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The d-leucine amino acid residue necessary for the synthesis of BMS-561392, 1, was employed as a chiral directing group for a diastereoselective enolate amination to establish the quaternary chiral center. Enhanced diastereomeric ratios were observed while conducting the enolate amination with 1-chloro-1-nitrosocyclopentane 6 in the presence of LiCl. Analogies are drawn between known tertiary amide amino alcohol chiral auxiliaries which have been used to effect diastereoselective enolate alkylations and aminations. Once the stereochemical features of 1 were established, an efficient reaction sequence was devised to complete its synthesis. During the course of this research, accelerated reaction calorimetry (ARC) data substantiated that the aminating agent 1-chloro-1-nitrosocyclopentane 6 was not safe to use as a neat compound. Consequently, a preparation and use of 6 as a stock solution in methyl tert-butyl ether (MTBE) was developed that rendered it safe for use.

Additional information is presented for the transformation of a kinetic resolution into a dynamic kinetic resolution of the isobutyl ester 5b to form the acid 2 in high yield and ee via the intermediacy of a thioester 6c, (Pesti, J. A.; Yin, J.; Zhang, L.-H; Anzalone, L. J. Am. Chem. Soc. 2001, 123, 11075−11076.). The development of optimized reaction conditions for the preparation of 6c, its dynamic kinetic resolution to 2, and the scale-up of both reactions into a pilot plant are described.

The synthesis of efavirenz (DMP 266) involves a highly enantioselective asymmetric reaction of ketone 2a with lithium cyclopropylacetylide 3a in the presence of (1R,2S)-pyrrolidinylnorephedrine (PN...

This report describes a new convergent, selective, and economical synthesis of DMP 777,1 ending with the coupling of the chiral β-lactam half of the molecule (1) to the chiral amine as the isocyanate (2). Other steps involve the coupling of the β-lactam 3 to the phenolic moiety under phase-transfer conditions, followed by resolution of the resulting piperazine derivative using a chiral acid, and recycling of the undesired enantiomer also under phase-transfer conditions. The chiral amine 4 was produced efficiently starting from (R)-α-methylbenzylamine and the corresponding butyrophenone.