syntheses of diverse natural products via dual-mode lewis...

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G. Du et al. AccountSyn lett

SYNLETT0 9 3 6 - 5 2 1 4 1 4 3 7 - 2 0 9 6© Georg Thieme Verlag Stuttgart · New York2017, 28, A–Maccounten

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Syntheses of Diverse Natural Products via Dual-Mode Lewis Acid Induced Cascade Cyclization ReactionsGuangyan Du1 Gaopeng Wang Wenjing Ma Qianqian Yang Wenli Bao Xuefeng Liang Lizhi Zhu Chi-Sing Lee*

Laboratory of Chemical Genomics, School of Chemical Biology and Bio-technology, Peking University Shenzhen Graduate School, Shenzhen University Town, Xili, Shenzhen 518055, P. R. of [email protected]

(±)-platencin(formal synthesis)

OO

NH

OH

OH

HO2C

O

O OHOH

(+)-phomactin A(core synthesis)

H

(±)-clavukerin A(formal synthesis)

HO

H

OH

aglycone of(±)-dendronobiloside A

(racemic synthesis)HO2C

OH

OH

NH

O

O

O

(±)-platensimycin(formal synthesis)

O

O

O

O

H

O

H

(–)-teucvidin(asymmetric

Michael/Conia-ene cascade cyclization

Diels–Alder/carbocyclization cascade

cyclization

Prins/Conia-ene cascade cyclization

+σπ π

= dual-mode Lewis acid,

πσ

π

πσ = σ-electrons, = π-electrons

LA

LA

LA

LA

LA

synthesis)

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Received: 03.02.2017Accepted after revision: 15.03.2017Published online: 06.04.2017DOI: 10.1055/s-0036-1588777; Art ID: st-2017-a0083-a

Abstract The σ/π-binding properties of a series of Lewis acids wasstudied using DFT calculations. The results led to the identification ofZn(II)/In(III) as a suitable dual-mode Lewis acid for use in promoting cas-cade cyclization reactions. Based on this finding, we developed threenew types of dual-mode Lewis acid induced cascade cyclization reac-tions and have demonstrated the utilities of each process in naturalproduct synthesis.1 Introduction2 Dual-Mode Lewis Acids3 Prins/Conia-Ene Cascade Reaction and its Applications4 Diels–Alder/Carbocyclization Cascade Reaction and Applications4.1 First Generation Diels–Alder/Carbocyclization Cascade Reaction

and its Application4.2 Second Generation Diels–Alder/Carbocyclization Cascade Reac-

tion and its Applications5 Michael/Conia-Ene Cascade Reaction and its Applications6 Conclusion

Key words dual-mode, Lewis acids, cascade cyclization, bicyclic, natu-ral products synthesis

1 Introduction

The continuously expanding need for healthcare has re-quired that greater attention be given to the discovery ofnew drugs. Because of their diverse structural scaffolds andwide ranging bioactivities, natural products represent analmost unlimited family of substances that can be em-ployed for the development of new drugs.2 Many drugs that

are derived from natural products, such as taxol and arte-misinin, have played effective roles in saving human lives.However, the continuing discovery of new drugs has beenhampered by the lack of a stable supply of natural productsfrom the natural source. Consequently, the production ofnew pharmaceutical agents to combat life-threatening dis-eases demands that efficient and versatile synthetic meth-odologies be devised to prepare natural products and theiranalogs.

Cascade reactions,3 the benefits of which include atomeconomy, and reduced time and labor, are promising meth-ods that can be utilized to prepare a variety of substancesfor biological evaluations. Synthetic sequences that employthese types of processes are typically more efficient thanthose that utilize multiple steps and more traditional pro-cedures. The cascade reaction concept has dramaticallychanged the way synthetic chemists design strategies to ac-cess structurally complex molecules.

We have had a long-standing interest in the develop-ment of dual-mode Lewis acid induced cascade cycliza-tions. Dual-mode Lewis acids can play an important role inpromoting cascade reactions because they serve to activatereactions of both the starting materials as well as interme-diates through different types of σ- and π-binding modes.As shown in Figure 1, a single dual-mode Lewis acid can in-duce an intermolecular or intramolecular cascade cycliza-tion sequence leading to the formation of polycyclic frame-works bearing multiple functional groups and stereogeniccenters. Moreover, reversible processes4,5 such as theMichael and the Diels–Alder (DA) reactions can be driven in

© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–M

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a forward direction when coupled with subsequent irre-versible processes such as Conia-ene or carbocyclization re-actions.6,7 Based on this analysis, we have developed a se-ries of cascade cyclization reactions and demonstrated theirutility in the synthesis of natural products. This account is a

revised and updated version of an article describing theseefforts that was published in the Chinese Journal of OrganicChemistry,8 which unfortunately is not easily accessed bythe general organic chemistry community.

