Synthesis of Bufadienolide Cinobufagin via Late-Stage Singlet Oxygen Oxidation/Rearrangement Approach.

This manuscript describes a concise synthesis of cinobufagin, a natural steroid of the bufadienolide family, from readily available dehydroepiandrosterone (DHEA), as well as its α5-epimer derived from 3-epi-andosterone. This synthesis features expedient installation of the 17ß-pyrone moiety with the 14ß,15ß-epoxide and the 16ß-acetoxy group using a photochemical regioselective singlet oxygen [4 + 2] cycloaddition followed by CoTPP-promoted in situ endoperoxide rearrangement to provide a 14ß,16ß-bis-epoxide in 64% yield with a 1.6:1 d.r. This ß,ß-bis-epoxide intermediate was subsequently subjected to a regioselective scandium(III) trifluoromethanesulfonate catalyzed House-Meinwald rearrangement to establish the 17ß-configuration. The synthesis of cinobufagin is achieved in 12 steps (LLS) and 7.6% overall yield, and we demonstrate that it could be used as a platform for the subsequent medicinal chemistry exploration of cinobufagin analogs such as cinobufagin 5α-epimer.

FDA-Approved Oximes and Their Significance in Medicinal Chemistry.

Despite the scientific advancements, organophosphate (OP) poisoning continues to be a major threat to humans, accounting for nearly one million poisoning cases every year leading to at least 20,000 deaths worldwide. Oximes represent the most important class in medicinal chemistry, renowned for their widespread applications as OP antidotes, drugs and intermediates for the synthesis of several pharmacological derivatives. Common oxime based reactivators or nerve antidotes include pralidoxime, obidoxime, HI-6, trimedoxime and methoxime, among which pralidoxime is the only FDA-approved drug. Cephalosporins are ß-lactam based antibiotics and serve as widely acclaimed tools in fighting bacterial infections. Oxime based cephalosporins have emerged as an important class of drugs with improved efficacy and a broad spectrum of anti-microbial activity against Gram-positive and Gram-negative pathogens. Among the several oxime based derivatives, cefuroxime, ceftizoxime, cefpodoxime and cefmenoxime are the FDA approved oxime-based antibiotics. Given the pharmacological significance of oximes, in the present paper, we put together all the FDA-approved oximes and discuss their mechanism of action, pharmacokinetics and synthesis.

Effective microwave-assisted approach to 1,2,3-triazolobenzodiazepinones via tandem Ugi reaction/catalyst-free intramolecular azide-alkyne cycloaddition.

A novel catalyst-free synthetic approach to 1,2,3-triazolobenzodiazepinones has been developed and optimized. The Ugi reaction of 2-azidobenzaldehyde, various amines, isocyanides, and acids followed by microwave-assisted intramolecular azide-alkyne cycloaddition (IAAC) gave a series of target heterocyclic compounds in moderate to excellent yields. Surprisingly, the normally required ruthenium-based catalysts were found to not affect the IAAC, only making isolation of the target compounds harder while the microwave-assisted catalyst-free conditions were effective for both terminal and non-terminal alkynes.