SYNTHESIS OF MONOPROTECTED 2-ALKYLIDENE-1,3-PROPANEDIOLS BY AN UNUSUAL S(N)2' MITSUNOBU REACTION

A simple and efficient route to monoprotected (E)- and (Z)-2-alkylidene-1,3-propanediols is described. The key step involves an unusual regio- and stereoselective S(N)2' Mitsunobu reaction of substituted 3-hydroxy-2-methylenealkanoates which are readily available from a Baylis-Hillman reaction between methyl acrylate and an aldehyde. These allylic alcohols, when treated with PPh(3), a carboxylic acid, and DEAD in THF at temperatures ranging from -40 degrees C to 22 degrees C, produced the corresponding 2-alkylidene-3-hydroxypropanoate derivatives (or (E)-2-(hydroxymethyl)-3-substituted-2-alkenoate derivatives) in >70% with S(N)2':S(N)2 ratio of 22:1 to >50:1. It was found that weak and bulky carboxylic acids and low temperatures favor S(N)2' addition. The reaction conditions were effective for alkyl substituted derivatives, but the addition of Et(3)N to the Mitsunobu conditions was necessary to improve the S(N)2':S(N)2 ratios for the vinyl 19 and phenyl 20 derivatives. The monoprotected (Z)- and (E)-2-alkylidene-1,3-propanediols can be efficiently synthesized by a three-step sequence involving either a transesterification, protection, and DIBAL-H reduction (>80% overall yield) or by the chemoselective reduction, protection, and ester cleavage (67% overall yield).