Biographical Sketches

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(from left to right) Guangyan Du receivedhis B.A. in Applied Chemistry from East Chi-na University of Science and Technology in2009. He then joined Professor Chi-SingLee’s group at the Peking University Shen-zhen Graduate School as a graduate student,where he focused on studies of the synthesisof phomactin A using the Prins/Conia-enecascade cyclization strategy. He is currentlya postdoctoral research fellow in ProfessorNathanael S. Gray’s laboratory in HarvardMedical School, where his efforts focus ondeveloping kinase inhibitors. GaopengWang received his B.S. in Physical Chemistryin 2013 from Heinan Polytechnic Universityand his M.S. in Chemistry and Chemical En-gineering in 2016 from Jiangxi Science andTechnology University. He is currently a re-search associate in Professor Chi-Sing Lee’slaboratory, and his studies focus on naturalproduct synthesis using a Diels–Alder/carbo-cyclization cascade cyclization strategy.Wenjing Ma received her B.S. in Pharma-ceutical Sciences from Zhengzhou Universi-ty in 2012. She is currently a fifth-yeargraduate student in Professor Chi-Sing Lee’slaboratory in Peking University ShenzhenGraduate School, and her investigations fo-

cus on total the synthesis of ent-kaurene-re-lated natural products. Qianqian Yangreceived her B.S. in Pharmaceutical Sciencesfrom Shandong University at Weihai in2012. She is currently a fifth-year graduatestudent in Professor Chi-Sing Lee’s laborato-ry in Peking University Shenzhen GraduateSchool, and her efforts focus on the totalsynthesis of natural products using theDiels–Alder/carbocyclization cascade cy-clization strategy. Wenli Bao received herB.S. in Pharmaceutical Sciences from Liaon-ing Normal University in 2012. She is a fifth-year graduate student in Professor Chi-SingLee’s laboratory in Peking University Shen-zhen Graduate School, and her studies focuson the total synthesis of natural products us-ing the Prins/Conia-ene cascade cyclizationstrategy. Xuefeng Liang received his B.S. inChemistry from Sun Yat-sen University in2012. He is currently a fifth-year graduatestudent in Professor Chi-Sing Lee’s laborato-ry in Peking University Shenzhen GraduateSchool, and his work focuses on the totalsynthesis of natural products using the Mi-chael/Conia-ene cascade cyclization strate-gy. Lizhi Zhu received his B.S. in Chemistryfrom Sichuan University in 2009. He then

joined Professor Chi-Sing Lee’s group in thePeking University Shenzhen GraduateSchool as a graduate student, where he fo-cused on the synthesis of platensimycin andplatencin using the Diels–Alder/carbocyclization cascade cyclizationstrategy. He is currently a postdoctoral re-search fellow in Professor Chi-Sing Lee’sgroup, and his studies focus on the totalsynthesis of ent-kaurene-related naturalproducts. Chi-Sing Lee received his B.A. inChemistry from Indiana University of Penn-sylvania in 1992, and his Ph.D. in Chemistry(in Professor Craig J. Forsyth’s laboratory)from the University of Minnesota at TwinCities. After graduating, he spent two yearsin Pharmacia and Upjohn as a postdoctoralfellow. He then joined The University ofHong Kong as a lecturer in 2001 and CityUniversity of Hong Kong as a research fellowin 2003. Lee then joined Peking UniversityShenzhen Graduate School as a principle in-vestigator and his studies focus on develop-ing new types of dual-mode Lewis acidinduced cascade cyclizations for naturalproduct synthesis.


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Figure 1 Dual-mode Lewis acid induced cascade cyclization strategies

2 Dual-Mode Lewis Acids

During a search for suitable dual-mode Lewis acids thatcan be employed in new cascade cyclization reactions, wedetermined the binding enthalpies of a variety of Lewis ac-ids and their σ-/π-binding companions, which include pro-pene/acetaldehyde and styrene/benzaldehyde, by usingdensity functional theory (DFT) calculations. As shown inTable 1, Lewis acids derived from main group elements,such as MgX2 and AlX3, generally have stronger σ-bindingthan π-binding abilities, while transition-metal-based Lewisacids, including AuCl and Pd(OAc)2 have stronger π-bindingthan σ-binding abilities. π-Binding in these cases involvesback-bonding between the filled d orbitals of the transitionmetal to the π* orbitals of the substrates. The trends seen inthese results are consistent with those arising from B3LYP-based calculations reported earlier by Yamamoto.9

To promote one-pot sequential cyclization reactions,Lewis acids need to have slightly higher σ-binding enthalp-ies and sufficiently strong σ-/π-binding abilities. Inspectionof the plot (Figure 2) of the π-binding enthalpies (ΔHπ)against the differences in the π/σ-binding enthalpies (ΔHπ –ΔHσ), arising from the calculations, shows that Zn(II)-,In(III)-, and Fe(III)-based Lewis acids (box in Figure 2) havesimilar π-binding enthalpies ranging from –10 to –30 kcalmol–1 and σ/π-binding enthalpy differences (ΔHπ – ΔHσ) inthe range of 2 to 7 kcal mol–1. However, we expected thatFe(III)-based systems might not be suitable dual-modeLewis acids for cascade cyclization reactions owing to theirability to oxidize 1,3-dicarbonyl compounds. With these re-sults in mind, we initiated studies aimed at developingdual-mode Lewis acid induced cascade cyclization reac-

tions that could serve as efficient methods to synthesizescaffolds of natural products that have important biologicalactivities.

