Synthesis of the camptothecin core

The post of today deals with the synthesis of the camptothecin core.

This synthesis described by Fortunak in 1996, has an intramolecular Diels-Alder [4+2] cycloaddition as key step between an unactivated alkyne and a imidate generated in situ by action of Me3OBF4 on a N-arylamide.

Tetrahedron Letters, Vol. 37, No. 32, pp. 5679-5682, 1996

This synthesis has been recently improved by Yao et al. using a mixture of Ph3PO and Tf2O (2:1) instead of Me3OBF4, by this methodology a wide range of tetracyclic "camptothecin-like" molecules has been synthesized.

Organic Letters, ASAP, April 14, 2007

Synthesis of methyl 5-methylpicolinate or methyl 5-methylpyridine-2-carboxylate

The post of today concerns a very beautiful synthesis of the pyridine ring, and more precisely of methyl pyridine-2-carboxylate. This synthesis has been described by Danheiser et al. and with a "imination" of the Meldrum's acid with sodium nitrite (NaNO2) followed by tosylation (TosCl). The tosylimine obtained has been engaged in aluminium catalyzed (Et2AlCl) Diels-Alder reaction with isoprene as diene (of course other dienes can be used, see reference), the bicyclic spiro compound has been treated by sodium methylate, N-chlorosuccinimide in a THF/MeOH mixture to give the desired methyl 5-methylpyridinecarboxylate.

Ref: Organic Syntheses, Vol. 80, p.133 (2003).