Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies

Abstract

α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursors: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center.

Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations

“…12,13,14 Preliminary studies (Scheme 1) suggested that an internal mechanism (i.e. reductive elimination) is a lower-energy pathway than the corresponding external mechanism involving attack of the enolate onto an η 3 -allyl complex; it was later discovered that η 1 -allylpalladium carboxylate 5 was found to be the resting state of the catalyst and that decarboxylation was likely rate-limiting.…”

Construction of tertiary chiral centers by Pd-catalyzed asymmetric allylic alkylation of prochiral enolate equivalents

“…3 Over the last decade, our laboratory has reported Pd-catalyzed decarboxylative allylic alkylation reactions (Scheme 1). Since our initial efforts in this area, leading to the formation of α-quaternary ketones 2 from racemic β-ketoesters 1 in good yields and enantioselectivities using ( S )-4-( tert -butyl)-2-(2-(diphenylphosphino)phenyl)-4,5-dihydrooxazole [( S )- t -BuPHOX] 4 as a chiral ligand, 5 we have expanded the scope 6 and demonstrated the use of these methods in a number of applications. 7 We recently developed the asymmetric allylic alkylation, giving α-quaternary lactams 4 from racemic β-amidoesters 3 using ( S )-2-(2-(bis(4-(trifluoromethyl)phenyl)phosphino)-5-(trifluoromethyl)phenyl)-4-( tert -butyl)-4,5-dihydrooxazole [( S )-(CF 3 ) 3 - t -BuPHOX] 8 as a chiral ligand.…”

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

“…A recent addition developed by our laboratory is the allylic alkylation of nonstabilized enolate precursors to form α-quaternary carbonyl compounds (Scheme 1) [3]. Once the key stereocenter is set by this chemistry, further elaboration allows access to many bioactive small molecules.…”