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