Journal
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
Volume 2018, Issue 29, Pages 4006-4012Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/ejoc.201800517
Keywords
Biased agonists; Enantiopurity; PZM21; Medicinal chemistry; Opioids
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Funding
- National Institute on Drug Abuse, National Institutes of Health, U.S. [DA044775, DA040693]
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PZM21 (1) was recently reported as a biased agonist of the mu-opioid receptor (MOR) with improved antinociceptive effects and reduced side effects compared with traditional opioid-based analgesics. The original synthesis of PZM21 with the desired (S,S) configuration required the separation of a diastereomeric mixture in the final step by using chiral HPLC. A concise synthesis of 1 has now been developed in the enantiomeric pure form starting with commercially available l-alanine and proceeding via a chiral aziridine as a key intermediate. The final product was obtained as the (S,S) diastereomer in seven steps in 22.5% yield from l-alanine. This synthetic strategy could be readily applied to the development of PZM21 analogues at the thiophenyl position.
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