Synfacts 2020; 16(02): 0121
DOI: 10.1055/s-0039-1691433
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Diastereoselective Pyrrolidine Synthesis Using a Sulfinamide Annulating Agent

Contributor(s):
Philip Kocienski
Shi Q. * Marcoux D. * et al. Bristol-Myers Squibb, Princeton, USA
One-Step Diastereoselective Pyrrolidine Synthesis Using a Sulfinamide Annulating Agent.

Org. Lett. 2019;
21: 9198-9202
Further Information

Publication History

Publication Date:
21 January 2020 (online)

 

Significance

A recent synthesis of the RORγt inverse agonist E (J. Med. Chem. 2019, 63, 9931) featured an aza-Michael addition of metallated carbamate B to Michael acceptor A followed by cyclization of adduct C to give pyrrolidine rac-D as a single diastereoisomer in 75% yield. The conversion of rac-D into the target molecule E then required four steps including an SFC separation of enantiomers. An asymmetric variant of the pyrrolidine annulation has now been developed that obviates the need for chromatographic resolution. Thus, the dia­stereoselective aza-Michael addition of chiral sulfinamide F to sulfone A afforded adduct G which then cyclized to give pyrrolidine ent-H in 75% yield and dr = 49:1.


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Comment

The novel and versatile annulating reagent F is crystalline and stable at room temperature for more than one year. Moreover, the sulfinamide group renders the corresponding products crystalline. The annulation reaction possesses a wide scope, as a variety of singly and doubly activated Michael acceptors provide the corresponding pyrrolidines in moderate to high yields with excellent diastereoselectivities (24 examples).


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