Enantioselective Desymmetrization ofpara-Quinamines through an Aminocatalyzed Aza-Michael/Cyclization Cascade Reaction

Abstract

An unprecedented organocatalytic asymmetric desymmetrization of para-quinamines leading to functionalized hydroindoles, a common motif in many alkaloids, has been reported. The ability of diarylprolinol silyl ethers to promote iminium and enamine activation of α,β-unsaturated aldehydes in one catalytic cycle is the centerpiece of the strategy involving a challenging aza-Michael/intramolecular cyclization cascade reaction. A range of prochiral para-quinamines and α,β-unsaturated aldehydes were investigated to afford 16 examples of hydroindoles possessing four contiguous stereocenters including one quaternary carbon. The hydroindole structures include multiple orthogonal functionalities, which underwent various transformations.

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…[43] Coeffard, Greck,a nd co-workers demonstrated the desymmetrization of prochiral para-quinamines 49 in the synthesis of hydroindole molecules 50 possessing four stereogenic centers. [44] Thed omino aza-Michael/ Michaelr eactiono f49 and a,b-unsaturated aldehydes 42 promoted by the chiral diphenylprolinol silyl ether catalyst 51 yielded compounds 50 in good to high stereoselectivities (Scheme 13). Thee lectronic factors of the substituents were found to have almostn egligible effects on this domino reaction.…”

“…However, the steric effects of the R 1 substituent were found to lowert he product yields significantly. [44] Thea symmetric synthesis of regioisomeric pyrazolidine derivatives (53 and 54)t hrough ad omino azaMichael/hemiaminalization reactionb etween a,b-unsaturateda ldehydes 42 andd isubstituted hydrazines 52 was performed by Wang andc o-workers. [45] Using the prolinols ilyl ether catalyst (S)-45,t he major regioisomers 53 were isolated in good yieldsw ith high ee and dr values(Scheme14).…”

Organocatalytic enantioselective desymmetrisation

“…202 Stereocontrol afforded low to moderate drs of 2 : 1-5 : 1, although enantiomeric excess of the major diastereoisomer was greater than 90% in most cases. 202 Stereocontrol afforded low to moderate drs of 2 : 1-5 : 1, although enantiomeric excess of the major diastereoisomer was greater than 90% in most cases.…”

Nitrogen‐Bridged, Natural Product Like Octahydrobenzofurans and Octahydroindoles: Scope and Mechanism of Bridge‐Forming Reductive Amination via Caged Heteroadamantanes

“…In our ongoing efforts to develop innovative scaffolds for the European Lead Factory (ELF) drug discovery initiative, we became interested in work by Johnson and Corbett and separately, Coeffard, Greck et al, describing enantio‐ and diastereoselective organocatalyzed annulations of quinols and quinamines ( 6 ) with α,β‐unsaturated aldehydes (Scheme ). In a compelling application of the bicyclic products 7 , Johnson reported one example of a reductive amination to give 8a , in which the existing rings were bridged via an aza‐Michael addition, enabled by an uncommon exo – endo epimerization at C‐3 proven by deuterium incorporation , .…”