Digest Paper Total synthesis of natural and pharmaceutical products powered by organocatalytic reactions Bing-Feng Sun Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China article info Article history: Received 1 December 2014 Revised 5 March 2015 Accepted 9 March 2015 Available online 17 March 2015 Keywords: Total synthesis Organocatalytic reactions Natural products abstract Organocatalysis has emerged as the third pillar of modern asymmetric catalysis in the past two decades. Applying organocatalytic reactions in total synthesis is currently a highly dynamic research area. This Digest focuses on selected recent examples of total synthesis of natural and pharmaceutical products enabled by organocatalytic reactions, highlighting the importance of organocatalytic reactions in fostering structures of biological importance. Ó 2015 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). Contents Introduction.......................................................................................................... 2133 Total syntheses enabled by general base catalysis ........................................................................... 2134 Dixon’s synthesis of nakadomarin A 7 .................................................................................. 2134 Fan’s synthesis of lycoramine, galanthamine, and lunarine 9 ............................................................... 2134 Zhu’s synthesis of trigonoliimine A 10 .................................................................................. 2135 Total syntheses powered by enamine catalysis .............................................................................. 2135 Hayashi’s and Ma’s syntheses of oseltamivir 11,12 ........................................................................ 2135 Ma’s synthesis of zanamivir, laninamivir, and CS-8958 13 .................................................................. 2135 Thomson’s synthesis of GB 17 14 ...................................................................................... 2136 Total syntheses powered by iminium catalysis .............................................................................. 2137 MacMillan’s synthesis of diazonamide A 15 ............................................................................. 2137 Hong’s synthesis of conicol 16 ........................................................................................ 2137 MacMillan’s synthesis of strychnine, akuammicine, kopsinine, kopsanone, aspidospermidine, and vincadifformine 17 ................. 2137 Wu’s synthesis of kopsinine and aspidofractine 18 ........................................................................ 2138 Sun and Lin’s synthesis of englerin A/B, orientalol E/F, and oxyphyllol 19 ..................................................... 2139 Total syntheses featuring Brønsted acid catalysis ............................................................................ 2139 Zhu’s synthesis of rhazinilam and leucomidine B 20 ...................................................................... 2139 List’s synthesis of estrone 21 ......................................................................................... 2140 Conclusions and perspectives ............................................................................................ 2140 Acknowledgments ..................................................................................................... 2140 References and notes .................................................................................................. 2140 Introduction Natural products play pivotal roles in drug discovery. Approximately two thirds of all small-molecule drugs approved during 1981–2010 have their origins in natural products. 1 In the process of drug discovery, organic synthesis provides the most transformative power that can build natural or designed molecules of interest. The art and science of organic synthesis have evolved tremendously since its inception. 2 ‘Can we synthesize the molecule?’ is no longer the question. Nowadays, armed with the strategies and methodologies developed over the past decades, synthetic chemists have been endowed with the capability to http://dx.doi.org/10.1016/j.tetlet.2015.03.046 0040-4039/Ó 2015 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). E-mail address: [email protected]Tetrahedron Letters 56 (2015) 2133–2140 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Transcript
Tetrahedron Letters 56 (2015) 2133–2140
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier .com/ locate/ tet le t
Digest Paper
Total synthesis of natural and pharmaceutical products poweredby organocatalytic reactions
http://dx.doi.org/10.1016/j.tetlet.2015.03.0460040-4039/� 2015 Published by Elsevier Ltd.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Organocatalysis has emerged as the third pillar of modern asymmetric catalysis in the past two decades.Applying organocatalytic reactions in total synthesis is currently a highly dynamic research area. ThisDigest focuses on selected recent examples of total synthesis of natural and pharmaceutical productsenabled by organocatalytic reactions, highlighting the importance of organocatalytic reactions infostering structures of biological importance.� 2015 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://
Natural products play pivotal roles in drug discovery.Approximately two thirds of all small-molecule drugs approvedduring 1981–2010 have their origins in natural products.1 In the
