Development of Highly Active Chiral Titanium Catalysts for the Enantioselective Addition of Various Organometallic Reagents to Aldehydes

Abstract

The catalytic enantioselective carbonyl addition reaction has long attracted the interest of chemists because of its synthetic importance. Although many highly enantioselective reactions have been developed, with few exceptions the reactions are carried out at relatively high catalyst loadings, making them less practical for scale-up applications. In addition, organometallic reagents employed as carbon nucleophiles have been limited to those with relatively low reactivity, such as diorganozincs and arylboronic acids. In an effort to enhance the practicality, a highly active and enantioselective chiral titanium catalyst system was recently developed in our laboratory, enabling the enantioselective carbonyl addition reaction to aldehydes using various organometallic reagents (RM; M = MgX, Li, BY2 , ZnX, AlMe2 ) at lower catalyst loadings (≤5 mol %).

3‐Mono‐Substituted BINOL Phosphoric Acids as Effective Organocatalysts in Direct Enantioselective Friedel–Crafts‐Type Alkylation of N‐Unprotected α‐Ketiminoester

“…In these reactions, 3,3'-disubstituted BINOL-derived phosphorica cids 1 (Figure 1) are mostf requently used for highly enantioselective reactions.O nt he other hand, 3-monosubstitutedB INOL-derived phosphoric acids 2 are less frequently used as catalysts [4] and, to the best of our knowledge,s imple 3-monosubstituted BINOL-derived phosphoric acidsw ithout any polar functionalitieso nt he 3-sub-stituenth ave not been used in highly enantioselective reactions. This fact is surprising because the parent 3-monosubstituted BINOL derivatives [5] and their phosphoramidite analogues [6] are good ligands for several catalytic enantioselective reactions. Herein, we report that simple 3-mono-substituted chiral BINOL-phosphoric acids are even more selective organocatalysts than 3,3'-disubstituted analogsi nd irect enantioselective Friedel-Crafts-type alkylation of N-unprotected a-ketiminoester.T he origin of the observed high enantioselectivity with the 3-monosubstituted catalyst is also discussed.This work emerged from our recent focus on the utility of Nunprotected ketimines in direct catalytic nucleophilica ddition reactions.…”

Readily Available Highly Active [Ti]-Adamantyl-BINOL Catalysts for the Enantioselective Alkylation of Aldehydes

“…1 These alcohols are key compounds serving as both starting materials and resolving agents, which are used in the preparation of pharmaceuticals or intermediates. 1,2…”

Enantioselective vinylation of aldehydes with the vinyl Grignard reagent catalyzed by magnesium complex of chiral BINOLs

“…Because of greatly reactive, however, the catalytic asymmetric addition of Grignard reagents to aldehydes is typically challenging . Only recently successful strategies were developed in access to highly enantiopure secondary alcohols via catalytic asymmetric Grignard reactions . The groups of Harada, Xu, and Yus utilized superstoichiometric Ti (O i ‐Pr) 4 to transmetallate RMgX (Br, Cl) to less reactive R‐Ti (O i ‐Pr) 3 , and then R‐Ti (O i ‐Pr) 3 highly enantioselectively delivered R group to aldehydes catalyzed by chiral diol‐Ti (O i ‐Pr) 2 complexes.…”

“…[1][2][3][4][5][6][7][8][9][10] Only recently successful strategies were developed in access to highly enantiopure secondary alcohols via catalytic asymmetric Grignard reactions. [11][12][13] The groups of Harada, [14][15][16] Xu, 17,18 and Yus 19,20 utilized superstoichiometric Ti (Oi-Pr) 4 to transmetallate RMgX (Br, Cl) to less reactive R-Ti (Oi-Pr) 3 , and then R-Ti (Oi-Pr) 3 highly enantioselectively delivered R group to aldehydes catalyzed by chiral diol-Ti (Oi-Pr) 2 complexes. Our group demonstrated that the additive bis([2-[N,N′-dimethylamino)]thyl) ether (BDMAEE) effectively deactivated the reactivity of Grignard reagents and then similarly transmetallated R functional group of RMgBr to R-Ti (Oi-Pr) 3 by using stoichiometric Ti (Oi-Pr) 4 .…”