An improved total synthesis of tunicamycin V

Katsuhiko Mitachi; David Mingle; Michio Kurosu

doi:10.1016/j.mex.2023.102095

An improved total synthesis of tunicamycin V

MethodsX. 2023 Feb 26:10:102095. doi: 10.1016/j.mex.2023.102095. eCollection 2023.

Authors

Katsuhiko Mitachi¹, David Mingle¹, Michio Kurosu¹

Affiliation

¹ Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN 38163, USA.

Abstract

The tunicamycins are important biochemical tools to study N-linked glycosylation and protein misfolding in cancer biochemistry fields. We reported a convergent synthesis of tunicamycin V with 21% overall yield from D-galactal. We have further optimized our original synthetic scheme by increasing the selectivity of azidonitration of the galactal derivative and developing a one-pot Büchner-Curtius-Schlotterbeck reaction. An improved synthetic scheme reported here enables the synthesis of tunicamycin V in 33% overall yield. In this article, we describe detailed procedures for a gram-scale synthesis of the key intermediate 12 and synthesizing 100 mg of tunicamycin V (1) from commercially available D-galctal-4,5-acetonide. All chemical steps have been repeated multiple times.•Highly selective azidonitration of N-(((3aR,4R,7aR)-2,2-dimethyl-3a,7a-dihydro-4H-[1,3]dioxolo[4,5-c]pyran-4-yl)methyl)acetamide (D-galctal-4,5-acetonide) to form 2-azido-2-deoxy-α/β-D-galactopyranoside derivatives.•Optimized Büchner-Curtius-Schlotterbeck (BCS) reaction procedure for the tunicamycin core structure.•Full detail on the 15-chemical step synthesis of tunicamycin V.

Keywords: A practical synthesis of tunicamycin V; Azidonitration; Büchner-Curtius-Schlotterbeck reaction; Practical synthesis; Tunicamycins.