process of drug discovery, organic synthesis provides the mosttransformative power that can build natural or designed moleculesof interest. The art and science of organic synthesis have evolvedtremendously since its inception.2 ‘Can we synthesize themolecule?’ is no longer the question. Nowadays, armed with thestrategies and methodologies developed over the past decades,synthetic chemists have been endowed with the capability to
2134 B.-F. Sun / Tetrahedron Letters 56 (2015) 2133–2140
conquer almost any known natural product if given sufficientresources, efforts, and time. The ideal synthesis is gaining increas-ing attention from synthetic chemists to confront the demand frominterdisciplinary scientific community as well as industry to pro-duce sufficient amount of desired compounds in sustainable ways.3
Organocatalysis has emerged as the third pillar of modernasymmetric catalysis, along with metal catalysis and biocatalysis.4
Organocatalytic reactions usually feature mild reaction conditions,adequate functional group tolerance, insensitivity toward air andmoisture, as well as their diverse catalytic mechanisms.5 Themetal-free nature of organocatalytic reactions meets the demandsof green chemistry. The ability of organocatalysis to effect cascadereactions and one-pot tandem transformations is of particularimportance and has attracted significant attention from the chemi-cal synthesis community. To combine organocatalysis with metalcatalysis is a highly dynamic arena. These efforts have culminatedin a number of elegant total syntheses of natural products withbiological significance. A number of elegant reviews have appearedhighlighting respective topics in this research area.6 This Digestfocuses on selected recent examples of total synthesis of naturaland pharmaceutical products enabled by organocatalytic reactions.These examples are grouped in terms of the mechanisms of theorganocatalytic reactions applied in the total syntheses, includinggeneral base catalysis,5a enamine catalysis,5b iminium catalysis,5c
and Brønsted acid catalysis.5d
Total syntheses enabled by general base catalysis
Dixon’s synthesis of nakadomarin A7
Construction of an all-carbon quaternary center usually consti-tutes a significant challenge in total synthesis, especially when thequaternary stereogenic carbon is surrounded by ring systems. Thisis the case in the total synthesis of nakadomarin A (1).Nakadomarin A was isolated by Kobayashi and co-workers in1997 from a sponge collected off the coast of the Kerama Islands,Okinawa, and exhibits significant bioactivities. This molecule
N
O
MeOOC
O
O2N
+
N
O
MeOOC
O
O2NN
N
NO2
OO
O2
3 5 6
15 mol % 4
57%91/9 dr
hex-5-enamineHCHO
Scheme 1. Dixon’s synthesi
R2MOMO CN
O
O
OI
MeOMOMO
COMeCN
O
OIN
NH
NH
S
CF3
CF3
MeMe
98% yield, 80% ee;(74% yield, 99% ee
after one recrystallization)
OM
11a (R1 = H, R2 = OMe)11b (R1 = Br, R2 =H)
12
13
14
1) t-BuONa2) PTSA
3) NaBH44) MsOH
OH
O
O
O OEt NH
O
NBocHN
Boc
Heck
O
NHR
1819 20
1) L2) C
E
3) H4) D
R1
NHN
O NH
NH
CF3F3C
OH
O
O
Br
O OEt
Scheme 2. Fan’s syntheses of lycoramine (8
contains a synthetically challenging 8/5/5/5/15/6 hexacyclic ringsystem containing a quaternary carbon. Prior to Dixon’s synthesis,the average step count of the three total syntheses of nakadomarinA reached 34. In 2009, Dixon’s total synthesis reshaped the land-scape. Pivoting on an organocatalytic diastereoselective Michaeladdition reaction, Dixon and co-workers amazingly telescopedthe total synthesis of nakadomarin A into less than fifteen steps(longest linear sequence) (Scheme 1). The Michael reactionbetween 2 and 3 under the action of 15 mol % of 4 delivered a91/9 diastereomeric mixture favoring the desired 5 in 57% yield.When LHMDS or KHMDS was employed in the place of the catalyst4 to promote this reaction, a diastereoselectivity of 1.5/1 wasobserved. Notably, the configuration of the nascent quaternarycarbon was dictated by the strong facial bias of the enolate of the5/8 bicyclic framework. It was through the hydrogen bondinginteractions between the thiourea catalyst 4 and the nitroalkene3 that the stereochemistry of the newly generated tertiary carbonwas effectively controlled. The subsequent nitro-Mannich/lactamization cascade formed the piperidone ring of 6. Selectivereductions transformed 6 to aminol which underwent furan/iminium cyclization to pentacyclic 7. The camphorsulfonic acid-assisted Z-selective RCM reaction annulated the 16-memberedmacrocycle and finalized the total synthesis. This synthesis formedthe basis of Dixon’s second generation route for nakadomarinA, where the geometric selectivity issue in the formation of themacrocycle was addressed by virtue of alkyne metathesis.8
Fan’s synthesis of lycoramine, galanthamine, and lunarine9
Lycoramine (8), galanthamine (9) and lunarine (10) arehydrodibenzofuran alkaloids with biological significance. In par-ticular, galanthamine possesses acetylcholinesterase inhibitiveactivity, and is clinically used for the treatment of mild to moder-ate Alzheimer’s disease and various other memory impairments. In2011, Fan and co-workers reported the collective total synthesis ofthese three molecules (Scheme 2). The stereochemistry-definingstep is the asymmetric Michael addition reaction of 11 and 12
HNN
OHN
N H
F3C CF3
NO
N
H
NO
N
H
nakadomarin A (1)4
7
1) Bu3SnHAIBN
2) LiAlH4
3) Dibal-Hthen HCl
Gubbs I(+)-CSA
62%63/37 Z/E
s of nakadomarin A (1).
eO O
H
CN
OMe
MeN
OOMe
MeN
OOH OH
H H
Lycoramine (8) Galanthamine (9)
OMeO
H
O
O
NO2
OMe
N
O O
MeOOC
1) glycol, H+
2) Dibal-H
3) MeNO2, TEA4) MsCl, TEA
1) NaBH42) LiAlH4
3) ClCO2Me, TEA4) (HCHO)n, TFA
L-Selectride,then LiAlH4
1) TBSOTf, TEA2) Pd(OAc)23) L-Selectride,
then LiAlH4
OH
O NH NH
O
NH
O
Lunarine (10)
1516
17
iOH6F5OH,DCI
ClIPEA
), galanthamine (9), and lunarine (10).