+σπ π

πσ

π

(a) Intermolecular cascade

(b) Intramolecular cascade

= dual-mode Lewis acid, πσ = σ-electrons, = π-electronsLA

LA

LA

LA

LA

Table 1 Binding Enthalpies (kcal mol–1) of Lewis Acids Toward Pro-pene/Acetaldehyde and Styrene/Benzaldehyde and the Differences10

Entry Lewis acid R = Me (R = Ph)

ΔHπ – ΔHσ

1 AuCl –41.9 (–39.8) –26.9 (–28.2) –15.0 (–11.6)

2 Pd(OAc)2 –16.8 (–15.9) –3.2 (–3.7) –13.6 (–12.2)

3 AuCl3 –45.6 (–46.3) –33.9 (–35.8) –11.7 (–10.5)

4 CuCl –37.8 (–36.2) –30.7 (–32.7) –7.1 (–3.5)

5 AgCl –27.3 (–25.7) –20.5 (–21.6) –6.8 (–4.1)

6 AgOTf –34.9 (–34.6) –28.4 (–29.3) –6.5 (–5.3)

7 CuI –33.7 (–32.4) –28.0 (–29.3) –5.7 (–3.1)

8 CuCl2 –24.9 (–26.2) –21.7 (–23.1) –3.2 (–3.1)

9 Ni(acac)2 –7.4 (–6.7) –5.2 (–5.1) –2.2 (–1.6)

10 Cu(OAc)2 –10.3 (–10.0) –10.6 (–10.4) 0.3 (0.4)

11 HgCl2 –13.1 (–13.5) –14.4 (–15.1) 1.3 (1.6)

12 FeBr3 –28.9 (–28.6) –30.8 (–33.5) 1.9 (5.1)

13 ZnI2 –18.8 (–19.0) –21.3 (–23.1) 2.5 (4.1)

14 FeCl3 –29.3 (–28.9) –32.1 (–33.8) 2.8 (5.1)

15 ZnBr2 –20.7 (–21.5) –23.8 (–23.7) 3.1 (2.2)

16 Zn(OTf)2 –24.4 (–25.0) –27.5 (–30.0) 3.1 (5.0)

17 ZnCl2 –20.5 (–20.5) –24.1 (–25.7) 3.6 (5.2)

18 BF3 –6.7 (–4.9) –11.5 (–12.6) 4.8 (7.7)

19 BCl3 –5.6 (–3.9) –11.4 (–14.1) 5.8 (10.2)

20 InBr3 –22.8 (–22.4) –28.6 (–31.0) 5.8 (8.6)

21 InCl3 –23.1 (–22.2) –29.5 (–32.4) 6.4 (10.2)

22 TiCl4 –5.9 (–5.3) –12.4 (–12.9) 6.5 (7.6)

23 In(OTf)3 –14.2 (–15.0) –20.8 (–25.1) 6.6 (10.1)

24 SnCl4 –7.3 (–6.2) –15.4 (–17.1) 8.1 (10.9)

25 MgBr2 –19.0 (–20.4) –28.2 (–30.9) 9.2 (10.5)

26 MgCl2 –18.6 (–19.9) –28.0 (–30.4) 9.4 (10.5)

27 AlMe2Cl –12.8 (–11.7) –23.3 (–24.7) 10.5 (13.0)

28 AlEt2Cl –13.4 (–12.4) –24.2 (–25.5) 10.8 (13.1)

29 AlCl3 –20.4 (–19.7) –31.8 (–35.0) 11.4 (15.3)

R O RR R OLewis acid (LA)

LALA

or or

R OR


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Figure 2 Plot of π-binding enthalpies (ΔHπ) versus the differences in the π/σ-binding enthalpies (ΔHπ – ΔHσ).

3 Prins/Conia-Ene Cascade Reaction and its Applications

The phomactin family is a new class of platelet-activat-ing factor antagonist isolated from a marine fungus.11

Phomactin A (Figure 3) is the most structurally complexmember of this family and, as a result, it has attracted sig-nificant attention among synthetic chemists.12 The polycy-clic skeleton of phomactin A contains a highly substituted1-oxadecalin ring system,13–19 which is a common structur-al motif in other natural products such as cortistatin A andsuctorientalin D (Figure 3).20 Consequently, our efforts werefocused on the development of a dual-mode Lewis acid in-duced Prins/Conia-ene cascade cyclization reaction thatwould produce the appropriately functionalized oxadecalinring system.21

As shown in Figure 3, we anticipated that dual-modeLewis acids would promote Prins reactions between β-ketoesters I and hex-5-ynal II via σ-binding with the aldehydemoiety in II. Moreover, we reasoned that subsequent Conia-ene reactions of the tetrahydropyran intermediates III,formed in this manner, would also be induced by the samedual-mode Lewis acids through π-binding with the alkyneand σ-binding with the β-keto ester. We anticipated thatthe overall cascade process would generate the 1-oxadeca-lin ring system. The results of an exploratory investigationusing a variety of β-keto esters and Lewis acids showed thatstrong σ-Lewis acids induce only the Prins-type reactiongiving the tetrahydropyran intermediate III, while strong π-Lewis acids cause decomposition of the aldehyde substrateII. Significantly, in a manner that is consistent with the the-oretical study, this effort demonstrated that InCl3 was anideal dual-mode Lewis acid catalyst for the overall processthat produces the desired 1-oxadecalin products in highyields.

We next explored the substrate scope of the cascade cy-clization process. The results (Table 2) show that InCl3-me-diated cascade reactions of different substituted β-keto es-ters (Table 2, entries 1–6) with hex-5-ynal proceed smooth-ly in dichloromethane at 40 °C to form the corresponding 1-oxadecalins in reasonable to high yields. Despite steric hin-drance, a β-keto ester containing methyl groups at R3 and R4

also undergoes the Prins/Conia-ene cascade cyclization re-action in modest yield (Table 2, entry 5). Moreover, the re-sults show that the presence of a stereogenic center createdby methyl substitution at the α position of the ketone moi-ety in the β-keto ester does not affect the stereoselectivityof the reaction. In this case, a 3:1 diastereomeric mixture isgenerated initially (Table 2, entry 6). In addition, usingpent-4-ynal as the substrate led to a 5,6-fused bicyclic scaf-fold (Table 2, entry 7).

