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Synlett 2010(19): 2923-2927  
DOI: 10.1055/s-0030-1259015
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Concise Synthesis of Bengamide E and Analogues via E-Selective Cross-Metathesis Olefination

Safiul Alam, Hamid Dhimane*
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS/Université Paris Descartes, UFR Biomédicale, 45, Rue des Saints-Pères, 75270 Paris cedex 06, France
Fax: +33(1)42864050; e-Mail: hamid.dhimane@parisdescartes.fr;
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Publication History

Received 2 September 2010
Publication Date:
03 November 2010 (online)

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Abstract

A modular, eight-step synthesis of bengamide E and six analogues from a common chiral pool has been developed. The key step in this approach is a cross-metathesis coupling of various commercial terminal olefins and a common alkene bearing the required stereogenic centers of bengamides lateral chain, which was easily derived from α-d-glucoheptonic-γ-lactone. Complete E-selectivity, and up to 92% yield were achieved for this crucial cross-metathesis step.

Key words

bengamide - analogues - cross-metathesis - stereoselective olefination - isomerization

10

Aldehyde 3 is highly hygroscopic and sensitive to both acid and base; it should be freshly prepared and dehydrated by azeotropic evaporations with i-PrOAc prior to its use.

11

Our initial attempt to carry out the Julia-Kocienski methylenation of aldehyde 3 led to the required olefin 4 in poor yields (<10%).

13

Use of PTSA as catalyst in toluene at 80 ˚C gave similar yields; however, in large-scale batches, we observed transprotection of the acetonide, thus leading to the corresponding bisorthoester. Orthoester 6 was found to be stable at r.t. in the solid state; however, it undergoes gradual hydrolysis (into methyl formiate and diol 2) on standing in CDCl3.

15

The CM adducts 5 could not be quantitatively recovered from the reaction mixtures; aromatic compounds 5e-g could not be fully separated from substrate 4, while the aliphatic ones 5a-d were always contaminated with the substrate isomer 4′.

22

No CM reaction was observed with: H2C=CHTMS, H2C=CHO-t-Bu, H2C=CHOAc, H2C=CHSO2Me, N-vinylimidazole.