Tiacumicin A

Tiacumicin B (1, also known as fidaxomicin or difimicin) is a marketed drug for the treatment of Clostridium difficile infections. The biosynthetic pathway of 1 has been studied in Dactylosporangium aurantiacum subsp. hamdenensis NRRL 18085 and has enabled the identification of TiaM as a tailoring dihalogenase. Herein we report the isolation, structure elucidation, and bioactivity evaluation of 14 tiacumicin congeners (including 11 new ones) from the tiaM-inactivated mutant. A new tiacumicin congener, 3, with a propyl group at C-7‴ of the aromatic ring was found to exhibit improved antibacterial activity.

The commercial macrolide antibiotic fidaxomicin was synthesized in a highly convergent manner. Salient features of this synthesis include a β-selective noviosylation, a β-selective rhamnosylation, a ring-closing metathesis, a Suzuki coupling, and a vinylogous Mukaiyama aldol reaction. Careful choice of protecting groups and fine-tuning of the glycosylation reactions led to the first total synthesis of fidaxomicin. In addition, a relay synthesis of fidaxomicin was established, which gives access to a conveniently protected intermediate from the natural material for derivatization. The first total synthesis of a related congener, tiacumicin A, is presented.

We give a full account of the total synthesis of tiacumicin B (Tcn-B), a natural glycosylated macrolide with remarkable antibiotic properties. Our strategy is based on our experience with the synthesis of the tiacumicin B aglycone and on unique 1,2-cis-glycosylation steps. We used sulfoxide anomeric leaving-groups in combination with a remote 3-O-picoloyl group on the donors that allowed highly β-selective rhamnosylation and noviosylation that rely on H-bond-mediated aglycone delivery. The rhamnosylated C1-C3 fragment was anchored to the C4-C19 aglycone fragment by a Suzuki-Miyaura cross-coupling. Ring-size-selective Shiina macrolactonization provided a semiglycosylated aglycone that was engaged directly in the noviolysation step with a virtually total β-selectivity. Finally, a novel deprotection method was devised for the removal of a 2-naphthylmethyl ether on a phenol, and efficient removal of all the protecting groups provided synthetic tiacumicin B.