Figure 3 Dual-mode Lewis acid induced Prins/Conia-ene cascade reaction and 1-oxadecalin-related natural products

RO

O O

R'HO

O

Prinsreaction

O

RO

O O

R'

I

II

III

O

1-oxadecalin

R'

OE

E = CO2R

O

O OHOH

H

phomactin A

OO

OAc

O

O

AcO O

i-PrOsuctorientalin D

H

Conia-enereaction

H

A B

C

D

= dual-mode Lewis acid

+

LA

LA

LA

LA

cortistatin A(Ar = isoquinolin-7-yl)

O

OH

H2NH

HO

Ar

one-pot cascadecyclization

dual-modeLewis acid


E


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Table 2 Substrate Scope of the Prins/Conia-Ene cascade Reaction

The utility of the Prins/Conia-ene cascade reaction inthe synthesis of the tricyclic core of phomactin A wasprobed next. As shown in Scheme 1, the Prins/Conia-enecascade cyclization reaction of the dimethyl-substituted β-keto ester 1 with the dimethyl-substituted hex-5-ynal 2proceeds smoothly using In(OTf)3 as the dual-mode Lewisacid to form the desired cis-1-oxadecalin 3 as a single dia-stereomer. We found that although Zn(II) and In(III) halidesalso promote the cascade cyclization, they cause dealkoxy-carbonylation of 3, probably as a consequence of the nucle-ophilicity of the halide ions. Epoxidation of the exocyclicdouble bond in 3, followed by sequential dealkoxycarbon-ylation/epoxide-opening using TBAF generates 5, which un-dergoes cyclic acetal formation promoted by MeOH/cat.TsOH to produce the C ring of phomactin A. However, thecyclized hemiacetal 6 formed prior to acetal formation isunstable in CDCl3 owing to rapid generation of a dehydra-

tion product (by NMR analysis). This four-step sequenceclearly demonstrates the utility of the new dual-modeLewis acid induced Prins/Conia-ene cascade cyclization fora concise synthesis of phomactin A.

The next goal of this investigation was to develop anasymmetric Prins/Conia-ene reaction that takes advantageof substrate control and to explore its application to an en-antioselective synthesis of phomactin A. Because of theconcern that the D ring (E)-alkene moiety in the targetmight be sensitive to strong oxidants, such as m-CPBA, a γ-hydroxylation strategy was explored as an alternative pro-tocol for formation of the C ring. As shown in Scheme 2, re-action of the chiral ynal 7 with β-keto ester 8 using In(OTf)3in refluxing acetonitrile forms only the Prins product 9. Ex-ecution of the subsequent Conia-ene reaction requires ad-dition of ZnI2 in refluxing toluene.

This process produces the 1-oxadecalin product 10 as asingle diastereoisomer. The high diastereoselectivity of thePrins reaction is rationalized by invoking the transitionstate (TS), in which the In3+ ion is chelated to both the β-keto ester carbonyls and the OBn moiety. This chelationmodel may also explain the ineffectiveness of In(OTf)3 forthe subsequent Conia-ene reaction due to the unfavorableorientation of the terminal alkyne caused by the chelation.α′-Hydroxylation of 10 followed by dealkoxycarbonylativeenone formation with TBAF and protection of the free alco-hol as the triethylsilyl ether forms 12 as a single diastereo-isomer. The results of a screen of several strong basesshowed that the γ-hydroxylation of 12 takes place efficient-ly using t-BuLi followed by treatment with the Davis re-agent, 2-(phenylsulfonyl)-3-phenyl oxaziridine. The processforms the desired tricyclic product 13 in 63% yield. The en-couraging results arising from the two model studies de-scribed above suggest that both the epoxidation/dealkoxy-carbonylation and γ-hydroxylation strategies will be appli-cable to a pathway for the enantioselective total synthesisof phomactin A.

4 Diels–Alder/Carbocyclization Cascade Re-action and Applications

4.1 First Generation Diels–Alder/Carbocyclization Cascade Reaction and its Application

The cis-hydrindane scaffold containing an all-carbonquaternary center at the ring junction is a common struc-tural feature in many biologically active natural products.22

As shown in Figure 4, our strategy for construction of thissynthetically challenging motif involves the use of a dual-mode Lewis acid mediated Diels–Alder (DA) cycloadditionreaction between an electron-rich siloxy-substituted dieneIV and an electron-deficient enone dienophile V. It was an-ticipated that the formed silyl enol ether group in VI wouldundergo Lewis acid promoted carbocyclization with the

Entry n R1 R2 R3 R4 Yield (α:β)

1 2 Et H Ph H 73

2 2 Et H n-Hep H 72

3 2 Et H i-Pr H 81

4 2 Et H c-Hex H 72

5 2 Et H Me Me 52

6 2 Me Me Ph H 71 (R2: 3:1)

7 1 Et H Ph H 70

R1O

O O

HO

O

H+

InCl3 (1 equiv)

CH2Cl2, 40 °CO

O

R3

OR1O

H R4

R2

R3

R4

R2

n

n

Scheme 1 Construction of the tricyclic core of (±)-phomactin A

m-CPBA95%

(dr = 4:1)

