2.24 (m, 2H), 2.16 (ddd, J =

14.8, 7.6, 7.6 Hz, 1H), 2.05 (s, 3H), 1.87–1.69 (m, 6H), 1.64–1.49 (m, 5H), 1.25–1.24 (m, 26H),

0.88 (t, J = 7.2 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 171.0, 138.7, 138.4, 134.9, 129.2, 128.8,

128.6, 128.5, 128.4, 126.3, 126.2, 117.9, 101.0, 100.4, 73.7, 73.4, 73.1, 71.2, 70.6, 42.22,

42.18,41.8, 40.8, 37.2, 37.1, 35.1, 32.2, 30.5, 29.95, 29.91, 29.83, 29.78, 29.6, 25.4, 23.0, 21.6,

14.4; HRMS (ESI) calcd for C45H69O7 [M H]+: 721.5043 Found: 721.5053.

(R)-1-((2S,4S,6R)-6-(((2R,4S,6R)-6-((R)-2-Acetoxyheptadecyl)-2-phenyl-1,3-dioxan-4-

yl)methyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-yl acrylate (I-35):

To a stirred solution of I-34 (71.3 mg, 98.9 µmol) in dichloromethane (0.5 mL) at room

temperature was added N,N'-dicyclohexylcarbodiimide (40.8 mg, 198 µmol), followed by acrylic

acid (10 µL, 148 µmol) and 4-dimethylaminopyridine (0.6 mg, 4.9 µmol). The resulting mixture

was stirred at the same temperature for 20 h, diluted with Et2O (10 mL) and filtered through filter

66

paper. The filtrate was concentrated under reduced pressure. The crude residue was purified by

flash chromatography (5 to 15% EtOAc in hexanes) on silica gel (15 mL) to afford I-35 (47.0

mg, 61%) as a colorless oil.


= –13.1 (CH2Cl2, c = 0.72); IR (neat):

2924, 2853, 1725, 1453, 1405, 1375, 1341, 1241, 1194, 1113, 1021 cm-1

; 1H NMR (400 MHz,

CDCl3) δ 7.52–7.46 (m, 4H), 7.38–7.31 (m, 6H), 6.35 (dd, J = 17.6, 1.6 Hz, 1H), 6.06 (dd, J =

17.6, 10.4 Hz, 1H), 5.82–5.73 (m, 1H), 5.76 (dd, J = 10.4, 1.6 Hz, 1H), 5.50 (s, 2H), 5.24–5.19

(m, 1H), 5.12 –5.07 (m, 2H), 4.12–4.05 (m, 2H), 3.98–3.92 (m, 1H), 3.89–3.83 (m, 1H), 2.44–

2.39 (m, 2H), 2.18–2.06 (m, 2H), 2.05 (s, 3H), 1.88–1.68 (m, 6H), 1.64–1.47 (m, 5H), 1.25–1.24

(m, 26H), 0.88 (t, J = 6.8 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 170.9, 166.0, 138.82, 138.77,

133.4, 131.0, 128.9, 128.8, 128.7, 128.4, 128.3, 126.4, 126.2, 118.5, 100.9, 100.4, 74.3, 73.7,

73.3, 73.1, 71.2, 70.5, 41.9, 40.9, 40.0, 39.2, 37.3, 36.7, 35.1, 32.2, 29.93, 29.89, 29.82, 29.78,

29.59, 25.4, 22.9, 21.5, 14.4; HRMS (ESI) calcd for C48H71O8 [M H]+: 775.5149 Found:

775.5156.

(R)-1-((2R,4R,6S)-6-(((2S,4R,6S)-6-(((R)-6-Oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-2-

phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadecan-2-yl acetate (I-36):

To a stirred solution of I-35 (40.5 mg, 52.3 µmol) in dichloromethane (5 mL) at room

temperature was added the Grubbs first-generation catalyst (2.2 mg, 2.6 µmol) under N2. The

resulting solution was degassed by two freeze−pump−thaw cycles, and then heated to reflux.

After 2 h, the mixture was cooled to room temperature, and dimethyl sulfoxide was added. The

67

stirring was then continued for another 2 h. The mixture was concentrated under reduced


hexanes) on silica gel (10 mL) to afford I-36 (29.3 mg, 75%) as a colorless oil.


= +6.04 (CH2Cl2, c = 0.63); IR (neat):

2924, 2853, 1735, 1453, 1377, 1342, 1244, 1113, 1025 cm-1

; 1H NMR (400 MHz, CDCl3) δ

7.51–7.45 (m, 4H), 7.39–7.32 (m, 6H), 6.89 (ddd, J = 9.6, 5.6, 2.0 Hz, 1H), 6.04 (dd, J = 9.6, 2.0

Hz, 1H), 5.55 (s, 1H), 5.50 (s, 1H), 5.23–5.17 (m, 1H), 4.73–4.66 (m, 1H), 4.20–4.05 (m, 3H),

3.89–3.83 (m, 1H), 2.51 (dddd, J = 18.4, 10.8, 2.4, 2.4 Hz, 1H), 2.41 (ddd, J = 18.4, 5.2, 5.2 Hz,

1H), 2.23 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 2.15 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 2.05 (s, 3H),

1.97–1.91 (m, 1H), 1.89–1.82 (m, 1H), 1.79–1.69 (m, 2H), 1.64–1.50 (m, 6H), 1.26–1.25 (m,

26H), 0.88 (t, J = 6.8 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 170.9, 164.6, 145.5, 138.8, 138.7,

129.0, 128.8, 128.5, 128.4, 126.3, 126.2, 121.5, 100.9, 100.5, 74.8, 73.7, 73.4, 73.1, 72.8, 71.2,

41.9, 40.9, 40.6, 37.2, 36.6, 35.1, 32.2, 29.93, 29.89, 29.82, 29.76, 29.6, 29.5, 25.4, 22.9, 21.5,


Ethyl 2-((2S,4S,6S)-6-(((2R,4R,6R)-6-((R)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-

phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetate (I-37):

To a stirred solution of I-31 (0.785 g, 1.25 mmol) in dimethylformamide (2.5 mL) at room

temperature was added tert-butyldimethylsilyl chloride (0.348 g, 2.31 mmol), followed by

imidazole (0.196 g, 2.88 mmol). The resulting mixture was stirred at the same temperature for 14

h. The reaction was quenched by adding water (10 mL) and extracted with Et2O (3 × 40 mL).

68

The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and

concentrated under reduced pressure. The crude residue was purified by flash chromatography (2

to 5% EtOAc in hexanes) on silica gel (35 mL) to afford I-37 (0.880 g, 96%) as a colorless oil.


= –16.9 (CH2Cl2, c = 1.06); IR (neat):

2926, 2855, 1737, 1462, 1388, 1344, 1254, 1112, 1027 cm-1

; 1H NMR (400 MHz, CDCl3) δ

7.50–7.47 (m, 4H), 7.38–7.32 (m, 6H), 5.58 (s, 1H), 5.51 (s, 1H), 4.36–4.31 (m, 1H), 4.17 (q, J =

7.6 Hz, 2H), 4.17–4.13 (m, 1H), 4.13–4.07 (m, 1H), 4.03–3.99 (m, 2H), 2.74 (dd, J = 15.6, 7.2

Hz, 1H), 2.53 (dd, J = 15.6, 6.0 Hz, 1H), 2.15 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 1.84–1.81 (m,

1H), 1.79–1.69 (m, 2H), 1.65–1.51 (m, 7H), 1.48–1.43 (m, 2H), 1.28–1.25 (m, 26H), 0.90 (s,

9H), 0.88 (t, J = 7.6 Hz, 3H), 0.05 (s, 6H); 13

C NMR (100 MHz, CDCl3) δ 171.0, 139.1, 138.6,

128.9, 128.8, 128.42, 128.39, 126.28, 126.27, 100.8, 100.5, 73.5, 73.4, 73.34, 73.27, 68.1, 60.9,

43.6, 42.0, 41.3, 38.5, 37.7, 36.6, 32.2, 30.2, 29.94, 29.91, 29.8, 29.6, 26.2, 24.7, 22.9, 18.4, 14.5,

14.4, –4.0, –4.3; HRMS (ESI) calcd for C48H79O7Si [M H]+: 795.5595 Found: 795.5599.

2-((2S,4S,6S)-6-(((2R,4R,6R)-6-((R)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-phenyl-

1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetaldehyde (I-38):






69





= –21.2 (CH2Cl2, c = 1.06); IR (neat):

2926, 2854, 1727, 1459, 1404, 1343, 1254, 1112, 1058, 1027 cm-1


δ 9.86 (s, 1H), 7.50–7.47 (m, 4H), 7.38–7.33 (m, 6H), 5.60 (s, 1H), 5.50 (s, 1H), 4.47–4.41 (m,

1H), 4.19–4.14 (m, 1H), 4.10–4.05 (m, 1H), 4.05–3.98 (m, 2H), 2.83 (ddd, J = 16.8, 7.2, 2.0 Hz,

1H), 2.64 (ddd, J = 16.8, 4.8, 1.6 Hz, 1H), 2.15 (ddd, J = 14.0, 6.8. 6.8 Hz, 1H), 1.83–1.69 (m,

3H), 1.64–1.50 (m, 4H), 1.49–1.43 (m, 2H), 1.28–1.25 (m, 26H), 0.90 (s, 9H), 0.88 (t, J = 7.6

Hz, 3H), 0.05 (s, 6H); 13

C NMR (100 MHz, CDCl3) δ 200.6, 139.1, 138.4, 129.1, 128.8, 128.5,

128.4, 126.3, 101.0, 100.6, 73.4, 73.34, 73.29, 72.1, 68.1, 49.6, 43.6, 41.9, 38.5, 37.7, 36.7, 32.2,

30.2, 29.95, 29.92, 29.86, 29.6, 26.2, 24.7, 22.9, 18.4, 14.4, –3.9, –4.3; HRMS (ESI) calcd for

C46H75O6Si [M H]+: 751.5333 Found: 751.5338.

(S)-1-((2R,4R,6R)-6-(((2R,4R,6R)-6-((R)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-

phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-ol (I-39):


added a solution of (R,R)-Leighton reagent (0.390, 0.703 mmol) in dichloromethane (2 mL)




70

and the filtrate was extracted with Et2O (3 × 40 mL). The combined organic layers were washed





= –7.9 (CH2Cl2, c = 0.95); IR (neat):

3443, 2926, 2854, 1641, 1461, 1405, 1388, 1342, 1254, 1057, 1027 cm-1

; 1H NMR (400 MHz,

CDCl3) δ 7.51–7.47 (m, 4H), 7.38–7.32 (m, 6H), 5.83(dddd, J = 17.6, 10.4, 7.2, 7.2 Hz, 1H),

5.56 (s, 1H), 5.50 (s, 1H), 5.16–5.12 (m, 2H), 4.22–4.16 (m, 1H), 4.15–4.10 (m, 1H), 4.09–3.98

(m, 4H), 2.33–2.19 (m, 2H), 2.15 (ddd, J = 14.0, 6.8, 6.8 Hz, 1H), 1.83–1.69 (m, 4H), 1.67–1.51

(m, 5H), 1.48–1.43 (m, 2H), 1.28–1.25 (m, 26H), 0.90 (s, 9H), 0.88 (t, J = 7.6 Hz, 3H), 0.05 (s,

6H); 13

C NMR (100 MHz, CDCl3) δ 139.1, 138.8, 134.9, 128.9, 128.8, 128.5, 128.4, 126.3,

118.3, 100.9, 100.5, 74.4, 73.5, 73.42, 73.38, 68.1, 67.3, 43.6, 42.5, 42.3, 42.0, 38.5, 37.7, 36.9,

32.2, 30.2, 29.93, 29.90, 29.8, 29.6, 26.2, 24.7, 22.9, 18.4, 14.4, –4.0, –4.3; HRMS (ESI) calcd

for C49H81O6Si [M H]+: 793.5802 Found: 793.5804.

(S)-1-((2S,4S,6R)-6-(((2R,4R,6R)-6-((R)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-

phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-yl acrylate (I-40):

To a stirred solution of I-39 (0.253 g, 0.319 mmol) in dichloromethane (1.0 mL) at room

temperature was added N,N'-dicyclohexylcarbodiimide (78.6 mg, 0.383 mmol), followed by

acrylic acid (28 µL, 0.383 mmol) and 4-dimethylaminopyridine (2.0 mg, 16.4 µmol). The

resulting mixture was stirred at the same temperature for 20 h, diluted with Et2O (10 mL) and

71

filtered through filter paper. The filtrate was concentrated under reduced pressure. The crude




= +10.6 (CH2Cl2, c = 0.65); IR (neat):

2926, 2854, 1725, 1461, 1405, 1341, 1295, 1255, 1192, 1027 cm-1


δ 7.51–7.49 (m, 4H), 7.39–7.32 (m, 6H), 6.40 (dd, J = 17.6, 1.6 Hz, 1H), 6.12 (dd, J = 17.6, 10.4

Hz, 1H), 5.82 (dd, J = 10.4, 1.6 Hz, 1H), 5.77 (dddd, J = 17.6, 10.4, 7.2, 7.2 Hz, 1H), 5.50 (s,

2H), 5.40–5.34 (m, 1H), 5.10–5.06 (m, 2H), 4.11–4.05 (m, 2H), 4.03–3.98 (m, 2H), 3.92–3.87

(m, 1H), 2.47–2.34 (m, 2H), 2.15 (ddd, J = 14.0, 7.2, 7.2 Hz, 1H), 1.91 (ddd, J = 14.8, 9.6, 3.6

Hz, 1H), 1.81 (ddd, J = 14.8, 9.2, 3.6 Hz, 1H), 1.76–1.61 (m, 4H), 1.56–1.43 (m, 5H), 1.28–1.25

(m, 26H), 0.90 (s, 9H), 0.88 (t, J = 7.6 Hz, 3H), 0.05 (s, 6H); 13


165.9, 139.1, 138.8, 133.5, 130.9, 128.9, 128.7, 128.4, 126.3, 126.2, 118.3, 100.6, 100.4, 73.6,

73.4, 73.2, 70.3, 68.1, 43.6, 42.0, 40.3, 39.5, 38.4, 37.7, 37.3, 32.2, 30.2, 29.90, 29.94, 29.8, 29.6,

26.2, 24.7, 22.9, 18.4, 14.4, –4.0, –4.3; HRMS (ESI) calcd for C52H83O7Si [M H]+: 847.5908

Found: 847.5912.

(S)-6-(((2S,4S,6R)-6-(((2R,4R,6R)-6-((R)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-

phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)methyl)-5,6-dihydro-2H-pyran-2-

one (I-41):



72







= –15.8 (CH2Cl2, c = 0.24); IR (neat):

2925, 2854, 1726, 1461, 1453, 1380, 1343, 1250, 1140, 1058, 1027 cm-1

; 1H NMR (400 MHz,

CDCl3) δ 7.51–7.46 (m, 4H), 7.39–7.31 (m, 6H), 6.88 (ddd, J = 9.6, 6.0, 3.2 Hz, 1H), 6.03 (dd, J

= 9.6, 2.4 Hz, 1H), 5.58 (s, 1H), 5.50 (s, 1H), 4.83–4.76 (m, 1H), 4.30–4.25 (m, 1H), 4.17–4.11

(m, 1H), 4.10–4.06 (m, 1H), 4.06–3.98 (m, 2H), 2.41–2.29 (m, 2H), 2.15 (ddd, J = 14.0, 6.8, 6.8

Hz, 1H), 1.98 (ddd, J = 14.4, 9.6, 2.0 Hz, 1H), 1.88 (ddd, J = 14.4, 10.0, 2.4 Hz, 1H), 1.78–1.70

(m, 3H), 1.64–1.61 (m, 1H), 1.57–1.43 (m, 5H), 1.28–1.25 (m, 26H), 0.90 (s, 9H), 0.88 (t, J =

7.6 Hz, 3H), 0.05 (s, 6H); 13

C NMR (100 MHz, CDCl3) δ 164.5, 145.3, 139.0, 138.7, 128.9,

128.7, 128.4, 128.3, 126.24, 126.20, 121.6, 100.7, 100.5, 74.1, 73.35, 73.31, 72.2, 68.0, 43.5,

42.0, 41.8, 38.4, 37.7, 37.2, 32.1, 30.1, 30.0, 29.89, 29.85, 29.8, 29.6, 26.2, 24.7, 22.9, 18.3, 14.3,

–4.0, –4.3; HRMS (ESI) calcd for C50H79O7Si [M H]+: 819.5595 Found: 819.5602.

(S)-6-((2S,4S,6S,8S,10R)-2,4,6,8,10-pentahydroxypentacosyl)-5,6-dihydro-2H-pyran-2-one

(or ent-cryptocaryol A) (I-42):



73




= –13.4 (MeOH, c = 0.10); IR (neat):

3313, 2918, 2850, 1721, 1456, 1329, 1258, 1137, 1073, 1027 cm-1

; 1H NMR (500 MHz,

CD3OD) δ 7.04 (ddd, J = 9.5, 6.0, 2.5 Hz, 1H), 5.97 (dd, J = 9.5, 2.5 Hz, 1H), 4.74–4.68 (m,

1H), 4.09 (dddd, J = 9.0, 6.5, 6.5, 2.5 Hz, 1H), 4.04–3.96 (m, 3H), 3.82–3.77 (m, 1H), 2.45 (ddd,

J = 19.0, 5.0, 5.0 Hz, 1H), 2.36 (dddd, J = 19.0, 11.5, 2.5, 2.5 Hz, 1H), 1.94 (ddd, J = 14.5, 9.5,

2.5 Hz, 1H), 1.71–1.55 (m, 7H), 1.52–1.50 (m, 2H), 1.46–1.40 (m, 2H), 1.32–1.25 (m, 26H),

0.89 (t, J = 7.0 Hz, 3H); 13

C NMR (125 MHz, CD3OD) δ 167.0, 148.6, 121.4, 76.6, 70.2, 69.9,

69.1, 68.2, 66.6, 46.0, 45.9, 45.8, 45.3, 43.9, 39.3, 33.1, 31.0, 30.9, 30.84, 30.81, 30.5, 26.8, 23.8,

14.5.14

(S)-1-((2S,4S,6R)-6-(((2S,4S,6S)-6-((R)-2-hydroxyheptadecyl)-2-phenyl-1,3-dioxan-4-


To a flask with I-40 (95.5 mg, 0.113 mmol) was added a solution of tetra-n-butylammonium

fluoride (1 M, 5 mL, 5 mmol) at room temperature. The resulting mixture was stirred at the same

temperature for 3 h. The reaction was quenched by adding saturated aqueous sodium

bicarbonate, and extracted with Et2O (3 × 30 mL). The combined organic layers were washed



(20 mL) to afford I-43 (75.0 mg, 91%) as a colorless oil.

74


= +20.8 (CH2Cl2, c = 0.65); IR (neat):

2923, 2853, 1723, 1453, 1405, 1342, 1295, 1193, 1112, 1026 cm-1


δ 7.51–7.47 (m, 4H), 7.38–7.32 (m, 6H), 6.40 (d, J = 18.0 Hz, 1H), 6.12 (d, J = 18.0, 10.4 Hz,

1H), 5.82 (d, J = 10.4 Hz, 1H), 5.77 (dddd, J = 17.6, 10.0, 7.2, 7.2 Hz, 1H), 5.55 (s, 1H), 5.49 (s,

1H), 5.37 (dddd, J = 9.2, 5.6, 5.6, 3.6, 1H), 5.10–5.06 (m, 2H), 4.22-4.05 (m, 3H), 3.98–3.86 (m,

2H), 2.47–2.34 (m, 2H), 2.16 (ddd, J = 14.0, 7.2, 7.2 Hz, 1H), 1.90 (ddd, J = 14.0, 9.6, 3.2 Hz,

1H), 1.83–1.73 (m, 3H), 1.71–1.62 (m, 4H), 1.53–1.43 (m, 3H), 1.28–1.25 (m, 26H), 0.88 (t, J =

7.2 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 165.8, 138.71, 138.68, 133.4, 130.8, 128.90, 128.86,

128.7, 128.4, 128.3, 126.2, 126.1, 118.3, 100.9, 100.4, 74.6, 73.5, 73.4, 73.1, 70.2, 68.4, 42.6,

41.9, 40.3, 39.4, 38.0, 37.2, 36.7, 32.1, 29.87, 29.81, 29.79, 29.5, 25.9, 22.9, 14.3, 14.2; HRMS

(ESI) calcd for C46H69O7 [M H]+: 733.5043 Found: 733.5043.

(S)-1-((2S,4S,6R)-6-(((2R,4S,6R)-6-((R)-2-acetoxyheptadecyl)-2-phenyl-1,3-dioxan-4-


To a stirred solution of I-43 (75.0 mg, 0.102 mmol) in dichloromethane (1 mL) at 0 °C was

added triethylamine (29 µL, 0.204 mmol), followed by 4-dimethylaminopyridine (2.0 mg, 16

µmol) and acetic anhydride (15 µL, 0.159 mmol). The resulting mixture was stirred at the same

temperature for 1.5 h. The reaction was quenched by adding methanol (0.1 mL), and diluted with

Et2O (20 mL). The mixture was washed with brine, dried over anhydrous Na2SO4, filtered and


to 15% EtOAc in hexanes) on silica gel (20 mL) to afford I-44 (74.0 mg, 96%) as a colorless oil.

75


= +11.2 (CH2Cl2, c = 0.72); IR (neat):

2924, 2854, 1726, 1453, 1406, 1374, 1268, 1242, 1193, 1147, 1113, 1026 cm-1

; 1H NMR (400

MHz, CDCl3) δ 7.52–7.50 (m, 4H), 7.38–7.32 (m, 6H), 6.40 (dd, J = 17.6, 1.2 Hz, 1H), 6.12 (dd,

J = 17.6, 10.4 Hz, 1H), 5.82 (dd, J = 10.4, 1.6 Hz, 1H), 5.77 (dddd, J = 16.8, 10.0, 7.2, 7.2 Hz,

1H), 5.50 (s, 2H), 5.37 (dddd, J = 8.8, 5.6, 5.6, 3.2 Hz, 1H), 5.21 (dddd, J = 9.2, 6.0, 6.0, 3.6 Hz,

1H), 5.10–5.06 (m, 2H), 4.12–4.05 (m, 2H), 3.92–3.83 (m, 2H), 2.47–2.33 (m, 2H), 2.16 (ddd, J

= 14.4, 7.2, 7.2 Hz, 1H), 2.04 (s, 3H), 1.94–1.71 (m, 6H), 1.66–1.62 (m, 2H), 1.60–1.47 (m, 3H),

1.26–1.23 (m, 26H), 0.88 (t, J = 7.6 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 170.9, 165.8,

138.75, 138.71, 133.4, 130.8, 128.9, 128.72, 128.69, 128.33, 128.31, 126.16, 126.14, 118.3,

100.4, 73.7, 73.5, 73.1, 71.2, 70.2, 41.9, 40.8, 40.3, 39.4, 37.2, 35.1, 32.1, 29.88, 29.86, 29.85,

29.77, 29.71, 29.6, 25.3, 22.9, 21.5, 14.3; HRMS (ESI) calcd for C48H71O8 [M H]+: 775.5149

Found: 775.5156.

(R)-1-((2R,4R,6S)-6-(((2S,4R,6S)-6-(((S)-6-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-2-







76




= –13.6 (CH2Cl2, c = 0.51); IR (neat):

2923, 2853, 1735, 1453, 1377, 1343, 1244, 1140, 1119, 1058, 1025 cm-1

; 1H NMR (400 MHz,

CDCl3) δ 7.52–7.47 (m, 4H), 7.39–7.32 (m, 6H), 6.88 (ddd, J = 9.6, 5.2, 2.8 Hz, 1H), 6.03 (ddd,

J = 9.6, 1.6, 1.6 Hz, 1H), 5.58 (s, 1H), 5.50 (s, 1H), 5.21 (dddd, J = 9.6, 6.8, 6.8, 3.6 Hz, 1H),

4.79 (m, J = 9.6, 9.6, 5.6, 2.8 Hz, 1H), 4.30–4.24 (m, 1H), 4.16–4.06 (m, 2H), 3.89–3.84 (m,

1H), 2.40–2.30 (m, 2H), 2.16 (ddd, J = 13.6, 6.8, 6.8 Hz, 1H), 2.04 (s, 3H), 1.97 (ddd, J = 14.8,

9.6, 2.0 Hz, 1H), 1.91–1.82 (m, 2H), 1.80–1.69 (m, 3H), 1.65–1.49 (m, 5H), 1.26–1.23 (m, 26H),

0.88 (t, J = 7.6 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 170.9, 164.5, 145.3, 138.7, 129.0, 128.7,

128.4, 128.3, 126.3, 126.1, 121.6, 100.7, 100.4, 74.1, 73.7, 73.3, 73.1, 72.2, 71.2, 41.9, 41.7,

40.8, 37.2, 35.1, 32.1, 30.1, 29.89, 29.84, 29.77, 29.73, 29.6, 25.3, 22.9, 21.5, 14.3; HRMS (ESI)

calcd for C46H67O8 [M H]+: 747.4836 Found: 747.4833.

(2S,4S,6R,8R,10R)-2,4,6,8-tetrahydroxy-1-((S)-6-oxo-3,6-dihydro-2H-pyran-2-yl)

pentacosan -10-yl acetate (I-46):

To a flask with I-45 (22.7 mg, 30.4 µmol) was added a solution of acetic acid (2.5 mL, 80%) in



MeOH in EtOAc) on silica gel (10 mL) to afford I-46 (13.0 mg, 75%) as a white amorphous

solid.

77


= –23.9 (MeOH, c = 0.20); IR (neat):

3407, 2918, 2850, 1710, 1650, 1467, 1426, 1377, 1255, 1105, 1051 cm-1

; 1H NMR (400 MHz,

CDCl3) δ 7.04 (ddd, J = 9.6, 5.6, 2.8 Hz, 1H), 5.97 (dd, J = 9.6, 1.6 Hz, 1H), 5.07 (dddd, J = 9.6,

6.4, 6.4, 2.8 Hz, 1H), 4.74–4.67 (m, 1H), 4.08 (dddd, J = 9.2, 6.8, 6.8, 2.4 Hz, 1H), 4.01–3.92

(m, 2H), 3.81–3.75 (m, 1H), 2.45 (ddd, J = 18.4, 5.2, 5.2 Hz, 1H), 2.36 (dddd, J = 18.4, 11.2, 2.8,

2.8 Hz, 1H), 2.03 (s, 3H), 1.94 (ddd, J = 14.4, 9.6, 2.8 Hz, 1H), 1.72 (ddd, J = 14.4, 9.2, 2.8 Hz,

1H), 1.67–1.54 (m, 10 H), 1.28–1.25 (m, 26H), 0.89 (t, J = 6.8 Hz, 3H); 13

C NMR (125 MHz,

CDCl3) δ 173.1, 167.0, 148.6, 121.4, 76.6, 72.8, 69.93, 69.85, 67.5, 66.6, 45.9, 45.8, 45.3, 43.9,

43.3, 36.0, 33.1, 31.0, 30.8, 30.73, 30.69, 30.62, 30.5, 26.3, 23.8, 21.2, 14.5.14

2-((2S,4S,6S)-6-(((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-

yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetaldehyde (I-47):










= –19.9 (CH2Cl2, c = 0.95); IR (neat):

2948, 2918, 2861, 1725, 1612, 1513, 1453, 1344, 1248, 1112, 1027 cm-1

; 1H NMR (400 MHz,

78

CDCl3) δ 9.86 (t, J = 1.6 Hz, 1H), 7.49–7.44 (m, 4H), 7.38–7.33 (m, 6H), 7.26 (d, J = 8.8 Hz,

2H), 6.86 (d, J = 8.8 Hz, 2H), 5.58 (s, 1H), 5.52 (s, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.47–4.39 (m,

1H), 4.43 (d, J = 12.0 Hz, 1H), 4.19–4.10 (m, 1H), 4.10–4.00 (m, 2H), 3.78 (s, 3H), 3.67 (ddd, J

= 9.2, 9.2, 5.2 Hz, 1H), 3.58 (ddd, J = 9.2, 5.2, 5.2 Hz, 1H), 2.83 (ddd, J = 16.8, 7.2, 2.0 Hz, 1H),

2.63 (ddd, J = 16.8, 5.2, 1.6 Hz, 1H), 2.15 (ddd, J = 14.0, 6.8, 6.8 Hz, 1H), 1.93 (dddd, J = 13.2,

8.0, 5.2, 5.2 Hz, 1H), 1.84 (dddd, J = 13.2, 8.0, 5.2, 5.2 Hz, 1H), 1.80–1.73 (m, 2H), 1.69–1.43

(m, 3H); 13

C NMR (100 MHz, CDCl3) δ 200.6, 159.4, 139.0, 138.4, 130.7, 129.6, 129.1, 128.9,

128.5, 128.4, 126.3, 114.0, 101.0, 100.7, 74.0, 73.29, 73.23, 72.9, 72.1, 65.9, 55.5, 49.6, 41.9,

37.1, 36.7, 36.3; HRMS (ESI) calcd for C33H39O7 [M H]+: 547.2696 Found: 547.2698.

