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Synfacts 2015; 11(7): 0681
DOI: 10.1055/s-0034-1380900
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of DZ-2384

Contributor(s):
Philip Kocienski
Ding H, DeRoy PL, Perreault C, Larivée A, Siddiqui A, Caldwell CG, Harran S, Harran PG * University of California, Los Angeles and Joyant Pharmaceuticals, Dallas, USA; Paraza Pharma, Montréal, Canada
Electrolytic Macrocyclizations: Scalable Synthesis of a Diazonamide-Based Drug Development Candidate.

Angew. Chem. Int. Ed. 2015;
54: 4818-4822
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Further Information

Publication History

Publication Date:
17 June 2015 (online)

 
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Key words

DZ-2384 - diazonamide A - macrocyclization - anodic oxidation

Significance

Diazonamide A, a metabolite of the ascidian Diazona angulata, displays potent in vitro activity against human colon cancer. DZ-2384 is a truncated analogue of diazonamide A that is 10- to 50-fold more efficacious than diazonamide A as an anti-mitotic agent in rodents. The synthesis of DZ-2384 proceeded in 13 total operations and 5.7% overall yield from l-tert-leucine.


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Comment

The key step of the synthesis depicted is a macrocyclization initiated by an anodic oxidation of A at a graphite surface. Anodic oxidation of 60 grams of A gave 21 grams of a mixture of B (major) and its epi-C10,C11 diastereoisomer C (minor, dr = 2.7:1), which was separated from unreacted A (11.0 g) by silica gel chromatography. Separation of the diastereoisomers was achieved after hydrogenolysis of the Cbz group.


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