Photomediated ring contraction of saturated heterocycles

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.

Late-stage diversification of indole skeletons through nitrogen atom insertion

“…1A). In contrast, complementary approaches that can directly modify the underlying core skeleton of a molecule are less common, despite their potential to expand the accessible chemical space (4)(5)(6)(7)(8)(9)(10)(11). Formal single atom insertion reactions to modify aromatic moieties have proven to be especially challenging given the inherent inertness of aromatic carbon-based skeleton towards cleavage of a carbon-carbon bond (12).…”

Violet‐blue Light Induces “Natural” Photodynamic Plasma Disinfection with Endogenous Sensitizers

“…There are other examples of success with violet and blue light in microbe inactivation (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Even other examples are emerging with violet-blue or blue light in synthetic organic (22)(23)(24)(25)(26)(27)(28) and photopolymerization reactions (29), and naturally, there is a history of blue light therapy in neonatal jaundice (30)(31)(32)(33). Yet, following Maclean and coworker's first accomplishment of microbe reduction to decent levels is the secondary challenge of protecting the sample against protein photooxidation (34)(35)(36)(37).…”

Synform Issue 2022/1

“…1 Recent reports in this area have included nitrogen deletion, 2 single-atom insertion, 3 and ring contractions. 4 Through a collaboration involving researchers at the University of California-Berkeley in Prof. Richmond Sarpong's laboratory and at the research labs of Merck & Co., Inc., Kenilworth, NJ, USA -known as MSD outside of the US and Canada -a light-mediated ring contraction of saturated six-membered heterocycles to five-membered rings that relocates the heteroatom from an endocyclic to exocyclic position has been achieved. This academia/industry partnership started as part of the "Disruptive Chemistry" initiative at MSD -an effort focused on developing enabling chemical reactions of importance for industrial applications, including novel scaffold changes to precisely edit molecules.…”