Instant Macrocyclizations via Multicomponent Reactions

Abstract

Macrocycles fascinate chemists due to both their structure and their applications. However, we still lack efficient and sustainable synthetic methods, giving us straightforward access to them. Herein, a rapid macrocyclization utilizing a two-step, one-pot approach based on orthogonal multicomponent reaction (MCR) tactics is introduced. This synthetic protocol, which is based on Ugi and Groebke–Blackburn–Bienaymé reactions with isocyanides tethered to alkyl tosylates, yields medium sized macrocycles that are otherwise difficult to achieve. Single crystal structures reveal conformational reorganization via intramolecular hydrogen bonding, and modeling studies profile the synthesized libraries.

C1 functionalization of imidazo heterocycles via carbon dioxide fixation

“…Treatment with DBU gave rise to medium-sized macrocycles. 53 After treatment of the GBB-3CR adducts without the phenolic group, such as 2a–j , with NaHCO 3 , we observed deprotection of –OTs group and formation of 4 instead of re-fixing of CO 2 (Scheme 2).…”

“…First of all, it would give access to a variety of imidazo[1,2- a ]-heterocycles, including, the privileged scaffold imidazo[1,2- a ]pyridine, a well-known moiety in many marketed drugs, such as zolpidem, minodronic acid, etc. 52 Secondly, we hypothesized that our recently developed isocyano alkyl tosylates 1a–c in a GBB-3CR 53 can constitute an excellent mode I-substrate 11 with a nucleophilic center (X δ − , highlighted in cyan), which triggers the CO 2 incorporation, combined with an electrophilic site (LG δ + , highlighted in green) (Scheme 1D).…”

Origin of Octafluorocyclopentene Polyelectrophilicity

“…Moreover, the dynamic changes in the conformation of macrocycles, along with their high surface area in certain protein−protein interactions, make them promising candidates for potential therapies in the treatment of various diseases and conditions. 13 Prompted by these successes, we have undertaken a more general overview of the reaction of OFCP with various nucleophiles. We have characterized the electrophilicity of OFCP in reactions with various nucleophiles and compared its electrophilicity with that of other common electron-deficient alkenes.…”

“…The resulting macrobicylic structures are being studied by the Harran group as stable shape mimics of diverse loop structures that mediate intracellular protein–protein interactions. Moreover, the dynamic changes in the conformation of macrocycles, along with their high surface area in certain protein–protein interactions, make them promising candidates for potential therapies in the treatment of various diseases and conditions …”

Multicomponent Reaction-Based Heteroannulations: A Direct Access to Fused Tetrazolo Piperazinones and 1,4-Diazepanones

“…In continuation to our interest in bifunctional isocyanides, 47 48 we employed the ethyl isocyanoalkanoates 9a and 9b and the ethyl isocyano(het)arylcarboxylates 9c and 9d as versatile building blocks, exploiting both their -NC and -CO 2 Et functionalities (Scheme 1 ). Our aim was to apply a UT-4CR to provide easy and direct access to fused tetrazolo-1,4-diazepinones and tetrazolopiperazinones as a screening deck for future high-throughput screening.…”