Development of a Chromane-Forming Heck Reaction: Bisphosphine Mono-Oxide Mediated Regioselectivity Perturbed by Solvent-Based Peroxide Formation

Doggett, Adrian; Hay, Michael; McKenna, Shane; Saurer, Eric M.; Steinhardt, Sarah E.; Tan, Yee Sun; Wilbert, Christopher R.; Wisniewski, Steven R.

doi:10.1021/acs.oprd.3c00105

Cited by 3 publications

(2 citation statements)

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“…As both peptide resins were TFA-cleaved in parallel and in an identical manner, significantly increased Met oxidation during the cleavage of the resin from NBP SPPS seemed unlikely. On the other hand, considering that NMP is readily oxidized to a hydroperoxide byproduct (NMP-OOH) upon standing and as during the SPPS of our Met peptide a several years old R&D batch of NBP was used, we hypothesized that NBP was oxidized to the corresponding hydroperoxide (NBP-OOH) which then caused Met oxidation during the synthesis. To test this theory, we analyzed the batch of NBP at hand by HPLC, which revealed the presence of a 1.75% impurity (Table S20, peak 8).…”

Section: Resultsmentioning

confidence: 99%

“…In summary, we report that NBP, a dipolar aprotic solvent that has recently gained increasing usage rates in organic chemistry in general and in peptide synthesis in particular as a viable greener alternative for the hazardous solvent DMF, is susceptible to form hydroperoxide NBP-OOH under a wide range of conditions. While the formation of hydroperoxide NMP-OOH from the structurally related pyrrolidinone NMP and its impact on Heck coupling has been reported, our LC-HRMS assessment of batches of NMP containing NMP-OOH and NBP containing NBP-OOH revealed that aerial oxidation and subsequent processes for NMP and NBP, respectively, proceed by mechanistically distinct pathways. Specifically, while air-exposed NMP has a proclivity to form NMP-OOH followed by deoxygenation to NMP-OH and then oxidation to NMS, for NBP the NBP-OOH formed upon initial oxidation deoxygenates to NBP-OH but then rather than getting oxidized to NBS appears to dehydrate to DNBP, which in turn appears to rearrange to an NBP isomer of a yet undetermined structure.…”

Section: Discussionmentioning

confidence: 99%

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Advancing Sustainable Peptide Synthesis by Solvent Quality Control: Understanding and Mitigating Hydroperoxide in 1-Butyl-2-pyrrolidinone (NBP)

Pawlas,

El-Dine,

Bargen

et al. 2024

Org. Process Res. Dev.

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While numerous studies aimed at producing peptides in a sustainable manner have recently been reported, the impact of the quality of starting materials on sustainability in peptide synthesis has been less investigated. Here we report that NBP, a greener dipolar aprotic solvent suitable for use in SPPS, readily undergoes air oxidation to the corresponding hydroperoxide (NBP-OOH), which adversely affects oxidation-sensitive amino acids and peptides. Air, light, elevated temperatures, and common peptide synthesis reagents such as DIC accelerated the rate of NBP oxidation. LC-HRMS analyses revealed that air-induced NBP degradation proceeds via a different mechanism than the previously elucidated degradation of the closely related NMP while GC− MS of NBP containing NBP-OOH showed that standard GC-based analytical methods are unsuitable for NBP-OOH detection, warranting implementation of improved methods for NBP analyses. Assessment of NBP-OOH-induced Met, Trp, Cys, and Tyr breakdown revealed not only that NBP-OOH degrades all these oxidation-prone substrates, but it was also discovered that DITU, previously reported to suppress N-oxyl radical-induced peptide breakdown, constitutes an efficient suppressant of hydroperoxideinduced degradation. Studies on aerial oxidation of additional greener dipolar aprotic solvents DMSO and DMPU revealed that while the former is stable and does not cause oxidation, the latter is oxidized extensively upon air exposure and degrades oxidationprone substrates to a significant extent. On the other hand, air bubbling of NBP, DMSO, and DMPU proved to have an unexpected positive effect on the stability of the α-amino-bound Fmoc group, a finding that may be leveraged to minimize premature Fmoc loss during peptide synthesis. Overall, our studies on understanding and mitigating hydroperoxide formation in greener solvents for peptide synthesis illustrate the importance of a thorough quality assessment of starting materials during the development of sustainable synthetic methods.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%