NO2
OMe
CN COOMeNO2
OMe
MeOOC
NC
SeO2Ph
NO2
OMe
MeOOC
NH
N3
HN
N
OMe
N
HN
HN
O
N
OMe
N
NH N
SeO2Ph
3) , NaBH(OAc)3
HN
OHC
1) NaN32) HCl, MeOH
1) Ph3P2) Raney Ni
3) PPTS,HC(OMe)3
POCl3
Trigonoliimine A (21)22
23
24
2526 27 28
OBu-nN
NHOH
Scheme 3. Zhu’s synthesis of trigonoliimine A (21).
B.-F. Sun / Tetrahedron Letters 56 (2015) 2133–2140 2135
catalyzed by thiourea 13. This reaction with 11a resulted in anearly quantitative yield of 14 with good enantioselectivity whichcould be further enhanced to 99% ee after one recrystallization.Compound 14 was converted to 15 by intramolecular condensationand conjugate addition. The nitrile was reduced to aldehyde andcondensed with nitromethane to give 16. By a sequence involvingreduction, N-protection and Pictet–Spengler cyclization, nitroalk-ene 16 was elaborated into the tetracyclic intermediate 17, whichcould be readily advanced into lycoramine (8) and galanthamine(9), respectively, via conventional transformations. In the synthesisof lunarine (10), 11b and 12 was converted to 19 via a similarsequence as for the synthesis of 16, except that the catalyst 18was employed in the starting Michael addition reaction and HWEolefination was used to generate the unsaturated ester. A Heckcoupling reaction between 19 and acrylamide gave 20, from whichlunarine (10) was readily generated.
Zhu’s synthesis of trigonoliimine A10
Cinchona-alkaloid-based catalysts represent a group of privi-leged organocatalysts for promoting conjugate addition reactions,including those generating quaternary carbons. These are powerfulbifunctional catalysts; usually the quinuclidine moiety in the cata-lyst activates the nucleophile, while the functional group OH orthiourea at C60 or C9 activates the electrophile, both via hydrogenbonding interactions. Recently, Zhu and co-workers developed acinchona alkaloid-catalyzed Michael addition reaction. In this reac-tion, various a-aryl-a-isocyanoacetates add to vinyl phenylse-lenone under the action of 60-OH cinchona alkaloids, providingsynthetically useful isocyano-bonding quaternary carbons in goodyields and enantioselectivity. By virtue of this new methodology,they nicely demonstrated the total synthesis of trigonoliimine A(21) (Scheme 3). The Michael addition reaction of 22 and 23 cat-alyzed by 24 delivered 25 in 62% yield and 87% ee. This compoundwas converted to 27 by a sequence involving nucleophilic displace-ment of the phenylselenone by sodium azide, acidic hydrolysis ofthe isocyano group, and reductive amination of the resultant aminewith aldehyde 26. The azide and the nitro groups in 27 weresuccessively reduced before being transformed to the aza-spirocompound 28, which was eventually exposed to POCl3 to effectthe Bischler–Napieralski reaction to furnish trigonoliimine A (21).
Total syntheses powered by enamine catalysis
Hayashi’s and Ma’s syntheses of oseltamivir11,12
Influenza strikes the world in seasonal epidemics, leading tohundreds of thousands of annual deaths. The influenza viruses
O CHO
COOBu-tO2N
+
NH
OTMS
PhPh
COOEt(EtO)2P(O)
ClCH2COOH
30
31
32
NO2
CHOO
t-BuO2C
33 35
O
NO2
t-BuO2C
34
Cs2CO35
Scheme 4. Hayashi’s synthe
have glycoproteins on their surfaces that bind to sialic acids foundon the surface of human erythrocytes and on the cell membranesof the upper respiratory tract. Widely used anti-influenza drugsare sialic acid analogs that inhibit the viral enzyme neuraminidase,thereby interfering with the proliferation of viruses. Oseltamivir(29) is the first orally active neuraminidase inhibitor commerciallydeveloped for the fight against both influenza A and influenza Bviruses. Efficient synthesis of this molecule containing threecontiguous stereocenters in short steps with a good overallyield is highly desirable, and challenging. In 2009, Hayashi andco-workers achieved this goal by realizing the synthesis ofoseltamivir in three one-pot operations with an amazingly highoverall yield (Scheme 4).11 This efficient synthesis relied heavilyon the Michael addition reaction of 30 and 31 catalyzed by5 mol % of 32-ClCH2COOH via an enamine mechanism, whichgenerated the multi-functional 33 in quantitative yield with 96%ee. The subsequent domino reaction of 33 with vinylphosphonate34 delivered cyclohexenecarboxylate 35 with an undesiredconfiguration at C5. p-Toluenethiol was then employed to givethe conjugate addition product 36 with the C5 configurationrectified. These three steps were integrated into the one-potoperation which supplied 36 in 70% overall yield. After anothertwo well executed one-pot operations, the total synthesis of osel-tamivir was eventually accomplished with 57% overall yield fromnitroolefin 31.
