Direct Asymmetric α‐Selective Mannich Reaction of β,γ‐Unsaturated Ketones with Cyclic α‐Imino Ester: Divergent Synthesis of Cyclocanaline and Tetrahydro Pyridazinone Derivatives

Abstract

The first regio‐, diastereo‐, and enantioselective direct Mannich reaction of β,γ,‐unsaturated ketones with benzoxazinone cyclic imines was enabled by Lewis acid/Brønsted base cooperative catalysis. The dinuclear zinc complex catalyzed the reaction of a broad range of β,γ‐unsaturated ketones to proceed at the α‐site exclusively, leading to corresponding adducts with two consecutive tertiary carbon stereocenters in diastereomeric ratios of up to >20:1 and enantioselectivities generally in the 90–99 % ee range. These products were used as general intermediates in the synthesis of multisubstituted cyclocanalines, tetrahydro pyridazinones, and 4H‐furo[2,3‐b][1,4]benzoxazine derivatives.

Zn-ProPhenol catalyzed asymmetric inverse-electron-demand Diels–Alder reaction

“…Based on the current experimental results and previous reports, 17 a plausible reaction pathway was suggested in Scheme 2. Treatment of ZnEt 2 with ligand L 4 delivered the dinuclear Zn-ProPhenol complex in situ .…”

Organocatalytic enantioselective Mannich and retro-Mannich reactions and combinations of these reactions to afford tetrasubstituted α-amino acid derivatives

“…The 1,4-benzoxazinone ring structure is often present in bioactive molecules. 7,8 Thus, Mannich reaction products bearing the benzoxazinone moiety could be useful for drug discovery. 7 In addition, benzoxazinone-derived cyclic amino esters can be transformed into other derivatives by reactions on the ester group and the deprotection of the phenol group attached to the amine group.…”

“…7 In addition, benzoxazinone-derived cyclic amino esters can be transformed into other derivatives by reactions on the ester group and the deprotection of the phenol group attached to the amine group. 1 a ,7 a , e ,8 The use of cyclic ketimino esters avoids potential hydrolysis of the imine during Mannich reactions. Whereas catalytic enantioselective Mannich reactions involving 1,4-benzoxazinone-derived aldimino esters, 5 c ,8 other cyclic aldimino esters, 9 or acyclic aldimino esters 10 to afford α-amino acid derivatives have been reported, 5 c ,8–10 only a small number of examples of Mannich reactions of the corresponding ketimino esters to afford tetrasubstituted α-amino acid derivatives have been reported.…”

“…1 a ,7 a , e ,8 The use of cyclic ketimino esters avoids potential hydrolysis of the imine during Mannich reactions. Whereas catalytic enantioselective Mannich reactions involving 1,4-benzoxazinone-derived aldimino esters, 5 c ,8 other cyclic aldimino esters, 9 or acyclic aldimino esters 10 to afford α-amino acid derivatives have been reported, 5 c ,8–10 only a small number of examples of Mannich reactions of the corresponding ketimino esters to afford tetrasubstituted α-amino acid derivatives have been reported. 1,5,11 Highly enantioselective Mannich reactions of ketimino esters in which a simple alkyl group (such as a methyl group) is substituted on the imine carbon of the ketimino ester ( i.e.…”

Multicomponent Enantioselective Synthesis of Tetrahydropyridazinones Employing Chiral α,β-Unsaturated Acylammonium Salts

“…The potential of developing efficient routes to optically active, substituted pyridazinones, which have seen only limited interest, − provided a further impetus to study the described catalytic, asymmetric MCR involving unsaturated acylammonium catalysis. We envisioned a type of three-component MCR process, which may be more aptly named a sequential component process, involving the initial in situ α-amination of a malonate with an azodicarboxylate, leading to the formation of an α-hydrazino malonate (Scheme ).…”