Concise and stereocontrolled synthesis of the southern γ-butyrolactone subunit of polycavernoside A

Article abstract of DOI:10.1016/S0040-4039(00)01839-6

The southern γ-butyrolactone subunit 8 of polycavernoside A was readily assembled by a novel and connective methodology involving an initial ene-reaction followed by an intramolecular oxidative cyclisation. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01839-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10219–10222
Concise and stereocontrolled synthesis of the southern
g-butyrolactone subunit of polycavernoside A
Raphae¨l Dumeunier and Istva´n E. Marko´*
Universite´ catholique de Louvain, De´partement de Chimie, Baˆtiment Lavoisier, Place Louis Pasteur 1,
B-1348 Louvain-la-Neuve, Belgium
Received 19 October 2000; accepted 20 October 2000
Abstract
The southern g-butyrolactone subunit 8 of polycavernoside A was readily assembled by a novel and
connective methodology involving an initial ene-reaction followed by an intramolecular oxidative cyclisa-
tion. © 2000 Published by Elsevier Science Ltd.
Keywords: ene reactions; oxidation; silicon; lactones; polycavernoside A.
In the preceding communication, we have disclosed some of our results on the establishment
of an efficient and connective novel methodology for the rapid and stereocontrolled assembly of
silyl-substituted g-butyrolactones 3, based upon a tandem ene-reaction/oxidative cyclisation of
aldehydes 1 with allylsilane 2.1 Subsequent functionalisation of 3 afforded a simple preparation
of variously substituted exo-methylene-g-butyrolactones 4 (Fig. 1).
TMS
OTBS
TMS
H
i, ii
iii
+
(74-80%)
(55-80%)
R
O
O
O
R
O
3
R
O
4
1
2
Figure 1. i=Et2AlCl; ii=TBAF/THF then TPAP/NMO; iii=LDA/TMSCl then NBS then TBAF
In this article, we wish to report an expedient synthesis of the southern g-butyrolactone
subunit of polycavernoside A 5,2 a marine toxin isolated by Yasumoto et al. in 1992 and
responsible for fatal human intoxication on the island of Guam,3 using as a key-step our novel
ene/oxidative cyclisation methodology. Our retrosynthetic analysis is described in Fig. 2.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01839-6

10220
OH
OH
Me
6
O
Me
COOR
X
O
+
O
O
O
O
O
HO
O
O
OH
5
7
Me
TMS
OTBS
O
O
OH
O
+
OP
Me
2
9
8
Figure 2.
Cleavage of the macrocyclic lactone and a-ketol functions of 5 generated two fragments 6 and
7 of approximately the same molecular size. Removal of the polyene portion of subunit 7
afforded butyrolactone 8, which was further disconnected, by application of the ene-oxidative
cyclisation retron, to the allylsilane 2 and the key aldehyde 9. Our synthesis of 8 is illustrated in
Fig. 3.
5% CuCl.Phen / O2
TMS
Et2AlCl
5% DBAD / 8% DMAP
OBn
OBn
O
+
CH2Cl2
(52%)
5% tBuOK / FC6H5 / 85°C
(93%)
OTBS
OBn
HO
O
11
2
10
1. LDA / TMSCl
2. NBS / -78°C
TBSO
TMS
O
OH
1. TBAF / THF
TMS
OBn 2. TPAP / NMO
3. TBAF / -78°C
(74%)
13
12
(99% ; d.e. = 75%)
O
O
H2 / Pd-C
O
O
EtOAc
Me
OH
OBn
(>95%)
8
14
(d.e. >95%)
Figure 3.

