Chapter 6 Towards the syntheses of natural protoilludanes and linear triquinanes from cycloundecadienynes

STRATEGIES AND T A C T I C S IN O R ( ; A N I C S Y N T H E S I S , V()L. 5 9 2004 Elsevier Ltd. All rights reserved.

Chapter 6

TOWARDS THE SYNTHESES OF NATURAL PROTOILLUDANES AND LINEAR TRIQUINANES CYCLOUNDECADIENYNES

FROM

Anne-Lise Dhimane and Max Malacria Laboratoire de Chimie Organique, UMR 7611, B. 229, UniversitO Pierre et Marie Curie, Paris VI, 4, Place Jussieu

I.

Introduction

153

II.

En route to natural protoiiludane family

155

A. B. C. D. E. F. G.

155 155 156 159 160 163 166

III.

Biomimetic strategy Targets: protoilludenol and illudol Preliminary studies Retrosynthetic analysis Synthesis of macrocyclic precursor via path A Synthesis of macrocyclic precursor via path B Total synthesis ofepi-illudol

En route to linear triquinane synthesis

167

A. B. C. D. E.

167 171 173 175 176

Retrosynthetic analysis Synthesis of common precursor 59 Synthesis and radical reactivity o f a Z,E-precursor via path E Synthesis o f a E,E-precursor via path F Radical cascade to linear triquinane

IV. Conclusion

177

References

179

I.

Introduction

In this account we are going to tell the story of the evolution of a synthetic strategy dedicated to radical transannular cascade as a methodology to reach natural sesquiterpenes. Toward the end of the eighties, the idea to build a

154

ANNE-LISE

DHIMANE

AND MAX MALACRIA

tricyclic skeleton in a transannular radical manner appeared to us as a unique challenge. We were inspired by the biosynthetic sequence of all the humulene-derived sesquiterpenes, which proceeds via a carbocationic transannular cascade from the eleven-membered triene humulene leading to the tricyclic 4,6,5-skeleton of the C-7 protoilludane cation [Scheme 1].l

SCHEME 1. Biosynthetic pathway to the sesquiterpene family. At that time, in the laboratory, we had just demonstrated the synthetic power of the highly regioselective and stereoselective 5-exo-dig tin hydride mediated radical cyclization of bromomethyldimethylsilyl (BMDMS) propargylic ethers such as 2 [Scheme 21.2 In particular, when an ultimate Tamao oxidation is applied, the bis-allylic diol moiety 3, frequently found in natural products is created. The hydroxymethyl propenyl framework 4 is accessible as well by choosing a fluoride treatment.

6

NAq'URAL PROTOILLUDANES AND LINEAR q'RIQUINANES

155

S C H E M E 2. Radical cyclization of bromomethyldimethylsilyl (BMDMS) propargylic ethers 2.

II.

En route to natural protoilludane family

A. BIOMIMETIC STRATEGY

Thus having all these tools in our hands, it was obvious to imagine the following biomimetic strategy to reach the tricyclic system of a sesquiterpenic natural protoilludane possessing the above-mentioned dihydroxyl (as in 5) or methyl hydroxyl (as in 1) functions with the unsaturation present at the right place [Scheme 3]. We anticipated that a well-chosen eleven-membered BMDMS ether of a cycloalkadienyne such as 7, would be able to generate the suitable vinyl radical 6. This highly reactive and appropriately oriented vinyl radical should allow the success of the first unfavorable 4-exo-trig process of this transannular cascade. Finally the driving force would be the more favorable 6-exo-trig transannular cyclization achieving the construction of the protoilludane framework. This concept of a transannular radical cascade was new and highly motivating. B. TARGETS : PROTOILLUDENOLAND ILLUDOL

Illudol 5 3 was the perfect candidate for this synthetic challenge 4 because of its unusual tricyclic structure containing a methylenecyclobutane moiety and

156

ANNE-LISE DHIMANE AND MAX MALACRIA

S C H E M E 3. Retrosynthetic biomimetic pathway to illudol 5 or protoiiludenol 1.

five contiguous stereogenic centers. At that time, illudol was the sole natural member belonging to the protoilludane family. It was isolated from a poisonous mushroom Clitocybe illudens, renamed Omphalotus olearus, and nicknamed Jack-O'Lantern because of its bioluminescence. Three total syntheses of illudol 5 were already published. The two first were based on classical cycloadditions strategies [Scheme 4] such as [2+2] cycloaddition employing diethoxyethylene as starting material to construct the cyclobutane in precursors 8 and 9 and a Diels-Alder reaction or enlargement of a cyclopentane for the six-membered ring present in 10. 5 The more recent was the more elegant synthesis [Scheme 5], assembling the protoilludane framework 11 from an acyclic enediyne precursor 12 in a one-step cobalt-catalyzed [2+2+2] cycloaddition. 6 On the other hand, protoilludenol 1 was described as the key biosynthetic intermediate of this humulene-derived sesquiterpene family [Scheme 1].7 That is why we focused our synthetic plans on both of these two highly valuable targets. The major class of true fungi called Basidiomycete has now enlarged its members to epi-illudol, tsugicolines A, B and C, armillol and derivatives that all belong to the same series of sesquiterpene metabolites and several of which exhibit antibacterial properties, s C. PRELIMINARY STUDIES

Having a look at the target cyclodienyne precursor 7, one can easily ask :

6

NATURAL P R O T O I L L U D A N E S AND LINEAR T R I Q U I N A N E S

157

SCHEME 4. Total syntheses of illudol 5 based on classical cycloadditions.

are you sure that the first cyclization emplying the ~-silyl radical will be the 5-exo-dig process and not the competitive 5-exo-trig one? That was the reason we began a preliminary study to check the chemoselectivity of radical cyclization of BMDMS propargylic and allylic ethers in ct and or' positions in both acyclic and cyclic systems [Scheme 6]. The radical cyclization of acyclic precursors 13 have provided a slight selectivity in favor of the triple bond that can be explained by steric control on the approach of the initial ct-silyl radical to the unsaturations. Interestingly, a total dig chemoselectivity is observed when R 3, the group present at the 5-exo-trig attack position, is a methyl group. 9 In our synthetic plan to reach protoilludanes, the enyne moiety is part of an eleven-membered ring. We then studied the behavior of the same mixed BMDMS allylic and propargylic ether framework now as part of an elevenmembered model [Scheme 7].

