PostDoc Journal Journal of Postdoctoral Research Vol. 3, No. 6, June 2015 www.postdocjournal.com

Novel Bis(indole) Alkaloid Dragmacidin D: Synthetic Quest for the Last 13 Years Debashis Mandal, Ph. D. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA Email: debashismandal@fas.harvard.edu Abstract Dragmacidin D, a bis(indole) alkaloid was isolated from deep water marine sponge in 1992 and 1998. The structural feature consists of two unsymmetrically substituted indole moiety connected through a pyrazinone linker and has a polar aminoimidazole moiety. Due to remarkable structural features and diverse biological properties, dragmacidin D has attracted attention from synthetic community. In this review, the syntheses of dragmacidin D for the last 13 years are briefly summarized. Keywords : Dragmacidin, alkaloid, marine sponge, pyrazinone. Isolation and biological activities

Dragmacidin D, a novel bis(indole) alkaloid, was isolated from a deep-water marine sponge of the genus Spongosorites by Wright and co-workers in 1992.1 Subsequently, Capon and co-workers reported the isolation and structure determination of dragmacidin D from a Spongosorites collected during a trawling operation off the southern coast of Australia in 1998.2 It displays a broad array of biological activity including the growth inhibition of feline leukemia virus, fungal pathogens Cryptococcus neoformans and Candida albicans, and the P388 and A549 tumor cell lines. It is also a selective potent inhibitor of serine-threonine protein phosphatases PP1 and neutral nitric oxide synthase (bNOS) in the presence of inducible NOS (iNOS). The ability of selective bNOS growth inhibition may be useful in a variety of therapeutic areas including the treatment of Alzheimer’s, Parkinson’s, and Huntington’s diseases. Beyond its biological activities, dragmacidin D comprises two differentially substituted indoles connected through a pyrazinone linker and a polar aminoimidazole unit. Due to its unique chemical structure and promising biological activities, it has been selected as a synthetic target by many chemists.

Syntheses of ()-dragamcidin D was reported by Brian M. Stoltz in 2002 using Suzuki–Miyaura

cross-coupling reactions as key reactions,3 by Itami in 2011 using direct C–H coupling reactions5 and synthesis of key intermediate by Sasaki in 2011.6,7 Asymmetric synthesis was reported by Capon and Jia in 2015.8

Brian M. Stoltz (2002)3

Brian M. Stoltz reported the first synthesis of ()-dragmacidin D using halogen-selective Suzuki–Miyaura coupling reactions as key steps. The retrosynthetic sequences for the synthesis of dragmacidin D was using metal catalyzed cross-coupling approach: synthesis of the central bis(indolyl)pyrazine moiety using two sequential palladium catalyzed Suzuki–Miyaura couplings between metalated indole moieties 2, 4 and 5-bromo-2-iodo-3 methoxypyrazine 3. Formation of a polar, unstable aminoimidazole ring was planned at the late stage of the synthesis. Vinyl bromide derivative 5 and nitromethane could be viewed as four-carbon equivalent of the aminoimidazole moiety. The vinyl bromide could be connected to the indole moiety through another Suzuki coupling reaction followed by functionalization with nitromethane and the guanidine moiety would lead to the formation of the aminoimidazole unit (Scheme 1).

Scheme 1. Retrosynthetic planning by Stoltz

The Suzuki–Miyaura coupling approach for the construction of the bis(indolyl)pyrazinone framework of dragmacidin D is discussed below (Scheme 2). Firstly, the coupling partners were synthesized. The synthesis of 3,4,7-trisubstituted indole subunit 12 was commenced with 1-(benzyloxy)-4- bromo-2- nitrobenzene 6. Treatment of 6 with vinyl Grignard reagent gave indole 7 in 33% yield through the Bartoli indole synthesis. SEM protection of the indole nitrogen followed by the treatment with t-BuLi and dioxaborolane 9 produced dioxaborolanated indole 10 in 68% yield. Then Suzuki coupling between dioxaborolanated indole 10 and vinyl bromide 5 furnished coupling product 11 in 83%

