Ir-Catalyzed Double Asymmetric Hydrogenation of 3,6-Dialkylidene-2,5-diketopiperazines for Enantioselective Synthesis of Cyclic Dipeptides

An Ir/spiro­[4,4]-1,6-nonadiene-based
phosphine-oxazoline ligand
(SpinPHOX) complex-catalyzed double asymmetric hydrogenation of 3,6-dialkylidene-1,4-dimethylpiperazine-2,5-diones
has been developed, providing efficient and practical access to a
wide variety of chiral 3,6-disubstituted-2,5-diketopiperazines in
high yields with exclusive cis-diastereo- and excellent
enantioselectivities (>99% de, up to 98% ee). The synthetic utilities
of the protocol have been demonstrated in a gram scale synthesis of 6a and efficient construction of chiral products 8, 14, and 17 as well as a 2-butenyl-bridged
bicyclic diketopiperazine 10 and hydroxydiketopiperazine 11. With an analogous achiral Ir catalyst, the hydrogenation
of enantiopure monohydrogenated intermediate 7a gave cis-6a as the only product, indicating that
the second-step hydrogenation of the titled transformation is a chiral
substrate controlled process. The reaction profile study for asymmetric
hydrogenation (AH) of 5a revealed that the concentration
of the monohydrogenation intermediate 7a remained at
a low level (<8%) during the course of hydrogenation. The hydrogenation
of 5a to 6a proceeded significantly faster
than that of its half-hydrogenated intermediate (S)-7a, indicating that the titled reaction involves primarily
a processive mechanism, in which a single catalyst molecule performs
consecutive hydrogenation of the two CC double bonds in substrate 5a without dissociation of the partially reduced 7a. The present protocol represents a rare example of asymmetric catalytic
consecutive hydrogenation of heterocycles and provides an alternative
way for efficient construction of cyclic dipeptides.