In 2010, Ma and co-workers demonstrated their total synthesisof oseltamivir based on a similar strategy (Scheme 5).12 Notably,Ma and co-workers introduced nitroenamides as useful Michaelacceptors. By applying 38 in their total synthesis of oseltamivir,they significantly improved the step economy of the syntheticroute. Their efforts have laid the basis for development of a practi-cal industrial process for the production of oseltamivir.
Ma’s synthesis of zanamivir, laninamivir, and CS-895813
Recently, Ma’s group reported the total synthesis of three rele-vant neuraminidase inhibitors, zanamivir (42), laninamivir (43),and CS-8958 (44) (Scheme 6). This organocatalytic and scalablesynthesis relied on a Michael addition reaction involving nitroe-namide 45. With 5 mol % of thiourea 46, the Michael addition ofacetone to nitroenamide 45 proceeded smoothly, providing 47 in72% yield and 98% ee after recrystallization. The subsequentanti-selective Henry reaction of 47 with 48 was realized withCuBr2 in the presence of ligand 49. Products 50a and 50b were thenelaborated into zanamivir (42) and laninamivir (43), respectively,through the same sequence involving functional group trans-formations. CS-8958 (44) was obtained by esterification of 43.
STolO COOEt
NO2
t-BuO2C
TolSH
70% from 31O COOEt
NH2
AcHN
Oseltamivir (29)36
COOEt
82% from 36
6 steps(2 one-pot operations)
one-pot operation
sis of oseltamivir (29).
O CHO
AcHNNO2
+
STolO COOEt
NO2
AcHN
NH
OTMS
NaphNaph COOEt(EtO)2P(O)
TolSH
one-pot operation54% over three steps
PhCOOH
O COOEt
NH2
AcHN
Oseltamivir (29)
37
38
39
41
NO2
CHOO
AcHN
4085%
2 steps
Scheme 5. Ma’s synthesis of oseltamivir (29).
NHBoc
NO2
45
46
4750a: R = MOM50b: R = Me
O
NHBocO2N
48a/48b (R = MOM / Me)O2NBocHN O
ORO
O CHO HO
O
OR
NH NH2
NH
StBuN
OBn
Me
zanamivir (42): R = Hlaninamivir (43): R = Me
O COOH
HNAcHN
HOR
HOOH
NH
NH2
O COOH
HNAcHN
HOMe
OOH
NH
NH2
n-C7H15
O
CS-8958 (44)
N
OHF3CHO
PhPh
CuBr2
1) Zn, HOAc2) AcCl, TEA
n-C7H15C(OMe)3HCl, MeOH
49
3) SeO24) NaClO2
5) HCl6) guanidination
O
Scheme 6. Ma’s syntheses of zanamivir (42), laninamivir (43), and CS-8958 (44).
Scheme 8. MacMillan’s synthesis of diazonamide A (57).
2136 B.-F. Sun / Tetrahedron Letters 56 (2015) 2133–2140
Thomson’s synthesis of GB 1714
Organocatalytic intramolecular Michael addition reactions canbe powerful tools for construction of cyclic compounds with twocontiguous stereogenic centers. Thomson and co-workers demon-strated this strategy in their total synthesis of GB 17 (51)(Scheme 7). In the presence of 5 mol % ent-32-TFA, 52 underwentan annulating Michael addition reaction, affording 53 in a nearlyquantitative yield. This highly effective stereocontrol was exertedby the catalyst, not the substrate, as evidenced by the similar result
obtained with 520. Through the intramolecular Michael additionreaction of (Z)-olefin 54, compound 53 could be elaborated into55 and 7-epi-55 as a 1/1 mixture diastereomeric at C7. The geome-try of the olefin played a critical role in determining the stereo-chemistry of the addition product; with the (E)-olefin 540 as thesubstrate, the Michael addition proceeded with the undesiredsense of stereochemistry at C16 and the C6 stereocenter epimer-ized under the conditions, leading to formation of 550. 7-epi-55could be equilibrated upon exposure to base to give a 3/2 mixture
NH
OTMS
PhPh
ent-32
HOAc
HO
OH
NO2
Me Me
CHO
O
O2N
HOH
H
MeO OMe
CHO
O
HOH
H
OH
O
HO
Me
H
H
Conicol (67)6869
71
72 73
MeO
OMeO 1) RhCl(PPh3)3
2) H2, Pd/C
3) Amberlyst 154) DABCO5) Dibal-H
1) AcCl, TEA2) Li/NH3
55% yield from 6999% eeO
O2N
HOO
H
H
70
Scheme 9. Hong’s synthesis of conical (67).
B.-F. Sun / Tetrahedron Letters 56 (2015) 2133–2140 2137
of 55 and 7-epi-55 and recycled. Compound 55 was transformed to56 by conversion of the carbonyl to the olefin and the subsequentallylation, before being further advanced into GB 17 (51).
