Electrophilic Activation of α,β‐Unsaturated Amides: Catalytic Asymmetric Vinylogous Conjugate Addition of Unsaturated γ‐Butyrolactones

Abstract

Although catalytic asymmetric conjugate addition reactions have remarkably advanced over the last two decades, the application of less electrophilic α,β-unsaturated carboxylic acid derivatives in this useful reaction manifold remains challenging. Herein, we report that α,β-unsaturated 7-azaindoline amides act as reactive electrophiles to participate in catalytic diastereo- and enantioselective vinylogous conjugate addition of γ-butyrolactones in the presence of a cooperative catalyst comprising of a soft Lewis acid and a Brønsted base. Reactions mostly reached completion with as little as 1 mol % of catalyst loading to give the desired conjugate adducts in a highly stereoselective manner.

α,β‐Unsaturated Amides as Dipolarophiles: Catalytic Asymmetric exo‐Selective 1,3‐Dipolar Cycloaddition with Nitrones

“…The 7‐azaindoline amides are characterized by their intrinsic stability and acquired reactivity in the presence of suitable Lewis acids, which is ascribed to a conformational change in the amide geometry; the stable E ‐conformer is switched to a Z ‐conformer via bidentate coordination (Figure ). The activated Z ‐conformer elicits acquired reactivity to allow for catalytic enolization (nucleophilic activation) and also serves as a Michael acceptor when conjugated with a double bond (electrophilic activation) . Given the electrophilic activation mode of the α,β‐unsaturated amide by Lewis acids, we began screening chirally decorated Lewis acidic catalysts for a 1,3‐DC reaction of amide 1 a and nitrone 2 a (Table ).…”

ChemInform Abstract: Nucleophilic and Electrophilic Activation of Non‐Heteroaromatic Amides in Atom‐Economical Asymmetric Catalysis

“…Shibasakia nd co-workersr eported that non-heteroaromatic 7-azaindoline amides 54 conjugated with an unsaturated bond, as discussed in Section 2.4 for nucleophilic (deprotonative) activation, served as suitable substrates for electrophilic activation (Scheme13). [32] In addition to the solid state, 54 also preferred the E conformation in solution, as indicated by the unusually downfield-shifted signalf or the a-proton in the 1 HNMR spectrum, which was due to the hydrogen-bondingi nteraction with the pyridyln itrogen of the 7-azaindoline. The conformational change to Z,d riven by the formation of the Cu I complex 55 through ab identate conformation,w as traced by 1 HNMR spectroscopy and X-ray crystallography.T hist ype of complexation is reminiscent of the activation mode of the 7-azaindoline amide, as discussed above, and the enhanced electrophilicity at the b-carbonw as evidenced by smooth and highly stereoselective conjugatea ddition of butenolides 56.…”

“…The choice of chiral phosphine ligands enabled access to the products 59 and 60 bearing quaternary and tertiarys tereogenic centers. [32] The catalyst loading could be reduced to as little as 0.1 mol %, suggesting little product inhibition to disturb the catalysis.…”

Nucleophilic and Electrophilic Activation of Non‐Heteroaromatic Amides in Atom‐Economical Asymmetric Catalysis

“…In contrast, non‐heteroaromatic amides are poorly reactive due to the attenuated polarity of the carbonyl group resulting from amide conjugation. Shibasaki and co‐workers reported that non‐heteroaromatic 7‐azaindoline amides 54 conjugated with an unsaturated bond, as discussed in Section 2.4 for nucleophilic (deprotonative) activation, served as suitable substrates for electrophilic activation (Scheme ) . In addition to the solid state, 54 also preferred the E conformation in solution, as indicated by the unusually downfield‐shifted signal for the α‐proton in the 1 H NMR spectrum, which was due to the hydrogen‐bonding interaction with the pyridyl nitrogen of the 7‐azaindoline.…”

“…The active carbon nucleophile was generated in situ by the coexisting Brønsted base catalyst (Barton's base). The choice of chiral phosphine ligands enabled access to the products 59 and 60 bearing quaternary and tertiary stereogenic centers . The catalyst loading could be reduced to as little as 0.1 mol %, suggesting little product inhibition to disturb the catalysis…”