Synthesis of a Tiacumicin B Protected Aglycone

Abstract

Tiacumicin B is an antibiotic endowed with the remarkable ability to interact with a new biological target, giving it an inestimable potential in the context of the ever-growing and worrisome appearance of resistances of bacteria and mycobacteria to antibiotics. The synthesis of an aglycone of tiacumicin B ready for glycosylation is reported. The key steps of this approach are a [2,3]-Wittig rearrangement, a Pd/Cu-catalyzed allene-alkyne cross-coupling, a E-selective cross-metathesis, and a final ring-size selective macrolactonization.

Synthesis and Molecular Editing of Callyspongiolide, Part 1: The Alkyne Metathesis/trans‐Reduction Strategy

“…Despite considerable experimentation, neither trans ‐hydrostannation nor trans ‐hydrosilylation proved viable. Changing the catalyst ([Cp*Ru(MeCN) 3 ]PF 6 , [Cp*RuCl] 4 ), reagent (Bu 3 SnH, BnMe 2 SiH, (EtO) 3 SiH), solvent (CH 2 Cl 2 or neat) and reaction temperature did not lead to any meaningful conversion . Moreover, it should be noted that attempted trans ‐hydrostannation under free radical conditions could not solve the problem either: rather, isomerization of the Z ‐configured enoate in 42 with formation of 44 was the only outcome, while no addition to the triple bond took place under the chosen conditions.…”

“…BnMe 2 SiH, (EtO) 3 SiH), solvent( CH 2 Cl 2 or neat) [48] and reaction temperature did not lead to any meaningfulc onversion. [49] Moreover,i ts hould be noted that attempted trans-hydrostannation under free radical conditions could not solve the problem either: [50] rather,i somerizationo ft he Z-configured enoate in 42 with formation of 44 was the only outcome, while no addition to the tripleb ond took place under the chosen conditions.…”

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

“…Our synthesis of 2 was robust enough to be scaled up. The cross‐coupling of 2 with the rhamnoside 21 proceeded cleanly, requiring only slight modifications of the previously used reaction conditions . This convergent step provided the ester 22 in a 79 % yield (Scheme ).…”

“…Originally, we had imagined glycosylating our aglycone sequentially, a viable pathway. However, we finally opted for a less traditional but more convergent retrosynthetic plan in which Tcn‐B was disconnected into fragments A , and B , and the known 2 , all equivalent in size and complexity. We chose as the first move to assemble A together with 2 , then close the macrolactone, and install B at the very end.…”

“…We chose as the first move to assemble A together with 2 , then close the macrolactone, and install B at the very end. The Suzuki coupling developed during our aglycone synthesis was considered robust enough to allow assembly of 2 with A , instead of the small silylated C1–C3 fragment formerly involved, thus adding convergence. This approach reduces risks of failure since rhamnosylation conditions needed for the synthesis of A can be developed using the structurally simple C1–C3 fragment as the acceptor.…”