1-((2S,4S,6S)-6-(((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-

yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadec-3-yn-2-one (I-48):

To a stirred solution of 1-pentadecyne (0.976 g, 4.68 mmol) in tetrahydrofuran (12 mL) at –78

°C was added a solution of n-butyllithium (1.82 M, 1.9 mL, 3.51 mmol) in hexane slowly via

syringe under N2. The resulting mixture was stirred at the same temperature for 30 min, and then

transferred to a stirred solution of I-47 (1.28 g, 2.34 mmol) in tetrahydrofuran (12 mL) at –78 °C

via syringe under N2. After the addition, the flask was taken out of the dry ice-acetone bath, kept

in the ambient environment for 8 min with stirring, and immersed in the bath again. The reaction

was quenched by adding saturated aqueous ammonium chloride (20 mL), and extracted with

Et2O (3 × 60 mL). The combined organic layers were washed with brine, dried over anhydrous

Na2SO4, filtered and concentrated under reduced pressure.

79

The crude residue was dissolved in dichloromethane (12 mL). The resulting solution was cooled

to 0 °C, and Dess–Martin periodinane (1.49 g, 3.51 mmol) was added. After 2 h at the same

temperature, the reaction was quenched by adding saturated aqueous sodium bicarbonate (10

mL) and sodium sulfite (0.884 g, 7.02 mmol). The mixture was stirred at room temperature for

30 min, and extracted with Et2O (3 × 60 mL). The combined organic layers were washed with





= –13.9 (CH2Cl2, c = 0.60); IR (neat):

2925, 2854, 2211, 1673, 1612, 1513, 1454, 1344, 1248, 1112, 1028 cm-1

; 1H NMR (400 MHz,

CDCl3) δ 7.49–7.45 (m, 4H), 7.38–7.32 (m, 6H), 7.26 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz,

2H), 5.58 (s, 1H), 5.53 (s, 1H), 4.50–4.40 (m, 1H), 4.48 (d, J = 11.2 Hz, 1H), 4.43 (d, J = 11.2

Hz, 1H), 4.16–4.01 (m, 3H), 3.78 (s, 3H), 3.67 (ddd, J = 9.2, 8.4, 5.2 Hz, 1H), 3.58 (ddd, J = 9.2,

5.2, 5.2 Hz, 1H), 3.01 (dd, J = 16.4, 7.2 Hz, 1H), 2.73 (dd, J = 16.4, 5.6 Hz, 1H), 2.36 (t, J = 7.2

Hz, 2H), 2.14 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 1.93 (dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H),

1.85(dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.82–1.72 (m, 2H), 1.70–1.66 (m, 1H), 1.60–1.48 (m,

3H), 1.40–1.35 (m, 1H), 1.28–1.25 (m, 20H), 0.88 (t, J = 7.2 Hz, 3H); 13

C NMR (100 MHz,

CDCl3) δ 185.0, 159.3, 138.9, 138.5, 130.7, 129.5, 128.9, 128.7, 128.3, 126.22, 126.20, 113.9,

100.7, 100.6, 95.6, 81.2, 73.9, 73.2, 73.1, 72.8, 72.7, 65.8, 55.4, 51.5, 41.9, 37.0, 36.5, 36.3, 32.1,


C48H65O7 [M H]+: 753.4730 Found: 753.4733.

80

(R)-1-((2R,4R,6R)-6-(((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-

yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadec-3-yn-2-ol (I-49):

To a stirred solution of I-48 (1.80 g, 2.39 mmol) in triethylamine (14.8 mL, 106 mmol) at 0 °C

was added formic acid (4.0 mL, 106 mmol) under N2. After the white smoke subsided, (R)-

RuCl[(1R,2R)-p-TsNCH(C6H5)CH(C6H5)NH2](η6-mesitylene) (74.0 mg, 120 µmol) was added.

The resulting mixture was stirred at room temperature for 12 h. The reaction was quenched by

adding water (20 mL), and extracted with Et2O (3 × 50 mL). The combined organic layers were


pressure. The crude residue was purified by flash chromatography (5 to 40% EtOAc in hexanes)

on silica gel (80 mL) to afford I-49 (1.76 g, 98%) as a colorless oil.


= +0.87 (CH2Cl2, c = 1.25); IR (neat):

3449, 2924, 2854, 1612, 1513, 1454, 1406, 1344, 1248, 1112, 1028 cm-1

; 1H NMR (400 MHz,


2H), 5.58 (s, 1H), 5.52 (s, 1H), 4.68–4.62 (m, 1H), 4.47 (d, J = 11.6 Hz, 1H), 4.42 (d, J = 11.6

Hz, 1H), 4.38–4.32 (m, 1H), 4.15-4.00 (m, 3H), 3.78 (s, 3H), 3.66 (ddd, J = 9.2, 8.4, 5.2 Hz, 1H),

3.57 (ddd, J = 9.2, 5.6, 5.6 Hz, 1H), 2.21 (td, J = 7.2, 2.0 Hz, 2H), 2.14 (ddd, J = 14.0, 7.2, 7.2

Hz, 1H), 2.07 (ddd, J = 14.0, 9.6, 3.2 Hz, 1H), 1.92 (dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.85

(dddd, J = 14.0, 8.0, 5.2, 5.2 Hz, 1H), 1.75 (ddd, J = 14.0, 6.0, 6.0 Hz, 1H), 1.70–1.64 (m, 2H),

1.62–1.49 (m, 4H), 1.39–1.36 (m, 1H), 1.28–1.25 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H); 13

C NMR

(100 MHz, CDCl3) δ 159.2, 138.9, 138.5, 130.6, 129.4, 128.8, 128.6, 128.3, 128.2, 126.14,

126.11, 113.9, 100.6, 100.5, 85.7, 80.9, 74.2, 73.9, 73.3, 73.1, 72.7, 65.7, 59.9, 55.3, 43.2, 41.8,

81

37.0, 36.7, 36.2, 32.0, 29.78, 29.75, 29.6, 29.5, 29.2, 29.0, 28.8, 22.8, 18.8, 14.2; HRMS (ESI)

calcd for C48H67O7 [M H]+: 755.4887 Found: 755.4886.

(S)-1-((2R,4R,6R)-6-(((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-

yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadecan-2-ol (I-50):


temperature was added triethylamine (6.46 mL, 46.4 mmol), followed by o-

nitrobenzenesulfonylhydrazide (5.03 g, 23.2 mmol). The resulting mixture was stirred at the


bicarbonate (20 mL), and extracted with Et2O (3 × 50 mL). The combined organic layers were





= –5.4 (CH2Cl2, c = 1.00); IR (neat):

3467, 2924, 2853, 1735, 1613, 1513, 1455, 1343, 1248, 1112, 1028 cm-1

; 1H NMR (400 MHz,


2H), 5.54 (s, 1H), 5.52 (s, 1H), 4.47 (d, J = 11.6 Hz, 1H), 4.42 (d, J = 11.6 Hz, 1H), 4.21–4.15

(m, 1H), 4.15–4.00 (m, 3H), 3.99–3.94 (m, 1H), 3.78 (s, 3H), 3.67 (ddd, J = 9.2, 8.4, 5.2 Hz,

1H), 3.57 (ddd, J = 9.2, 5.6, 5.6 Hz, 1H), 2.26–2.19 (m, 1H), 2.14 (ddd, J = 14.0, 7.2, 7.2 Hz,

1H), 1.93 (dddd, J = 14.0, 8.4, 5.2, 5.2 Hz, 1H), 1.85 (dddd, J = 14.0, 8.4, 5.2, 5.2 Hz, 1H), 1.80–

1.75 (m, 1H), 1.72–1.62 (m, 4H), 1.54–1.45 (m, 3H), 1.28–1.25 (m, 26H), 0.88 (t, J = 6.8 Hz,

82

3H); 13

C NMR (100 MHz, CDCl3) δ 159.3, 138.9, 138.7, 130.7, 129.5, 128.9, 128.8, 128.4,

128.3, 126.22, 126.20, 114.0, 100.9, 100.6, 74.6, 74.0, 73.4, 73.3, 72.8, 68.4, 65.8, 55.4, 42.6,

41.9, 38.0, 37.1, 36.8, 36.3, 32.1, 30.5, 29.88, 29.85, 29.83, 29.81, 29.6, 25.9, 22.9, 14.3; HRMS

(ESI) calcd for C48H71O7 [M H]+: 759.5200 Found: 759.5199.

tert-butyl(((S)-1-((2S,4S,6S)-6-(((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-

dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadecan-2-yl)oxy)dimethylsilane (I-51):

To a stirred solution of I-50 (1.71 g, 2.25 mmol) in dimethylformamide (5.0 mL) at room

temperature was added tert-butyldimethylsilyl chloride (0.679 g, 4.51 mmol), followed by

imidazole (0.383 g, 5.63 mmol). The resulting mixture was stirred at the same temperature for 14

h. The reaction was quenched by adding water (20 mL) and extracted with Et2O (3 × 50 mL).



to 15% EtOAc in hexanes) on silica gel (80 mL) to afford I-51 (1.85 g, 94%) as a colorless oil.


= +0.96 (CH2Cl2, c = 1.36); IR (neat):

2925, 2854, 1613, 1513, 1463, 1388, 1342, 1249, 1112, 1059, 1028 cm-1

; 1H NMR (400 MHz,


2H), 5.53 (s, 1H), 5.50 (s, 1H), 4.48 (d, J = 11.6 Hz, 1H), 4.43 (d, J = 11.6 Hz, 1H), 4.12–3.98

(m, 5H), 3.78 (s, 3H), 3.68 (ddd, J = 9.2, 9.2, 5.2 Hz, 1H), 3.58 (ddd, J = 9.6, 5.6, 5.6 Hz, 1H),

2.14 (ddd, J = 14.0, 6.8, 6.8 Hz, 1H), 1.93 (dddd, J = 14.0, 8.4, 5.2, 5.2 Hz, 1H), 1.86 (dddd, J =

14.0, 8.4, 5.2, 5.2 Hz, 1H), 1.77–1.62 (m, 4H), 1.56–1.43 (m, 5H), 1.28–1.25 (m, 26H), 0.90 (s,

83

9H), 0.88 (t, J = 7.6 Hz, 3H), 0.05 (s, 6H); 13

C NMR (100 MHz, CDCl3) δ 159.3, 139.1, 139.0,

130.7, 129.5, 128.72, 128.67, 128.3, 126.2, 114.0, 100.6, 100.5, 73.9, 73.4, 72.8, 68.1, 65.9, 55.4,

43.5, 42.0, 38.4, 37.7, 37.1, 36.3, 32.1, 30.1, 29.89, 29.85, 29.79, 29.6, 26.2, 26.1, 24.7, 22.9,

18.3, 14.3, –4.0, –4.3; HRMS (ESI) calcd for C54H85O7Si [M H]+: 873.6065 Found: 873.6058.

2-((2S,4S,6S)-6-(((2S,4S,6S)-6-((S)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-phenyl-1,3-

dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)ethanol (I-52):


water (0.5 mL), followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.43 g, 6.32 mmol)

under N2. The resulting mixture was stirred at the same temperature for 2 h. The reaction was

quenched by adding saturated aqueous sodium bicarbonate (20 mL), and filtered through a pad

of Celite. The filtrate was extracted with Et2O (3 × 40 mL). The combined organic layers were





= +10.6 (CH2Cl2, c = 1.30); IR (neat):

3436, 2923, 2854, 1720, 1454, 1379, 1343, 1254, 1112, 1057, 1027 cm-1

; 1H NMR (400 MHz,

CDCl3) δ 7.52–7.47 (m, 4H), 7.39–7.33 (m, 6H), 5.57 (s, 1H), 5.51 (s, 1H), 4.17–4.07 (m, 3H),

4.05–3.99 (m, 2H), 3.89–3.82 (m, 2H), 2.19–2.12 (m, 2H), 1.97–1.89 (m, 1H), 1.88–1.82 (m,

1H), 1.80–1.69 (m, 2H), 1.66–1.60 (m, 2H), 1.58–1.44 (m, 4H), 1.28–1.25 (m, 26H), 0.90 (s,

9H), 0.89 (t, J = 7.6 Hz, 3H), 0.06 (s, 6H); 13

C NMR (100 MHz, CDCl3) δ 139.0, 138.6, 128.9,

84

128.7, 128.4, 128.3, 126.2, 100.9, 100.5, 76.2, 73.41, 73.35, 73.29, 68.0, 60.4, 43.5, 41.9, 38.4,

38.2, 37.6, 36.8, 32.1, 30.1, 29.86, 29.83, 29.81, 29.77, 29.5, 26.14, 26.08, 24.7, 22.9, 18.3, 14.3,

–4.0, –4.4; HRMS (ESI) calcd for C46H77O6Si [M H]+: 753.5489 Found: 753.5489.

2-((2R,4R,6R)-6-(((2S,4S,6S)-6-((S)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-phenyl-

1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)acetaldehyde (I-53)

To a stirred solution of I-52 (0.820 g, 1.09 mmol) in dichloromethane (8.0 mL) at 0 °C was

added Dess–Martin periodinane (0.693 g, 1.63 mmol). After 2 h at the same temperature, the

reaction was quenched by adding saturated aqueous sodium bicarbonate (20 mL) and sodium

sulfite (0.412 g, 3.27 mmol). The mixture was stirred at room temperature for 30 min, and

extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine, dried

over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was

purified by flash chromatography (5 to 30% EtOAc in hexanes) on silica gel (60 mL) to afford I-

53 (0.510 g, 62%) as a colorless oil.


= +16.6 (CH2Cl2, c =1.17); IR (neat):

2926, 2854, 1727, 1461, 1388, 1343, 1255, 1112, 1060, 1027 cm-1


δ 9.87 (s, 1H), 7.52–7.46 (m, 4H), 7.39–7.32 (m, 6H), 5.60 (s, 1H), 5.51 (s, 1H), 4.47–4.41 (m,

1H), 4.20–4.14 (m, 1H), 4.11–4.06 (m, 1H), 4.06–3.99 (m, 2H), 2.83 (ddd, J = 17.2, 7.2, 2.0 Hz,

1H), 2.64 (ddd, J = 17.2, 4.8, 1.6 Hz, 1H), 2.16 (ddd, J = 14.4, 7.2. 7.2 Hz, 1H), 1.84–1.79 (m,

1H), 1.77–1.69 (m, 2H), 1.66–1.60 (m, 2H), 1.57–1.50 (m, 2H), 1.49–1.44 (m, 2H), 1.28–1.25

(m, 26H), 0.90 (s, 9H), 0.88 (t, J = 7.6 Hz, 3H), 0.06 (s, 6H); 13


85

200.5, 139.0, 138.4, 129.0, 128.7, 128.4, 128.3, 126.2, 100.9, 100.5, 73.3, 73.26, 73.21, 72.1,

68.0, 49.6, 43.5, 41.9, 38.4, 37.6, 36.6, 32.1, 30.1, 29.87, 29.83, 29.78, 29.5, 26.1, 24.7, 22.9,

18.3, 14.3, –4.0, –4.4; HRMS (ESI) calcd for C46H75O6Si [M H]+: 751.5333 Found: 751.5338.

(R)-1-((2S,4S,6S)-6-(((2S,4S,6S)-6-((S)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-phenyl-

1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-ol (I-54):






and the filtrate was extracted with EtOAc (3 × 40 mL). The combined organic layers were





= +5.5 (CH2Cl2, c = 1.00); IR (neat):

3474, 2925, 2854, 1460, 1388, 1342, 1255, 1111, 1058, 1027 cm-1


δ 7.50–7.47 (m, 4H), 7.38–7.32 (m, 6H), 5.89–5.79 (m, 1H), 5.57 (s, 1H), 5.50 (s, 1H), 5.16–

5.12 (m, 2H), 4.22–4.16 (m, 1H), 4.15–4.10 (m, 1H), 4.09–3.98 (m, 4H), 2.33–2.19 (m, 2H),

2.15 (ddd, J = 14.4, 7.2, 7.2 Hz, 1H), 1.83–1.62 (m, 8H), 1.54–1.43 (m, 3H), 1.28–1.25 (m,

26H), 0.90 (s, 9H), 0.88 (t, J = 7.6 Hz, 3H), 0.05 (s, 6H); 13

C NMR (100 MHz, CDCl3) δ 139.1,

86

138.7, 134.9, 128.9, 128.7, 128.4, 128.3, 126.3, 118.3, 100.9, 100.5, 74.4, 73.5, 73.36, 73.32,

68.0, 67.2, 43.5, 42.5, 42.3, 42.0, 38.4, 37.7, 36.9, 32.1, 30.1, 29.89, 29.85, 29.8, 29.6, 26.2, 24.7,

22.9, 18.4, 14.3, –4.0, –4.3; HRMS (ESI) calcd for C49H81O6Si [M H]+: 793.5802 Found:

793.5804.

(R)-1-((2R,4R,6S)-6-(((2S,4S,6S)-6-((S)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-

phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-yl acrylate (I-55):

To a stirred solution of I-54 (0.430 g, 0.542 mmol) in dichloromethane (2.0 mL) at room

temperature was added N,N'-dicyclohexylcarbodiimide (0.223 g, 1.08 mmol), followed by

acrylic acid (78 µL, 1.08 mmol) and 4-dimethylaminopyridine (3.3 mg, 27 µmol). The resulting

mixture was stirred at the same temperature for 20 h, diluted with Et2O (10 mL) and filtered

through filter paper. The filtrate was concentrated under reduced pressure. The crude residue was

purified by flash chromatography (2 to 15% EtOAc in hexanes) on silica gel (30 mL) to afford I-

55 (0.365 g, 80%) as a colorless oil.


= –9.7 (CH2Cl2, c = 0.53); IR (neat):

2926, 2854, 1725, 1454, 1405, 1341, 1255, 1192, 1112, 1050, 1027 cm-1

; 1H NMR (400 MHz,


17.6, 10.4 Hz, 1H), 5.82 (dd, J = 10.4, 1.6 Hz, 1H), 5.77 (dddd, J = 17.6, 10.4, 7.2, 7.2 Hz, 1H),

5.50 (s, 2H), 5.40–5.34 (m, 1H), 5.10–5.06 (m, 2H), 4.11–4.05 (m, 2H), 4.03–3.98 (m, 2H),

3.92–3.87 (m, 1H), 2.47–2.34 (m, 2H), 2.15 (ddd, J = 14.0, 7.2, 7.2 Hz, 1H), 1.91 (ddd, J = 14.8,

9.6, 3.6 Hz, 1H), 1.81 (ddd, J = 14.8, 9.2, 3.2 Hz, 1H), 1.78–1.61 (m, 4H), 1.56–1.43 (m, 5H),

87

1.28–1.25 (m, 26H), 0.90 (s, 9H), 0.88 (t, J = 7.6 Hz, 3H), 0.05 (s, 6H); 13

C NMR (100 MHz,

CDCl3) δ 165.9, 139.1, 138.7, 133.5, 130.8, 128.9, 128.7, 128.3, 126.2, 126.1, 118.3, 100.5,

100.4, 73.5, 73.4, 73.2, 70.2, 68.0, 43.5, 42.0, 40.3, 39.4, 38.4, 37.6, 37.2, 32.1, 30.1, 29.89,

29.85, 29.8, 29.6, 26.2, 24.7, 22.9, 18.3, 14.3, –4.0, –4.3; HRMS (ESI) calcd for C52H83O7Si [M

H]+: 847.5908 Found: 847.5912.

(R)-6-(((2R,4R,6S)-6-(((2S,4S,6S)-6-((S)-2-((tert-butyldimethylsilyl)oxy)heptadecyl)-2-

phenyl-1,3-dioxan-4-yl)methyl)-2-phenyl-1,3-dioxan-4-yl)methyl)-5,6-dihydro-2H-pyran-2-

one (I-56):









= +14.1 (CH2Cl2, c = 0.96); IR (neat):

2926, 2854, 1725, 1517, 1461, 1382, 1343, 1249, 1112, 1059, 1027 cm-1

; 1H NMR (400 MHz,

CDCl3) δ 7.52–7.47(m, 4H), 7.39–7.31 (m, 6H), 6.88 (ddd, J = 9.6, 5.6, 3.2 Hz, 1H), 6.03 (d, J =

9.6 Hz, 1H), 5.59 (s, 1H), 5.51 (s, 1H), 4.83–4.76 (m, 1H), 4.30–4.25 (m, 1H), 4.17–4.11 (m,

1H), 4.10–4.06 (m, 1H), 4.06–3.98 (m, 2H), 2.42–2.29 (m, 2H), 2.15 (ddd, J = 14.0, 6.8, 6.8 Hz,

88


3H), 1.65–1.62 (m, 1H), 1.57–1.45 (m, 5H), 1.28–1.25 (m, 26H), 0.90 (s, 9H), 0.88 (t, J = 7.6

Hz, 3H), 0.05 (s, 6H); 13

C NMR (100 MHz, CDCl3) δ 164.5, 145.3, 139.0, 138.7, 128.9, 128.7,

128.4, 128.3, 126.24, 126.20, 121.6, 100.7, 100.5, 74.1, 73.35, 73.31, 72.2, 68.0, 43.5, 42.0, 41.8,

38.4, 37.7, 37.2, 32.1, 30.1, 30.0, 29.89, 29.85, 29.8, 29.6, 26.2, 24.7, 22.9, 18.3, 14.3, –4.0, –

4.3; HRMS (ESI) calcd for C50H79O7Si [M H]+: 819.5595 Found: 819.5602.

(R)-1-((2R,4R,6S)-6-(((2R,4R,6R)-6-((S)-2-hydroxyheptadecyl)-2-phenyl-1,3-dioxan-4-


To a flask with I-55 (0.150 g, 0.177 mmol) was added a solution of tetra-n-butylammonium

fluoride (1 M, 3.5 mL, 3.5 mmol) at room temperature. The resulting mixture was stirred at the


bicarbonate (10 mL), and extracted with Et2O (3 × 30 mL). The combined organic layers were





= –17.2 (CH2Cl2, c = 0.30); IR (neat):

3497, 2924, 2853, 1724, 1553, 1454, 1405, 1342, 1269, 1193, 1113, 1027 cm-1

; 1H NMR (400

MHz, CDCl3) δ 7.51–7.47 (m, 4H), 7.38–7.32 (m, 6H), 6.40 (dd, J = 18.0, 1.6 Hz, 1H), 6.12 (d, J

= 18.0, 10.4 Hz, 1H), 5.82 (d, J = 10.4, 1.6 Hz, 1H), 5.77 (dddd, J = 17.6, 10.0, 7.2, 7.2 Hz, 1H),

5.55 (s, 1H), 5.49 (s, 1H), 5.37 (dddd, J = 9.2, 5.6, 5.6, 3.6, 1H), 5.10–5.06 (m, 2H), 4.22-4.05

89

(m, 3H), 3.98–3.86 (m 2H), 2.47–2.33 (m, 2H), 2.16 (ddd, J = 14.0, 7.2, 7.2 Hz, 1H), 1.90 (ddd,

J = 14.0, 9.6, 3.2 Hz, 1H), 1.83–1.73 (m, 3H), 1.71–1.62 (m, 4H), 1.53–1.43 (m, 3H), 1.28–1.25

(m, 26H), 0.88 (t, J = 7.2 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 165.9, 138.72, 138.69, 133.5,

130.9, 128.93, 128.89, 128.7, 128.4, 128.3, 126.2, 126.1, 118.3, 100.9, 100.4, 74.6, 73.5, 73.4,

73.1, 70.2, 68.4, 42.6, 41.9, 40.3, 39.4, 38.0, 37.2, 36.7, 32.1, 29.89, 29.86, 29.83, 29.81, 29.6,

25.9, 22.9, 14.3, 14.2; HRMS (ESI) calcd for C46H69O7 [M H]+: 733.5043 Found: 733.5043.

(R)-1-((2R,4R,6S)-6-(((2S,4R,6S)-6-((S)-2-acetoxyheptadecyl)-2-phenyl-1,3-dioxan-4-


To a stirred solution of I-57 (0.115 g, 0.157 mmol) in dichloromethane (0.6 mL) at 0 °C was

added triethylamine (66 µL, 0.471 mmol), followed by 4-dimethylaminopyridine (2.0 mg, 16

µmol) and acetic anhydride (30 µL, 0.314 mmol). The resulting mixture was stirred at the same

temperature for 1 h. The reaction was quenched by adding methanol (0.1 mL), and diluted with

Et2O (20 mL). The mixture was washed with brine, dried over anhydrous Na2SO4, filtered and


to 20% EtOAc in hexanes) on silica gel (25 mL) to afford I-58 (87.0 mg, 72%) as a colorless oil.


= –10.9 (CH2Cl2, c = 0.75); IR (neat):

2924, 2854, 1726, 1453, 1405, 1371, 1241, 1193, 1146, 1113, 1023 cm-1

; 1H NMR (400 MHz,


17.2, 10.4 Hz, 1H), 5.82 (dd, J = 10.4, 1.2 Hz, 1H), 5.77 (dddd, J = 17.6, 10.4, 7.2, 7.2 Hz, 1H),

5.50 (s, 2H), 5.37 (dddd, J = 9.2, 6.0, 6.0, 3.6 Hz, 1H), 5.21 (dddd, J = 9.2, 6.4, 6.4, 3.6 Hz, 1H),

90

5.10–5.06 (m, 2H), 4.12–4.05 (m, 2H), 3.92–3.83 (m, 2H), 2.47–2.33 (m, 2H), 2.16 (ddd, J =

14.4, 7.2, 7.2 Hz, 1H), 2.04 (s, 3H), 1.94–1.87 (m, 2H), 1.85–1.79 (m, 2H), 1.78–1.71 (m, 2H),

1.66–1.62 (m, 2H), 1.60–1.48 (m, 3H), 1.26–1.23 (m, 26H), 0.88 (t, J = 7.6 Hz, 3H); 13

C NMR

(100 MHz, CDCl3) δ 170.9, 165.8, 138.75, 138.71, 133.4, 130.8, 128.9, 128.72, 128.69, 128.33,

128.31, 126.16, 126.14, 118.3, 100.4, 73.7, 73.5, 73.1, 71.2, 70.2, 41.9, 40.8, 40.3, 39.4, 37.2,


C48H71O8 [M H]+: 775.5149 Found: 775.5156.

(S)-1-((2S,4S,6R)-6-(((2R,4S,6R)-6-(((R)-6-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-2-


To a stirred solution of I-58 (80 mg, 0.103 mmol) in dichloromethane (12 mL) at room

temperature was added the Grubbs first-generation catalyst (8.5 mg, 10 µmol) under N2. The





hexanes) on silica gel (25 mL) to afford I-59 (54 mg, 70%) as a colorless oil.


= +11.8 (CH2Cl2, c = 0.55); IR (neat):

2924, 2853, 1736, 1453, 1377, 1343, 1244, 1140, 1118, 1058, 1025 cm-1

; 1H NMR (400 MHz,

CDCl3) δ 7.52–7.47 (m, 4H), 7.39–7.32 (m, 6H), 6.88 (ddd, J = 9.6, 5.6, 3.2 Hz, 1H), 6.03 (ddd,

J = 9.6, 1.6, 1.6 Hz, 1H), 5.58 (s, 1H), 5.50 (s, 1H), 5.21 (dddd, J = 9.6, 6.8, 6.8, 3.6 Hz, 1H),

4.83–4.76 (m, 1H), 4.30–4.25 (m, 1H), 4.16–4.06 (m, 2H), 3.90–3.84 (m, 1H), 2.40–2.30 (m,

91

2H), 2.16 (ddd, J = 13.6, 6.8, 6.8 Hz, 1H), 2.04 (s, 3H), 1.97 (ddd, J = 14.8, 9.6, 2.0 Hz, 1H),

1.91–1.82 (m, 2H), 1.80–1.69 (m, 3H), 1.65–1.49 (m, 5H), 1.26–1.23 (m, 26H), 0.88 (t, J = 7.6

Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 170.8, 164.5, 145.3, 138.7, 128.9, 128.7, 128.4, 128.3,

126.3, 126.1, 121.6, 100.7, 100.4, 74.1, 73.7, 73.2, 73.0, 72.2, 71.2, 41.9, 41.7, 40.8, 37.2, 35.1,


C46H67O8 [M H]+: 747.4836 Found: 747.4833.

