A short approach to the synthesis of the ritonavir and lopinavir core and its C-3 epimer via cross metathesis

A short synthesis of hydroxyethylene dipeptide isostere, a core unit of the HIV-protease inhibitors ritonavir and lopinavir, its C-3 epimer and C2 symmetric diamino diol is described. The crucial aspects of the synthesis are self-cross metathesis and exploitation of C2-symmetric of the metathesis product 8 to obtain the required skeleton.

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(S)-tert-Butyl 1-phenylbut-3-en-2-yl carbamateC18H21NO2[α]D25=+13.8 (c 0.5, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (2S)

tert-Butyl (2S,5S,E)-1,6-diphenylhex-3-ene-2,5-diyl dicarbamateC28H38N2O4[α]D25=-12.3 (c 1.2, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (2S,5S,E)

tert-Butyl (2S,3S,5S)-3-hydroxy-1,6-diphenylhexane-2,5-diyl dicarbamateC28H40N2O5[α]D25=-14.25 (c 1.0, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (2S,3S,5S)

tert-Butyl (2S,3R,5S)-3-hydroxy-1,6-diphenylhexane-2,5-diyl dicarbamateC28H40N2O5[α]D25=-11.2 (c 0.5, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (2S,3R,5S)

tert-Butyl (2S,5S)-3-oxo-1,6-diphenylhexane-2,5-diyl dicarbamateC28H38N2O5[α]D25=+18.18 (c 2.0, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (2S,5S)

tert-Butyl (2S,3S,4S,5S)-3,4-dihydroxy-1,6-diphenylhexane-2,5-diyl dicarbamateC28H40N2O6[α]D25=-12.2 (c 0.5, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (2S,3S,4S,5S)