Efficient total synthesis of bioactive natural products: a personal record.

Personal Account

THE CHEMICAL RECORD

Efficient Total Synthesis of Bioactive Natural Products: A Personal Record Yun Zhang,[a] Jianxian Gong,*[a] and Zhen Yang*[a,b] Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055 (P. R. China) E-mail: [email protected] E-mail: [email protected] [b] Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, and Beijing National Laboratory for Molecular Science (BNLMS), Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871 (P. R. China)

[a]

Received: March 12, 2014 Publised online: July 14, 2014 Dedicated to Professor K. C. Nicolaou on the occasion of his 68th birthday and Professor Henry N. C. Wong on the occasion of his 64th birthday.

ABSTRACT: In this account, we have highlighted our most recent works towards the total synthesis of bioactive natural products, which have resulted in the development of several novel synthetic methods. Inspired and guided by strategies based on diversity-oriented synthesis, we have successfully applied the novel synthetic methodologies developed in our lab to the total synthesis of a diverse collection of structurally challenging targets. We have also documented the evolution of these synthetic strategies. The total syntheses described in this account have been organized from the perspective of different molecules whilst still alluding to the parallel synthetic strategies involved. DOI 10.1002/tcr.201402015 Keywords: Diels–Alder reactions, natural products, Pauson–Khand reactions, synthetic methods, total synthesis

Introduction “Daring ideas are like chessmen moved forward; they may be beaten, but they may start a winning game.”—Johann Wolfgang von Goethe

The development of novel approaches for the efficient total synthesis of complex natural products has led to significant advances in organic syntheses, and enhanced the rate with which complex and diverse natural product molecules with potential benefits to society can be constructed. Furthermore, inspired by their desire to access increasingly complex natural products, synthetic chemists continue to explore the development of innovative synthetic methods that will pave the way for the total synthesis of complicated molecules. Diversity-

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oriented synthesis (DOS) was first described by Stuart Schreiber in 2000,[1] and is aimed at the efficient synthesis of a collection of structurally complex and diverse small molecules, which can then be screened in terms of their ability to modulate a biological pathway in cells or organisms, without regard for any particular protein target. Based on the DOS strategy, we became interested in the development of novel synthetic methodologies and strategies that would enable us to synthesize diverse compound collections for biological evaluation. Based on the large collection of molecules successfully synthesized in the authors’ laboratory over the last ten years, this account has been organized from the perspective of instructive design and

Chem. Rec. 2014, 14, 606–622

© 2014 The Chemical Society of Japan and Wiley-VCH, Weinheim

E f f i c i e n t To t a l S y n t h e s i s o f B i o a c t i v e N a t u r a l P r o d u c t s

based on synthetic transformations that allowed for significant improvements in our designed methods, such as the Pauson– Khand reaction (PKR), as well as the Diels–Alder (DA) and ring-closing metathesis (RCM) reactions. Furthermore, as well as simply describing our efforts towards the total synthesis of complicated molecular scaffolds, we have highlighted cases where organocascade catalysis and collective natural product synthesis allowed for the efficient construction of diverse natural product motifs bearing common molecular scaffolds. Although it may be possible for organic chemists to construct any known natural product when they are given enough time and resources, the expedient and efficient total synthesis of natural products should always be based on the development of improved synthetic methods. Architecturally complex natural products generally provide the driving force for the development of new methods for the construction of the desired scaffold. Given that the development of key synthetic methodologies nearly always provides a greater insight into the fragments involved in the formal synthesis of natural products, we always aim for the development of new synthetic methodologies and strategies with the greatest possible impact. For this reason, our interest in the construction of complex scaffolds has been focused predominantly on the development of methodologies for C–C bond formation, and transition-metal-catalyzed transformations have been recognized as one of the most powerful and widely used annulation methods in this regard. Our early efforts towards the development of ligands for C–C bond forming reactions demonstrated the feasibility of thiourea ligands in a

Yun Zhang studied chemistry at Tianjin University, where she received her BS degree in 2011. She continued her Ph.D. studies in Chemistry at Peking University under the supervision of Professor Zhen Yang and Professor Tuoping Luo. The total synthesis of natural products based on new transition-metalcatalyzed processes is the main interest of her research. Jianxian Gong received his Ph.D. from Peking University in 2012 under the supervision of Professor Zhen Yang. After a year of postdoctoral research at Memorial Sloan-Kettering Cancer Center, he returned to China and joined Professor Zhen Yang’s group as a postdoctoral research fellow at Peking University Shenzhen Graduate School. His research interests include the total synthesis of bioactive natural products and the development of new synthetic methods.

Chem. Rec. 2014, 14, 606–622

series of Pd-catalyzed cross-coupling reactions, including carbonylative annulation reactions and the Pd/Co-catalyzed PKR,[2] which allowed for the total synthesis of crisamicin A, the construction of the FGH moiety of micrandilactone A,[3] and the total synthesis of schindilactone A. In this article, we have reviewed our most recent natural product total syntheses, with particular emphasis on those that involved the use of a PKR, DA reaction or RCM reaction as the key steps. The Pauson–Khand cycloaddition[4] is one of the primary methods for incorporating cyclopentanes, as exemplified by the diastereoselective formal synthesis of coriolin.[5] In the same vein, the DA reaction represents a pivotal and efficient method for the construction of unsaturated six-membered rings,[6] and was first applied to the total syntheses of complex molecules by Woodward et al,[7] who provided a sound foundation of the use of DA reactions in total synthesis. The importance and reliability of the RCM reaction has long been utilized and expanded upon in target-oriented synthesis.[8] In this review, we describe our repertoire of highly efficient total syntheses, which highlight the many promising aspects of method development, as well as providing enough material to meet biological demand.