(3S,5S,7R,9R,11S)-hexacosane-1,3,5,7,9,11-hexaol (I-60):



under reduced pressure. The crude residue was purified by flash chromatography (2.5 to 7.5%



= +2.8 (MeOH, c = 0.20); IR (neat):

3356, 2923, 2851, 1728, 1552, 1510, 1467, 1379, 1260, 1095, 1037 cm-1

; 1H NMR (500 MHz,

CD3OD) δ 4.04–3.95 (m, 3H), 3.93 (ddd, J = 9.0, 9.0, 5.0 Hz, 1H), 3.82–3.77 (m, 1H), 3.69 (t, J

= 7.0 Hz, 2H), 1.75–1.70 (m, 1H), 1.69–1.53 (m, 7 H), 1.52–1.49 (m, 2H), 1.47–1.40 (m, 2H),

1.28–1.25 (m, 26H), 0.89 (t, J = 7.0 Hz, 3H); 13

C NMR (125 MHz, CD3OD) δ 70.22, 70.16,

69.1, 68.9, 68.2, 60.1, 46.0, 45.8, 45.5, 45.3, 41.0, 39.3, 33.1, 30.9, 30.84, 30.82, 30.5, 26.8, 23.8,


92

(S)-1-((2S,4S,6R)-6-(((2S,4S,6S)-6-(2-((4-methoxybenzyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-

yl)methyl)-2-phenyl-1,3-dioxan-4-yl)heptadecan-2-yl acetate (I-61):

To a stirred solution of I-50 (89.0 mg, 0.117 mmol) in dichloromethane (1 mL) at 0 °C was

added pyridine (47 µL, 0.585 mmol), followed by acetic anhydride (17 µL, 0.176 mmol) and 4-

dimethylaminopyridine (1.0 mg, 8.2 µmol). The mixture was stirred at the same temperature for

5 h. The reaction was quenched by adding water (10 mL), and extracted with EtOAc (3 × 20

mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4,


chromatography (5 to 20% EtOAc in hexanes) on silica gel (25 mL) to afford I-61 (92.0 g, 98%)

as a colorless oil.


= –2.4 (CH2Cl2, c = 1.30); IR (neat):

2923, 2853, 1737, 1513, 1453, 1372, 1342, 1245, 1112, 1026 cm-1


δ 7.52–7.46 (m, 4H), 7.38–7.32 (m, 6H), 7.26 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 5.53

(s, 1H), 5.50 (s, 1H), 5.22 (dddd, J = 10.0, 7.0, 7.0, 3.5 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.43

(d, J = 12.0 Hz, 1H), 4.13–4.03 (m, 3H), 3.90–3.85 (m, 1H), 3.78 (s, 3H), 3.68 (ddd, J = 9.0, 8.5,

5.5 Hz, 1H), 3.58 (ddd, J = 9.5, 5.5, 5.5 Hz, 1H), 2.16 (ddd, J = 14.5, 7.0, 7.0 Hz, 1H), 2.05 (s,

3H), 1.96–1.90 (m, 1H), 1.88–1.83 (m, 2H), 1.78–1.72 (m, 2H), 1.71–1.68 (m, 1H), 1.65–1.62

(m, 1H), 1.59–1.48 (m, 4H), 1.28–1.25 (m, 26H), 0.89 (t, J = 7.5 Hz, 3H); 13

C NMR (125 MHz,

CDCl3) δ 170.8, 159.3, 139.0, 138.8, 130.7, 129.5, 128.7, 128.6, 128.32, 128.29, 126.2, 126.1,

114.0, 100.7, 100.4, 74.0, 73.7, 73.3, 73.1, 72.8, 71.2, 65.8, 55.4, 42.0, 40.8, 37.2, 37.1, 36.3,

93

35.1, 32.1, 29.88, 29.85, 29.84, 29.76, 29.71, 29.5, 25.3, 22.9, 21.5, 14.3; HRMS (ESI) calcd for

C50H73O8 [M H]+: 801.5305 Found: 801.5286.

(S)-1-((2S,4S,6R)-6-(((2S,4S,6S)-6-(2-hydroxyethyl)-2-phenyl-1,3-dioxan-4-yl)methyl)-2-

phenyl-1,3-dioxan-4-yl)heptadecan-2-yl acetate (I-62):

To a stirred solution of I-61 (90.0 mg, 0.112 mmol) in dichloromethane (2.0 mL) at 0 °C was

added water (0.1 mL), followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (76.5 mg, 0.337

mmol) under N2. The resulting mixture was stirred at the same temperature for 2 h. The reaction

was quenched by adding saturated aqueous sodium bicarbonate (10 mL), and filtered through a

pad of Celite. The filtrate was extracted with EtOAc (3 × 15 mL). The combined organic layers

were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced


hexanes) on silica gel (20 mL) to afford I-62 (55 mg, 72%) as a colorless oil.


= +11.5 (CH2Cl2, c = 0.95); IR (neat):

3436, 2924, 2854, 1737, 1453, 1374, 1342, 1242, 1113, 1026 cm-1


δ 7.52–7.48 (m, 4H), 7.39–7.32 (m, 6H), 5.57 (s, 1H), 5.50 (s, 1H), 5.21 (dddd, J = 9.5, 6.5, 6.5,

3.5 Hz, 1H), 4.17–4.06 (m, 3H), 3.89–3.81 (m, 3H), 2.16 (ddd, J = 14.0, 7.0, 7.0 Hz, 1H), 2.15–

2.10 (m, 1H ), 2.05 (s, 3H), 1.94–1.88 (m, 1H), 1.87–1.79 (m, 2H), 1.78–1.69 (m, 3H), 1.65–1.48

(m, 4H), 1.28–1.25 (m, 26H), 0.88 (t, J = 6.8 Hz, 3H); 13

C NMR (125 MHz, CDCl3) δ 170.9,

138.7, 138.6, 129.0, 128.7, 128.5, 128.3, 126.2, 126.1, 100.9, 100.4, 76.3, 73.7, 73.4, 73.1, 71.2,

94

60.5, 41.8, 40.8, 38.2, 37.2, 36.8, 35.1, 32.1, 29.88, 29.85, 29.76, 29.71, 29.5, 25.3, 22.9, 21.5,


(3S,5S,7S,9S,11S)-1,3,5,7,9-pentahydroxyhexacosan-11-yl acetate (I-63):






= +9.4 (MeOH, c = 0.34); IR (neat):

3356, 2918, 2850, 1737, 1468, 1376, 1245, 1088, 1054, 1024 cm-1

; 1H NMR (500 MHz,

CD3OD) δ 5.07 (dddd, J = 10.0, 7.0, 7.0, 3.0 Hz, 1H), 4.00–3.90 (m, 3H), 3.77 (dddd, J = 9.5,

8.0, 5.0, 3.0 Hz, 1H), 3.69 (t, J = 7.0 Hz, 1H), 2.03 (s, 3H), 1.75–1.69 (m, 2H), 1.67–1.53 (m,

10H), 1.28–1.25 (m, 26H), 0.89 (t, J = 7.0 Hz, 3H); 13

C NMR (125 MHz, CD3OD) δ 173.1, 72.9,

70.1, 69.9, 68.9, 67.5, 60.1, 45.8, 45.5, 45.3, 43.3, 41.0, 36.0, 33.1, 30.8, 30.73, 30.69, 30.6, 30.5,

26.4, 23.8, 21.2, 14.5; HRMS (ESI) calcd for C28H57O7 [M H]+: 505.4104 Found: 505.4114.

(2R,4R,6S,8S,10S)-2,4,6,8-tetrahydroxy-1-((R)-6-oxotetrahydro-2H-pyran-2-yl)pentacosan-

10-yl acetate (I-64):

To a stirred solution of I-10 (7.6 mg, 13 µmol) in EtOAc (0.5 mL) at room temperature was

added Pd/C (10% wt/wt, 2.8 mg, 2.6 µmol) under N2. The resulting mixture was stirred under H2

95

(1 atm). After 2 h, the mixture was filtered through filter paper and washed with EtOAc (3 × 5

mL). The filtrate was concentrated under vacuum. The crude residue was purified by flash

chromatography (1 to 5% MeOH in EtOAc) on silica gel (4 mL) to afford I-64 (5.0 mg, 66%) as

a colorless oil.


= –8.7 (MeOH, c = 0.37); IR (neat): 3387,

2919, 2851, 1732, 1467, 1442, 1375, 1246, 1109, 1082, 1048 m-1

; 1H NMR (500 MHz, CD3OD)

δ 5.07 (dddd , J = 9.5, 6.5, 6.5, 3.0 Hz, 1H), 4.60 (dddd, J = 10.5, 10.5, 3.0, 3.0 Hz, 1H), 4.06

(dddd, J = 9.5, 7.0, 7.0, 2.5 Hz, 1H), 4.00–3.93 (m, 2H), 3.78 (dddd, J = 9.5, 8.5, 5.5, 3.0 Hz,

1H), 2.59 (ddd, J = 17.5, 7.0, 7.0 Hz, 1H), 2.43 (ddd, J = 17.5, 7.5, 7.5 Hz, 1H), 2.03 (s, 3H),

1.95–1.87 (m, 3H), 1.80 (ddd, J = 14.5, 10.0, 2.5 Hz, 1H), 1.71 (ddd, J = 14.5, 9.5, 3.0 Hz, 1H),

1.66 (ddd, J = 14.0, 4.5, 4.5 Hz, 1H), 1.63–1.50 (m, 10H), 1.28–1.25 (m, 26H), 0.89 (t, J = 8.0

Hz, 3H); 13

C NMR (100 MHz, CD3OD) δ 175.0, 173.1, 78.9, 72.8, 69.89, 69.85, 67.5, 66.8, 45.9,

45.8, 45.2, 45.0, 43.2, 36.0, 33.1, 30.8, 30.74, 30.70, 30.6, 30.5, 30.2, 29.4, 26.3, 23.8, 21.2, 19.4,


96

Position cryptocaryol A (reported)* cryptocaryol A (synthesized) *δH

3 5.97 (dd, 9.8, 1.9) 5.97 (dd, 9.6, 2.5),

4 7.04 (ddd, 9.8, 6.0, 2.3) 7.04 (ddd, 9.6, 6.0, 2.8),

5a 2.45 (m) 2.45 (ddd, 19.2, 5.2, 5.2),

5b 2.36 (ddt, 18.5, 11.8, 2.6) 2.36 (dddd, 19.2, 11.6, 2.8, 2.8),

6 4.71 (m) 4.74–4.67 (m)

7a 1.94 (ddd, 14.5, 9.7, 2.3) 1.94 (ddd, 14.8, 9.6, 2.8)

7b 1.67 (m) 1.71–1.55 (m)

8 4.08 (m) 4.09 (dddd, 8.8, 6.4, 6.4, 2.4)

9 1.68 (m) 1.71–1.55 (m)

10 3.97 (m) 4.04–3.96 (m)

11 1.63 (m) 1.71–1.55 (m)

12 4.00 (m) 4.04–3.96 (m)

13 1.59 (m) 1.71–1.55 (m)

14 4.02 (m) 4.04–3.96 (m)

15 1.50 (m) 1.52–1.49 (m)

16 3.79 (m) 3.82–3.77 (m)

17 1.43 (m) 1.46–1.40 (m)

18 1.32 (m) 1.32–1.25 (m)

19–28 1.29–1.27 (br m) 1.32–1.25 (m)

29 1.29 (m) 1.32–1.25 (m)

30 1.27 (m) 1.32–1.25 (m)

31 0.89 (t, 6.9) 0.89 (t, 6.8)

Table S1. 1H NMR assignments of reported cryptcocaryol A and synthesized cryptocaryol A.

*δH (multiplicity, coupling constant (J) in Hz)

97

Position cryptocaryol A (reported) δC cryptocaryol A (synthesized) δC

2 167.0 167.0

3 121.4 121.4

4 148.6 148.6

5 31.0 31.0

6 76.6 76.6

7 43.9 43.9

8 66.6 66.6

9 46.0 46.0

10 69.9 69.9

11 45.3 45.3

12 70.2 70.2

13 45.9 45.9

14 68.3 68.2

15 45.8 45.8

16 69.1 69.1

17 39.3 39.3

18 26.8 26.8

19–28 30.5–31.0 30.5–31.0

29 33.2 33.1

30 23.8 23.8

31 14.5 14.5

Table S2. 13

C NMR assignments of reported cryptcocaryol A and synthesized cryptocaryol A.

98

Position cryptocaryol B

(reported) *δH cryptocaryol B

(synthesized)*δH 6-epi-ent-cryptocaryol B *δH

3 5.97 (dd, 9.7, 1.8) 5.97 (dd, 9.6, 1.6) 5.98 (ddd, 9.6, 2.4)

4 7.04 (ddd, 9.7, 6.0, 2.4) 7.04 (ddd, 9.6, 5.6, 2.8) 7.05 (ddd, 9.6, 6.0, 2.4)

5a 2.45 (dt, 18.7, 4.9) 2.45 (ddd, 18.4, 5.2, 5.2) 2.54 (dddd, 18.8, 5.6, 4.0, 0.8)

5b 2.36 (ddt, 18.7, 11.6, 2.4) 2.36 (dddd, 18.4, 11.2, 2.8, 2.8) 2.39 (dddd, 18.8, 11.6, 2.4, 2.4)

6 4.70 (m) 4.74–4.67 (m) 4.68 (dddd, 10.4, 6.8, 6.8, 3.6)

7a 1.94 (ddd, 14.3, 9.8, 2.3) 1.94 (ddd, 14.4, 9.6, 2.8) 1.97 (ddd, 14.4, 7.2, 7.2) (7a or 7b)

7b 1.65 (m) 1.67–1.54 (m) 1.86 (ddd, 14.0, 6.4, 5.2) (7a or 7b)

8 4.08 (m) 4.08 (dddd, 9.2, 6.4, 6.4, 2.4) 4.02–3.93 (m)

9 1.62 (m) 1.67–1.54 (m) 1.67–1.56 (m)

10 3.96 (m) 4.01–3.92 (m) 4.02–3.93 (m)

11a 1.65 (m) 1.67–1.54 (m) 1.67–1.56 (m)

11b 1.57 (m) 1.67–1.54 (m) 1.67–1.56 (m)

12 3.96 (m) 4.01–3.92 (m) 4.02–3.93 (m)

13 1.62 (m) 1.67–1.54 (m) 1.67–1.56 (m)

14 3.78 (m) 3.81–3.75 (m) 3.81–3.77 (m)

15a 1.72 (ddd, 14.6,12.9, 3.0) 1.72 (ddd, 14.4, 9.2, 2.8) 1.75–1.68 (m)

15b 1.57 (m) 1.67–1.54 (m) 1.67–1.56 (m)

16 5.07 (m) 5.07 (dddd, 9.2, 6.4, 6.4, 2.8) 5.08 (dddd, 9.6, 6.4, 6.4, 2.8)

17 1.59 (m) 1.67–1.54 (m) 1.67–1.56 (m)

18–30 1.34–1.28 (br m) 1.28–1.25 (br m) 1.29–1.27 (br m)

31 0.89 (t, 7.0) 0.89 (t, 6.8) 0.90 (t, 6.8)

2' 2.03 (s) 2.03 (s) 2.04 (s)

Table S3. 1H NMR assignments of reported cryptcocaryol B, synthesized cryptocaryol B and 6-

epi-ent-cryptocaryol B. *δH (multiplicity, coupling constant (J) in Hz)

99

Position cryptocaryol B δC

1

(reported)

cryptocaryol B δC2 (δC

2–

δC1)

(synthesized)

6-epi-ent-cryptocaryol B

δC3 (δC

3– δC

1)

2 167.0 167.0 (0.0) 167.0 (0.0)

3 121.4 121.4 (0.0) 121.4 (0.0)

4 148.6 148.6 (0.0) 148.4 (–0.2)

5 31.0 31.0 (0.0) 30.8 (–0.2)

6 76.6 76.6 (0.0) 77.4 (0.8)

7 43.9 43.9 (0.0) 43.3 (–0.6)

8 66.6 66.6 (0.0) 67.5 (0.9)

9 45.8 45.8 (0.0) 45.4 (–0.4)

10 69.87 69.84 (–0.03) 69.77 (–0.1)

11 45.3 45.3 (0.0) 45.0 (–0.3)

12 69.93 69.91 (–0.02) 69.84 (–0.09)

13 45.9 45.9 (0.0) 45.9 (0.0)

14 67.5 67.5 (0.0) 67.6 (0.1)

15 43.3 43.3 (0.0) 43.1 (–0.2)

16 72.9 72.9 (0.0) 72.9 (0.0)

17 36.0 36.0 (0.0) 36.0 (0.0)

18 26.4 26.3 (–0.1) 26.3 (–0.1)

19–28 31.0–30.5 31.0–30.5 (0.0) 30.8–30.2 (–0.3)

29 33.1 33.1 (0.0) 33.1 (0.0)

30 23.8 23.8 (0.0) 23.8 (0.0)

31 14.5 14.5 (0.0) 14.5 (0.0)

1' 173.2 173.1 (–0.1) 173.1 (–0.1)

2' 21.2 21.2 (0.0) 21.2 (0.0)

Table S4. 13

C NMR assignments of reported cryptocaryol B, synthesized cryptocaryol B and 6-

epi-ent-cryptocaryol B.

100

(S)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-L-leucinate (II-1)

To a stirred solution of II-25 (20.0 mg, 33.2 µmol) in acetic formic anhydride (1.5 mL) at room

temperature was added Pd/C (10% wt/wt, 3.5 mg, 3.3 µmol) under N2. The resulting mixture was

stirred under H2 (1 atm) for 1h. The mixture was filtered through a pad of Celite, and washed

with EtOAc. The filtrate was concentrated under reduced pressure. The crude residue was

purified by flash chromatography (30% EtOAc in hexanes) on silica gel (2 mL) to afford II-1

(14.7 mg, 80%) as a colorless oil.

Data for II-1: Rf = 0.27 (30% EtOAc in hexanes); [α]D23

= –33.7 (CHCl3, c = 0.48); IR (neat)

3380, 2926, 2854, 1823, 1738, 1666, 1553, 1467, 1378, 1253, 1187, 1123 cm-1

; 1H NMR (500

MHz, CDCl3) δ 8.22 (s, 1H), 5.91 (d, J = 8.0 Hz, 1H), 5.05–5.00 (m, 1H), 4.69 (ddd, J = 9.0, 9.0,

5.0 Hz, 1H), 4.29 (ddd, J = 7.5, 5.0, 5.0 Hz, 1H), 3.22 (ddd, J = 7.5, 7.5, 4.0 Hz, 1H), 2.17 (ddd,

J = 15.0, 7.5, 7.5 Hz, 1H), 2.00 (ddd, J = 15.0, 4.5, 4.5 Hz, 1H), 1.84–1.78 (m, 1H), 1.77–1.63

(m, 4H), 1.61–1.53 (m, 2H), 1.47–1.41 (m, 1H), 1.32–1.24 (m, 25H), 0.972 (d, J = 6.5 Hz, 3H),

0.967 (d, J = 6.5 Hz, 3H), 0.885 (t, J = 6.5 Hz, 3H), 0.878 (t, J = 7.0, 3H); 13

C NMR (100 MHz,

CDCl3) δ 171.92, 170.75, 160.60, 74.76, 72.76, 57.03, 49.60, 41.56, 38.70, 34.05, 31.89, 31.47,

29.60, 29.53, 29.42, 29.33, 29.29, 28.96, 27.61, 26.70, 25.09, 24.88, 22.87, 22.68, 22.51, 21.73,

14.12, 14.01 (CDCl3, δ 77.0 ppm, for comparison with existing papers); MALDI-TOF/CCA-

HRMS calcd for C29H53NO5Na [M Na]+: 518.3816, found 518.3814.

101


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J. Org. Chem.

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Org. Lett. 2010,

1556

J. Org. Chem.

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Synthesis

2006, 3888

Org. Lett.

2006, 4497

CHO

(1H)

8.21 (s) 8.22 (s) 8.22 (s) 8.22 (s) 8.22 (s) 8.23 (s) 8.23 (s)

8.07 (d, 12) 8.06 (d, 11.5)

2''-NH

(1H) 6.43 (d, 9) 5.91 (d, 8.5) 5.90 (d, 8.5) 5.96 (d, 8.4) 5.91 (d, 8.1) 6.05 (d, 8.5) 5.92 (d, 8.7)

5

(1H) 5.03 (m) 5.03–5.00 (m)

5.03 (dddd, 7.0,

6.5, 5.5, 4.0)

5.06–4.99 (m,

1H) 5.05–5.00 (m) 5.02 (m, 1H) 5.10–4.98 (m)

2''

(1H)

4.68 (ddd, 9, 9,

5)

4.69 (ddd, 9.0, 9.0,

5.0)

4.69 (ddd, 13.0,

8.5, 4.0)

4.68 (td, 8.7,

4.1) 4.71–4.66 (m) 4.68 (m,1H)

4.70 (dt, 8.4,

4.8)

3

(1H)

4.32 (ddd, 9, 5,

4)

4.29 (ddd, 7.5, 5.0,

5.0)

4.29 (ddd, 8.0,

4.5, 4.5)

4.32–4.27 (m,

1H)

4.29(dt, 7.3,

4.7) 4.28 (m, 1H)

4.23 (ddd, 8.4,

4.2, 3.9)

2

(1H)

3.24 (ddd, 7.5,

7.5, 4)

3.22 (ddd, 7.5, 7.5,

4.0)

3.21 (ddd, 11.5,

4.5, 4.0 )

3.22 (ddd, 7.9,

7.2, 4.1)

3.22 (dt, 7.1,

3.2)

3.22 (dt, 7.6,

3.9)

3.28 (dt, 7.2,

3.9)

4, 4a

(2H)

1.9–2.25 (m,

2H)

2.17 (ddd, 15.0,

7.5, 7.5)

2.16 (dt, 15.0,

8.0, 7.0)

2.21–2.12 (m,

1H)

2.15–2.10 (m,

1H)

2.25–2.11 (m,

1H)

2.24–1.96 (m,

2H)

2.00 (ddd, 15.0,

4.5, 4.5)

2.01 (dt, 15.0,

4.5, 4.0)

1.99 (ddd, 14.9,

4.7, 4.1)

2.08–2.00 (m,

1H) 2.02 (m, 1H)

CH2

(33H) 1.15–1.85 (m) 1.84–1.78 (m, 1H)

1.85–1.50 (m,

6H)

1.86–1.49 (m,

7H)

1.85–1.51 (m,

7H)

1.80–1.15 (m,

33H)

1.85–1.53 (m,

5H)

1.77–1.63 (m, 4H)

1.61–1.53 (m, 2H)

1.47–1.41 (m, 1H) 1.50–1.15 (m,

27H)

1.49–1.03 (m,

26H)

1.41–1.15 (m,

26H)

1.27 (br s,

26H)

1.32–1.24 (m,

25H)

5'', 5'''

(6H)

0.97 (d, 6, 6H) 0.972 (d, 6.5, 3H) 1.05–0.82 (m,

12H)

0.97 (dd, 6.1,

2.5, 6H) 0.96 (t, 6.3, 6H)

0.95 (d, 5.2,

6H)

0.98 (dd, 6.3,

1.5, 6H)

0.967 (d, 6.5, 3H)

16, 6'

(6H) 0.89 (t, 7, 6H) 0.885 (t, 6.5, 3H) 0.89 (t, 6.9, 3H) 0.89 (t, 6.5, 6H)

0.87 (distorted

t, 6H)

0.89 (t, 6.6,

3H)

0.878 (t, 7.0, 3H) 0.88 (t, 6.9, 3H)

Table S5. 1H NMR assignments of THL. *δH (multiplicity, coupling constant (J) in Hz)

102


1987, 1086

This

Work

J. Org. Chem.

2012, 4885

Org. Lett.

2010, 1556

J. Org. Chem.

2009, 4508

Synthesis

2006, 3888

Org. Lett.

2006, 4497

1, 1'' 171.93 171.92 171.9 171.9 171.9 171.9 172.2

170.73 170.75 170.7 170.7 170.7 170.8 171.0

1''' 160.83 160.60 160.6 160.6 160.5 160.7 160.8

3, 5 74.74 74.76 74.7 74.7 74.7 74.8 75.0

72.63 72.76 72.7 72.7 72.7 72.6 73.0

2, 2'' 57.07 57.03 57.0 57.0 57.0 56.9 57.3

49.76 49.60 49.6 49.6 49.6 49.7 49.9

4, 6, 9

12, 13,

14, 1', 2',

3' 4', 3'',

41.44 41.56 41.5 41.5 41.5 41.4 41.8

38.73 38.70 38.7 38.7 38.7 38.7 38.9

34.07 34.05 34.0 34.0 34.0 34.0 34.3

31.93 31.89 31.9 31.9 31.8 31.9 32.1

31.51 31.47 31.4 31.4 31.4 31.2 32.0

29.63 29.60 29.6 29.6 29.6 29.6 29.93

29.63 29.60 29.71

29.57 29.53 29.5 29.5 29.5 29.65

29.46 29.42 29.4 29.4 29.4 29.4 29.56

29.35 29.33 29.3 29.3 29.3 29.3 29.51

29.35 29.29 29.3 29.2 29.2 29.49

7, 8, 10,

11

28.99 28.96 28.9 28.9 28.9 28.8 29.40

27.67 27.61 27.6 27.6 27.6 27.7 27.8

26.73 26.70 26.7 26.7 26.6 26.8 27.0

25.12 25.09 25.1 25.0 25.0 25.2 25.3

4'' 24.93 24.88 24.9 24.8 24.8 24.9 25.1

5'' or 5''' 22.87 22.87 22.8 22.8 22.8 22.8 23.1

15, 5' 22.69 22.68 22.7 22.6 22.6 22.7 22.89

22.53 22.51 22.5 22.5 22.5 22.5 22.86

5'' or 5''' 21.78 21.73 21.7 21.7 21.7 21.7 22.0

16, 6' 14.10 14.12 14.1 14.1 14.1 14.1 14.3

14.00 14.01 14.0 14.0 14.0 14.0

unknown 21.9 25.8

Table S6. 13

C NMR assignments of THL.

Notes: 1) Residual solvent signal was used as reference: CDCl3 δc 77.0 ppm. (77.23 ppm for Org. Lett. 2006,

4497)

2) The paper (J. Org. Chem. 2012, 4885) reported one extra peak at 21.9 ppm. The paper (J. Org. Chem.

2009, 4508) reported one extra peak at 25.8 ppm.

103

(3S,4S)-3-Hexyl-4-((S)-2-hydroxytridecyl)oxetan-2-one (II-4b)

To a stirred solution of II-24 (56.6 mg, 0.142 mmol) in dichloromethane (1.5 mL) at 0 °C was

added 1,2-ethanedithiol (36 µL, 0.426 mmol), followed by boron trifluoride diethyl etherate (18

µL, 0.142 mmol) under N2. The resulting mixture was stirred at the same temperature for 30 min.

The reaction was quenched by adding saturated aqueous sodium bicarbonate (5 mL), and




II-4b (42.0 mg, 83%) as a white solid.

Data for II-4b: mp 60.5–62.0 °C; Rf = 0.39 (20% EtOAc in hexanes); [α]D22

= –10.4 (CHCl3, c =

0.42); IR (neat) 3544, 2956, 2922, 2851, 1816, 1726, 1467, 1101 cm-1

; 1H NMR (500 MHz,

CDCl3) δ 4.47 (ddd, J = 6.0, 6.0, 4.5 Hz, 1H), 3.81–3.75 (m, 1H), 3.31 (ddd, J = 8.5, 6.5, 4.0 Hz,

1H), 2.01 (ddd, J = 14.5, 8.5, 7.5 Hz, 1H), 1.90 (ddd, J = 15.5, 6.0, 3.5 Hz, 1H), 1.84 (dddd, J =

13.5, 10.0, 6.5, 6.5 Hz, 1H), 1.74 (dddd, J = 14.0, 9.0, 9.0, 6.0 Hz, 1H), 1.61 (brs, 1H), 1.53–1.49

(m, 2H), 1.47–1.37 (m, 3H), 1.34–1.24 (m, 23H), 0.883 (t, J = 7.0 Hz, 3H), 0.878 (t, J = 7.0 Hz,

3H); 13

C NMR (100 MHz, CDCl3) δ 171.5, 76.4, 69.5, 57.0, 41.4, 37.9, 32.1, 31.7, 29.83, 29.81,

29.75, 29.70, 29.5, 29.1, 28.0, 27.0, 25.6, 22.9, 22.7, 14.3, 14.2; MALDI-TOF/CCA-HRMS

calcd for C22H42O3Na [M Na]+: 377.3026, found 377.3021.

68

104

(S)-2-((S)-2-(Methoxymethoxy)tridecyl)oxirane (II-6a)

To a stirred solution of II-11 (0.36 g, 1.49 mmol) in dichloromethane (7 mL) at 0 °C was added

chloromethyl methyl ether (0.17 mL, 2.23 mmol) under N2, followed by N,N-

diisopropylethylamine (0.61 mL, 3.73 mmol). The resulting mixture was stirred at the same

temperature for 24 h. The reaction was quenched by adding water (10 mL), and extracted with

EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous

Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by

flash chromatography (2.5 to 20% EtOAc in hexanes) on silica gel (30 mL) to afford 6a (0.380 g,


Data for II-6a: Rf = 0.33 (10% EtOAc in hexanes); [α]D23

= +0.2 (CH2Cl2, c = 1.18); IR (neat)

2922, 2853, 1466, 1260, 1149, 1098, 1036 cm-1

; 1H NMR (500 MHz, CDCl3) δ 4.67 (s, 2H),

3.73 (dddd, J = 6.0, 6.0, 6.0, 6.0 Hz, 1H), 3.38 (s, 3H), 3.05–3.01 (m, 1H), 2.76 (dd, J = 4.5, 4.5

Hz, 1H), 2.47 (dd, J = 5.0, 2.5 Hz, 1H), 1.79–1.70 (m, 2H), 1.64–1.53 (m, 2H), 1.39–1.22 (m,

18H), 0.87 (t, J = 7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 95.5, 75.6, 55.8, 49.8, 46.9, 37.6,

34.7, 32.1, 29.89, 29.84, 29.81, 29.80, 29.5, 25.6, 22.9, 14.3; MALDI-TOF/CCA-HRMS calcd

for C17H34O3Na [M Na]+: 309.2400, found 309.2410.