Total syntheses powered by iminium catalysis
MacMillan’s synthesis of diazonamide A15
Diazonamides are a structurally unique family of marine natu-ral products isolated by Fenical and co-workers. Among these,diazonamide A (57) was identified to be a potent antimitotic agent,exhibiting cytotoxicity toward a variety of human cancer cell linesthrough interaction with ornithine d-amino-transferase, amitochondrial matrix protein. Total synthesis of this moleculehas been intensely explored in the past two decades, with theoriginal structure being corrected by Harren and co-workersthrough synthetic studies. One of the major synthetic challengeslies in the construction of the C10 quaternary carbon. In 2011,MacMillan’s group contributed the total synthesis of 57 coveringtwenty steps from commercial materials (Scheme 8). Thus, seg-ments 58 and 59 were assembled via Suzuki coupling and furtherconverted to 60. Under the action of 61-TCA, the Michael additionreaction of 60 and propynal went on efficiently, providing 62 witha diastereoselectivity of over 20/1. This reaction established theC10 quaternary center and the complete benzofuranoindoline core.Notably, when rac-61 was tested for this reaction, 1/1 dr wasresulted, indicating the formation of the C10 stereocenter wasdominated by the catalyst. Compound 62 was subjected to protect-ing group manipulations, oxidative cleavage, and macrocyclizationby intramolecular aldol reaction, furnishing 63, which was furtheradvanced into 64 via oxidative aromatization and Ag+ promotedamidation. Formation of the second oxazole ring followed bydebenzylation and triflation generated 65, which was subjectedto a tandem borylation/annulation to yield 66. After initial bromi-nation of the activated indoline E-ring and hydrolysis of the indolyltriflate, a sequence involving chlorination/debromination/desilyla-tion was then carried out to furnish diazonamide A (57). Thissynthesis elegantly blended organocatalysis and transition-metalcatalysis to attain unprecedented synthetic efficiency.
Hong’s synthesis of conicol16
In the past century, total synthesis has been playing an indis-pensible role in determining the structure of natural products. In2010, Hong and co-workers accomplished the catalytic enantiose-lective total synthesis of conicol (67) and settled the stereochemi-cal issue of this molecule (Scheme 9). Hong’s approach to thismolecule features a domino oxa-Michael–Michael–Michael-aldolreaction sequence. By employing ent-32-AcOH as the catalyst, thefirst stage of this one-pot sequence involved the oxa-Michaeladdition of 68 and 69 and the ensuing intramolecular Michaeladdition, furnishing compound 70. In the second stage, enal 71was introduced and the Michael-aldol cascade reaction proceededto give tricyclic 72. This one-pot sequence delivered 72 in 55%overall yield with 99% ee. The stereochemistry of this tandemreaction was established unambiguously through X-raycrystallographic analysis of relevant products, thus certifying thestereochemistry of the target molecule. By trimming off the
undesired functionalities, compound 72 was transformed to73, which was further subjected to acylation and deacetoxylationto give (+)-conicol (67). This asymmetric total synthesisdetermined the absolute configuration of (+)-conicol, which hadpreviously been a mystery due to the lack of an efficient analyticalmethod.
MacMillan’s synthesis of strychnine, akuammicine, kopsinine,kopsanone, aspidospermidine, and vincadifformine17
In nature, simple building blocks could be assembled rapidly toform highly complex and diverse molecular architectures viaenzyme-catalyzed cascade reactions, as exemplified by the biosyn-thesis of terpenoids. These biological pathways are distinctive fromgeneral chemical synthesis where ‘stop-and-go’ protocols are pre-vailing with significantly lower efficiency. Therefore, to mimic nat-ure’s strategies has been a constant attraction for syntheticchemists. In 2011, MacMillan and co-workers marked a milestonein this arena. By realizing an organocatalytic cascade reaction, theyachieved the collective synthesis of six structurally complex ter-pene indole alkaloids, strychnine (74), akuammicine (75), kopsi-nine (76), kopsanone (77), aspidospermidine (78) andvincadifformine (79), each with high step economy (Scheme 10).In particular, they accomplished the shortest asymmetric synthesisof strychnine (74), the best-known strychnos alkaloid(Scheme 10A). This collective total synthesis was centered on aone-flask, asymmetric Diels–Alder/elimination/conjugate additionorganocascade reaction that coined the key tetracyclic core of thetargets. In this reaction, by forming the