Enantioselective and Regioselective Organocatalytic Conjugate Addition of Malonates to Nitroenynes

Abstract

The first catalytic asymmetric conjugate addition of 1,3-dicarbonyl compounds to nitroenynes catalyzed by cinchona alkaloid-based thiourea organocatalysts has been developed. The 1,4-addition adducts were obtained solely, in moderate to good yields (up to 93%) with good enantioselectivities (up to 99% ee). This protocol affords a conceptually different entry to the precursors of pharmaceutically important chiral β-alkynyl acid derivatives and synthetically useful chiral nitroalkynes. Notably, the protocol worked well with both aryl- and alkyl-substituted alkynyl substrates.

Mutually Complementary Metal‐ and Organocatalysis with Collective Synthesis: Asymmetric Conjugate Addition of 1,3‐Carbonyl Compounds to Nitroenynes and Further Reactions of the Products

“…After a single recrystallization, the ee of the product 4b could reach 99%. Additionally, dimethyl malonate afforded the desired 1,4‐addition product 4c in 98% yield with 94% ee (entry 2) whereas this substrate gave 56% yield and 87% ee under our previous organocatalytic conditions 13. For comparative purposes, diethyl malonate was employed as the nucleophile to react further with various nitroenynes.…”

“…Considering the biological and pharmacological importance of chiral β‐alkynyl acids as well as the potential synthetic versatility of asymmetric 1,4‐addition adducts of malonates to nitroenynes, we turned our attention to a metal catalysis strategy and envisioned that metal catalysis could work as a complementary catalysis strategy to solve the significant problems of our previous organocatalytic version 13. Despite the potentials of chiral nickel(II)‐diamine complexes in asymmetric catalysis, the application of this class of catalysts in regioselective conjugate addition of nitroenynes has not been reported.…”

“…The conjugate addition worked well not only with electron‐neutral (entry 3), electron‐rich (entries 4 and 5), and electron‐deficient aryl alkynyl substrates (entries 6 and 7), but also with alkyl‐substituted alkynyl substrates (entries 8–10). The absolute configurations of 4a and 4c–f and 4h–j were determined by comparing the retention time of HPLC of products with those in literature data 13…”

“…The second possible reason is that, different from nitroolefins, nitroenynes have the problem of competitive bis‐Michael addition probably due to the linear structure of the triple bond. Recently, we reported the first catalytic asymmetric addition of malonates to nitroenynes promoted by chiral organocatalysts 13. However, this protocol suffers from the following significant drawbacks or limitations: (i) the reaction yield generally is not good due to the competitive bis‐Michael addition; (ii) the substrate scope is limited, for example, di‐ tert ‐butyl malonate is not reactive; (iii) the catalyst loading is high (10 mol%).…”

Recent applications of <em>Cinchona</em> alkaloid-based catalysts in asymmetric addition reactions

“…Li et al developed the first catalytic asymmetric conjugate addition of 1,3-dicarbonyl compounds to nitroenynes. 42 The 1,4-addition products were obtained in moderate-to-good yields (up to 93%) with good enantioselectivity (up to 99% EE) using Cinchona alkaloid-derived thiourea 44c. The protocol worked well with both aryl-and alkyl-substituted nitroenyne substrates, thus providing a conceptually different entry to the precursors of pharmaceutically important chiral β-alkynyl acid derivatives and synthetically useful chiral nitroalkynes.…”