yield. Hydrogenation of the terminal olefin of 11 with H2, Pd/C followed by C3-selective bromination, lithiation, treatment with dioxaborolane produced 3,4,7-trisubstituted indole derivative 12 in 66% yield. 5-Bromo-2-iodo-3-methoxypyrazine (3) was synthesized from 5-bromo-3-methoxypyrazin-2-amine (13) by the treatment with HI and NaNO2 in 58% yield. Bromoindole boronic acid derivative 16 was synthesized from 6-bromoindole (14) in three steps with good yield. N-tosyl protection of 6-bromoindole (14) followed by treatment with Hg(OAc)2 generated 15 in 97% yield. Reaction of 15 with BH3·THF/H2O provided bromoindole boronic acid derivative 16 in 85% yield.

NH

N

O

HN

Br

HNHO

NHHN

NH₂OCOCF₃

dragmacidinD(1)

NROR

B(OR)₂

N

N

OMe

I

Br

N

Br(RO)₂B

R

Suzuki–Miyauracoupling

2

3

4OTBS

Br

B(OR)₂

CH₃NO₂

5

Br

NO₂

OBn

Br

OBn

N

R

Bpin

OBn

N

SEM

OBn

N

SEMOBn

N

SEM

TBSO Bpin

MgBr

THF,–40ºC

[33%]

t-BuLi,THF,–78ºC

BO

OOi-Pr

[74%] Br

Pd(PPh₃)₄,Na₂CO₃,

benzene,MeOH,80ºC

[83%]

1.H₂,Pd/C,benzene,RT

2.NBS,THF,RT

3.t-BuLi,9,THF,–78ºC

[66%,3steps]

610

1112

9

5Suzuki–Miyauracoupling

NaH,SEMCl

[92%]

R=H(7)

R=SEM(8)

TBSO

TBSO(pinB–Oi-Pr)

Mandal 89

Scheme 2. Synthesis of Suzuki–Miyaura coupling partners

After completion of the synthesis of Suzuki–Miyaura coupling partners, they were subjected to sequential Suzuki couplings for the formation of bis(indolyl)pyrazine 18. The Suzuki coupling between 5-bromo-2-iodo-3-methozxy pyrazine (3) and 6-bromo-N-tosylindole-3-yl boronic acid

16 proceeded smoothly to give the selective coupling product 17 in 71% yield. The next Suzuki coupling between bromopyrazine 17 and pinacol boronate 12 furnished the desired bis(indolyl)pyrazine 18 in 82% yield.

Scheme 3. Completion of (±)-dragmacidin D synthesis

N

N NH₂

OMeBr N

N I

OMeBr

HI,NaNO₂

H₂O,CH₃CN,50ºC

[58%]13 3

HN

Br

N

Br

N

BrAcOHg (HO)₂B

Ts Ts1.TsCl,KOH,H₂O

Bu₄NHSO₄,toluene

2.Hg(OAc)₂,CH₃CO₂H

H₂O,HClO₄

[97%,2steps]

1.BH₃·THF

2.H₂O

[85%,2steps]14 15 16

N

N I

OMeBr

N

Br(HO)₂B

Ts

+

N

Br

Ts

N

NBr OMe

N

N

OMe

N

NBnO

Br

OTBS

SEM

Ts

OBn

N

SEM

TBSO B OO

+

Pd(PPh₃)₄,MeOH,benzene

Na₂CO₃,H₂O,RT

[71%]

Pd(PPh₃)₄,MeOH,benzene

Na₂CO₃,H₂O,50ºC

[82%]

3 16

17

12

18

Suzuki–Miyauracoupling

N

N

OMe

N

NBnO

SEM

Ts

1.HF·py

[86%,2steps]

N

N

OMe

N

NBnO

SEM

TsO

O₂N

1.Et₃N,CH₃NO₂

[98%,2steps]

N

N

OMe

HN

HNBnO

Br

OO₂N

[99%,2steps]

19 20

HO

2.Dess–Martin[O]

1.KOH,EtOH2.LiBF₄,CH₃CN

thenNaOH,H₂O

Br Br

21

NH

N

O

HN

HNHO

1.SnCl₂·2H₂O,EtOAc

[86%,2steps]

(±)-dragmacidinD(1)

NHHN

NH₂

3.NH₂CN,EtOH,60ºC

thenCF₃CO₂H,H₂O,CH₃CN

[86%]

OCOCF₃

Br

2.TMSI,CH₃CN,50ºC

2.Dess–Martin[O]

90 Journal of Postdoctoral Research June 2015: 87–97

Bis(indolyl)pyrazinone 18 was converted to aldehyde 19 through two step sequence.