(2R,3S)-2-Hexyl-3-((S)-2-(methoxymethoxy)tridecyl)oxirane (II-6b)

To a stirred solution of II-23 (0.211 g, 0.646 mmol) in dichloromethane (4 mL) at room

temperature was added chloromethyl methyl ether (98 µL, 1.29 mmol) under N2, followed by

105

N,N-diisopropylethylamine (0.267 mL, 1.62 mmol) and 4-dimethylaminopyridine (2 mg). The

resulting mixture was stirred at the same temperature for 24 h. The reaction was quenched by

adding water (10 mL), and extracted with EtOAc (3 × 20 mL). The combined organic layers



on silica gel (30 mL) to afford II-6b (0.202 g, 85%) as a colorless oil.

Data for II-6b: Rf = 0.42 (10% EtOAc in hexanes); [α]D20

= +1.3 (CH2Cl2, c = 0.51); IR (neat)

2925, 2855, 1467, 1378, 1150, 1100, 1041 cm-1

; 1H NMR (400 MHz, CDCl3) δ 4.67 (s, 2H),

3.73 (dddd, J = 6.0, 6.0. 6.0, 6.0 Hz, 1H), 3.39 (s, 3H), 3.05 (ddd, J = 7.0, 4.5, 4.5 Hz, 1H), 2.92–

2.88 (m, 1H), 1.78 (ddd, J = 15.0, 5.0, 5.0 Hz, 1H), 1.70 (ddd, J = 15.0, 6.0, 6.0 Hz, 1H), 1.63–

1.55 (m, 2H), 1.52–1.47 (m, 3H), 1.38–1.24 (m, 25H), 0.88 (t, J = 6.5 Hz, 3H), 0.87 (t, J = 7.0

Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 95.5, 75.9, 56.7, 55.7, 54.3, 34.7, 33.0, 32.1, 32.0,

29.89, 29.84, 29.80, 29.5, 29.4, 28.2, 26.8, 25.6, 22.9, 22.8, 14.29, 14.24; MALDI-TOF/CCA-

HRMS calcd for C23H46O3Na [M Na]+: 393.3339, found 393.3350.

106

Chapter 2. Total Synthesis of Tetrahydrolipstatin and Stereoisomers via a Highly Regio-

and Diastereoselective Carbonylation of Epoxyhomoallylic Alcohols

General Procedure for Carbonylation of Epoxides

In a nitrogen glove box, a 4 mL glass vial equipped with a Teflon-coated magnetic stir bar

was charged with the appropriate amount of [ClTPPAl]+[Co(CO)4]

− and tetrahydrofuran. The

vial was placed in the glove box freezer at –30 °C along with a custom-made, six-well high-

pressure reactor (see Section A: General Information) to cool for 30 minutes. (In the absence of

CO, isomerization of the epoxide to ketone products69

can be minimized by keeping the

temperature of the reactor below 0 °C.) The appropriate amount of epoxide (also cooled at –30

°C for 30 minutes) was then added to the vial. After adding a cap with a Teflon-coated septum

pierced by a 20 G needle (to prevent the reaction solvent from refluxing into the reactor

chamber), the vial was placed quickly into the reactor. Subsequently, the reactor was sealed,

taken out of the glove box, placed in a well-ventilated hood, and pressurized with carbon

monoxide (900 psi). The reactor was then heated to 50 °C and the reaction mixture stirred for the

specified time. The reactor was cooled on dry ice for 10 minutes and carefully vented in a fume

hood. The crude reaction mixture was concentrated under reduced pressure and then purified via

flash column chromatography or preparative HPLC.

(S)-Pentadec-1-en-4-ol (II-7a)

To a stirred solution of dodecanal II-8a (1.91 g, 10.4 mmol) in dichloromethane (30 mL) at 0 °C

was added a solution of (S,S)-Leighton reagent (7.91 g, 14.3 mmol) in dichloromethane (10 mL)

107

via syringe, followed by scandium triflate (128 mg, 0.260 mmol) under N2. The resulting mixture

was stirred at the same temperature for 8 h. The reaction was quenched by adding 1 N

hydrochloric acid (20 mL). The formed solid was filtered through a fritted funnel, and the filtrate

was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine,



mL) to afford II-7a (1.87 g, 80%, ee = 96%) as a colorless oil.

Data for II-7a: Rf = 0.34 (10% EtOAc in hexanes); [α]D20

= –4.1 (CH2Cl2, c = 1.05); IR (neat)

3347, 2922, 2853, 1641, 1466, 1275 cm-1

; 1H NMR (400 MHz, CDCl3) δ 5.88–5.78 (m, 1H),

5.16–5.12 (m, 2H), 3.67–3.61 (m, 1H), 2.34–2.27 (m, 1H), 2.13 (ddd, J = 15.2, 7.6, 7.6 Hz, 1H),

1.56 (s, 1H), 1.49–1.42 (m, 3H), 1.34–1.24 (m, 17H), 0.88 (t, J = 6.8 Hz, 3H); 13

C NMR (100

MHz, CDCl3) δ 135.1, 118.3, 70.9, 42.1, 37.0, 32.1, 29.85, 29.82, 29.80, 29.5, 25.9, 22.9, 14.3.70

(S,Z)-Henicos-7-en-10-ol (II-7b)

To a stirred suspension of palladium/calcium carbonate (5% wt/wt, 30.4 mg, 14.3 µmol) in

methanol (5 mL) at room temperature was added quinoline (36.9 mg, 0.286 mmol). The mixture

was stirred at the same temperature for 0.5 h. A solution of II-21 (0.441 g, 1.43 mmol) in

methanol (2 mL) was added to the mixture. The resulting mixture was stirred under H2 (1 atm)

atmosphere. After 18 h, the mixture was concentrated. The crude residue was purified by flash

chromatography (2 to 8% EtOAc in hexanes) on silica gel (30 mL) to afford II-7b (0.425 g,


108

Data for II-7b: Rf = 0.31 (10% EtOAc in hexanes); [α]D21

= –2.0 (CH2Cl2, c = 1.82); IR (neat)

3341, 2955, 2921, 2853, 1465, 1378, 1275, 1127, 1080, 1030 cm-1


δ 5.60–5.54 (m, 1H), 5.43–5.37 (m, 1H), 3.61 (dddd, J = 6.0, 6.0, 6.0, 6.0 Hz, 1H), 2.23–2.20 (m,

2H), 2.07–2.02 (m, 2H), 1.52 (s, 1H), 1.49–1.42 (m, 3H), 1.37–1.22 (m, 25H), 0.88 (t, J = 7.0

Hz, 6H); 13

C NMR (100 MHz, CDCl3) δ 133.7, 125.3, 71.7, 37.0, 35.5, 32.1, 31.9, 29.88, 29.85,

29.82, 29.5, 29.2, 27.6, 26.0, 22.9, 22.8, 14.30, 14.27; HRMS (CI) calcd for C21H41O [M – 1]+:

309.3157, found 309.3153.

(R,Z)-Henicos-7-en-10-ol (ent-II-7b)

To a stirred suspension of palladium-calcium carbonate (5% wt/wt, 150 mg, 70.7 µmol) in

methanol (10 mL) at room temperature was added quinoline (182 mg, 1.47 mmol). The mixture

was stirred at the same temperature for 0.5 h. A solution of ent-II-21 (2.18 g, 7.07 mmol) in

methanol (2 mL) was added to the mixture. The resulting mixture was stirred under H2 (1 atm)

atmosphere. After 7 h, the mixture was concentrated. The crude residue was purified by flash

chromatography (2 to 8% EtOAc in hexanes) on silica gel (30 mL) to afford ent-II-7b (1.91 g,


Data for ent-II-7b: Rf = 0.31 (10% EtOAc in hexanes); [α]D21

= +1.8 (CH2Cl2, c = 1.92); IR

(neat) 3341, 2955, 2921, 2853, 1465, 1378, 1275, 1127, 1080, 1030 cm-1

; 1H NMR (400 MHz,

CDCl3) δ 5.59–5.53 (m, 1H), 5.43–5.36 (m, 1H), 3.63 (dddd, J = 6.0, 6.0, 6.0, 6.0 Hz, 1H), 2.21

(t, J = 6.4 Hz, 2H), 2.07–2.02 (m, 2H), 1.62 (s, 1H), 1.49–1.42 (m, 3H), 1.36–1.22 (m, 25H),

0.87 (t, J = 6.8 Hz, 6H); 13

C NMR (100 MHz, CDCl3) δ 133.7, 125.3, 71.7, 37.0, 35.5, 32.1,

109

31.9, 29.88, 29.86, 29.82, 29.5, 29.2, 27.6, 26.0, 22.9, 22.8, 14.30, 14.28; HRMS (CI) calcd for

C21H41O [M – H]+: 309.3157, found 309.3153.

Pentadec-2-yn-4-one (II-8b)

To a stirred solution of II-8c (22.0 g, 90.2 mmol) in tetrahydrofuran (50 mL) at –15 °C was

added a solution of 1-propynylmagnesium bromide (0.5 M, 216 mL, 108 mmol) in

tetrahydrofuran via syringe slowly under N2. The resulting mixture was stirred at the same

temperature for 0.5 h. The reaction was quenched by adding saturated aqueous ammonium

chloride (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were



on silica gel (350 mL) to afford II-8b (20.1 g, 99%) as a colorless oil.

Data for II-8b: Rf = 0.44 (10% EtOAc in hexanes); IR (neat) 2922, 2853, 2219, 1673, 1466,

1275, 1164 cm-1

; 1H NMR (400 MHz, CDCl3) δ 2.50 (t, J = 7.6 Hz, 2H), 2.00 (s, 3H), 1.67–1.58

(m, 2H), 1.30–1.20 (m, 16H), 0.86 (t, J = 6.8 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 188.6,

89.9, 80.4, 45.6, 32.1, 29.76, 29.75, 29.6, 29.5, 29.1, 24.2, 22.8, 14.3, 4.2; MALDI-TOF/CCA-

HRMS calcd for C15H26ONa+ [M Na]

+: 245.1876, found 245.1864.

110

N-Methoxy-N-methyldodecanamide (II-8c)

To a stirred solution of ethyl laurate (10.7 g, 46.9 mmol) in tetrahydrofuran (80 mL) at –15 °C

was added N,O-dimethylhydroxylamine hydrochloride (6.85 g, 70.3 mmol), followed by a

solution of isopropylmagnesium chloride in tetrahyrofuran (2 M, 47 mL, 94 mmol) via syringe

slowly under N2. The resulting mixture was stirred at the same temperature for 30 min. The

reaction was quenched by adding saturated aqueous ammonium chloride (100 mL) and extracted




II-8c (10.2 g, 89%) as a colorless oil.

Data for II-8c: Rf = 0.29 (20% EtOAc in hexanes); IR (neat) 2925, 2854, 1672, 1466, 1414,

1383, 1177, 1119 cm-1

; 1H NMR (400 MHz, CDCl3) δ 3.68 (s, 3H), 3.18 (s, 3H), 2.41 (t, J = 7.2

Hz, 2H), 1.66–1.58 (m, 3H), 1.34–1.24 (m, 15H), 0.87 (t, J = 6.4 Hz, 3H); 13

C NMR (100 MHz,

CDCl3) δ 61.3, 32.0, 29.75, 29.64, 29.59, 29.57, 29.47, 24.8, 22.8, 14.2; MALDI-TOF/CCA-

HRMS calcd for C14H30NO2+ [M H]

+: 244.2271, found 244.2285.

71

(S)-tert-Butyl pentadec-1-en-4-yl carbonate (II-9)

To a stirred solution of II-7a (2.24 g, 9.89 mmol) in tetrahydrofuran (33 mL) at 0 °C was added

a solution of n-butyllithium (1.8 M, 5.9 mL, 10.6 mmol) in hexane via syringe slowly under N2.

After 15 min, a solution of di-tert-butyl dicarbonate (4.32 g, 19.8 mmol) in tetrahydrofuran (10

111

mL) was added via syringe slowly. The resulting mixture was stirred at 0 °C for 1.5 h, and

warmed to room temperature. The stirring was continued for 1.5 h. The reaction was quenched

by adding saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (3 × 80



chromatography (1 to 4% EtOAc in hexanes) on silica gel (60 mL) to afford II-9 (3.02 g, 93%)

as a colorless oil.

Data for II-9: Rf = 0.22 (hexanes); [α]D22

= –13.7 (CH2Cl2, c = 1.44); IR (neat) 2923, 2854,

1737, 1466, 1368, 1253, 1164 cm-1

; 1H NMR (500 MHz, CDCl3) δ 5.78 (dddd, J = 17.0, 10.0,

7.0, 7.0 Hz, 1H), 5.11–5.05 (m, 2H), 4.68 (dddd, J = 7.0, 6.0, 6.0, 6.0 Hz, 1H), 2.35–2.32 (m,

2H), 1.60–1.53 (m, 2H), 1.47 (s, 9H), 1.31–1.24 (m, 18H), 0.88 (t, J = 7.0 Hz, 3H); 13

C NMR

(100 MHz, CDCl3) δ 153.6, 133.9, 117.9, 81.8, 76.8, 38.9, 33.9, 32.1, 29.81, 29.73, 29.70, 29.6,

29.5, 28.0, 25.5, 22.9, 14.3; HRMS (ESI) calcd for C20H39O3 [M H]+: 327.2899, found

327.2907.

(4S,6S)-4-(Iodomethyl)-6-undecyl-1,3-dioxan-2-one (II-10)

To a stirred solution of II-9 (2.59 g, 7.93 mmol) in acetonitrile (25 mL) at –20 °C was added

iodine (6.03 g, 23.8 mmol) in one portion under N2. The resulting mixture was stirred at the same

temperature for 2.5 h. The reaction was quenched by adding water (40 mL), and extracted with



112

flash chromatography (5 to 25% EtOAc in hexanes) on silica gel (60 mL) to afford II-10 (2.12 g,

67%) as a white solid.

Data for II-10: mp 65–66 °C; Rf = 0.34 (20% EtOAc in hexanes); [α]D22

= –11.4 (CH2Cl2, c =

1.07); IR (neat) 3055, 2927, 2855, 1752, 1398, 1265, 1189, 1105 cm-1

; 1H NMR (400 MHz,

CDCl3) δ 4.48–4.40 (m, 2H), 3.40 (dd, J = 10.4, 4.4 Hz, 1H), 3.25 (dd, J = 10.4, 7.2 Hz, 1H),

2.38 (ddd, J = 14.4, 3.2, 3.2 Hz, 1H), 1.80–1.71 (m, 1H), 1.69–1.59 (m, 2H), 1.55–1.44 (m, 1H),

1.42–1.36 (m, 1H), 1.35–1.25 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H); 13


148.7, 78.7, 77.3, 35.3, 33.4, 32.1, 29.77, 29.67, 29.57, 29.50, 29.4, 24.6, 22.9, 14.3, 5.5;

MALDI-TOF/CCA-HRMS calcd for C16H29IO3Na [M Na]+: 419.1054, found 416.1059.

(S)-1-((S)-Oxiran-2-yl)tridecan-2-ol (II-11)

To a stirred solution of II-10 (0.58 g, 1.46 mmol) in methanol (20 mL) at room temperature was

added potassium carbonate (0.81 g, 5.85 mmol) in one portion. The resulting mixture was stirred

at the same temperature for 10 h. The reaction was quenched by adding water, and extracted with



flash chromatography (5 to 20% EtOAc in hexanes) on silica gel (30 mL) to afford 11 (0.350 g,



= –8.4 (CH2Cl2, c = 1.23); IR (neat)

3418, 2921, 2852, 1466, 1260, 1025 cm-1

; 1H NMR (500 MHz, CDCl3) δ 3.90–3.85 (m, 1H),

3.08 (dddd, J = 7.0, 4.0, 4.0, 3.0 Hz, 1H), 2.78 (dd, J = 4.5, 4.5 Hz, 1H), 2.49 (dd, J = 5.0, 2.5

Hz, 1H), 1.98 (br s, 1H), 1.84 (ddd, J = 14.5, 4.0, 4.0 Hz, 1H), 1.54–1.47 (m, 3H), 1.44–1.40 (m,

113

1H), 1.35–1.24 (m, 17H), 0.87 (t, J = 7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 70.7, 50.9,

46.8, 39.9, 37.7, 32.1, 29.83, 29.78, 29.5, 25.7, 22.9, 14.3; MALDI-TOF/CCA-HRMS calcd for

C15H30O2Na [M Na]+: 265.2138, found 265.2124.

Methyl (3S,5S)-3-hydroxy-5-(methoxymethoxy)hexadecanoate (II-12)

According to a modified literature procedure:72

In a nitrogen glove box, an 8 mL glass vial

equipped with a Teflon-coated magnetic stir bar was charged with dicobalt octacarbonyl

(Co2(CO)8) (35.8 mg, 0.105 mmol, 10 mol %) and 3-hydroxypyridine (20.0 mg, 0.210 mmol, 20

mol %). Tetrahydrofuran (1.0 mL) was added to the vial, followed by (II-6a) (0.301 g, 1.05

mmol). After taking the vial out of the glove box, methanol (1.0 mL) was added to the vial and

the vial was placed quickly into a custom-made six-well high-pressure reactor. Subsequently, the

reactor was sealed, placed in a well-ventilated hood, purged three times with carbon monoxide,

and then pressurized to 900 psi. The reactor was then heated to 60 °C and the reaction mixture

was stirred for 16 hours. The reactor was cooled on dry ice for 10 minutes and carefully vented

in a fume hood. The crude reaction mixture was concentrated under reduced pressure and then

purified via flash column chromatography (10 to 20% EtOAc in hexanes) on silica gel (60 mL)

to afford II-12 (0.322 g, 89%) as a colorless oil.


= +28.9 (CH2Cl2, c = 0.51); IR (neat)

3467, 2925, 2854, 1738, 1467, 1439, 1204, 1151, 1099, 1038 cm-1


δ 4.70 (d, J = 7.0 Hz, 1H), 4.63 (d, J = 7.0 Hz, 1H), 4.23–4.18 (m, 1H), 3.79 (dddd, J = 8.5, 5.5,

5.5, 5.5 Hz, 1H), 3.71 (s, 3H), 3.38 (s, 3H), 2.54–2.46 (m, 2H), 1.76 (ddd, J = 14.0, 8.5, 8.5 Hz,

1H), 1.64 (ddd, J = 14.0, 4.0, 4.0 Hz, 1H), 1.57–1.52 (m, 2H), 1.32–1.24 (m, 18H), 0.88 (t, J =

114

7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 173.0, 95.4, 76.8, 67.2, 56.0, 51.9, 41.8, 40.9, 34.4,

32.1, 29.96, 29.82, 29.80, 29.78, 29.5, 25.1, 22.9, 14.3; MALDI-TOF/CCA-HRMS calcd for

C19H38O5Na [M Na]+: 369.2611, found 369.2609.

(R)-1-((S)-Oxiran-2-yl)tridecan-2-yl 4-nitrobenzoate (II-13)

To a stirred solution of II-11 (0.78 g, 3.22 mmol) in tetrahydrofuran (12 mL) at 0 °C was added

triphenylphosphine (1.73 g, 6.60 mmol) and 4-nitrobenzoic acid (1.08 g, 6.44 mmol) under N2. A

solution of diisopropyl azodicarboxylate (1.30 g, 6.44 mmol) in tetrahydrofuran (3 mL) was

added slowly via syringe. The resulting mixture was stirred at the same temperature for 1.5 h.





II-13 (1.25 g, 99%) as a colorless oil.

Data for II-13: Rf = 0.19 (15% Et2O in hexanes); [α]D21

= –9.2 (CHCl3, c = 0.23); IR (neat)

2925, 2854, 1724, 1608, 1529, 1350, 1275, 1103, 1015 cm-1

; 1H NMR (500 MHz, CDCl3) δ 8.30

(ddd, J = 9.0, 2.0, 2.0 Hz, 2H), 8.21 (ddd, J = 9.0, 2.0, 2.0 Hz, 2H), 5.36 (dddd, J = 7.5, 7.5, 5.0,

5.0 Hz, 1H), 3.02 (dddd, J = 7.0, 4.5, 4.5, 2.5 Hz, 1H), 2.75 (dd, J = 4.5, 4.5 Hz, 1H), 2.47 (dd, J

= 5.0, 2.5 Hz, 1H), 1.99 (ddd, J = 14.5, 8.0, 5.0 Hz, 1H), 1.86 (ddd, J = 14.5, 7.0, 4.5 Hz, 1H),

1.83–1.72 (m, 2H), 1.43–1.31 (m, 4H), 1.30–1.22 (m, 14H), 0.87 (t, J = 7.0 Hz, 3H); 13

C NMR

115

(100 MHz, CDCl3) δ 164.4, 150.7, 136.0, 130.9, 123.8, 74.2, 49.2, 47.0, 37.6, 34.4, 32.1, 29.78,

29.70, 29.63, 29.55, 29.51, 25.5, 22.9, 14.3; HRMS (ESI) calcd for C22H34NO5 [M H]+:

392.2437, found 392.2431.

(R)-1-((S)-Oxiran-2-yl)tridecan-2-ol (II-14)

To a stirred solution of II-13 (3.32 g, 8.49 mmol) in methanol (17 mL) at 0 °C was added

potassium carbonate (2.35 g, 17.0 mmol). The resulting mixture was stirred at the same




flash chromatography (10 to 40% EtOAc in hexanes) on silica gel (50 mL) to afford II-14 (1.84

g, 90%) as a white solid.


= –13.3 (CHCl3, c =

0.36); IR (neat) 3396, 2916, 2848, 1464, 1265, 1057 cm-1

; 1H NMR (500 MHz, CDCl3) δ 3.84–

3.79 (m, 1H), 3.15 (dddd, J = 7.0, 4.0, 4.0, 3.0 Hz, 1H), 2.82 (dd, J = 4.5, 4.5 Hz, 1H), 2.61 (dd,

J = 5.0, 3.0 Hz, 1H), 1.95 (br s, 1H), 1.83 (ddd, J = 14.5, 8.5, 4.0 Hz, 1H), 1.62 (ddd, J = 14.5,

6.0, 3.5 Hz, 1H), 1.53–1.39 (m, 3H), 1.34–1.24 (m, 17H), 0.88 (t, J = 7.0 Hz, 3H); 13

C NMR

(100 MHz, CDCl3) δ 69.5, 50.5, 47.0, 39.1, 37.8, 32.1, 29.84, 29.82, 29.78, 29.54, 25.7, 22.9,

14.3; HRMS (ESI) calcd for C15H30O2Na [M Na]+: 265.2144, found 265.2143.

116

(S)-2-((R)-2-(Methoxymethoxy)tridecyl)oxirane (II-15)

To a stirred solution of II-14 (1.73 g, 7.14 mmol) in dichloromethane (15 mL) at 0 °C was added

chloromethyl methyl ether (0.81 mL, 10.7 mmol) under N2, followed by N,N-

diisopropylethylamine (2.95 mL, 17.9 mmol). The resulting mixture was stirred at the same




flash chromatography (0 to 10% EtOAc in hexanes) on silica gel (50 mL) to afford II-15 (1.94 g,



= –18.2 (CHCl3, c = 0.48); IR (neat)

2925, 2854, 1467, 1150, 1100, 1041 cm-1

; 1H NMR (500 MHz, CDCl3) δ 4.69 (s, 2H), 3.77

(dddd, J = 7.0, 6.0, 6.0, 4.5 Hz, 1H), 3.39 (s, 3H), 3.04 (dddd, J = 7.0, 4.5, 4.0, 2.5 Hz, 1H), 2.80

(dd, J = 4.5, 4.5 Hz, 1H), 2.50 (dd, J = 5.0, 3.0 Hz, 1H), 1.76 (ddd, J = 14.5, 8.0, 5.0 Hz, 1H),

1.62 (ddd, J = 14.5, 7.0, 4.5 Hz, 1H), 1.59–1.50 (m, 2H), 1.38–1.24 (m, 18H), 0.88 (t, J = 7.0 Hz,

3H); 13

C NMR (100 MHz, CDCl3) δ 95.8, 75.6, 55.8, 49.9, 47.7, 38.1, 35.1, 32.1, 29.92, 29.84,

29.82, 29.79, 29.54, 25.4, 22.9, 14.3; HRMS (ESI) calcd for C17H34O3Na [M Na]+: 309.2406,

found 309.2400.

Methyl (3S,5R)-3-hydroxy-5-(methoxymethoxy)hexadecanoate (II-16)

According to a modified literature procedure:72

In a nitrogen glove box, an 8 mL glass vial

equipped with a Teflon-coated magnetic stir bar was charged with dicobalt octacarbonyl

117

(Co2(CO)8) (35.9 mg, 0.105 mmol, 10.1 mol %) and 3-hydroxypyridine (19.5 mg, 0.205 mmol,

19.7 mol %). Tetrahydrofuran (1.2 mL) was added to the vial, followed by (13) (0.299 g, 1.04

mmol). After taking the vial out of the glove box, methanol (1.2 mL) was added to the vial and

the vial was placed quickly into a custom-made six-well high-pressure reactor. Subsequently, the

reactor was sealed, placed in a well-ventilated hood, purged three times with carbon monoxide,

and then pressurized to 900 psi. The reactor was then heated to 60 °C and the reaction mixture

stirred for 16 hours. The reactor was cooled on dry ice for 10 minutes and carefully vented in a

fume hood. The crude reaction mixture was concentrated under reduced pressure and then

purified via flash column chromatography (10 to 20% EtOAc in hexanes) on silica gel (60 mL)

to afford II-16 (0.315 g, 87%) as a colorless oil.


= –29.2 (CH2Cl2, c = 0.94); IR (neat)

3481, 2925, 2854, 1740, 1466, 1438, 1376, 1205, 1150, 1101, 1039 cm-1

; 1H NMR (500 MHz,

CDCl3) δ 4.68 (d, J = 7.0 Hz, 1H), 4.66 (d, J = 7.0 Hz, 1H), 4.29 (dddd, J = 10.5, 8.0, 5.0, 3.0

Hz, 1H), 3.81 (dddd, J = 9.0, 6.0, 6.0, 3.0 Hz, 1H), 3.70 (s, 3H), 3.04 (s, 3H), 2.52–2.44 (m, 2H),

1.65 (ddd, J = 14.5, 9.5, 3.0 Hz, 1H), 1.60–1.55 (m, 1H), 1.56 (ddd, J = 14.5, 8.5, 2.5 Hz, 1H),

1.52–1.45 (m, 1H), 1.32–1.22 (m, 18H), 0.87 (t, J = 7.0 Hz, 3H); 13


173.0, 96.5, 75.7, 64.9, 56.0, 51.9, 41.8, 41.2, 35.1, 32.1, 29.94, 29.82, 29.80, 29.77, 29.5, 25.4,

22.9, 14.3; MALDI-TOF/CCA-HRMS calcd for C19H38O5Na [M Na]+: 369.2611, found

369.2600.

118

(S)-Pentadec-2-yn-4-ol (II-17)

To a stirred solution of II-8b (7.90 g, 35.5 mmol) in triethylamine (49.5 mL, 355 mmol) at 0 °C

was added formic acid (13.4 mL, 355 mmol) slowly under N2. After the white smoke subsided,

(S)-RuCl[(1S,2S)-p-TsNCH(C6H5)CH(C6H5)NH2](η6-mesitylene) (110 mg, 178 µmol) was

added. The resulting mixture was stirred at room temperature for 12 h. The reaction was

quenched by adding water (20 mL), and extracted with EtOAc (3 × 100 mL). The combined

organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated


EtOAc in hexanes) on silica gel (180 mL) to afford II-17 (6.60 g, 83%, brsm 93%, ee = 95.5%)

as a white solid.

Data for II-17: mp 36.5–37.5 °C; Rf = 0.27 (10% EtOAc in hexanes); [α]D23

= +2.1 (CH2Cl2, c =

1.37); IR (neat) 3355, 2921, 2853, 1466, 1340, 1266, 1147, 1113, 1031 cm-1

; 1H NMR (500

MHz, CDCl3) δ 4.32–4.27 (m, 1H), 2.00 (brs, 1H), 1.82 (d, J = 2.5 Hz, 3H), 1.69–1.58 (m, 2H),

1.43–1.37 (m, 2H), 1.30–1.20 (m, 16H), 0.86 (t, J = 6.5 Hz, 3H); 13


80.9, 80.7, 62.8, 38.3, 32.1, 29.81, 29.79, 29.74, 29.72, 29.50, 29.47, 25.4, 22.8, 14.3, 3.7;

HRMS (EI) calcd for C15H27O [M – 1]+: 223.2062, found 223.2058.

