Abstract
Efforts are described towards the total synthesis of the bacterial macrolide rhizoxin F, which is a potent tubulin assembly and cancer cell growth inhibitor. A significant amount of work was expanded on the construction of the rhizoxin core macrocycle by ring-closing olefin metathesis (RCM) between C(9) and C(10), either directly or by using relay substrates, but in no case was ring-closure achieved. Macrocycle formation was possible by ring-closing alkyne metathesis (RCAM) at the C(9)/C(10) site. The requisite diyne was obtained from advanced intermediates that had been prepared as part of the synthesis of the RCM substrates. While the direct conversion of the triple bond formed in the ring-closing step into the C(9)-C(10) E double bond of the rhizoxin macrocycle proved to be elusive, the corresponding Z isomer was accessible with high selectivity by reductive decomplexation of the biscobalt hexacarbonyl complex of the triple bond with ethylpiperidinium hypophosphite. Radical-induced double bond isomerization, full elaboration of the C(15) side chain, and directed epoxidation of the C(11)-C(12) double bond completed the total synthesis of rhizoxin F.
Highlights
Rhizoxin (1) (Figure 1) is a 16-membered macrolide that was first isolated in 1984 from the plant pathogenic fungus Rhizopus chinensis by Iwasaki and co-workers [1] (for the elucidation of the absolute configuration of rhizoxin (1) by means of X-ray crystallography cf. [2])
We have reported the total synthesis of rhizoxin F (2) via ring-closing alkyne metathesis (RCAM) [20]; in this communication, we briefly touched upon our numerous futile attempts at ring-closing olefin metathesis (RCM)-based ring closure
One possible strategy for the synthesis of rhizoxin F (2) that would meet our predefined boundary conditions is outlined in Scheme 1
Summary
Rhizoxin (1) (Figure 1) is a 16-membered macrolide that was first isolated in 1984 from the plant pathogenic fungus Rhizopus chinensis by Iwasaki and co-workers [1] (for the elucidation of the absolute configuration of rhizoxin (1) by means of X-ray crystallography cf. [2]). (For example, the IC50 value of 1 against the mouse P388 leukemia cell line is 0.16 nM [10].) Rhizoxin (1) had been suggested to bind to the β-subunit of the α/β-tubulin heterodimer at the same site as maytansine, and this binding site was proposed to be distinct from either the vinblastine or the colchicine site [14,15] These hypotheses have recently been confirmed experimentally by means of X-ray crystallography on complexes of α/β-tubulin with rhizoxin F (2) and maytansine, respectively [8]. Our group has a long-standing interest in the chemistry, medicinal chemistry, and pharmacology of bioactive macrocyclic natural products In this context, we were interested to develop a new synthetic approach towards rhizoxins that would be based on ring-closing olefin metathesis (RCM), which, somewhat surprisingly, had not been investigated as part of any of the previous total syntheses of a rhizoxin variant. We disclose full details on these attempts and on the successful total synthesis of 2 based on macrocyclization by RCAM
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