Backbone stabilized peptidomimetics containing statine-like structural elements: Diastereospecific synthesis of trisubstituted cyclic ureas and 1,4-diazepan-2-ones

2-Aminobenzyl substituted 4-amino-3-hydroxy-5-phenyl pentanoic acid (AHPPA) is the central structural element of highly active HIV-protease inhibitors . To obtain conformationally less flexible statine analogs, we stabilized A HPPA via ring formations, e.g. by reaction with 1,1'-carbonyl diimidazole t o give six-membered ureas. Reaction of AHPPA with chloroacetyl chloride lea ds to 1,4-diazepan-2-ones, whereas BOC protected AHPPA is transformed in a two step sequence to 7(S)-benzyl-6-chloro-4-(4-methoxybenzyl)-2-[1,4]-diaze pane-5(S)-carboxylic acid ethylester, likely assisted by transannular influ ence of N-4. TBDMS protection strategy allows the cyclization of 2-aminoben zyl substituted 4-amino-3-hydroxy-5-phenylpentanal to 7(R)-benzyl-6(S)-hydr oxy-5(R)-hydromethyl-4-(4-methoxybenzyl)-(1,4)-diazepan-2-one and 4(R)-benz pl-5(S)-hydroxy-6(R)-hydroxymethyl-1-(4-methoxybenzyl)-tetrahydro-pyrimidin -2-one. In this way, backbone stabilized peptidomimetics containing statine -like structural elements are obtained. 3(R)-(7(R)-Benzyl-6(S)-hydroxy-4-(4 -methoxybenzyl)-2-oxo-[1,4]-diazepan-5-yl)-acrylic acid ethylester showed t he highest activity against RN-protease in this series with a Ki value of a bout 600 nM.