(R)-Pentadec-2-yn-4-ol (ent-II-17)

To a stirred solution of II-8b (3.24 g, 14.6 mmol) in triethylamine (20.3 mL, 146 mmol) at 0 °C

was added formic acid (5.5 mL, 146 mmol) slowly under N2. After the white smoke subsided,

119

(R)-RuCl[(1R,2R)-p-TsNCH(C6H5)CH(C6H5)NH2](6-mesitylene) (46.0 mg, 74.0 µmol) was

added. The resulting mixture was stirred at room temperature for 40 h. The reaction was




EtOAc in hexanes) on silica gel (100 mL) to afford ent-II-17 (2.75 g, 85%, ee = 96%) as a white

solid.

Data for ent-II-17: mp 36–37 °C; Rf = 0.27 (10% EtOAc in hexanes); [α]D21

= –5.5 (CH2Cl2, c =

1.13); IR (neat) 3322, 2918, 2850, 1467, 1316, 1266, 1148, 1064 cm-1

; 1H NMR (400 MHz,

CDCl3) δ 4.34–4.29 (m, 1H), 1.84 (d, J = 2.0 Hz, 3H), 1.74 (d, J = 5.2 Hz, 1H), 1.70–1.60 (m,

2H), 1.45–1.38 (m, 2H), 1.31–1.21 (m, 16H), 0.87 (t, J = 6.8 Hz, 3H); 13

C NMR (100 MHz,

CDCl3) δ 81.0, 80.7, 63.0, 38.4, 32.1, 29.84, 29.82, 29.77, 29.75, 29.54, 29.50, 25.4, 22.9, 14.3,

3.7; HRMS (EI) calcd for C15H27O [M – H]+: 223.2062, found 223.2058.

(S)-Pentadec-1-yn-4-ol (II-18)

To a flask with oil-free potassium hydride (4.61 g, 115 mmol) at 15 °C was added 1,3-

diaminopropane (45 mL) via syringe slowly under N2. The mixture was stirred at the same

temperature for 1.5 h. A solution of II-17 (6.45 g, 28.7 mmol) in 1,3-diaminopropane (30 mL)

was added to the mixture. The resulting mixture was warmed to room temperature, and stirred

for 18 h. The reaction was quenched by pouring onto ice, and extracted with EtOAc (3 × 80 mL).


120


to 15% EtOAc in hexanes) on silica gel (200 mL) to afford II-18 (5.16 g, 80%) as a colorless oil.


= –0.5 (CH2Cl2, c = 2.26); IR (neat)

3313, 2921, 2852, 1465, 1377, 1275, 1260, 1128, 1066, 1033 cm-1


δ 3.76–3.70 (m, 1H), 2.40 (ddd, J = 16.5, 5.0, 2.5 Hz, 1H), 2.29 (ddd, J = 16.5, 6.5, 2.5 Hz, 1H),

2.12 (d, J = 4.5 Hz, 1H), 2.03 (t, J = 2.5 Hz, 1H), 1.54–1.49 (m, 2H), 1.44–1.37 (m, 1H), 1.33–

1.20 (m, 17H), 0.86 (t, J = 6.5 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 81.1, 70.9, 70.0, 36.3,

32.1, 29.77, 29.72, 29.69, 29.5, 27.5, 25.7, 22.8, 14.2.73

(R)-Pentadec-1-yn-4-ol (ent-II-18)

To a flask with oil-free potassium hydride (1.85 g, 46.2 mmol) at 15 °C was added 1,3-

diaminopropane (20 mL) via syringe slowly under N2. The mixture was stirred at the same

temperature for 1 h. A solution of ent-II-17 (2.59 g, 11.5 mmol) in 1,3-diaminopropane (10 mL)

was added to the mixture. The resulting mixture was warmed to room temperature, and stirred

for 18 h. The reaction was quenched by pouring onto ice, and extracted with EtOAc (3 × 80 mL).



to 20% EtOAc in hexanes) on silica gel (80 mL) to afford ent-II-18 (2.01 g, 78%) as a colorless

oil.

Data for ent-II-18: Rf = 0.27 (10% EtOAc in hexanes); [α]D23

= +0.6 (CH2Cl2, c = 2.50); IR

(neat) 3400, 2916, 2849, 1465, 1377, 1275, 1260, 1128, 1092, 1066, 1033 cm-1

; 1H NMR (400

MHz, CDCl3) δ 3.79–3.71 (m, 1H), 2.43 (ddd, J = 16.8, 4.8, 2.8 Hz, 1H), 2.31 (ddd, J = 16.8,

121

6.8, 2.8 Hz, 1H), 2.05 (t, J = 2.8 Hz, 1H), 1.97 (d, J = 4.8 Hz, 1H), 1.53–1.49 (m, 2H), 1.44–1.37

(m, 1H), 1.32–1.20 (m, 17H), 0.86 (t, J = 6.4 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 81.1, 70.9,

70.1, 36.4, 32.1, 29.83, 29.81, 29.76, 29.74, 29.71, 29.5, 27.5, 25.8, 22.9, 14.3.

(S)-tert-Butyldimethyl(pentadec-1-yn-4-yloxy)silane (II-19)

To a stirred solution of II-18 (3.32 g, 14.8 mmol) in dimethylformamide (15 mL) at room

temperature was added imidazole (2.52 g, 37.0 mmol), followed by tert-butyldimethylsilyl

chloride (4.46 g, 29.6 mmol) under N2. The resulting mixture was stirred at the same temperature

for 16 h. The reaction was quenched by adding water (20 mL) and extracted with EtOAc (3 × 50



chromatography (0 to 1% EtOAc in hexanes) on silica gel (100 mL) to afford II-19 (4.83 g,



= –17.5 (CH2Cl2, c = 1.13); IR (neat) 2955, 2925,

2854, 1463, 1361, 1256, 1099, 1045 cm-1

; 1H NMR (500 MHz, CDCl3) δ 3.81–3.76 (m, 1H),

2.32–2.30 (m, 2H), 1.96 (t, J = 3.0 Hz, 1H), 1.64–1.57 (m, 1H), 1.54–1.46 (m, 1H), 1.40–1.34

(m, 1H), 1.30–1.20 (m, 17H), 0.89 (s, 9H), 0.88 (t, J = 6.5 Hz, 3H), 0.08 (s, 3H), 0.06 (s, 3H);

13C NMR (100 MHz, CDCl3) δ 82.1, 71.1, 69.9, 36.8, 32.1, 29.84, 29.79, 29.5, 27.6, 26.0, 25.3,

22.9, 18.3, 14.3, –4.3, –4.5; HRMS (EI) calcd for C21H41OSi [M – 1]+: 337.2927, found

337.2930.

122

(R)-tert-Butyldimethyl(pentadec-1-yn-4-yloxy)silane (ent-II-19)

To a stirred solution of ent-II-18 (1.53 g, 6.82 mmol) in dimethylformamide (7 mL) at room

temperature was added imidazole (1.16 g, 17.1 mmol), followed by tert-butyldimethylsilyl

chloride (2.05 g, 13.6 mmol) under N2. The resulting mixture was stirred at the same temperature

for 13 h. The reaction was quenched by adding water (20 mL) and extracted with Et2O (3 × 25



chromatography (0 to 1% EtOAc in hexanes) on silica gel (50 mL) to afford ent-II-19 (4.31 g,


Data for ent-II-19: Rf = 0.25 (hexanes); [α]D24

= +16.8 (CH2Cl2, c = 1.64); IR (neat) 2955, 2925,

2854, 1463, 1257, 1099, 1045 cm-1

; 1H NMR (400 MHz, CDCl3) δ 3.82–3.76 (m, 1H), 2.37–2.26

(m, 2H), 1.97 (t, J = 2.8 Hz, 1H), 1.64–1.57 (m, 1H), 1.54–1.46 (m, 1H), 1.41–1.34 (m, 1H),

1.32–1.21 (m, 17H), 0.89 (s, 9H), 0.86 (t, J = 6.4 Hz, 3H), 0.08 (s, 3H), 0.06 (s, 3H); 13

C NMR

(100 MHz, CDCl3) δ 82.1, 71.2, 69.9, 36.9, 32.1, 29.86, 29.85, 29.6, 27.6, 26.1, 25.3, 23.0, 18.3,

14.3, –4.3, –4.4; HRMS (EI) calcd for C21H41OSi [M – H]+: 337.2927, found 337.2930.

(S)-tert-Butyl(henicos-7-yn-10-yloxy)dimethylsilane (II-20)

To a stirred solution of II-19 (2.75 g, 8.12 mmol) in tetrahydrofuran (9 mL) and

hexamethylphosphoramide (6 mL) at –20 °C was added n-butyllithium (1.8 M, 5.4 mL, 9.75

mmol) via syringe slowly under N2. After 1 h at the same temperature, 1-iodohexane was added

in one portion. The resulting mixture was stirred at –20 °C for 1 h, warmed slowly to room

123

temperature, and stirred at the temperature for 11 h. The reaction was quenched by adding water

(20 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with



mL) to afford II-20 (3.67 g, 88%) as a colorless oil.


= –12.0 (CH2Cl2, c = 1.23); IR (neat) 2955, 2925,

2854, 1741, 1463, 1361, 1257, 1097, 1046 cm-1

; 1H NMR (500 MHz, CDCl3) δ 3.75–3.70 (m,

1H), 2.28–2.24 (m, 2H), 2.15–2.11 (m, 2H), 1.63–1.56 (m, 1H), 1.50–1.44 (m, 2H), 1.40–1.34

(m, 2H), 1.32–1.24 (m, 23H), 0.88 (s, 9H), 0.90–0.87 (m, 6H), 0.07 (s, 3H), 0.05 (s, 3H); 13

C

NMR (100 MHz, CDCl3) δ 82.0, 77.6, 71.8, 36.9, 32.1, 31.6, 29.90, 29.88, 29.85, 29.82, 29.6,

29.2, 28.8, 28.0, 26.1, 25.3, 22.9, 22.8, 19.0, 18.3, 14.31, 14.26, –4.3, –4.5; HRMS (CI) calcd for

C27H53OSi [M – 1]+: 421.3866, found 421.3861.

(R)-tert-Butyl(henicos-7-yn-10-yloxy)dimethylsilane (ent-II-20)

To a stirred solution of ent-II-19 (7.60 g, 22.4 mmol) in tetrahydrofuran (8 mL) and

hexamethylphosphoramide (8 mL) at –20 °C was added n-butyllithium (2.5 M, 9.4 mL, 23.6

mmol) via syringe slowly under N2. After 1 h at the same temperature, 1-iodohexane (4.3 mL,

29.1 mmol) was added in one portion. The resulting mixture was stirred at –20 °C for 1 h,

warmed slowly to room temperature, and stirred at the temperature for 20 h. The reaction was



124


EtOAc in hexanes) on silica gel (200 mL) to afford ent-II-20 (8.80 g, 93%) as a colorless oil.

Data for ent-II-20: Rf = 0.25 (hexanes); [α]D23

= +11.6 (CH2Cl2, c = 1.05); IR (neat) 2956, 2927,

2856, 1464, 1361, 1254, 1099, 1048 cm-1

; 1H NMR (500 MHz, CDCl3) δ 3.75–3.71 (m, 1H),

2.31–2.21 (m, 2H), 2.14 (dddd, J = 7.0, 7.0, 2.5, 2.5 Hz, 2H), 1.63–1.55 (m, 1H), 1.50–1.44 (m,

2H), 1.40–1.34 (m, 2H), 1.33–1.24 (m, 23H), 0.89 (s, 9H), 0.90–0.86 (m, 6H), 0.07 (s, 3H), 0.06

(s, 3H); 13

C NMR (100 MHz, CDCl3) δ 82.0, 77.6, 71.8, 36.9, 32.1, 31.6, 29.91, 29.89, 29.86,

29.83, 29.6, 29.2, 28.8, 28.0, 26.1, 25.4, 22.9, 22.8, 19.0, 18.3, 14.34, 14.28, –4.2, –4.5; HRMS

(CI) calcd for C27H53OSi [M – H]+: 421.3866, found 421.3861.

(S)-Henicos-7-yn-10-ol (II-21)

To a flask with II-20 (0.968 g, 2.29 mmol) was added a solution of tetra-n-butylammonium

fluoride (1 M, 12 mL, 12 mmol) in tetrahydrofuran at room temperature. The resulting mixture

was stirred at the same temperature for 14 h. The reaction was quenched by adding saturated

aqueous sodium bicarbonate, and extracted with EtOAc (3 × 30 mL). The combined organic

layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under

reduced pressure. The crude residue was purified by flash chromatography (0 to 4% EtOAc in

hexanes) on silica gel (30 mL) to afford II-21 (0.678 g, 96%) as a colorless oil.


= +1.5 (CH2Cl2, c = 3.63); IR (neat)

3373, 2955, 2922, 2853, 1465, 1378, 1275, 1261, 1126, 1085, 1032 cm-1

; 1H NMR (500 MHz,

CDCl3) δ 3.70–3.66 (m, 1H), 2.40 (dddd, J = 16.5, 5.0, 2.5, 2.5 Hz, 1H), 2.26 (dddd, J = 16.5,

6.5, 2.5, 2.5 Hz, 1H), 2.17 (m, 2H), 1.92 (s, 1H), 1.53–1.48 (m, 4H), 1.44–1.34 (m, 3H), 1.32–

125

1.25 (m, 21H), 0.89 (t, J = 7.0 Hz, 3H), 0.88 (t, J = 7.0, 3H); 13


83.4, 76.3, 70.4, 36.4, 32.1, 31.5, 29.84, 29.81, 29.78, 29.5, 29.1, 28.7, 27.9, 25.8, 22.9, 22.7,

18.9, 14.3, 14.2; HRMS (EI) calcd for C21H40O [M]+: 308.3079, found 308.3074.

(R)-Henicos-7-yn-10-ol (ent-II-21)

To a flask with ent-II-20 (4.68 g, 11.1 mmol) was added a solution of tetra-n-butylammonium

fluoride (1 M, 50 mL, 50 mmol) in tetrahydrofuran at room temperature. The resulting mixture

was stirred at the same temperature for 24 h. The reaction was quenched by adding saturated

aqueous sodium bicarbonate, and extracted with EtOAc (3 × 80 mL). The combined organic

layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under

reduced pressure. The crude residue was purified by flash chromatography (2 to 8% EtOAc in

hexanes) on silica gel (80 mL) to afford ent-II-21 (3.20 g, 94%) as a colorless oil.


= –1.7 (CH2Cl2, c = 3.20); IR

(neat) 3367, 2955, 2922, 2853, 1466, 1378, 1275, 1261, 1126, 1085, 1032 cm-1

; 1H NMR (400

MHz, CDCl3) δ 3.71–3.65 (m, 1H), 2.40 (dddd, J = 16.8, 4.8, 2.4, 2.4 Hz, 1H), 2.26 (dddd, J =

16.8, 6.8, 2.4, 2.4 Hz, 1H), 2.16 (dddd, J = 7.2, 7.2, 2.4, 2.4 Hz, 2H), 1.88 (s, 1H), 1.53–1.45 (m,

4H), 1.44–1.36 (m, 3H), 1.35–1.25 (m, 21H), 0.89 (t, J = 6.8 Hz, 3H), 0.88 (t, J = 6.8, 3H); 13

C

NMR (100 MHz, CDCl3) δ 83.5, 76.3, 70.4, 36.4, 32.1, 31.5, 29.85, 29.82, 29.79, 29.5, 29.1,

28.8, 27.9, 25.8, 22.9, 22.8, 18.9, 14.3, 14.2; HRMS (EI) calcd for C21H40O [M]+: 308.3079,

found 308.3074.

126

(S)-1-((2S,3R)-3-Hexyloxiran-2-yl)tridecan-2-ol (II-23)

To a stirred solution of II-7b (0.408 g, 1.31 mmol) in dichloromethane (4 mL) at 0 °C was added

vanadyl acetylacetonate (6.7 mg, 26 µmol), followed by a solution of tert-butyl hydroperoxide

(5.5 M, 0.36 mL, 1.97 mmol) in decane slowly via syringe. The resulting mixture was stirred at

the same temperature for 2 h, and warmed to room temperature slowly. After 21 h, the reaction

was quenched by adding water (10 mL) and sodium sulfite (0.497 g, 3.94 mmol). After 30 min,

the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed



(30 mL) to afford II-23 (0.403 g, 94%) as a colorless oil.


= –3.2 (CH2Cl2, c = 1.31); IR (neat)

3427, 2955, 2922, 2853, 1465, 1378, 1275, 1261, 1128, 1110, 1070, 1038 cm-1

; 1H NMR (500

MHz, CDCl3) δ 3.93–3.88 (m, 1H), 3.12 (ddd, J = 8.0, 4.0, 4.0 Hz, 1H), 2.91 (ddd, J = 6.0, 5.0,

5.0 Hz, 1H), 2.28 (s, 1H), 1.80 (ddd, J = 14.5, 4.0, 4.0 Hz, 1H), 1.56–1.45 (m, 5H), 1.44–1.39

(m, 1H), 1.37–1.24 (m, 25H), 0.88 (t, J = 6.5 Hz, 3H), 0.87 (t, J = 7.0 Hz, 3H); 13

C NMR (100

MHz, CDCl3) δ 71.0, 56.5, 55.6, 37.6, 34.8, 32.1, 31.9, 29.81, 29.79, 29.76, 29.5, 29.3, 28.1,

26.6, 25.7, 22.8, 22.7, 14.26, 14.20; MALDI-TOF/CCA-HRMS calcd for C21H42O2Na [M

Na]+: 349.3077, found 349.3070.

127

(R)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-ol (ent-II-23)

To a stirred solution of ent-II-7b (1.85 g, 5.96 mmol) in dichloromethane (8 mL) at 0 °C was

added vanadyl acetylacetonate (31.6 mg, 0.119 µmol), followed by a solution of tert-butyl

hydroperoxide (5.5 M, 1.6 mL, 8.94 mmol) in decane slowly via syringe. The resulting mixture

was stirred at the same temperature for 2 h, and warmed to room temperature slowly. After 6 h,

the reaction was quenched by adding water (30 mL) and sodium sulfite (2.25 g, 17.9 mmol).

After 30 min, the mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers



on silica gel (60 mL) to afford ent-II-23 (1.74 g, 90%) as a colorless oil.


= +3.9 (CH2Cl2, c = 1.42); IR

(neat) 3459, 2955, 2922, 2853, 1465, 1378, 1275, 1261, 1128, 1110, 1070, 1038 cm-1

; 1H NMR

(400 MHz, CDCl3) δ 3.93–3.88 (m, 1H), 3.12 (ddd, J = 8.0, 4.0, 4.0 Hz, 1H), 2.91 (ddd, J = 6.4,

6.4, 4.4 Hz, 1H), 2.32 (s, 1H), 1.80 (ddd, J = 14.4, 4.0, 4.0 Hz, 1H), 1.56–1.45 (m, 6H), 1.44–

1.39 (m, 1H), 1.37–1.24 (m, 24H), 0.88 (t, J = 6.5 Hz, 3H), 0.87 (t, J = 7.0 Hz, 3H); 13

C NMR

(100 MHz, CDCl3) δ 71.1, 56.5, 55.7, 37.6, 34.9, 32.1, 31.9, 29.81, 29.79, 29.79, 29.5, 29.3,

28.1, 26.6, 25.7, 22.9, 22.7, 14.30, 14.24; MALDI-TOF/CCA-HRMS calcd for C21H42O2Na [M

Na]+: 349.3077, found 349.3070.

128

(3S,4S)-3-Hexyl-4-((S)-2-(methoxymethoxy)tridecyl)oxetan-2-one (II-24)

The general procedure for carbonylation of epoxides was followed using II-6b (99.1 mg 0.267

mmol), [ClTPPAl]+[Co(CO)4]

− (2.8 mg, 0.0026 mmol, 0.97 mol %) and tetrahydrofuran (0.53

mL) for 12 hours. The crude residue was purified by flash column chromatography (5 to 15%

EtOAc in hexanes) on silica gel (30 mL) to afford II-24 (86.0 mg, 81%) as a colorless oil.


= –10.5 (CH2Cl2, c = 0.44); IR (neat)

2926, 2855, 1825, 1467, 1378, 1151, 1123, 1099, 1039 cm-1

; 1H NMR (500 MHz, CDCl3) δ 4.65

(d, J = 7.0 Hz, 1H), 4.62 (d, J = 7.0 Hz, 1H), 4.42 (ddd, J = 6.5, 6.5, 4.0 Hz, 1H), 3.66 (dddd, J =

5.5, 5.5, 5.5, 5.5 Hz, 1H), 3.37 (s, 3H), 3.25 (ddd, J = 7.5, 7.5, 4.5 Hz, 1H), 2.12 (ddd, J = 14.5,

7.0, 6.0 Hz, 1H), 1.94 (ddd, J = 14.5, 6.0, 5.5 Hz, 1H), 1.86–1.80 (m, 1H), 1.79–1.71 (m, 1H),

1.62–1.50 (m, 1H), 1.49–1.44 (m, 1H), 1.42–1.36 (m, 1H), 1.35–1.24 (m, 25H), 0.884 (t, J = 7.0

Hz, 3H), 0.879 (t, J = 7.5 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 171.7, 95.9, 75.3, 75.0, 57.1,

55.9, 39.1, 34.4, 32.1, 31.7, 29.83, 29.77, 29.5, 29.2, 28.0, 26.9, 25.5, 22.9, 22.7, 14.3, 14.2;

MALDI-TOF/CCA-HRMS calcd for C24H46O4Na [M Na]+: 421.3288, found 421.3268.

(S)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-L-leucinate

(II-25)

To a stirred solution of II-4b (19.6 mg, 55.3 µmol) in dichloromethane (1 mL) at room

temperature was added N-Cbz-L-Leu-OH (44.0 mg, 166 µmol), followed by N,N-

129

dicyclohexylcarbodiimide (45.4 mg, 221 µmol) and 4-dimethylaminopyridine (1 mg). The

resulting mixture was stirred at the same temperature for 22 h. The mixture was diluted with

hexanes and filtered through a pad of Celite. The filtrate was concentrated under reduced

pressure. The crude residue was purified by flash chromatography (5% EtOAc in hexanes) on

silica gel (2 mL) to afford II-25 (31.0 mg, 93%) as a colorless oil.


= –24.1 (CHCl3, c = 0.56); IR (neat)

3357, 2926, 2855, 1824, 1727, 1524, 1467, 1333, 1262, 1218, 1171, 1121, 1048 cm-1

; 1H NMR

(500 MHz, CDCl3) δ 7.37–7.30 (m, 5H), 5.11 (s, 2H), 5.08 (d, J = 8.5 Hz, 1H), 5.02–4.98 (m,

1H), 4.34 (ddd, J = 9.0, 9.0, 5.0 Hz, 1H), 4.30–4.26 (m, 1H), 3.20 (ddd, J = 7.0, 7.0, 4.0 Hz, 1H),

2.15 (ddd, J = 15.0, 7.5, 7.5 Hz, 1H), 1.96 (ddd, J = 15.0, 4.5, 4.5 Hz, 1H), 1.82–1.67 (m, 3H),

1.65–1.57 (m, 3H), 1.51 (ddd, J = 14.0, 9.5, 5.5 Hz, 1H), 1.46–1.41 (m, 1H), 1.32–1.24 (m,

25H), 0.947 (d, J = 6.0 Hz, 3H), 0.939 (d, J = 6.0 Hz, 3H), 0.882 (t, J = 6.5 Hz, 3H), 0.878 (t, J =

7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 172.7, 171.1, 156.1, 136.4, 128.7, 128.4, 128.3,

74.8, 72.5, 67.2, 57.2, 52.9, 41.8, 38.8, 34.2, 32.1, 31.7, 29.82, 29.73, 29.63, 29.54, 29.49, 29.2,


C36H59NO6Na [M Na]+: 624.4235, found 624.4238.

74

(R)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-D-leucinate

(ent-II-25)

The general procedure for carbonylation of epoxides was followed using ent-II-28 (76.8 mg,

0.164 mmol), [ClTPPAl]+[Co(CO)4]

− (3.0 mg, 0.0027 mmol, 1.6 mol %) and tetrahydrofuran

130

(0.28) mL for 24 hours. The crude residue was purified by preparative HPLC to afford ent-II-25

(60.3 mg, 75%) as a colorless oil.


= +20.3 (CHCl3, c = 1.06); IR

(neat) 3355, 2923, 2855, 1823, 1731, 1522, 1456, 1369, 1333, 1264, 1219, 1121, 1029 cm-1

; 1H

NMR (400 MHz, CDCl3) δ 7.37–7.30 (m, 5H), 5.11 (s, 2H), 5.08 (d, J = 8.5 Hz, 1H), 5.02–4.98

(m, 1H), 4.34 (ddd, J = 8.8, 8.8, 5.2 Hz, 1H), 4.30–4.26 (m, 1H), 3.20 (ddd, J = 7.2, 7.2, 4.4 Hz,


3H), 1.65–1.57 (m, 3H), 1.55–1.47 (m, 1H), 1.46–1.41 (m, 1H), 1.32–1.24 (m, 25H), 0.97–0.94

(m, 6H), 0.89–0.86 (m, 6H); 13

C NMR (100 MHz, CDCl3) δ 172.7, 171.0, 156.1, 136.4, 128.7,

128.4, 128.3, 74.7, 72.5, 67.2, 57.2, 53.0, 41.8, 38.9, 34.2, 32.1, 31.7, 29.80, 29.73, 29.62, 29.52,

29.48, 29.2, 27.8, 26.9, 25.3, 25.0, 23.1, 22.9, 22.7, 21.9, 14.3, 14.2; MALDI-TOF/CCA-HRMS

calcd for C36H59NO6Na [M Na]+: 624.4235, found 624.4242.

(S)-1-((2S,3R)-3-Hexyloxiran-2-yl)tridecan-2-yl formyl-L-leucinate (II-26)

To a stirred solution of II-28 (175 mg, 0.305 mmol) in tetrahydrofuran (2 mL) at room

temperature was added Pd/C (10% wt/wt, 32 mg, 30.6 µmol) under N2. The resulting mixture

was then stirred at the same temperature under H2 (1 atm) for 2 h. The mixture was filtered

through a pad of Celite, and washed with EtOAc. The filtrate was concentrated under reduced

pressure. The residue was dissolved in dichloromethane (1 mL). Then a premixed mixture of

N,N-dicyclohexylcarbodiimide (314 mg, 1.53 mmol) and formic acid (35 µL, 0.918 mmol) in

dichloromethane (4 mL) was added to the solution. After 5 min, the mixture was diluted with

131



on silica gel (2 mL) to afford II-26 (113 mg, 79%) as a colorless oil.


= –21.3 (CH2Cl2, c = 0.77); IR (neat)

3301, 2957, 2926, 2855, 1740, 1668, 1528, 1467, 1382, 1274, 1253, 1195 cm-1

; 1H NMR (500

MHz, CDCl3) δ 8.21 (s, 1H), 6.07 (d, J = 9.0 Hz, 1H), 5.09 (dddd, J = 8.0, 8.0, 5.0, 4.5 Hz, 1H),

4.72 (ddd, J = 8.5, 8.5, 5.0 Hz, 1H), 2.93 (ddd, J = 7.5, 4.0, 4.0 Hz, 1H), 2.87 (ddd, J = 6.0, 6.0,

4.5 Hz, 1H), 1.87 (ddd, J = 14.5, 4.5, 4.5 Hz, 1H), 1.74–1.58 (m, 5H), 1.52–1.39 (m, 4H), 1.36–

1.24 (m, 25H), 0.96 (d, J = 6.0 Hz, 3H), 0.95 (d, J = 6.0 Hz, 3H), 0.885 (t, J = 6.5 Hz, 3H), 0.871

(t, J = 6.5 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 172.2, 160.8, 74.3, 56.4, 53.8, 49.9, 41.9,

34.3, 32.7, 32.1, 31.9, 29.79, 29.74, 29.64, 29.55, 29.52, 29.3, 28.1, 26.7, 25.4, 25.1, 23.0, 22.9,

22.7, 22.1, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for C28H53NO4Na [M Na]+: 490.3867,

found 490.3861.

(S)-1-((2S,3R)-3-Hexyloxiran-2-yl)tridecan-2-yl formyl-D-leucinate (II-27)

To a stirred solution of II-32 (45.5 mg, 79.3 µmol) in tetrahydrofuran (2 mL) at room

temperature was added Pd/C (10% wt/wt, 8.4 mg, 7.93 µmol) under N2. The resulting mixture




N,N-dicyclohexylcarbodiimide (65.1 mg, 317 µmol) and formic acid (9.0 µL, 238 µmol) in

132




on silica gel (2 mL) to afford II-27 (30.5 mg, 82%) as a colorless oil.


