Catalytic asymmetric approaches towards enantiomerically enriched diarylmethanols and diarylmethylamines

Abstract

Enantiopure diarylmethanols and diarylmethylamines are important intermediates for the synthesis of pharmaceutically relevant products with antihistaminic, antiarrhythmic, diuretic, antidepressive, laxative, local-anesthetic and anticholinergic properties. Furthermore, they have been used as precursors for 1,1-diarylalkyl moieties, which occur in other antidepressants as well as in antimuscarinics and endothelin antagonists. In this critical review catalytic strategies towards enantioenriched diarylmethanols and diarylmethylamines are discussed, including methods for asymmetric carbon-carbon bond formations by aryl transfer reactions to aldehydes and arylimines, respectively, and enantioselective reductions of diarylketones.

A Chiral Nitrogen Ligand for Enantioselective, Iridium‐Catalyzed Silylation of Aromatic C−H Bonds

“…[15] Although methods are known for the synthesis of chiral unsymmetrical diarylmethanols, such methods are not suitable for the synthesis of the corresponding unsymmetrical diarylmethanols containing one or two ortho-substituted aryl groups. [15][16] Moreover, rhodium catalysts that led to high site selectivity for reaction with enantioenriched, unsymmetrical diarylmethanols [10] did not lead to high selectivity for reaction with one enantiomer over another, even when one of the aryl groups was ortho substituted (see the supporting information for details).To determine if our newly developed catalyst system (L25-Ir) would resolve the two enantiomers of such diarylmethanols, rac-3a was subjected the catalyst system at 50 °C for 12 h. The desired silylation product 4a and the unreacted product 3a were obtained with 76% ee and 97% ee respectively, corresponding to a selectivity factor (s) [17] of 40 (SI, Table 2, entry 1). The reaction at 40 °C for 12 h occurred with an s value of 88, but only 20% of the product was obtained (SI, Table 2, entry 2).…”

“…Such chiral unsymmetrical diarylmethanols are important precursors for the synthesis of some existing pharmaceuticals, such as neobenodine, [14] an antihistaminic and anticholinergic agent. [15] Although methods are known for the synthesis of chiral unsymmetrical diarylmethanols, such methods are not suitable for the synthesis of the corresponding unsymmetrical diarylmethanols containing one or two ortho-substituted aryl groups. [15][16] Moreover, rhodium catalysts that led to high site selectivity for reaction with enantioenriched, unsymmetrical diarylmethanols [10] did not lead to high selectivity for reaction with one enantiomer over another, even when one of the aryl groups was ortho substituted (see the supporting information for details).…”

Mannich and O‐Alkylation Reactions of Tetraalkoxyresorcin[4]arenes — The Use of Some Products in Ligand‐Assisted Reactions.

“…45,46 The related enantioselective synthesis of diarylmethanols and diarylmethylamines has been reviewed recently. 47 Ligand-assisted alkynylation reactions of aldehydes using alkynylzinc reagents have also been reported recently; 48 they provide an interesting and valuable route to chiral propargylic alcohols. 49 We were interested in exploring the possible use of our chiral resorcin [4]arene derivatives in the latter type of reaction.…”

Function of an N-Heterocyclic Carbene Ligand Based on Concept of Chiral Mimetic

“…The substituent R on the sp 2 N group in the carbene ligand 3 may be conformationally flexible, but if the complexation of 3 and metal is reflected by the asymmetric center in 3, a more stable complex 4a, in which the substituent R on the sp 2 N group is fixed, is expected to be selectively formed (Fig. 2).10) Herein we would like to report our investigations 5) on Rh-catalyzed enantioselective arylation of aromatic aldehydes 5 with arylboronic acids and enantioselective intramolecular a-arylation of amides 7 with the novel N-heterocyclic carbene (NHC) ligand 3 (Chart 1).Rh-Catalyzed Enantioselective Arylation of Aromatic Aldehydes with Arylboronic Acids Rh-catalyzed arylation of aromatic aldehydes with arylboronic acids was reported by Miyaura in 1998.11) The corresponding diarylmethanols were obtained in good yields, and with as a chiral ligand, a product with 41% ee was formed in enantioselective Rh-catalyzed phenylation 4,6,[13][14][15][16][17] of 1-naphthaldehyde with PhB(OH) 2 . A recent attempt by Bolm using planar chiral imidazolium salts as NHC ligand precursors attained moderate enantioselectivity (up to 38% ee).…”

“…11) The corresponding diarylmethanols were obtained in good yields, and with MeO-MOP 12) as a chiral ligand, a product with 41% ee was formed in enantioselective Rh-catalyzed phenylation 4,6,[13][14][15][16][17] of 1-naphthaldehyde with PhB(OH) 2 . A recent attempt by Bolm using planar chiral imidazolium salts as NHC ligand precursors attained moderate enantioselectivity (up to 38% ee).…”