Total Synthesis of Tiacumicin B: Implementing Hydrogen Bond Directed Acceptor Delivery for Highly Selective β‐Glycosylations

Abstract

A total synthesis of tiacumicin B, a natural macrolide whose remarkable antibiotic properties are used to treat severe intestinal infections, is reported. The strategy is in part based on the prior synthesis of the tiacumicin B aglycone, and on the decisive use of sulfoxides as anomeric leaving groups in hydrogen‐bond‐mediated aglycone delivery (HAD). This new HAD variant permitted highly β‐selective rhamnosylation and noviosylation. To increase convergence, the rhamnosylated C1–C3 fragment thus obtained was anchored to the C4–C19 aglycone fragment by adapting the Suzuki–Miyaura cross‐coupling used for the aglycone synthesis. Ring‐size‐selective macrolactonization provided a compound engaged directly in the noviolysation step with virtually total β selectivity. The final efficient removal of all the protecting groups provided synthetic tiacumicin B.

Chemistry and Biology of the Clinically Used Macrolactone Antibiotic Fidaxomicin

“…A further total synthesis of another member of the fidaxomicin family, tiacumicin A ( 10 ), followed in 2018 by our group . Recently, Roulland and coworkers also achieved their total synthesis of 1 using optimized glycosyl‐donors for selective β ‐glycosylation . In the following section, the different approaches will be presented and compared.…”

“…Recently, Roulland and coworkers published the second total synthesis of fidaxomicin, addressing the issue of the challenging β ‐selective glycosylations . In contrast to the total synthesis of Gademann and coworkers, they performed the rhamnosylation (instead of the noviosylation) early in the synthesis on a macrocycle precursor fragment ( Scheme ).…”

Modern Synthetic Methods for the Stereoselective Construction of 1,3-Dienes

“…The 1,3-diene structural moiety represents the key framework of many natural [ 1 , 2 , 3 , 4 ] and non-natural [ 5 ] products displaying a broad spectrum of biological activities [ 6 ]. Representative examples of natural products containing the 1,3-diene motif are the vitamin D2 precursor ergosterol (ergosta-5,7,22-trien-3-β-ol) [ 7 ], the potent cytotoxic agent zampanolide [ 8 ] and the macrolide antibiotic tiacumicin B [ 9 , 10 ] ( Figure 1 ). Apart from natural dienes, synthetic ones have also aroused great pharmacological interest.…”

Synthesis and Biological Evaluation of Iodinated Fidaxomicin Antibiotics

“…Besides total synthesis studies, [32][33][34][35][36][37][38][39] only a few examples of synthetic modifications on fidaxomicin are known to date. [29,[40][41][42][43] Researchers from Abbott Laboratories investigated the replacement of chloride by implementation of bromide into the natural product, by supplying the fermentation broth of Dactylosporangium aurantiacum subsp.…”