This proposal seeks support to develop a fundamentally new approach to amide and peptide chemical synthesis, one that complements existing methods based on dehydrative amide synthesis using carboxylic acids and amines. Bromonitroalkanes serve as carboxylic acid surrogates in a direct amide synthesis that utilizes an amine acceptor and an activating agent (a halonium ion). The concise preparation of amides derived from nonnatural amino acids, common constituents of biologically active linear and cyclic peptides that have been isolated from natural sources, is a central theme. Without this new paradigm, alternative chemical methods would provide access to the desired amides at the cost of a large number of steps, and the contamination of intermediates and products by stereoisomers that are difficult to remove. The practical chemical synthesis of biologically active peptides is an immediate goal. In the short term, peptides of modest size (~10 residues) will be prepared and diversified using the principles of medicinal chemistry. In the long term, use of this novel amide synthesis will be used in combination with conventional methods to provide access to large peptides (e.g. biologics) modified site-specifically with nonnatural amino acids.

Public Health Relevance

This proposal describes the development of new synthetic methods to prepare amide and peptide (polyamide) small molecules. Peptides have increasingly impacted human health through their use as therapeutics (so-called biologics) and the development of innovative new methods for their synthesis stands to further accelerate the discovery and development of peptide therapeutics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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Vanderbilt University Medical Center
Schools of Arts and Sciences
United States
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Schwieter, Kenneth E; Johnston, Jeffrey N (2015) Enantioselective Synthesis of D-α-Amino Amides from Aliphatic Aldehydes. Chem Sci 6:2590-2595
Schwieter, Kenneth E; Johnston, Jeffrey N (2015) Enantioselective Addition of Bromonitromethane to Aliphatic N-Boc Aldimines Using a Homogeneous Bifunctional Chiral Organocatalyst. ACS Catal 5:6559-6562
Schwieter, Kenneth E; Shen, Bo; Shackleford, Jessica P et al. (2014) Umpolung amide synthesis using substoichiometric N-iodosuccinimide (NIS) and oxygen as a terminal oxidant. Org Lett 16:4714-7
Makley, Dawn M; Johnston, Jeffrey N (2014) Silyl imine electrophiles in enantioselective catalysis: a Rosetta Stone for peptide homologation, enabling diverse N-protected aryl glycines from aldehydes in three steps. Org Lett 16:3146-9
Pigza, Julie A; Han, Jeong-Seok; Chandra, Aroop et al. (2013) Total synthesis of the Lycopodium alkaloid serratezomine A using free radical-mediated vinyl amination to prepare a ýý-stannyl enamine linchpin. J Org Chem 78:822-43
Davis, Tyler A; Dobish, Mark C; Schwieter, Kenneth E et al. (2012) Preparation of H,(4) PyrrolidineQuin-BAM (PBAM). Organic Synth 89:380-393
Leighty, Matthew W; Shen, Bo; Johnston, Jeffrey N (2012) Enantioselective synthesis of ýý-oxy amides via Umpolung amide synthesis. J Am Chem Soc 134:15233-6
Chandra, Aroop; Johnston, Jeffrey N (2011) Total synthesis of the chlorine-containing hapalindoles K, A, and G. Angew Chem Int Ed Engl 50:7641-4
Srinivasan, Jayasree M; Mathew, Priya A; Williams, Amie L et al. (2011) Stereoselective synthesis of complex polycyclic aziridines: use of the Bronsted acid-catalyzed aza-Darzens reaction to prepare an orthogonally protected mitomycin C intermediate with maximal convergency. Chem Commun (Camb) 47:3975-7
Johnston, Jeffrey N (2011) A chiral N-phosphinyl phosphoramide: another offspring for the sage phosphoric acid progenitor. Angew Chem Int Ed Engl 50:2890-1

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