Cyanohydrin acetonide couplings are a very effective methodology for the synthesis of polyol chains. We report a detailed investigation of the alkylation and reductive decyanation of 4-cyano-2,2-dimethyl-1,3-dioxanes (cyanohydrin acetonides). The various parameters influencing the reaction were investigated, including the choice of base, electrophile, time, and temperature. It was found that LHMDS was greatly superior to LDA in the alkylation of allylic and propargylic halides, but no such difference was found with saturated alkylating agents. The minor side products obtained from these reactions were identified, and methods for their minimization were developed. These studies led to a greater understanding of these alkylation reactions which were key steps in the convergent synthesis of polyene macrolide antibiotics like roxaticin and roflamycoin.