Copper(I)-Catalyzed Asymmetric Synthesis of α-Allenylamines and β-Lactams through Regioselective Mannich-Type Reactions

Abstract

Herein, a copper­(I)-catalyzed alkynylogous Mannich-type reaction is developed, which starts from pyrazoleamides of alkynyl-substituted acetic acids and provides an array of chiral α-allenylamine derivatives in high regio-, diastereo-, and enantioselectivities. This reaction enjoys broad substrate scopes on both pyrazoleamides and N-Boc-aldimines. Moreover, a copper­(I)-catalyzed cascade cyclization of pyrazoleamides of but-2-ynoic acid is disclosed, which involves an α-selective Mannich-type reaction as a key step and delivers a series of chiral β-lactams containing a pyrazole moiety in high enantioselectivity. In light of some mechanism studies, the deprotonation step is found as the rate-determining step in this cyclization. Propargyl copper­(I) species are proposed as the operating nucleophiles in both reactions. Finally, the synthetic utility of the alkynylogous product is demonstrated by the transformations of the product to chiral α,β-unsaturated lactones. Furthermore, a gram-scale preparation of chiral β-lactam and its following transformations proved its synthetic versatility.

Recent Developments in Enantioselective Domino Reactions. Part B: First Row Metal Catalysts

“…In 2022, a closely related catalyst system was employed by Yin et al to achieve an enantioselective cascade cyclization of aldimines 131 with pyrazoleamides 132 derived from but-2-ynoic acid. [41] This domino reaction employed 5 mol% of Cu(MeCN) 4 PF 6 as precatalyst, the same quantity of (R)-Segphos as chiral ligand and 20 mol% of Barton's base in o-xylene as solvent. Performed at room temperature, the reaction resulted in the formation of a series of chiral β-lactams 133 containing a pyrazole moiety with moderate to good yields (44-73%) and good to high enantioselectivities (77-92% ee), as presented in Scheme 34.…”

“…In 2022, a closely related catalyst system was employed by Yin et al. to achieve an enantioselective cascade cyclization of aldimines 131 with pyrazoleamides 132 derived from but‐2‐ynoic acid [41] . This domino reaction employed 5 mol% of Cu(MeCN) 4 PF 6 as precatalyst, the same quantity of ( R )‐Segphos as chiral ligand and 20 mol% of Barton's base in o ‐xylene as solvent.…”

Progress in catalytic asymmetric α-functionalization of vinylogous nucleophilic species

“…A copper-catalyzed alkynylogous Mannich-type reaction was disclosed by Yin et al in 2022 (Scheme 65). 78 The reactions between alkynyl-substituted acetic acid-derived pyrazoleamides 287 and aldimines 73 were conducted in o -xylene at 25 °C under the catalysis of Cu( i )/ L14 complex and Barton's base, in which β-lactams 288 containing a pyrazole unit resulting from the α-addition were generated in good yields (48–73%) with good to excellent ee values (77–92%). The authors proposed a reaction pathway to explain the generation of chiral β-lactams.…”

Progress in Catalytic Asymmetric Reactions with 7-Azaindoline as the Directing Group

“…At present, the main types of directing groups are as follows: 2-oxazolidone (A) [29][30][31][32][33][34][35][36][37][38][39][40], tetrahydropyrrole 2,5-dione (B) [41][42][43], pyrazole or 3,5-dimethylpyrazole (C or D) [44][45][46][47][48][49][50][51][52][53][54][55][56], and 8-aminoquinoline (E) [57][58][59][60][61][62][63][64][65]. They coordinate with metals to form stable five-or six-membered ring complexes that control the stereoselectivity of the reaction through a specific chiral environment (Scheme 1).…”