Generation of Quaternary Stereocenters by Asymmetric Michael Reactions: Enamine Regiochemistry as Configuration Switch

Abstract

Regioselective enamine formation from cyclic beta-diketones 1 is obtained by the appropriate choice of activating agent: Brønsted acid catalyzed condensation gives endocyclic enamines 3 as the thermodynamically favored products. Activation with Lewis acid BF(3).OEt(2) affords betaines 8 as intermediate products, which can be reacted with L-valine diethylamide (2) to preferentially furnish exocyclic enamines 4 as kinetic products. Derivatives with quaternary stereocenters were accessible from both isomeric enamines by using asymmetric, copper(II)-catalyzed Michael reactions at ambient temperature. Both regioisomers afford the triketones 7 with the same constitution but bearing the opposite absolute configuration at the quaternary stereocenter. Thus, both enantiomers of the product are prepared by using the same chiral auxiliary derived from L-valine.

Enantioselective Access to Robinson Annulation Products and Michael Adducts as Precursors

“…Christoffers group has developed a method to control the formation of either the kinetic exocyclic enamine 220 or the thermodynamic endocyclic enamine 179 whose regiochemical ratio relies mainly on the ring size. [124] Scheme 49. Configurationally switched asymmetric Michael addition governed by the enamine regiochemistry.…”

“…TheC hristoffers group has developed am ethod to control the formation of either the kinetic exocyclic enamine 178 or the thermodynamic endocyclic enamine 180,w hose regiochemical ratio relies mainly on the ring size. [124]…”

Computational studies on the copper(II) catalyzed Michael reaction

“…Modern metal catalyzed variants allow for the use of base-free conditions [1][2][3][4][5][6][7][8][9]. Enantioselectivity could be achieved starting from (chiral) enamines 3 made from b-diketones 1 and an amino acid derivative 2 which is used as a chiral auxiliary in stoichiometric quantities [10][11][12][13](Scheme 1).…”

Enantioselektive Synthese von Robinson‐Anellierungsprodukten und Michael‐Addukten als Vorstufen

“…Aufsätze clischen Enamins 178 oder thermodynamischen endocyclischen Enamins 180,d eren regiochemisches Verhältnis hauptsächlich von der Ringgrçße abhängt [124]. …”