Regiodivergent Glycosylations of 6-Deoxy-erythronolide B and Oleandomycin-Derived Macrolactones Enabled by Chiral Acid Catalysis

Abstract

This work describes the first example of using chiral catalysts to control site-selectivity for the glycosylations of complex polyols such as 6-dEB and oleandomycin-derived macrolactones. The regiodivergent introduction of sugars at the C3, C5 and C11 positions of macrolactones was achieved by selecting appropriate chiral acids as catalysts or through introduction of stoichiometric boronic acid-based additives. The BINOL-based CPAs were used to catalyze highly selective glycosylations at the C5 positions of macrolactones (up to 99:1 rr) whereas the use of SPINOL-based CPAs resulted in selectivity switch and glycosylation of the C3 alcohol (up to 91:9 rr). Additionally, the C11 position of macrolactones was selectively functionalized through traceless protection of the C3/C5 diol with boronic acids prior to glycosylation. The investigation of the reaction mechanism for the CPA-controlled glycosylations revealed the involvement of covalently linked anomeric phosphates rather than oxocarbenium ion pair as the reactive intermediates.

Catalytic activation of glycosyl phosphates for stereoselective coupling reactions

“…We sought to establish whether the diphenylphosphoric acid generated as a stoichiometric by-product has any effect on the glycosylation reaction. In prior work by Schmidt and coworkers (6,(17)(18)(19), Fairbanks and coworkers (20), Toshima and coworkers (21), Nagorny and coworkers (22,23), Galan and coworkers (24), Bennett and coworkers (25), and others (26,27), phosphoric acids have been shown to be competent catalytic activators in glycosylation reactions involving different types of donors. However, in the model system, addition of exogenous diphenylphosphoric acid was shown to have no detectable effect on either reaction rate or α/β selectivity.…”

Experimental and Computational Studies on Regiodivergent Chiral Phosphoric Acid Catalyzed Cycloisomerization of Mupirocin Methyl Ester

“…In particular, Zimmerman group's reaction exploration tools were used to facilitate the accurate and fast search of relevant reactions paths and transition states . These tools have previously been used in the elucidation of fine mechanistic details of phosphoric acid‐catalyzed spiroketalizations, glycosylations, and intramolecular aza‐Michael reactions . Here, the single‐ended growing string method (GSM) was employed to detail the mechanism of phosphoric acid‐catalyzed intramolecular ERO.…”

“…The endo pathway was preferred minutely by 0.16 kcal mol −1 , a number that, although within the error of the computational methods, agrees with the small intrinsic endo selectivity that is observed with achiral phosphoric acids experimentally (Figure , TS endo vs. TS exo and Table , entry 7). An alternative mechanism through epoxide opening and involving a phosphate intermediate was ruled out because the barrier was substantially higher (≈8.3 kcal mol −1 , TS P ) than the concerted pathways.…”

“…Our group has a long‐standing interest in the application of chiral phosphoric acids (CPAs) to control the regio‐ and stereoselective functionalization of natural products . In our recent efforts, we demonstrated that CPAs could mimic enzymatic processes and control the regioselectivity and/or stereoselectivity of acetalization, spiroketalization, and glycosylation reactions. Inspired by the endo regiocontrol exhibited by the epoxide hydrolase Lsd19, which catalyzes the selective formation of lasalocid A rather than its kinetically favored regioisomer isolacid A (Figure B), we sought to investigate the possibility of controlling the formation of the exo and endo products through CPA catalysis.…”

Recent Developments in Stereoselective Chemical Glycosylation

“…In 2017, the Nagorny group described the use of chiral phosphoric acids to control both the stereoselectivity and regioselectivity of glycosylations with complex polyol acceptors 26 and 27 . The stereo‐ and regioselectivity of the reaction appeared to be dependent on the catalyst backbone.…”