Asymmetric Total Synthesis of Fostriecin

Fostriecin (20, CI-920) is a novel metabolite of Streptomyces pulveraceus that was first isolated in 1983 by a research group at Warner Lambert-Parke Davis.22 It displays antitumor activity against a broad range of cancerous cell lines in vitro. This activity is suggested to be intimately related to the potent and highly selective inhibitory activity against serine/threonine phosphatase PP2A.23 In fact, fostriecin is the most selective protein phosphatase inhibitor reported to date, and it 

Lewis acid-Lewis base two-center asymmetric catalyst (32 or 33) developed in our group.30 

We began our synthesis by finding the optimum reaction conditions for the catalytic asymmetric cyanosilylation of ketone 28 (Table 1). Based on previous studies,30 the titanium complex of a D-glucose derived ligand (catalyst 32 or 33) generally gives (/ )-ketone cyanohydrins, which is required for a synthesis of natural fostriecin. 

we employed the timed catalyst 33 containing a benzoyl group at the catechol moiety30b under high concentration ( 12 M to THF), and the product was obtained in synthetically acceptable reaction time, yield, and enantioselectivity (entry 6). The reaction was performed on a 50-g scale without any difficulty (entry 7). The chiral ligand was recovered in 95% yield after silica gel column chromatography, and could be used at least several times without any loss of catalyst activity. 

Our proposed transition state model for this catalytic enantioselective cyanosilylation of ketone is shown as 35.30a The titanium acts as a Lewis acid to activate the substrate ketone, while the phosphine oxide acts as a Lewis base to activate TMSCN. The intramolecular transfer of the activated cyanide to the activated ketone should give the ( )-cyanohydrin in high selectivity. The successful results described above clearly demonstrate the practicality of our asymmetric catalyst for cyanosilylation of ketones. 

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Fujii, K., Maki, K., Kanai, M., Shibasaki, M. Formal Catalytic Asymmetric Total Synthesis of Fostriecin. Org. Lett. 2003, 5, 733-736. 

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