Gene Expression Enabling Synthetic Diversification of Natural Products: Chemogenetic Generation of Pacidamycin Analogs

Abstract

Introduction of prnA, the halogenase gene from pyrrolnitrin biosynthesis, into Streptomyces coeruleorubidus resulted in efficient in situ chlorination of the uridyl peptide antibotic pacidamycin. The installed chlorine provided a selectably functionalizable handle enabling synthetic modification of the natural product using mild cross-coupling conditions in crude aqueous extracts of the culture broth.

One-pot access to l-5,6-dihalotryptophans and l-alknyltryptophans using tryptophan synthase

“…6 The ability to functionalise tryptophan is attractive as it provides a handle for selectively tuning the properties of the free amino acid or the amino acid as a component of a natural product or a peptide. We have previously demonstrated a new paradigm in natural product analogue generation, Genochemetics, 7 in which gene installation enables the biosynthetic introduction of a chemically orthogonal handle into a natural product, enabling selective synthetic diversification. Specifically, we demonstrated that we could engineer the production of the antibiotic pacidamycin bearing a 7-chlorotryptophan, the halogen handle enabled synthetic diversification through Suzuki-Miyaura cross coupling chemistry to produce a new array of natural product analogues.…”

“…Specifically, we demonstrated that we could engineer the production of the antibiotic pacidamycin bearing a 7-chlorotryptophan, the halogen handle enabled synthetic diversification through Suzuki-Miyaura cross coupling chemistry to produce a new array of natural product analogues. 7 The requirement for halotryptophans has stimulated many synthetic studies. Since the first chemical synthesis of 7-chlorotryptophan reported by Rydon and Tweddle, 8 despite many advances, the best methods currently available are multi-step, lack generality or require specialised procedures.…”

Polymer precursors from catalytic reactions of natural oils

“…Indeed, the interest of developing the Suzuki-Miyaura reaction in water resides in the potential to generate novel bioactive molecules. 247 These two criteria -the use of chlorinated reagents, the use of water as a solvent -have been targeted in the recent years using various strategies. For instance, the development of phosphine ligands permitting the solubility of the palladium complex in water has been considered.…”

The Suzuki–Miyaura Cross-Coupling as a Versatile Tool for Peptide Diversification and Cyclization

“…Further optimization indicated that a related ligand, bearing sulfonated m-xylene groups instead of phenyl (TXPTS), allowed for work at a lower temperature (40 • C) while still presenting excellent yields and significantly improved conversions when introducing a phenyl substituent on the 7-position. Alteration of the ligand to sulfonated 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl (SSPhos) was necessary to maintain the applicability of the Suzuki-Miyaura reaction on 7-Cl-tryptophans, as beautifully illustrated by derivatization of the natural product chloropacidamycin in mixed aqueous conditions (water/acetonitrile (AcN) 5:1) [96]. The synthesis of 7-vinyltryptophan 29 with potassium vinyltrifluoroborate and PdCl 2 (dppf), starting from 7-iodotryptophan 28 in mixed aqueous conditions ( Figure 6B), broadened the scope of halotryptophan derivatization, along with the derivatization of unprotected bromotryptophan and bromotryptophan-containing dipeptides [97].…”