Unnatural amino acids provide an abundantly rich source of structural and functional diversity for the development of innovative materials and peptide mimetics. Such structural motifs play a particularly crucial role in drug discovery, featuring in a number of commercially available pharmaceuticals for the treatment of diseases. Despite their biological relevance, non-canonical amino acids (particularly heterocyclic ?-amino acid variants) represent synthetically challenging targets. The goal of the proposed research is therefore to provide a robust platform for the synthesis of unnatural ?-amino acids, with a focus on heterocyclic variants, and to facilitate their rapid incorporation into therapeutic leads. The frst specific aim of this study is to develop a C-H functionalization approach for the preparation of unnatural amino acids from novel ?-amino acid sulfinate building blocks. Metal sulfinate salts are known precursors to alkyl radical intermediates capable of participating in the efficient and high-yielding oxidative C-H functionalization of heteroaromatic substrates. By preparing a small toolbox of amino acid sulfinate derivatives, rapid access to a diverse library of heterocyclic amino acid variants will be possible through programmed reaction with heteroaromatic substrates under oxidative C-H functionalization conditions. Reaction of the sulfinate-derived alkyl radical intermediate with a variety of radical acceptors will also be probed, with the aim of enhancing the diversity of unnatural amino acids accessible using the proposed methodology. Given the growing pharmaceutical relevance of peptide drugs and peptidomimetics bearing non-native structural motifs, new methods for the rapid incorporation of unnatural amino acids into peptide drug leads are in high demand. As such, the second specific aim of the proposed research is to develop a platform for the efficient, late-stage incorporation of unnatural amino acids into therapeutic peptide targets. The proposed methodology entails the synthesis of amino acids bearing latent sulfinate functionalities and the incorporation of these stable sulfinate derivatives into target peptides using solid-phase peptide synthesis (SPPS). Following construction of the peptide backbone, the latent sulfinate may be unmasked (on-resin or in solution) to provide an amino acid sulfinate poised for C-H functionalization. This methodology will therefore enable the late-stage introduction of structural diversity and complexity, facilitatng the rapid preparation of peptide drug analogues, which would otherwise require de novo synthesis. The proposed research aims will therefore expedite the process of drug development, greatly increasing the accessibility of non-native amino acid building blocks and facilitating their incorporation into novel therapeutic leads.

Public Health Relevance

The proposed research aims to provide a new and efficient approach to preparing amino acids not traditionally found in nature. These important molecules will add considerable diversity to the chemical building blocks currently available for the development of new therapeutics and will serve to greatly enhance our abilities to prevent and treat human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM117816-01
Application #
9051380
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lees, Robert G
Project Start
2016-02-15
Project End
2019-02-14
Budget Start
2016-02-15
Budget End
2017-02-14
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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deGruyter, Justine N; Malins, Lara R; Baran, Phil S (2017) Residue-Specific Peptide Modification: A Chemist's Guide. Biochemistry 56:3863-3873
Edwards, Jacob T; Merchant, Rohan R; McClymont, Kyle S et al. (2017) Decarboxylative alkenylation. Nature 545:213-218
deGruyter, Justine N; Malins, Lara R; Wimmer, Laurin et al. (2017) CITU: A Peptide and Decarboxylative Coupling Reagent. Org Lett 19:6196-6199
Malins, Lara R; deGruyter, Justine N; Robbins, Kevin J et al. (2017) Peptide Macrocyclization Inspired by Non-Ribosomal Imine Natural Products. J Am Chem Soc :
Qin, Tian; Cornella, Josep; Li, Chao et al. (2016) A general alkyl-alkyl cross-coupling enabled by redox-active esters and alkylzinc reagents. Science 352:801-5