Pd(0)-Catalyzed Chemo-, Diastereo-, and Enantioselective α-Quaternary Alkylation of Branched Aldehydes

Abstract

Quaternary carbon stereocenters are ubiquitous in a wide variety of organic compounds and drug molecules. Highly enantioselective construction of such quaternary carbon centers poses a singular challenge due to the steric repulsion between the four different carbon substituents. Herein, we report a novel strategy to control the enantioselective construction of chiral α-quaternary aldehydes from racemic α-branched aldehydes. Distinct from the established chiral α-quaternary aldehyde synthesis, this project employed a chiral π-allyl–Pd complex neighboring the enolate to determine both the enantio- and diastereoselectivity. The synthetic utility of the products has been highlighted by a series of derivatizations, and the potential of this method has been extended to the synthesis of chiral α-quaternary ketones. Furthermore, this reaction exemplifies the themes of step and atom economy, in addition to the principles of diversity-oriented synthesis.

Catalytic Asymmetric α-Functionalization of α-Branched Aldehydes

“…Aldehydes with a tethered allyl carbonate moiety 48 upon treatment with the palladium catalyst C55 would evolve into a chiral π-allyl-Pd complex neighboring the enolate ( I-4 ). Formal [3+2] coupling of this intermediate with the acceptor reaction partner, e.g., nitroolefins, ketones, and imines, then provides the corresponding cyclization adducts 52 / 53 with up to three new stereocenters in good yields and usually high enantio- and diastereoselectivity ( Scheme 26 ) [ 91 ]. A palladium-centered highly ordered transition state model TS-11 was proposed to explain the stereochemical course of the reaction observed.…”

Palladium-catalysed enantio- and regioselective (3 + 2) cycloaddition reactions of sulfamidate imine-derived 1-azadienes towards spirocyclic cyclopentanes

“…2a). [44][45][46][47][48][49][50][51][52][53][54][55] In comparison, their employment as two-atom synthons has been scarcer, 31,34,47,50 among which there are only two examples of (3 + 2) cycloaddition reactions with BDAs known, with chemoselectivity for C]N versus C]C addition being a potential challenge. 31,34 The preference for (4 + n) reactions of BDAs is due to the favoured attack of the intermediate sulfonamide anion on the pendant Pd-Fig.…”

Cooperative Tertiary Amine/Palladium-Catalyzed Sequential [4 + 3] Cyclization/[1,3]-Rearrangement for Stereoselective Synthesis of Spiro [Methylenecyclopentane-1,3′-oxindolines]

“… , In recent years, significant efforts have been made to develop simple and practical methods to access these architectures . The representative developing methods probably include the transition-metal-catalyzed Conia-ene reaction of alkynes and the cycloaddition reaction of 2-acyl-methylenecyclopentanes with electron-deficient alkenes . However, the existing routes mainly focus on the synthesis of methylenecyclopentane scaffolds containing an α-acyl quaternary carbon stereocenter, and it is still challengeable and also limited for the formation of methylenecyclopentane derivatives containing a β-acyl quaternary carbon stereocenter, which seems to be more important and wider distribution in the natural products and pharmaceuticals .…”