Synthesis of Tetracyclic ABCD Ring Cores of Camptothecins

1,6-dihydro-6-oxo-2-pyridinecarbonitrile - intramolecular Diels-Alder reaction - camptothecins

Significance

<P>A concise synthetic sequence has been developed for the parent and substituted ABCD ring cores of the camptothecin family of alkaloids. This two-step synthesis starts by N-alkylation of the 2-pyridone 1 with 3-bromo-1-phenylpropyne (Curran’s protocol: D. P. Curran and co-workers Tetrahedron Lett. 1995, 36, 8917-8920) to give 2, followed by DBU-induced cyclization, presumably involving an intramolecular hetero-Diels-Alder reaction, to produce the target tetracyclics 3 in good overall yield. The scope and limitations of this method were not sufficiently investigated.</P>

Comment

<P>Considerable effort has been expended on the synthesis of the antitumor camptothecin alkaloids (see review below). In comparison with previous radical cyclization and other intramolecular Diels-Alder approaches involving multisteps from easily available starting materials (e.g., W. R. Bowman et al. J. Chem. Soc., Perkin Trans. 1, 2002, 58-68; J. M. D. Fortunak et al. Tetrahedron Lett. 1996, 37, 5679-5682), the new method establishes a short process for the formation of the parent and substituted ABCD ring cores of the campto­thecins with respectable yields in the cyclization step. This heteroannulation strategy may have wider application.</P>

Review

<P>W. Du Tetrahedron 2003, 59, 8649-8687.</P>