Fostriecin

Example 30 Bialy and Waldman in their synthesis of protein phosphates 2A inhibitor (4S, 5S, 6S, lOS, US, 12S) cytostatin have found that application of the fluorenylmethyl protecting group (Fm) allowed successful formation of the phosphate moiety [62]. Initial experiments with the methoxybenzyl group, successfully employed in the synthesis of fostriecin [63] failed. The 2-cyanoethyl protecting group was also not suitable because that one 2-cya-noethyl group could be removed without destroying the whole molecule (Examples 25 and 26). 

Trost and coworkers employed a magnesate reagent in the formal synthesis of fostriecin (Scheme 18). Stereoselective addition of the corresponding alkenylmagnesium to a-alkoxyketone proceeded smoothly in 75% yield with more than 20 1 diastereoselectivity. 

CATALYTIC ASYMMETRIC TOTAL SYNTHESIS OF (-)-STRYCHNINE AND FOSTRIECIN... 

The development of highly efficient asymmetric catalysts is one of the most intensively investigated research fields today.1 Catalytic asymmetric reactions are extremely powerful in terms of the practicality and atom economy.2 The power of asymmetric catalysis is rapidly growing, so as to be applicable to syntheses of natural products with complex structures. We call total syntheses using catalytic asymmetric reactions in key steps catalytic asymmetric total syntheses . In this chapter, we describe our recent success in catalytic asymmetric total syntheses of (-)-strychnine and fostriecin. Both of the total syntheses involve catalytic asymmetric carbon-carbon bond forming reactions using bifunctional catalysts developed in our group3 as key steps. 

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... 

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 describe herein our recent achievement of total syntheses of (-)-strychnine and fostriecin. The key stereocenters were constructed using catalytic asymmetric reactions developed in our group. Catalytic asymmetric reactions that can produce versatile chiral building blocks with high practicality should ensure further efficient total synthesis of complex molecules in future. 

A possible way to induce enantioselectivity in the aldol reaction is to empioy a chirai catalyst. M. Shibasaki and coworkers developed a bifunctional catalyst, (S)-LLB (L=lanthanum LB=lithium binaphthoxide), which could be successfully applied in direct catalytic asymmetric aldol reactions. An improved version of this catalyst derived from (S)-LLB by the addition of water and KOH was utilized in the formal total synthesis of fostriecin. ... 

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

M. Jeyaraman, S. Tanguy, RA. Fandrich, A. Lukas, E. Kardami, Ischemia-induced dephosphorylation of cardiomyocyte connexin-43 is reduced by okadaic acid calyculin A but not fostriecin, Mol Cell Biochem 242, 129-134 (2003). 

Other important natural products, such as crocacin D (46), 9,80 bafilomycin Ai (47), i 2 poly-cephalin C (48), 3 dictyostatin (49), 4 (+)-tubelactomidn A (50), fostriecin (51a) and 8-epi-fostriecin (51b),86 87 archazolid B (52), and apoptolidin (53) have been synthesized by using the alkenyl-alkenyl coupling are shown in Figure 5.4.1. 

Benzyldimethylsilylacetylene was prepared by the reaction of HC=CMgBr with the silyl chloride as part of a Fostriecin synthesis. 

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