A stereoselective synthesis of (+)-malyngolide via a ring-closing olefin metathesis

Article abstract of DOI:10.1016/S0040-4039(00)00884-4

A very short and stereoselective synthesis of the non-natural enantiomer of malyngolide from L-erythrulose is described. Key features of the synthesis are the Felkin-Anh diastereoselective allylation of a poly-oxygenated ketone and the allylation/metathesis/allylic oxidation protocol recently described by our group. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00884-4

Tetrahedron Letters 41 (2000) 5511±5513
A stereoselective synthesis of (+)-malyngolide via a
ring-closing ole®n metathesis
Miguel Carda,a Encarnacion Castillo,a Santiago Rodrõgueza and J. Alberto Marcob,*
a
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Department of Quimica Inorganica y Organica, University of Jaume I, Castellon, E-12080 Castellon, Spain
b
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Department of Quimica Organica, University of Valencia, E-46100 Burjassot, Valencia, Spain
Received 6 April 2000; accepted 1 June 2000
Abstract
A very short and stereoselective synthesis of the non-natural enantiomer of malyngolide from l-erythrulose
is described. Key features of the synthesis are the Felkin±Anh diastereoselective allylation of a poly-
oxygenated ketone and the allylation/metathesis/allylic oxidation protocol recently described by our group.
# 2000 Elsevier Science Ltd. All rights reserved.
Keywords: malyngolide; ring-closing metathesis; diastereoselective allyltin addition.
(^)-Malyngolide is a naturally ocurring d-lactone isolated from the alga Lyngbya majuscula
Gomont and displays antibiotic activity against pathogenic species belonging to genera such as
Staphylococcus, Mycobacterium, Pseudomonas and other related genera.1 Total syntheses of this
metabolite, both of the naturally occurring enantiomer and of its antipode (+)-malyngolide, have
been previously published by other groups, including two very recent ones by Hoppe, Tanaka
and their respective co-workers.2 In the present communication, we present another approach to
(+)-malyngolide based on our recently described methodology of sequential allylation/metathesis/
allylic oxidation.3 The starting material is l-erythrulose, currently developed by our group as a
useful C4 chiron.4 Our retrosynthetic analysis of (+)-malyngolide is shown in Scheme 1.
Scheme 1.
* Corresponding author. Fax: 34-96-3864328; e-mail: alberto.marco@uv.es
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00884-4

5512
The synthetic sequence depicted above relies on a stereoselective nucleophilic allylation of a
suitably protected erythrulose derivative. This has previously been achieved for 3,4-di-O-benzyl
erythrulose derivatives under conditions of chelation control.4 Unfortunately, the synthetically
much more convenient erythrulose acetals5 were found to decompose in the presence of certain
Lewis acids or to react unstereoselectively under other allylation conditions.6 After extensive
experimentation, we found that treatment of the silylated l-erythrulose acetonide 15 (Scheme 2,
TPSˆt-butyldiphenylsilyl) with allyl tri-n-butyltin in the presence of the mild Lewis acid
7
.
MgBr2 Et2O furnished allylcarbinol 2 as an essentially single stereoisomer in a very good
chemical yield. Unexpectedly, the con®guration of the new stereogenic centre corresponded to
that predicted by the Felkin±Anh model and was thus opposite to that which was expected from a
chelation control.4,8 Desilylation of 2 and subsequent tosylation a€orded 3, which was treated
with base to yield epoxide 4. Nucleophilic opening of the oxirane ring with an in situ generated n-
octylcuprate reagent9 gave rise to the tertiary carbinol 5, which was then O-alkylated with
methallyl chloride. This provided ether 6, which was then exposed to ring-closing metathesis
conditions3 in the presence of Grubbs benzylidene ruthenium catalyst.10 Dihydropyran 7 was
formed in an excellent 92% yield. Allylic oxidation with the CrO3/3,5-DMP complex3 yielded the
a,b-unsaturated d-lactone 8, which was then subjected to oxidative cleavage of the dioxolane ring
with periodic acid in Et2O.11 The intermediate aldehyde was not puri®ed but immediately reduced
with NaBH4 in isopropanol to yield dehydromalyngolide 9.12 Lactone 9 was then stereoselectively
converted into (+)-malyngolide by catalytic hydrogenation.13 The described physical and spectral
properties of both malyngolide and its dehydro derivative were coincident with those of our
products.2,14
Scheme 2. Reaction conditions: (a) allylSnBu3, MgBr2, CH2Cl2, ^40ꢀC. (b) TBAF, THF, RT. (c) TsCl, NEt3, DMAP,
CH2Cl2, Á. (d) KH, THF, RT. (e) Me(CH2)7MgI, CuI, THF, ^30ꢀC. (f) KH, methallyl chloride, THF, Á. (g) 3%
PhCHˆRuCl2(PCy3)2, CH2Cl2, Á. (h) CrO3/3,5-DMP, CH2Cl2, ^20ꢀC. (i) H5IO6, Et2O, RT, then NaBH4 (1.2 equiv.)/
iPrOH, 0ꢀC. (j) H2, Pd/C (Ref. 13).
A derivative of the commercially available l-erythrulose was the starting material in the
synthesis of (+)-malyngolide described above. A key step was the stereoselective nucleophilic
allylation of its carbonyl group under nonchelation (Felkin±Anh) control. The synthesis of the
naturally occurring (^)-malyngolide therefore requires either d-erythrulose derivatives as the
starting material,15 or stereoselective allylations of l-erythrulose derivatives to be performed

5513
under chelation control.4,16 Both possibilities are currently being explored by our group and the
results will be reported in due course.
Acknowledgements
This research has been supported by the Spanish Ministry of Education (DGICYT project
PB98-1438), by BANCAIXA (project P1B99-18) and by the Conselleria de Educacio de la
Generalitat Valenciana (project GV-99-77-1-02). E.C. thanks the latter institution for a pre-doctoral
fellowship.
References
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malyngolide: Kogure, T.; Eliel, E. L. J. Org. Chem. 1984, 49, 576±579.
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12. When the reduction of the aldehyde with NaBH4 was conducted for 18 h at room temperature, malyngolide was
formed in 15% yield, together with 60% of 9. Attempts at achieving a complete saturation of the conjugated CˆC
bond by increasing the reaction time and/or the amount of NaBH4 were unsuccessful however, and led only to
reduction of the lactone carbonyl group.
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22
22
14. Optical rotations: 9, ‰aŠ +13.9 (CHCl3, c 1.5); (+)-malyngolide, ‰aŠ +12.3 (CHCl3, c 1), lit.2c for (+)-malyngolide,
D
D
22
‰aŠ +12.4 (CHCl3, c 2).
D
15. Marco, J. A.; Carda, M.; Gonzalez, F.; Rodrõguez, S.; Murga, J. Liebigs Ann. Chem. 1996, 1801±1810.
16. Castillo, E., Ph.D. Thesis, Univ. Jaume I, Castellon, Spain, 2000.