Recent Syntheses of the Exemplified Natural Products Caribenol A Caribenol A is a norditerpene that was first isolated in 2007 from the West Indian gorgonian octocoral Pseudopterogorgia

Zhen Yang studied medicinal chemistry at Shenyang College of Pharmacy and earned a Ph.D. at The Chinese University of Hong Kong in 1992 under the guidance of H. N. C. Wong. He carried out postdoctoral research on natural product synthesis with K. C. Nicolaou at The Scripps Research Institute in La Jolla, CA, and joined its faculty in 1995. In 1998, he moved to the Institute of Chemistry and Cell Biology of Harvard Medical School as an institute fellow before returning to China as a professor at Peking University in 2001. His research is devoted to the total synthesis of natural products and chemical biology.


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THE CHEMICAL RECORD

H

CO2Et

2 Me CO Me 2 O

O

Me

1 (prepared in 5 steps)

TBSO

Me

O

Me

Me

4


3 steps

HO

CO2Me Me

O

Me TBSO

H

H

5 Me

6 Me

4 steps

O

O Me Me

O

key step Me

H H

7

Me

BHT, toluene 120 oC (92%)

key step

Diels-Alder reaction

O Me

Me

5 steps I

CO2Me

H Me

O2, K2CO3 P(OEt)3 DMF, 60 oC (66%)

O

Me

oxidation Me

A

H

4

Me

D

5

OH B1

C

8

H Me

Caribenol A (8)

Fig. 1. Total synthesis of caribenol A.

elisabethae by Rodríguez et al.,[9] who were interested in identifying novel anti-infective and anticancer leads. The strong inhibitory activity of caribenol A against H37Rv has attracted considerable attention as a potential treatment for tuberculosis. Furthermore, caribenol A has demonstrated MIC values of >128 μg/mL and in vitro antiplasmodial activity against chloroquine-resistant Plasmodium falciparum W2 with an IC50 value of 20 μg/mL. Structurally, caribenol A consists of an unprecedented tetracyclic ring core bearing all-cis substituents at C1, C4, C5 and C8, as well as a potentially labile 2-hydroxyfuran-2(5H)-one motif (Figure 1). In light of the synthetic challenges and biological activity associated with this compound, we developed a convergent total synthesis of caribenol A, which involved the use of an intramolecular Diels–Alder (IMDA) reaction as the key step (Figure 1).[10] The synthesis of the DA precursor started from three fragments, two of which contained a single stereocenter. In contrast to our previous experience in this area,[11] this work demonstrated that the carbonyl group at C5 was crucial for efficiently reducing the LUMO energy of the highly activated dienophile as well as promoting the overlap between the diene and the dienophile. In practice, the DA reaction of ester 4 was conducted in the presence of butylated hydroxytoluene at elevated temperature to afford 5 bearing all-cis-methyl groups at C1, C4 and C8 in quantitative yield. Cyclohexadiene 5 was further elaborated to lactone 6 via a three-step hydrogenation–reduction–esterification reaction sequence. The A ring was then diastereoselectively tuned via sequential deprotection, oxidation and hydrogenation reactions, followed by a Pd-catalyzed Negishi coupling reaction between the


resulting enolate and ZnMe2. In the second key step, exposure of 7 to O2 under basic conditions, according to the procedure originally developed by Corey and Ensley,[12] allowed for the successful installation of the hydroxyl group at C5 and completed the total synthesis of caribenol A. (−)-Flueggine A and (+)-Virosaine B One of the several emerging classes of Securinega alkaloids includes (−)-flueggine A and (+)-virosaine B, which were isolated from the twigs and leaves of Flueggea virosa by Ye et al.[13] in 2011 and 2012, respectively. Flueggine A has been reported to exhibit modest activities in three breast cancer cell lines, with IC50 values of 60 ± 4 (MCF-7), 86 ± 9 (MDA-MB-231), and 68 ± 7 μM (MCF-7/ADR).[13b] Virosaine B showed no cytotoxic activity against MCF-7, MDA-MB-231, HepG2, HepG2/ADM, HL-60, K562 or Hep2 cells, but did exhibit significant inhibitory activity towards the growth of MCF-7 and MDA-MB-231 cells, with IC50 values of 135 ± 5 and 147 ± 3 nM.[13b] Compared with other Securinega alkaloids, (−)-flueggine A and (+)-virosaine B both contain unprecedented isoxazolidine and 7-oxa-1-azabicyclo[3.2.1]octane rings (Figure 2). Significant research efforts have been devoted to the total synthesis of the Securinega alkaloids.[14] To synthesize enough material to allow for the effective evaluation of the biological properties of these compounds, we developed novel synthetic strategies for the total synthesis of (−)-flueggine A (19) and (+)-virosaine B (20).[15] Starting from the commercially available Weinreb amide 9, a four-step sequence provided access to enynes 10 and 11 (Figure 2). Inspired by the methodology developed by Honda et al.[16] for the construction of the core structure of (−)-securinine, we targeted enynes 10 and 11 as the precursors for the RCM reactions because it was envisaged that these sterically less encumbered terminal olefins would react first with the ruthenium catalyst. When we first began our study towards the total synthesis of 19 and 20, no methodology was available for the successful intramolecular reaction of “an active ester-carbene complex” with an alkyne to form an α,β-unsaturated lactone. Following an extensive investigation, it was established that the treatment of enynes 10 and 11 with Zhan-1b catalyst (14) afforded dihydrobenzofuranones 12 and 13, respectively, and that subsequent sequential allylic bromination, deprotection and N-alkylation reactions provided ample quantities of (−)norsecurinine (15) and (+)-allonorsecurinine (16). Subsequent sequential [2,3]-Meisenheimer rearrangement, [1,3]sigmatropic rearrangement and oxidation allowed for the conversion of 15 to nitrone 17, which was subjected to a 1,3-dipolar cycloaddition reaction with 15 in refluxing toluene to afford (−)-flueggine A (19) in good yield. This 1,3-dipolar cycloaddition supported the biogenetic pathway, and the same strategy was applied to the synthesis of (+)-virosaine B (20).