TBAF

O

O OH

H

O

O OCH3

H

cat. TsOHMeOH

O

OOO

O

HO

O

In(OTf)3, MeCN4 Å MS, 0 to 70 °C

O

O

O

HO

H

O

O

OOO

H

(66%, single diastereomer)

tricyclic core of(±)-phomactin A

1

2

(±)-3

(±)-4(±)-5(±)-6

55%(in 2 steps)

A B

C

TMS

H

HO TMS

TMS

O

O OHOH

H

phomactin A

A B

C

D


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terminal alkyne group. The results of a preliminary effort,in which a variety of Lewis acids were explored, showedthat ZnBr2 is the optimal dual-mode Lewis acid for catalyz-ing this DA/carbocyclization cascade cyclization reactionwhich produces the desired cis-hydrindane product effi-ciently.23

As the results in Table 3 show, the process takes placebetween dienes and dienophiles that possess a variety of R1,R2 and R3 substituents, each of which generate cis-hydrin-dane products in good yields and with modest to high levelsof endo selectivity. The reaction using N-phenylmaleimide

as the dienophile occurs to give the endo product exclusive-ly (Table 3, entry 3). Acrolein, not having a substituent at R1,undergoes the process to produce a mixture of double bondregioisomeric products, which is transformed into the α,β-unsaturated ketone by addition of a catalytic amount of tri-flic acid or triethylamine. Under these conditions, the alde-hyde moiety is epimerized and leads to the exo product (Ta-ble 3, entry 6). Finally, a slight increase in the steric size ofthe R1 substituent leads to a reduction in the efficiency andendo selectivity of the reaction (Table 3, entry 7).

Scheme 2 Enantioselective synthesis of the tricyclic core of (+)-phomactin A

O

7

O

O O

HO

TMS

8

In(OTf)3 MeCN

O

O

H

9

O

O

TMS

BnO

ZnI2toluenereflux

46% from 7

TS

more favorabletransition state for 9

KHMDSDavis reagent

78%

O

O

BnO

H

OH

11

O OTMS

O

O

BnO

H

OTES

12

10

1. TBAF2. TESCl 61% 2 steps

O

O OH

H

A B

C OTESBnO

13

t-BuLiDavis reagent

63%

O

O

BnO

H

O OTMS

OH

O

O

O

O In3+H

Bn

TMS

BnO

Figure 4 Dual-mode Lewis acid induced DA/carbocyclization cascade reaction

OTIPS

R1

R1

OTIPS

EWG

+

R3R2

R3

R2 EWG

IV

V

VI

carbo-cyclization

H

RO

RO

dendronobiloside A

R =

O

OH

HOHO

OHO

dendrobine

H

NH H

O

O

O

OHH

aplykurodinone-1

OR1

R2 EWG

R3

cis-hydrindanes

dual-modeLewis acid H

LA

LA

= dual-mode Lewis acidLA one-pot cascadecyclization

Diels–Aldercycloaddition


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Table 3 Substrate Scope of the DA/Carbocyclization Cascade Reaction

To demonstrate the potential applicability of the Diels–Alder/carbocyclization cascade process to natural productsynthesis, the hydrindane product 14 (from Table 1, entry1) was utilized as the starting material in a route for thepreparation of the aglycone of (±)-dendronobiloside A,22b

which contains the cis-hydrindane core possessing five con-tiguous stereogenic centers including the all-carbon quater-nary center at the ring junction. As shown in Scheme 3, se-lective reduction of the aldehyde moiety in 14 followed byprotection of the primary alcohol produces 16. Saegusa oxi-dation followed by diastereoselective installation of the iso-propyl group generates the enone 18. Hydroboration–oxi-dation of 18 brings about simultaneous stereoselective re-duction of the ketone moiety and transformation of theexocyclic double bond to form the corresponding primaryalcohol along with introduction of the stereogenic center atC6. After selective protection of the primary alcohols, elim-ination of the secondary alcohol in 20 using the Burgess re-agent forms the endocyclic double bond in 21. Deprotectionof the silyl ethers with TBAF followed by hydrogenationthen produces the aglycone of (±)-dendronobiloside. Thissynthetic route is based on a DA/carbocyclization cascadecyclization reaction requiring only nine steps and occurs ina 24% overall yield starting from 14.

Scheme 3 Construction of the aglycone of (±)-dendronobiloside A

4.2 Second Generation Diels–Alder/Carbocycliza-tion Cascade Reaction and its Applications

The ent-kaurenoids represent a large family of naturalproducts that share the same tetracyclic core, but have dif-ferent oxygenation and skeletal rearrangement patterns.Members of this class of natural products display low toxic-ity and a variety of important biological activities, such asantitumor, antibacterial and anti-inflammatory proper-ties.24 The seco A ring derivatives, platensimycin25and pla-tencin,26 have potent activities against methicillin-resistantStaphylococcus aureus (MRSA) and vancomycin-resistantEnterococcus (VRE). Their modes of antibacterial action in-volve inhibition of fatty acid biosynthesis in fasciclin 2(FASII). Because of their interesting structures and biologi-cal properties, the ent-kaurenoids have attracted the atten-tion of the synthetic community.27

One of our long-term goals in this area is to develop aDA/carbocyclization-cascade-cyclization-based strategy forconstruction of the ent-kaurene core structure that can beemployed in designing a general synthetic approach tomembers of this class of natural products, including platen-simycin and platencin. As shown in Figure 5, DA cycloaddi-tion of the bicyclic or tricyclic enones VII with a siloxy-sub-stituted diene is potentially achievable by using σ-bindingof a dual-mode Lewis acid with the enone. The silyl enolether formed in this manner is expected to undergo in situLewis acid promoted intramolecular carbocyclization withthe terminal alkyne to afford the bicyclo[3.2.1]octane IX orthe tetracyclic framework of ent-kaurene X.

