Large-scale preparation of key building blocks for the manufacture of fully synthetic macrolide antibiotics

Abstract

Key building blocks for the production of fully synthetic macrolides have been scaled-up in first time pilot plant and kilo-lab campaigns. These building blocks have supported the discovery of new macrolide antibiotics as well as ongoing preclinical studies.

Enantioselective Hydrogenation of Activated Aryl Imines Catalyzed by an Iron(II) P-NH-P′ Complex

“…The significance of asymmetric imine hydrogenation in the context of pharmaceutical and agricultural industries has been reviewed extensively. [1][2][3][4][5][6][7][8] To date, large scale AH processes have been predominantly developed with precious metal catalysts based primarily on iridium, [9][10][11][12] and rhodium 13 while ruthenium complexes are often used in asymmetric transfer hydrogenation (ATH) processes. 10,14,15 Imines are generally challenging substrates to reduce in a stereoselective manner.…”

Practical Synthesis of Iboxamycin, a Potent Antibiotic Candidate, in Amounts Suitable for Studies in Animal Infection Models

“…18 After sparging with carbon dioxide with care to control the exotherm, the carboxylic acid 12 was obtained as an amorphous white solid after extractive isolation (35.7 g, 72%). Amide bond formation between 12 and (R,R)pseudoephenamine ( 13) 19 by mixed anhydride activation of 12 with pivaloyl chloride provided pseudoephenamide 10 as white needles after extractive isolation and recrystallization from 1:1 ethyl acetate-hexanes (56.0 g, first crop, mp 111-112 °C, 8.0 g, second crop, 84% total). An additional 3.3 g of product (4%, total yield 88%) was obtained by flash chromatography of the residue obtained from concentration of the mother liquors using acetone-hexanes as eluent.…”

The quest for supernatural products: the impact of total synthesis in complex natural products medicinal chemistry

“…Many of the resulting synthetic macrolides exhibit antimicrobial activity comparable with erythromycin and some exhibit improved activity over the semisynthetic macrolides including telithromycin and overcome drug resistance. 77,78…”

“…5) exhibited bryostatin-like behavior, acting as functional antagonists. The progress in the synthesis of bryostatin analogues with improved PKC binding affinity and functional activity has been summarized in detailed reviews by Wender et al 76 and Zhang et al 78…”