Chem. Rec. 2014, 14, 606–622



O

O

O

O H

H

O O

N

N

toluene reflux

3 steps (74%)

H O

15 +

(77%)

(-)-Norsecurinine (15)

17

3 steps (33%) Me H N Boc

4 steps (32%)

Me

O

12 MesN NMes Cl Cl Ru Me

H N Boc

Zhan-1b (14) O

(5 mol%) Zhan-1b

Me O

toluene reflux (67%)

O H

11

O

O

H

NBoc

13

3 steps (69%) O

O

m-CPBA

H O

DCE O

SO2NMe2

O

Me

4 steps (23%)

H

NBoc

10

Me

H

O

H

toluene reflux (64%)

O N Me H N Me Boc

HO

O

(5 mol%) Zhan-1b

O

H

O

H

O

N

O HO

HO

H

H

N

H

(-)-Flueggine A (19)

9

O

N

H

AcOH 45oC (76%)

(+)-Virosaine B (20)

2 steps (82%)

N

H

O

N

O

18

(+)-Allonorsecurinine (16)

Fig. 2. Total syntheses of (−)-flueggine A and (+)-virosaine B.

Pentalenolactone A Methyl Ester Pentalenolactone A methyl ester was first isolated as a sesquiterpene derivative from the culture broths of Streptomyces UC5319 as a new biogenetically related cometabolite belonging to the pentalenolactone family, which includes pentalenolactones A, B, D, E, F, G, H, O and P,[17] bearing a common angularly fused tricyclic pentanoic lactone scaffold. Biological evaluation of this compound revealed that it exhibited a broad range of activities, including antibacterial, antifungal, antiviral, and antitumor activities, as well as being an inhibitor of glycolysis.[18] Since the first reported total synthesis of pentalenolactone (30) by Danishefsky in 1978,[19] numerous other syntheses have appeared in the literature towards 30,[20] pentalenolactones E and F,[21] pentalenolactone G,[22] deoxynorpentalenolactone H,[23] and pentalenolactone P.[24]

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Biosynthetic studies of compounds belonging to the pentalenolactone family have demonstrated that the hydrocarbon pentalenene is the parent intermediate for all of the other members of the pentalenolactone family. Careful consideration of compounds belonging to this structural class, however, suggests that they differ from each other in terms of the functionalities on their A ring as well as the nature of the group in the α position of the carbonyl group in the C ring. With this in mind, we proposed intermediate 28 as a platform for the collective total synthesis of the entire family of compounds, as well as any closely related analogues, and subsequently accomplished the first total synthesis of pentalenolactone A methyl ester in 18 steps and an overall yield of 0.4% (Figure 3).[25] Our synthesis started with the construction of the 5,5fused bicyclic system via the PKR of a 1,6-enyne according to a similar strategy to that used previously for the synthesis of



THE CHEMICAL RECORD

Fig. 3. Total synthesis of pentalenolactone A methyl ester.

methyl deoxynorpentalenolactone H.[23] Although this strategy effectively confirmed that the stereoselectivities of the allylic and propargylic substituents were correct, the introduction of the lactone was synthetically long-winded and low yielding, which suggested that the PKR substrate was particularly sensitive to the reaction conditions. It was envisaged that a telescoped intramolecular Michael/ olefination (TIMO) cascade reaction would allow for the complex architecture around the congested stereocenter to be rapidly constructed, and we consequently evaluated the highly functionalized 1,6-enyne 21 as the potential substrate for the PKR (Figure 3). The minimization of the steric interaction between the pre-installed TMS and CH2OTBS groups acted as a driving force for the reaction and allowed for the formation of cyclopentanone 22 as a single diastereoisomer. Subsequent methylation of the enone followed by decarboxylation of one of the methyl esters afforded the alcohol, which esterified with a phosphonate side chain to afford the TIMO precursor 23. Once again, the introduction of the TMS group provided the necessary driving force to initiate the Michael addition, which was successfully applied to the TIMO to give α-methylene-δpentyrolactone 24. A subsequent series of functional group interconversions, including methylation via the Stille coupling of an enol triflate, which occurred with inversion of the stereochemistry at C1, and epoxidation of the exocyclic methylene


using the reduction–epoxidation–oxidation sequence reported by Danishefsky et al.[26] in their synthesis of compounds belonging to the pentalenolactone family, completed our total synthesis of pentalenolactone A methyl ester 26. This strategy also allowed for the formal synthesis of pentalenolactone without inversion of the C1 stereochemistry. Schindilactone A Schindilactone A (31) and micrandilactone A (32) are nortriterpenoids that were isolated by Sun et al.[27] from plants belonging to the Schisandraceae species, which are mainly distributed throughout Southern China, where they are used as traditional herbal medicines for the treatment of rheumatic lumbago and stomach disorders. The dried berries of these plants are often referred to as wu wei zi or schisandra, and are commonly marketed as dietary supplements, as well as being displayed as an ingredient in beer. The challenges posed by the structural complexity of these compounds are quite clear, in that they possess a unique ketal moiety spanning a 7–8 fused carbocyclic core that links the highly oxygenated framework of the ABC fragment to the FGH moiety bearing eight contiguous chiral centers (Figure 4). Several research efforts towards the development of fragment-based strategies for the synthesis of micrandilactone A have been described in the literature,

Chem. Rec. 2014, 14, 606–622



O

O Me

O

A O

HO

F

H

E

H

O

G

D

C

O B

Me

O O

Me MeH

H O O

O

Me

key step

reaction

O

33

O

OTES

OH

Me

H

O O

Me H

35

Me

O

O

O

OTES

Me

BrMg

H

Br

36 OTBS 2. OtBu

PdCl2,CuF2 [P(o-tol)3]2 THF, 75 oC (85%)

OTES O

C

O

E

38

BnO

OH

Me

O

key step

O

Me

O

H H O

G

O

BnO

H H

44

O

carbonylative annulation

Me

H

O

Me H

O

BnO

O

Pd(OAc)2 47, CuCl2, CO THF, 70 oC (78%)

