One-Pot, Four-Step Organocatalytic Asymmetric Synthesis of Functionalized Nitrocyclopropanes

Abstract

The asymmetric synthesis of functionalized nitrocyclopropanes has been achieved by a one-pot, four-step method catalyzed by (S)-diphenylprolinol TMS ether, which joins two sequential domino reactions, namely a domino sulfa-Michael/aldol condensation of α,β-unsaturated aldehydes with 1,4-dithiane-2,5-diol, and a domino Michael/α-alkylation reaction of the derived chiral dihydrothiophenes with bromonitromethane. The title compounds were obtained in 27-45% yields, with high levels of diastereoselectivity (93:7 to 100:0 dr) and generally good enantioselectivities (up to 95:5 er).

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…[90] De Risi and co-workers reported an asymmetric synthesiso f6 -nitro-2-aryl-3-thiabicyclo[3.1.0]hexane-1-carbaldehydes 202 via two successive domino reactions performed in ao ne-pot manner (Scheme 51). [91] Thef irst domino sulfa-Michael/aldolc ondensation of a,b-unsaturated aldehydes 42 with 1,4-dithiane-2,5-diol (200)t hat was catalyzed by (S)-45 providedt he intermediates 201.T hese intermediates then underwent as econd domino Michael/a-alkylation reaction with bromonitromethane (203)u nder the action of Et 3 Nt oy ield the enantioenriched 202 in moderate yields and high dr and ee values (Scheme 51). [91] Most recently Mukherjee and co-worker reported the synthesiso fe nantioenriched 3,4-unsubstituted 2H-thiochromenes 206 via an asymmetric domino sulfa-Michael/Julia-Kocienski alkenationr eaction (Scheme 52) between 2-mercaptobenzaldehydes 204 and 205.T he iminium intermediacy andt he Julia-Kocienskia lkenation pathwayo ft his domino protocol were evidenced by ESI-MSanalysisofthe reactionintermediates.…”

“…[91] Thef irst domino sulfa-Michael/aldolc ondensation of a,b-unsaturated aldehydes 42 with 1,4-dithiane-2,5-diol (200)t hat was catalyzed by (S)-45 providedt he intermediates 201.T hese intermediates then underwent as econd domino Michael/a-alkylation reaction with bromonitromethane (203)u nder the action of Et 3 Nt oy ield the enantioenriched 202 in moderate yields and high dr and ee values (Scheme 51). [91] Most recently Mukherjee and co-worker reported the synthesiso fe nantioenriched 3,4-unsubstituted 2H-thiochromenes 206 via an asymmetric domino sulfa-Michael/Julia-Kocienski alkenationr eaction (Scheme 52) between 2-mercaptobenzaldehydes 204 and 205.T he iminium intermediacy andt he Julia-Kocienskia lkenation pathwayo ft his domino protocol were evidenced by ESI-MSanalysisofthe reactionintermediates. [92] Enantioenriched dihydrothiopyrano [2,3-b]indoles 208 were synthesized by Zhou and co-workers via an asymmetric domino sulfa-Michael/aldolc ondensation reactionb etween 2-mercaptoindole-3-carbaldehydes 207 ande nals 42 catalyzed by (S)-45.T he desired productsw ere obtained in high yields and good to high ee values(Scheme53).…”

1,4‐Dithiane‐2,5‐diol: An Attractive Platform for the Synthesis of Sulfur‐Containing Functionalized Heterocycles

“…tal conditions. [42,43] Thus, the reaction between 1 and cinnamaldehyde was carried out in dichloromethane instead of toluene at 40°C for 2 h, under inert atmosphere and in the presence of the commercially available chiral diphenylprolinol trimethylsilyl ether as catalyst (20 mol-%) and benzoic acid (10 mol-%) as additive.…”

Asymmetric Desymmetrization of Oxetanes for the Synthesis of Chiral Tetrahydrothiophenes and Tetrahydroselenophenes

“…Alternatively, through organocatalysis, Jørgensen and Wang pioneered the use of β‐mercapto carbonyl compounds to participate in a domino process initiated by asymmetric sulfa‐Michael addition to electron‐deficient olefins (Scheme b) –. This strategy was later extended to various other olefin and thiol partners with different catalysts –. While these reactions generally gave high enantioselectivities, they uniformly required the establishment of a C2 stereogenic center, which is presumably crucial to good asymmetric induction during the enantiodetermining sulfa‐Michael addition step.…”