Total Synthesis of Tunicamycin V

Abstract

The total synthesis of tunicamycin V is described. This strategy is based on the initial construction of tunicaminyluracil, which is regarded to play an important role in the observed biological activities. The key to the synthesis was a Mukaiyama aldol reaction followed by a furan-oxidation to construct the undecose skeleton, a [3,3] sigmatropic rearrangement of a cyanate, and a highly selective trehalose-type glycosylation.

GlcNAc-1-P-transferase–tunicamycin complex structure reveals basis for inhibition of N-glycosylation

“…We synthesized tunicamycin-MurNAc as described in the recently published total synthesis of tunicamycin V (see Supplementary Note 1 for details) 37 . In brief, the analog was synthesized by assemblage of a trichloroacetimidate of MurNAc N -methylamide derivative S5 as a glycosyl donor and a suitably protected tunicaminyluracil S6 as a glycosyl acceptor 37 . Namely, treatment of S5 and S6 with TfOH in Et 2 O at 0 °C provided the desired 11′-β-1″-α-glycoside S7 in 69% yield in a highly stereoselective manner.…”

“…Based on our structural analysis of the tunicamycin binding site, we designed a tunicamycin analog that replaces the GlcNAc sugar moiety in tunicamycin with a MurNAc sugar ( Fig. 5a ), which we synthesized as described in the recently published total synthesis of tunicamycin V ( Supplementary Note 1 ) 37 . The rationale for this chemical modification is that (1) the binding pocket of hGPT formed by loop E tightly packs around the GlcNAc sugar ( Fig.…”

Synthesis and biological evaluation of a MraY selective analogue of tunicamycins

“…Selective construction of the 11′--1′′--trehalose-type linkage out of four possible anomers was achieved by treatment of 8 and 9 [26] with TfOH in Et2O/CH2Cl2 at 0 °C.…”

Mechanism of action of nucleoside antibacterial natural product antibiotics

“…The biosynthetic gene cluster for the tunicamycin antibiotics has been identified in Streptomyces chartreusis [6], and the biosynthetic pathway has been shown to involve an unusual radical SAM enzyme TunM in the assembly of the tunicamine sugar [7]. A total synthesis of tunicamycin V was reported in 2017 by Ichikawa and co-workers [8], which has enabled the synthesis of tunicamycin analogues for structure-activity study [9]. A lipidtruncated analogue and an analogue lacking the GlcNAc sugar both lost 1000-fold in MraY inhibition activity but retained some enzyme inhibition, while an analogue lacking the nucleoside base was completely inactive [9].…”