Chemo- and Regioselective Syntheses of Enantiopure Aminopyrrolidinones as Building Blocks for Constrained Peptidomimetics
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Starting from natural asparagine the synthesis of the N-protected enantiomerically pure 3and 4-aminopyrrolidinones (I) and (3) was accomplished. The incorporation of these building blocks into conformationally constrained peptidomimetics was demonstrated by the synthesis of the potential dopamine receptor modulator (14b) (B-PAOPA). Furthermore, Freidinger y-Iactams including the protected dipeptide mimetics (Sa-c) and (9) were prepared. The optical integrity of the synthesis was established by NMR analysis of the ureas (IOa,b). Conformationally constrained peptide analogs represent an important family of compounds employed for the development of enzyme inhibitors and receptor ligands.Additionally, interesting insights into the biologically active conformation of natural peptides are provided. Because of their ability to serve as conformationally rigidized surrogates of peptide secondary structures, lactam-bridged peptidomimetics including Freidinger lactams (I) have proven particularly useful.) As an extension to these studies. the first investigations on the incorporation ofB-amino acid derived lactams (Homo-Freidinger lactams, II) were reported. very recently:-6 So far, only few synthetic methods for the construction of these molecular scaffolds in enantiomerically pure form are descibed in the literature.7.8 In this paper. we present a practical ex-chiral pool approach to 3and 4-dibenzylaminopyrrolidinones which can serve as useful and flexible synthetic intermediates for the preparation of y-lactam bridged peptidomimetics of type I and n. respectively. Our strategy was based on selective transformations of asparagine as a versatile bifunctional amino acid. Thus, cyclic imide formation of the benzyl protected asparagine derivative (2) 6.91U followed by regioselective reduction of the sterically less hindered carbonyl function should lead to the (lamino lactam (1). On the other hand, the B-amino regioisomer should be approached by chemoselective reduction of the ester group of 2. followed by activation of the thus formed primary alcohol and cyclization. ~Bn2 1. cyciization ~Bn2 1. chemoselective ~Bn2 (yO 2. regioselective : 0 reduction ~ reduction Dn 2. cyciization < > , o NH2 H o H 1 2 3 In practice. refluxing of the central intermediate (2) in toluene afforded the projected imide (4a) in high 9190 yield (Scheme I). Regioselective reduction of 4a was attempted by a two-step procedure involving reduction with LiEt,BH and treatment of the thus formed hydroxylactam with a mixture of Et3SiH and BF/Etp. ~Bn2 gO o R 4a: R = H 4b: R = Bn ~H2
[1] P. Gmeiner,et al. Beta-analogs of PLG (L-prolyl-L-leucyl-glycinamide): ex-chiral pool syntheses and dopamine D2 receptor modulating effects. , 1998, Bioorganic & medicinal chemistry letters.