Total Synthesis of Tiacumicin B: Study of the Challenging β‐Selective Glycosylations**

Abstract

We report here 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-cisglycosylation steps. It features the conclusive use of sulfoxide anomeric leaving-groups in combination with a remote 3-O-picoloyl group on the donors allowing highly b-selective rhamnosylation and noviosylation that rely on H-bond-mediated Aglycone Delivery (HAD). 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 semi-glycosylated aglycone that was engaged directly in the noviolysation step with a virtually total b-selectivity. Finally, a novel deprotection method was devised for the removal of a 2-naphthylmethylidene (Nap) ether on a phenol and efficient removal of all the protecting groups provided synthetic tiacumicin B.

Cooperative Bifurcated Chalcogen Bonding and Hydrogen Bonding as Stereocontrolling Elements for Selective Strain-Release Septanosylation

“…The recognition of NCIs, particularly classical hydrogen bonding (HB) as a powerful stereocontrolling force in controlling anomeric selectivity is elegantly demonstrated through the field defining HB-mediated aglycone delivery (HAD) strategy pioneered by Demchenko and Yasomanee by installing the highly tractable picoloyl (pico) directing group (Figure a) . This strategy has later found important applications in natural product synthesis such as the access of tiacumicin B . Subsequent developments of other variants of directing groups for HAD such as Yang’s quinolinecarbonyl (quin) based groups and more recently, Li’s 2-(diphenylphosphinoyl)­acetyl (DPPA) groups also shown substantial robustness in accessing challenging polysaccharides.…”

Single Atom Editing of the Glycosylated Natural Product Fidaxomicin Improves Acid Stability and Retains Antibiotic Activity

“…Thus, introducing the b-anomer of 1-thiosugars allows to control the configuration of the glycosidic linkage, that proved challenging to access for glycosylation of the aglycone. 39 Therefore, we next aimed to synthesize a per-O-protected 1-thio-b-D-noviose derivative.…”

Macrolides from rare actinomycetes: Structures and bioactivities

“…Most of the isolated compounds are characterised by an 18-membered macrolactone attached to two sugars, noviose and rhamnose. Both sugar moieties are esterified by a different substitution pattern such as 3-methylpropanoate, propanoate or acetate esters or homodichloroorsellinic acid at different positions [66]. Six compounds, named tiacumicins A-F, were isolated from the broth of Dactylosporangium aurantiacum subsp.…”