Nucleophile-Dependent Z/E- and Regioselectivity in the Palladium-Catalyzed Asymmetric Allylic C–H Alkylation of 1,4-Dienes

Abstract

The asymmetric allylic alkylation (AAA), which features employing active allylic substrates, has historical significance in organic synthesis. The allylic C−H alkylation is principally more atom-and step-economic than the classical allylic functionalizations and thus can be considered a transformative variant. However, asymmetric allylic C−H alkylation reactions are still scarce and yet underdeveloped. Herein, we have found that Z/E-and regioselectivities in the Pd-catalyzed asymmetric allylic C−H alkylation of 1,4-dienes are highly dependent on the type of nucleophiles. A highly stereoselective allylic C−H alkylation of 1,4-dienes with azlactones has been established by palladium-chiral phosphoramidite catalysis. The protocol proceeds under mild conditions and can accommodate a wide scope of substrates, delivering structurally divergent α,αdisubstituted α-amino acid surrogates in high yields and excellent levels of diastereo-, Z/E-, regio-, and enantioselectivities. Notably, this method provides key chiral intermediates for an efficient synthesis of lepadiformine marine alkaloids. Experimental and computational studies on the reaction mechanism suggest a novel concerted proton and two-electron transfer process for the allylic C−H cleavage and reveal that the Z/E-and regioselectivities are governed by the geometry and coordination pattern of nucleophiles.

Nucleophile Coordination Enabled Regioselectivity in Palladium‐Catalyzed Asymmetric Allylic C−H Alkylation

“…In recent years, we– and others have reported that phosphoramidite ligands are compatible with Pd‐catalyzed allylic C−H functionalizations, some of which enable a diverse range of regio‐ and stereoselective allylic C−H alkylation reactions of 1,4‐dienes with various soft carbon nucleophiles (Scheme A). By means of DFT calculations, we identified that the geometry and coordination pattern of nucleophiles lead to different bond‐forming transition states and thereby determine the Z / E selectivites and regioselectivities (Scheme B) . For instance, the allylic C−H alkylation of 1,4‐dienes with pyrazol‐5‐ones and 5‐aryl‐substituted thiazol‐4(5 H )‐ones greatly favor branched E ‐dienyl products via the inner‐sphere transition‐state TS1 , while branched Z ‐dienyl products were obtained via the inner‐sphere TS2 upon using azlactones as nucleophiles .…”

“…By means of DFT calculations, we identified that the geometry and coordination pattern of nucleophiles lead to different bond‐forming transition states and thereby determine the Z / E selectivites and regioselectivities (Scheme B) . For instance, the allylic C−H alkylation of 1,4‐dienes with pyrazol‐5‐ones and 5‐aryl‐substituted thiazol‐4(5 H )‐ones greatly favor branched E ‐dienyl products via the inner‐sphere transition‐state TS1 , while branched Z ‐dienyl products were obtained via the inner‐sphere TS2 upon using azlactones as nucleophiles . In contrast, the outer‐sphere TS3 became dominant and linear E ‐dienyl products were given when 5‐alkyl‐substituted thiazol‐4(5 H )‐ones were used .…”

Nucleophile Coordination Enabled Regioselectivity in Palladium‐Catalyzed Asymmetric Allylic C−H Alkylation

“…In recent years, we– and others have reported that phosphoramidite ligands are compatible with Pd‐catalyzed allylic C−H functionalizations, some of which enable a diverse range of regio‐ and stereoselective allylic C−H alkylation reactions of 1,4‐dienes with various soft carbon nucleophiles (Scheme A). By means of DFT calculations, we identified that the geometry and coordination pattern of nucleophiles lead to different bond‐forming transition states and thereby determine the Z / E selectivites and regioselectivities (Scheme B) . For instance, the allylic C−H alkylation of 1,4‐dienes with pyrazol‐5‐ones and 5‐aryl‐substituted thiazol‐4(5 H )‐ones greatly favor branched E ‐dienyl products via the inner‐sphere transition‐state TS1 , while branched Z ‐dienyl products were obtained via the inner‐sphere TS2 upon using azlactones as nucleophiles .…”

“…By means of DFT calculations, we identified that the geometry and coordination pattern of nucleophiles lead to different bond‐forming transition states and thereby determine the Z / E selectivites and regioselectivities (Scheme B) . For instance, the allylic C−H alkylation of 1,4‐dienes with pyrazol‐5‐ones and 5‐aryl‐substituted thiazol‐4(5 H )‐ones greatly favor branched E ‐dienyl products via the inner‐sphere transition‐state TS1 , while branched Z ‐dienyl products were obtained via the inner‐sphere TS2 upon using azlactones as nucleophiles . In contrast, the outer‐sphere TS3 became dominant and linear E ‐dienyl products were given when 5‐alkyl‐substituted thiazol‐4(5 H )‐ones were used .…”

Recent Advances in Azlactone Transformations

“…[74] The α,α-disubstituted α-amino acid derivatives Scheme 47. [74] The α,α-disubstituted α-amino acid derivatives Scheme 47.…”