corresponding iminiumspecies with catalyst 81, propynal was activated toward theDiels–Alder [4+2] cycloaddition with 2-vinyl indole 80, engender-ing iminium 83. The ensuing elimination and hydrolysis provided84, which underwent intramolecular conjugate addition to deliver82 in 82% yield and 97% ee. Employment of the selenide-substi-tuted 2-vinyl indole, such as 80, as the diene component wascritical for the success. Use of the corresponding methyl-sulfide-substituted 2-vinyl indole as the diene component would lead toa different product due to the mitigated propensity of the sulfideto undergo elimination. Treatment of 82 with Wilkinson’s catalystto effect decarbonylation followed by introduction of a car-bomethoxy group with COCl2/MeOH and reduction with Dibal-Hresulted in 85 as an inconsequential mixture of olefin isomers.N-alkylation and ester reduction gave 86 as a proper Heck sub-strate. The Heck cyclization-lactol formation and the subsequentdebenzylation gave the Wieland–Gumlich aldehyde, which wasconverted to strychnine (74) following the know procedure. Thistotal synthesis delivered strychnine in 12 steps and 6.4% overallyield from commercially available materials, constituting theshortest route to enantioenriched strychnine to date. Notably, inthe Heck cyclization, the PMB protecting group was believed criti-cal in facilitating regioselective b-hydride elimination away fromthe indoline ring methine since formation of the N-PMB-substi-tuted enamine would accompany destabilizing allylic strain. Thisdestabilizing factor was envisioned in the synthesis of akuam-micine (75). Thus, compound 85 was subjected to cleavage of thePMB group with concomitant isomerization of the alkene inconjugation with the ester group. After installation of the iodoallyl
NH
CO2Me
NHBoc
NH
NH COOMe97102 103
O
NH COOMe
kopsinine (76)
NH
NHBoc
NHR2
NH
1) 98, TCA, acrolein2) NaBH4
1) CH2=CHSO2Ph2) Raney Ni
100 101
64%, 93% eeNH
OTMS
ArAr
TCA(Ar = 3,5-(CF3)2C6H3)
CO2Me CO2Me
CO2Me
98
99
OH OH
NH
N
COOMe
NBocCHO
NBocNBoc NBoc
aspidofractine (96)
N
N
COOMeCHO
1) MsCl, TEA2) TFA3) Na2CO3
HCOOH, Ac2O
Scheme 11. Wu’s synthesis of kopsinine (76) and aspidofractine (96).
N SeMe
NHBoc
PMB
N
NBocCHO
PMBN
NH
PMB COOMeN
PMB
IN
OH
OH
NH
N
O
HH HHO
H
H
N
N
O
H
H
HO
H
80 8285 86 87
88
NH COOMe
IN Me
HNH COOMe
N
MeH
MeN
NHt-Bu
O1-Nap
TCA81
O
N SeMe
NHBoc
BnN
NBocCHO
Bn80' 82'
NBn
N
NBn
N
COOMe
NH
N
COOMe
N
N
COOMeBn
R
R = SO2Ph
NH
N
COO-NH
HN
COOH
H
NH
NO
89 9091
9293
N
NBocCHO
Bnent-82'
N
N
H
I
N
N
HNH
N
HMe N
H
N
MeCOOMe
kopsinine (76)kopsanone (77)
aspidospermidine (78) vincadifformine (79)94
95
N
NH
PMBSeMe
Boc
NHR2
N
NH
CHO
PMB
Boc
strychnine (74)akuammicine (75)
1) Wilkinson cat.2) COCl2, MeOH3) Dibal-H; TFA
1) N-allylation2) Dibal-H
1) [Pd]2) PhSH,
TFA
malonic acid1) PhSH, TFA2) N-allylation
[Pd]
1) TMSI, TEA2) CH2=CHPPh3Br
MeOH; thent-BuOK
1) COCl2MeOH
2) H2, Pd/C CH2=CHSO2Ph
Raney Ni
neat, 200 oC HCl
3) TFA4) N-allylation
Pd(PPh3)4 H2, Pd(OH)21) Ph3P=CH22) NaCNBH3
1) DMSO,(COCl)2
2) n-BuLi,NCCO2Me
83 84
82%, 97% ee
A)
B)
C)
83%, 97% ee
81
propynal
BnBn
Scheme 10. MacMillan’s syntheses of indole alkaloids 74–79.
2138 B.-F. Sun / Tetrahedron Letters 56 (2015) 2133–2140
side chain, the Heck cyclization of 88 was set in motion to produceakuammicine (75).
The total synthesis of kopsinine (76) and kopsanone (77)employed a slightly modified precursor 820 obtained from 800 viathe organocascade reaction (Scheme 10B). Conjugate addition ofthe revealed amine to the vinylphosphonium bromide producedthe corresponding ylide that underwent olefination with thevicinal aldehyde to furnish 89. Compound 89 was converted viaconventional procedures to 90, and the latter was further subjectedto [4+2] cycloaddition reaction with vinylsulfone to access 91 witha [2.2.2] bicyclic framework. After desulfurization with Raneynickel, the total synthesis of kopsinine (76) was accomplished in14% overall yield spanning 9 steps from commercial materials.Further, kopsinine was demethylated to give 92, which wasconverted to kopsanone (77) simply by heating without solvent.
Heck cyclization was also featured in the synthesis of the lasttwo natural products (Scheme 10C). From ent-820, 94 was obtainedvia a sequence involving Wittig reactin, enamine saturation, N-Bocdeprotection and N-allylation. The subsequent Heck cyclizationprovided 95, the precursor for both aspidospermidine (78) andvincadifformine (79). This accomplishment of the collectivesyntheses of six complex natural products in 6.4–24% yields with9–12 steps have highlighted the capability of organocatalysis,which combined with metal catalysis may provide rapid accessto complex molecular architectures.
