Mechanistic Investigation, Wavelength-Dependent Reactivity, and Expanded Reactivity of N-Aryl Azacycle Photomediated Ring Contractions.

Under mild blue-light irradiation, α-acylated saturated heterocycles undergo a photomediated one-atom ring contraction that extrudes a heteroatom from the cyclic core. However, for nitrogenous heterocycles, this powerful skeletal edit has been limited to substrates bearing electron-withdrawing substituents on nitrogen. Moreover, the mechanism and wavelength-dependent efficiency of this transformation have remained unclear. In this work, we increased the electron richness of nitrogen in saturated azacycles to improve light absorption and strengthen critical intramolecular hydrogen bonding while enabling the direct installation of the photoreactive handle. As a result, a broadly expanded substrate scope, including underexplored electron-rich substrates and previously unsuccessful heterocycles, has now been achieved. The significantly improved yields and diastereoselectivities have facilitated reaction rate, kinetic isotope effect (KIE), and quenching studies, in addition to the determination of quantum yields. Guided by these studies, we propose a revised ET/PT mechanism for the ring contraction, which is additionally corroborated by computational characterization of the lowest-energy excited states of α-acylated substrates through time-dependent DFT. The efficiency of the ring contraction at wavelengths longer than those strongly absorbed by the substrates was investigated through wavelength-dependent rate measurements, which revealed a red shift of the photochemical action plot relative to substrate absorbance. The elucidated mechanistic and photophysical details effectively rationalize empirical observations, including additive effects, that were previously poorly understood. Our findings not only demonstrate enhanced synthetic utility of the photomediated ring contraction and shed light on mechanistic details but may also offer valuable guidance for understanding wavelength-dependent reactivity for related photochemical systems.

C-C Bond Cleavage Approach to Complex Terpenoids: Development of a Unified Total Synthesis of the Phomactins.

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.

C-H/C-C Functionalization Approach to N-Fused Heterocycles from Saturated Azacycles.

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-ß-lactams from precursor α-ketoamide derivatives under mild, visible light conditions. Selective cleavage of the distal C(sp2)-C(sp3) bond in α-hydroxy-ß-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.

Single-atom logic for heterocycle editing.

Medicinal chemistry continues to be impacted by new synthetic methods. Particularly sought after, especially at the drug discovery stage, is the ability to enact the desired chemical transformations in a concise and chemospecific fashion. To this end, the field of organic synthesis has become captivated by the idea of 'molecular editing'-to rapidly build onto, change or prune molecules one atom at a time using transformations that are mild and selective enough to be employed at the late stages of a synthetic sequence. In this Review, the definition and categorization of a particularly promising subclass of molecular editing reactions, termed 'single-atom skeletal editing', are proposed. Although skeletal editing applies to both cyclic and acyclic compounds, this Review focuses on heterocycles, both for their centrality in medicinal chemistry and for the definitional clarity afforded by a focus on ring systems. A classification system is presented by highlighting methods (both historically important examples and recent advances) that achieve such transformations, with the goal to spark interest and inspire further development in this growing field.

Photomediated ring contraction of saturated heterocycles.

Saturated heterocycles are found in numerous therapeutics and 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.

Synthesis of Bridged Bicyclic Amines by Intramolecular Amination of Remote C-H Bonds: Synergistic Activation by Light and Heat.

The construction of complex aza-cycles is of interest to drug discovery due to the prevalence of nitrogen-containing heterocycles in pharmaceutical agents. Herein we report an intramolecular C-H amination approach to afford value-added and complexity-enriched bridged bicyclic amines. Guided by density functional theory and nuclear magnetic resonance investigations, we determined the unique roles of light and heat activation in the bicyclization mechanism. We applied both light and heat activation in a synergistic fashion, achieving gram-scale bridged aza-cycle synthesis.

C─C Cleavage Approach to C─H Functionalization of Saturated Aza-Cycles.

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-ß-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-ß-lactams. Computational studies have provided insight into the origin of the complementary C─C cleavage processes.