One‐Pot Quinine‐Catalyzed Synthesis of α‐Chiral γ‐Keto Esters: Enantioenriched Precursors of cis‐α,γ‐Substituted‐γ‐Butyrolactones

Abstract

A highly enantioselective one‐pot synthesis of important building blocks, α‐chiral γ‐keto esters, has been developed by combining a quinine‐catalyzed Michael addition of malononitrile to trans‐enones followed by magnesium monoperoxyphthalate (MMPP) oxidation. These synthons proved to be useful reagents for a simple access to challenging cis‐α,γ‐disubstituted γ‐butyrolactones in good diastereoselectivity and high enantiocontrol.magnified image

Chiral-at-Metal Rh(III) Complex Catalyzed Cascade Reduction-Michael Addition Reaction

“…13 C NMR {1H} (100 MHz, CDCl 3 ): δ = 187. 5,141.6,136.3,135.2,131.0 (q,J = 32.6 Hz),130.7,130.0,129.3,129.2,129.2,125.8 (q, J = 3.6 Hz), 123.9 (q, J = 270.6 Hz), 121.9, 114.8, 113.9, 49.3, 47.7, 45.0, 41.9, 41.7, 23.5, 23.3. 19 F NMR {1H} (376 MHz, CDCl 3 ): δ = −62.73.…”

“…in medicines, pesticides, and dyes, is a classic equivalent of malonic acid derivatives in organic synthesis . It can serve as a nucleophile where the methylene group tends to lose a proton and form stabilized carbanion to undergo various reactions such as Knoevenagel condensation, Gewald reaction, Claisen condensation, Michael addition, and Mannich reaction . In addition, the malononitrile substituent in the obtained products can undergo further transformation to form carboxylic acid, ester, or amide groups .…”

Double Asymmetric Hydrogenation of (E)‐2‐Substituted‐4‐oxo‐2‐alkenoic Acids: An Efficient Synthesis of Chiral α, γ‐Disubstituted γ‐Butyrolactones

“…[14][15][16][17][18][19] In these approaches, Alessandra Lattanzi and coworkers employed one-pot quinine-catalyzed Micheal reaction and sequential magnesium monoperoxyphthalate (MMPP) oxidation to synthesize α-chiral γ-keto esters which could be converted to chiral α, γ-disubstituted γ-butyrolactones through further reduction of carbonyl group and lactonization (Scheme 1a). [20,21] Xumu Zhang's group reported a two-step method to establish the chiral α, γ-disubstituted γ-butyrolactones through asymmetric hydrogenation of the C=C bond of α-methylene-γ-keto carboxylic acids and following catalytic reduction of the ketone moiety (Scheme 1b). [22] In addition, with a two-enzyme cascade of ene reductase (old yellow enzyme, OYE1) and alcohol dehydrogenase (ADH), enantiomerically pure anti-2,4-dimethylbutyrolactone was obtained in good yield (Scheme 1c).…”

“…Although various investigations have been focused on their asymmetric synthesis, only few synthetic approaches have been reported to obtain enantioenriched α , γ ‐disubstituted γ ‐butyrolactones with good diastereoselectivities [14–19] . In these approaches, Alessandra Lattanzi and coworkers employed one‐pot quinine‐catalyzed Micheal reaction and sequential magnesium monoperoxyphthalate (MMPP) oxidation to synthesize α ‐chiral γ ‐keto esters which could be converted to chiral α , γ ‐disubstituted γ ‐butyrolactones through further reduction of carbonyl group and lactonization (Scheme 1a) [20,21] . Xumu Zhang's group reported a two‐step method to establish the chiral α , γ ‐disubstituted γ ‐butyrolactones through asymmetric hydrogenation of the C=C bond of α ‐methylene‐ γ ‐keto carboxylic acids and following catalytic reduction of the ketone moiety (Scheme 1b) [22] .…”

Visible-Light-Promoted Carbene Insertion and Decarbonylation for the Synthesis of α-Substituted γ-Ketoesters

“…3, 138.6, 136.5, 133.3, 128.9, 128.6, 128.1, 127.8, 127.5, 61.1, 46.6, 42.8, 14.1; HRMS (ESI-TOF) m/z [M + Na] + calcd for C 18 H 18 O 3 Na 305.1148, found 305.1145butanoate (4c). 20,21 Synthesized according to General Procedure 2. The obtained product was a white solid (78% yield, 22 mg, V petroleum ether /V ethyl acetate = 10/1, R f = 0.7): mp 93.…”