Quaternary Chiral Center via Diastereoselective Enolate Amination Enables the Synthesis of an Anti-inflammatory Agent

Abstract

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.

A modular, low footprint and scalable flow platform for the expedient α-aminohydroxylation of enolizable ketones

“…Procedures based on chlorine gas were amongst the earliest reported. 65,84,[90][91][92][93][94][95][96] Given the hazards related with the handling of Cl 2 gas on a preparative scale, a procedure relying on its in situ generation from aqueous H 2 O 2 / HCl was reported by Terent'ev for the preparation of various α-chloronitroso compounds. 97 Alternative methods based on N-chloroderivatives such as N-tert-butyl-chlorocyanamide, 98 N,N′-dichloro bis(2,4,6-trichlorophenyl)urea, 99 79 or N-chlorosuccinimide, 82 provided a low atom economy 100 and a high environmental factor (E-factor).…”

“…Compared to other ethereal solvents, MTBE is considered as a safer option since it does not form potentially explosive peroxides and does not react with tBuOCl. 65,104 A column packed with glass beads (φ = 0.1 mm) was inserted before the membrane separator to enhance the extraction efficiency, giving tBuOCl in 98% yield (ESI, Fig. S1 and Table S3 †).…”

“…[57][58][59][60][61][62] (c) Large scale preparation of anti-inflammatory drug candidate BMS-561392 involving a key electrophilic α-aminohydroxylation using 1a. 65 (d) This work significantly extends the scope of the α-aminohydroxylation with α-chloronitroso derivatives such as 1a to primary, secondary and tertiary enolizable substrates under scalable flow conditions. Fig.…”

“…65 This protocol was developed at Bristol-Myers Squibb and required labor-and energy-intensive conditions. Besides, the authors indicated that "data substantiated that the aminating agent 1-chloro-1nitrosocyclopentane was not safe to use" 65 on such a preparative scale. The unstable and explosive nature of 1a imposed −78°C for the effective amination of a leucine-derived enolizable amide.…”

“…The unstable and explosive nature of 1a imposed −78°C for the effective amination of a leucine-derived enolizable amide. 65 With increasingly restrictive legislations both at the R&D and commercial scales, the use of reactive and potentially hazardous chemicals has become limiting if not impossible with conventional batch reactors. The concept of chemical generators under continuous flow conditions has been extensively documented by Kappe, [66][67][68][69][70][71][72] hence providing a robust answer for exploiting reactive intermediates yet benefiting from all the safety and process advantages of continuous flow operation.…”