Enabling, Decagram-Scale Synthesis of Macrocyclic MCL‑1 Inhibitor ABBV-467

ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to a phase I clinical trial for the treatment of multiple myeloma. Due to its large size and structural complexity, ABBV-467 is a challenging synthetic target. Herein, we describe the synthesis of ABBV-467 on a decagram scal...

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Bibliographic Details
Published in:	Journal of organic chemistry 2023-11, Vol.88 (22), p.15562-15568
Main Authors:	Brady, Patrick B., Sorensen, Bryan K., Risi, Roberto M., Curtin, Michael L., Mantei, Robert A., Florjancic, Alan S., Mastracchio, Anthony, Ji, Cheng, Kunzer, Aaron R., Lai, Chunqiu, Storer, Gregory E., Chan, Vincent S., Henry, Rodger F., Souers, Andrew J., Michaelides, Michael R., Judd, Andrew S., Hansen, T. Matthew
Format:	Article
Language:	eng
Subjects:	Antineoplastic Agents - pharmacology Hydrogenation Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors
Online Access:	Get full text
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Summary:	ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to a phase I clinical trial for the treatment of multiple myeloma. Due to its large size and structural complexity, ABBV-467 is a challenging synthetic target. Herein, we describe the synthesis of ABBV-467 on a decagram scale, which enabled preclinical characterization. The strategy is convergent and stereoselective, featuring a hindered biaryl cross coupling, enantioselective hydrogenation, and conformationally preorganized macrocyclization by C–O bond formation as key steps.
ISSN:	0022-3263 1520-6904