Direct organocatalytic asymmetric Michael reaction of fluorine hemiaminal-type nucleophile to 4-nitro-5-styrylisoxazoles

Abstract

Herein, we report a chiral bifunctional thiourea catalyzed asymmetric Michael addition reaction between 2-(trifluoromethyl)oxazol-5(2H)-one as a direct C-2-position nucleophile to 4-nitro-5-styrylisoxazoles for the first time.

Asymmetric Phase Transfer Catalysed Michael Addition of γ-Butenolide and N-Boc-Pyrrolidone to 4-Nitro-5-styrylisoxazoles

“…Diastereoisomers syn-9a-f were obtained in good isolated yields and good enantioselectivity, up to 74% ee. The data collated, alongside a previously reported 1 H NMR titration experiment of Cinchona-based quaternary ammonium salts and 4-nitroisoxazoles [48], allowed discussing a stereochemical model which is herein presented (Scheme 3) to justify the observed enantioselectivity. We have demonstrated that a solution of catalysts such as 15 and 4-nitroisoxazoles 1a establishes a tight complex via H-bonding of the ammonium N + C-H and the nitro group.…”

“…Compounds 1 are stable solids and reacted in Michael reactions as an acceptor. A special feature of compounds 1 is the presence of two electrophilic centres that can be independently reacted [29,30], with the exocyclic "soft" one that found extensive application in 1,6-conjugate enantioselective additions particularly under organocatalytic conditions [44][45][46][47][48][49][50][51][52][53]. Compounds 1 were also used in a large-scale industrial context, for example in the preparation of active pharmaceutical ingredients (APIs) (R)-Baclophen [54] and (S)-Pregabalin [55].…”

Synthesis of Nirmatrelvir: Development of an Efficient, Scalable Process to Generate the Western Fragment

“…The generation of oxazolone 20 has been described in the literature via approaches that are similar to those described here and also by the treatment of tert -leucine with TFAA. The formation of 20 was confirmed under each of these conditions by nuclear magnetic resonance analysis. − While inconsequential for the outcome of the reaction, the stereochemistry of the carbon bearing the trifluoromethyl group remains unclear in the mechanism proposed.…”

Organocatalytic Asymmetric Tandem Cyclization/Michael Addition via Oxazol-5(2H)-One Formation: Access to Perfluoroalkyl-Containing N,O-Acetal Derivatives

“…Among the known optical pure compounds containing trifluoromethyl group at the stereogenic carbon center, a number of important drug compounds, including a non-nucleoside inhibitor of HIV-1 (efavirenz), a selective inhibitor of cathepsin K (odanacatib), and an oral small molecule glycine transporter-1 inhibitor (bitopertin), have high pharmaceutical values (Scheme ). In addition to the strategy of direct trifluoromethylation reagents, the strategy of using substrates containing trifluoromethyl group to participate in asymmetric reactions and construct chiral trifluoromethyl-containing compounds has received increasing attention …”