Diversity oriented synthesis: concise entry to novel derivatives of Yohimbine and Corynanthe alkaloids

Abstract

A novel MCAP-cycloaddition sequence has been applied to the facile synthesis of β-carboline intermediates to gain rapid access to novel derivatives of yohimbine-like and corynanthe-like compounds that may be easily diversified by cross-coupling reactions and N-derivatizations to generate small compound libraries.

Evolution of a strategy for preparing bioactive small molecules by sequential multicomponent assembly processes, cyclizations, and diversification

“…Accordingly, reaction of 79 and 80 with trans-crotonyl chloride ( 7) and silyl enol ether 52 led to the production of aldehydes 81 and 82, but in this case the use of TMSOTf was not required (Scheme 11). 70,71 When 81 and 82 were heated with 59, stereoselective [3 + 2]-dipolar cycloadditions ensued to deliver isoxazolidines 83 and 84. Cleavage of the N,O-bonds in 83 and 84 was induced with nickel boride to produce amino alcohols such as 85 that could be subsequently N-alkylated, as exemplified by the preparation of 86 via reductive amination with piperonal.…”

Multicomponent Assembly Processes for the Synthesis of Diverse Yohimbine and Corynanthe Alkaloid Analogues

“…9,10 More recently we reported a useful extension of this general approach to DOS for the facile synthesis of compounds containing the octahydroindolo[2,3- a ]quinolizine-2-amine scaffold. 11 We herein report the application of this strategy to the rapid synthesis of a 180-member library of these compounds, many of which possess substitution patterns that were heretofore unknown.…”

“…During the course of developing concise syntheses of 2 and 3 , we discovered a novel Mannich-type multicomponent assembly process (MCAP) that inspired the subsequent development of a number of three- and four-component MCAPs that generate highly functionalized intermediates. The combination of these MCAPs in tandem with various ring closing reactions that are enabled by selective pairing of resident functional groups has led to a powerful strategy for the diversity oriented synthesis (DOS) of a broad array of unique heterocycles comprising the benzodiazepine, benzoxazocine, benzazocine, isoindolinone, tetrahydrobenzonaphtheridine, pyridazine, norbenzomorphan, 2-aryl piperidine, and tetrahydroisoquinoline scaffolds. , More recently we reported a useful extension of this general approach to DOS for the facile synthesis of compounds containing the octahydroindolo­[2,3- a ]­quinolizine-2-amine scaffold . We herein report the application of this strategy to the rapid synthesis of a 180-member library of these compounds, many of which possess substitution patterns that were heretofore unknown.…”