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Synfacts 2007(4): 0343-0343  
DOI: 10.1055/s-2007-968289
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of N1999A2

Contributor(s):Philip Kocienski, Thomas Snaddon
N. Ji, H. O’Dowd, B. M. Rosen, A. G. Myers*
Harvard University, Cambridge, USA
Enantioselective Synthesis of N1999A2
J. Am. Chem. Soc.  2006,  128:  14825-14827  
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Further Information

Publication History

Publication Date:
23 March 2007 (online)

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Key words

hydrozirconation - Sonogashira coupling - alkyne-alkyne coupling - carbolithiation

Significance

N1999A2 is an enediyne antibiotic that damages DNA by radical means. Noteworthy in this synthesis is the deft use of mild organometallic processes and a carefully wrought protecting group strategy to accomplish construction of the very sensitive target.

Review

Chemistry and Biology of the Enediyne Anticancer Antibiotics K. C. Nicolaou, W.-M. Dai Angew. Chem. Int. Ed. 1991, 30, 1387-1530.

Comment

Treatment of bisalkyne F with Cu(OAc)2 gave G via intramolecular alkyne-alkyne coupling. Addition of LHMDS followed by t-BuLi gave H via lithium-bromine exchange followed by intramolecular carbolithiation. This step suffered from poor scalability and all subsequent intermediates (including K) were unstable in neat form. Despite such adversity, N1999A2 was accessed in six further steps.

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