Highly Enantioselective Synthesis of Alkylpyridine Derivatives through a Michael/Michael/Aldol Cascade Reaction

Abstract

A method for the synthesis of pyridine derivatives based on a triple cascade reaction catalyzed by chiral secondary amines was developed. The resulting cyclohexenes (three C–C bonds were formed) were obtained in good yields with good diastereoselectivities and excellent enantioselectivities.

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…[102] In 2012, Hong andc o-workersd evelopedatotal synthetic route towards (+ +)-galbulin (243)o nt he basis of an organocatalytic asymmetric domino Michael/Michael/aldol condensation reactiona ssociated with kinetic resolution as the key feature.T he corresponding domino reactiono ft he racemic keto aldehyde (AE)-241 and the a,b-unsaturated aldehyde 42a in the presence of diphenylprolinol silyl ether( S)-45 as the chiral catalyst provided the adduct 242 as as ingle enantiomer of the desired diastereomer. Only (S)-241 took part in the reactiona si tp rovided the sterically favorable transition state, [103] while (R)-241 remained unreacted in the reactionp ot.…”

“…Pyridine‐substituted cyclohexenal derivatives 240 were synthesized by Rios and co‐workers via an asymmetric domino Michael/Michael/aldol condensation reaction, employing enals 42 and 2‐(pyridin‐2‐yl)acetonitrile ( 239 ) as the substrates and ( S )‐ 45 as the catalyst (Scheme ) …”

Enantioselective direct Mannich-type reactions of 2-benzylpyridine N-oxides catalyzed by chiral bis(guanidino)iminophosphorane organosuperbase

“…The principal strategy for overcoming the obstacle is the introduction of additional strong electron-withdrawing groups on either the azaarenes rings or the α-carbon atoms for acidity enhancement. 5 On the other hand, the application of azaarene N-oxides, which serve as azaarene surrogates having higher electron-deficient properties, is an alternative strategy. The N-oxide moiety increases the acidity of the α-proton in the 2-alkyl substituent, 6 and thus facilitates deprotonation.…”

Enantioselective Synthesis of Alkyl Azaarenes

“…In 2017 Rios reported a Michael-Michael-aldol cascade reaction, between 2-pyridineacetonitrile 18 and α,β-unsaturated aldehydes 19. [4] The final products, possessing a chiral quaternary center in α-position, were obtained in 33 to 72% yields, 3 : 1 to 6 : 1 diastereoselectivity and 87 to 99% enantioselectivity (Scheme 6, top). The mechanism (Scheme 6, bottom) starts with the nucleophilic attack of 18 to the β position of the electrophilic iminium ion intermediate 21, giving the intermediate 22, that is shown as the most stable conformer.…”