Asymmetric Vinylogous Aldol Reaction of α‐ketoesters with 3‐alkylidene oxindoles

Abstract

An efficient enantioselective vinylogous aldol reaction of 3‐alkylidene oxindoles with α‐ketoesters by a bifunctional thiourea catalyst derived from cinchona alkaloid has been disclosed here. The simultaneous H‐bond directing dual activation of vinylogous nucleophile and electrophile afforded high yield (upto 92%) while obtaining excellent stereocontrol (upto 99% ee).magnified image

New Developments of the Principle of Vinylogy as Applied to π-Extended Enolate-Type Donor Systems

“…In 2017, Singh and colleagues put in place an asymmetric aldol procedure exploiting 3-alkylidene oxindoles 800 as vinylogous pronucleophiles and α-keto esters 801 as electrophilic counterparts ( Scheme 204 ). 522 The authors hypothesized (and proved) that the cinchona-derived thiourea bifunctional organocatalyst C2 could be able, at the same time, to activate and orient the reactant partners leading to α,β-unsaturated aldol adducts 802 in a stereocontrolled manner. Among the tested organocatalysts, the thiourea C2 gave the best results, affording Z -configured δ-hydroxy esters 802 in yields ranging from 34 to 92% and enantiomeric excesses from 79 to 99%.…”

Bifunctional Cinchona Alkaloid Catalyzed Vinylogous Michael Reaction of 3–Alkylideneoxindole with 4‐Oxo‐enoates: A Route to Chiral γ‐Keto Alkylideneoxindole Esters

“…The absolute configuration of vinylogous Michael adduct 3 n was determined to be S on the basis of its single crystal X‐ray analysis (Figure ) and that of the rest of Michael adducts 3 were assigned by analogy. On the basis of previous studies on cinchona alkaloid‐derived thiourea catalyzed vinylogous Michael reactions, the observed stereochemistry of 3 can be explained with the proposed transition state depicted in Scheme . The chiral catalyst C3 , at first, deprotonates 3‐alkylidene‐2‐oxindole 1 by its quinuclidine moiety and presumably activates both the electrophile 3‐aroyl acrylate 2 and the nucleophilic S ‐cis dienolate of 3‐alkylidene‐2‐oxindole simultaneously through multiple hydrogen‐bonding interactions with thiourea and ammonium salt.…”

Enantioselective Vinylogous Reactions of 3-Alkylidene Oxindoles

“…α-Oxo esters are another type of activated ketone that has been employed in the vinylogous transformation of 3alkylideneoxindoles (Scheme 5). 9 The most important features are: (i) aliphatic oxo esters and C-6 or C-7 substituted oxindoles were unreactive; and (ii) yields were sometimes moderate. The proposed mechanism was very similar to that given in Scheme 4.…”