H O

BnO

O

42 8 steps O

Me

OTES

O

Me H

Me

F

O

O Me

O

H

OTES

[Co2(CO)8] TMTU Me O Me H benzene 70oC (74%)

41

OTES

PKR O

O

Me H

O

key step

Me

O

O

THF, 0 oC Me t H (88%) Me 37 BuO

OTES

40

Me

Me

1. AgClO4.H2O acetone 30 oC (82%)

Me

OTES

O Me

4 steps

OTBS Br

H

Grubbs II catalyst MgBr2, DCM, 30 oC (65%)

key step (RCM Rx) O

OTES

O B

O

39

O

Me

O

3 steps

OBn

H

OTBS

O

O

O

O Me

O MeO MeO

Et2AlCl toluene 0 oC (65%)

34

H

O

H O OH

Micrandilactone A (32)

OTBS Diels-Alder

MeO

O

Me MeH

Schindilactone A (31)

Me OH H O G

H

D

C

O B

OH

F

E

A O

H

H H

Me

O

20

13

22

H

23

OH

BnO

Me H

OH

43

2 steps

O AcO O Me

Me

H

Me

O H

O OH

45

H O

Dieckmann-type rearrangement

H O

H Me

O

key step

Me

LiHMDS THF, -78 oC

O

A

HO

Me

O Me H

O

O Me

Me

H

OH

H O

46

H O

H Me

O

DMP, NaHCO 3, CH2Cl 2 (60%) for last two steps

O Me

Me N

N

S ligand A (47)

HO

O

O

O Me

Me

H Me

O

H O H

Me H H O O

Me Schindilactone A (31)

Fig. 4. Total synthesis of schindilactone A.

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THE CHEMICAL RECORD

including: (1) an approach involving the efficient construction of the western fragment and ABC tricyclic ring system using DA, Horner–Wadsworth–Emmons cascade and RCM reactions as the key steps;[28] (2) an approach directed at the FGH ring system using a cobalt/thiourea-catalyzed PKR and palladium/thiourea-mediated carbonylation reaction as the key steps;[3] and (3) an approach involving the synthesis of a 7,8fused ring fragment via a [3,3]-sigmatropic rearrangement process.[29] These efforts effectively provided a blueprint for the total synthesis of schindilactone A according to a 29-step linear sequence,[30] which started with DA reaction of 33 and 34 for the construction of the BC precursor 35. Subsequent sequential Grignard addition–lactonization, α-hydroxylation, hydroxyl protection and cyclopropanation reactions provided access to dibromocyclopropane 36, which underwent a silver perchlorate–mediated ring-expansion reaction, followed by Pd-catalyzed cross-coupling of the resulting seven-membered vinyl bromide to give 37. The task of obtaining the unfavorable entropic and enthalpic eight-membered ring was initiated via a diastereoselective Grignard addition, which was effectively controlled by the steric bulk of the TES protecting group, followed by the construction of the D ring via an in situ esterification reaction. The potential for double-bond isomerization was eliminated through direct α-hydroxylation, which occurred in a regio- and diastereoselective manner because of the steric bulk of the pre-installed TES protecting group. Subsequent protection of the alcohol followed by Grignard addition to the D-ring lactone gave the RCM precursor 39. Pleasingly, the treatment of 39 with Grubbs’ second-generation catalyst allowed for the RCM reaction and MgBr2-mediated in situ epimerization of the hemiketal to give the fused eight-membered moiety 40. The F ring was constructed by the intramolecular cobalt/thiourea-catalyzed PKR of 40, which gave 42 diastereoselectively. Based on previous model studies, it was possible to construct compound 44, consisting of a fused pyran-γ-lactone moiety, via the carbonylative annulation of 43 catalyzed by palladium and the thiourea ligand 47. A two-step sequence, including the conversion of the TES ether to the corresponding acetate ester and cleavage of the benzyl protecting group, followed by the Dieckmann-type condensation of the acetate to the nearby lactone gave 46. Dess–Martin oxidation of the allylic alcohol completed the first total synthesis of schindilactone A in 29 steps and an overall yield of 0.17%. Maoecrystal V Since the characterization of diterpenoid maoecrystal V by Sun et al.[31] in 2004, following its isolation from the leaves of Isodon eriocalyx in a yield of 0.00004%, chemists have been attracted by its striking molecular architecture and remarkable biological activities. Maoecrystal V has been reported to display


highly selective activity towards HeLa cells (IC50 = 60 nM), whilst being nontoxic towards K562, A549, BGC-823 and CNE cells. From a structural perspective, maoecrystal V consists of a gem-dimethyl cyclohexenone ring (ring A), which is spiroannulated to a lactone ring (ring C) and fused with the strained tetrahydrofuran (THF) ring (ring B). Ring B is also annulated with a bridged bicyclo[2.2.2]octanone ring system (rings D/E) bearing six stereocenters, three of which are contiguous quaternary centers. Given its fascinating structure and distinguished biological activity, several groups have directed significant research efforts towards the development of efficient strategies for the synthesis of this compound.[32] To date, three groups have successfully completed the total synthesis of maoecrystal V using an IMDA reaction as the key step.[33] Total Synthesis of Maoecrystal V by Yang’s Group In 2011, we reported the first total synthesis of maoecrystal V (54) using a Rh-catalyzed O–H insertion, Wessely oxidative dearomatization and IMDA reaction as the key steps (Figure 5).[33a] In light of the potential disadvantages associated with the 1,4-diketone polarity effect during the joining of the A and D/E rings, we proposed the late-stage allylic oxidation of the C1 position. The C10 quaternary stereocenter of 48 was initially installed using a Pd(OAc)4-mediated oxidative arylation reaction. Compound 48 was subsequently converted to diazo ester 49 in four steps, after which 49 was elaborated to lactone 50 bearing an oxa-bridge motif via a Rh-catalyzed O–H insertion reaction. Phosphonate 50 was subjected to a Horner–Wadsworth–Emmons (HWE) reaction to give dienophile 51 with the correct stereogenic center. Treatment of 51 with Pb(OAc)4 in acetic acid led to the oxidative dearomatization of the phenol, which was followed by a direct IMDA reaction to give the C16 epimers 52 and 53. Although the facial selectivity of the IMDA reaction was not optimal, this reaction sequence allowed for the pentacyclic skeleton of maoecrystal V to be efficiently constructed in only ten steps. Compound 52 was finally transformed into maoecrystal V (54) bearing an α,β-unsaturated ketone on its A ring in seven steps. Thus, we accomplished the first total synthesis of maoecrystal V in 17 steps and an overall yield of 1.2%. Total Synthesis of Maoecrystal V by Danishefsky’s Group In 2012, Danishefsky et al.[33b] reported the total synthesis of maoecrystal V in 32 steps and an overall yield of 0.08% using an IMDA reaction as the key step prior to the construction of the strained B ring (Figure 6). One of the major difficulties associated with their initial efforts was exerting some control over the facial selectivity of the IMDA reaction and the C5 methyl group, which generally resulted in an unintended reduction.[32c,32i,33b] Danishefsky’s group overcame this

