Abstract
Oxazoles and thiazoles are commonly found moieties in nonribosomal peptides (NRPs) and ribosomally synthesized post-translationally modified peptides (RiPPs), which are important biomolecules present in the environment and in natural waters. From previous studies, they seem susceptible to oxidation by singlet oxygen (1O2); therefore, we designed and synthesized model oxazole- and thiazole-peptides and measured their 1O2 bimolecular reaction rate constants, showing slow photooxidation under environmental conditions. We reasoned their stability through the electron-withdrawing effect of the carboxamide substituent. Reaction products were elucidated and support a reaction mechanism involving cycloaddition followed by a series of rearrangements. The first 1O2 bimolecular reaction rate constant for a RiPP, the thiazole-containing peptide Aerucyclamide A, was measured and found in good agreement with the model peptide's rate constant, highlighting the potential of using model peptides to study the transformations of other environmentally relevant NRPs and RiPPs.
Highlights
Amino acid-based oxazoles and thiazoles are formed from the cyclization of serine, threonine, and cysteine side chains onto the peptide backbone and are common features of nonribosomal peptides (NRPs) and ribosomally encoded posttranslationally modified peptides (RiPPs).[1,2]
We are interested in NRP and RiPP natural products since they have the potential to act as water contaminants and as ecologically important biomolecules
Such oxazole and thiazole peptides have been isolated from sunlight-dwelling photosynthetic algae, cyanobacteria, sea slugs, and sponges.[2−11] the prevalence of these peptidic heterocycles would seem counterintuitive if they are as reactive toward singlet oxygen (1O2), a ubiquitous oxidant in sunlit natural waters, as previously studied oxazoles and thiazoles.[12−15] earlier work by Nakamura et al and by Wasserman et al showed that phenyl-substituted oxazoles react quickly with 1O2 with rate constants on the order of 107− 108 M−1 s−1, translating to a half-life of only 4 days for the highest rate constant in the presence of a typical fresh water 1O2 concentration of 1.4 × 10−14 M (Scheme 1).[16,17]
Summary
Amino acid-based oxazoles and thiazoles are formed from the cyclization of serine, threonine, and cysteine side chains onto the peptide backbone and are common features of nonribosomal peptides (NRPs) and ribosomally encoded posttranslationally modified peptides (RiPPs).[1,2] We are interested in NRP and RiPP natural products since they have the potential to act as water contaminants and as ecologically important biomolecules (e.g., metal-binding siderophores). A C-5 methyl substitution leads to an increase in the 1O2 bimolecular rate constant, with methoxazole peptide 2, which contains the C-5 methyl, reacting 6 times faster than oxazole peptide 1a, which does not This result is consistent with the methyl group increasing the electron density on the C-5, and accelerating the reaction with 1O2. Combined organic fractions were successively washed with a 1 M HCl aqueous solution and brine, dried over MgSO4, filtered, and concentrated under vacuum to yield the desired amide as a white solid (2.81 g, 13.0 mmol, 94%): 1H NMR (400 MHz, CDCl3) δ 5.88 (s, 1H, broad), 5.41 (s, 1H, broad), 5.01 (s, 1H, broad), 3.97−3.94 (m, 1H), 2.20−2.14 (m, 1H), 1.45 (s, 9H), 1.00−0.92 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.1, 156.1, 59.6, 30.8, 28.5, 19.4, 17.8.
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