Aldehyde 19 was then transformed into -nitroketone 20 using CH3NO2 folowed by Dess–Martin oxidation in 98% yield. Removal of the N-tosyl protecting group using ethanolic KOH followed by LiBF4 promoted hydrolysis of N-SEM

provided 21 in 99% yield. Reduction of the -

nitro to an -amino group using SnCl2 followed by iodotrimethylsilane (TMSI) mediated removal of the O-benzyl and methyl ethers were accomplished in 86% yield. Finally, the

conversion of the -aminoketone to an aminoimidazole moiety by the treatment with NH2CN followed by CF3CO2H led the completion

of ()-dragmacidin D in 86% yield. Itami and Yamaguchi (2011)5

In the first synthesis of ()-dragmacidin D, Stoltz used Pd(0)-catalyzed Suzuki–Miyaura cross-coupling reactions as the key reactions. It can be emphasized that the cross-coupling reaction is one of the most reliable method for the formation of C–C bonds in total synthesis as exemplified by Stoltz’s work. However, several steps are required for the activation of both coupling partners (organometalics and organic halides) prior to cross coupling. Recently, adapting the concept of “cross-coupling” into “direct-coupling” has shed new light in the field of organic synthesis.4 Aiming for a step-

economical synthesis of dragmacidin D, Itami et al have planned to convergently connect its building blocks using direct C–H couplings. The retrosynthetic planning is shown in Scheme 4. Dragmacidin D has a bis(indolyl)pyrazinone unit at its core and a polar aminoimidazole moiety. The aminoimidazole unit is connected to the C4 position through a sp3 carbon bridge. The most direct way to install the two-indole moieties on to the central pyrazinone is C–H/C–H coupling reaction. To enhance the reactivity and to control the regioselectivity in the coupling, it was planned to capitalize on the tautomeric switch between pyrazinone and pyrazine N-oxide. Firstly, connecting the indole derivative 22 with the most acidic C2-carbon of pyrazine N-oxide 23 was planned through an indole–azine C–H/C–H coupling reaction. The installation of 6-bromoindole on the pyrazinone form could be envisioned through an oxidative Friedel–Crafts-type C–H/C–H coupling reaction. This sequence was designed so that the oxidation state of the central pyrazine moiety would remain unaltered throughout the synthesis. On the other hand, the thiophene moiety with an oxygen substituent at C3 position could be envisaged as a four-carbon unit equivalent of the aminoimidazole side chain. Thiophene derivative 25 could be then connected to the indole moiety through a C4-selective thiophene–indole C–H/C–I coupling reaction.

Scheme 4. C–H coupling strategy for the synthesis of dragmacidin D At the outset of the synthesis, the sequential key C–H couplings were planned: the indole–

thiophene C–H/C–X coupling, the indole–azine C–H/C–H coupling, followed by the Friedel–

HN

H

NRO

I

H

S

HC–H/C–Icoupling

C–H/C–Hcoupling

C–H/C–HcouplingRO

NHRH₂N

NH

N⁺

N

Br

O–

NH

N H

H ONH

N

O

HN

HNHO

NHHN

NH₂OCOCF₃

(±)-dragmacidinD(1)

DirectC–Hcouplings

22

23 24

14

25

26

Br

R

Mandal 91

Crafts type C–H/C–H coupling. Synthesis began with the iodoindole derivative 27, which was easily synthesized through a known four steps

from the commercially available 7-(benzyloxy)indole. Final sequence toward dragmacidin D synthesis is shown in Scheme 5.