Wu’s synthesis of kopsinine and aspidofractine18
Indole alkaloids comprise a rich source of appealing targets thatform a test base for new synthetic methodologies. Recently, Wuselected kopsinine (76) and aspidofractine (96) as the synthetic
3) CH2CHMgBr4) Ac2O5) HCOONH4
Pd(Ph3P)4
O
OHC HO
61O
OTMS
CHO
+
110
109MeNO2
63%111/112= 2.4/1
TFA
O
H
115
1) LDA, PhNTf2
2) Pd(Ph3P)4,TEA
OO
OHO
1) mCPBA2) Dibal-H
H
116
dr 7/1
OHO
orientalol F (106)
H
OHO
H
OHHOHO
H
H
oxyphyllol (107: R = H)orientalol E (108)
OHO
H
H
HO
N
NO
N
NO
O
N
NO
OendoadditionO O
Si
O
SiSi
α-faceapproach
TS1TS2
O
OHC HO
englerin A (104):R = HOCH2CO
OORO
H
H
englerin B (105): R = H
O
Ph
112 111
117113
1) EtMgBr2) DMP
114
3) NaBH44) TPAP, NMO
H2, Pd/C
1) 9-BBN,H2O2
2) H2, Pfaltz cat.(dr 1/2.5)
1) AcOCH2COCl2) Yamaguchi's
conditions
3) K2CO3MeOH
104/105 = 1.2/1
H2,Crabtree's cat.
1) Ac2O2) CrO3
Bu4NIO4
3) K2CO3MeOH
Scheme 12. Sun and Lin’s syntheses of 7,10-epoxy guaianoids 104–108.
B.-F. Sun / Tetrahedron Letters 56 (2015) 2133–2140 2139
targets to demonstrate their organocatalytic method (Scheme 11).In this exquisite Michael addition/aza-Michael addition/cyclizationcascade reaction, 97 reacted with propynal under the catalysis of98 to deliver the key tetracyclic 99 directly, presumably via theintermediacy of 100 and 101. In the second catalysis by 98, theconjugate addition of compound 99 to acrolein proceeded to fur-nish, after reduction, dienamine 102, which underwent the [4+2]cycloaddition/desulfurization sequence to give 103. After forma-tion of the last ring by nucleophilic substitution, the total synthesisof kopsinine (76) was accomplished in a concise manner. The end-game N-formylation of kopsinine provided aspidofractine (96).
Sun and Lin’s synthesis of englerin A/B, orientalol E/F, andoxyphyllol19
7,10-Epoxy guaianoids represent a small group of sesquiterpenenatural products. These structurally exquisite natural productshave aroused significant attention from the synthesis communitysince englerin A and englerin B were disclosed by Beutler and co-workers to possess potent cytotoxicity toward renal cell carci-noma. In early 2013, Sun, Lin, and co-workers demonstrated howan organocatalytic [4+3] cycloaddition reaction could be tamedfor the production of a collection of natural products includingenglerin A (104), englerin B (105), orientalol F (106), oxyphyllol(107), and orientalol E (108) (Scheme 12). The [4+3] cycloadditionreaction catalyzed by 61-TFA involved the unsymmetrically substi-tuted furan 109 and dienal 110, affording two regioisomers in aratio of 2.4/1 favoring the desirable 111. The TMS group wasdeemed to play a critical role in the stereochemical guidance: thebenzyl group and t-butyl group of catalyst 61 occupy the a faceof iminium 113, while the even bulkier TMS group blocks its b face,forcing 109 to approach from the a face through the endo
120
O
O
O
O
Et H
RO
MeO
O
O
EtOHC
MeOO
N3
EtS
S N
EtCOOMe
NO2
M
NO2
BrO COOMe
O2NOP
O
NP
O
O
R
R
R
R
OH O
118 (R = Me)119 (R = H)
121
124125
126 129
MeOH121 (0.1 eq.)
RT
95%, 84% eefor 119
1) ethanedithiol2) LiBH43) TMSCHN2
4) MsCl5) NaN3
1) IBX2) Ph3P
DMF100 oC
126
129toluene90 oC
Scheme 13. Zhu’s synthesis of rhazinila
orientation. The regioselectivity could be rationalized by thepreference of the postulated transition state TS1 over TS2.Compound 111 was subjected to a sequence to give 114, whichwas triflated before undergoing Heck cyclization to furnish guaianetriene 115. Selective epoxidation of the trisubstituted olefinfollowed by SN20-type hydride delivery provided allylic alcohol116, which after hydrogenation with Pd/C gave orientalol F (106).Formal hydration of the disubstituted olefin via the hydrob-oration/oxidation procedure generated diol 117, which wasreadily converted into englerin A (104) and englerin B (105)by esterification and saponification. The directed hydrogenationof 116 with Crabtree’s catalyst resulted in oxyphyllol (107).Eventually, a three-step sequence involving acylation, chemoselectiveand stereospecific C–H oxidation, and saponification producedorientalol E (108).
