Formal asymmetric synthesis of (+)-tofacitinib

Tofacitinib is an efficient and selective Janus kinase 3 (JAK3) inhibitor, and is used as an immunosuppressant drug for the treatment of rheumatoid arthritis and transplant patients. Herein we report a concise formal asymmetric synthesis of tofacitinib from homochiral 1,3-dioxolanone 10b, which was elaborated through a highly stereoselective Michael addition followed by solvent-free removal of the chiral auxiliary and ring cyclization to furnish chiral imide 8. The preparation of tofacitinib’s precursor 16 could be obtained after reduction of 8 followed by sequential oxidation, reductive amination and S_NAr reactions.     

1,2-diphenylethylenediamine linked chiral Ti(IV) complex--a new entry to the highly enantioselective silylcyanation of aliphatic and aromatic aldehydes

Highly enantioselective silylcyanation of aliphatic and aromatic aldehydes was achieved by using a 1,2-diphenylethylenediamine linked chiral Ti(IV) complex as the catalyst.     

Simultaneous quantitation of urinary cotinine and acrylonitrile-derived mercapturic acids with ultraperformance liquid chromatography–tandem mass spectrometry

Acrylonitrile (AN), a widely used industrial chemical also found in tobacco smoke, has been classified as a possible human carcinogen (group 2B) by the International Agency for Research on Cancer. AN can be detoxified by glutathione S-transferase (GST) to form glutathione (GSH) conjugates in vivo. It can be metabolically activated by cytochrome P450 2E1 to form 2-cyanoethylene oxide, which can also be detoxified by GST to generate GSH conjugates. The GSH conjugates can be further metabolized to mercapturic acids (MAs), namely, N-acetyl-S-(2-cyanoethyl)cysteine (CEMA), N-acetyl-S-(2-hydroxyethyl)cysteine (HEMA), and N-acetyl-S-(1-cyano-2-hydroxyethyl)cysteine (CHEMA). This study developed an ultraperformance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method to quantitatively profile the major AN urinary metabolites (CEMA, HEMA, and CHEMA) to assess AN exposure, as well as analyze urinary cotinine (COT) as an indicator for tobacco smoke exposure. The limits of quantitation were 0.1, 0.1, 1.0, and 0.05 μg/L for HEMA, CEMA, CHEMA, and COT, respectively. This method was applied to analyze the three AN-derived MAs in 36 volunteers with no prior occupational AN exposure. Data analysis showed significant correlations between the level of COT and the levels of these MAs, suggesting them as biomarkers for exposure to low levels of AN. The results demonstrate that a highly specific and sensitive UPLC-MS/MS method has been successfully developed to quantitatively profile the major urinary metabolites of AN in humans to assess low AN exposure.     

Enantioselective Addition of Dialkylzincs to Aldehydes Catalyzed by (−)‐MITH

An effective catalytic system that imparts high enantioselectivity has been disclosed for the synthesis of optically active alcohols, which may undergo further chemical transformations. The enantioselective alkylation of aldehydes with dialkylzincs to afford the corresponding optically active alcohols with excellent enantioselectvities has been achieved in the presence of 0.1–0.5 mol % of the camphor‐derived chiral ligand (?)‐2‐exo‐morpholinoisobornane‐10‐thiol (MITH) ( 1 ) at room temperature or at 0 °C.     

An Efficient and Neutral Catalyst for the Ketalization of Carbonyl Compounds

An efficient ketalization of aldehydes, ketones, and α,β-unsaturated aldehydes using thiazolium salt 1 as a neutral catalyst is described.