New Entries in Lewis Acid−Lewis Base Bifunctional Asymmetric Catalyst:  Catalytic Enantioselective Reissert Reaction of Pyridine Derivatives

Abstract

The first catalytic enantioselective Reissert reaction of pyridine derivatives that affords products with excellent regio- and enantioselectivity is described. The key for success is the development of new Lewis acid-Lewis base bifunctional asymmetric catalysts containing an aluminum as a Lewis acid and sulfoxides or phosphine sulfides as a Lewis base. These reactions are useful for the synthesis of a variety of chiral piperidine subunits, and catalytic enantioselective formal synthesis of CP-293,019, a selective D4 receptor antagonist, was achieved. Preliminary mechanistic studies indicated that both sulfoxides and phosphine sulfides can activate TMSCN as a Lewis base. In addition, the sulfoxides with appropriate stereochemistry might stabilize a highly enantioselective bimetallic complex (a presumed active catalyst) through internal coordination to aluminum.

Asymmetric Multicomponent Reactions (AMCRs): The New Frontier

“…[228] The Mannich AMCR has been applied for the derivatization of tyrosine residues of chymotrypsinogen, which permitted the easy modification of the protein, while preserving the native function. [229] The enantioselective version of this reaction with l-proline has been expanded to a significant number of symmetric and nonsymmetric ketones as the source of the nucleophile, as well as different aldehydes.…”

Synthesis of new fused isoquinolines via reissert compounds

“…Non-alkylated Reissert compounds 2 can undergo a similar transformation into imidazo [ [18]. 1-Benzylisoquinolines can be used to establish 1,3-bridged isoquinolines by intramolecular Mannich-type reaction [19].…”

Recent progress in Lewis acid-Lewis base bifunctional asymmetric catalysis

“…To the active catalyst 8, the substrate ketoimine 5 is incorporated. An intramolecular cyanide transfer from the gadolinium cyanide to the activated substrate should define the enantioselectivity (9). Here, the bimetallic complex plays multiple roles; a gadolinium atom works as a Lewis acid to activate a ketoimine, a gadolinium cyanide works as a nucleophile, and the phosphine oxide works as a Lewis base to activate the nucleophile.…”

“…from 14 and 15, containing either chiral sulfoxides or phosphine sulfides as Lewis bases (Scheme 6) [9]. Thus, using a catalyst generated from Et 2 AlCl and 14 in a 1:2 ratio (5 mol %) and FmocCl as an acylating reagent, product 13a was obtained with excellent regio-and enantioselectivity (regioselectivity = 50:1).…”

“…On the other hand, D-glucose-derived ligands 3 and 4 complexed with titanium or lanthanide metals promoted general catalytic enantioselective cyanation of ketones [6] and ketoimines [7]. In this manuscript, we describe recent progress in this field; specifically, the catalytic enantioselective Strecker reaction of ketoimines with broad substrate generality and high catalyst turnover [8], and the first catalytic enantioselective Reissert reaction of pyridine derivatives [9].…”