158

ANNE-LISE

DHIMANE

AND MAX MALACRIA

SCHEME 5. Total synthesis of illudol 5 via a [2+2+2] strategy.

SCHEME 6. Dig vs. trig chemoselectivity in acyclic systems. Heterocycle 16 was chosen for the ease of its preparation by a classical etherification reaction and was submitted to radical cyclization conditions. Gratifyingly, the chemoselectivity was total, three products were isolated, all resulting from an initial 5-exo-dig cyclization. The major dienediol 17 was formed from direct reduction of initially generated vinyl radical 20, while diols 18 and 19 were formed via both limiting forms 21 and 22 of the allylic radical formed by a 1,6-hydrogen transfer from the allylic position to the vinyl radical. Bicyclic derivative 18 results from transannular 7-exo-trig cyclization, and diene 19 from direct reduction of the allylic radical.

6

NATURAL PROTOILLUDANES AND LINEAR TRI(~UINANES

S C H E M E 7. C h e m o s e l e c t i v i t y

dig vs. trig in

159

an e l e v e n - m e m b e r e d cyclic system.

With such a result in our hands, we were really confident in our project, being convinced that the radical cascade would begin following a 5-exodigonal cyclization on the cycloundecadienyne BMDMS ether 23. D. RETROSYNTHETIC ANALYSIS

Our first approach following path A [Scheme 8] involved an intramolecular Horner-Wadsworth-Emmons olefination to stereoselectively create the disubstituted double bond in order to reach the desired macrocycle 23 from ketophosphonate 25. The intramolecular version of Horner-Wadsworth-Emmons olefination was well documented as an efficient strategy to build the 13-membered ring of cembranolides. In particular, successful preparations of highly functionalized medium-sized rings were performed under the mild conditions described by Masamune. ~~ The required enynal 25 could be prepared from the commercially available neryl (Z-series) or geranyl (E-series) acetates derived from natural nerol or geraniol, respectively. The desired stereochemistry of the trisubstituted double bond is thus fixed from the beginning of the synthesis. The dibromoolefin moiety, which is known as a

160

A N N E - L I S E D H I M A N E A N D MAX M A L A C R I A

direct precursor of the corresponding alkyne, could be easily prepared using the Corey-Fuchs reaction of the aldehyde resulting from the chemoselective ozonolysis of the gem-dimethyl double bond of these precursors. A second route (path B) relies on either a nucleophilic 1,2-addition of the acetylide of dienynal 24 (R 3 = H) to the co-enal entity !~ or on an intramolecular Nozaki-Hiyama-Kishi-Takai (NHKT) type ring closure between the iodo alkyne and enal moieties of precursor 24 (R 3 = I) 12.

SCHEME 8. Retrosynthetic pathways to protoilludane skeletons. This latter compound was envisioned to arise via two different pathways. The first path C considered the same nerol or geraniol approach as the one anticipated for aldehyde 25. The second approach, path D, started from commercially available isoprene monoxide derived from natural isoprene. The idea was to stereoselectively create the E-trisubstituted double bond in precursor 26 by a novel palladium(0)-catalyzed alkylation of the corresponding vinyloxirane with a non-stabilized lithium ester enolate. E. SYNTHESIS OF MACROCYCLIC PRECURSOR VIA PATH A

First, we embarked on path A and as expected, the required enynol 32 was

6

161

NATURAL PR()TOILI~UI)ANES AND LINEAR TRIf~UINANES

prepared in 11 steps in 30% overall yield from neryl acetate 27 using classical functional modifications [Scheme 9]. Alkyne 29 was easily prepared from the aldehyde, regioselectively produced by ozonolysis of neryl acetate, OAc

OAc 1. (t)0 3, CH2CI2,-78~ (il) Me2S

1. K2CO3, MeOH, r.t.

2. CBr4(2 equiv) PPh 3 (4 equiv), CH2CI2

2. n-BuLi, (3 equiv) THF, -78 to 20~ B r 28, 54%, 2 steps

27

OH

Me

1. LAH, Et20, 0~ 2. DHP, PPTS CH2CI2 r.t.

1. PPh 3, CCI 4 J

2./-PrCO2Me, n-BuLi THF

29, 75%, 2 steps

3. n-BuLi, CICO2Me

30, 83%, 2 steps

THP

HO 1. CH3P(O)(OMe) 2, n-BuLi 2. PPTS, MeOH

MeO2C.f~" (MeO)2 31, 93%, 2 steps

32, 97%, 2 steps

SCHEME9. Preparationof Z-enyno132from neryl acetate. using the Corey-Fuchs procedure through dibromoolefin 28. Enynol 29 was subsequently transformed into the corresponding allylic chloride.

