Total Synthesis of the Glycosylated Macrolide Antibiotic Fidaxomicin

Abstract

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.

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

“…Selective tosylation in 2,6‐lutidine gave 12 , whose reduction with LAH provided the desired rhamnose derivative 13 . Gademann's conditions allowed assembly of the ester 8 together with 13 , giving selectively 14 . The free phenol of 14 was protected as the Nap ether 15 , and the rhamnoside O3 position was esterified with picolinic acid.…”

“…[7] In 2015 the groups of Gademann [8] and Altmann 9] published the first two syntheses of the aglycone of Tcn-B, and the group of Zhu [10] the synthesis of a diastereomer. Nonetheless, only Gademann was capable of completing the total synthesis of Tcn-B, providing the following answers to the b-glycosylations problem: [11,12] a) The Helferichs protocol (activating agent: HgO (excess) /HgBr 2(cat) ) [13] was used to noviosylate the C4-C13 aglycone fragment (a/b: 1/3, b: 54 %), as the cyclic aglycone gave only a adducts whatever the conditions. b) The rhamnosylation was carried out on the macrolide, using an imidate donor (a/b: 1/4, b: 62 %).…”

“…Gademanns conditions allowed assembly of the ester 8 together with 13, giving selectively 14. [11] The free phenol of 14 was protected as the Nap ether 15, and the rhamnoside O3 position was esterified with picolinic acid. This sequence led to the expected donor 16, ready for the glycosylation of alcohol 18 [21] (Scheme 3).…”

Chemistry and Biology of the Clinically Used Macrolactone Antibiotic Fidaxomicin

“…Finally, in 2015 our group accomplished the assembly of natural product 1 and published the first total synthesis thereof . A further total synthesis of another member of the fidaxomicin family, tiacumicin A ( 10 ), followed in 2018 by our group .…”