Fluorogenic Diversification of Unprotected Bromotryptophan by Aqueous Mizoroki–Heck Cross‐Coupling

Abstract

Fluorescent styryl‐tryptophans have been synthesized by a Mizoroki–Heck cross‐coupling from unprotected bromotryptophan in aqueous medium showing promising spectrophotometric properties for possible application in fluorescence labelling of biomolecules. Moreover, this strategy permits a modular combination of biocatalytic halogenation by using immobilized FAD‐dependent tryptophan halogenases and Pd‐mediated chemocatalysis in a multistep one‐pot process.

Heck Diversification of Indole‐Based Substrates under Aqueous Conditions: From Indoles to Unprotected Halo‐tryptophans and Halo‐tryptophans in Natural Product Derivatives

“…The 4‐bromo‐tryptophan 23 is highly unreactive and even using TXPTS as ligand, only a small trace of product may be perceived from the reaction. Curiously, the sole application of Heck cross‐coupling to tryptophan reported in the literature is the functionalisation of 4‐bromo‐tryptophan 23 in the synthesis of clavicipitic acid (reported as 91 % conversion using conventional heating); we have been unable to reproduce this conversion using either the system that we have developed or their conditions with alkene 1,1‐dimethylallyl alcohol, TPPTS, Pd(OAc) 2 and NaOH as base. Forcing the reaction by MW heating to 130 °C for 2 h we were finally able to obtain a conversion of around 15 %.…”

“…Whilst this manuscript was being prepared, the first Mizoroki–Heck coupling of a halo‐tryptophan was reported. In this study free, unprotected 7‐bromo‐tryptophan was derivatised with 6 different styrenes . Excitingly, as observed with the Suzuki–Miyaura cross‐coupling of tryptophan, these tryptophan‐7‐styrene products were shown to be fluorogenic, thus again opening up the way for fluorescence modulation of halo‐tryptophans.…”

“…(C) Heck modification of iodinated nucleoside triphosphates . (D) Reported Heck modification of 7‐bromo‐tryptophan with styrenes . (E), (F) Heck modification of a series of indoles and tryptophans, respectively.…”

Size‐Dependent Cellular Uptake of RGD Peptides

“…Halotryptophans can selectively be synthesized by biocatalytic halogenation effecting regioselective bromination of the indole ring. They represent versatile handles for chemoselective installation of aryl moieties by cross‐coupling reactions, which can eventually be used to generate fluorescent probes . In particular, a large aromatic system as in the pyrene derivative ( 1 ) permits an excitation ( λ ex : 365 nm) suitable for biological applications (Figure S1 in the Supporting Information).…”

Late‐Stage Diversification of Tryptophan‐Derived Biomolecules

“…Very recently, we reported on the utilisation of an aqueous MHC to react unprotected 7‐bromotryptophan with different substituted styrenes . To find suitable reaction conditions, a catalyst system consisting of Pd(OAc) 2 as Pd source and the water‐soluble phosphine ligand TPPTS was tested because it had been successfully used by Yokoyama et al.…”