Scheme 5. Synthesis of ()-dragmacidin D

The iodoindole derivative 27 was treated with the 3-(triisopropylsilyloxy) thiophene 28 in the presence of a catalytic system 10 mol% Pd(OAc)2, 20 mol% P[OCH(CF3)2]3, and 1.0 equiv Ag2CO3 in 1,4-dioxane at 140 ºC to give the desired C4 coupling product 29 in 60% yield. Although 3.0 equiv of thiophene 28 was used but 86% of unreacted thiophene was recovered after the reaction. Removal of the triisopropylsilyl group using Bu4NF/CH3CO2H followed by the treatment with Raney Ni, allowed for concomitant reduction of the thiophene and debenzylation to

afford the corresponding methyl ketone 30 in a one-pot process in 77% yield. Deprotection of N-tosyl group followed by methoxymethyl (MOM) protection delivered the bis-MOM protected indole 31 in 91% yield after two steps. Then the bis-MOM indole was coupled with pyrazine N-oxide in the presence of 10 mol% Pd(OAc)2, and 3.0 equiv AgOAc in 1,4-dioxane at 120 ºC to produce the C3 selective indole–azine C–H/C–H coupling product in 50% yield after one recycle. The low yield in the indole–azine C–H/C–H coupling reaction could be

10mol%Pd(OAc)₂20mol%P[OCH(CF₃)₂]₃

1.0equivAg₂CO₃

1,4-dioxane,140ºC

S(i-Pr)₃SiO

HNBnO

I

Ts

+

b(C4)

NBnO

S(i-Pr)₃SiO

Ts

27(1.0equiv) 28(3.0equiv)29[60%]

C–H/C–Icoupling

2.RaneyNi

[77%onepot] NHO

O

Ts

N⁺

N

O–

HNMOMO

N⁺

NO

O–

MOM

10mol%Pd(OAc)₂3.0equivAgOAc

1,4-dioxane,120ºC

[50%,onerecycle]

C–H/C–Hcoupling

NH

N

O

MOMO

O

N

MOM

H

NH

N

HN

Br

NH

HO

O

[57%,2steps]

50%CF₃SO₃H,Air

HN

Br

HC–H/C–Hcoupling

O

NMOMO

O

MOM

H

30

31233233

34

14

1.Mg(OMe)₂2.MOMCl,NaH

[91%,2steps]

1.Bu₄NF

NH

N

HN

Br

NH

HO

O

Br

O

35

i-Pr₂NEt,TMSOTf

thenNBS;CF₃CO₂H

[73%]

(±)-dragmacidinD

HNNHBoc

NH₂

thenCF₃CO₂H

[51%]

+(CF₃CO₂)₂O

92 Journal of Postdoctoral Research June 2015: 87–97

accounted from the low reactivity of indole 31 at C3 position. The low reactivity of indole 31 at C3 position could be explained on the basis that the C4 ketomethyl moiety sterically and electronically opposed the functionalization at the C3 position of indole. However, the starting materials, indole and pyrazine N-oxide were recovered quantitatively, and can be resubjected for the C–H/C–H coupling reaction to furnish the coupling product in 50% yield. Despite the moderate yield, the reaction produced the coupling product regioselectively. Treatment of the coupling product with trifluoroacetic anhydride furnished the C2-pyrazinone 33. Notably, the ratio of desired pyrazinone 33 over the undesired regioisomeric pyrazinone was 5:1. The Friedel–Crafts type oxidative C–H/C–H coupling reaction between (indolyl)pyrazinone 33 and 6-bromoindole in the presence of CF3SO3H and air at 80 ºC afforded the coupling product bis(indolyl)pyrazinone 34 with concomitant removal of the two MOM groups in 57% yield after two steps. The next aim was to install a polar aminoimidazole moiety to complete the synthesis of dragmacidin D

(Scheme 5). For this purpose, firstly the -

bromination of ketone moiety of 34 gave -bromo ketone 35. Indole 34 was treated with excess of TMSOTf in the presence of i-Pr2NEt to produce the corresponding silyl enol ether. The silyl enol ether was then selectively brominated using N-bromosuccinimide in the presence of

CF3CO2H to provide -bromoketone 35. Finally,

the transformation of a -bromoketone to N-Boc aminoimidazole moiety using (Boc)guanidine followed by CF3CO2H mediated deprotection of

the Boc group led to the completion of ()-dragmacidin D synthesis efficiently and step-economically in a total of 15 synthetic operations. Makoto Sasaki (2008, 2011)6,7

Makoto Sasaki reported the synthesis of the left-hand fragment of dragmacidin D followed by the synthesis of key advanced intermediate toward the synthesis of dragmacidin D using sequential Sonogashira and Suzuki–Miyaura coupling reactions in 2008 followed by 2011.

