Asymmetric and Site-Selective [3 + 2]-Annulations for the Synthesis of High-Value Bicyclic Lactams

Abstract

Asymmetric and site-selective formal [3 + 2]-annulations of γ-alkyl-β,γ-unsaturated γ-lactams with α,β-unsaturated aldehydes have been developed. These organocatalysed transformations yield high value enantioenriched bicyclic γ-lactams with up to four new stereocenters (sometimes including a quarternary carbon). The overall transformation starts from simple and readily accessible furans and oversees a rapid, controlled, and dramatic enhancement in 3D complexity.

The reticent tautomer: exploiting the interesting multisite and multitype reactivity of 4-pyrrolin-2-ones

“…Our idea was to employ LUMO-lowering organocatalysis in the [3 + 2]-annulations of the 4-pyrrolin-2-ones 2r with α,β-unsaturated aldehydes 57 (Scheme 12) in a transformation that could selectively generate up to four new stereocentres. 29 The enantioenriched bicyclic lactam products that we would be synthesising lack general and effective syntheses, and, furthermore, they could serve as very useful intermediates in the synthesis of a range of important asymmetric alkaloid targets. 30 When these ideas were implemented 29 a very interesting switch in mechanism was observed dependent on the degree of substitution of the lactam nitrogen (2r → 59 or 2r → 60, Scheme 13).…”

“…These examples 29,32 represent the first time that efforts have focused on substitution at C-3, and, thus, they complete our tour around the 4-pyrrolin-2-one 2 framework which has shown that each of the contiguous centres (C-3 to C-5 and then on to the nitrogenfour contiguous centres in total) which make up the framework of the pyrrolidone can be manipulated and substituted, at will, by choosing one from a range of mild reactions. The reactivities at each position are exceptional in their complementarity such that regioselectivity has never been a problem.…”

Singlet Oxygen and Dyes: Synthesis with Visible Light is Where the Future Lies

“…The most exciting nascent work in my group focuses on two new areas: building enantioselectivity into our cascades and in developing “dual role” sequences. Recently, enantioselectivity has been introduced by partnering our singlet oxygen technologies with organocatalysis (also a high scorer in sustainability metrics) . By dual role sequences, we mean photocatalysts or dyes that fulfill two roles at different stages of the sequence – using light switches to access even more reaction pathways.…”

Merging singlet-oxygen induced furan oxidations with organocatalysis: synthesis of enantiopure cyclopentanones and hydrindanes

“…10 However, one fundamental pillar remained that, unless incorporated into the strategy, would limit its utility because of the homo-chiral world we live in: we needed to turn these racemic synthetic technologies into enantioselective ones. By combining the enantioselective bond forming power of organocatalysis, 11 which often also scores high in sustainability metrics, with such cascades, 12 we have now achieved a big step forward towards meeting this fundamental challenge.…”

“…Recently, we achieved the syntheses of a number of fused N-containing [5,5]-bicycles 12 via organocatalysed reactions of 4-pyrrolin-2-ones, 17 but we now wanted to target some allcarbon skeletons with greater ubiquity and value, namely, enantiopure cyclopentanones, as well as important fused bicyclic congeners, and we hoped to do this by commandeering the enedione (of type 1i, Scheme 1) produced upon photooxygenation of furan substrates. Enediones should be extremely versatile due to their multisite and multi-type reactivity; features that lend themselves to their participation in domino reactions and/or complexity building sequences.…”