Chem. Rec. 2014, 14, 606–622



O

P

O

OEt OEt N2

O

MeO2C Me O

Me

OMOM

OMOM OH

4 steps

Me Me

Me Me


OMOM O O

key step

O Rh-catalyzed P O O-H insertion Me Me EtO

49

OEt

50

a. OAc

Me

Me

Rh2(OAc)4 PhH reflux (95%)

O O

Me

Me

O O

tBuOK,

THF (HCHO)n, 0 oC (95%)

b. TFA DCM (90%) Me

key step OMOM O O

IMDA reaction

53 (40%) AcO Me O

Pb(OAc)4, AcOH then PhMe, 145oC

O

Me Me Me

51

O O

Me

O

52 (36%) 7 steps 1

2 3

5

4

Me

18

H Me 17

16 15 E 10 9 11

A

Me

O

O

B

6

19

OC O 7

D

13 14

8

12

O

Maoecrystal V (54) Fig. 5. Total synthesis of maoecrystal V by Yang’s group.

O

OTBS

O

key step

IMDA reaction

4 steps 10

CO2Me

O

55 H O

Me

Me

O

O

toluene sealed tube1 166 oC then TBAF SO2Ph THF

Me

O

Maoecrystal V (54)

O

57

OH

O

O O

59

O

3 steps O

OMOM

9 steps O O

56

14 steps

O

exo-glycal epoxide/ rearrangement

HO O

O

58

Fig. 6. Total synthesis of maoecrystal V by Danishefsky’s group.

Chem. Rec. 2014, 14, 606–622



THE CHEMICAL RECORD

problematic scenario, however, using a revised route, which involved the presentation of the A ring in an achiral form in the IMDA precursor 56. This alternative route began with the alkenylation of an enolate to provide the first quaternary center at C10, and compound 55 was then used as a platform for the construction of the IMDA precursor 56 through sequential reduction, oxidation and acylation reactions. The application of a thermal IMDA reaction followed by elimination of phenylsulfinate gave the unsaturated lactone 57. The synthesis of the strained hydrofuran B was successfully addressed using an exo-glycal epoxide/rearrangement sequence, because of the failure of the direct cyclization strategy and the disadvantages associated with the external delivery of a hydrogen atom to the β face of C5. The completion of the revised route to maoecrystal V still required the installation of the gem-dimethyl cyclohexenone functionality on the A ring of 59, and this was achieved, albeit with an epimeric stereocenter at C16, in nine more steps.

Total Synthesis of Maoecrystal V by Zakarian’s Group Zakarian et al.[33c] also reported a total synthesis of maoecrystal V that used an IMDA reaction to efficiently build up the molecular complexity (Figure 7). The factor that distinguished this particular synthesis from all of the others was that it started from the east wing of maoecrystal V and involved the early construction of the tetrahydrofuran ring. With diazoester 63 in hand, Rh-catalyzed C–H insertion followed by alkylation gave 64 with the B ring intact as well as the C9 quaternary carbon center. These features of the system were introduced at an early stage in an attempt to avoid any of the issues associated with the strained nature of the system during the latter stages of the synthesis. Experimental work towards removal of the linking functional groups revealed that the use of a silyl tether effectively facilitated the stereoselective IMDA reaction as well as the facile removal of the tether in 66.[34] Compound 66 was then converted to selenocarbonate 67 via the removal of the

OPMB

HO

60 O

CO2Me

62 Cl

N2

O

O

CO2Me OPMB

3 steps

O

OH

O

Rh2(OAc)4 CH2Cl2 dr 10:1

O

PMBO Me

OEt OEt

OBn O

OBn CO2Me OPMB

9

LDA, THF Et2Zn BnOCH2Cl dr 9:1

63

61

O

O

key step

O

64 4 steps OBn

O

EtO

IMDA reaction

EtO O Si O Me Me

Me

66

toluene 110oC (95%)

Si O OPMB

O

65

3 steps OBn O

PMBO Me

SePh

67

O

Me

radical cyclization

O O

Me O

Me

key step

O

O O

H Me

O

OBn O

PMBO Me

(Me3Si)3SiH AIBN, PhH 80oC (55%)

O

68

7 steps

1. RCM (CH2Cl)2, 80 oC DMP, DCM (86% in 2 steps)

Maoecrystal V (54)

O O

Me

OH Me

O

O O

Me

69

H Me

O

Fig. 7. Total synthesis of maoecrystal V by Zakarian’s group.


