Background and Research Objective:
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a family of natural products with a broad range of biological activities. These peptide macrocycles offer a unique solution to several issues arising in drug development, specifically in targeting and modulating areas of proteins deemed “undruggable.” This bioactivity has spurred several investigations into their total synthesis. However, previous syntheses of RiPPs are lengthy and low-yielding due to their linear nature, often forming an initial C-C cross-link between two amino acid residues before establishing stereocenters and functional handles to build upon (1). This research aims to simplify and optimize the full synthesis of RiPPs through a convergent method while simultaneously exploring a new diastereoselective approach to metallaphotoredox reactions.
Methodology:
As shown in Figure 1, the proposed convergent method includes the initial construction of functionalized linear peptide chains containing alkyl and aryl bromides that are then bound together and eventually cyclized in a final C-C cross-linking step. This research project aims to explore and optimize the chemistry of these steps individually in preparation for future exploration of total RiPP synthesis.
Figure 1: The overall proposed strategy for the convergent synthesis of the subclass of RiPPs containing C(sp2)-C(sp3) linkages.
The primary focus of this project is to optimize the synthesis of C(sp2)-C(sp3) crosslinks between a scope of various alkyl and aryl bromides containing amino acid derivatives. To broaden the range of RiPPs that can be synthesized, the crosslinking of different amino acid derivatives containing aryl and alkyl bromides is to be explored. The proposed diastereoselective metallaphotoredox reaction shown in Scheme 1 has successfully been carried out in the Blakey Lab, forming crosslinks at high yields using aryl bromides containing phenylalanine and tyrosine derivatives. However, aryl bromides containing tryptophan derivatives have proven difficult, with a few of them yielding no desired product when used. Consequently, this project will explore methods of alternative access to the desired product when using these tryptophan derivatives, such as switching out the bulky tosyl group on the heterocyclic amine of the highlighted reagent for one that is smaller to avoid any sterics that may be hindering stereoselectivity. I plan to synthesize and test derivatives of these products in this reaction to assess this hypothesis that reducing steric bulk will increase yield.
Scheme 1: The optimized conditions of the proposed diastereoselective metallaphotoredox cross-electrophile coupling reaction and the yield retained when this reaction was performed on several aryl bromide reagents containing Tryptophan derivatives.
Alkyl bromides containing dipeptide derivatives will also be made and subjected to the same reaction conditions to determine the compatibility of other functional groups, as shown in Scheme 2. This will help to test the hypothesis that the proposed crosslinking method can be applied to longer chains of amino acids. These dipeptide bonds will be synthesized using various amino acids and methods pertaining to each, such as the coupling of threonine and phenylalanine using manual solution phase peptide coupling techniques followed by the Appel reaction to create functional alkyl bromide reagents.
Scheme 2: The proposed metallaphotoredox cross-linking reaction of a threonine-phenylalanine dipeptide derivative with an aryl bromide reagent
References:
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Synthesis of Ribosomally Synthesized and Post-Translationally Modified Peptides Containing C–C Cross-Links David Laws III, Eleda V. Plouch, and Simon B. Blakey Journal of Natural Products 2022 85 (10), 2519-2539 DOI: 10.1021/acs.jnatprod.2c00508