Total Synthesis of the Tiacumicin B (Lipiarmycin A3/Fidaxomicin) Aglycone

Abstract

Tiacumicin B (lipiarmycin A3, fidaxomicin) is an atypical macrolide antibiotic which is used for the treatment of Clostridium difficile infections. Tiacumicin B is also a potent inhibitor of Mycobacterium tuberculosis, but due to its limited oral bioavailability is unsuitable for systemic therapy. To provide a basis for structure-activity studies that might eventually lead to improved variants of tiacumicin B, we have developed an efficient approach to the synthesis of the tiacumicin B aglycone. The synthesis features a high-yielding intramolecular Suzuki cross-coupling reaction to effect macrocyclic ring closure. Key steps in the synthesis of the macrocyclization precursor were a highly selective, one-pot Corey-Peterson olefination and an ene-diene cross-metathesis reaction. Depending on the reaction conditions, the final deprotection delivered either the fully deprotected tiacumicin B aglycone or partially protected versions thereof.

Final Demonstration of the Co-Identity of Lipiarmycin A3 and Tiacumicin B (Fidaxomicin) through Single Crystal X-ray Analysis

“…One year later, three different groups independently reported [17,18,19] the enantioselective synthesis of the tiacumicin B aglycon and of the putative lipiarmycin aglycon, followed by the first total synthesis of fidaxomicin [20]. The latter synthetic compound proved to be identical to a commercial sample of tiacumicin B from Dactylosporangium auranticum , thus confirming the structure assigned and substantiating our work on the lipiarmycin–tiacumicin co-identity.…”

Total Synthesis of the Endocannabinoid Uptake Inhibitor Guineensine and SAR Studies

“…Ester saponification and subsequent amide bond formation via the acid chloride proceeded smoothly.T he remaining undesired Z-D 4,5 isomer could be removed at this stage by flash chromatography,t hus providing dienamide 8 as as ingle isomer in 84 %o verall yield from ester 7.P alladium-catalyzed hydrostannylationo ft he terminal alkyne moiety followed by in situ treatment of the resulting stannane with iodine then gave vinyl iodide 9 in 64 %y ield. Both the yield and purity of the coupling product could be significantly improved by the use of thallium ethoxide [18,19] as an additive, which also reduced the reaction time to 5-10 min. 90 %p ure; isolation of the intermediate stannane prior to tin-iodide exchange did not yield material of higher purity.…”

Enantioselective Synthesis of the C23–C33 Fragment of Aetheramide A and Its C32 Epimer

“…Thus, coupling of ( R , R )‐ 2 with ( R )‐ 3 at 20 °C provided the desired key aetheramide precursor ( R , R , R )‐ 1 within 1 h in an excellent 91 % yield with 97 % ee (Scheme ). The successful course of the reaction under these mild reaction conditions was enabled by the use of thallium(I) ethoxide as a base [TlOEt is converted into thallium(I) hydroxide by reaction with water] , . By analogy, coupling of ( R , S )‐ 2 with ( R )‐ 3 gave rise to the hitherto unknown diastereoisomer ( R , S , R )‐ 1 in 79 % yield with 97 % ee…”