Griseofulvin, synthesis

Scheme 16.21 Relay of stereochemical information in griseofulvin synthesis.

It iaterferes with the synthesis of the hyphal walls, the biosynthesis of nucleic acids, and the synthesis of chitin. The iateraction with microtubules has also been described. The sensitivity of a cell seems to depend particularly on the abiUty to form griseofulvin—nucleic acid complexes. Further information concerning griseofulvin is available (21). 

Griseofulvin was first isolated in 1938 by Oxford (10) et. al., (1939) its total synthesis was accomplished in 1960 and following years in several laboratories (Brossi et al., 1960 (11) Grove, 1963 (12) Mutant strains of P. patulum are used for the commercial production of the antibiotic by fermentation (9). 

Fig. 4.12. Synthesis of non-racemic griseofulvin based on intramolecular oxonium ylide formation [1262],...

Ethyl 3(2H)-benzofuranone-2-carboxylate (95, Scheme 24) undergoes Michael addition with but-3-en-2-one in the presence of sodium methoxide. The resultant adduct 96 on boiling with molar aqueous sodium hydroxide yields the tetrahydro-2-dibenzofuranone 97. ° Similar reactions were encountered during the synthesis of griseofulvin. ... 

Numerous examples of natural products with the benzo[6]furan nucleus have been identified. It occurs under many guises dibenzofurans, /3-coumaranones, a-pyranobenzo[6]furans, y-pyranobenzo[6]furans, and the spiro-2,3-dihydrobenzofurans such as griseofulvin. Many of the natural benzo[6]furans have physiological, pharmacological and toxic properties and as a result an active interest exists in their chemical synthesis. 

Griseofulvin [126-07-8] (54) contains the phloroglucinol nucleus. It is an important oral antifungal agent in humans and animals, elaborated by certain strains of Penicillium. One synthesis of griseofulvin is based on the appropriately substituted phloroglucinol (196). Uvaretin [584494)6-2] (55), which is extracted from Uvaria acuminata, inhibits lymphocytic leukemia (200). 

Grafting rates up to 40% could be reached through the reaction at full conversion of the corresponding amounts of P-cyclodextrin and the PMHS homopolymer. This was achieved according to the synthesis method described in the Materials and methods section. The PMHS-CD(20), PMHS-CD(30) and PMHS-CD(40) derivatives were prepared and the residual Si-H groups were capped with n-pentene. They were evaluated for their emulsification and loading with griseofulvin. 

Danishefsky and Walker have employed the cycloaddition of 1 with 6 in a new synthesis of the antifungal agent griseofulvin (8). 

Synthesis of (+)-griseofulvin (3).5 The key step in a recent asymmetric synthesis of this antifungal reagent is the decomposition of the diazo ketone 1 with rhodium(ll) pivalate to provide 2 in 62% yield as the only isolablc product. 

Chemical synthesis of griseofulvin is economically not feasible, since a number of intermediate steps are involved in the final product formation. 

The synthesis of griseofulvin by the Merck group represents the second approach to the antifungal antibiotic [6]. 

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