Scheme 6. Sasaki’s synthetic strategy for dragmacidin D

NH

N

O

HN

HNHO

dragmacidinD

NHHN

NH₂OCOCF₃

Br

NH

N

O

HN

NMeO

NN

SPh

Br

Ts

MOM

NH

N₃

O

HN

NMeO

NN

SPh

Br

Ts

MOM

O

NH₂

NMeO

NN

SPh

Ts

MOM

N₃

Cl O

HN

BrO

NN

SPh

MOMCO₂Et

NHBoc

NMeO

Ts

Br

B(OH)₂HN

MeO

Br

Asymmetrichydrogenation

Staudingercyclization

Oxidation

+

Suzuki–Miyauracoupling

+

Sonogashiracoupling

3637

39

3841 4042

C6"'

Mandal 93

The synthetic strategy is comprised of a final stage asymmetric hydrogenation of the alkene moiety of intermediate 36 for the incorporation of an asymmetric carbon center at C6”’ in dragmacidin D (Scheme 6). The central pyrazinone ring in 36 could be formed via Staudinger/aza-Wittig reaction followed by oxidation of 37. Acylation of azidoamine 39 with oxaacetylchloride 38 could lead to the formation of 37. Azidoamine 39 could be formed via Suzuki coupling between imidazolylboronic acid 40 and indolylvinyl bromide 41, which in turn could be synthesized from 4-bromo-7-methoxy indole through Sonogashira coupling followed by Mannich-type Friedel–Crafts reaction. For the synthesis of advanced intermediate 37, Suzuki–Miyaura coupling partners 40 and 41

were synthesized (Scheme 7). The imidazole nitrogen was protected using methoxymethyl chloride to give the N-MOM imidazole 44 in 99% yield. Treatment of N-MOM imidazole with n-BuLi followed by diphenyldisulfide at –78 ºC produced the phenylsulfide imidazole 45 in 62% yield. Next, reaction of phenylsulfide imidazole with n-BuLi followed by trimethyl borate and acidic work-up furnished imidazole boronic acid derivative 40 in 77% yield. In the synthesis of indolylglycine fragment 46, 4-bromo-7-methoxy-indole (42) was reacted with p-anisidine and ethyl glyoxylate in CH2Cl2 to produce 46 in 83% yield. Tosyl protection of the indole nitrogen followed by removal of the amine protecting group using cerium ammonium nitrate (CAN) furnished amine 48. Then, the free amine group was protected as an N-Boc group using Boc2O.

Scheme 7. Synthesis of Suzuki–Miyaura coupling fragments

94 Journal of Postdoctoral Research June 2015: 87–97

The Sonogashira coupling between 4-bromoindole derivative 49 and ethynyltriisopropylsilane delivered the coupling product 50 in 92% yield. Tetra-butylammonium fluoride-facilitated deprotection of triisopropylsilyl group followed by bromination of the alkyne moiety using HBr·CH3CO2H afforded vinyl bromide 41, the precursor of the subsequent Suzuki–Miyaura coupling reaction. The Suzuki–Miyaura coupling reaction between

vinyl bromide 41 and imidazole boronic acid 40 delivered the coupling product 52 in 61% yield. Then, the carboxylic ester of 52 was reduced to primary alcohol using LiBH4 followed by tosyl protection of alcohol in 61% yield. Replacement of OTs group by azide using NaN3 delivered azide 54. CF3CO2H facilitated N-Boc deprotection followed by condensation with oxaacetylchloride led the synthesis of advanced intermediate 37.

