Libraries of 2,3,4,6,7,11b-Hexahydro-1H-pyrido[2,1-a]isoquinolin-2-amine Derivatives via a Multicomponent Assembly Process/1,3-Dipolar Cycloaddition Strategy

Abstract

A Mannich-type multicomponent assembly process/1,3-dipolar cycloaddition strategy has been developed for the rapid and efficient construction of a parent tetrahydroisoquinoline fused isoxazolidine scaffold, which was subsequently functionalized using well-established protocols to access a diverse 70-membered library of novel 2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline-2-amine derivatives.

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

“…We have previously reported the development of several novel MCAPs for the synthesis of fused-tetrahydroisoquinoline scaffolds, 9 and it occurred to us that we might apply this chemistry to the synthesis of unique scaffolds derived from 9 . Compounds containing the pyrimidinedione ring exemplified in 39 are known to exhibit hypotensive, diuretic, and anti-anoxic effects.…”

“…20 We thus envisioned that compounds related to 41 having substituents on the indole ring might be attractive compounds for screening. In previous work, we discovered that reaction of the hydrochloride salt of 7 with o -azidobenzoyl chloride ( 40 ) provided a novel entry to 41 , 9a so we queried whether this chemistry might also be applied to bromo-substituted analogs of 41 . In order to establish the underlying feasibility of this approach to rutaecarpine derivatives, imine 9 and o -azidobenzoyl chloride ( 40 ) were heated in refluxing 1,2-dichloroethane to furnish 42 , which is known as a selective COX-2 inhibitor, 21 in 63% yield.…”

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

“…A nitrone dipolar cycloaddition also served as a key step to access novel tetrahydroisoquinolines as is illustrated by the preparation of 75 (Scheme 10). 49,64 A three-component MCAP involving imine 46, trans-crotonyl chloride (7), and 52 provided the aldehyde 70. This MCAP was optimally performed using sub-stoichiometric quantities of TMSOTf, and the crude aldehyde 70 thus obtained was treated with 59 to furnish a nitrone that cyclized upon heating to deliver isoxazolidine 71 as a single diastereomer.…”

Expedient Synthesis of Norbenzomorphan Library via Multicomponent Assembly Process Coupled with Ring-Closing Reactions

“…7 In the MCAP step of the sequence, three or more reactants are combined to give versatile intermediates, which are endowed with different functional groups that can be paired in a variety of ways to enable cyclizations by numerous ring closing reactions. This basic strategy for DOS has been recently applied to the rapid syntheses of novel benzoxazocines, 8 benzazocines, benzodiazepines, 9 and tetrahydroisoquinolines, 10 as well as isoindolinones, 11 tetrahydrobenzonaphtheridines, pyridazines and norbenzomorphans. We now report the application of this strategy to the preparation of a large set of diversely substituted norbenzomorphans based upon 5 ; we also present select biological screening data that reveal useful activities not previously associated with this class of compounds.…”