Ring-Closing Metathesis Approaches towards the Total Synthesis of Rhizoxins

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.

Construction of the Bicyclic Carbon Framework of Euphosalicin

“…Accordingly, the necessary moiety was installed by treating the aldehyde 64 with the modified trifluoroborate salt 74 (see Supporting Information) to give the compound 75 in 56% yield (Scheme ). Regrettably, the efforts only resulted in the cleavage of the tether and no macrocyclization occurred …”

Steglich esterification: A versatile synthetic approach toward the synthesis of natural products, their analogues/derivatives

“…Due to their biological significance, the Steglich esterification reaction has been extremely advantageous in synthesizing natural products [ [13] , [14] , [15] ]. The derivatives and analogues of natural products have also been synthesized via Steglich esterification, possessing striking medicinal properties i.e., anticancerous, antimicrobial, antiviral and antiinflammatory etc.…”

Synthesis of Bioactive Macrocycles Involving Ring-Closing Metathesis Strategy

“…4 In addition, several other macrocycles reported in the literature are the building blocks of distinguished natural products with significant pharmacological properties like antibiotic, 5 antiviral, 6 immunosuppressing, 7 and more. [8][9][10][11][12][13][14][15] Owing to the broad spectrum of biological activities, several routes have been developed for the synthesis of various macrocycles on a large scale. Quite a few of them include the Dieckmann condensation, 16 Stille coupling, 17 radical reactions, 18 semipinacol rearrangement, 19 homologation of cyclic ketones with diazo compounds, 20 and ring-closing metathesis (RCM) reactions.…”