and Relevance 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 rising cost due to the large number of steps required to prepare complex peptides, 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. In the long term, this innovative approach to 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) and heterocyclic small molecules. Peptides have increasingly impacted human health through their use as therapeutics ? so-called biologics ? while heterocycles are platforms common to drug development. The development of innovative new methods for their synthesis stand to further accelerate the discovery and development of a wide range of therapeutics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Yang, Jiong
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Vanderbilt University Medical Center
Schools of Arts and Sciences
United States
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Batiste, Suzanne M; Johnston, Jeffrey N (2018) Evidence for Ion-Templation During Macrocyclooligomerization of Depsipeptides. J Am Chem Soc 140:4560-4568
Tokumaru, Kazuyuki; Bera, Kalisankar; Johnston, Jeffrey N (2017) 1,3,4-Oxadiazole and Heteroaromatic-Fused 1,2,4-Triazole Synthesis using Diverted Umpolung Amide Synthesis. Synthesis (Stuttg) 49:4670-4675
Tokumaru, Kazuyuki; Johnston, Jeffrey N (2017) A convergent synthesis of 1,3,4-oxadiazoles from acyl hydrazides under semiaqueous conditions. Chem Sci 8:3187-3191
Lim, Victoria T; Tsukanov, Sergey V; Stephens, Amanda B et al. (2016) Enantioselective Synthesis of ?-Bromonitroalkanes for Umpolung Amide Synthesis: Preparation of tert-Butyl ((1R)-1-(4-(benzyloxy)phenyl)-2-bromo-2-nitroethyl)carbamate. Organic Synth 93:88-99
Batiste, Suzanne M; Johnston, Jeffrey N (2016) Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control. Proc Natl Acad Sci U S A 113:14893-14897
Schwieter, Kenneth E; Johnston, Jeffrey N (2015) Enantioselective Synthesis of D-?-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
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
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
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

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