162

ANNE-LISE

DHIMANE

AND MAX MALACRIA

Treatment of the latter with lithium methyl isobutyrate enolate, generated in situ, afforded the methyl nonenyoate 30. Similar attempts at the nucleophilic substitution either from the corresponding allylic bromide or mesylate gave low yields of the desired product. Reduction of ester 30 with LAH, followed by DHP protection of the resulting alcohol and subsequent addition of the corresponding lithium actetylide to methyl chloroformate, led to the expected ynoate 31. Treatment of ester 30 with lithium dimethoxyphosphonate afforded the desired [3-ketophosphonate and a THP ether cleavage produced alcohol 32. OH L

1. Swern oxidation

_

i~ ~ j J

2. LiCI, MeCN, 2 mmol/L slow addition of DBU, 50~ 33

26%, 2 steps (MeO)2OP

32

Me3NO acetone

degradatio

002(00)8 CH2012 ~/--OH

1. Swern oxidation (MeO)2OP

2. LiCI, MeCN 2 mmol/L O__ ~ O o . g C Q O slow addition of DBU, 20~ OC-Co CO OC" / OC 34, quant.

OC 0 OC.".. II O O - L ~ , ~ OC.. I/Xl OoCc'C~~

..

/

.....

35, 34%, 2 steps

SCHEME 10. lntramolecularHomer-Wadsworth-Emmonsapproach (path A) to protoilludenol 1 from enynoi precursor32. Finally, Swem oxidation produced quantitatively the aldehyde precursor for the macrocyclization step [Scheme 10]. We then focused on different experimental procedures. No macrocycle was isolated when we proceeded by

6

NATURAL PROTOILLUDANES

AND LINEAR TRIQUINANES

163

slow addition of the substrate to a LiC1/DBU solution in acetonitrile. ~3 In contrast, slow addition of DBU to a substrate/LiC1 solution in acetonitrile at 50~ afforded the expected cycloundecadienynone 33 in 26 % yield after an optimization study conducted to lower the addition rate (from 67x10 -3 to 9.5xl0-3mmol-h -l) and the base proportion (from 5 to 1.3 equiv.). Assuming that the linear arrangement of the triple bond prevented an efficient closure, we anticipated that a possible solution to this problem could be associated with the geometrical transformation resulting from the protection of the triple bond as a cobalt cluster complex, which would lead to bond angles of around 142~ ~4 The complexation conducted on alcohol 32 gave quantitatively the hexacarbonyldicobalt complex, which upon exposure to the previous optimized Swern oxidation-cyclization sequence underwent complete degradation. Finally, the desired complexed macrocycle 35 could be obtained in 34~ yield using room temperature and 1.1 equiv, of DBU. The decomplexation challenge was first studied on a model acyclic substrate, which showed that among the three usual methods, i.e. CAN, F e 3+ and Me3NO, only the last was efficient, but when these neutral mild conditions were applied to our cobalt-complex 35, the direct precursor of ynone 33, only intractable materials were obtained. A completely identical strategy allowed the preparation in 11 steps of the (E)-phosphonate equivalent of 32 in 19% overall yield from geranyl acetate 36. But from that substrate, both macrocyclization procedures were unsuccessful. F. SYNTHESIS OF MACROCYCLIC PRECURSOR VIA PATH B

Next, we turned our attention to the NHKT ~5 strategy proposed as a second strategy (paths B and C, Scheme 8). In that case, the annelation step would deliver a hydroxyl group instead of a ketone function [Scheme 11 ]. The exchange from a triangular carbon to a tetrahedral should release some strain and render the formation of this highly strained macrocycle easier'. The required dienynal 40 was synthesized in 13 steps and 7% overall yield from geranyl acetate 36, following an identical approach as described previously. Silylated enyne was easily prepared following the four-step sequence previously described (vide infra, Scheme 10) but using a final

164

ANNE-LISE

HO

AcO 1. ozonolysis 2. Wittig 3. OAc-deprotection

DHIMANE

AND MAX MALACRIA

1. (i) n-BuLi (3 equiv.) THF, -78~ (ii) TMSCI,-78~

2. LiCI, 2, 6-1utidine, MsCI 3./-PrCO2Me, n-BuLi, THF 4. LAH, Et20, 0~ r 37, 37%, 3 steps

36 OH

1. Swern oxidation 2. EtO2CCH2P(O)(OEt)2 LiCI, NEt3

/--OH

3. DIBAL-H, CH2CI2 TMS

TMS

39, 60%, 3 steps

38, 56%, 4 steps

/-=O 1. Swern oxidation 2. KF, DMSO, MeOH 3. NIS, AgNO3, acetone

40, 59%, 3 steps

SCHEME 11. Preparation of E, E-dienynal40 from geranyl acetate 36. TMSC1 quench to generate, after acidic hydrolysis, the corresponding Csilylated alcohol. Chlorination under Collington-Meyers conditions followed by nucleophilic alkylation and final LAH reduction produced the desired alcohol 38. Swern oxidation followed by olefination under the mild conditions of Masamune and Roush, stereoselectively provided the Eunsaturated ester, which was reduced with DIBAL-H to allylic alcohol 39.

6

NATURAL

PR(YFOILLUDANES

AND

LINEAR

165

TRIQUINANES

Finally, a Swern oxidation followed by desilylation of the triple bond gave the corresponding enal, which was submitted to mild iodination conditions to furnish the expected precursor 40. ~O 1. THF, 0.015 moI.L -1 slow addition on a suspension of CrCI 2

I

OBMDMS ,~...~..~__~ .,,

2. BMDMSCI, 4-DMAP NEt3' CH2CI2

40

41, 56%, 2 steps I

.

1. Bu3SnH F " " / ~ 1. Bu3SnH 2. TBAF, DM or 2. Tamao oxid. many products formed no tricyclic structure R

OH

R = H , OH SCHEME 12. Intramolecular Nozaki-Hiyama-Kishi-Takai approach (paths B and C) to protoilludenol ! from E,E-dienynai precursor 40.

