Catalyst-Controlled Asymmetric Synthesis of Fostriecin and 8-epi-Fostriecin

Abstract

Catalytic asymmetric synthesis of the natural antibiotic fostriecin (CI-920) and its analogue 8-epi-fostriecin and evaluation of their biological activity are described. We used four catalytic asymmetric reactions to construct all of the chiral centers of fostriecin and 8-epi-fostriecin; cyanosilylation of a ketone, Yamamoto allylation, direct aldol reaction, and Noyori reduction, two of which were developed by our group. Catalytic enantioselective cyanosilylation of ketone 13 produced the chiral tetrasubstituted carbon at C-8. Both enantiomers of the product cyanohydrin were obtained with high enantioselectivity by switching the center metal of the catalyst from titanium to gadolinium. Yamamoto allylation constructed the C-5 chiral carbon in the alpha,beta-unsaturated lactone moiety. A direct catalytic asymmetric aldol reaction of an alkynyl ketone using LLB catalyst constructed the chirality at C-9 with the introduction of a synthetically versatile alkyne moiety, which was later converted to cis-vinyl iodide, the substrate for the subsequent Stille coupling for the triene synthesis. Noyori reduction produced the secondary alcohol at C-11 from the acetylene ketone 6 with excellent selectivity. Importantly, all the stereocenters were constructed under catalyst control in this synthesis. This strategy should be useful for rapid synthesis of stereoisomers of fostriecin.

Total Synthesis and Evaluation of Cytostatin, Its C10−C11 Diastereomers, and Additional Key Analogues: Impact on PP2A Inhibition

“…Cross-assay comparisons are particularly interesting since IC 50 values for fostriecin inhibition of PP2A are not only dependent on the assay enzyme concentration, but also the phosphorylated substrate used in the assay. 7,9 In preceding efforts related to the fostriecin family of natural products, we determined the stereochemical configuration of fostriecin (2) and reported its first total synthesis. 10 Subsequent to this work, a number of additional synthetic efforts have been described including eight total or formal syntheses of 2, each highlighting the utility of alternative asymmetric synthetic methods for the construction of the 4 chiral centers of 2 in a stereoselective manner.…”

Structure-Activity Relationship Studies of Fostriecin, Cytostatin, and Key Analogs, with PP1, PP2A, PP5, and (β12–β13)-Chimeras (PP1/PP2A and PP5/PP2A), Provide Further Insight into the Inhibitory Actions of Fostriecin Family Inhibitors

“…Following the first total synthesis of fostriecin (Boger et al, 2001), at least nine total or formal syntheses have been reported (Chavez and Jacobsen, 2001;Esumi et al, 2002;Reddy and Falck, 2002;Miyashita et al, 2003;Maki et al, 2005;Trost et al, 2005). The total synthesis of cytostatin (Bialy and Waldmann, 2004;Lawhorn et al, 2006;Jung et al, 2008) and cytostatin analogs (Lawhorn et al, 2006;Jung et al, 2008) have also been reported.…”

Metal-catalyzed asymmetric aldol reactions

“…The heteropolymetallic catalyst LLB-KOH (70) was used in order to shorten the reaction times by enhancing the catalytic activity of LLB complex, giving aldol adducts 69a-d in modest to good enantioselectivities (Scheme 11). 30 Shibasaki and co-workers 31 reported the use of (S)-LLB (74) catalyst in the formal total synthesis of fostriecin (75) and 8-epi-fostriecin (8-epi-75). The best reaction condition to the system of interest for fostriecin (75) afforded the aldol adduct 73 in good yield using ketone 71 and aldehyde 72 and the two-center Lewis acid-Brønsted base catalyst (S)-LLB (74) (Scheme 12).…”