Chem. Rec. 2014, 14, 606–622



gem-diethoxy substituents followed by specific desilylation. Radical cyclization of 67 allowed for the linking of the formyl radical to the enol ether double bond to give lactone 68, which was converted to 69 via a seven-step sequence. With 69 in hand, the synthesis was well poised for the final construction of maoecrystal V through sequential RCM and oxidation reactions. Fusarisetin A (+)-Fusarisetin A (70) is a tetramic acid–based natural product with promising anticancer properties that was first isolated from the soil fungus Fusarium sp. FN080326 in 2011.[35] This compound has been reported to exhibit potent inhibitory activity towards the metastasis of MDA-MB-231 breast cancer cells, as well as inhibiting acinar morphogenesis (77 μM), cell migration (7.7 μM), and cell invasion (26 μM) in the same cell line without any significant cytotoxicity, and has consequently elicited considerable levels of biological interest. In contrast, the activities of (−)-70 and 80 against these targets are much less pronounced.[36] In light of the interesting biological properties of these compounds and the challenges associated with the construction of their complex molecular architecture, there has been considerable interest in their synthesis, with several groups succeeding in the total synthesis of both (−)-fusarisetin A[37] and (+)-fusarisetin A.[38] The first total synthesis of (−)-fusarisetin A was accomplished by Li et al.[37b] and resulted in the revision of the reported absolute configuration. Equisetin (80), which is another secondary metabolite from Fusarium sp. with a lower oxidation state than that of fusarisetin A, was proposed to be the biosynthetic precursor of fusarisetin A by Theodorakis et al.[37a] Gao et al.[38c] recently suggested that fusarisetin A and equisetin were both biosynthetic derivatives of the polyenoylamino acid 82. Recently, Theodorakis and co-workers reported structure– function studies by synthesizing fusarisetin A analogues to interrogate the biological significance.[39] From a structural perspective, the spiroskeleton of rings C and E, bearing a quaternary stereocenter at the angular position of the 5,5,5fused tricyclic scaffold, could be made from amide 75 via a Dieckmann-type cyclization reaction followed by hemiacetalization. This particular approach was also adopted by Li and Theodorakis in their syntheses of (−)-fusarisetin A, as well being used by Gao and Theodorakis in their syntheses of (+)-fusarisetin A. The trans-decalin unit (i.e., the A/B ring system) has generally been constructed using an IMDA reaction. This strategy was first used by Dixon et al.[40] to synthesize 74, and was also applied to the synthesis of (−)-fusarisetin A by the Li and Theodorakis groups. In contrast to this general strategy, our strategy involved the use of an intramolecular PKR for the construction of the tricyclic A/B/C ring system.

Chem. Rec. 2014, 14, 606–622

Total Synthesis of (−)-Fusarisetin A by Li’s Group Li et al.[37b] completed the first reported total synthesis of (−)fusarisetin A in 2012 (Figure 8). During the course of this particular total synthesis, Li’s group solved one of the major challenges associated with the construction of pentacyclic targets by developing a strategy for the sequential construction of the trans-decalin fragment and the 5,5,5-fused tricyclic moiety bearing a quaternary stereogenic center at its angular position. Starting from (S)-citronellal, Li’s group used a tenstep sequence to provide access to precursor 71, which underwent a BF3·OEt2-promoted IMDA reaction to give transdecalin 72 as a single diastereomer. The O-allylation hydrofuran product was kinetically favored over the C-allylation product, and the Pd(OAc)2-catalyzed C–O bond activation reaction consequently allowed for the construction of the thermally favored allylic C–C bond. A three-step reaction sequence involving aminolysis, selective oxidation of the terminal olefin, and reduction gave diol 75. Subsequent Dieckmann condensation and spontaneous hemiketalization reactions completed the total synthesis of (−)-fusarisetin A. Total Synthesis of (+)-Fusarisetin A by Gao’s Group Gao’s synthesis of (+)-fusarisetin A started from (R)-citronellal (77), which was rapidly and stereoselectively converted to aldehyde 78 by a linear seven-step sequence, which included a Wittig reaction, HWE olefination and Dess–Martin periodinane (DMP) oxidation (Figure 9). Compound 78 was converted to 79 via a one-pot diastereoselective IMDA reaction/BF3·Et2O-promoted Roskamp reaction sequence. Subsequent sequential aminolysis and Dieckmann cyclization reactions according to Danishefsky’s procedure gave equisetin (80).[41] The MnIII-mediated oxidation of 80 followed by in situ reduction of the resulting endoperoxide 81 completed the total synthesis of (+)-fusarisetin A (70) in 13 steps and an overall yield of 4.2%. In their second-generation synthesis of (+)fusarisetin A, Gao et al.[38c] proposed a strategy for the biomimetic synthesis of 70 and 80 via an IMDA reaction using polyenoylamino acid 82 as the key intermediate. The structure of peroxyfusarisetin 81 was proven by X-ray crystallographic analysis and the material itself could be synthesized from 80 using MnIII/O2 or a reactive oxygen species (ROS) produced by visible light chemistry. Total Synthesis of (+)-Fusarisetin A by Theodorakis’s Group Theodorakis et al.[37a] proposed 80 as the biosynthetic precursor of 70 in the total synthesis of (−)-fusarisetin A, and this proposal inspired them to develop an optimized scalable total synthesis of (+)-fusarisetin A (Figure 10). Starting from (R)citronellal (77), Theodorakis’s group successfully synthesized



THE CHEMICAL RECORD

O

key reaction

O

AcO

O

IMDA

O

St-Bu

H

H

PBu3, Pd(OAc)2 (75%)

HO O

Me Me

H Me

Me

H H OH

O

H

Me H

74

NaOMe, MeOH (41%) N

OH OH O

Me H H

H

H

3 steps Me

Me O O

OCH2CF3

O

75

H

Dieckmann condensation

Me

CO2Me

N

H

H

73

72

O

O Me

Me

71

O

H

CF3CH2OH (90%)

Me

Me

AgTFA Et3N

OAc

H

BF3.OEt2 (63%)

F3CH2CO

St-Bu

Me

H

(-)-Fusarisetin A (70) Fig. 8. Total synthesis of (−)-fusarisetin A by Li’s group.

Fig. 9. Total synthesis of (+)-fusarisetin A by Gao’s group.


