Synthetic Studies toward the Preparation of Phosphonate Analogs of Sphingomyelin and Ceramide 1-Phosphate Using Pentacovalent Organophospholene Methodology

Model studies for the syntheses of phosphonate analogs of sphingomyelin and ceramide 1-phosphate are described. The pentacovalent oxaphospholene 3b (derived from methyl vinyl ketone and triethyl phosphite) readily condensed with dialkyl azodicarboxylates (R = Et, t-Bu, CH2CCl3) to form β-hydrazido γ-ketophosphonates 5 and 8 in excellent yields. Cleavage of the N−N bond in 5a (R = Et) or 5b (R = t-Bu) via standard methods was unsuccessful. Upon reduction with NaBH4, 8 produced the oxazolidinone 9 (93%) as a diastereomeric mixture of 3:1. Treatment of 9 with Zn/HOAc/acetone at rt readily cleaved the N−N bond to form 11 (78−83%). Confirmation of stereochemical assignments in 11 (3:1, trans:cis) was accomplished via NOE experiments.