10221
Oxidation of the monoprotected alcohol 10, using a modification of our recently reported
copper-catalysed aerobic oxidation protocol,4 delivered the desired aldehyde 11 in 97% isolated
yield. Subsequent ene reaction between aldehyde 11 and allylsilane 2, catalysed by Et2AlCl,
generated the required enolsilane 12, which was submitted to a chemoselective oxidative–desilyl-
ation procedure, affording in excellent yield the desired a-(trimethylsilylmethyl)-lactone 13 (d.e.:
75%). Transformation of 13 into the corresponding a-methylenelactone 14, via the one-pot
protocol described in Fig. 3, proceeded smoothly and afforded product 14 in 74% yield. Finally,
catalytic hydrogenation using Pd/C in EtOAc,5 reduced the exo-methylene CꢀC double bond
and simultaneously removed the benzyl protecting group, directly producing the syn-disubstit-
uted lactone 8 in quantitative yield and as a single diastereoisomer, possessing the correct
stereochemistry and functionality for further transformation into the southern portion of
polycavernoside A.6
The extremely high selectivity observed during the catalytic hydrogenation of the exo-methyl-
ene double bond of 14 appeared rather surprising in light of previous results obtained in the
reduction of 5-substituted exo-methylene g-butyrolactones.7 Closer examination of the products
formed during the early stages of the hydrogenation revealed that a rapid, metal-catalysed,
isomerisation of the exocyclic double bond of 14 into the endocyclic position took place,
generating butenolides 15 and 16. A subsequent, and more sluggish, reduction of this trisubstit-
uted alkene eventually afforded the final product 8. It thus transpires that the high facial
selectivity observed in the formation of 8 results from a 1,2-diastereocontrol, the bulky side
chain at C5 directing the approach of the reductant from the a-face of butenolides 15 and 16
(Fig. 4).
O
O
O
H2 / Pd-C
EtOAc
O
O
O
+
OBn
Me
OBn
Me
OH
14
15
16
Figure 4.
In summary, we have reported a concise and efficient synthesis (five steps, 35% overall yields)
of the southern lactone subunit 8 of polycavernoside A, using as a key-step our recently
disclosed ene/oxidative cyclisation methodology. Current efforts are now being directed towards
delineating the full scope of this connective methodology, defining an enantioselective version
and completing the total synthesis of polycavernoside A 5. The results of these investigations
will be reported in due course.
Acknowledgements
Financial support of this work by the Universite´ catholique de Louvain, the Actions de
Recherche Concerte´es (convention 96/01-197), the Fonds pour la Formation a` la Recherche
dans l’Industrie et dans l’Agriculture (FRIA) and the Fonds de la Recherche Fondamentale
Collective (dossier no. 2.4571.98) and the Fond National de la Recherche Scientifique (R.D.,
Aspirant du FNRS) is gratefully acknowledged. I.E.M. is thankful to Merck & Co. for its
continuous support and for receiving the Merck Young Investigator Award.

10222
References
1. Leroy, B.; Dumeunier, R.; Marko´, I. E. Tetrahedron Lett. 2000, 41, 10215.
2. Two total syntheses of polycavernoside A have been published so far: (a) Fujiwara, K.; Murai, A.; Y.-Yamashita,
M.; Yasumoto, T. J. Am. Chem. Soc. 1998, 120, 10770. (b) Paquette, L. A.; Barriault, L.; Pissarnitski, D. J. Am.
Chem. Soc. 1999, 121, 4542. For the establishment of the relative stereochemistry of polycavernoside A, see: (a)
Hayashi, N.; Mine, T.; Fujiwara, K.; Murai, A. Chem. Lett. 1994, 2143. (b) Fujiwara, K.; Amano, S.; Oka, T.;
Murai, A. Chem. Lett. 1994, 2147. (c) Fujiwara, K.; Amano, S.; Murai, A. Chem. Lett. 1995, 191. (d) Fujiwara,
K.; Amano, S.; Murai, A. Chem. Lett. 1995, 855. For other synthetic studies, see: (a) Johnston, J. N.; Paquette,
L. Tetrahedron Lett. 1995, 36, 4341. (b) Paquette, L.; Pissarnitski, D.; Barriault, L. J. Org. Chem. 1998, 63, 7389.
3. Yamashita, M. Y.; Haddock, R. L.; Yasumoto, T. J. Am. Chem. Soc. 1993, 115, 1147.
4. Marko´, I. E.; Giles, P. R.; Tsukazaki, M.; Chelle´-Regnaut, I.; Gautier, A.; Brown, S. M.; Urch, C. J. J. Org.
Chem. 1999, 64, 2433 and references cited therein.
5. Kempf, D. J. J. Org. Chem. 1986, 51, 3921.
6. All new compounds display spectroscopic and analytical data in full agreement with their proposed structures.
Lactone 8 is identical in all respect (except optical rotation) with material previously published in the literature
(Reference 2).
7. For some selected references on the hydrogenation of exo-methylene g-butyrolactones, see: (a) Hanessian, S.;
Abad-Grillo, T.; McNaughton-Smith, G. Tetrahedron 1997, 53, 6281. (b) Chen, M. S.; Liu, R. S. Tetrahedron Lett.
1998, 39, 9465. For exo–endo isomerisation before reduction, see: (a) Alper, H.; Lee, C. W. J. Org. Chem. 1995,
60, 499. (b) Chen, M. S.; Kesavaran, N.; Liu, R. S. J. Org. Chem. 1999, 64, 8311.
.