The slow addition of the iodoalkyne 40 (0.015 mol.L -i in THF) to a suspension of chromium (II) chloride (1.6 mol.L -1 in THF) produced the desired (E,E)-cycloundecadienynol 23 (R 1 = R 2 = H) in 62% yield [Scheme 12]. The bromethyldimethylsilyl (BMDMS) ether 41 was prepared in quantitative yield by silylation using BMDMSC1, DMAP, Et3N in dichloromethane. This compound was submitted to the usual tin-mediated radical cyclization conditions (41 0.025 mol.L -~ Bu3SnH 2xl0-4mol.h -1 AIBN, benzene reflux) followed by Tamao oxidation (H202, KHCO3, KF) to lead to many products with no tricyclic structure detected after many separation procedures. Neither of these approaches appears to solve the synthetic challenge to reach protoilludenol 5. Nevertheless, the Nozaki-Hiyama-Kishi-Takai

166

A N N E - L I S E D H I M A N E A N D MAX M A L A C R I A

(NHKT) ring closure appeared particularly efficient compared to the HomerWadsworth-Emmons one in the formation of these particularly strained eleven-membered rings. That was the reason why we persevered with the synthetic route to the natural sesquiterpene illudol. G.

TOTAL

S Y N T H E S I S O F EPI-ILLUDOL

For such a challenge, undecadienynal 24, possessing a protected hydroxyl moiety (R ! = OTBS), had to be constructed. To find a straightforward entry to the requisite intermediate, we turned our attention to a direct and stereoselective access to trisubstituted allylic alcohols from isoprene monoxide. We managed (Pd(OAc)2 1%, dppe 2.5%) to efficiently reach hexenoate 26 (90% yield, as a 80 : 20 (E : Z) mixture of stereomers) in one-step by addition of the lithium enolate of ethyl isobutyrate to the Jt-allylpalladium complex resulting from the oxidative addition of vinyloxirane 42 [Scheme 13]. 16 The fast and easy preparation of dienynal 46 was thus possible as depicted in Scheme 13, following classical functional modifications. A TBS protection, followed by a LAH reduction of the ester afforded the monoprotected diol. The corresponding aldehyde, prepared by Swern oxidation, was engaged under the mild olefination conditions of Masamune and Roush to give E-et,[3unsaturated ester 43. Reduction of the latter with DIBAL-H, followed by Swern oxidation of the resulting allylic alcohol gave the enal. Aldehyde acetalization using the Otera procedure was necessary to allow the mild and quite efficient formation of diene 44. A classical TBAF desilylation furnished the allylic alcohol. One should note that we optimized the oxidation of the latter using SO3-pyridine complex, the so-called Von Doering modification of the Moffatt oxidation. ~vNucleophilic addition of propargylic Grignard to the aldehyde led to the homopropargylic alcohol 45. Silylation of the secondary alcohol was conducted using the imidazole-DMF conditions and a final acidic deprotection gave the expected undecadienynal 46. Upon dropwise treatment with LiHMDS base generated in situ, acetylenic aldehyde 46 (0.8 mol.L ~) in benzene at room temperature underwent a clean but incomplete macrocyclization to provide the desired dienynol 47 in 39% yield with 23% of recovered starting material. The NHKT approach was more successful as previously described and produced cycloundecadienynol 47 in 88% yield as an inseparable mixture of

6

NATURAL PROTOILLUDANES AND LINEAR TRIQUINANES

167

two diastereomers in a 3 : 1 ratio from the corresponding iodoalkyne precursor 48. At this stage of the synthesis, it was impossible to ascertain the relative configuration of the two stereogenic centers. BMDMS ether 49 was prepared in quantitative yield by classical silylation [Scheme 14]. Precursor 49 was submitted to the Bu3SnH-AIBN classical radical cyclization conditions-Tamao oxidation sequence, following the same procedure as for BMDMS ether 41 [Scheme 12]. The 4,6,5-tricyclic framework of monosilylated protoilludane skeleton was isolated very cleanly in 47% yield as a unique diastereomer. Surprisingly, the Tamao oxidation did not affect the tert-butyldimethylsilyl ether link, and a subsequent TBAF treatment was needed to finally obtain the tricyclic sesquiterpene 54. After complete characterization by spectroscopic measurements, we detected differences between our structure and the illudol described in the literature. After carefully comparing the original NMR spectra kindly provided by K.P.C. Vollhardt, we were sure that we had prepared a diastereomer of the natural occurring sesquiterpene illudol [Scheme 15]. At that time, Nasini's group had performed new extraction studies of Basidiomycete mushrooms. In 1989, this group isolated a new natural product from Clitocybe candicans which was directly linked to illudol family, epi-illudol, epimeric at the allylic hydroxyl position. ~8 This group kindly provided us with an original sample of their natural product, which was in all aspects identical to our synthetic production. That means in our major diastereomer 47, the two secondary alcohols have the anti relationship. We thus accomplished the first diastereoselective total synthesis of natural epi-illudol 54 in 10% overall yield over 19 steps. !!1.

