Water enables new catalytic reactions for otherwise unreactive substrate systems. Under the "on water" reaction conditions, extremely unreactive β,β-disubstituted nitroalkenes smoothly underwent enantioselective Michael addition reactions with dithiomalonates using a chiral squaramide catalyst, affording both enantiomers of highly enantioenriched Michael adducts with all-carbon-substituted quaternary centers. The developed "on water" protocol was successfully applied for the scalable one-pot syntheses of chiral GABA analogs with all-carbon quaternary stereogenic centers at the β-position, which might show highly interesting pharmaceutical properties.
Scheme 4. Facile conversion of the thioesters (R)-4 into the corresponding aldehydes (R)-5 under the Fukuyama reduction conditions. [21] M.S. = molecular sieves, TBS = tert-butyldimethylsilyl.Scheme 5. Utility of the aldol products 3 a, 3 i, and 3 m in the asymmetric syntheses of valuable drug intermediates. Scheme 3. Substrate scope. General reaction conditions: 1 (0.5 mmol), 2 (3.0 equiv), and C9 (30 mol %) in 2.5 mL of MTBE/THF (9:1) at 20 8C. [a] Using HQN-1-Np-SA (C11) as a catalyst. [b] After single recrystallization. [c] The reactions were performed at 10 8C.
In this study, dithiomalonates (DTMs) were demonstrated to be exceptionally efficient Mannich donors in terms of reactivity and stereoselectivity in cinchona-based-squaramide-catalyzed enantioselective Mannich reactions of diverse imines or α-amidosulfones as imine surrogates. Owing to the superior reactivity of DTMs as compared to conventional malonates, the catalyst loading could be reduced to 0.1 mol % without the erosion of enantioselectivity (up to 99 % ee). Furthermore, by the use of a DTM, even some highly challenging primary alkyl α-amidosulfones were smoothly converted into the desired adducts with excellent enantioselectivity (up to 97 % ee), whereas the use of a malonate or monothiomalonate resulted in no reaction under identical conditions. The synthetic utility of the chiral Mannich adducts obtained from primary alkyl substrates was highlighted by the organocatalytic, coupling-reagent-free synthesis of the antidiabetic drug (-)-(R)-sitagliptin.
2. Experimental Details and Characterization of Compounds 2.1 Synthesis and Characterization of Hydrazine Catalyst 2,3-Diazobicyclo[2.2.1]heptane bis-trifluoroacetic acid 9: Prepared according to the reported procedure 1 for the preparation of 2,3-diaza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid di-tert butyl ester. This material (1.49 g, 5.0 mmol) was treated with trifluoroacetic acid (TFA) (1.9 mL, 25.0 mmol) in CH2Cl2, and the mixture was heated to reflux in an oil bath for 3 h. After full conversion of starting material as monitored by thin layer chromatograph (TLC), excess TFA was removed in vacuo. The crude material was triturated with Et2O to generate a white solid. After vacuum filtration, the solid was washed with Et2O (3 x 10 ml) and dried under vacuum to yield the title compound as a white powder in 65% yield (1.06 g, 3.25 mmol). 1 H NMR (500 MHz, DMSO-d6) δ 3.95 (s, 2H),
A broadly applicable biomimetic enantioselective decarboxylative catalytic aldol reaction of trifluoromethyl ketones with malonic acid half-thioesters (MAHTs) is described. Utilizing cinchona-based thioureas as highly efficient polyketide synthase-mimic catalysts, chiral tertiary aldols, β-trifluoromethyl-β-hydroxy thioesters, were obtained in up to 99% yield and 95% ee. Facile transformation of the thioester moiety of the aldol adducts showcases the synthetic utility of this biomimetic aldol protocol to deliver a range of chiral trifluoromethylated tertiary aldol pharmacophores.
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