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-alkyliden e-1,3-propanediols is described. The key step involves an unusual regi o- and stereoselective S(N)2' Mitsunobu reaction of substituted 3-hydr oxy-2-methylenealkanoates which are readily available from a Baylis-Hi llman 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 reac tion conditions were effective for alkyl substituted derivatives, but the addition of Et(3)N to the Mitsunobu conditions was necessary to im prove the S(N)2':S(N)2 ratios for the vinyl 19 and phenyl 20 derivativ es. The monoprotected (Z)- and (E)-2-alkylidene-1,3-propanediols can b e efficiently synthesized by a three-step sequence involving either a transesterification, protection, and DIBAL-H reduction (>80% overall y ield) or by the chemoselective reduction, protection, and ester cleava ge (67% overall yield).