Total syntheses featuring Brønsted acid catalysis
Zhu’s synthesis of rhazinilam and leucomidine B20
Desymmetrization represents an effective strategy for generat-ing chiral all-carbon quaternary centers. The desymmetrization ofprochiral diesters via enzymatic hydrolysis has been a powerfulmethod. Nevertheless, it is less efficient for long-chain-bridgeddiesters, such as dimethyl 118 (Scheme 13), which is the keyprecursor in several indole alkaloid syntheses accomplishedby Kuehne. Recently, Zhu and co-workers developed a catalyticdesymmetrization method to access 119 enantioselectively(Scheme 13). This desymmetrization was realized by the alcoholy-sis of bicyclic bislactone 120 catalyzed by the chiral Brønsted acid121. Aldehyde 119 was secured in 95% yield and 84% ee, and wasutilized for the total synthesis of rhazinilam (122) and leucomidine
NO2 N+
EteOOC
Br- N
EtMeOOC
NO2
N
Et
HN ORhazinilam (122)
NH
EtCOOMe
COOMeO
N
EtCOOMe
HO OO2N
HN
O
H
NH
MeMeOOC
Leucomidine B (123)
127 128
131 130
Ag2CO3
1) H2, Pd/C2) KOH3) EDC,
70%1/1 dr
H2, Pd/Cthen 110 oC
40% for 123plus 40% isomer
m (122) and leucomidine B (123).
O
MeOMeO
O
O
O
MeO
O
MeOH
H
H
O
HOH
H
HOO
1) BrMgCH=CH2
133 134
136
135 139 132
136 (5 mol %)
95%, 93% ee
H2, Pd/C;TFA, Et3SiH BBr3
71% 75%
MeO
O
O
137 MeO
O
138
OHO2S N
HSO2
NO2O2N
SF6
F6SSF6
F6S
2)
olefinisomerization
Prinscyclization
dehydration&
olefin isomerization
Scheme 14. List’s synthesis of estrone (132).
2140 B.-F. Sun / Tetrahedron Letters 56 (2015) 2133–2140
B (123). Compound 119 was converted to 124 before being elabo-rated into tetrahydropyridine 125, the common precursor to thetwo natural products. The N-allylation of 125 by 126 produced imi-nium salt 127, which upon heating in toluene in the presence ofAg2CO3 under an inert atmosphere delivered 128. Reduction ofthe nitro group and lactamization engendered rhazinilam (122).On the other hand, heating the mixture of 125 and 129 resultedin 130 as a 1/1 diastereomeric mixture, probably via the inter-mediacy of 131, before further proceeding to leucomidine B (123).
List’s synthesis of estrone21
Steroids have captured the imagination of synthetic chemistsfor decades owing to their appealing molecular architecture as wellas their biological significance. While the female sex hormoneestrone (132) has been the target of numerous syntheses, thesynthesis developed by Torgov in 1963, albeit racemic, appearedparticularly efficient. Recently, List and co-workers achieved theasymmetric synthesis of 132 by virtue of a catalytic enantioselec-tive Torgov cyclization (Scheme 14). The substrate 134 was readilyprepared from 133 via a two-step procedure. Torgov cyclizationentails strong acidic conditions. In List’s work, a highly Brønstedacidic disulfonimide was selected out as the catalyst. Thus, in thepresence of only 5 mol % of 136 at low temperature for 4 days,the Torgov cyclization of 134 went on smoothly to deliver 135 in95% yield and 93% ee. After one recrystallization, 135 could beisolated in 88% yield with 99.8% ee. The Torgov cyclization of 134presumably involves these consecutive reactions: (1) isomeriza-tion of 134–137; (2) Prins reaction of 137 that ends in depro-tonation furnishing 138 as an olefin mixture; and (3)dehydration and olefin isomerization. The strong acidic conditionsare necessary that ensure the final product as the desiredthermodynamically most stabilized one. Torgov diene was thenhydrogenated to give 139, which furnished estrone (132) afterdemethylation.
Conclusions and perspectives
Organocatalytic reactions generally involve convenient, mild,and metal-free conditions, and are amenable to the constructionof molecular architectures with complexity and diversity inenantioselective manner. These virtues bestow them an edge insynthesis of natural and pharmaceutical products. Selected con-tributions summarized in this Digest highlight the importance oforganocatalytic reactions in fostering structures of interest,particularly quaternary stereogenic carbons and polycyclic sys-tems embedded in complex molecules with biological significance.We hope this Digest will inspire more efforts in applyingorganocatalytic transformations in total synthesis of complexnatural products. On the other hand, organocatalytic reactions
are still underdeveloped, and some of the organocatalytic reactionsare far from being satisfactory. Therefore, further development oforganocatalytic reactions in both breadth and depth is anticipated.
Acknowledgments
Financial supports from the National Natural ScienceFoundation of China (Grant Nos. 21172246, 21290180,21472210) and the Youth Innovation Promotion Association,Chinese Academy of Sciences are gratefully appreciated.
References and notes
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