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.

Epoxyalcohol Route to Hydroxyethylene Dipeptide Isosteres. Stereodivergent Synthesis of the Diaminoalcohol Core of Ritonavir and its C-2 Epimer.

BENEDETTI, FABIO;BERTI, FEDERICO;NORBEDO, STEFANO
2002-01-01

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 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/1690086
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