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
Key words
RORγt inverse agonist - annulation - asymmetric aza-Michael reaction - pyrrolidine
ring formation - 5-
exo-tet cyclization
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.
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).
