No abstract

Saturated heterocycles are found in numerous therapeutics as well as bioactive natural products and are abundant in many medicinal and agrochemical compound libraries. To access new chemical space and function, many methods for functionalization on the periphery of these structures have been developed. Comparatively fewer methods are known for restructuring their core framework. Herein, we describe a visible light-mediated ring contraction of α-acylated saturated heterocycles. This unconventional transformation is orthogonal to traditional ring contractions, challenging the paradigm for diversification of heterocycles including piperidine, morpholine, thiane, tetrahydropyran, and tetrahydroisoquinoline derivatives. The success of this Norrish Type II variant rests on reactivity differences between photoreactive ketone groups in specific chemical environments. This strategy was applied to late-stage remodeling of pharmaceutical derivatives, peptides, and sugars.

Saturated cyclic amines (aza-cycles) are ubiquitous structural motifs found in pharmaceuticals, agrochemicals, and bioactive natural products. Given their importance, methods that directly functionalize aza-cycles are in high demand. Herein, we disclose a fundamentally different approach to functionalizing cyclic amines which relies on C−C cleavage and attendant cross-coupling. The initial functionalization step is the generation of underexplored N-fused bicyclo α-hydroxy-β-lactams under mild, visible light conditions using a Norrish−Yang process to affect α-functionalization of saturated cyclic amines. This approach is complementary to previous methods for the C−H functionalization of aza-cycles and provides unique access to various cross-coupling adducts. In the course of these studies, we have also uncovered an orthogonal, base-promoted opening of the N-fused bicyclo α-hydroxy-β-lactams. Computational studies have provided insight into the origin of the complementary C−C cleavage processes.

Herein we report the synthesis of substituted indolizidines and related N-fused bicycles from simple saturated cyclic amines through sequential C–H and C–C bond functionalizations. Inspired by the Norrish–Yang Type II reaction, C–H functionalization of azacycles is achieved by forming α-hydroxy-β-lactams from precursor α-ketoamide derivatives under mild, visible light conditions. Selective cleavage of the distal C­(sp2)–C­(sp3) bond in α-hydroxy-β-lactams using a Rh-complex leads to α-acyl intermediates which undergo sequential Rh-catalyzed decarbonylation, 1,4-addition to an electrophile, and aldol cyclization, to afford N-fused bicycles including indolizidines. Computational studies provide mechanistic insight into the observed positional selectivity of C–C cleavage, which depends strongly on the groups bound to Rh trans to the phosphine ligand.

The rearrangement of carbon–carbon (C–C) single bonds in readily available carbocyclic scaffolds can yield uniquely substituted carbocycles that would be challenging to construct otherwise. This is a powerful and often non-intuitive approach for complex molecule synthesis. The transition-metal-mediated cleavage of C–C bonds has the potential to broaden the scope of this type of skeletal remodeling by providing orthogonal selectivities compared to more traditional pericyclic and carbocation-based rearrangements. To highlight this emerging technology, a unified, asymmetric, total synthesis of the phomactin terpenoids was developed, enabled by the selective C–C bond cleavage of hydroxylated pinene derivatives obtained from carvone. In this full account, the challenges, solutions, and intricacies of Rh­(I)-catalyzed cyclobutanol C–C cleavage in a complex molecule setting are described. In addition, details of the evolution of strategies that ultimately led to the total synthesis of phomactins A, K, P, R, and T, as well as the synthesis and structural reassignment of Sch 49027, are given.