Scheme 8. Synthesis of an advanced intermediate toward the synthesis of dragmacidin D

Asymmetric Synthesis: Capon and Jia (2015)8

During the isolation and structure elucidation of dragmacidin D by Capon and co-workers in 1998,

the optical rotation []D was determined +12º.

However, the absolute stereochemistry at C6”’ of dragmacidin D remained unresolved still 2015. Robert J. Capon and Yanxing Jia reported the first asymmetric total synthesis of (+)-dragmacidin D and established the R absolute configuration at C6’’’. The retrosynthetic analysis comprised: installment of aminoimidazole moiety at the final stage of synthesis from bis(indolyl)pyrazinone 55. The central pyrazinone unit of compound 55

was planned to synthesize through the condensation between indole moiety 56 and 6-bromoindole acid chloride 38 followed by oxidative aromatization. Compound 56 could be synthesized from 57 using known chemistry. The installment of stereogenic center of indole 57 was envisioned using Evan’s chiral auxiliary. Compound 58 was planned to synthesize from 59 which could be synthesize through Heck coupling of ortho-indoaniline 60 and butaldehyde 61.

41

NN MOM

SPh

B(OH)₂40

+CO₂Et

NHBoc

NMeO

NN

SPh

Ts

MOM

52

NHBoc

NMeO

Ts

Br

Pd(PPh₃)₄,Cs₂CO₃

1,4-dioxane,NaOEt100ºC[61%] NHBoc

NMeO

NN

SPh

Ts

MOM

OTs

53

NHBoc

NMeO

NN

SPh

Ts

MOM

N₃

54

NH₂

NMeO

NN

SPh

Ts

MOM

N₃

NH

N₃

O

HN

NMeO

NN

SPh

Br

Ts

MOM

O

39

DMF,80ºC[77%]

NaN₃

Cl O

HN

BrO

38

DMAP,Et₃N,toluene

[72%]37

Suzuki–Miyauracoupling

CO₂Et 1.LiBH₄

2.TsCl,Et₃N,

DMAP[61%,2steps]

CF₃CO₂H

CH₂Cl₂

95 Journal of Postdoctoral Research June 2015: 87–97

Scheme 9. Retrosynthetic Analysis for Asymmetric Synthesis

Asymmetric synthesis is commenced with the reaction between 2-iodo-6-benzoxyaniline 61 and butaldehyde 60 in the presence of Pd(OAc)2 to give indole 62 in 70% yield. N-Boc protection of indole N-H using (Boc)2 followed by chemoselective iodination at C-4 position of indole using NIS in the presence of AcOH produced 4-iodoindole 63 in 88% yield. Heck reaction between 63 and Evan’s chiral auxiliary derivative 64 in presence of Pd(OAc)2, Ag2CO3 under ligand-free conditions gave 58 in 82% yield (E/Z 7:2, which are not separable using flash column chromatography). Reaction of 58 with methyl cuprate generated from MeMgBr and CuBr2·SMe2 followed by removal of Evan’s chiral auxiliary using MeOMgBr generated the desired methyl ester 57 in 90% yield. The newly stereogenic center is formed in this reaction and the configuration was confirmed S. Compound 57 was converted to amine 56 in seven step sequence in 63% yield. Compound 57 was treated with HF·pyr to deprotect the OTBDPS group followed by Mitsunobu reaction with PPh3 and diphenylphosphoryl azide (DPPA) generated the corresponding azide. Staudinger reduction of azide using PPh3, deprotection of indole N-Boc using TFA, selective Boc protection of primary amine using (Boc)2O followed by reaction with

DDQ/TMSN3 and reduction of azide using NaBH4/NiCl2 generated amine 56. Condensation of amine 56 with 6-bromoindole oxalyl chloride 38 followed by dprotection of NHBoc using TFA and DDQ promoted oxidative aromatization generated (bisindolyl)pyrazinone 55 in 50% yield. For the installment of aminoimidazole moiety final three-step sequence was followed. Pyrazinone 55 was reacted with pyrazole-1-carboxamidine 66 in presence of Et3N, DMAP to generate 67 in 80% yield. Reduction of methyl ester using DIBAL-H generated aza-hemiacetal, which in presence of TFA formed the aminoimidazole ring followed by removal of SEM protection produced pyrazinone moiety. Finally, deprotection of OBn group using BBr3 completed the asymmetric synthesis of (+)-dragmacidin D in 20% yield. Conclusion

