Catalytic diastereo- and enantioselective additions of versatile allyl groups to N–H ketimines

Abstract

There are countless biologically active organic molecules that contain one or more N-containing moieties and broadly applicable and efficient catalytic transformations that deliver them diastereo- and/or enantioselectively are much sought after. Various methods for enantioselective synthesis of α-secondary amines are available (e.g., from additions to protected/activated aldimines), but those involving ketimines are much less common. There are no reported additions of carbon-based nucleophiles to unprotected/unactivated (or N-H) ketimines. Here, we report a catalytic, diastereo- and enantioselective three-component strategy for merging an N-H ketimine, a monosubstituted allene and B2(pin)2, affording products in up to 95% yield, >98% diastereoselectivity and >99:1 enantiomeric ratio. Utility of the approach is highlighted by synthesis of the tricyclic core of a class of compounds that have been shown to possess anti-Alzheimer activity. Stereochemical models, developed with the aid of DFT calculations, which account for the observed trends and levels of enantioselectivity are presented.

Copper(I)‐Catalyzed Enantio‐ and Diastereodivergent Borylative Coupling of Styrenes and Imines

“…[5][6][7] TheP rocter group [8] and Cao,L iao,a nd coworkers [9] independently developed acopper-catalyzed enantio-and diastereoselective borylative coupling of allenes or dienes with aldimines to provide g-boryl amine derivatives (Scheme 1a,b). [10] These precedents proceed through in situ generated allycopper species as reactive nucleophiles to imines,a nd only one specific diastereomer of the products is accessible. [10] These precedents proceed through in situ generated allycopper species as reactive nucleophiles to imines,a nd only one specific diastereomer of the products is accessible.…”

3‐Mono‐Substituted BINOL Phosphoric Acids as Effective Organocatalysts in Direct Enantioselective Friedel–Crafts‐Type Alkylation of N‐Unprotected α‐Ketiminoester

“…Herein, we report that simple 3-mono-substituted chiral BINOL-phosphoric acids are even more selective organocatalysts than 3,3'-disubstituted analogsi nd irect enantioselective Friedel-Crafts-type alkylation of N-unprotected a-ketiminoester.T he origin of the observed high enantioselectivity with the 3-monosubstituted catalyst is also discussed.This work emerged from our recent focus on the utility of Nunprotected ketimines in direct catalytic nucleophilica ddition reactions. [7] Such N-unprotected ketimines are useful, [8] but their use in direct catalytic enantioselective nucleophilic addition reactions remains elusive. [9] To this end, we are interested in direct catalytic enantioselective Friedel-Crafts-type alkylation of N-unprotected a-ketiminoester 3.…”

“…This work emerged from our recent focus on the utility of Nunprotected ketimines in direct catalytic nucleophilica ddition reactions. [7] Such N-unprotected ketimines are useful, [8] but their use in direct catalytic enantioselective nucleophilic addition reactions remains elusive. [9] To this end, we are interested in direct catalytic enantioselective Friedel-Crafts-type alkylation of N-unprotected a-ketiminoester 3.…”

Copper(I)‐Catalyzed Enantio‐ and Diastereodivergent Borylative Coupling of Styrenes and Imines

“…Hoveyda and co-workers reported coppercatalyzed borylative difucntionalization of allenes applicable to N-H ketimines (Scheme 1c). [10] These precedents proceed through in situ generated allycopper species as reactive nucleophiles to imines,a nd only one specific diastereomer of the products is accessible.…”