Access to Chiral GABA Analogues Bearing a Trifluoromethylated All-Carbon Quaternary Stereogenic Center through Water-Promoted Organocatalytic Michael Reactions

Abstract

Water enables the highly challenging enantioselective Michael addition of sterically congested β-trifluoromethylβ-arylor -alkyl-substituted nitroolefins with dithiomalonates. Under on-water conditions, the reaction rates were remarkably accelerated as a result of enforced hydrophobic interactions between catalysts and reactants. Takemoto-type thiourea catalysts are very effective for this transformation, affording highly enantioenriched Michael adducts that provide simple access to chiral γ-aminobutyric acid (GABA) analogues with a β-trifluoromethylated quaternary stereocenter.

Advances in Catalytic Asymmetric Construction of Quaternary Stereogenic Centers by Conjugate Addition to β,β‐Disubstituted Nitroalkenes

“…[71] Building on our previous work [30] about hydrophobically driven asymmetric catalysis, [69,72] we further explored the water-enabled enantioselective Michael addition of sterically congested β-trifluoromethyl (β-CF 3 )-β-(hetero)aryl-and -alkyl-substituted nitroalkenes (88) with dithiomalonates (89), promoted by a Takemoto-type bifunctional catalyst Cat-13 (Scheme 24). [31] A remarkable reaction rate increase was observed under "on-water" reaction condition because of the enforced hydrophobic interactions between the catalyst and reactants. At a catalyst loading of 15 mol%, various β-CF 3 -β-(hetero)aryl and β-CF 3 -β-alkyl nitroalkenes were converted to the desired products (90) bearing all-carbon quaternary stereocenter in moderate to high yields and good to excellent enantioselectivities (up to 97% yield and 96% ee).…”

“…[5] The β‐nitro compounds with quaternary stereocenters formed via conjugate addition to β,β‐disubstituted nitroalkenes can be easily transformed into several important species such as β 2,2 ‐amino acids and γ‐aminobutyric acids (GABAs) [6,7,8] . Therefore, the past few decades have witnessed the extensive development of catalytic asymmetric conjugate additions to β,β‐disubstituted nitroalkenes and the emergence of the corresponding elegant strategies [9–60] …”

Pentafluorophenyl‐Substituted Proline‐Derived Chiral Urea for “On Water” Asymmetric Hydrogen‐Bonding Catalysis

“…Schreiner [6a] and Rueping [6b] independently demonstrated in their pioneering studies that noncovalent organocatalysis can be achieved, and even amplified, under aqueous conditions. Shortly thereafter, Song and Bae reported a series of elegant organocatalytic reactions facilitated by hydrogen bonding (HB) activation under “on water” conditions, employing cinchona‐based squaramides and Takemoto‐type urea as catalysts [6c–h] . The efficiency was enhanced with catalysts possessing higher levels of hydrophobicity [6d] .…”

Asymmetric Michael Addition in Synthesis of β-Substituted GABA Derivatives

“…Another urea catalyst (S,S)-31 (Scheme 7) containing the pyrrolidine moiety was designed to catalyze in brine media [46] the enantioselective addition of dithiomalonate to otherwise unreactive β-CF 3 -β,β-disubstituted nitroalkenes 30 providing corresponding Michael adducts 32 with a β-trifluoromethylated quaternary stereocenter [47]. In brine media the use of 15 mol% of urea catalyst (S,S)-31 as well as the addition of o-xylene as additive was required for obtaining high yield and enantioselectivity of adducts 32 at 0 • C. In the absence of cosolvent, the achieved enantioselectivity of Michael adducts 32 was lower.…”