= +2.9 (CH2Cl2, c = 1.42); IR (neat)

3296, 2957, 2925, 2855, 1740, 1668, 1529, 1467, 1381, 1273, 1253, 1193, 1144 cm-1

; 1H NMR

(500 MHz, CDCl3) δ 8.20 (s, 1H), 6.11 (d, J = 9.0 Hz, 1H), 5.09 (dddd, J = 7.5, 7.5, 5.0, 5.0 Hz,

1H), 4.72 (ddd, J = 9.0, 9.0, 5.0 Hz, 1H), 2.97 (ddd, J = 8.0, 4.0, 4.0 Hz, 1H), 2.89–2.86 (m, 1H),

1.88 (ddd, J = 14.5, 5.0, 5.0 Hz, 1H), 1.75–1.58 (m, 5H), 1.49–1.38 (m, 4H), 1.36–1.24 (m,


7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 172.4, 160.8, 74.3, 56.4, 53.6, 49.7, 41.9, 34.0, 32.6,

32.1, 31.9, 29.79, 29.70, 29.65, 29.51, 29.47, 29.3, 28.1, 26.7, 25.5, 25.0, 23.0, 22.9, 22.7, 22.0,

14.29, 14.24; HRMS (ESI) calcd for C28H53NO4Na [M Na]+: 490.3867, found 490.3853.

Acetic formic anhydride

To a flask with acetic anhydride (2.0 mL, 21.2 mmol) at room temperature was added formic

acid (0.88 mL, 23.3 mmol). The resulting mixture was stirred at reflux for 1.5 h. The mixture

was used directly for next step.

133

(S)-1-((2S,3R)-3-Hexyloxiran-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-L-leucinate (II-28)

To a stirred solution of II-23 (100 mg, 0.306 mmol) in dichloromethane (1.5 mL) at room

temperature was added N-Cbz-L-Leu-OH (122 mg, 0.459 mmol), followed by N,N-

dicyclohexylcarbodiimide (126 mg, 0.612 mmol) and 4-dimethylaminopyridine (4 mg). The



pressure. The crude residue was purified by flash chromatography (10% EtOAc in hexanes) on

silica gel (2 mL) to afford II-28 (175 mg, 99%) as a colorless oil.


= –14.1 (CH2Cl2, c = 1.06); IR (neat)

3336, 2957, 2926, 2855, 1726, 1527, 1467, 1333, 1262, 1218, 1171, 1048 cm-1

; 1H NMR (500

MHz, CDCl3) δ 7.36–7.30 (m, 5H), 5.17 (d, J = 8.5 Hz, 1H), 5.13–5.06 (m, 1H), 5.10 (s, 2H),

4.38 (ddd, J = 9.0, 9.0, 5.0 Hz, 1H), 2.95–2.91 (m, 1H), 2.87–2.84 (m, 1H), 1.83 (ddd, J = 15.0,

4.5, 4.5 Hz, 1H), 1.73 (ddd, J = 14.0, 7.0, 7.0 Hz, 1H), 1.69–1.60 (m, 3H), 1.55–1.39 (m, 5H),

1.35–1.24 (m, 25H), 0.96 (d, J = 6.0 Hz, 3H), 0.94 (d, J = 6.0 Hz, 3H), 0.889 (t, J = 7.0 Hz, 3H),

0.877 (t, J = 7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 172.9, 156.1, 136.4, 128.8, 128.7,

128.32, 128.25, 74.0, 67.1, 56.4, 53.7, 52.9, 41.9, 34.2, 32.6, 32.1, 31.9, 29.82, 29.80, 29.75,

29.66, 29.53, 29.4, 28.1, 26.7, 25.4, 25.0, 23.1, 22.9, 22.7, 22.0, 14.31, 14.25; MALDI-

TOF/CCA-HRMS calcd for C35H59NO5Na [M Na]+: 596.4285, found 596.4294.

134

(R)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-D-leucinate (ent-II-

28)

To a stirred solution of ent-II-23 (47.0 mg, 0.144 mmol) in dichloromethane (1.0 mL) at room

temperature was added N-Cbz-D-Leu-OH (76.4 mg, 0.288 mmol), followed by N,N-

dicyclohexylcarbodiimide (73.9 mg, 0.360 mmol) and 4-dimethylaminopyridine (2 mg). The




on silica gel (10 mL) to afford ent-II-28 (82.0 mg, 99%) as a colorless oil.


= +11.9 (CHCl3, c = 0.82); IR

(neat) 3341, 2926, 2855, 1728, 1526, 1456, 1334, 1264, 1218, 1048 cm-1

; 1H NMR (500 MHz,

CDCl3) δ 7.36–7.30 (m, 5H), 5.17 (d, J = 8.5 Hz, 1H), 5.13–5.06 (m, 1H), 5.10 (s, 2H), 4.38

(ddd, J = 9.0, 9.0, 5.0 Hz, 1H), 2.95–2.91 (m, 1H), 2.87–2.84 (m, 1H), 1.83 (ddd, J = 15.0, 4.5,

4.5 Hz, 1H), 1.73 (ddd, J = 14.0, 7.0, 7.0 Hz, 1H), 1.69–1.60 (m, 3H), 1.55–1.39 (m, 5H), 1.35–

1.24 (m, 25H), 0.96 (d, J = 6.0 Hz, 3H), 0.94 (d, J = 6.0 Hz, 3H), 0.890 (t, J = 7.0 Hz, 3H), 0.877

(t, J = 7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 172.8, 156.1, 136.5, 128.7, 128.7, 128.33,

128.25, 74.0, 67.1, 56.4, 53.7, 53.0, 41.9, 34.3, 32.7, 32.1, 31.9, 29.82, 29.81, 29.75, 29.66,

29.56, 29.4, 28.1, 26.7, 25.4, 25.0, 23.1, 22.9, 22.7, 22.0, 14.31, 14.25; MALDI-TOF/CCA-

HRMS calcd for C35H59NO5Na [M Na]+: 596.4285, found 596.4283.

135

(S)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-L-leucinate (II-1)

The general procedure for carbonylation of epoxides was followed using II-26 (69.8 mg, 0.149


− (3.4 mg, 0.0031 mmol, 2.1 mol %), and tetrahydrofuran (0.30

mL) for 24 hours. The crude residue was purified by preparative HPLC to afford II-1 (59.4 mg,


(S)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-yl 4-nitrobenzoate (II-29)

To a stirred solution of ent-II-23 (1.08 g, 3.31 mmol) in tetrahydrofuran (6 mL) at 0 °C was

added triphenylphosphine (1.78 g, 6.78 mmol), followed by p-nitrobenzoic acid (1.10 g, 6.62

mmol) under N2. A solution of diisopropyl azodicarboxylate (94%, 1.42 g, 6.62 mmol) in

tetrahydrofuran (4 mL) was added to the solution slowly via syringe. The resulting mixture was

stirred at the same temperature for 40 min. The reaction was quenched by adding saturated

aqueous sodium bicarbonate (10 mL), and extracted with EtOAc (3 × 30 mL). The combined


under reduced pressure. The crude residue was purified by flash chromatography (2 to 10% Et2O

in hexanes) on silica gel (40 mL) to afford II-29 (1.50 g, 96%) as a colorless oil.

136


= –2.3 (CH2Cl2, c = 0.69); IR (neat)

2926, 2855, 1725, 1608, 1530, 1467, 1349, 1275, 1102, 1015 cm-1


δ 8.29 (d, J = 8.5 Hz, 2H), 8.21 (d, J = 8.5 Hz, 2H), 5.35 (ddd, J = 7.5, 7.5, 5.5, 5.5 Hz, 1H), 3.03

(ddd, J = 7.0, 4.5, 4.5 Hz, 1H), 2.91 (ddd, J = 6.0, 6.0, 4.5 Hz, 1H), 2.01 (ddd, J = 14.5, 7.5, 5.0

Hz, 1H), 1.86–1.76 (m, 3H), 1.51–1.45 (m, 3H), 1.40–1.24 (m, 25H), 0.88–0.86 (m, 6H); 13

C

NMR (100 MHz, CDCl3) δ 164.4, 150.7, 136.0, 130.9, 123.7, 74.6, 57.0, 53.8, 34.5, 32.9, 32.1,

31.9, 29.79, 29.71, 29.65, 29.57, 29.51, 29.3, 28.1, 26.7, 25.5, 22.9, 22.7, 14.3, 14.2; MALDI-

TOF/CCA-HRMS calcd for C28H45NO5Na [M Na]+: 498.3190, found 498.3193.

(S)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-ol (II-30)

To a stirred solution of II-29 (1.56 g, 3.28 mmol) in methanol (7 mL) at 0 °C was added

potassium carbonate (0.91 g, 6.58 mmol). The resulting mixture was stirred at the same





g, 80%) as a colorless oil.


= +14.4 (CH2Cl2, c =

1.63); IR (neat) 3459, 2955, 2922, 2853, 1465, 1378, 1275, 1261, 1128, 1110, 1070, 1038 cm-1

;

1H NMR (400 MHz, CDCl3) δ 3.87–3.81 (m, 1H), 3.15 (ddd, J = 8.8, 4.4, 4.4 Hz, 1H), 2.96

(ddd, J = 6.0, 6.0, 4.4 Hz, 1H), 1.81 (brs, 1H), 1.74 (ddd, J = 14.4, 8.0, 4.4 Hz, 1H), 1.56 (ddd, J

= 14.4, 8.0, 4.4 Hz, 1H), 1.55–1.40 (m, 6H), 1.35–1.22 (m, 24H), 0.88 (t, J = 6.4 Hz, 3H), 0.87

137

(t, J = 6.8 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 70.4, 57.4, 54.6, 37.9, 35.2, 32.10, 31.95,

29.84, 29.81, 29.78, 29.5, 29.4, 28.2, 26.7, 25.8, 22.9, 22.8, 14.30, 14.25; MALDI-TOF/CCA-


(2S,3R)-2-Hexyl-3-((S)-2-(methoxymethoxy)tridecyl)oxirane (II-31)

To a stirred solution of II-30 (0.325 g, 1.00 mmol) in dichloromethane (3 mL) at room

temperature was added chloromethyl methyl ether (0.151 mL, 2.00 mmol) under N2, followed by

N,N-diisopropyl-ethylamine (0.413 mL, 2.50 mmol) and 4-dimethylaminopyridine (3 mg). The

resulting mixture was stirred at the same temperature for 11 h. The reaction was quenched by

adding water (10 mL), and extracted with EtOAc (3 × 20 mL). The combined organic layers



on silica gel (30 mL) to afford II-31 (0.309 g, 84%) as a colorless oil.


= +8.9 (CH2Cl2, c = 1.77); IR (neat)

2922, 2854, 1466, 1275, 1099, 1037 cm-1

; 1H NMR (400 MHz, CDCl3) δ 4.68 (s, 2H), 3.75

(dddd, J = 7.6, 5.6, 5.6, 5.6 Hz, 1H), 3.38 (s, 3H), 3.05 (ddd, J = 7.2, 4.4, 4.4 Hz, 1H), 2.95–2.91

(m, 1H), 1.78 (ddd, J = 14.4, 7.2, 4.4 Hz, 1H), 1.60 (ddd, J = 14.4, 7.2, 4.8 Hz, 1H), 1.58–1.55

(m, 2H), 1.52–1.47 (m, 3H), 1.38–1.24 (m, 25H), 0.88 (t, J = 6.4 Hz, 3H), 0.87 (t, J = 6.8 Hz,

3H); 13

C NMR (100 MHz, CDCl3) 95.8, 75.9, 57.4, 55.8, 54.6, 35.1, 33.2, 32.1, 32.0, 29.92,

29.84, 29.81, 29.78, 29.5, 29.4, 28.3, 26.7, 25.4, 22.9, 22.7, 14.30, 14.24; MALDI-TOF/CCA-


138

(S)-1-((2S,3R)-3-Hexyloxiran-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-D-leucinate (II-32)

To a stirred solution of II-23 (32.0 mg, 98.0 µmol) in dichloromethane (0.8 mL) at room

temperature was added N-Cbz-D-Leu-OH (39.0 mg, 147 µmol), followed by N,N-

dicyclohexylcarbodiimide (40.2 mg, 196 µmol) and 4-dimethylaminopyridine (1 mg). The






= +2.5 (CH2Cl2, c = 0.90); IR (neat)

3346, 2956, 2926, 2855, 1727, 1529, 1468, 1334, 1262, 1220, 1200, 1119, 1049 cm-1

; 1H NMR

(500 MHz, CDCl3) δ 7.37–7.29 (m, 5H), 5.20 (d, J = 8.5 Hz, 1H), 5.10 (s, 2H), 5.10–5.05 (m,

1H), 4.38 (ddd, J = 9.0, 9.0, 5.5 Hz, 1H), 3.00–2.97 (m, 1H), 2.88–2.85 (m, 1H), 1.86 (ddd, J =

14.5, 4.5, 4.5 Hz, 1H), 1.74 (ddd, J = 14.0, 7.0, 7.0 Hz, 1H), 1.69–1.59 (m, 3H), 1.55–1.39 (m,

5H), 1.37–1.24 (m, 25H), 0.96 (d, J = 7.0 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H), 0.887 (t, J = 6.5 Hz,

3H), 0.875 (t, J = 6.5 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 172.9, 156.1, 136.5, 128.7, 128.3,

128.2, 73.9, 67.1, 56.4, 53.5, 52.9, 42.0, 34.0, 32.5, 32.1, 31.9, 29.81, 29.71, 29.66, 29.51, 29.50,

29.35, 28.1, 26.7, 25.5, 25.0, 23.1, 22.9, 22.7, 22.0, 14.30, 14.26; MALDI-TOF/CCA-HRMS

calcd for C35H59NO5Na [M Na]+: 596.4285, found 596.4265.

139

(R)-1-((2S,3R)-3-Hexyloxiran-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-D-leucinate (II-34)

To a stirred solution of II-23 (32.4 mg, 99.2 µmol) in tetrahydrofuran (0.5 mL) at 0 °C was

added triphenylphosphine (53.4 mg, 203 µmol) and N-Cbz-D-Leu-OH (52.5 mg, 198 µmol)

under N2. A solution of diisopropyl azodicarboxylate (42.6 mg, 198 µmol) in tetrahydrofuran

(0.5 mL) was added slowly via syringe. The resulting mixture was stirred at the same







= +11.9 (CHCl3, c = 0.93); IR (neat)

3338, 2926, 2857, 1729, 1523, 1461, 1335, 1261, 1215, 1119, 1049 cm-1

; 1H NMR (500 MHz,


(ddd, J = 9.0, 9.0, 5.0 Hz, 1H), 2.94–2.88 (m, 2H), 1.86 (ddd, J = 15.0, 7.5, 4.5 Hz, 1H), 1.76–

1.60 (m, 5H), 1.54–1.42 (m, 4H), 1.36–1.24 (m, 25H), 0.96 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 7.0

Hz, 3H), 0.888 (t, J = 7.0 Hz, 3H), 0.876 (t, J = 7.0 Hz, 3H); 13


172.8, 156.1, 136.4, 128.7, 128.3, 128.2, 74.1, 67.1, 57.0, 53.7, 52.9, 42.0, 34.3, 32.6, 32.1, 31.9,

29.81, 29.76, 29.67, 29.58, 29.54, 29.4, 28.2, 26.7, 25.3, 24.9, 23.1, 22.9, 22.8, 22.0, 14.32,

14.26; MALDI-TOF/CCA-HRMS calcd for C35H59NO5Na [M Na]+: 596.4285, found

596.4304.

140

(S)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-L-leucinate (ent-II-

34)









= –15.9 (CHCl3, c = 1.58); IR

(neat) 3339, 2926, 2857, 1729, 1523, 1461, 1335, 1262, 1216, 1049 cm-1

; 1H NMR (500 MHz,



1.59 (m, 5H), 1.54–1.42 (m, 4H), 1.36–1.24 (m, 25H), 0.96 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 7.0

Hz, 3H), 0.888 (t, J = 7.0 Hz, 3H), 0.876 (t, J = 7.0 Hz, 3H); 13


172.8, 156.1, 136.4, 128.7, 128.3, 128.2, 74.1, 67.1, 57.0, 53.7, 52.8, 42.1, 34.3, 32.6, 32.1, 31.9,

29.80, 29.76, 29.67, 29.58, 29.54, 29.3, 28.2, 26.7, 25.3, 24.9, 23.1, 22.9, 22.7, 22.0, 14.32,

14.26; MALDI-TOF/CCA-HRMS calcd for C35H59NO5Na [M Na]+: 596.4285, found

596.4283.

141

(R)-1-((2S,3R)-3-Hexyloxiran-2-yl)tridecan-2-yl formyl-D-leucinate (II-35)



was then stirred at the same temperature under H2 (1 atm) for 0.5 h. The mixture was filtered



N,N-dicyclohexylcarbodiimide (85.3 mg, 416 µmol) and formic acid (9.4 µL, 249 µmol) in




hexanes) on silica gel (10 mL) to afford II-35 (26.0 mg, 67%) as a colorless oil.


= +12.1 (CHCl3, c = 0.62); IR (neat)

3289, 2926, 2856, 1739, 1669, 1523, 1462, 1380, 1267, 1193 cm-1


δ 8.21 (s, 1H), 6.01 (d, J = 9.0 Hz, 1H), 5.09 (dddd, J = 7.0, 7.0, 5.5, 5.5 Hz, 1H), 4.73 (ddd, J =

9.0, 9.0, 4.5 Hz, 1H), 2.95–2.90 (m, 2H), 1.88 (ddd, J = 14.5, 7.5, 4.0 Hz, 1H), 1.72–1.60 (m,

5H), 1.59–1.39 (m, 4H), 1.38–1.24 (m, 25H), 0.97 (d, J = 6.0 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H),

0.887 (t, J = 7.0 Hz, 3H), 0.873 (t, J = 6.5 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 172.3, 160.7,

74.4, 57.0, 53.6, 49.7, 42.0, 34.2, 32.5, 32.1, 31.9, 29.80, 29.75, 29.65, 29.53, 29.3, 28.1, 26.7,

25.4, 25.0, 23.1, 23.0, 22.9, 22.7, 22.0, 14.30, 14.25; HRMS (ESI) calcd for C28H53NO4Na [M

Na]+: 490.3867, found 490.3845.

142

(S)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-yl 4-methylpentanoate (II-36)

To a stirred solution of ent-II-23 (21.2 mg, 64.9 µmol) in tetrahydrofuran (0.5 mL) at 0 °C was

added triphenylphosphine (34.9 mg, 133 µmol) and 2-methylvaleric acid (15.1 mg, 130 µmol)

under N2. A solution of diisopropyl azodicarboxylate (28.0 µL, 130 µmol) in tetrahydrofuran





flash chromatography (2.5 to 5% EtOAc in hexanes) on silica gel (20 mL) to afford II-36 (20.0



= –6.2 (CHCl3, c = 0.50); IR (neat)

2926, 2857, 1735, 1462, 1378, 1266, 1177, 1107 cm-1

; 1H NMR (500 MHz, CDCl3) 5.05 (ddd, J

= 13.0, 7.0, 5.5 Hz, 1H), 2.95 (ddd, J = 6.5, 4.5, 4.5 Hz, 1H), 2.92–2.88 (m, 1H), 2.31 (d, J = 7.0

Hz, 1H), 2.29 (d, J = 7.0 Hz, 1H), 1.81 (ddd, J = 14.5, 7.5, 5.0 Hz, 1H), 1.71 (ddd, J = 14.5, 6.5,

5.0 Hz, 1H), 1.63–1.59 (m, 2H), 1.57–1.40 (m, 5H), 1.38–1.24 (m, 26H), 0.91–0.86 (m, 12H);

13C NMR (100 MHz, CDCl3) δ 173.8, 72.4, 57.1, 54.2, 34.6, 34.0, 33.0, 32.9, 32.1, 32.0, 29.83,

29.74, 29.71, 29.61, 29.54, 29.4, 28.2, 27.9, 26.7, 25.4, 22.9, 22.8, 22.4, 14.32, 14.26; HRMS

(ESI) calcd for C27H53O3 [M H]+: 425.3995, found 425.3996.

143

(S)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-D-leucinate (II-37)









= –2.4 (CHCl3, c = 1.50); IR (neat)

3339, 2926, 2857, 1728, 1525, 1461, 1379, 1335, 1262, 1216, 1119, 1049 cm-1

; 1H NMR (500

MHz, CDCl3) δ 7.37–7.29 (m, 5H), 5.16 (d, J = 8.5 Hz, 1H), 5.12–5.06 (m, 1H), 5.10 (s, 2H),

4.36 (ddd, J = 8.5, 8.5, 5.0 Hz, 1H), 2.96–2.89 (m, 2H), 1.88 (ddd, J = 14.0, 7.5, 5.0 Hz, 1H),

1.76–1.68 (m, 2H), 1.67–1.59 (m, 3H), 1.54–1.41 (m, 4H), 1.37–1.24 (m, 25H), 0.96 (d, J = 7.0

Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H), 0.888 (t, J = 7.0 Hz, 3H), 0.875 (t, J = 7.0 Hz, 3H); 13

C NMR

(100 MHz, CDCl3) δ 173.0, 156.1, 136.4, 128.7, 128.3, 128.2, 73.9, 67.1, 57.1, 53.9, 52.8, 42.1,

34.4, 32.9, 32.1, 31.9, 29.80, 29.70, 29.66, 29.51, 29.4, 28.2, 26.7, 25.3, 24.9, 23.1, 22.9, 22.7,

22.0, 14.30, 14.26; MALDI-TOF/CCA-HRMS calcd for C35H59NO5Na [M Na]+: 596.4285,

found 596.4316.

144

(3R,4R)-3-Hexyl-4-((S)-2-(methoxymethoxy)tridecyl)oxetan-2-one (II-38)



− (1.6 mg, 0.0015 mmol, 1.0 mol %) and tetrahydrofuran (0.30

mL) for 12 hours. The crude residue was purified by preparative HPLC to afford II-38(50.5 mg,



= +45.2 (CH2Cl2, c = 0.82); IR (neat)

2926, 2855, 1825, 1467, 1390, 1152, 1118, 1101, 1040 cm-1

; 1H NMR (500 MHz, CDCl3) δ 4.68

(d, J = 7.0 Hz, 1H), 4.64 (d, J = 7.0 Hz, 1H), 4.44 (ddd, J = 6.5, 6.5, 4.5 Hz, 1H), 3.70 (ddd, J =

12.0, 6.0, 6.0 Hz, 1H), 3.38 (s, 3H), 3.21 (ddd, J = 8.0, 8.0, 4.5 Hz, 1H), 1.95–1.89 (m, 2H), 1.82

(dddd, J = 13.5, 10.5, 6.0, 6.0 Hz, 1H), 1.74 (dddd, J = 13.5, 9.0, 9.0, 6.0 Hz, 1H), 1.62–1.56 (m,

1H), 1.52–1.48 (m, 1H), 1.46–1.42 (m, 1H), 1.40–1.35 (m, 1H), 1.34–1.24 (m, 24H), 0.880 (t, J

= 7.0 Hz, 3H), 0.875 (t, J = 7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 171.7, 96.0, 75.3, 74.6,

56.7, 55.9, 40.1, 34.9, 32.1, 31.7, 29.9, 29.82, 29.80, 29.76, 29.5, 29.1, 27.9, 27.0, 25.0, 22.9,

22.7, 14.3, 14.2.75

(S)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-D-leucinate (II-39)



− (2.6 mg, 0.0024 mmol, 5.6 mol %) and tetrahydrofuran (0.25)

145

mL for 3 days. The crude residue was purified by flash column chromatography (50% Et2O in



= –5.3 (CHCl3, c = 0.17); IR (neat)

3325, 2957, 2927, 2855, 1824, 1740, 1685, 1511, 1467, 1379, 1252, 1188, 1125 cm-1

; 1H NMR

(500 MHz, CDCl3) δ 8.21 (s, 1H), 5.87 (d, J = 8.0 Hz, 1H), 5.03 (dddd, J = 7.5, 7.5, 5.0, 5.0 Hz,

1H), 4.66 (ddd, J = 8.5, 8.5, 5.5 Hz, 1H), 4.35 (ddd, J = 8.0, 5.0, 4.0 Hz, 1H), 3.22 (ddd, J = 7.5,

7.5, 4.5 Hz, 1H), 2.18 (ddd, J = 15.0, 7.5, 7.5 Hz, 1H), 2.02 (ddd, J = 15.0, 5.0, 4.5 Hz, 1H),

1.84–1.77 (m, 1H), 1.76–1.71 (m, 1H), 1.70–1.64 (m, 3H), 1.60–1.53 (m, 2H), 1.47–1.41 (m,

1H), 1.38–1.24 (m, 25H); 0.970 (d, J = 6.5 Hz, 3H), 0.967 (d, J = 6.5 Hz, 3H), 0.882 (t, J = 7.0

Hz, 3H), 0.879 (t, J = 7.0, 3H); 13

C NMR (100 MHz, CDCl3) δ 172.4, 171.2, 160.8, 74.8, 72.8,

57.2, 49.8, 41.6, 38.7, 34.0, 32.1, 31.6, 29.8, 29.7, 29.6, 29.5, 29.4, 29.2, 27.8, 26.9, 25.4, 25.0,

23.0, 22.9, 22.7, 22.0, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for C29H53NO5Na [M Na]+:

518.3816, found 518.3813.

(R)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-D-leucinate (ent-II-1)

(R)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-L-leucinate (ent-II-39)

The general procedure for carbonylation of epoxides was followed using 102.7 mg (0.2196

mmol) (R)-1-((2R,3S)-3-hexyloxiran-2-yl)tridecan-2-yl formyl-D,L-leucinate, 12.8 mg (0.0117

mmol, 5.33 mol %) [ClTPPAl][Co(CO)4], and 0.50 mL tetrahydrofuran for 3 days. The crude

residue was purified by flash column chromatography (50% Et2O in hexanes) on silica gel (30

146

mL) to afford a mixture of ent-II-1 and ent-II-39 (90.0 mg, 82%) as a colorless oil. The mixture

of ent-II-1 and ent-II-39 was separated with HPLC.


= +22.3 (CHCl3, c = 0.45); IR (neat)

3304, 2956, 2926, 2855, 1823, 1739, 1671, 1523, 1467, 1381, 1252, 1193, 1124 cm-1

; 1H NMR

(500 MHz, CDCl3) δ 8.22 (s, 1H), 5.91 (d, J = 8.5 Hz, 1H), 5.05–5.00 (m, 1H), 4.69 (ddd, J =

9.0, 9.0, 5.0 Hz, 1H), 4.29 (ddd, J = 7.5, 5.0, 5.0 Hz, 1H), 3.22 (ddd, J = 7.5, 7.5, 4.0 Hz, 1H),


1.77–1.63 (m, 4H), 1.61–1.53 (m, 2H), 1.47–1.41 (m, 1H), 1.32–1.24 (m, 25H), 0.973 (d, J = 6.5

Hz, 3H), 0.965 (d, J = 6.5 Hz, 3H), 0.884 (t, J = 6.5 Hz, 3H), 0.877 (t, J = 7.0, 3H); 13

C NMR

(100 MHz, CDCl3) δ 171.9, 170.8, 160.6, 74.8, 72.8, 57.0, 49.6, 41.6, 38.7, 34.1, 31.89, 31.5,

29.6, 29.5, 29.4, 29.3, 29.3, 29.0, 27.6, 26.7, 25.1, 24.9, 22.9, 22.7, 22.5, 21.7, 14.1, 14.0

(CDCl3, δ 77.0 ppm); MALDI-TOF/CCA-HRMS calcd for C29H53NO5Na [M Na]+: 518.3816,

found 518.3780.


= +4.4 (CHCl3, c = 0.81); IR (neat)

3307, 2926, 2855, 1824, 1740, 1687, 1523, 1467, 1380, 1251, 1190, 1125 cm-1

; 1H NMR (500



4.5 Hz, 1H), 2.17 (ddd, J = 15.0, 7.5, 7.5 Hz, 1H), 2.01 (ddd, J = 15.0, 5.0, 4.5 Hz, 1H), 1.84–

1.77 (m, 1H), 1.76–1.71 (m, 1H), 1.70–1.64 (m, 3H), 1.60–1.53 (m, 2H), 1.47–1.41 (m, 1H),

1.38–1.24 (m, 25H), 0.970 (d, J = 6.5 Hz, 3H), 0.967 (d, J = 6.5 Hz, 3H), 0.882 (t, J = 7.0 Hz,

3H), 0.879 (t, J = 7.0, 3H); 13

C NMR (100 MHz, CDCl3) δ 172.4, 171.2, 160.8, 74.8, 72.7, 57.1,

49.8, 41.6, 38.7, 34.0, 32.1, 31.6, 29.8, 29.7, 29.6, 29.5, 29.4, 29.1, 27.8, 26.8, 25.4, 25.0, 23.0,

147

22.9, 22.7, 22.0, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for C29H53NO5Na [M Na]+:

518.3816, found 518.3813.

(S)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-L-leucinate (ent-II-41)

To a stirred solution of ent-II-43 (10.0 mg, 16.6 µmol) in tetrahydrofuran (1 mL) at room


then stirred at the same temperature under H2 (1 atm) for 2 h. The mixture was filtered through a

pad of Celite, and washed with EtOAc. The filtrate was concentrated under reduced pressure.