Entry R1 R2 R3 R4 Yield endo/exo

1 Me H CHO H 96 12

2 Me H COMe H 92 6

3 Me H –CON(Ph)CO– 93 endo only

4 Me Me COMe H 85 17

5 Me CN CO2Et H 91 2.3

6 H H CHO H 70 (enone) exo only

7 n-Pr H CHO H 88 5.6

OTIPS

R1

R3

OR1

+ R4R2

R2 R3

R4

ZnBr2 (0.2 equiv)

MeCN, 0 to 60 °CH

O

HCHO

O

H

97%

: R = H : R = TIPS

RO

TIPSOTf(±)-14 (±)-15(±)-16

71% (in 2 steps)

TMSOTf; thenPd(OAc)2

O

H

TIPSO

(±)-17

i-PrMgClCuBr⋅SMe2

TMSClthen TBAF

O

H

HO

(±)-18

85% BH3⋅THF;then H2O2

86%

OH

H

OR

RO

: R = H : R = TBS

TBSCl 98%

(±)-19(±)-20

Burgessreagent 52%

H

TBSO

OTBS

(±)-21

1. TBAF 2. Pd/C, H2

95%(in 2 steps) H

HO

OH

aglycone of (±)-dendronobiloside A

12

6

12

6

1 2

6

12

6

12

6

12

61

2

6

NaBH4, THFpent-2,4-dione


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Figure 5 Second generation DA/carbocyclization cascade reaction

In a study exploring this process, we observed that, aswith the DA/carbocyclization cascade reaction, ZnBr2 is aneffective dual-mode Lewis acid.10,28 The substrate scope ofthe cascade cyclization process was explored using severalsubstituted dienophiles and siloxy-substituted dienes. Asthe results displayed in Table 4 demonstrate, the reactionsproceed smoothly under the optimized conditions to formthe target tricyclic products in 75–91% yields with good lev-els of diastereoselectivity. Methyl substituents at differentpositions in the starting enones do not affect the efficiencyof the cyclization reaction, and yet they guide high levels offacial selectivity in the DA cycloadditions (Table 4, entries2–4). These observations suggest that an enantioselectiveversion of the process is possible when appropriate substit-uents are present at either the α- or γ-positions of the start-ing enone.

To demonstrate the utility of this highly efficient cas-cade cyclization reaction, the tricyclic diketone 22 (fromentry 1 in Table 4) was employed as a common starting ma-terial for the synthesis of platensimycin and platencin. Asshown in Scheme 4, the two ketone groups in 22 can be dif-ferentiated by converting both into silyl enol ethers, fol-lowed by selective epoxidation of the less hindered silylenol ether with magnesium monoperoxyphthalate(MMPP). This two-step protocol forms the α-hydroxy ke-tone 24 in a high yield and with an excellent level of diaste-reoselectivity. The diol formed by hydroxy-directed reduc-tion of the ketone group in 24 is converted into the endocy-clic double bond in 25 by treatment with I2, PPh3, andimidazole in refluxing toluene. Silyl enol ether formationfollowed by epoxidation with MMPP forms the α-hydroxyketone 26, which undergoes equilibration under acidic con-

ditions to generate the thermodynamically more stable α-hydroxy ketone 27. Acetylation of the alcohol group in 27followed by deacetylation with SmI2 produces 28. Finally,reduction of the ketone group in 28 followed by acid-cata-lyzed cyclization to install the ether bridge produces an in-termediate in Snider’s previous formal synthesis of platen-simycin.27j

Table 4 Substrate Scope of the Second Generation DA/Carbocycliza-tion

O

OTIPSOR

VII

VIII

OHOOH

oreskaurin COH

H

OH

H

O

O

O

O

OR

OOOH

OH

H

AcO

taibaihenryiin A

O

O

NH

OOH

OH

HO2C

O

NH

OOH

OH

HO2C

platensimycin platencin

H

OH

O

OH

OH

H

O

maoyecrystal J

IX

X

H

ent-kaurene

A

C

B

H

1

3 58

13

10

11

15

17

18

D

H

OH

dual-modeLewis acid LA one-pot cascade

cyclization

LAO

OR

OTIPS

carbo-cyclization

LA

Diels–Aldercycloaddition

=

Entry n R R′ Yield (α:β)

1 1 – – 86

2 1 1-methyl – 81 (8:1)

3 1 2-methyl – 88 (α only)

4 1 3-methyl – 85 (16:1)

5 1 4-methyl – 80

6 1 3,3-dimethyl – 80

7 1 5-(OTBS) – 75 (7:1)

8 2 – – 82

9 1 – 6,6-dimethyl 79

10 1 – 7-methyl 91

O

O

OZnBr2 (1.5 equiv)CH2Cl2, r.t., 12 h

R R' R R'

OTIPSn n

+1

2

3

4

5 67 1

2

3

4

5

6 7


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Scheme 4 A formal synthesis of (±)-platensimycin

