Synthesis of (-)-(4R,5R)-muricatacin using a regio- and stereospecific ring-opening of a vinyl epoxide

Article abstract of DOI:10.1016/S0040-4039(00)00497-4

Total synthesis of (-)-muricatacin, a natural acetogenin, has been achieved using as a key step a regio- and stereospecific ring-opening of a substituted vinyl epoxide under Lewis acid catalysis. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00497-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3833–3835
Synthesis of (−)-(4R,5R)-muricatacin using a regio- and
stereospecific ring-opening of a vinyl epoxide
Christophe Baylon,a Guillaume Prestat,a Marie-Pierre Heck a,∗ and Charles Mioskowski a,b,∗
aCEA-CE Saclay, Service des Molécules Marquées, Bât 547, Département de Biologie Cellulaire et Moléculaire,
F-91191 Gif sur Yvette cedex, France
bLaboratoire de Synthèse Bio-organique associé au CNRS, Faculté de Pharmacie, Université Louis Pasteur,
74 route du Rhin BP24, F-67401 Illkirch, France
Received 17 February 2000; accepted 18 March 2000
Abstract
Total synthesis of (−)-muricatacin, a natural acetogenin, has been achieved using as a key step a regio- and
stereospecific ring-opening of a substituted vinyl epoxide under Lewis acid catalysis. © 2000 Elsevier Science Ltd.
All rights reserved.
Keywords: acetogenin; muricatacin; epoxide; ring-opening.
In the preceding article we presented the Lewis acid-catalyzed ring-opening of vinyl epoxides to β-
hydroxy allyl-ethers.1 To study the stereoselectivity of this reaction we have developed a new route to
(−)-muricatacin 1 using the epoxide ring-opening reaction as a key step (Scheme 1).
Scheme 1.
Acetogenins are natural products isolated from a worldwide family of tropical plants called
Annonaceae.2 Their antitumoral, immunosuppressive, pesticidal and antimicrobial bioactivities have
attracted increasing interest. (−)-Muricatacin 1 is the simplest of the known native Annonaceous
acetogenins related to γ-lactone and was isolated from the seeds of Annona muricata.3 Since its isolation
in 1991, several syntheses of muricatacin4 and its analogs5 have been described in the literature.
In this paper we report an asymmetric synthesis of (−)-muricatacin 1 using our new methodology
based on the opening of alkenyl epoxides. This reaction is shown to be stereospecific.
The strategy involves the preparation of the key compound 5 from functionalized vinyl epoxide 3
(Scheme 2).
∗
Corresponding authors. E-mail: heck@dsvidf.cea.fr (M.-P. Heck), mioskow@aspirine.u-strasbg.fr (C. Mioskowski)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00497-4
tetl 16776

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Scheme 2. (i): (a) SO3·pyridine, NEt3, CH2Cl2, DMSO; (b) (EtO)2P(O)CH2CO2Et, NaH, THF; (ii): DMPMOH, BF3·Et2O,
CH2Cl2; (iii): (a) NaH, BnBr, DMF; (b) DDQ, CH2Cl2/H2O
(2S,3R)-2,3-Epoxypentadecanol 26 was prepared in three steps from propargylic alcohol as previously
described in the literature.4d Oxidation of epoxyalcohol 2 using SO3·pyridine in CH2Cl2:DMSO (5:1)
afforded the corresponding epoxyaldehyde, which was immediately subjected to olefination with trie-
thylphosphonoacetate giving α,β-unsaturated ester 3 in 91% yield. Treatment of 3 with one molar
equivalent of 3,4-dimethoxybenzylalcohol (DMPMOH) following the previously reported procedure,1
allowed access to alcohol 4 in 52% yield.7 This yield is slightly lower than those obtained using
nonsubstituted vinyl epoxides,1 but is still good considering the five consecutive electrophilic centers
(C1 to C5) present in compound 3. In order to study the stereoselectivity of the ring-opening reaction,
alcohol 4 was treated with NaH and benzylbromide followed by selective deprotection with DDQ to lead
to allylic alcohol 5 in 65% yield. Compound 5 was then esterified by both R and S Mosher’s reagents.8
The 19F NMR of the MTPA-esters showed that the enantiomeric excess was >98%. Measurements of
1
1
the ∆δ taken from H NMR spectroscopy using H–1H COSY allowed the assignment of the absolute
configuration9 of stereocenter C4. The values of ∆δ obtained are in accordance with an R configuration.10
With respect to these experimental results, the reaction appears to be stereospecific and to proceed with
an inversion of configuration in the reaction center. The reaction mechanism therefore follows an SN2
pathway as expected. Using enantio-assigned alcohol 5, the synthesis of (−)-muricatacin 1 was achieved
as reported in Scheme 3.
Scheme 3. (i): (a) Ni(OAc)2, NaBH4, EtOH; (b) p-TSOH, C6H6; (ii): H2, Pd/C, EtOH
Compound 5 was hydrogenated in the presence of a P-2 nickel catalyst using a known procedure.4j
Lactonization to 6 was completed by treatment of the crude product with p-toluenesulfonic acid in
benzene. Finally, benzyl ether 6 was deprotected to give the desired (4R,5R)-muricatacin 1. The spec-
troscopic data (1H and 13C NMR, IR, MS) and the optical rotation of 1 were in close agreement with
reported values (obs. [α]D21=−22, c=0.5, CHCl3; lit. [α]D25=−23.3, c=0.5, CHCl3).4j More convenien-
tly, hydrogenation of 4 followed by treatment with trifluoroacetic acid 5a afforded muricatacin 1.
In summary, a novel and enantiospecific synthesis of (4R,5R)-muricatacin has been accomplished
using a regio- and stereospecific opening of substituted epoxide 3 with one molar equivalent of DMP-
MOH. Our strategy allows the synthesis of all possible stereoisomers of muricatacin 1. Indeed all the
stereoisomers of 2 can be easily prepared by Sharpless epoxidation on Z or E allylic alcohol using (+)-
DET or (−)-DET.
Condensation of alcohol on vinyl epoxide using equal amounts of both partners has not previously been
reported in the literature. Our investigations permitted this regio- and stereospecific ring-opening reaction
using catalytic amounts of BF3·Et2O. This methodology allows the preparation of useful asymmetric
intermediates as illustrated by the synthesis of (−)-muricatacin.

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Acknowledgements
Financial support was provided in part by the Commissariat à l’Energie Atomique (fellowships for
G.P. and C.B.).
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