Diastereoselective synthesis of pyrrolidine derivatives via a one-pot nitro-Mannich/hydroamination cascade using base and gold catalysis

Abstract

An efficient one-pot nitro-Mannich/hydroamination cascade reaction for the synthesis of substituted pyrrolidines bearing three stereocentres is reported. Proceeding under the control of a combination of base and gold(I) catalysts, the cascade reaction affords the pyrrolidine products in high yields with good to excellent diastereoselectivities.

1,3-Carbon D–A strategy for [3 + 2] cycloadditions/annulations with imines: synthesis of functionalized pyrrolidines and related alkaloids

“…Dixon and co-workers reported a very similar diastereoselective base-metal catalyzed one-pot nitro-Mannich/hydroamination cascade strategy for substituted pyrrolidine synthesis. 47 Very recently, the same group developed asymmetric version of this cascade reaction for the synthesis of substituted pyrrolidines bearing three stereocentres. 48 The combination of bifunctional organocatalysis 108 and gold catalysis used in conjunction with N-Cbz imines 106 afforded pyrrolidines 109 in good yields with excellent enantioselectivities (Scheme 24).…”

Diastereoselective C−H Bond Amination for Disubstituted Pyrrolidines

“…The prevalence of 2,5-disubstituted pyrrolidines in natural products, [1] pharmaceuticals, [2] and synthetic applications [3] has inspired the emergence of numerous stereoselective methodologies [4] for the synthesis of these N-heterocycles. However, more atom-economical, efficient, and general processes to access complex architectures featured in many of these N-containing compounds are highly desirable.…”

One-Pot Asymmetric Nitro-Mannich/Hydroamination Cascades for the Synthesis of Pyrrolidine Derivatives: Combining Organocatalysis and Gold Catalysis

“… 3 Cascade reactions are typically resource-efficient and can rapidly build up molecular complexity without the need for isolation of the intermediate compounds. As part of our ongoing research program into cascade reactions using nitro-Mannich 4 and hydroamination 5 reactions, we envisaged that a nitro-Mannich/hydroamination cascade 6 could provide an efficient method to access trisubstituted pyrrolidine derivatives in an enantioselective fashion. Building on our previous diastereoselective pyrrolidine synthesis employing a nitro-Mannich/hydroamination cascade with N - p -toluenesulfonyl-protected imines, 6c we postulated that the effective combination of an imine protecting group and an organocatalyst would allow this cascade reaction to be conducted in an asymmetric fashion, resulting in a new methodology to produce enantioenriched pyrrolidine heterocycles.…”