Enantioselective Synthesis of the Chiral Pyrrolidine Fragment of Upadacitinib via Chiral Auxiliary Directed Diastereoselective 1,3-Dipolar Cycloaddition

An efficient and elegant enantioselective synthesis of the key chiral pyrrolidine fragment of Upadacitinib (ABT-494) has been described. Oppolzer’s chiral sultam-directed asymmetric 1,3-dipolar cycloaddition was employed as a convenient tool to obtain the desired level of concomitant diastereoselect...

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Bibliographic Details
Published inOrganic process research & development Vol. 26; no. 6; pp. 1794 - 1802
Main Authors Sampath, Magesh, Jayaraman, Sembian Ruso, Eda, Vishnuvardhan Reddy, Potham, Rajendar, Budhdev, Rajeev Rehani, Sen, Saikat, Bandichhor, Rakeshwar, Oruganti, Srinivas
Format Journal Article
LanguageEnglish
Published American Chemical Society 17.06.2022
Subjects
enantioselectivity
JAK inhibitor
Upadacitinib
chiral auxiliary
1,3-dipolar cycloaddition
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Summary:An efficient and elegant enantioselective synthesis of the key chiral pyrrolidine fragment of Upadacitinib (ABT-494) has been described. Oppolzer’s chiral sultam-directed asymmetric 1,3-dipolar cycloaddition was employed as a convenient tool to obtain the desired level of concomitant diastereoselectivity and enantioselectivity in the construction of the 3,4-syn substituted pyrrolidine moiety. The synthesis process was demonstrated as a proof of study on a lab scale and was refined during scale-up to allow for easy disengagement of the chiral auxiliary and its subsequent reuse.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.1c00454