Development of Catalytic Asymmetric 1,4-Addition and [3 + 2] Cycloaddition Reactions Using Chiral Calcium Complexes

Abstract

Catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium species prepared from calcium isopropoxide and chiral bisoxazoline ligands have been developed. Glycine Schiff bases reacted with acrylic esters to afford 1,4-addition products, glutamic acid derivatives, in high yields with high enantioselectivities. During the investigation of the 1,4-addition reactions, we unexpectedly found that a [3 + 2] cycloaddition occurred in the reactions with crotonate derivatives, affording substituted pyrrolidine derivatives in high yields with high enantioselectivities. On the basis of this finding, we investigated asymmetric [3 + 2] cycloadditions, and it was revealed that several kinds of optically active substituted pyrrolidine derivatives containing contiguous stereogenic tertiary and quaternary carbon centers were obtained with high diastereo- and enantioselectivities. In addition, optically active pyrrolidine cores of hepatitis C virus RNA-dependent polymerase inhibitors and potential effective antiviral agents have been synthesized using this [3 + 2] cycloaddition reaction. NMR spectroscopic analysis and observation of nonamplification of enantioselectivity in nonlinear effect experiments suggested that a monomeric calcium species with an anionic ligand was formed as an active catalyst. A stepwise mechanism of the [3 + 2] cycloaddition, consisting of 1,4-addition and successive intramolecular Mannich-type reaction was suggested. Furthermore, modification of the Schiff base structure resulted in a modification of the reaction course from a [3 + 2] cycloaddition to a 1,4-addition, affording 3-substituted glutamic acid derivatives with high diasterero- and enantioselectivities.

A N,N′‐Dioxide–Copper(II) Complex as an Efficient Catalyst for the Enantioselective and Diastereoselective Mannich‐Type Reaction of Glycine Schiff Bases with Aldimines

“…It can facilitate the deprotonation of the active proton of the glycine Schiff base 1 to form a chiral copper enolate in situ, and thus simplify the catalytic procedure. [13] To our delight, preliminary experimental results confirmed this hypothesis. 2 , and CuA C H T U N G T R E N N U N G (acac) 2 showed moderate to good catalytic activity for the reaction (Table 1, entries 1-3).…”

Unusual Ester‐Directed Regiochemical Control in endo‐Selective Asymmetric 1,3‐Dipolar Cycloadditions of Azomethine Ylides with β‐Sulfonyl Acrylates

“…Ligand 1 e, bearing two bromine atoms at the 3,3'-positions of the TF-BiphamPhos backbone, emerged as the most effective chiral ligand and provided endo-4 a in high yield and excellent enantioselectivity of 96 % (Table 1, entry 6). A subsequent survey of solvent effects indicated that EtOAc was the solvent of choice in terms of the reactivity and enantioselectivity (Table 1, entries [6][7][8].…”

Chiral Ca-, Sr-, and Ba-Catalyzed Asymmetric Direct-Type Aldol, Michael, Mannich, and Related Reactions

“…Kobayashi et al focused on chiral bisoxazoline (Box) ligands bearing methylene moieties with acidic hydrogen atoms as chiral ligands for preparation of chiral Pr) 2 were effective in the asymmetric 1,4-addition reactions of glycine Schiff bases with α,β-unsaturated esters or amides [46][47][48]. They then screened several non-or α-substituted acrylic esters bearing alkyl, phenyl, and chloro groups.…”

“…Vinyl sulfone also worked; however, a moderate yield with a low enantioselectivity was observed (entry 13). Kobayashi et al have also investigated the synthesis of optically active 3-substituted glutamic acid derivatives [47,48]. A problem that needs to be solved to realize the desired reactions with β-substituted α,β-unsaturated esters, such as methyl crotonate, is that chiral pyrrolidine derivatives via [3+2] cycloaddition were obtained exclusively (vide infra) and that the desired 1,4-addition adducts were not obtained.…”