En route to linear triquinane synthesis

A. RETROSYNTHETIC ANALYSIS

By following the same type of cascade of radical transannular cyclizations, we believed that a powerful synthetic strategy could be developed if by a simple modification, it would allow a completely different and still highly selective reaction pathway to occur. We were thus motivated to follow the same strategy of transannular radical cascade, switching the BMDMS-ether tether from one propargylic position to the other inside the

168

ANNE-LISE

DHIMANE

AND MAX MALACRIA

EtO

1. TBSCI, 4-DMAP Et3N, CH2CI2, r.t. ' ~ O 2. LAH, Et20 0~ to r.t.

1. Pd(OAc)2 1% dppe 2.5%, THF ~ O

2

THF '

OE

OH

42

26, 90%

3. Swern oxidation 4. EtO2CCH2P(O)(EtO)2 LiCI, Et3N, MeCN

O et

O 1. DIBAL-H, CH2CI2, -78~ to r.t. 2. Swern oxidation 3. (HOCH2)2, HO(Bu)2SnOSn(Bu)2NCS benzene rfx

"~OTBS

~OTBS

43, 98%, 4 steps

44, 83%, 3 steps O

1.TBAF, THF r.t. O .O 2. DMSO, SO'3-pyridine "1/ complex, Et3N -.~ CH2CI2, r.t. ............ A

1. TBSCI imidazole DMF

3. propargyl Grignard Et20,-40~ ~

2. APTS acetone H20, A

.

"~" v

J OH

45, 54%, 3 steps

46, 80%, 2 steps

HOHMDSLi, THF, r.t.

OTBS

47, 39%

SCHEME 13. Intramolecularacetylideaddition approach(pathsB and D) to cycloundecadienynol47 from isoprenemonoxide42.

6

169

NATURAL PROTOILLUDANES AND LINEAR TRIQUINANES

o= k NIS, AgNO3 acetone, r.t.

"

in THF, 0.015 moI.L -1 slow addition

46

HO

y

on a suspension TBS

of CrCI 2

I

OTBS 47, 88% 2 diastereomers (31)

48,81%

BMDMSCI, 4-DMAP NEt3, CH2CI2 OTBS 49, quant.

SCHEME 14. IntramolecularNozaki-Hiyama-Kishi-Takaiapproach (path B) to BMDMS precursor 49 from dienynal 46. cycloundecadienyne precursor, to open a new route to the highly popular triquinane framework of type 55. Wiser from our experience, we anticipated that the disubstituted double bond geometry would be crucial for the success of the transannular cascade. That was the reason why we planned to prepare both Z- and E-stereoisomers of the disubstituted double bond. Now, the main change, compared to the epiilludol synthesis, concerned the ether linkage in the requisite precursor 56, which is here in the homoallylic position. Nevertheless we decided to keep the same NHKT-macrocyclization as a key-step to reach the elevenmembered ring. We envisioned two different precursors to 56, one with only

170

ANNE-LISE

I ~Si-O

DHIMANE

AND

MAX

MALACRIA

1. Bu3SnH,AIBN, OH OH benzene,reflux ~ ~ .... ~..,,,

Br--/~

OTBS

49

2. H202,KHC03,KF, MeOH,THF 3. n-Bu4NF,THF

..

47%

epi-illudol

OH

54

,T

I

~Si-O

~Si-O

-

5-exo-dig 4-(H-exo)-exo- trig I 9-(H-endo)-endo trig

OTBS

51

6-exo-trig / 5-endo trig

[

I ~Si-O

:

53

OTBS

OTBS

"~Si-O

o

OTBS

52

SCHEME 15. Radicaltransannularcascadeto epi-illudol54. one ether moiety, which could be prepared from 13,7-unsaturated aldehyde 57 (path E), and a second one, which possessed two ether functions at both propargylic positions and could be formed from ct,13-unsaturated aldehyde 58 (path F). Both dienynal precursors 57 and 58 could be formed from a common heptenal 59. The synthesis of this latter compound was envisioned via two convergent pathways ways G and H, through the common precursor heptenoate 60, starting respectively from commercially available isoprene monoxide 42 and but-3-yn-l-ol.

6

171

NATURAL P R O T O I L L U D A N E S AND LINEAR T R I Q U I N A N E S

a

Radical Br F ",,L~ cascade'~ ~ S ~ o E ~

H 55

R

!

HO

56

linear triquinane

R=H

= OMe path F x•R

path E

"el!

,

57

pat 42

TBSO

I

G,

EtO...~O ,~,

TBSO

\

~ H G

i;

59'

path H OH

SCHEME 16. Retrosyntheticpathwaysto lineartriquinane skeletons. B. SYNTHESIS OF COMMON PRECURSOR 59

In pursuing path G, we kept the previous Pd(0)-allylic substitution key step [Scheme 17]. Starting from isoprene monoxide 42, we separated E- from Z-isomer to keep a pure E-hexenoate 26 (72% yield). This allylic alcohol was then homologated efficiently into the corresponding homoallylic alcohol following a four-step sequence described by Leopold 19 9oxidation to generate the enal moiety, Wittig reaction to conjugated diene 61, hydroboronation at

172

ANNE-LISE

['...

Et

OH

1. DMSO, Et3N SO3-pyridine CH2CI2, r.t. 2. Ph3P+CH3Br n-BuLi, THF, r.t.

(E)-26 72% from isoprene monoxide

DHIMANE

AND MAX MALACRIA

Et 1. (0 (Sia)2BH, THF, 0~ (il) H202, NaOH, THF, 0~ 2.TBSCI, 4-DMAP 61, 77%, 2 steps Et3N,CH2CI2

O I

"- CO2Et

."

