A bioinspired and biocompatible ortho-sulfiliminyl phenol synthesis

Feng Xiong,Xinhao Zhang,Tian-Yu Sun,Yi Lu,Liang Lu,Qian Wu,Ying Chen,Jie Jack Li,Dingyuan Yan,Jing Zhao,Wei-Yin Sun,Wei Wei

doi:10.1038/ncomms15912

Abstract

Synthetic methods inspired by Nature often offer unique advantages including mild conditions and biocompatibility with aqueous media. Inspired by an ergothioneine biosynthesis protein EgtB, a mononuclear non-haem iron enzyme capable of catalysing the C–S bond formation and sulfoxidation, herein, we discovered a mild and metal-free C–H sulfenylation/intramolecular rearrangement cascade reaction employing an internally oxidizing O–N bond as a directing group. Our strategy accommodates a variety of oxyamines with good site selectivity and intrinsic oxidative properties. Combining an O–N bond with an X–S bond generates a C–S bond and an S=N bond rapidly. The newly discovered cascade reaction showed excellent chemoselectivity and a wide substrate scope for both oxyamines and sulfenylation reagents. We demonstrated the biocompatibility of the C–S bond coupling reaction by applying a coumarin-based fluorogenic probe in bacterial lysates. Finally, the C–S bond coupling reaction enabled the first fluorogenic formation of phospholipids, which self-assembled to fluorescent vesicles in situ.

Highlights

Optimization of the reaction conditions. Especially those catalysed by transition metals, a directing group typically escorts the metal catalyst towards the neighbouring ortho-position and dictates the site selectivity
At the outset of this study, compounds 1 with those bonds were firstly screened to couple with a thionating reagent N-ethylthiophthalimide 2a under previously reported metal catalysed conditions[48,49,50] for similar reactions (Fig. 2a)
To probe the scope of the transition metal-free cascade C–S and S 1⁄4 N bond formation, we examined a series of oxyamide substrates (Table 1)

Summary

Introduction

The desired sulfenylation reagent and oxidizing X–N bond needs to accomplish the following two tasks (Fig. 1b): (i) sulfur transfer[38,39]. We report a rationally designed and metal-free coupling method to synthesize sulfilimines via an internal oxidantdirecting strategy for the cascade formation of C–S and S 1⁄4 N bonds at room temperature. At the outset of this study, compounds 1 with those bonds were firstly screened to couple with a thionating reagent N-ethylthiophthalimide 2a under previously reported metal catalysed conditions[48,49,50] for similar reactions (Fig. 2a).

Results

Conclusion