A formal synthesis of platencin was also achieved start-ing with diketone 22. As shown in Scheme 5, reduction ofboth the ketone groups in this substance to alcohols fol-lowed by selective protection of the less hindered hydroxymoiety as the TBS silyl ether forms 30 as a roughly 3:1 mix-ture of diastereoisomers. Because the two newly generatedstereogenic centers in 29 are removed at a later stage of thesynthetic route, all of the diastereomers were used for nextstep. Dess–Martin (DMP) oxidation of the free alcohol in 30followed by Saegusa oxidation provides enone 32. Treat-ment of 32 with H2O2 under basic conditions generates theepoxide 33, which undergoes Warton rearrangement upontreatment with hydrazine in MeOH/AcOH to generate theallylic alcohol 34. After several protection and functionalgroup manipulation steps, the bicyclo[3.2.1]octane moietyin xanthate 34 was converted into the corresponding bicy-clo[2.2.2]octane scaffold using Yoshimitsu’s protocol.29 Fi-nally, removal of the p-methoxybenzyl (PMB) ether underoxidative conditions and oxidation of the resulting alcoholforms the intermediate in Nicolaou’s synthesis of the target,which can be converted into platencin using the literatureprocedure.27i

5 Michael/Conia-Ene Cascade Reaction and its Applications

Although Michael addition reactions are powerful toolsto construct C–C bonds,30 their synthetic applications arelimited by their reversible nature. A strategy we have de-vised for the construction of the 5,7- and 6,6-bicyclic ringstructural motifs in many natural products such asthapsigargin, clavukerin A and teucvidin31,32 (Figure 6) over-comes this limitation by coupling reversible Michael reac-tions with subsequent irreversible Conia-ene reactions.Specifically, we envisaged that dual-mode Lewis ac-id/amine-induced intramolecular Michael additions of XI,which are expected to form six- or seven-membered ringsystems, followed by an irreversible Conia-ene reaction in-duced by the same Lewis acid would generate the desired5,7- and 6,6-bicyclic ring systems (XIII and XIV, respectively).

A survey of different combinations of dual-mode Lewisacids and amines led to the observation that theMichael/Conia-ene cascade cyclizations of appropriate sub-strates proceed smoothly using ZnI2/Et2NH in refluxing di-chloroethane, and that these processes form the desired5,7-fused bicyclic and 6,6-fused bicyclic compounds in highyields and with high levels of diastereoselectivity.33

OTMS

OTMS

O

O

HO

H H

TMSCl, NaI HMDS, r.t.

O

OHO

OHO

O

O

HH

H

H

65% from 2281% (based on recovered

starting material)(single diastereomer)

MMPP, 0 °Cthen aq HCl

1. NaBH4, THF –78 to –20 °C2. PPh3, Imidazole I2, toluene, reflux

1. TBSOTf, Et3N2. MMPP, r.t. then aq HCl

(100%, singlediastereomer)

aq HClovernight

1. Ac2O, Et3N 2. SmI2, 0 °C

1. K-selectride –78 °C to r.t.

85%

2. TFA, 0 °C

75%

Snider's intermediate

85%

H

O

O

90%

(±)-22 (±)-23 (±)-24

(±)-25(±)-26(±)-27

(±)-28


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Figure 6 Dual-mode Lewis acid induced Michael/Conia-ene cascade reaction

This is exemplified by the Michael/Conia-ene cascadereaction of β-keto ester 38, which proceeds smoothly toform the 5,7-fused bicyclic product 39 in 78% yield andwith a diastereomeric ratio (dr) of 3:1 (Scheme 6). It is

worth noting that the enamine derived from 38 can under-go either 1,2- or 1,4-addition to the enone moiety to pro-duce either a respective five- or seven-membered interme-diate (Scheme 6). In fact, only the seven-membered inter-mediate, generated in situ, can undergo the subsequent

Scheme 5 A formal synthesis of (±)-platencin

1. DDQ2. DMP

82%

O H OPMB

Nicolaou's intermediate

(in 3 steps)

OH

H OPMBS

SNaH, CS2,then MeI

95%

AIBN, n-Bu3SnH benzene, reflux

H2O2, NaOHMeOH

96%

NH2NH2, AcOH;MeOH, 0 °C to r.t.93%

OTBS

O

H

O

OTBSH

HO

DMP90%

HOTBS

OLDA, TMSCl;

then Pd(OAc)2

87%

HOTBS

O

1. PMBCl, NaH2. TBAF

90%OH

HPMBO

H

O

O

NaBH4, MeOH

97%, dr = 3:1

∗∗

HOH

OHTBSCl (1.2 equiv)imidazole, CH2Cl2

80%, dr = 3:1

∗∗

HOTBS

OH

(±)-22(±)-29 (±)-30

(±)-31(±)-32(±)-33

(±)-34 (±)-35

(±)-36

(±)-37

OE

H

O

HO

E

H

HO

Michaelreaction

O H

O

OO

O

O

OHOH

O

OO

O

O

O

H

H

H

H

dehydrocostuslactone

clavukerin A

thapsigarginteucvidin

H

clerodaneskeleton

tri-nor-guaiane

O

Oguaianolideskeleton

O

O

E

XI: E = CO2R

H

m = 2n = 1

amine

m = 1n = 2

m n

O

O

E

H

m n

XII

5

XIII

XIV

= dual-mode Lewis acidLAone-pot cascade

cyclization

LA

LA

Conia-enereaction

LAdual-modeLewis acid

OO

H

O

OH

H

O

Scheme 6 Formal synthesis of (±)-clavukerin A

EtO

O O

HO

O

HO

H

O

H

E

S

SH

O

H H

NaOHEtOHheat

(±)-clavukerin A

ZnI2, tolueneheat

HSCH2CH2SH BF3·OEt2

(±)-39(±)-40

(±)-42

OE

H

(±)-41

Raney Ni

78%dr = 3:1

85%74%

70%

Ref. 34

38

OEtO

EtO

O O

NEt2H

EtO

O O

HNEt2

Et2NH Et2NH

1,2-addition 1,4-addition


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Conia-ene reaction to generate the desired 5,7-bicyclicfused ring system found in 39. This result indicates that theirreversible Conia-ene reaction serves to drive the equilibri-um mixture of adducts formed by Michael addition to thedesired cyclized product.