1. LAH, Et20, O~ ram2.

60, 57%, 2 steps

Swern oxidation

59, 93%, 2 steps

path (3 28%, 6 steps

SCHEME 17. Synthesis of common precursor 59 from hexenoate (E)-26 (path G). the less hindered terminal position and finally H202 oxidation to the homoallylic alcohol. After a simple TBS-protection, the common ester 60 was obtained cleanly. A LAH reduction-Swern oxidation sequence afforded the desired aldehyde 59. On another hand, after standard protection of the 3-butyn-l-ol and acylation of the triple bond, the resulting ynoate was submitted to stereoselective Mukaiyama-Kobayashi conditions in order to get enoate 63 as a single E-stereoisomer 20. Further classical functional transformations furnished the common ester 60. First, reduction of the ester moiety with LAH, and Collington-Meyers conditions were applied to convert the allylic alcohol thus obtained into the corresponding chloride. Finally, alkylation of this chloride with the lithium enolate of ethyl iso-butyrate provided the desired heptenoate 60. This second approach is less direct but more effective, producing 60 in 53% isolated yield in 7 steps from butynol compared to 28% yield and 6 steps from isoprene monoxide [Scheme 18].

6

173

NATURAL PR(YI'()ILLUI)ANES ANI) LINEAR "I'RIQUINANES

I

1. TBSCI, Et3N 4-DMAP, CH2CI2

CO l 2Me 1. PhSNa, MeOH, 0~ [

~

I

'"] OH

2.n-BuLi,CICO2Me, THF ~l OTBS

2. MeMgBr, CuBr.Me2S THF, -78~

62, quant., 2 steps ,"-.. CO2Et

MeO2C

1. LAH, Et20, -30 to 0~ 2. MsCi, lutidine, LiCI 3. Me2CHCO2Et, LDA, THF

63, 62%, 2 steps

path H 53%, 7 steps

60, 86%, 3 steps

S C H E M E 18. Synthesis o f common precursor 60 from but- 3- yn- l- ol (path H).

C. SYNTHESIS AND RADICAL REACTIVITY OF A Z,E-PRECURSORVIA PATH E

A Wittig reaction employing heptenal 59 with the phosphonium ylide 64, prepared from the corresponding iodide with n-BuLl as base, furnished the expected 1,4-enyne in 79% yield [Scheme 19]. A straightforward treatment of the latter with TBAF in order to achieve deprotection of both silylated functions led to a mixture of the required dienynol 65 and the corresponding vinylallene isomer. We assume that the basic medium (due to the use of TBAF) was responsible for the formation of this side-product. Ultimately, the solution was to first manage the selective KF deprotection of the triple bond (K2CO3-MeOH is also efficient), followed by mild acidic cleavage of the TBS ether, to cleanly obtain dienynol 53. Initial iodination of the triple bond with the iodine-morpholine complex followed by a Dess-Martin oxidation of the homoallylic alcohol achieved the formation of the NHKTmacrocyclization precursor aldehyde 66. Carefully controlled, slow addition of iodoalkyne 66 in THF to a suspension of chromium chloride produced the desired macrocyclic propargylic alcohol 67 in a disappointing 14% yield over three steps, along with 27% of a mixture of deiodated ct,13-and 13,yunsaturated aldehydes 68. The BMDMS silylation step gave as expected the BMDMS ether 69.

174

ANNE-LISE

1. TMS 59

---64

DHIMANE

AND MAX MALACRIA

1.12,morpholine benzene, 70~

~__ P+Ph31-r

n-BuLi, THF/HMPT 98/1 2. KF. 2 H20,DMF 3. HCI 5%, EtOH, 0~

2. Dess-Martin periodinane CH2CI2

'~

65, 71%, 3 steps

in THF, 102moI.L 1

.o,,,

slow addition on a suspension of CrCI2 HO 67, 14%, 3 steps

66

68, 27% of a

mixture of enals

[

BMDMSCI imidazole

''S~

69, 50%

~BMDMSO SCHEME 19. Synthesis of Z, E-cycloundecadienyneprecursor 69 from common precursor 59. We assume that the intramolecular NHKT procedure is a particularly efficient method to build highly strained eleven-membered rings when the iodo alkyne moiety closes easily on conjugated enals (yield up to 88%), but quite evidently is less efficient in the case of easily enolizable aldehydes. In any case, the radical cascade precursor 69 was submitted to classical Bu3SnH-AIBN conditions to first generate the ct-silyl radical 71 [Scheme 20]. Our experiment revealed that, after the usual first 5-exo-dig process, the vinyl radical 72 preferred the transannular 6-endo-trig mode over the expected 5-exo-trig one. The bicyclo[4.5.0]undecadiene 70 was isolated after Tamao oxidation, among other intractable material, in 30% yield as an inseparable mixture of four diastereomers, of which two were major in a 1 to 1 proportion. 2~

6

175

NATURAL PROTOILLUDANES AND LINEAR TRIQUINANES

1. Bu3SnH,AIBN L 2. Tamaooxid. HO HO

.~~i~,0

/

69

70, 30% ~4diastereomers

m

6-(~t-endo) -endo- trig /

5-exo-dig 9

/St-o -

71

72

7-(rt-exo) -exo-trig

"~" ~.

/~L-O 73

-

SCHEME 20. Radical cyclizations cascade of Z, E-cycloundecadienyne precursor 69.

