{"id":370,"date":"2016-04-21T21:07:20","date_gmt":"2016-04-22T02:07:20","guid":{"rendered":"http:\/\/www.bocsci.com\/blog\/?p=370"},"modified":"2016-06-22T02:38:32","modified_gmt":"2016-06-22T07:38:32","slug":"enantioselective-synthesis-of-janus-kinase-inhibitor-incb018424-via-an-organocatalytic-aza-michael-reaction","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/enantioselective-synthesis-of-janus-kinase-inhibitor-incb018424-via-an-organocatalytic-aza-michael-reaction\/","title":{"rendered":"Enantioselective Synthesis of Janus Kinase Inhibitor INCB018424 via an Organocatalytic Aza-Michael Reaction"},"content":{"rendered":"

Janus kinases (JAKs) are crucial signal transducers for a variety of cytokines, growth factors, and interferons. Inhibition of JAKs has advanced the basic and clinical studies of tyrosine kinase inhibitors as anticancer, anti-in\ufb02ammation, and antiallograft rejection agents. It has been suggested that inhibition of JAKs can be bene\ufb01cial for patients with myeloproliferative disorders and in\ufb02ammatory conditions such as rheumatoid arthritis. INCB018424<\/a> was discovered as an inhibitor of JAKs and is currently under clinical development.<\/p>\n

In view of its structural features, we envisioned that INCB018424 could be prepared from suitable chiral \u03b2-amino carbonyl compounds. The catalytic asymmetric aza-Michael reaction is a powerful method for the synthesis of these compounds. Although the use of transition metal complexes with chiral ligands is well-documented, the use of organo-catalysts in asymmetric aza-Michael reactions offers a unique advantage by not requiring metal removal from drug substance in large scale production.<\/p>\n

In organocatalytic aza-Michael reactions, the acceptors are activated either by hydrogen bonding of the organocatalysts to the carbonyl group of the acceptors or by imminium formation between \u03b1,\u03b2-unsaturated aldehydes and the organocatalysts. J\u00f8rgensen reported the successful use of proline-derived organocatalysts in the addition of nitrogen-containing heterocycles such as triazoles and tetrazoles to \u03b1,\u03b2-unsaturated aldehydes. We envisioned that the extension of J\u00f8rgensen\u2019s chemistry to the aza-Michael addition of substituted pyrazoles<\/a> to aldehyde using suitable organocatalysts would provide an ef\ufb01cient asymmetric synthetic route to INCB018424.<\/p>\n

The synthesis of Michael donor<\/a> via a Suzuki coupling of protected pyrazole pinacol borate and the protected chlorodeazapurine. 4-Iodo-1H- pyrazole or 4-bromo-1H-pyrazole was treated with ethyl vinyl ether to give the protected pyrazoles respectively. Halogen-magnesium exchange of the protected pyrazoles followed by addition of borate afforded the pyrazole pinacol borate in good yield. Treatment of compound 5 with NaH and 2-(trimethylsilyl)ethoxyethyl chloride (SEM-Cl) afforded the SEM-protected in 89% yield. Suzuki coupling of the SEM-protected product with pyrazole pinacol borate furnished the intermediate which was hydrolyzed in situ to give the key Michael donor in 82% yield for two steps.<\/p>\n

On the basis of the mechanism proposed by J\u00f8rgenson, it was conceivable that the enantioselectivity could be improved by the modulation of steric hindrance of the organocatalyst. Catalyst (R)-2 was purchased from a commercial source and catalysts (R)-3 and (R)-4 were synthesized according to literature procedures (see experimental details in the Supporting Information).<\/p>\n

 <\/p>\n

 <\/p>\n

 <\/p>\n

References\uff1a<\/p>\n

Qiyan Lin,* David Meloni, Org. Lett., Vol. 11, No. 9, 2009<\/p>\n","protected":false},"excerpt":{"rendered":"

Janus kinases (JAKs) are crucial signal transducers for a variety of cytokines, growth factors, and interferons. Inhibition of JAKs has advanced the basic and clinical studies of tyrosine kinase inhibitors […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[181],"tags":[209],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/370"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=370"}],"version-history":[{"count":3,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/370\/revisions"}],"predecessor-version":[{"id":448,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/370\/revisions\/448"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=370"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=370"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=370"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}