Chem. Rec. 2014, 14, 606–622



Fig. 10. Total synthesis of (+)-fusarisetin A by Theodorakis’s group.

the trans-decalin moiety in a stereoselective manner using an IMDA reaction, and proceeded to complete the total synthesis of (−)-equisetin (80) using similar chemistries to those previously published in the literature, albeit without any protecting groups. Under the optimized oxidation conditions, 80 underwent a 5-exo-trig metal-promoted oxygen reactive cyclization (ORC) reaction, which allowed for the construction of the C1–C6 bonds and the C/D rings. Theodorakis et al.[38a] also accomplished the protecting-group-free total synthesis of (+)fusarisetin A in eight steps and 5% yield, which enabled them to prepare 200 mg of (+)-70 for further investigations. Total Synthesis of (+)-Fusarisetin A by Yang’s Group In contrast to Theodorakis’s approach of using an IMDA reaction to construct the trans-decalin moiety, we used an intramolecular Co2(CO)8-mediated PKR to form the fused cyclopentenone system of 84 in a single step with concomitant formation of a unique C16 quaternary chiral center (Figure 11).[38b] The use of mesylate as a protecting group avoided the potential problems of ketone-mediated epimerization and secured the stereochemistries of the C6 and C7 positions. A series of protecting group transformations was then required to provide access to the enol triflate precursor 85, which was subjected to a Pd-catalyzed carbonylative esterification reaction to give the α,β-unsaturated ester 86. Subsequent epoxidation gave 87, which was subjected to a four-step reaction sequence, consisting of consecutive demesylation, reductive epoxide ring-opening, oxidation, and aminolysis reactions to give amide 88. Deprotection of 88 gave alcohol 89, which was subjected to a Dieckmann condensation reaction to give (+)-fusarisetin A in 16 steps and an overall yield of 1.3%.

Chem. Rec. 2014, 14, 606–622

Drimane-Type Sesquiterpenoids Drimane-type sesquiterpenoids are a class of natural products endowed with a disparate set of biological profiles, which are characterized by their structural diversity.[42] A large number of the compounds belonging to this structural class are oxygenated at C15 and have a characteristic [6-6-5] tricyclic system, such as kuehneromycin A (95) and antrocin (96). Some of the other compounds belonging to this class, such as anhydromarasmone (97) and marasmene (94), possess an additional ring system and are consequently based on a much more structurally complex [6-6-5-5] tetracyclic framework. This structural variety has captivated the imaginations of a number of research groups,[42] including our own,[44] and inspired several successful studies towards the total synthesis of compounds belonging to this structural class. Most of the synthetic strategies developed for the construction of these sesquiterpenoids have focused on the use of an IMDA reaction to deliver the tricyclic core structure.[43a,43c,45] Our initial goal in this endeavor was the development of a general strategy for the synthesis of compounds 94–97 starting from intermediate 90 (Figure 12). The trans relationship between the two alkynes and the nucleophilicity of the external nucleophiles were identified as critical parameters in terms of being able to control the cascade cyclization (i.e., 5-endo-dig cyclization to 6-exo-dig cyclization) and deliver the required [6-6-5] tricyclic skeleton. Following an extensive period of optimization, a suitable set of reaction conditions was successfully developed for the desired gold-catalyzed cascade reaction, which involved the treatment of diyne 92 with (IPr)AuCl/AgSbF6 and nucleophilic BnOH in CH2Cl2 at ambient temperature to give 93 in 54% yield. With the diastereoselective diyne 90 in hand, the application of



THE CHEMICAL RECORD

Me

OTBS

Me

H

key step Me PKR

H

H Me

Me

H

H Me 4 steps

O Me N

H

85

H

Me

H OTBS [O]

OMs

H

O COOMe

OTf

(65%)

Me

H Me (73%)

H OTBS H Me

Pd(PPh3)4, CO MeOH, 55 oC

H

87

O

5 steps

OMs Me

OMs Me

O

84

H OTBS

H

86

H OTBS H Me COOMe

COOMe

88

OTBS Me

OTBS

H

Me

H

Me Me

Co2(CO)8 PhMe, 120 oC OH (82%) Me 83 (prepared in 3 steps) Me

OH

key step Dieckmann condensation

H Me

H OH

H

H Me

O

O

NaOMe MeOH (73%)

H H H Me

Me N

H

Me O OH

Me

O N O Me

OH

(+)-Fusarisetin A (70) COOMe

89 OH

Fig. 11. Total synthesis of (+)-fusarisetin A by Yang’s group.

a similar gold-catalyzed cyclization reaction produced two contiguous stereogenic centers in one cascade. Subsequent functional group manipulations allowed for the successful synthesis of compounds 94–97 with far greater efficiency. In this way, we developed a unified strategy for the synthesis of drimane-type sesquiterpenoids based on a gold-catalyzed cascade reaction, which could be readily applied to the construction of other polycyclic scaffolds.

Cladiellins Several studies have recently been published towards the synthesis of cladiellins via the gold-catalyzed cascade reaction of 1,7-diynes. These studies proceeded according to the methods developed for the synthesis of compounds belonging to the drimane family, and allowed for the collective synthesis of nine biologically relevant members of the cladiellin family 98–106 (Figure 13).[46] To date, more than 100 cladiellins have been isolated, representing one of the largest subsets of natural compounds, which also possess a diverse range of biological activities.[47] The cladiellin natural products 98–106 contains several common features, including a hydroisobenzofuran ring with an


isopropyl group at C14 fused to the oxacyclononane unit, as well as six stereogenic centers at C1, C2, C3, C9, C10 and C14. It is noteworthy, however, that differences can exist between the C6, C7 and C11 substituents. In 1995, MacMillan and Overman published the first ever enantioselective approach to a 2,11-cyclized cembranoid ether that used a Prins–pinacol condensation–rearrangement sequence for the construction of the hydroisobenzofuran ring.[48] A similar strategy was also used for the synthesis of sclerophytin A, sclerophytin B and cladiell-11-ene-3,6,7triol.[49] For their syntheses of sclerophtyins A and B, which resulted in the structural revision of these compounds, Paquette et al.[50] used a DA reaction to allow for construction the A/B ring scaffold, followed by a Claisen rearrangement reaction to give the medium-ring system. Using a strategy based on a combination of Hoppe’s asymmetric homoaldol methodology and Kramer’s THF synthesis for the construction of the hydroisobenzofuran fragment, Hoppe et al.[51] reported the convergent total synthesis of (+)-vigulariol. Using a similar strategy for the introduction of the A/B ring system prior to construction of the medium-sized C ring, Campbell and Johnson applied a Lewis acid catalyzed [3 + 2] cycloaddition