D. SYNTHESIS OF A E,E-PRECURSOR VIA PATH F

This unexpected occurrence of a new transannular radical process from the vinyl radical generated inside a Z,E-cycloundecadienyne 69 encouraged us to prepare an E,E-precursor for a better understanding of factors that govern these transannular radical processes, in the hope of reaching the triquinane target. The difficulty of macrocyclization of a homopropargylic aldehyde by the NHKT ring closure guided us to choose the pathway F ( R - OMe) described in Scheme 16. Conjugated enal 58 could be the annelation precursor, thus probably bypassing the macrocyclization difficulty. Heptenal 59 was subjected to Horner-Wadsworth-Emmons olefination conditions described by Masamune and Roush ! la to stereoselectively furnish the E,E-nonadienoate. A TBAF mediated cleavage of the resulting silylated ether, followed by mild Dess-Martin oxidation of the homoallylic alcohol provided the [3,yunsaturated aldehyde. This latter was condensed with the in situ generated organocerium derivative of trimethylsilylacetylene to form 74 in 56% overall yield from 59. After a sequential deprotection of the silylated alkyne and protection of

176

A N N E - L I S E D H I M A N E A N D MAX M A L A C R I A

hydroxy group, the resulting enoate 75 was reduced with DIBAL-H into an allylic alcohol, which was smoothly oxidized with Dess-Martin periodinane [Scheme 21]. Mild iodination conditions gave the expected iodoalkyne precursor 58. As predicted, the classical intra-NHKT macrocyclization was efficient in this case (conjugated non-enolizable aldehyde) and the corresponding macrocycle 76 was obtained in 88% yield as a mixture of diastereomers (2 : 1). These diastereomers were particularly difficult to separate. However, we could enrich the mixture to a 3 : 1 ratio. Then, an Omethylation-desilylation-BMDMS-silylation sequence afforded the required radical precursor 77. 22 E. RADICAL CASCADE TO LINEAR TRIQUINANE

The BMDMS ether 77, subjected to reaction with Ph3SnH-AIBN followed by Tamao oxidation, led diastereoselectively to the 5,5,5-tricyclic skeleton of the desired triquinane framework 78 in 45% yield, along with a bicyclic diol 79 as a 2 : 1 mixture of diastereomers in 12% yield. The formation of triquinane 78 results from the now well-established 5exo-dig cyclization process from the initial et-silyl radical 80 to the vinyl radical 81, which then undergoes the transannular tandem 5-(Jt-endo)-exotrig followed by 5-exo-trig cyclization. The resulting radical 82, with a tetracyclic framework, finally routes via a stannane reduction-Tamao oxidation sequence, thus leading to 78. Alternatively, a minor 13-fragmentation process provides the stabilized amethoxy and allylic radical 83. Reduction of this species in a major endomode gives the isolated diol 79. The difference in regioselectivity between the transannular cyclizations of vinyl radicals 72 and 81 undoubtedly results from the geometric strain generated by the stereochemistry of the double bond. The 6-endo transannular cyclization which creates a seven-membered unsaturated ring is allowed when this disubstituted double bond stereochemistry is Z, as in vinyl radical 72. Instead, when a E-disubstituted double bond is present, as in vinyl radical 81, the 6-endo process becomes forbidden and the 5-exo / 5-exo transannular cascade occurs to form triquinane. This geometric factor exhibits a tremendous influence on the transannular cascade behavior and becomes much more important than the presence of a methyl group on the 5-exo position.

6

NATURAL

177

PR()~I~()ILLUI)ANES AND LINEAR TRIQUINANES

1. (EtO)2P(O)CH2COOEt ~ . . . ~ - / /TMS LiCl, Et3N, MeCN, r.t. H O , , y . , f f 2. TBAF, THF ~ 1. K2CO3, EtOH, r.t.

TBSO O

3. DMP, CH2CI2 4. TMSC~CLi, CeCl3 THF

I

O 2. TBSCl, imidazole DMF Et

74, 56%, 4 steps

59

T So

1. DiBAI-H TR.q(3 I/ / CH2CI2, r.t. - - " ' ' f " 2. DMP, 0H2012 _ /J

in THF, 10-2 moI.L-1

NIS AgNO3 = " " t f l l 3. acetone, r . t . ~/~CHO

slow addition on a suspension of CrCl2

/k 75, 83%, 2 steps

1.,.OTBS

"'oH 76, 88%

58, 60%, 5 steps

= ~,l.

OBMDMS

1. Nail, Mel, THF, 40~ 2. TBAF, THF 3. BMDMSCI, Et3N 4-DMAP, CH2CI2

"OMe 77, 2 dias. (3 : 1)

73%, 4 steps SCHEME 21. Synthesisof E, E-cycloundecadienyneprecursor 78 from common precursor 59. IV.

Conclusion

Our transannular cyclization synthetic strategy had proved to be feasible. By using the same E,E-cycloundecadienyne framework and just moving the

178

ANNE-LISE

DHIMANE

OH OH

AND MAX MALACRIA

OH OH

1. Ph3SnH, AIBN 77

lOOOlO

+

2. Tamao oxid.

prO-si/1- -

I

Me "I"] 78, 45% (1 dias)

Me

79, 12% (2 dias, 2:1)

i ---,,.I ""OMe 80

5-exo-dig /

O_____Si/1 -

O---_Si/1"

transannular cascade , , , , , , ~ ~

O..___Si ~

......

Io

....nM~ 5-(~-endo)-exo-trig H ~L,,,_(~ ....C)M~. ..... 5_exo_trig ~ H ---

/~ 8,

82

I

Me

t 83 I~-fragmentation

SCHEME 22. Radical transannular cascade of E, E-cycloundecadienyneprecursor 77. radical BMDMS ether trigger from one propargylic position to the other, we have a completely selective entry to either the natural protoilludane or the linear triquinane family. This approach has allowed us to achieve the first total synthesis of the naturally occurring sesquiterpene epi-illudol in a totally diastereoselective way. Since, we have been able to prepare several other members of this family" armillol, tsugicoline C23... and to discover a new radical cascade that will be published shortly. We were very pleased to open a new route to the linear triquinane skeleton and we are currently working on the total synthesis of natural triquinanes in our group. We hope to have shown you that perseverance in the face of synthetic

