Abatraot: An efficient and hiihly stereoselective route for preparing hydroxyethylene dipeptide isosteres from a-N,Ndibenzylamino ketones has been developed. In the last few years hydroxyethylene dipeptide isosteres ("peptide mimics') have generated considerable interest in the scientific community due to their potential therapeutic value as inhibitors of both HIV-protease and renin.1 These peptidomimetics consist of amino alcohol functionalii which almost invariably exhibii the (4S,5S) stereochemistry. They also typically possess a substituent at the C2 position with the indicated absolute configuration (Note: the R, Sdesignation may change depending upon the substituent priority). NH-Peptide ,_> NHR' 0 Hydroxyethylene dipeptide isostere 1 Many of the reported synthetic approaches to these isosteres make use of the lactone 1 as a key intermediate which is then further elaborated via a diastereoselective alkylation of the enolate and a subsequent ring opening.* Several groups have synthesized 1 from an u-amino aldehydss by reactions with: (a) homoenolate equivalents,* (b) lithium ethyl propiolate,*b or (c) allylic organometallic reagents.*c Alternatively, u-amino aldehydes have been converted to 1 via the intermediacy of the corresponding u-amino epoxides. *d In addition, approaches involving the synthesis of 1 from carbohydrate precursors, such as D-mannose,e or rketoesters derived from N-Cbz phenylalanine,a N-benzyl-N-Boc phenylalanine& and N-phthalimido phenylalaninek have been reported. However, virtually all of them suffer from at least one disadvantage (low chemical efficiency, poor diastereoselectivity, expe&ive starting materials, &c.) which makes them unattractive for scale-up. An exception &this is the elegant synthesis reported by the Merck group which was carried out on a multigram scale. Perhaps the only small disadvantage of this approach is that the starting a-amino akfehyde is sensitiie towards racemization under a variety of experimental condiiions.s Our goal was to develop a general synthetic route whiih was efficient, selective and