Synthesis of Monoprotected 2-Alkylidene-1,3-propanediols by an Unusual SN2' Mitsunobu Reaction

Article abstract of DOI:10.1021/jo00126a046

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_N2' 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 PPh3, a carboxylic acid, and DEAD in THF at temperatures ranging from -40 deg C to 22 deg C, produced the corresponding 2-alkylidene-3-hydroxypropanoate derivatives (or (E)-2-(hydroxymethyl)-3-substituted-2-alkenoate derivatives) in >70percent with S_N2':S_N2 ratio of 22:1 to >50:1.It was found that weak and bulky carboxylic acids and low temperatures favor S_N2' addition.The reaction conditions were effective for alkyl substituted derivatives, but the addition of Et3N to the Mitsunobu conditions was necessary to improve the S_N2':S_N2 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 (>80percent overall yield) or by the chemoselective reduction, protection, and ester cleavage (67percent overall yield).