The residue was dissolved in dichloromethane (0.5 mL). Then a premixed mixture of N,N-

dicyclohexylcarbodiimide (17.0 mg, 83.0 µmol) and formic acid (2.0 µL, 50.4 µmol) in

dichloromethane (0.5 mL) was added to the solution. After 5 min, the mixture was diluted with





= +12.6 (CHCl3, c = 0.55); IR

(neat) 3311, 2926, 2857, 1823, 1739, 1673, 1521, 1462, 1380, 1251, 1193, 1122 cm-1

; 1H NMR

(500 MHz, CDCl3) δ 8.21 (s, 1H), 5.94 (d, J = 8.5 Hz, 1H), 5.01(ddd, J = 7.0, 7.0, 5.5, 5.5 , 1H),


4.0 Hz, 1H), 2.09–2.00 (m, 2H), 1.86–1.79 (m, 1H), 1.76–1.63 (m, 4H), 1.61–1.54 (m, 2H),

1.47–1.41 (m, 1H), 1.38–1.24 (m, 25H), 0.972 (d, J = 6.0 Hz, 3H), 0.960 (d, J = 6.0 Hz, 3H),

0.883 (t, J = 7.0 Hz, 3H), 0.875 (t, J = 7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 172.2, 170.9,

148

160.8, 74.4, 72.7, 56.8, 49.8, 41.9, 39.1, 34.3, 32.1, 31.7, 29.8, 29.7, 29.6, 29.52, 29.50, 29.1,


C29H53NO5Na [M Na]+: 518.3816, found 518.3801.

(S)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-D-leucinate (ent-II-40)

To a stirred solution of ent-II-44 (10.0 mg, 16.6 µmol) in tetrahydrofuran (1 mL) at room











= +23.5 (CHCl3, c = 0.61); IR

(neat) 3353, 2926, 2857, 1822, 1739, 1684, 1462, 1380, 1251, 1189, 1124 cm-1

; 1H NMR (500



4.5 Hz, 1H), 2.10–2.00 (m, 2H), 1.85–1.78 (m, 1H), 1.77–1.53 (m, 6H), 1.49–1.42 (m, 1H),

1.38–1.24 (m, 25H), 0.975 (d, J = 6.0 Hz, 3H), 0.965 (d, J = 6.5 Hz, 3H), 0.89–0.87 (m, 6H); 13

C

149

NMR (100 MHz, CDCl3) δ 172.5, 171.1, 160.8, 74.5, 72.7, 56.9, 49.7, 41.9, 39.3, 34.4, 32.1,

31.7, 29.8, 29.7, 29.6, 29.5, 29.4, 29.1, 27.8, 27.0, 25.2, 25.1, 23.0, 22.9, 22.7, 22.1, 14.3, 14.2;

MALDI-TOF/CCA-HRMS calcd for C29H53NO5Na [M Na]+: 518.3816, found 518.3792.

150

Table S7. 1H NMR assignments of II-39. *δH (multiplicity, coupling constant (J) in Hz)

Position

Helv. Chim. Acta 1987,

70, 196.

(enatiomer) This Work

J. Med. Chem. 2008, 51,

6970.

CHO

(1H) 8.21 (s) 8.21 (s) 8.20 (s)

2''-NH

(1H) 5.88 (d, 8) 5.87 (d, 8.0) 6.19 (d, 8.0)

5

(1H) 5.09–4.96 (m) 5.03 (dddd, 7.5, 7.5, 5.0, 5.0) 5.03 (m)

2''

(1H) 4.67 (dt, 7.5, 7.5, 4.0) 4.66 (ddd, 8.5, 8.5, 5.5) 4.65 (m)

3

(1H) 4.36–4.25 (m, 1H) 4.35 (ddd, 8.0, 5.0, 4.0) 4.37 (m)

2

(1H) 3.22 (dt, 7.5, 7.5, 4.0) 3.22 (ddd, 7.5, 7.5, 4.5) 3.23 (m)

4, 4a

(2H) 2.26–1.97 (m) 2.18 (ddd, 15.0, 7.5, 7.5, 1H) 2.18 (m)

2.02 (ddd, 15.0, 5.0, 4.5, 1H) 2.00 (m)

CH2

(33H) 1.50–1.03 (m) 1.84–1.77 (m, 1H) 1.78–1.54 (m)

1.76–1.71 (m, 1H)

1.70–1.53 (m, 5H)

1.47–1.24 (m, 1H)

1.38–1.24 (m, 25H)

5'', 5'''

(6H)

1.03–0.94 (m) 0.970 (d, 6.5, 3H) 0.96 (m)

0.967 (d, 6.5, 3H)

16, 6'

(6H) 0.94–0.75 (m) 0.882 (t, 7.0, 3H) 0.89 (m)

0.879 (t, 7.0, 3H)

151

Position J. Med. Chem. 2008, 51,

6970. This Work

1, 1'' 172.27 172.40

171.07 171.21

1''' 160.77 160.78

3, 5 74.60 74.78

72.50 72.75

2, 2'' 56.99 57.16

49.69 49.77

4, 6, 9

12, 13, 14, 1', 2', 3'

4', 3'',

41.36 41.63

38.53 38.71

33.83 34.00

31.91 32.09

31.48 31.65

29.63 29.80

29.52 29.70

29.46 29.63

29.34 29.53

29.26 29.42

28.98 29.16

7, 8, 10, 11

27.64 27.79

26.68 26.86

25.21 25.38

24.87 25.03

4'' 22.82 23.01

5'' 5'''

15, 5'

22.69 22.88

22.53 22.72

21.86 22.03

16, 6' 14.12 14.32

14.03 14.24

Table S8. 13

C NMR assignments of II-39.

152

(R)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-L-leucinate (II-40)




mL for 24 hours. The crude residue was purified by preparative HPLC to afford 38 (46.5 mg,

72%, regioselectivity II-40: II-40a = 6:1; the ratio determined by 1H NMR) as a colorless oil.


= –21.5 (CHCl3, c = 0.36); IR (neat)

3353, 2925, 2855, 1822, 1736, 1685, 1461, 1380, 1272, 1187, 1125 cm-1

; 1H NMR (500 MHz,

CDCl3) δ 8.21 (s, 1H), 5.92 (d, J = 8.0 Hz, 1H), 5.04 (dddd, J = 7.0, 7.0, 5.5, 5.5 Hz, 1H), 4.68


Hz, 1H), 2.10–2.00 (m, 2H), 1.85–1.78 (m, 1H), 1.77–1.53 (m, 6H), 1.49–1.42 (m, 1H), 1.38–

1.24 (m, 25H), 0.976 (d, J = 6.5 Hz, 3H), 0.963 (d, J = 6.5 Hz, 3H), 0.89–0.87 (m, 6H); 13

C

NMR (100 MHz, CDCl3) δ 172.5, 171.1, 160.8, 74.5, 72.7, 56.9, 49.7, 41.9, 39.3, 34.4, 32.1,

31.7, 29.8, 29.7, 29.6, 29.5, 29.4, 29.1, 27.8, 27.0, 25.2, 25.0, 23.0, 22.9, 22.7, 22.1, 14.3, 14.2;


(R)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-L-leucinate (II-40)



153









154


Note: No 13

C NMR available for comparison.

Position


70, 196.

(enantiomer) This Work

CHO

(1H) 8.21 (s) 8.21 (s)

2''-NH

(1H) 5.93 (d, 8.5) 5.92 (d, 8.0)

5

(1H) 5.12–5.00 (m) 5.04 (dddd, 7.0, 7.0, 5.5, 5.5)

2''

(1H) 4.68 (dt, 8.5, 8.5, 5.0) 4.68 (ddd, 8.5, 8.5, 5.0)

3

(1H) 4.36–4.25 (m) 4.29 (ddd, 9.0, 4.5, 4.5)

2

(1H) 3.32 (dt, 8.0, 8.0, 5.0) 3.22 (ddd, 7.5, 7.5, 4.5)

4, 4a

(2H) 2.12–2.01 (m) 2.10–2.00 (m)

CH2

(33H) 1.90–1.06 (m) 1.85–1.78 (m, 1H)

1.77–1.53 (m, 6H)

1.49–1.42 (m, 1H)

1.38–1.24 (m, 25H)

5'', 5'''

(6H) 1.06–0.93 (m) 0.976 (d, 6.5, 3H),

0.963 (d, 6.5, 3H),

16, 6'

(6H)

0.93–0.77 (m) 0.89–0.87 (m)

155

(R)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl formyl-D-leucinate (II-41)




mL for 24 hours. The crude residue was purified by preparative HPLC to afford 39 (58.2 mg,

77%, regioselectivity II-41: II-41a = 5:1; the ratio determined by 1H NMR) as a colorless oil.


= –12.3 (CHCl3, c = 0.32); IR (neat)

3324, 2926, 2856, 1823, 1736, 1684, 1461, 1256, 1189, 1123 cm-1


δ 8.22 (s, 1H), 5.90 (d, J = 9.0 Hz, 1H), 5.04–4.99 (m, 1H), 4.71 (ddd, J = 8.5, 8.5, 4.5 Hz, 1H),


1.86–1.79 (m, 1H), 1.76–1.63 (m, 4H), 1.61–1.54 (m, 2H), 1.47–1.41 (m, 1H), 1.38–1.24 (m,


7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 172.2, 170.9, 160.7, 74.4, 72.8, 56.8, 49.8, 41.9,

39.1, 34.2, 32.1, 31.7, 29.8, 29.7, 29.6, 29.5, 29.4, 29.1, 27.9, 27.0, 25.2, 25.1, 23.0, 22.9, 22.7,

22.1, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for C29H53NO5Na [M Na]+: 518.3816, found

518.3843.

156


To a stirred solution of II-43 (16.0 mg, 26.6 µmol) in tetrahydrofuran (0.5 mL) at room




pressure. The residue was dissolved in dichloromethane (0.5 mL). Then a premixed mixture of

N,N-dicyclohexylcarbodiimide (27.3 mg, 133 µmol) and formic acid (3.0 µL, 79.8 µmol) in





157


Position


70, 196.

(enantiomer) This Work

Synthesis 1994, 1294

(enantiomer)

CHO

(1H) 8.25 (s) 8.22 (s) 8.12 (s)

2''-NH

(1H) 5.97 (d, 8) 5.90 (d, 9.0) 5.94 (d, 7.7)

5

(1H) 5.06–4.94 (m) 5.04–4.99 (m) 5.02 (m)

2''

(1H) 4.71 (dt, 9.0, 9.0, 5.0) 4.71 (ddd, 8.5, 8.5, 4.5) 4.72 (ddd, 8.9. 8.6. 4.3)

3

(1H) 4.33–4.20 (m, 1H) 4.26 (ddd, 8.5, 4.5, 4.5) 4.27 (m)

2

(1H) 3.29–3.20 (m) 3.23 (ddd, J = 7.0, 7.0, 4.0) 3.25 (ddd, 5.3, 4.2, 1.4)

4, 4a

(2H) 2.09–2.00 (m) 2.09–2.00 (m) 2.05 (m)

CH2

(33H) 1.87–1.04 (m) 1.86–1.79 (m, 1H) 1.70 (m, 7H)

1.76–1.63 (m, 4H) 1.30 (m, 26H)

1.61–1.54 (m, 2H)

1.47–1.41 (m, 1H)

1.38–1.24 (m, 25H)

5'', 5'''

(6H) 1.03–0.93 (m) 0.976 (d, 6.0, 3H) 0.982 (d, 6.2, 3H)

16, 6'

(6H)

0.964 (d, 6.0, 3H) 0.968 (d, 6.2, 3H)

0.93–0.78 (m) 0.887 (t, 7.0, 3H), 0.88 (m)

0.879 (t, 7.0, 3H);

158

Position Synthesis 1994, 1294 This Work

1, 1'' 172.2 172.2

170.8 170.9

1''' 160.7 160.7

3, 5 74.3 74.4

72.8 72.8

2, 2'' 56.8 56.8

49.8 49.8

4, 6, 9

12, 13, 14, 1', 2', 3'

4', 3'',

41.9 41.9

39.1 39.1

34.2 34.2

32.1 32.1

31.6 31.7

29.9 29.8

29.8 29.7

29.7 29.6

29.6 29.5

29.5 29.4

29.1 29.1

7, 8, 10, 11

27.8 27.9

26.9 27.0

25.1 25.2, 25.1

23.0 23.0

4'' 22.8 22.9

5'' 5'''

15, 5'

22.7 22.7

22.1 22.1

16, 6' 14.3 14.3

14.1 14.2

Table S11. 13

C NMR assignments of II-41.

159


To a stirred solution of II-43 (16.0 mg, 26.6 µmol) in tetrahydrofuran (0.5 mL) at room




pressure. The residue was dissolved in dichloromethane (0.5 mL). Then a premixed mixture of

N,N-dicyclohexylcarbodiimide (27.3 mg, 133 µmol) and formic acid (3.0 µL, 79.8 µmol) in





(S)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl 4-methylpentanoate (II-42)



− (0.8 mg, 0.0007 mmol, 2 mol %) and tetrahydrofuran (0.10) mL

for 24 hours. The crude residue was purified by preparative HPLC to afford II-42 (7.2 mg, 53%)

as a colorless oil.

160


= +16.4 (CHCl3, c = 0.52); IR (neat)

2925, 2855, 1826, 1736, 1466, 1378, 1269, 1178, 1121 cm-1

; 1H NMR (400 MHz, CDCl3) δ 4.96

(dddd, J = 7.2, 7.2, 5.2, 5.2 Hz, 1H), 4.26 (ddd, J = 8.8, 4.4, 4.4 Hz, 1H), 3.24 (ddd, J = 7.6, 7.6,

4.0 Hz, 1H), 2.32–2.28 (m, 2H), 2.10–1.97 (m, 2H), 1.85–1.75 (m, 1H), 1.74–1.67 (m, 1H),

1.61–1.44 (m, 5H), 1.34–1.24 (m, 26H), 0.92–0.86 (m, 12H); 13


173.7, 171.2, 74.9, 71.1, 56.9, 39.3, 34.6, 34.0, 32.8, 32.1, 31.7, 29.8, 29.71, 29.66, 29.54, 29.2,


C28H52O4Na [M Na]+: 475.3758, found 475.3733.

(S)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-L-leucinate

(ent-II-43)

The general procedure for carbonylation of epoxides was followed using ent-II-34 (83.0 mg,

0.145 mmol), [ClTPPAl]+[Co(CO)4]

− (3.2 mg, 0.0029 mmol, 2.0 mol %) and tetrahydrofuran

(0.30) mL for 24 hours. The crude residue was purified by preparative HPLC to afford ent-II-43

(70.2mg, 80%) as a colorless oil.


= +8.2 (CHCl3, c = 0.76); IR

(neat) 3348, 2926, 2855, 1823, 1729, 1525, 1467, 1336, 1263, 1219, 1171, 1120, 1050 cm-1

; 1H

NMR (400 MHz, CDCl3) δ 7.38–7.31 (m, 5H), 5.11 (s, 2H), 5.09 (d, J = 8.4 Hz, 1H), 5.01–4.96

(m, 1H), 4.36 (ddd, J = 8.8, 8.8, 4.8 Hz, 1H), 4.27–4.23 (m, 1H), 3.21 (ddd, J = 7.2, 7.2, 4.0 Hz,

1H), 2.02–1.99 (m, 2H), 1.83–1.76 (m, 1H), 1.74–1.67 (m, 2H), 1.66–1.57 (m, 3H), 1.55–1.49

(m, 1H), 1.46–1.40 (m, 1H), 1.36–1.24 (m, 25H), 0.97 (m, 6H), 0.89 (m, 6H); 13

C NMR (100

161

MHz, CDCl3) δ 172.7, 171.0, 156.1, 136.4, 128.7, 128.4,128.2, 74.4, 72.5, 67.2, 56.9, 52.9, 41.9,

39.2, 34.3, 32.1, 31.7, 29.80, 29.73, 29.64, 29.52, 29.51, 29.1, 27.8, 26.9, 25.2, 25.0, 23.1, 22.9,

22.7, 22.0, 14.3, 14.2; MALDI-TOF/CCA-HRMS calcd for C36H59NO6Na [M Na]+: 624.4235,

found 624.4243.

(R)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-D-leucinate

(II-43)

To a stirred solution of II-4b (20.0 mg, 56.4 µmol) in tetrahydrofuran (0.5 mL) at 0 °C was


under N2. A solution of diisopropyl azodicarboxylate (36.3 mg, 169 µmol) in tetrahydrofuran





flash chromatography (2.5 to 15% EtOAc in hexanes) on silica gel (10 mL) to afford II-43 (28.0



= –10.0 (CHCl3, c = 0.79); IR (neat)

3349, 2927, 2857, 1823, 1728, 1524, 1461, 1260, 1217, 1121, 1051 cm-1

; 1H NMR (500 MHz,

CDCl3) δ 7.38–7.31 (m, 5H), 5.11 (s, 2H), 5.09 (d, J = 8.5 Hz, 1H), 5.01–4.96 (m, 1H), 4.35


1.99 (m, 2H), 1.83–1.76 (m, 1H), 1.74–1.67 (m, 2H), 1.66–1.57 (m, 3H), 1.55–1.49 (m, 1H),

162

1.46–1.40 (m, 1H), 1.36–1.24 (m, 25H), 0.963 (d, J = 6.0 Hz, 3H), 0.951 (d, J = 6.0 Hz, 3H),

0.880 (t, J = 7.0 Hz, 3H), 0.877 (t, J = 7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 172.7, 171.0,

156.1, 136.4, 128.7, 128.4, 128.2, 74.4, 72.5, 67.1, 56.8, 52.9, 41.9, 39.2, 34.3, 32.1, 31.7, 29.80,

29.73, 29.64, 29.52, 29.50, 29.1, 27.8, 26.9, 25.2, 25.0, 23.1, 22.9, 22.7, 22.0, 14.3, 14.2;


(S)-1-((2R,3R)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-D-leucinate

(ent-II-44)




mL for 24 hours. The crude residue was purified by preparative HPLC to afford ent-II-44 (68.2



= +17.3 (CHCl3, c = 1.10); IR

(neat) 3349, 2926, 2855, 1823, 1725, 1521, 1467, 1336, 1265, 1221, 1199, 1122, 1049 cm-1

; 1H

NMR (400 MHz, CDCl3) δ 7.38–7.30 (m, 5H), 5.12 (d, J = 8.4 Hz, 1H), 5.11 (s, 2H), 5.05–5.00

(m, 1H), 4.36–4.29 (m, 2H), 3.21 (ddd, J = 7.2, 7.2, 4.0 Hz, 1H), 2.08–1.99 (m, 2H), 1.83–1.68

(m, 3H), 1.64–1.49 (m, 4H), 1.48–1.42 (m, 1H), 1.39–1.24 (m, 25H), 0.97–0.95 (m, 6H), 0.89–

0.86 (m, 6H); 13

C NMR (100 MHz, CDCl3) δ 173.1, 171.2, 156.2, 136.4, 128.7, 128.4, 128.2,

74.5, 72.4, 67.2, 56.9, 52.9, 41.9, 39.5, 34.4, 32.1, 31.7, 29.80, 29.68, 29.64, 29.52, 29.46, 29.1,


C36H59NO6Na [M Na]+: 624.4235, found 624.4250.

163

(R)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl ((benzyloxy)carbonyl)-L-leucinate

(II-44)

To a stirred solution of II-4b (18.0 mg, 50.8 µmol) in tetrahydrofuran (0.5 mL) at 0 °C was


under N2. A solution of diisopropyl azodicarboxylate (33 µL, 152 µmol) in tetrahydrofuran (0.5

mL) was added slowly via syringe. The resulting mixture was stirred at the same temperature for

0.5 h. The reaction was quenched by adding water (5 mL), and extracted with EtOAc (3 × 10



chromatography (5 to 15% EtOAc in hexanes) on silica gel (10 mL) to afford II-44 (22.0 mg,



= –26.2 (CHCl3, c = 0.51); IR (neat)

3356, 2926, 2855, 1823, 1720, 1523, 1467, 1335, 1263, 1221, 1198, 1171, 1121, 1050 cm-1

; 1H

NMR (500 MHz, CDCl3) δ 7.38–7.30 (m, 5H), 5.12 (d, J = 8.5 Hz, 1H), 5.10 (s, 2H), 5.05–5.00

(m, 1H), 4.36–4.29 (m, 2H), 3.21 (ddd, J = 8.0, 8.0, 4.0 Hz, 1H), 2.08–1.99 (m, 2H), 1.83–1.68

(m, 3H), 1.63–1.49 (m, 4H), 1.48–1.42 (m, 1H), 1.39–1.24 (m, 25H), 0.97–0.95 (m, 6H), 0.89–

0.86 (m, 6H); 13

C NMR (100 MHz, CDCl3) δ 173.1, 171.2, 156.2, 136.4, 128.7, 128.4, 128.2,

74.5, 72.4, 67.2, 56.9,, 52.9, 41.9, 39.5, 34.4, 32.1, 31.7, 29.81, 29.69, 29.64, 29.52, 29.47, 29.2,


C36H59NO6Na [M Na]+: 624.4235, found 624.4216.

164

Thermolysis of II-40 and II-40a

To a resealed tube was added β-lactone II-40 and II-40a (as a 2:1 mixture, 5.6 mg, 11.3 µmol).

The tube was sealed under Ar, and heated to 230 °C for 1 h. The crude residue was purified by

flash chromatography (30% EtOAc in hexanes) on silica gel (3 mL) to afford II-45 (2.6 mg,


Data for II-45: 1H NMR (500 MHz, CDCl3) 8.21 (s, 1H), 5.94 (d, J = 8.5 Hz, 1H), 5.47 (ddd, J =

15.0, 7.0, 7.0 Hz, 1H), 5.31 (ddd, J = 15.0, 7.0, 7.0 Hz, 1H); 4.88 (ddd, J = 13.0, 6.5, 6.5 Hz,

1H), 4.70 (ddd, J = 8.5, 8.5, 5.0 Hz), 2.30–2.21 (m, 2H), 1.99–1.95 (m, 2H), 1.72–1.63 (m, 2H),

1.57–1.51 (m, 3H), 1.33–1.24 (m, 26H), 0.97 (d, J = 6.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.89–

0.86 (m, 6H); 13

C NMR (100 MHz, CDCl3) δ 172.4, 160.5, 134.6, 124.5, 75.8, 49.8, 42.3, 37.4,

33.4, 32.8, 32.1, 31.9, 29.83, 29.73, 29.69, 29.54, 29.0, 25.4, 25.1, 23.0, 22.88, 22.84, 22.2,

14.30, 14.28. (For complete characterization see below)

(R,E)-Henicos-7-en-10-yl formyl-L-leucinate (II-45)

To a stirred solution of II-46 (49.0 mg, 158 µmol) in tetrahydrofuran (1 mL) at 0 °C was added

triphenylphosphine (82.9 mg, 316 µmol) and N-formyl-L-Leu-OH (50.3 mg, 316 µmol) under

N2. A solution of diisopropyl azodicarboxylate (71 µL, 316 µmol) in tetrahydrofuran (1 mL) was

added slowly via syringe. The resulting mixture was stirred at the same temperature for 2 h. The

165

reaction was quenched by adding water (5 mL), and extracted with EtOAc (3 × 10 mL). The



to 15% EtOAc in hexanes) on silica gel (15 mL) to afford II-45 (49.0 mg, 69%) as a colorless

oil.


= +4.0 (CHCl3, c = 1.35); IR (neat)

3293, 2925, 2855, 1739, 1666, 1530, 1467, 1380, 1273, 1252, 1195, 1144 cm-1

; 1H NMR (400

MHz, CDCl3) 8.20 (s, 1H), 6.05 (d, J = 8.8 Hz, 1H), 5.46 (ddd, J = 13.6, 6.8, 6.8 Hz, 1H), 5.30


Hz, 1H); 2.62–2.63 (m, 2H), 2.02–1.94 (m, 2H), 1.71–1.61 (m, 2H), 1.59–1.49 (m, 3H), 1.35–

1.24 (m, 26H), 0.97–0.93 (m, 6H), 0.89–0.85(m, 6H); 13

C NMR (100 MHz, CDCl3) δ 172.4,

160.6, 134.6, 124.4, 75.8, 49.8, 42.3, 37.4, 33.3, 32.7, 32.1, 31.9, 29.80, 29.70, 29.66, 29.55,

29.51, 29.0, 25.4, 25.0, 23.0, 22.9, 22.8, 22.2, 14.3; MALDI-TOF/CCA-HRMS C28H53NO3Na

[M Na]+: 474.3918, found 474.3916.

(S,E)-Henicos-7-en-10-ol (II-46)

To a stirred solution of II-7a (1.37 g, 6.05 mmol) in dichloromethane at room temperature was

added 1-octene (2.18 g, 19.5 mmol), followed by the Grubbs second-generation catalyst26

(275

mg, 0.32 mmol) under N2. The resulting mixture was degassed by two freeze−pump−thaw

cycles, and then heated to reflux. After 7.5 h, the mixture was concentrated, and the crude


mL) to afford II-46 (1.10 g, 59%, E:Z = 6:1) as a colorless oil.

166


= –3.0 (CH2Cl2, c = 0.93); IR (neat) 3396,

2924, 2854, 1719, 1466, 1378, 1263, 1072 cm-1

; 1H NMR (400 MHz, CDCl3) δ 5.54 (ddd, J =

13.6, 6.8, 6.8 Hz, 1H), 5.40 (ddd, J = 13.6, 6.8, 6.8 Hz, 1H), 3.62–3.54 (m, 1H), 2.26–2.19 (m,

1H), 2.08–1.99 (m, 3H), 1.47–1.40 (m, 3H), 1.36–1.24 (m, 25H), 0.89–0.86 (m, 6H); 13

C NMR

(100 MHz, CDCl3) δ 135.0, 126.0, 71.1, 40.9, 36.9, 32.9, 32.1, 31.9, 29.88, 29.86, 29.81, 29.6,

29.5, 29.0, 25.9, 22.9, 22.8, 14.32, 14.30; HRMS (EI) calcd for C21H42O [M]+: 310.3236, found

310.3245.

(R,Z)-Henicos-7-en-10-yl formyl-L-leucinate (II-47)

To a stirred solution of II-7b (32.4 mg, 104 µmol) in tetrahydrofuran (0.5 mL) at 0 °C was added

triphenylphosphine (54.8 mg, 209 µmol) and N-formyl-L-Leu-OH (33.2 mg, 209 µmol) under

N2. A solution of diisopropyl azodicarboxylate (44 µL, 209 µmol) in tetrahydrofuran (0.5 mL)

was added slowly via syringe. The resulting mixture was stirred at the same temperature for 2 h.

The reaction was quenched by adding water (5 mL), and extracted with EtOAc (3 × 10 mL). The



to 20% EtOAc in hexanes) on silica gel (15 mL) to afford II-47 (41.2 mg, 87%) as a colorless

oil.


= +12.8 (CHCl3, c = 1.26); IR (neat)

3293, 2925, 2855, 1739, 1667, 1530, 1467, 1380, 1332, 1273, 1252, 1195, 1144 cm-1

; 1H NMR

(400 MHz, CDCl3) 8.20 (s, 1H), 6.02 (d, J = 8.0 Hz, 1H), 5.52–5.45 (m, 1H), 5.33–5.26 (m, 1H),

167


2.04–1.99 (m, 2H), 1.74–1.62 (m, 2H), 1.58–1.51 (m, 3H), 1.34–1.24 (m, 26H), 0.97–0.93 (m,

6H), 0.89–0.86 (m, 6H); 13

C NMR (100 MHz, CDCl3) δ 172.5, 160.6, 133.3, 123.7, 75.9, 49.8,

42.3, 33.5, 32.1, 31.9, 29.8, 29.71, 29.68, 29.57, 29.52, 29.2, 27.6, 25.5, 25.0, 23.0, 22.9, 22.86,

22.81, 22.2, 14.3; MALDI-TOF/CCA-HRMS C28H53NO3Na [M Na]+: 474.3918, found

474.3903.

168

172.4 172.4 172.5

160.6 160.5 160.6

134.6 134.6 133.3

124.4 124.5 123.7

75.8 75.8 75.9

49.8 49.8 49.8

42.3 42.3 42.3

37.4 37.4 33.5

33.3 33.4 32.1

32.7 32.8 31.9

32.1 32.1

31.9 31.9

29.80–29.51 29.83–29.54 29.80–29.52

29.0 29.0 29.2

27.6

25.4 25.4 25.5

25.0 25.1 25.0

23.0 23.0 23.0

22.9

22.9 22.88 22.86

22.8 22.84 22.81

22.2 22.2 22.2

14.30 14.30 14.30

14.28 14.28 14.28

Table S12. 13

C NMR comparison of II-45 and II-47.

169

(R)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-yl formyl-D-leucinate (ent-II-26)

(R)-1-((2R,3S)-3-Hexyloxiran-2-yl)tridecan-2-yl formyl-L-leucinate (ent-II-27)

To a stirred solution of ent-II-23 (0.351 g, 1.08 mmol) in dichloromethane (2 mL) at room

temperature was added N-formyl-L-Leu-OH (0.189 g, 1.19 mmol), followed by N,N-

dicyclohexyl carbodiimide (0.443 g, 2.16 mmol) and 4-dimethylaminopyridine (5 mg). The




hexanes) on silica gel (40 mL) to afford a mixture of ent-II-26 and ent-II-27 (0.42 g, 86%) as a

colorless oil. The product contained two isomers ent-II-26 and ent-II-27, which were separated

by HPLC for characterization.


