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The stereoselective conjugate addition of (S)-(-)-1-(trimethylsilylamino)-2-(methoxymethyl)pyrrolidine (TMS-SAMP) to o-halide-substituted a,P-unsaturated esters 1 is utilized to prepare carbocyclic and heterocyclic p-amino acids 2 and 5 of high diastereo-and enantiomeric purity via the corresponding 0-hydrazino esters by selective intramolecular alkylation of the intermediate ester enolate or the hydrazino moiety. The auxiliary is removed by reductive N-N bond cleavage. The stereochemistry of the resulting trans-2-aminocycloalkanecarboxylic acids (2) and azacycloalk-2-ylacetic acid esters (5) is confirmed by NMR spectroscopy and polarimetry. A transition-state model for the highly diastereoselective conjugate addition of TMS-SAMP to enoates is presented.Enantiopure p-amino acids, although of less importance than the parent a-amino acidsll], are crucial structural features of numerous biologically active and natural products[*], as well as building blocks for p-lactam antibioticsf31. This is reflected in the ever increasing research activity in the field of their stereoselective Besides numerous syntheses employing C-N bond connections, the azaanalogous Michael addition to enoates offers an especially wide synthetic scope due to the possibility of diastereoselective alkylation of the intermediate ester e n o l a t e~ [~~~] .In the course of our investigations on the asymmetric conjugate additions of lithiated TMS-SAMP to a$-unsaturated esters affording P-hydrazino esters of high enantiomeric purity [7], we investigated the diastereo-and enantioselective preparation of a-alkyl-P-hydrazino esters of anti-and syn-configuration by alkylation of the intermediate ester enolates [']. The appropriate 0-amino acids were obtained by reductive N -N bond cleavage. We now wish to report the highly diastereo-and enantioselective conjugate addition of TMS-SAMP to w-halide-substituted enoates leading to both carbocyclic p-amino acids 2 by an intramolecular MichaelInitiated Ring Closure (MIRC)191 and heterocyclic 0-amino acids 5 by intramolecular alkylation of the hydrazino moiety. Amino acids of both kind exhibit an extraordinary variety of interesting properties both as derivatives and in the free form [sc]. The heterocyclic compounds are particularly interesting as precursors for alkaloid synthesis, while the carbocyclic compounds serve as important peptide mimetics. Results and DiscussionOur synthetic strategy leading to carbocyclic and heterocyclic p-amino acids A and E is described by the retrosynthetic analysis outlined in Scheme 1. Starting from w-halide-substituted enoates C we were able to prepare the intermediate ester enolates B by conjugate addition of the chiral ammonia equivalent TMS-SAMP. Subsequent ring-closure of the enolates B by intramolecular alkylation afforded the target compounds A. In an alternative protocol the enolate was quenched yielding F, which subsequently underwent intramolecular alkylation of the amino moiety (F + E). As indicated in Scheme 2, the appropriate enoate 1 was added dropwise to a solu...

Previously difficult to prepare, aliphatic and alicyclic trifluoromethylketones (e.g. 1 and 2), which are of pharmacalogic interest as potential enzyme inhibitors, can now be synthesized easily and efficiently. The one-step reaction starting with carbonic esters and trimethyl(trifluoromethyl)silane is induced by tetrabutylammonium fluoride in nonpolar, aprotic solvents and proceeds without formation of double-addition products.

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