The 5,7-bicyclic cyclized product 39, formed in theMichael/Conia-ene cascade cyclization described above,was employed in the synthesis of (±)-clavukerin A. Asshown in Scheme 6, protection of the aldehyde group in 39with 1,2-ethanedithiol followed by reduction using Raneynickel generates the corresponding methyl derivative 41. Fi-nally, dealkoxycarbonylation and subsequent double bondisomerization produces enone 42, which can be convertedinto (±)-clavukerin A using literature procedures.34

An asymmetric Michael/Conia-ene cascade cyclization,which utilizes substrate-control and takes advantage of thesix-membered chair-like nature of the transition state inthe Michael reaction, has been developed. As shown in

Scheme 7, the chiral substrate 4435 undergoes a highly dias-tereoselective intramolecular Michael reaction to form 45upon treatment with Zn(OTf)2/Et2NH. This observation is inaccord with a prediction based on of the more favorablechair-like transition state TS2. Subsequent addition ofIn(OTf)3 induces the Conia-ene reaction of 45 to producethe 6,6-bicyclic product 46 as a single diastereomer. Epox-ide 47 is then generated from 46 through several functionalgroup manipulation steps. Dealkoxycarbonylation of 47with TBAF induces epoxide ring opening and cyclization toform 48 containing a tricyclic core structure. The allyl sidechain is then installed using an O-allylation/Claisen rear-rangement protocol to produce 50 via 49. Oxidation of thefuran ring in 50 with N-chlorobenzenesulfonamide sodiumsalt followed by treatment with acid produces the α,β-un-saturated γ-lactone 51. Pinnick oxidation of the aldehyde in51 followed by esterification generates the correspondingmethyl ester 52. Finally, ozonolysis of the terminal alkene

Scheme 7 Total synthesis of (–)-teucvidin

O

O

OH 46% over 9 steps

O

O OTMS

O

Zn(OTf)2Et2NH,

DCE, r.t. O

Et2N

H

H

CO2R

O

OH O

O

then In(OTf)34 Å MS

72%

O

O O

CHO

46

43 44

45

TS2

CHO

O

O O

O

47

1. NaBH4 (1 equiv) THF/MeOH = 5:1 0 °C2. m-CPBA, CH2Cl23. DMP, CH2Cl2 77%, in 3 steps

CHO

O

48 (dr = 10:1)

*

KH, DMPU, DME allyl chloride

O

O49

O

CHO

50

DIPEA, 140 °C1,2-dichlorobenzene

92%, in 2 steps (dr = 3:1)

PhSO2NCl⋅Na,AcOH, MeOH,0 °C; then1 M HCl in ether1,4-dioxane, r.t.

87%

O

CHO

O

H

51

(–)-teucvidin

O

O

O

H

O

O

H 1. NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/THF = 5:1

2. CH2N2, MeOH

O3, then Me2S;then furan-3-yllithium

59% from 51

O

CO2Me

O

H

52

TMSTMS TMS

TBAF81%


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group followed by addition of furan-3-yllithium then in-stalls the spiro γ-lactone moiety stereoselectively, perhapsas a result of lithium chelation of the 1,4-dicarbonyl moi-ety,36 and completes the total synthesis of (–)-teucvidin.

6 Conclusion

In the efforts described above, we have studied the σ/π-binding properties of a series of Lewis acids by using DFTcalculations. The results show that Zn(II) and In(III) shouldbe suitable dual-mode Lewis acid catalysts for promotingcascade cyclization by both σ- and π-binding activation.Based on the results of the theoretical study, we designedthree new types of one-pot, dual-mode Lewis acid inducedcascade cyclization reactions which generate cis-1-oxa-decalin, cis-hydrindane, bicyclo[3.2.1]octane, cis-decalinand 5,7-bicyclic fused ring systems. These ring systems arecommon structural motifs in a variety of biologically activenatural products. More importantly, we demonstrated thatthe processes take place with high efficiencies and that theycan be incorporated into enantioselective syntheses of thetricyclic core structure of phomactin A, formal syntheses of(±)-clavukerin A, (±)-platensimycin and (±)-platencin, andtotal syntheses of the aglycone of (±)-dendronobiloside Aand (–)-teucvidin. The overall results of this investigationdemonstrate that the dual-mode Lewis acid induced cas-cade cyclization reactions can be incorporated into simpleand concise routes to generate the complex core structuresfound in the target natural products and their analoguesand, as a result, they serve as useful molecular tools in drugdiscovery. Studies focusing on the further development ofthese types of synthetic strategies are ongoing in our labo-ratory.

Acknowledgment

Financial support for this research project from the NationalNatural Science Foundation of China (Grant Nos.: 20972004,21072008, 21272012, 21572006), the Science, Technology andInnovation Committee of Shenzhen (JCYJ20140509093817686,JCYJ20150626111042525) and Peking University Shenzhen GraduateSchool is gratefully acknowledged.

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