title: Epoxyalcohol route to hydroxyethylene dipeptide isosteres. Stereodivergent synthesis of the diamino alcohol core of ritonavir and its C-2 epimer.
abstract: 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 alpha-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.
authors.affiliation: Department of Chemical Sciences, University of Trieste, Via Giorgieri 1, I-34127 Trieste, Italy. benedett@univ.trieste.it
authors.forename: Fabio
authors.initials: F
authors.lastname: Benedetti
authors.forename: Federico
authors.initials: F
authors.lastname: Berti
authors.forename: Stefano
authors.initials: S
authors.lastname: Norbedo
mesh_terms: D000438:Alcohols / Q000737:chemistry*; D000440:Butanols / Q000737:chemistry*; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D061466:Lopinavir; D015394:Molecular Structure; D011744:Pyrimidinones / Q000737:chemistry; D019438:Ritonavir / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D013237:Stereoisomerism
chemical_list: C473549:1,4-diamino-2-hydroxybutane; D000438:Alcohols; D000440:Butanols; D004151:Dipeptides; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D019438:Ritonavir