During last 13 years, the synthetic road for the synthesis of novel bis(indole) alkaloid dragmacidin D was garnished by various kinds of exciting chemistry. Since the first isolation of dragamcidin D in 1992, first synthesis of (±)dragmacidin D by Stoltz in 2002, efficient 15 step synthesis of (±)dragmacidin D by Itami in

NH

N

O

HN

HNHO

NHN

NH₂OCOCF₃

dragmacidinD(1)

Br

NH

N

O

HN

HNBnO

Br

O

MeO

NH₂

NHBoc

HNBnO

O

MeO

NBnO

Cl

O

O

HN

Br

Boc

N

O

OTBDPS

O

Ph

O

NBnO

Boc

N

O

OTBDPS

O

Ph

O

NBnO

BocOBn

NH₂

I

TBDPSO

O

+

55

38

56

5758596061

OTBDPS

96 Journal of Postdoctoral Research June 2015: 87–97

2011. In 2015, Capon and Jia confirmed the absolute configuration of setereogenic center of dragmacidin D to be R via the completion of

asymmetric synthesis of dragmacidin, which would lead to the detailed study of biological properties in future.

Scheme 10. Asymmetric Synthesis of Dragmacidin D

Acknowledgements

The author acknowledged no financial support.

References

1. Wright, A. E.; Pomponi, S. A.; Mc Carthy, P. J. Org. Chem. 1992, 57, 4772–4775. http://dx.doi.org/10.1021/jo00043a045

2. Capon, R. J.; Rooney, F.; Murray, L. M.; Collins, E.; Sim, A. T. R.; Rostas, J. A. P.; Carrol, A. R. J. Nat. Prod. 1998, 61, 660–662.

http://dx.doi.org/10.1021/np970483t PMid:9599272

3. Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179-13184. http://dx.doi.org/10.1021/ja027822b

4. (a) McMurray, L.; O'Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885. http://dx.doi.org/10.1039/c1cs15013h PMid:21390391

(b) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976. http://dx.doi.org/10.1039/c0cs00182a

HNBnO

OBn

NH₂

I

TBDPSO

O

+

626061

NBnO

Boc

63

I

NBnO

Boc

N

O

OTBDPS

O

Ph

O

58

2.NIS

Pd(OAc)₂

DABCO

[70%]

1.(Boc)₂O

OTBDPS OTBDPSN

O

O

Ph

O

NBnO

Boc

O

OTBDPS

57

NH₂

NHBoc

HNBnO

O

MeO

56

NH

N

O

HN

HNBnO

Br

O

MeO

55

N

N

OSEM

N

NBnO

Br

O

MeO

65

N

N

OSEM

N

NBnO

Br

O

MeO

67

NH₂

Boc

Boc

NH

NHBocBocN

Boc

Boc

(+)-dragmacidinD

OMe

1.MeMgBrCuBr·SMe₂

2.MeOMgBr

[90%]

1.HF/pyr.

2.Ph₃P,DEAD,DPPA

3.PPh₃

4.TFA

5.(Boc)₂O

6.DDQ,TMSN₃

7.NiCl₂,NaBH₄

Cl

O

O

HN

Br

57

1.Et₃N

2.TFA

3.NAHCO₃aq

4.DDQ

1.(Boc)₂O

2.SEMCl

3.LDA,CBr₄

Et₃N,DMAP

N NBocHN

NBoc

1.DIBAL-H

2.TFA

3.BBr₃

64

66

[88%]

[82%]

[63%][50%]

[54%]

[80%][20%]

Pd(OAC)₂,Ag₂CO₃

toluene

4.NaN₃

5.PPh₃

Mandal 97

PMid:21298176

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http://dx.doi.org/10.1002/anie.201106106 http://dx.doi.org/10.1002/anie.201106864 http://dx.doi.org/10.1002/anie.201201666 PMid:22887739

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