6

NATURAL

PROTOILLUDANES

179

AND LINEAR TRIQUINANES

problems is able to move mountains. The challenge and beauty of total

,,/ Br~Si~ 0

OH OH

OTBS

OH epi-illudol 54

49

OMe

OMe HO

Br.,,,]-- ~

45%

-

H

~Si\o~ \ 77

linear triquinane 78

SCHEME 23. Syntheses of natural protoilludane or linear triquinane according to the propargylic position of BMDMS ether.

synthesis lies in the requirement of finding the right path inside the maze of available synthetic solutions. Acknowledgments We would like to take this opportunity to express our gratitude to the talented and passionate students whose efforts and perseverance made these illudol and triquinane adventures possible:

Dr. Gilbert Agnel who initiated this story, Dr. Maryse Rychlet-Elliott for epi-

illudol, Dr. Christophe Ai'ssa for triquinane, Jean-Manuel Cloarec and Christophe Blaszykowski for their contributions to both protoilludane and triquinane projects. Thanks are due as well to Prof. K.P.C. Vollhardt for providing spectra of illudol and to Prof. G. Nasini for an original sample of epi-illudol. The financial support of C.N.R.S., M.R.E.S. and I.U.F. is also gratefully acknowledged.

References Morisaki, N., Furukawa, J., Kobayashi, H., lwasaki, S., lta'f, A., Nozoe, S., Otuka, S.,

Chem. Pharm. Bull. 1985, 33, 2783-2591.

180 2.

3. 4.

5.

ANNE-LISE

DHIMANE

AND

MAX

MALACRIA

(a) Magnol E., Malacria M., Tetrahedron Lett. 1986, 27, 2255-2258; (b) Journet, M., Malacria, M., J. Org. Chem. 1992, 57, 3085-3093; (c) Fensterbank, L., Malacria, M., Sieburth, S. M., Synthesis 1997, 813-854. Mc Morris, T.C., Nair, M. S. R., Anchel, M., J. Am.Chem. Soc. 1967, 89, 4562-4563. Semmelhack, M. F. "The Synthesis of Fomannosin and llludol" in Strategies and Tactics in Organic Synthesis." Ed. Lindberg, T. Academic Press: London 1984, vol. 1 p. 201-222. (a) Matsumoto, T., Miyano, K, Kagawa, S., Yu, S., Ogawa, J., Ichibara, A., Tetrahedron Lett. 1975, 16, 3521-3524; (b) Semmelhack, M. F., Tomoda, S., Nagaoka, H., Boettger, S. D., Hurst, K. M., J. Am. Chem. Soc. 1980, 102, 7567-7568 and ibid.

6.

1982, 104, 747-759. Johnson, E.P., Voilhardt, K. P. C.,J. Am. Chem. Soc. 1991, 113, 381-382.

7.

Morisaki, N., Furukawa, J., Kobayashi, H., Iwasaki, S., Ita'f, A., Nozoe, S., Otuka, S., Chem. Pharm. Bull. 1985, 33, 2783-2591.

8.

Arnone, A., De Gregorio, C., Meille, S. V., Nasini, G., Sidoti, G., J. Nat. Prod. 1999, 62, 51-53.

9. Agne|, G., Malacria, M., Tetrahedron Lett. 1990, 31, 3555-3558. 10. (a) Vlanchette, M.A., Chay, W., Davis, J.T., Essenfeld, A.P., Masamune, S., Roush, W.R., Sakai, T., Tetrahedron Lett. 1984, 25, 2183-2185 ; (b) Marshall, J.A., DeHoff, B.S., Tetrahedron 1987, 43, 4849-4860; (c) Tius, M.A., Fauq, A.H., J. Am. Chem. Soc. 1986, 108, 1035-1039; (d) Astles, P.C., Thomas, E.J,. Synlett 1989, 42-45. 11. Han, Q., Wiemer, D.F., J. Am. Chem. Soc. 1992, 114, 7692-7697. 12. (a) Crevisy, C., Beau, J.-M., Tetrahedron Lett. 1991, 32, 3171-3174; (b) Lu, Y.-F., Harwig, C. W., Failis, A. G., J. Org. Chem. 1993.58, 4202-4204. 13. Rychlet Elliott, M., Dhimane, A.L., Hamon, L., Malacria, M., Eur. J. Org. Chem. 2000. 155-163. 14. For an application of alkyne hexacarbonylcomplex in macrocyclic synthesis see: Magnus, P., Lewis, R.T., Hoffman, J.C., J. Am. Chem. Soc. 1988, 110, 6921-6923. 15. (a) Takai, K., Tagashira, M., Kuroda, T., Oshima, K., Utimoto, K., Nozaki, H., J. Am. Chem. Soc. 1986, 108, 6048-6050; (b) Jin, H., Uenishi, J-I., Christ, W. J., Kishi, Y., J. Am. Chem. Soc. 1986, 108, 5644-5646.

16. Rychlet Elliott, M., Dhimane, A.L., Malacria, M., Tetrahedron Lett. 1998, 39, 88498852. 17. Parikh, J.R., Von Doering, W.E., J. Am. Chem. Soc. 1967, 89, 5505-5506. 18. Arnone, A., Cardillo, R., di Modugno, V., Nasini, G. J. Chem. Soc., Perkin Trans. l 1989, 1995-2000.

6

NATI)RAL PROTOILLUDANES

AND LINEAR TRIQUINANES

181

19. Leopold, E.J., Org. Synth. Coll. 1990, 7, 258-263. 20. Kobayashi, S., Mukaiyama, T., Chem. Lett. 1974, 705-708. 21. A'fssa,C., Dhimane, A.L., Malacria, M., Synlett 2000, 1585-1588. 22. Dhimane, A.L., A'fssa, C., Malacria, M., Angew. Chem. Int. Ed. 2002, 41, 3284-3287. 23. Unpublished results, manuscript in preparation.