Dissertation/Thesis Abstract

Development of Phosphothreonine (pThr)-Embedded Peptides as Brønsted Acid Catalysts for Stereoselective Transformations
by Shugrue, Christopher Ryan, Ph.D., Yale University, 2019, 435; 13806414
Abstract (Summary)

Drawing inspiration from the incredible activities of enzymes, we have set out to develop miniaturized, peptide-based Brønsted acid catalysts. Natural post-translational modification product, phosphothreonine (pThr), can be used as a catalytic residue and appended to a myriad of minimal peptide sequences containing diverse functionality and biased toward adopting a variety of different secondary structures. This strategy hence provides a modular and tunable "active site". These phosphopeptides represent an intriguing new class of chiral phosphoric acid (CPA) catalysts, and one of the first families of non-C2-symmetric CPAs. Structurally distinct and more functional group-rich compared to BINOL-inspired CPAs, pThr-peptides offer heightened opportunities for the construction of noncovalent interactions (NCIs) between catalysts and substrates, an underexplored paradigm with known CPA catalyst scaffolds. We report herein pThr-embedded peptides as a versatile new class of CPAs, which exhibit complementary selectivities to C2-symmetric CPAs, in a number of reaction paradigms.

The application of pThr-based catalysts toward the reductions of quinolines is presented in Chapters 3 and 4. NAD(P)H mimic, Hantzsch ester, was found to be an exemplary hydride source, and quinolines containing functionality at the C8-position were reduced with enantioselectivities up to 95:5. Bisquinolines were also tolerated with high levels of enantioselectivity in both mono- and bis-reductions. To highlight the complementarity between BINOL- and pThr-based CPAs, both were added together in one pot and found to independently mediate the first and second reductions respectively, with good orthogonality. This observation demonstrates the tuning of reactivity of a conserved catalytic functionality, a phosphoric acid, owing to the dissimilarity of the chiral scaffolds.

The reductive potential of this pThr/HEH system was next applied toward the reductive amination of 3-amidocyclohexanones in Chapter 5, and e.r. of up to 93:7 were achieved. Indeed, while pThr catalysts favored the formation of cis products, BINOL-derived catalysts afforded the trans products selectively, offering another instance of complementarity between these two diverse CPA families.

In addition, phosphopeptides were found to mediate Baeyer–Villiger (BV) oxidations of cyclobutanones with aqueous hydrogen peroxide in Chapter 6. A number of NMR studies were conducted, which elucidated an intriguing network of NCIs between peptides (most importantly an acetamide-containing Dap(Ac) residue) and substrates.

Finally, Chapter 7 details our efforts in a related approach, chemoselective oxidations with aspartic acid (Asp)-containing peptides. This class of peracid catalyst can facilitate both electrophilic epoxidation reactions and nucleophilic BV oxidations. Given the proper choice of peptide sequence, the reactivity of this shared Asp-peracid could be switched between the two reaction paradigms. Computational analysis of the preferred ground-state conformations of substrates are also reported.

Ultimately, what arises from the work presented herein is a new class of CPA catalyst, pThr-based peptides, which are versatile for a number of reaction types. These phosphopeptides represent a radical departure from known C2-symmetric CPAs, and offer complementary selectivity profiles in numerous cases.

Indexing (document details)
Advisor: Miller, Scott J.
Commitee: Newhouse, Timothy R., Ellman, Jonathan A.
School: Yale University
Department: Chemistry
School Location: United States -- Connecticut
Source: DAI-B 81/3(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Chemistry, Organic chemistry
Keywords: Chiral phosphoric Acids, Enantioselective Catalysis, Hantzsch ester Reductions, Nmr, Peptides, Pure sciences
Publication Number: 13806414
ISBN: 9781088315170
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