Copper‐Catalyzed Enantioselective Conjugate Addition of Grignard Reagents to α,β‐Unsaturated Esters

Abstract

The development of catalyst systems for the enantioselective conjugate addition of organometallic reagents to a,b-unsaturated compounds has been the subject of intensive research over the past few decades.[1] Whereas extraordinary advances have been made in asymmetric 1,4-additions to enones, lactones, and nitroalkenes, [1][2][3][4][5] in the case of acyclic a,bunsaturated esters the progress has been limited, [6] despite the enormous synthetic potential of the resulting enantiopure bsubstituted esters as building blocks for natural product synthesis. [7,8] The lower intrinsic reactivity of a,b-unsaturated esters relative to that of enones, [9] and the challenge to control the different conformers present in acyclic unsaturated systems, may account for this paucity of versatile methodologies. To address these issues, several alternatives based on the use of different ester surrogates (i.e. oxazolidinones, pyrrolidinones, pyrazolidinones, acyl phosphonates, and imides), were developed successfully, with highly enantioselective Michael additions of soft nucleophiles resulting.[10] However, for alkyl metal compounds only an enantioselective conjugate addition of dialkyl zinc reagents to unsaturated N-acyl oxazolidinones has been reported to date.[11] Very recently, our research group described an alternative strategy based on a conjugate addition to alkylidene malonates that yields b-substituted esters after a decarboxylation step, but the method is restricted to the addition of dimethylzinc. [12,13] Therefore, despite these important achievements, general and efficient enantioselective conjugate additions of organometallic reagents to a,b-unsaturated esters remain a major challenge.

Enantioselective Cu‐Catalyzed 1,4‐Addition of Grignard Reagents to Cyclohexenone Using Taddol‐Derived Phosphine–Phosphite Ligands and 2‐Methyl‐THF as a Solvent

“…[4,7] Furthermore, Feringa and co-workers were able to apply this catalytic system to other substrates and in the synthesis of natural products. [8] However, the reaction of 3 with other relevant Grignard reagents such as iPrMgBr or PhMgBr proceeded only with low selectivity under these conditions, and also with an alternative catalyst (formed from 2 and CuBr-SMe 2 ) ee values did not exceed 54 % (R = iPr) and 40 % (R = Ph). Thus, the challenge remained open.…”

“…[8] However, the reaction of 3 with other relevant Grignard reagents such as iPrMgBr or PhMgBr proceeded only with low selectivity under these conditions, and also with an alternative catalyst (formed from 2 and CuBr-SMe 2 ) ee values did not exceed 54 % (R = iPr) and 40 % (R = Ph). Thus, the challenge remained open.Considering that chiral diphosphine ligands possess an obvious potential for the Cu-catalyzed 1,4-addition of Grignard reagents [7,8] we wondered whether phosphinephosphite ligands of type 7[9] (developed in our laboratory) would also be suited for this purpose.[10] These ligands are efficiently prepared from o-bromophenols 6 and chiral diols (such as Binol (2,2'-dihydroxy-1,1'-binaphthyl) [11] and Taddol (a,a,a'-tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5-dimethanol) [12] ), and the modular synthesis facilitates structural variation and optimization (Scheme 2). We herein report that compounds of this class indeed represent highly useful ligands for the Cu-catalyzed 1,4-addition of various Grignard Scheme 1.…”

Cu‐katalysierte asymmetrische Michael‐Additionen mit Mg‐, Zn‐ und Al‐Verbindungen: ein effizienter Weg zu chiralen Molekülen

“…96 % ee erhalten werden. [5] Interessanterweise können unter Verwendung von (S)-Tol-Binap (4) und in Gegenwart von CuI (1 Mol-%) stereoselektive Additionen sowohl an E-als auch an Z-konfigurierten ungesättigten Estern ((E)-5 und (Z)-5) durchgeführt werden, wobei man die beiden zueinander enantiomeren Michael-Addukte 6 und ent-6 in 93 bzw. 94 % ee erhält.…”

Biologically active Phytophthora mating hormone prepared by catalytic asymmetric total synthesis

“…In 2005, Qi et al (5) reported the purification of a Phytophthora mating hormone and revealed that the structure consists of an array of 1,5-stereogenic centers. Such structures can in principle be accessed by our recently developed powerful methodology of catalytic enantioselective conjugate addition of Grignard reagents (6)(7)(8)(9)(10)(11)(12)(13)(14) (Fig. 1).…”

“…Recently, we developed a highly enantioselective conjugate addition (CA) of Grignard reagents, in particular MeMgBr, to ␣,␤-unsaturated thioesters catalyzed by a copper bromide complex of Josiphos ligand (Fig. 1B) and applied this methodology in a diastereo-and enantioselective iterative route to deoxypropionate chains (6)(7)(8)(9)(10)(11)(12)(13)(14).…”