A stereoselective synthesis of hydroxyethylene dipeptide isosteres based on the 1,4-diamino-2-
hydroxybutane structure is described. Horner-Emmons olefination of phosphonates derived from
R-amino acids, stereoselective reduction of the resulting enones to allylic alcohols, and syn
epoxidation of the latter lead to enantiomerically pure 1-amino-2-hydroxy-3,4-epoxybutanes, key
intermediates in the synthesis. Reductive cleavage of the epoxy alcohols with Red-Al proceeds in
a highly regioselective way, giving 1-amino-2,4-dihydroxybutanes, from which diamino alcohol
hydroxyethylene isosteres are obtained by selective protection of the secondary 2-hydroxy group,
via cyclization to 1,3-oxazolidinone, and further elaboration of the 4-hydroxy. Both C-2 epimers of
1,4-diamino-2-hydroxybutanes are accessible by appropriate choice of the conditions for cyclization.
The approach is demonstrated by the synthesis of a series of six hydroxyethylene dipeptide isosteres,
including the diamino alcohol core of potent HIV-protease inhibitor ritonavir 18 and its C-2 epimer
11a.
