Stereoselectivity in Diels−Alder Reactions of Diene-Substituted N-Alkoxycarbonyl-1,2-dihydropyridines

Abstract

Diene substituent effects on the regiochemical and stereochemical outcomes of uncatalyzed Diels-Alder reactions of N-alkoxycarbonyl-1,2-dihydropyridines with both styrene and methyl vinyl ketone (MVK) were studied. Alkyl substitution on the diene in all cases examined resulted in a kinetic preference for 7-endo isomers (7-phenyl 51-96% exo and 7-acetyl 54-96% exo). For both dienophiles, the highest stereoselectivities (>or=89% endo) were observed with 5-methyl or 6-methyl substituents in the dihydropyridine. Theoretical calculations of the energies of gas phase endo and exo transition states at the RHF/3-21G(*) predict that total entropy, DeltaStotal, considerations favor endo cycloadducts for both dienophiles with DHP, while total energy considerations, DeltaEo, favor endo cycloadducts for styrene and exo cycloadducts for MVK. At this level, favored endo-phenyl isomers are correctly predicted for styrene reactions, but the calculation of 7-acetyl exo or endo isomer dominance is diene-substituent-dependent for MVK reactions. The preference for endo addition of MVK to the parent, 5-methyl, and 6-methyl-DHPs was successfully predicted by calculations at the B3LYP/6-31G* theory level.

Synthesis of Isoquinuclidines from Highly Substituted Dihydropyridines via the Diels–Alder Reaction

“…Isoquinuclidines have been used as intermediates in the preparation of tetrahydroisoquinoline alkaloids, piperidines, Iboga alkaloids, and the related Cantharanthus alkaloids, which have been developed as cancer therapeutics. Isoquinuclidines are most often prepared by a Diels–Alder reaction of 1,2-dihydropyridines generated by N -acylation followed by nucleophilic addition to pyridines. − However, the incorporation of an acyl protecting group attenuates the nucleophilicity of the dihydropyridine substrates . Moreover, reliance on pyridine inputs generally results in dihydropyridine products lacking a high degree of substitution .…”

Synthesis of spiro[indoline-3,1 $$^\prime $$ ′ -quinolizines] and spiro[indoline-3,4 $$^\prime $$ ′ -pyrido[1,2-a]quinolines] via three-component reactions of azaarenes, acetylenedicarboxylate, and 3-methyleneoxindoles

“…There is a 1,2-dihydropyridyl moiety in the above-prepared dihydrospiro[indoline-3,1 -quinolizin]-2-ones 1a – 1n . 1,2-Dihydropyridine is an effective diene for Diels–Alder reaction to construct versatile bridged heterocyclic compounds [ 27 – 33 ]. Thus, we proceeded to investigate the role of our spiro compounds 1a – 1n as dienophiles in Diels–Alder reactions.…”

Enantioselective Total Syntheses of Kuwanon X, Kuwanon Y, and Kuwanol A

“…Compared with the acetyl protected diene 7 (Table , entry 2), when diene 19 was used, the endo / exo stereoselectivity was changed from 1/5.3 to 1/1.2 without losing the enantioselectivity (from 94% to 90%). This indicates that different substitution in diene may contribute to different stereoselectivity in the asymmetric Diels–Alder cycloaddition. , With the raised HOMO in diene 19 , the cycloaddition transition state occurs earlier in the reaction pathway; hence, there is less steric demand one would need to overcome for the endo transition state in comparison to the exo transition state, and so the subtle improvement to 1.2/1 was possible …”