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Synfacts 2020; 16(03): 0247
DOI: 10.1055/s-0039-1691691
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a Macrocyclic Mcl-1 Inhibitor

Contributor(s):
Philip Kocienski
Rescourio G. * et al. Amgen Research, Cambridge, USA
Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an α-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere.

J. Med. Chem. 2019;
63: 10258-10271
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Further Information

Publication History

Publication Date:
18 February 2020 (online)

 
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Key words

Mcl-1 inhibitor - ring-closing metathesis - macrocyclization - Reformatsky reaction - α-hydroxy phenylacetic acids

Significance

Overexpression of the antiapoptotic protein Mcl-1 benefits survival of some cancer cells. The target molecule R is an inhibitor of Mcl-1. A key step in the synthesis depicted is the macro­cyclization of diene J by ring-closing metathesis.


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Comment

The addition of Reformatsky reagent F to the keto group in E generated a mixture of dia­stereoisomers G (dr = 2:1) that was later separated by column chromatography to give the desired ­diastereoisomer K.


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