A synthetic entry to pladienolide B and FD-895

Abstract

Presented within are syntheses of the pladienolide B and FD-895 side-chains, as well as models of the essential ring-closing metathesis and Stille coupling that will be used to complete the total synthesis of both products. Several analogs of the pladienolide B side-chain were also prepared in order to evaluate the scope of the methodology and to create a library of structures that could be used for stereochemical and SAR analyses.The pladienolides (1a-1g) are a set of highly bioactive macrocyclic polyketides isolated from an Okinawan strain of Streptomyces platensis ( Figure 1). 1 Previously, FD-895 (1h) was reported in 1994 from an isolate of Streptomyces hygroscopicus. 2 This family of macrolides (1a-1h) displays potent anti-proliferative and tumor suppressive activity when assayed in both cell culture and xenograft models. 2a,c Several members of the family, including pladienolide B (1b), inhibited tumor cell growth at low nanomolar concentrations. Subsequent cell cycle studies indicate that 1b blocks cell growth in both the G1 and the G2/M phase, suggesting a unique mode of action. In addition, pladienolide B (1b) has been shown to deliver potent tumor regression and inhibition of mouse xenografts.At the beginning of our studies, only the two dimensional structures of 1a-1h were known. This combined with lack of access to the compounds themselves or their producer strains meant that we would have to determine the stereochemistry de novo. 4 Given recent advances in NMR techniques and the use of libraries to elucidate the three dimensional configuration of natural products, 5 we felt that this study would provide an ideal platform to use chemical synthesis in concert with more traditional methods to determine the stereochemistry of these macrolides. 6 Moreover, the required general approaches to the stereochemistry of 1b and 1h are synthetic strategies that allow access to many analogs for future research on these promising lead compounds. In parallel, the methods developed in this research serve as a prelude to the total synthesis of the pladienolides and FD-895. 7Our general retrosynthetic analysis (Scheme 1) of the family began by visualizing a convergent union at the diene by a Stille coupling of side-chain 2 to core 3. Stannane 2 was ideal because conditions for tin insertion do not cause side reactions with the epoxide. 8 Stannane 2 could then be derived from alcohol 4 that would result from epoxidation of olefin 5 using a suitable method. 9 Olefin 5 would follow naturally from a Julia-Kociensky reaction of aldehyde 6 and sulfone 7. 10 Macrolide 3 would then be derived from a ring-closing metathesis of 8. In turn, 8 could be prepared by coupling of alcohol 9 and carboxylic acid 10. This two step ester formation -RCM has precedent in our laboratory. 11 As this article was being prepared, Kotake has indeed shown that this disconnection can be used to assemble pladienolide B (1b) and D (1d). 3With a synthetic plan in hand, we turned to evaluate the complexity of the proposed synthetic endeavor. Wit...

Design, synthesis and initial biological evaluation of a novel pladienolide analog scaffold

“…To date, only three approaches have been reported for the synthesis of these unique macrolides, 3, 15, 16 including a total synthesis of pladienolide B and D. 3 However, access to multi-gram quantities of totally synthetic pladienolides for in vivo studies remains a significant challenge, due to the synthetic complexity inherent to this class of compounds. Fortunately our pharmacophore design has allowed us to target simplified analogs of pladienolides that possess the potential to be potent and more drug-like than either FR901464 or pladienolide.…”

Twelve‐membered macrolactones: privileged scaffolds for the development of new therapeutics

“…Another prominent example in this field is pladienolide B ( 150 ), closely related to FD‐895. Pladienolide B is an extremely interesting example of how the discovery of a bioactive natural product can shed light on an entirely new disease target.…”

“…In this case, discovery and investigation of pladienolide B led to the spliceosome being recognized as a valid target for drug development . Several syntheses and analog development programs have been aimed at pladienolide B, as has been reviewed in depth by Maier . Notably, Kotake's 2007 seminal synthesis, as well as a partial synthesis from Burkart in the same year, of pladienolide B took advantage of RCM to generate the pladienolide macrolactone from a sterically hindered substrate, thus representing the first example of such a transformation in the synthesis of 12‐membered macrolides.…”

Enantioselective Total Synthesis of Pladienolide B: A Potent Spliceosome Inhibitor

“…To date, Kotake and co-workers reported the first total synthesis of the most active compounds, pladienolide B and D. 5 Skaanderup et al published a synthetic pathway to the macrocyclic core of the enantiomer of pladienolide B, while Burkart and co-workers have reported their efforts on constructing and modifying the side chain. 6 Recently, both Maier 7a and Webb 7b have reported progress in the development of pladienolide based analogs albeit with reduced biological activity. Our interest in pladienolide B arose from its novel mechanism of action and its unique structural features.…”

“…Our asymmetric synthesis of C 1 –C 8 segment is quite efficient and provides convenient access to other possible stereoisomers. Previous syntheses of this segment 5,6a,7a relied on terpene (nerol and R -linalool) modification strategies.…”