Total synthesis of azithromycin

Abstract

Azithromycin is semi-synthetic 15-membered macrolide. It showed a broad spectrum of antibacterial activity covering all significant bacteria that cause respiratory tract infections. The notable attributes of azithromycin are its unusual pharmacokinetics (high tissue distribution), metabolic stability and high tolerability. These properties have led in recent years to the widespread use of the azalide scaffold for the synthesis of new compounds with advantageous pharmacokinetics. Total synthesis of azithromycin 1 was accomplished through two different pathways. Their difference stems from the timing in the glycosylation of the cladinose sugar. While it was attached before macrolactonization in the first approach, the second route adopted later glycosylation after macrolactonization. In the first synthetic pathway, the lactone linkage and the $C_9$-$N_{9a}$ bond were cleaved to provide amine 11 and acid aldehyde 12. The amine fragment 11 was prepared via desymmetrization method, asymmetric ethylation and regioselective epoxide substitution. Preparation of the fragment 12 began with the known chiral building block 23 which comprises the absolute stereochemistry at $C_8$ position, and was highlighted by desymmetrization protocol which afforded the $C_6$ oxygenated quaternary center enantioselectively. Subsequently, prudent timing of glycosylation, crotylation reactions, and oxidation of terminal C-C double bond provided 73. The aldehyde functional group at $C_9$ of 12 was generated by oxidation of the corresponding alcohol. After connection of 11 and 12 by reductive amination, the 15-membered macrolactone ring of 1 would be constructed by Yamaguchi’s macrolactonization. In the second synthetic strategy, the cladinose carbohydrate, the lactone linkage and the $C_9$-$N_{9a}$ bond were disconnected to give the cladinoside 14, the western amino alcohol 81 and the eastern hydroxyl carboxylic acid 82. Since 14 contains a tertiary alcohol functionality, it was buil...