Asymmetric Phase-Transfer Catalytic aza-Michael Addition to Cyclic Enone: Highly Enantioselective and Diastereoselective Synthesis of Cyclic 1,3-Aminoalcohols

Abstract

The highly enantioselective aza-Michael reaction of tert-butyl β-naphthyl­methoxy­carbamate to cyclic enones has been accomplished by using a new cinchona alkaloid derived C(9)-urea ammonium catalyst under phase-transfer catalysis conditions with up to 98% ee at 0 °C. The resulting aza-Michael adducts can be converted to versatile intermediates by selective deprotection and the cyclic 1,3-aminoalcohols by diastereoselective reduction with up to 32:1, which have been widely used as important pharmacophores in pharmaceutical development.

Enantioselective Synthesis of (R)-Sitagliptin via Phase-Transfer Catalytic aza-Michael Addition

“…8d The hydrogenolysis of 14, utilizing Raney-Ni under atmospheric H 2 , 15 A plausible mechanism for the aza-Michael addition is depicted in Figure 2 based on insights from density functional theory (DFT) calculations. 16 Initially, the carbamate anion (10) forms an ionic complex with the quaternary ammonium cation or hydrogen bonding with the α−C−H of the ammonium cation of catalyst 9. Two notable π−π stacking interactions occur: one between the two phenyl groups of Scheme 3.…”

“…Procedure for the Preparation of Phase-Transfer Catalyst (10). Under an argon atmosphere, urea 10 (2 g, 3.46 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (17 mL) of a round-bottom flask (100 mL); then, 2,4-bis-(trifluoromethyl)benzyl bromide (778 μL, 4.15 mmol, 1.2 equiv) was added. The mixture was stirred at 60 °C for 24 h. After the reaction was finished, the mixture was concentrated under reduced pressure.…”

Weak Nucleophiles in the Aza‐Michael Reaction

“…The use a new Cinchona alkaloid derived C(9)-urea ammonium catalyst under phase-transfer catalysis conditions allows the preparation of chiral aza-Michael adducts 44 (cyclic β-aminoketones, βaminolactones and β-aminolactames) in high yields and enantioselectivity (up to 98% ee). [78] The conjugate nucleophilic addition of phthalimide and saccharin to α,β-unsaturated carbonyl compounds is significant because it provides the direct and short way to protected β-amino ketones and β-amino acid derivatives. The first communication on the successful aza-Michael addition of these imides to enals seems to be published in 2007.…”

A One-Pot Cascade Strategy toward Organocatalytic Enantioselective Construction of Fused Benzimidazoles

“…Notwithstanding these remarkable findings, to the best of our knowledge, the synthesis of polycyclic benzimidazole in a sequential stereoselective cascade manner under bifunctional organocatalytic conditions poses a formidable challenge and has never been documented. The demand for proficient organocatalytic synthesis of varied molecular architectures aided by the aza-Michael addition reaction is consistently rising. , In our ongoing efforts to leverage asymmetric Michael addition processes involving chiral organocatalysts, and drawing inspiration from our prior work, we hypothesized a one-pot odyssey toward the synthesis of polycyclic benzimidazoles employing o -diaminobenzene instead of TsNH 2 (Scheme C). We envision that a chiral cinchona-alkaloid-based bifunctional squaramide catalyst could be suitable for such a cascade reaction, which would yield fused chiral tricyclic benzimidazoles through on-site dihydrobenzimidazole formation, aza-Michael addition followed by oxidation reaction.…”

“…Our efforts to delineate the likely mechanism of this cascade reaction through control reaction, NMR studies, and mass spectrometric analysis have been fruitful (see the SI for more details). Based on mechanistic investigations, prior research, , and insights from chiral squaramide-catalyzed aza-Michael addition reactions, , the proposed transition state depicted in Scheme provides clarity on the observed absolute stereochemical outcomes. NiCl 2 (PPh 3 ) 2 acts as a Lewis acid, enhancing the enantioselectivity of the reaction from 92:8 to 95:5 (Table , entries 13 and 17).…”