An Efficient Large-Scale Synthesis of EDP-420, a First-in-Class Bridged Bicyclic Macrolide (BBM) Antibiotic Drug Candidate

Abstract

A multistep, practical, and cost-effective synthesis of novel bridged bicyclic macrolide drug candidate EDP-420 (1) is described. Starting from inexpensive and commercially available erythromycin A 9-oxime, the current chemical process involves a series of transformations: triacetylation, Pd-catalyzed O,O-bis-allylation (bridge formation), acid-catalyzed sugar cleavage, oxime reduction, acetylation, Os-catalyzed bridge olefin oxidative cleavage, Corey−Kim oxidation, bridge oxime formation, deprotection, and final purification. Multikilogram quantities have been synthesized.

Annulative Allylic Alkylation Reactions between Dual Electrophiles and Dual Nucleophiles: Applications in Complex Molecule Synthesis

“…Eur.J.2020, 26,1906 -1921 www.chemeurj.org 2019 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim of 47 followed by acidic hydrolysis of both the nitrile and the benzophenone imine afforded the target amino acid 48. Allylic substitution of 53 with chloropurine 54 followed by basic hydrolysisa fforded carbovir (55), whereas as imilar sequence with adenine (56)a st he nucleophile led to aristeromycin (57). For example, Trost and co-workers synthesized the novel bicyclic isoxazoline-2-oxide 51 by coupling meso-dibenzoate 49 with lithium nitronate 50,w hich underwent intermolecularCalkylation followed by intramolecular O-alkylation in the same pot (Scheme13).…”

“…[57] While evaluating other potentiall ead molecules, Or and coworkers used the same annulative allyic alkylation strategy to synthesize another type of bridged macrolide (Scheme 37). This ten-step route to EDP-420 wass uccessfully run on pilot plant scale and allowed access to three kilogramb atches of 163.…”

“…Hydride reduction of 52 followed by acylation afforded dicarbonate 53,s etting the stage fora nother Pd-catalyzed allylic alkylation reaction. Allylic substitution of 53 with chloropurine 54 followed by basic hydrolysisa fforded carbovir (55), whereas as imilar sequence with adenine (56)a st he nucleophile led to aristeromycin (57). [23] Several years later,T rost et al appliedasimilar strategy to their synthesis of (+ +)-valienamine (66;S cheme 14).…”

“…Eur.J.2020, 26,1906 -1921 www.chemeurj.org bridged macrolide antibiotic EDP-420 (163)c ommenced with an annulative allylic alkylation between isobutylene dicarbonate 126 d and protected erythromycin Ao xime 158. [57] On laboratory scale, this step provided 159 in 85 %y ield [58] but in the manufacturing route, this intermediate was directly hydrolyzed to afford 160 in roughly 60 %y ield over two steps. Severala spects of this transformation,w hich was performedo nk ilogram scale, are notable.…”

Advances in MRSA drug discovery: where are we and where do we need to be?

“…The long half-life and high systemic exposure of EDP-420 support once-daily dosage [76,77,78]. Recently, the company reported a relatively efficient large-scale synthesis of EDP-420 [79]. …”