An enantioselective synthesis of INCB018424 via organocatalytic asymmetric aza-Michael addition of pyrazoles (16 or 20) to (E)-3cyclopentylacrylaldehyde (23) using diarylprolinol silyl ether as the catalyst was developed. Michael adducts (R)-24 and (R)-27 were isolated in good yield and high ee and were readily converted to INCB018424.
Janus kinases (JAKs) are crucial signal transducers for a variety of cytokines, growth factors, and interferons. [1][2][3] Inhibition of JAKs has advanced the basic and clinical studies of tyrosine kinase inhibitors as anticancer, anti-inflammation, and antiallograft rejection agents. It has been suggested that inhibition of JAKs can be beneficial for patients with myeloproliferative disorders 4 and inflammatory conditions such as rheumatoid arthritis. 5 INCB018424 was discovered as an inhibitor of JAKs and is currently under clinical development. 6 In view of its structural features, we envisioned that INCB018424 could be prepared from suitable chiral Ξ²-amino carbonyl compounds. The catalytic asymmetric aza-Michael reaction is a powerful method for the synthesis of these compounds. 7 Although the use of transition metal complexes with chiral ligands is well-documented, 8 the use of organocatalysts in asymmetric aza-Michael reactions offers a unique advantage by not requiring metal removal from drug substance in large scale production.