Asymmetric Catalytic Access to Piperazin-2-ones and Morpholin-2-ones in a One-Pot Approach: Rapid Synthesis of an Intermediate to Aprepitant

Abstract

General experimental procedures, characterization data, copies of NMR spectra, and HPLC traces for compounds 3, 4, and 7 (PDF) FAIR data, including the primary NMR FID files, for compounds 3a−j, 4a−h, 7 (ZIP)

One‐Pot Catalytic Synthesis of Optically Active Drug (S)‐Clopidogrel

“…We initially focused on the optimization of the asymmetric epoxidation on alkene 3 a using multifunctionalised thiourea catalyst 4, synthesized by our group from quinidine and (R,R)di(1-naphthyl) substituted ethylendiamine (Table 1). [15] Catalyst 4 was employed, given the ability showed to provide the (R,R)configured epoxide with good enantioselectivity, [13,14] necessary to obtain the (S)-carboxylic acid derivative after the DROE step (Scheme 1e).…”

“…Next, we embarked on the optimization of the DROE step. In our previous work, [12,13] the bis‐nucleophile used, embedded in the same reagent, was readily set up to capture the α‐keto sulfone intermediate I intramolecularly, after epoxide ring‐opening in the DROC step (Table 2). Conversely, in the DROE step, after the selective ring‐opening of the epoxide by the secondary amine, the following displacement of the phenylsulfinic acid from the α‐keto sulfone intermediate I would occur by amine or methanol, giving rise to a mixture of ester and amide products.…”

“…General Information: 1 H NMR and 13 C NMR spectra were recorded on Bruker Avance III HD 600, Bruker Avance-400 or Bruker Avance-300 spectrometer in CDCl 3 . Chemical shifts for protons are reported using residual solvent protons (δ = 7.26 ppm for CDCl 3 ) as internal standard.…”

“…Chemical shifts for protons are reported using residual solvent protons (δ = 7.26 ppm for CDCl 3 ) as internal standard. Carbon spectra were referenced to the shift of the 13 C signal of CDCl 3 (δ = 77.0 ppm). Optical rotation of compounds was performed on a Jasco P-2000 digital polarimeter using WI (Tungsten-Halogen) lamp (λ = 589 nm).…”

“…The protocol enables the preparation of the ( R )‐configured products. We recently disclosed a multifunctionalised quinidine‐derived thiourea, useful to access the opposite enantiomer of the carboxylic acid derivatives with good enantioselectivity [13] . Consequently, we envisaged the possibility to expand the applicability of the one‐pot methodology to prepare enantioenriched ( S )‐clopidogrel (Scheme 1e).…”