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Synthesis 2007(4): 622-637  
DOI: 10.1055/s-2007-965893
FEATUREARTICLE
© Georg Thieme Verlag Stuttgart · New York

Enantioselective Total Synthesis of (+)-Scyphostatin, a Potent and Specific Inhibitor of Neutral Sphingomyelinase

Munenori Inouea, Wakako Yokotaa, Tadashi Katoh*b
a Sagami Chemical Research Center, 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan
b Department of Chemical Pharmaceutical Science, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Fax: +81(22)7270135; e-Mail: katoh@tohoku-pharm.ac.jp;
Further Information

Publication History

Received 4 August 2006
Publication Date:
18 January 2007 (online)

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Abstract

The total synthesis of (+)-scyphostatin, a specific and potent neutral sphingomyelinase inhibitor from a microorganism, was accomplished for the first time starting from d-arabinose and both enantiomers of methyl 3-hydroxy-2-methylpropionate. The method involves (a) stereoselective aldol coupling of a methyl 1,3-dioxolane-4-carboxylate with the Garner aldehyde to establish the asymmetric quaternary carbon center at C4, (b) ring-closing meta­thesis of the resultant diene to construct the cyclohexene ring, (c) Negishi coupling of a vinyl iodide and an alkyl iodide to form the requisite trisubstituted E-alkene, (d) formation of an amide from the cyclohexene segment and the trisubstituted E-alkene fatty acid segment, and (e) stereospecific formation of an epoxide ring from the mesylate of the amide formed from the two segments.

Key words

scyphostatin - sphingomyelinase - inhibitors - total synthesis - aldol reaction - Negishi coupling