= +15.6 (CHCl3, c = 0.42); IR

(neat) 3296, 2926, 2857, 1739, 1670, 1523, 1462, 1380, 1251, 1195 cm-1

; 1H NMR (500 MHz,

CDCl3) δ 8.21 (s, 1H), 6.07 (d, J = 9.0 Hz, 1H), 5.10 (dddd, J = 8.0, 8.0, 5.0, 4.5 Hz, 1H), 4.72


Hz, 1H), 1.87 (ddd, J = 14.5, 4.5, 4.5 Hz, 1H), 1.75–1.55 (m, 5H), 1.53–1.39 (m, 4H), 1.36–1.24

(m, 25H), 0.96 (d, J = 6.0 Hz, 3H), 0.95 (d, J = 6.0 Hz, 3H), 0.890 (t, J = 6.5 Hz, 3H), 0.876 (t, J

= 6.5 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 172.2, 160.8, 74.4, 56.4, 53.8, 49.9, 41.9, 34.3,

32.8, 32.1, 31.9, 29.81, 29.76, 29.66, 29.55, 29.54, 29.4, 28.1, 26.7, 25.4, 25.1, 23.0, 22.9, 22.8,

22.1, 14.3, 14.2; HRMS (ESI) calcd for C28H53NO4Na [M Na]+: 490.3867, found 490.3849.

170


= –2.2 (CHCl3, c = 0.54); IR (neat)

3290, 2926, 2857, 1739, 1670, 1523, 1462, 1380, 1269, 1193 cm-1


δ 8.21 (s, 1H), 6.04 (d, J = 8.5 Hz, 1H), 5.09 (dddd, J = 7.5, 7.5, 5.0, 5.0 Hz, 1H), 4.73 (ddd, J =

8.5, 8.5, 5.0 Hz, 1H), 2.98 (ddd, J = 8.0, 4.0, 4.0 Hz, 1H), 2.90–2.87 (m, 1H), 1.88 (ddd, J =

14.5, 4.5, 4.5 Hz, 1H), 1.74–1.54 (m, 5H), 1.50–1.40 (m, 4H), 1.38–1.24 (m, 25H), 0.96 (d, J =

6.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.887 (t, J = 7.0 Hz, 3H), 0.875 (t, J = 7.0 Hz, 3H); 13

C

NMR (100 MHz, CDCl3) δ 172.4, 160.7, 74.3, 56.4, 53.6, 49.7, 42.0, 34.0, 32.6, 32.1, 31.9,

29.81, 29.72, 29.66, 29.53, 29.47, 29.4, 28.1, 26.7, 25.5, 25.0, 23.1, 22.9, 22.8, 22.1, 14.30,

14.25; HRMS (ESI) calcd for C28H53NO4Na [M Na]+: 490.3867, found 490.3867.

171

Chapter 3. Total Synthesis of EBC-23

Tetradecanal (III-13)

To a stirred suspension of sulfur trioxide pyridine complex (107 g, 0.670 mol) in

dichloromethane/dimethyl sulfoxide (4:1, 500 mL) at 0 °C was added triethylamine (93.4 ml,

0.670 mol). After 15 min, a solution of 1-tetradecanol (50.0 g, 0.233 mol) in dichloromethane

(100 mL) was added to the mixture slowly via syringe. After 1 h at the same temperature, the

reaction was quenched by adding water, and extracted with dichloromethane (3 × 150 mL). The



to 5% EtOAc in hexanes) on silica gel (500 mL) t-o afford III-13 (43.9 g, 89%) as a colorless

oil.

Data for III-13: Rf = 0.39 (10% Et2O in Hexanes); IR (neat) 2953, 2915, 2850, 2715, 1728,

1471, 1411 cm-1

; 1H NMR (500 MHz, CDCl3) δ 9.75 (t, J = 1.5 Hz, 1H), 2.41 (td, J = 7.5, 2.0

Hz, 2H), 1.65–1.59 (m, 2H), 1.32–1.24 (m, 20H), 0.87 (t, J = 7.0 Hz, 3H); 13

C NMR (100 MHz,

CDCl3) δ 203.2, 44.1, 32.1, 29.84, 29.82, 29.76, 29.60, 29.54, 29.3, 22.9, 22.2, 14.3.76

1-((2S,4S,6S)-2-Phenyl-6-tridecyl-1,3-dioxan-4-yl)propan-2-one (III-16)

To a stirred solution of III-23 (0.776 g, 1.73 mmol) in tetrahydrofuran (5 mL) at –10 °C was

added a solution of methylmagnesium bromide (3 M, 0.87 mL, 2.60 mmol) in tetrahydrofuran

via syringe slowly under N2. The resulting mixture was stirred at the same temperature for 0.5 h.

172

The reaction was quenched by adding saturated aqueous ammonium chloride (20 mL) and




III-16 (0.558 g, 80%) as a white solid.

Data for III-16: Rf = 0.26 (10% EtOAc in Hexanes); mp: 47–48 °C; [α]D22

= –3.3 (CHCl3, c =

3.4); IR (neat) 2914, 2849, 1724, 1692, 1470, 1452, 1404, 1344, 1137, 1123, 1098, 1056, 1019

cm-1

; 1H NMR (500 MHz, CDCl3) δ 7.49–7.47 (m, 2H), 7.37–7.29 (m, 3H), 5.55 (s, 1H), 4.32

(dddd, J = 9.5, 8.0, 6.0, 2.5 Hz, 1H), 3.84 (dddd, J = 10.0, 7.5, 5.0, 2.5 Hz, 1H), 2.87 (dd, J =

16.0, 7.0 Hz, 1H), 2.56 (dd, J = 16.0, 6.0 Hz, 1H), 2.21 (s, 3H), 1.69 (ddd, J = 13.5, 2.5, 2.5 Hz,

1H), 1.70–1.63 (m, 1H), 1.55–1.44 (m, 2H), 1.42–1.35 (m, 2H), 1.32–1.25 (m, 20H), 0.89 (t, J =

7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 206.9, 138.7, 128.7, 128.3, 126.1, 100.7, 76.9, 73.2,

49.7, 36.9, 36.0, 32.1, 31.4, 29.81, 29.76, 29.73, 29.5, 25.2, 22.8, 14.3; MALDI-TOF/CCA-


(S)-Heptadec-1-en-4-ol (III-18)

To a stirred solution of III-13 (18.5 g, 87.1 mmol) in dichloromethane (150 mL) at 0 °C was

added a solution of (S,S)-Leighton reagent (58.3 g, 105 mmol) in dichloromethane (50 mL) via

syringe, followed by followed by scandium triflate (1.07 mg, 2.18 mmol) under N2. The resulting

mixture was stirred at the same temperature for 20 h. The reaction was quenched by adding 1 N

hydrochloric acid (100 mL). The formed solid was filtered through a fritted funnel, and the

173

filtrate was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with


residue was purified by flash chromatography (2.5 to 10% EtOAc in hexanes) on silica gel (250

mL) to afford III-18 (16.1 g, 73%) as a white solid.


= –4.0 (CHCl3, c =

0.61); IR (neat) 3331, 2955, 2922, 2851, 1642, 1470, 1341, 1264, 1070 cm-1

; 1H NMR (500

MHz, CDCl3) δ 5.87–5.79 (m, 1H), 5.14–5.11 (m, 2H), 3.66–3.61 (m, 1H), 2.32–2.27 (m, 1H),

2.16–2.10 (m, 1H), 1.64–1.58 (m, 1H), 1.48–1.42 (m, 3H), 1.32–1.22 (m, 20H), 0.88 (t, J = 7.0

Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 135.1, 118.3, 70.8, 42.1, 37.0, 32.1, 29.85, 29.80, 29.6,

25.9, 22.9, 14.3.77

Methyl (S)-3-(furan-2-yl)-3-hydroxypropanoate (III-19)

To a stirred suspension of III-24 (111 mg, 0.660 mol) in water (400 mL) at room temperature

was added sodium formate (449 g, 6.60 mol), followed by cetyl trimethylammonium bromide

(24.1 g, 66.0 mmol) and (S)-RuCl[(1S,2S)-p-TsNCH(C6H5)CH(C6H5)NH2](η6-mesitylene) (1.02

g, 1.65 mmol). The mixture was stirred at the same temperature for 3 d. The mixture was




III-19 (112 g, 99%) as a pale yellow oil.

Data for III-19: Rf = 0.35 (40% EtOAc in Hexanes); [α]D22

= –30.5 (CHCl3, c = 2.72); IR (neat)

3447, 2955, 1734, 1505, 1439, 1363, 1286, 1213, 1266, 1066, 1032, 1012 cm-1

; 1H NMR (500

174

MHz, CDCl3) δ 7.36 (d, J = 1.5 Hz, 1H), 6.32 (dd, J = 3.5, 2.0 Hz, 1H), 6.26 (d, J = 3.5 Hz, 1H),

5.13 (dd, J = 8.5, 4.0 Hz, 1H), 3.71 (s, 3H), 3.08 (br s, 1H), 2.89 (dd, J = 16.0, 8.0 Hz, 1H), 2.82

(dd, J = 16.0, 4.0 Hz, 1H); 13

C NMR (100 MHz, CDCl3) δ 172.5, 154.8, 142.4, 110.4, 106.5,

64.2, 52.1, 39.7.78

Ethyl (S,E)-5-hydroxyoctadec-2-enoate (III-21)

To a stirred solution of III-18 (14.6 g, 57.3 mmol) in dichloromethane (20 mL) at room

temperature was added ethyl acrylate (123 mL, 1.15 mol), followed by the Grubbs second-

generation catalyst (486 mg, 0.573 mmol) under N2. The resulting mixture was degassed by two

freeze−pump−thaw cycles, then warmed to room temperature and stirred at the same

temperature. After 16 h, the mixture was diluted with hexanes (400 mL), and purified by flash

chromatography (2.5 to 20% EtOAc in hexanes) on silica gel (400 mL) to afford III-21 (11.7 g,



= +2.5 (CHCl3, c =

1.01); IR (neat) 3404, 2955, 2918, 2849, 1723, 1695, 1655, 1472, 1369, 1332, 1319, 1177, 1072

cm-1

; 1H NMR (500 MHz, CDCl3) δ 6.97 (ddd, J = 15.0, 7.5, 7.5 Hz, 1H), 5.90 (ddd, J = 15.0,

1.5, 1.5 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 3.75 (dddd, J = 7.5, 7.5, 5.0, 5.0 Hz, 1H), 2.40 (dddd,

J = 14.0, 7.0, 4.5, 1.5 Hz, 1H), 2.31 (dddd, J = 14.0, 8.0, 8.0, 1.5 Hz, 1H), 1.65 (s, 1H), 1.50–

1.39 (m, 4H), 1.33–1.22 (m, 20H), 1.28 (t, J = 7.0 Hz, 3H), 0.87 (t, J = 7.0 Hz, 3H); 13

C NMR

(100 MHz, CDCl3) δ 166.5, 145.4, 124.0, 70.8, 60.5, 40.4, 37.3, 32.1, 29.86, 29.83, 29.82, 29.76,

29.73, 29.53, 25.8, 22.9, 14.4, 14.3; MALDI-TOF/CCA-HRMS calcd for C20H38O3Na [M

Na]+: 349.2713, found 349.2703.

175

Ethyl 2-((2S,4S,6S)-2-phenyl-6-tridecyl-1,3-dioxan-4-yl)acetate (III-22)

To a stirred solution of III-21 (1.22 g, 3.74 mmol) in tetrahydrofuran (10 mL) at 0 °C was added

benzaldehyde (0.38 mL, 3.73 mmol), followed by potassium tert-butoxide (42.0 mg, 0.373

mmol) under N2. The resulting mixture was stirred for 15 min. Then the addition of

benzaldehyde/ potassium tert-butoxide was repeated two more times. The mixture was passed

through a pad of silica gel, and the silica gel was washed with EtOAc (30 mL). The filtrate was

concentrated, and the crude residue was purified by flash chromatography (5% EtOAc in

hexanes) on silica gel (80 mL) to afford III-22 (0.936 g, 58%) as a white solid.

Data for III-22: Rf = 0.33 (10% Et2O in Hexanes); mp: 38–40 °C; [α]D23

= –5.2 (CHCl3, c =

3.31); IR (neat) 2925, 2854, 1738, 1466, 1456, 1372, 1346, 1177, 1149, 1114, 1028 cm-1

;

1H NMR (500 MHz, CDCl3) δ 7.51–7.48 (m, 2H), 7.37–7.30 (m, 3H), 5.56 (s, 1H), 4.31 (dddd, J

= 11.0, 6.5, 6.5, 2.5 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 3.84 (dddd, J = 11.0, 7.0, 5.0, 2.0 Hz, 1H),

2.73 (dd, J = 15.5, 7.0 Hz, 1H), 2.51 (dd, J = 15.5, 6.0 Hz, 1H), 1.73 (ddd, J = 13.0, 2.5, 2.5 Hz,

1H), 1.72–1.64 (m, 1H), 1.56–1.38 (m, 4H), 1.33–1.26 (m, 23H), 0.90 (t, J = 7.0 Hz, 3H);

13C NMR (100 MHz, CDCl3) δ 171.0, 138.8, 128.7, 128.3, 126.2, 100.7, 73.4, 60.7, 41.2, 36.7,


C27H44O4Na [M Na]+: 455.3132, found 455.3162.

176

N-methoxy-N-methyl-2-((2S,4S,6S)-2-phenyl-6-tridecyl-1,3-dioxan-4-yl)acetamide (III-23)

To a stirred solution of III-22 (1.85 g, 4.42 mmol) in tetrahydrofuran (16 mL) at –10 °C was

added N,O-dimethylhydroxylamine hydrochloride (0.647 g, 6.63 mmo), followed by a solution

of isopropylmagnesium chloride in tetrahyrofuran (2 M, 6.65 mL, 13.3 mmol) via syringer

slowly under N2. The resulting mixture was stirred at the same temperature for 30 min. The

reaction was quenched by adding saturated aqueous ammonium chloride (20 mL) and extracted




III-23 (1.60 g, 81%) as a colorless oil.


= –16.3 (CHCl3, c = 1.36); IR (neat)

2924, 2853, 1667, 1458, 1388, 1342, 1117, 1027 cm-1

; 1H NMR (500 MHz, CDCl3) δ 7.50–7.48

(m, 2H), 7.37–7.28 (m, 3H), 5.57 (s, 1H), 4.38 (dddd, J = 11.0, 7.0, 7.0, 2.5 Hz, 1H), 3.85 (dddd,

J = 11.0, 7.0, 5.0, 2.0 Hz, 1H), 3.67 (s, 3H), 3.20 (s, 3H), 2.98 (dd, J = 15.5, 6.0 Hz, 1H), 2.55

(dd, J = 15.5, 6.0 Hz, 1H), 1.80 (ddd, J = 13.0, 2.5, 2.5 Hz, 1H), 1.71–1.65 (m, 1H), 1.55–1.36

(m, 4H), 1.34–1.24 (m, 20H), 0.88 (t, J = 7.0 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 171.6,

138.9, 128.7, 128.3, 126.3, 100.8, 76.9, 73.7, 61.6, 38.4, 37.1, 36.1, 32.1, 29.85, 29.79, 29.76,

29.5, 25.2, 22.9, 14.3; MALDI-TOF/CCA-HRMS calcd for C27H45O4NNa [M Na]+: 470.3241,

found 470.3250.

177

Methyl 3-(furan-2-yl)-3-oxopropanoate (III-24)

To a flask with oil-free sodium hydride (83.5 g, 2.09 mol) was added tetrahydrofuran (600 mL)

followed by dimethyl carbonate (141 g, 1.67 mol) and potassium hydride (2.05 g, 50.0 mmol).

The mixture was heated to reflux. A solution of 2-acetylfuran II-20 (83.6 mL, 0.835 mol) in

tetrahydrofuran (200 mL) was added slowly via syringe. After addition, the reflux was continued

for 40 min. The reaction was quenched by pouring into a cooled mixture of acetic acid/water

(1:2, 500 mL) slowly. The mixture was extracted with EtOAc/hexanes (1:1, 3 × 200 mL). The


concentrated under reduced pressure. The crude residue was purified by flash chromatography

(10 to 40% EtOAc in hexanes) on silica gel (600 mL) to afford III-24 (120.8 g, 84%) as a pale

yellow oil.

Data for III-24: Rf = 0.33 (30% EtOAc in Hexanes); IR (neat) 2956, 2922, 2851, 1740, 1677,

1568, 1465, 1438, 1283, 1167, 1016 cm-1

; 1H NMR (500 MHz, CDCl3) δ 7.61 (dd, J = 2.0, 1.0

Hz, 1H), 7.28 (dd, J = 4.0, 0.5 Hz, 1H), 6.58 (dd, J = 3.5, 1.5 Hz, 1H), 3.86 (s, 2H), 3.74 (s, 3H);

13C NMR (100 MHz, CDCl3) δ 181.1, 167.6, 152.0, 147.3, 118.6, 112.9, 52.7, 45.3.

64,65

Methyl 2-((2S)-6-hydroxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)acetate (III-25)

To a stirred solution of III-19 (5.30 g, 31.1 mmol) in tetrahydrofuran/water at 0 °C (4:1, 60 mL)

was added sodium bicarbonate (5.23 g, 62.3 mmol) and sodium acetate trihydrate (4.24 g, 31.1

178

mmol). Then N-bromosuccinimide (5.54 g, 31.1 mmol) was added in portions to the mixture.

After 30 min, the reaction was quenched by adding saturated aqueous solution of sodium

bicarbonate and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed


crude residue was used directly for next step.


= –8.0 (CHCl3, c = 0.80); IR (neat)

3429, 2956, 1740, 1698, 1440, 1371, 1293, 1231, 1175, 1092, 1033 cm-1

; 1H NMR (500 MHz,

CDCl3) δ 6.91 (dd, J = 10.0, 3.5 Hz, 1H), 6.14 (d, J = 10.0 Hz, 1H), 5.63 (d, J = 3.5 Hz, 1H),

5.02 (dd, J = 7.5, 4.0 Hz, 1H), 3.70 (s, 3H), 3.01 (dd, J = 16.5, 3.5 Hz, 1H), 2.74 (dd, J = 16.5,

7.5 Hz, 1H); 13

C NMR (100 MHz, CDCl3) δ 195.0, 171.6, 144.7, 127.3, 87.9, 70.9, 52.2, 35.2;

MALDI-TOF/CCA-HRMS calcd for C8H10O3Na [M Na]+: 209.0420, found 209.0408.

Methyl (S)-2-(3,6-dioxo-3,6-dihydro-2H-pyran-2-yl)acetate (III-26)

To a stirred solution of III-25 (5.80 g, 31.1 mmol) in acetone (70 mL) at 0 °C was added Jones

reagent (2.5 M, 18.7 mL, 46.7 mmol) slowly via syringe. The resulting mixture was stirred at the

same temperature for 15 min. The reaction was quenched by adding isopropanol slowly and

filtered through Celite. The filtrate was extracted with EtOAc (3 × 80 mL). The combined


under reduced pressure. The crude residue was used directly for next step.


= –41.5 (CHCl3, c = 1.67); IR (neat)

3437, 3071, 2958, 1731, 1622, 1440, 1372, 1265, 1212, 1112 cm-1


179

δ 6.93 (d, J = 12.0 Hz, 1H), 6.85 (d, J = 12.0 Hz, 1H), 5.14 (t, J = 4.0 Hz, 1H), 3.70 (s, 3H), 3.25

(dd, J = 17.5, 4.5 Hz, 1H), 3.08 (dd, J = 17.5, 4.5 Hz, 1H); 13

C NMR (100 MHz, CDCl3) δ 191.9,

169.8, 160.2, 138.4, 135.5, 79.5, 52.5, 37.5; MALDI-TOF/CCA-HRMS calcd for C8H8O5Na [M

Na]+: 207.0264, found 207.0249.

Methyl 2-((2S,3R)-3-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)acetate (III-27)

To a stirred solution of III-26 (5.73 g, 31.1 mmol) in a mixed solvent of

dichloromethane/methanol (1:1, 100 mL) at –78 °C was added sodium boronhydride (1.77 g,

46.7 mmol). The resulting mixture was stirred at the temperature for 30 s. The reaction was

quenched by adding water (50 mL) and 1 N hydrochloride acid (50 mL) and extracted with



flash chromatography (30 to 80% EtOAc in hexanes) on silica gel (80 mL) to afford III-25 (2.16

g, 51%) as a white solid.


= –52.2 (MeOH, c

= 0.67); IR (neat) 3435, 2956, 2926, 1735, 1440, 1378, 1334, 1228, 1155, 1082, 1039 cm-1

;

1H NMR (500 MHz, CDCl3) δ 6.86 (dd, J = 10.0, 2.0 Hz, 1H), 5.99 (dd, J = 10.0, 2.0 Hz, 1H),

4.65 (ddd, J = 10.0, 6.0, 6.0 Hz, 1H), 4.51 (ddd, J = 8.0, 2.0, 2.0 Hz, 1H), 3.75 (s, 3H), 2.98 (br s,

1H), 2.93 (dd, J = 16.0, 5.5 Hz, 1H), 2.86 (dd, J = 16.0, 6.5 Hz, 1H); 13

C NMR (100 MHz,

CDCl3) δ 171.1, 162.6, 149.5, 120.3, 78.4, 66.3, 52.6, 37.6; MALDI-TOF/CCA-HRMS calcd for

C8H10O5Na [M Na]+: 209.0420, found 206.0407.

180

(2S,3S)-2-(2-Methoxy-2-oxoethyl)-6-oxo-3,6-dihydro-2H-pyran-3-yl 4-nitrobenzoate (III-

28)

To a stirred solution of III-27 (1.96 g, 10.6 mmol) in tetrahydrofuran (40 mL) at 0 °C was added

triphenylphosphine (5.71 g, 21.7 mmol) and 4-nitrobenzoic acid (3.55 g, 21.3 mmol) under N2. A

solution of diisopropyl azodicarboxylate (4.58 g, 21.3 mmol) in tetrahydrofuran (10 mL) was

added slowly via syringe. The resulting mixture was stirred at the same temperature for 1.5 h.





III-28 (2.60 g, 74%) as a white solid.


= +281.5 (CHCl3, c

= 1.89); IR (neat) 3114, 3080, 2999, 2956, 2856, 1731, 1609, 1530, 1439, 1343, 1267, 1099,

1014 cm-1

; 1H NMR (500 MHz, CDCl3) δ 8.30 (ddd, J = 8.5, 2.0, 2.0 Hz, 2H), 8.19 (ddd, J = 8.5,

2.0, 2.0 Hz, 2H), 7.13 (ddd, J = 10.0, 6.0 Hz, 1H), 7.32 (d, J = 10.0 Hz, 1H), 5.61 (dd, J = 5.5,

2.5 Hz, 1H), 5.14 (ddd, J = 7.0, 7.0, 2.5 Hz, 1H), 3.71 (s, 3H), 2.98 (dd, J = 16.5, 7.5 Hz, 1H),

2.85 (dd, J = 16.5, 7.0 Hz, 1H); 13

C NMR (100 MHz, CDCl3) δ 169.5, 163.8, 161.9, 151.1,


C15H13O8NNa [M Na]+: 358.0533, found 358.0560.

181

Methyl 2-((2S,3S)-3-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)acetate (III-29)

To a stirred solution of III-28 (2.40 g, 7.16 mml) in methanol/dichloromethane (3:1, 24 mL) at 0

°C was added triethylamine (2.00 mL, 14.3 mmol) in one portion via syringe under N2. The

resulting mixture was warmed to room temperature and stirred for 3 h. The mixture was

concentrated, and the crude residue was purified by flash chromatography (40 to 70% EtOAc in

hexanes) on silica gel (80 mL) to afford III-29 (0.705 g, 53%) as a white solid.


= +11.7 (CHCl3, c = 0.57); IR (neat)

3422, 2955, 1732, 1440, 1384, 1257, 1181, 1092, 1051, 1002 cm-1


δ 7.02 (dd, J = 10.0, 6.0 Hz, 1H), 6.12 (d, J = 10.0 Hz, 1H), 4.83 (ddd, J = 6.5, 6.5, 2.5 Hz, 1H),

4.26 (ddd, J = 9.0, 6.0, 2.5 Hz, 1H), 3.73 (s, 3H), 2.98 (dd, J = 17.0, 7.0 Hz, 1H), 2.92 (dd, J =

17.0, 7.0 Hz, 1H), 2.86 (d, J = 9.5 Hz, 1H); 13

C NMR (100 MHz, CDCl3) δ 170.8, 163.4, 144.4,

122.8, 77.2, 61.5, 52.4, 35.0; MALDI-TOF/CCA-HRMS calcd for C8H10O5Na [M Na]+:

209.0420, found 209.0409.

Methyl 2-((2S,3S)-3-((tert-butyldimethylsilyl)oxy)-6-oxo-3,6-dihydro-2H-pyran-2-yl)acetate

(III-30)

To a stirred solution of III-29 (0.705 g, 3.79 mmol) in dichloromethane (10 mL) at –78 °C was

added 2,6-lutidine (0.50 mL, 5.05 mmol), followed by trimethylsilyl trifluoromethanesulfonate

(0.80 mL, 4.42 mmol). The resulting mixture was stirred at the same temperature for 30 min. The

182

reaction was quenched by adding 1 N hydrochloric acid (50 mL) and extracted with EtOAc (3 ×

30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4,


chromatography (5 to 20% EtOAc in hexanes) on silica gel (70 mL) to afford III-30 (0.480 g,



= +178.2 (CHCl3, c = 1.76); IR

(neat) 2955, 2858, 1731, 1440, 1386, 1327, 1254, 1178, 1061 cm-1


δ 6.84 (dd, J = 9.5, 5.0 Hz, 1H), 6.08 (d, J = 9.5 Hz, 1H), 4.79 (ddd, J = 6.5, 6.5, 3.0 Hz, 1H),

4.33 (dd, J = 5.0, 2.5 Hz, 1H), 3.71 (s, 3H), 2.88 (dd, J = 17.0, 7.5 Hz, 1H), 2.84 (dd, J = 17.0,

6.5 Hz, 1H), 0.86 (s, 9H), 0.066 (s, 3H), 0.056 (s, 3H); 13

C NMR (100 MHz, CDCl3) δ 170.6,

162.9, 144.4, 122.5, 77.2, 61.9, 52.1, 34.8, 25.7, 18.1, –4.0, –4.9; MALDI-TOF/CCA-HRMS

calcd for C14H24O5NaSi [M Na]+: 323.1285, found 323.1270.

2-((2S,3S)-3-((tert-Butyldimethylsilyl)oxy)-6-oxo-3,6-dihydro-2H-pyran-2-yl)acetic acid

(III-31)

To a stirred solution of III-30 (115 mg, 0.383 mmol) in tetrahydrofuran/water (4:1, 5 mL) at 0

°C was added lithium hydroxide monohydrate (32.0 mg, 0.766 mmol) in one portion. The

resulting mixture was stirred at the same temperature for 5 min. The reaction was quenched by

adding 1 N hydrochloric acid (1 mL) and extracted with EtOAc (3 × 10 mL). The combined


183


EtOAc in hexanes) on silica gel (20 mL) to afford III-31 (82.0 mg, 75%) as a white solid.

Data for III-31: Rf = 0.29 (1% isopropanol in EtOAc); [α]D22

= +170.9 (CHCl3, c = 0.55);

IR (neat) 3034, 2936, 1742, 1709, 1432, 1255, 1194, 1069, 1098, 1033 cm-1

; 1H NMR (500

MHz, CDCl3) δ 6.50 (dd, J = 12.0, 7.0 Hz, 1H), 6.06 (dd, J = 12.0, 1.0 Hz, 1H), 5.84 (ddd, J =

6.5, 4.0, 1.5 Hz, 1H), 4.81 (dd, J = 4.5, 4.5 Hz, 1H), 2.80 (dd, J = 17.0, 5.0 Hz, 1H), 2.49 (d, J =

17.0 Hz, 1H), 0.85 (s, 9H), 0.033 (s, 3H), –0.012 (s, 3H); 13

C NMR (100 MHz, CDCl3) δ 175.5,

170.4, 147.7, 121.3, 82.2, 71.1, 39.8, 25.7, 18.1, –4.7, –5.0; MALDI-TOF/CCA-HRMS calcd for

C13H22O5NaSi [M Na]+: 309.1129, found 309.1143.

2-((2S,3R)-3-((tert-Butyldimethylsilyl)oxy)-6-oxo-3,6-dihydro-2H-pyran-2-yl)acetyl chloride

(III-17)

To a stirre solution of III-31 (29.5 mg, 0.103 mmol) in dichloromethane (0.5 mL) at 0 °C was

added 1-chloro-N,N,2-trimethyl-1-propenylamine III-32 (27.4 µL, 0.206 mmol) under N2. The

resulting mixture was warmed to room temperature and stirred for 0.5 h. The mixture was diluted

with dichloromethane, washed with brine, dried with NaSO4, filtered and concentrated under

reduced pressure. The crude reside III-17 was used directly for next step.

184

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