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.

The first enantioselective total synthesis of fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is reported. This novel glycosylated macrolide antibiotic is used in the clinic for the treatment of Clostridium difficile infections. Key features of the synthesis involve a rapid and high-yielding access to the noviose, rhamnose, and orsellinic acid precursors; the first example of a β-selective noviosylation; an effective Suzuki coupling of highly functionalized substrates; and a ring-closing metathesis reaction of a noviosylated dienoate precursor. Careful selection of protecting groups allowed for a complete deprotection yielding totally synthetic fidaxomicin.

The macrocyclic antibiotic mangrolide A has been described to exhibit potent activity against a number of clinically important Gram-negative pathogens. Reported is the first enantioselective total synthesis of mangrolide A and derivatives. Salient features of this synthesis include a highly convergent macrocycle preparation, stereoselective synthesis of the disaccharide moiety, and two β-selective glycosylations. The synthesis of mangrolide A and its analogues enabled the re-examination of its activity against bacterial pathogens, and only minimal activity was observed.

The macrocyclic antibiotic mangrolide Ah as been described to exhibit potent activity against an umber of clinically important Gram-negative pathogens.R eported is the first enantioselective total synthesis of mangrolide Aa nd derivatives.S alient features of this synthesis include ah ighly convergent macrocycle preparation, stereoselective synthesis of the disaccharide moiety,a nd two b-selective glycosylations. The synthesis of mangrolide Aa nd its analogues enabled the re-examination of its activity against bacterial pathogens,a nd only minimal activity was observed.

The unique 18-membered macrocyclic natural product mangrolide D was prepared in totally synthetic form. Key steps feature an Au-catalyzed glycosylation, aza-Michael addition, and LaLi3tris(binaphthoxide) catalyzed epoxidation. Detailed analysis of the constitution and configuration of the carbohydrate segment and the total synthesis of the revised structure led to structural revision of the originally proposed structure.