Three-Component Ag-Catalyzed Enantioselective Vinylogous Mannich and Aza-Diels−Alder Reactions with Alkyl-Substituted Aldehydes

Abstract

Efficient protocols for three-component catalytic enantioselective vinylogous Mannich (VM) reactions of alkyl-substituted aldimines (including those bearing heteroatom-containing substituents) and readily available siloxyfurans are presented. High efficiency and stereoselectivity is achieved through the use of o-thiomethyl-p-methoxyaniline-derived aldimines. Reactions, performed under an atmosphere of air and in undistilled THF, can be promoted in the presence of as little as 1 mol % of easily accessible amino acid-based chiral ligands and commercially available AgOAc. The desired products are obtained in 44% to 92% yield, and in up to >98:<2 diastereomer and >99:<1 enantiomer ratio (>98% ee). Removal of the N-activating group is performed through a one-vessel oxidation/ hydrolysis operation, which proceeds via a stable aza-quinone (characterized by X-ray crystallography). Evidence is presented indicating that reactions with chiral non-racemic aldehydes are subject to catalyst control: both substrate enantiomers react to afford the desired product diastereomers in high stereoselectivity. Aryl-and alkynyl-substituted o-thiomethyl-pmethoxyaniline-derived aldimines undergo Ag-catalyzed enantioselective VM more efficiently and with higher selectivity than the corresponding o-anisidyl substrates. Additionally, Ag-catalyzed azaDiels-Alder reactions of the alkyl-substituted aldimines bearing the structurally modified N-aryl unit afford enantiomerically enriched (up to 95% ee) products in up to 88% yield.

Catalytic, Enantioselective, Vinylogous Mannich Reactions

“…Subsequent investigations by the same group led to the identification of a more robust imine class containing the highly electron-rich ortho-thiomethyl-para-methoxyphenyl group as N-substituent that is less prone to decomposition [8]. When this type of substituted aniline was employed in a threecomponent vinylogous Mannich reaction with aliphatic aldehydes and silyloxy furans under otherwise identical reaction conditions, 5-alkyl-5-amino-substituted c-butenolides 22 were obtained in good yields and as essentially single stereoisomers (Table 5.2).…”

“…Silver-catalyzed vinylogous Mannich reaction of 2-silyloxy furan 17a with aliphatic imines according to Hoveyda, Snapper and coworkers[8].…”

The Vinylogous Aldol and Related Addition Reactions: Ten Years of Progress

“…Asymmetric Two-and Three-Component Ag-Catalyzed VMMnRs Involving 2-(Trimethylsilyloxy)furans[305][306][307] …”

5.10 Hetero-Diels–Alder Reactions

“…A direct three-component enantioselective aza-Diels-Alder reaction of aliphatic aldehydes, 4-methoxy-2-(methylthio)aniline and Danishefsky diene 1 is catalyzed by a silver(I) complex prepared from AgOAc and the phosphine ligand 136b (Scheme 33). 80 In the presence of the chiral silver(I) catalyst (5 mol%), the reaction is carried out under an atmosphere of air and in undistilled THF, to give the cycloadducts 141 in up to 88% yield with up to 95% ee.…”