Syn-selective Michael addition of amines to bis-enones: Synthesis of 1,3,4,7-tetrasubstituted (4R,5S,6S,7R)-hexahydro-5,6-dihydroxy-2H-1,3-diazepin-2-ones

O-protected 1,3,4,7-tetrasubstituted (4R,5S,6S,7R)-hexahydro-5,6-dihydroxy-2H-1,3-diazepin-2-ones 7a-d are seven-membered cyclic ureas useful as intermediates in the synthesis of HIV-proteinase inhibitors. We succeeded in preparing them using a three-step sequence starting from diethyl isopropylidene-L-tartrate 1. In a one-pot reaction 1 was transformed via an in situ generated aldehyde and subsequent Wittig reaction into the bis-enones 2a,b. Treatment with excess of primary amines resulted in a two-fold syn-selective Michael addition at low temperature that generated predominantly the C-2-symmetric 1,4-bis(aminoalkyl) derivatives 3a-d. Here we investigated the influence of reaction temperature and configuration of the starting bis-olefin on stereoselectivity. The cyclic ureas 6a-d were formed by treatment of 3a-d with phosgene at elevated temperature. We succeeded in extending this approach to asymmetric substituted cyclic ureas by controlled monoaddition of benzylamine to 2a, providing the monoaddition product 5a in good yields. Finally, conjugate addition of a second amine to 5a followed by cyclization gave the pseudo-C-2-symmetric cyclic urea 9.