Chem. Rec. 2014, 14, 606–622



OH

Me

OH

key reaction

gold-catalyzed cascade reaction BnOH [(IPr)AuCl] AgSbF6,DCM (96%)

Me

90

OBn

O

HO

O

H

O

4 steps H

H Me

Me

H

Me Me

91

H

Marasmene (94 )

2 steps OH

Me

Me

92

key reaction COOH

gold-catalyzed cascade reaction BnOH [(IPr)AuCl] AgSbF6, DCM (54%)

HO

OBn

O O

O

6 steps

O

CHO

H Me

Me

H

H

Me

93

Me

H

Kuehneromycin A (95 ) 4 steps

4 steps O

O O

H

O

O

O

H

H Me

OH

O

Me

H

Me

Anhydromarasmone (97 )

H Me

Antrocin (96 )

Fig. 12. Collective total syntheses of drimane-type sesquiterpenoids.

reaction to provide stereoselective access to the A/B ring fragment in their total synthesis of (+)-polyanthellin A.[52] In contrast, Molander et al.[53] completed the total synthesis of deacetoxyalcyonin acetate via the photochemical rearrangement of a cyclobutanone. Morken’s group used the Oshima– Utimoto reaction to allow for the stereoselective construction of the B ring, followed by sequential radical and RCM reactions to give the A and C rings, respectively, in their enantioselective synthesis of (−)-sclerophytin.[54] Several other groups have also designed synthetic strategies for the late-stage introduction of the hydroisobenzofuran system. For example, Crimmins et al.[55] completed the total syntheses of (−)ophirin B, 11-acetoxy-4-deoxyasbestinin D, (−)-astrogorgin, asbestinin-12, (+)-vigulariol and the purported structure of briarellin J via an IMDA reaction based on the preconstruction of the nine-membered cyclic ether substrate. The late-stage construction of the hydroisobenzofuran ring via a DA reaction was also reported by Kim et al.[56] and Gobbi et al.[47,57] in their separate syntheses of cladiellins. A thorough study of the synthesis of cladiellins suggested that the tricyclic compound 109, which could be accessed via an RCM reaction, could be used as a late-stage intermediate for the synthesis of cladiellins 98–106. The key step in the synthesis started with 1,7-diyne 107, which was obtained via sequential diastereoselective alkylation and asymmetric reduction reductions to give the

Chem. Rec. 2014, 14, 606–622

three stereogenic centers. The key step involved the goldcatalyzed cascade reaction of 107 with p-nitrobenzylic alcohol, which allowed for the successful construction of the [6,5] bicyclic skeleton on a gram scale. The resulting bicyclic ester 108 was then elaborated to the key tricyclic intermediate 109 in four steps. The development of an efficient process for the synthesis of this intermediate therefore enabled the total synthesis of cladiellins 98–106.

Summary and Outlook In summary, we have highlighted recent advances towards the total synthesis of bioactive natural products, with particular emphasis on the progress achieved during the course of the last ten years in the laboratories of the authors. The desire to discover novel practical routes for the construction of complex natural products invariably leads to the development of new and efficient synthetic methods. At the same time, efficient synthetic methods for constructing scaffolds with dramatic complexity and full functionality have set new standards for the planning and application of total synthesis. Trends in DOS continue to direct new strategies in total synthesis and will surely increase the efficiency of screening processes and the speed with which novel biologically active small molecules are discovered. A well-planned synthetic strategy is therefore a



THE CHEMICAL RECORD

Me H

OH

H

RO

Me

H H

H

OR O

O H H OH Me Me

Me

Me

Me

Me

H H Me

H O

H

O Me

H OH Me Me

Me

(-)-Sclerophytin A (R=H, 98) (+)-Deacetylpolyanthellin A (+)-Cladiella-6Z,11(17)-dien-3-ol (R=H, 100) (-)-Sclerophytin B (R=Ac, 99) (102) (+)-Polyanthellin A (R=Ac, 101) key reaction

HO

CO2Et

107 (prepared in 10 steps) H

H

H O

H

OR

H

H H O Me

Me

109

H

OH

H

Me

(-)-Cladiellisin (R=H, 103) (-)-Pachycladin C (R=Ac, 104)

H H Me

HO

Me

OO

OO

H Me Me OH

Me

H O

1. [(iPr)AuCl] AgSbF6 H OEt p-NO2PhCH2OH Me Me O (65%) 108 (R =p-NO2PhCH2)

H

Me

key reaction RCM Rx

O

Me Me

OR

H

gold-catalyzed cascade reaction

H

Me

Me

(-)-Pachycladin D (105)

Me

H

Me

(+)-Vigulariol (106)

Fig. 13. Collective total synthesis of cladiellins.

prerequisite for the development of remarkable and impressive feats in the field of natural product synthesis.

Acknowledgements The authors thank the National Basic Research 973 Program of China (Grant No. 2010CB833201), the National 863 Program (Grant No. 2013AA092903), the Natural Science Foundation of China (Grant No. 21372016) and the Shenzhen Basic Research Program (Grant Nos. JCYJ20130329180217059, GJHS20120628101219325, ZYC201105170335A, and ZYC201105170358A) for financial support.

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