Secondary metabolites synthesized by nonribosomal peptide synthetases (NRPSs) display diverse and complex topologies and possess an impressive range of biological activities1,2 Much of this diversity derives from a synthetic strategy that entails the oxidation of both the chiral amino acid building blocks and the assembled peptide scaffolds pre-3 and post-assembly2. The vancomycin biosynthetic pathway is an excellent example of the range of oxidative transformations that can be performed by the iron-containing enzymes involved in its biosynthesis.4 However, because of the challenges associated with using such oxidative enzymes to carry out chemical transformations in vitro, chemical syntheses guided by these principles have not been fully realized outside of nature.5 In this manuscript, we report that two small-molecule iron catalysts are capable of facilitating the targeted C—H oxidative modification of amino acids and peptides with preservation of α-center chirality. Oxidation of proline to 5-hydroxyproline furnishes a versatile intermediate that can be transformed to rigid arylated derivatives or flexible linear carboxylic acids, alcohols, olefins, and amines in both monomer and peptide settings. The value of this C—H oxidation strategy is demonstrated in its capacity for generating diversity: four 'chiral pool' amino acids are transformed to twenty-one chiral unnatural amino acids (UAAs) representing seven distinct functional group arrays; late-stage C—H functionalizations of a single proline-containing tripeptide furnish eight tripeptides, each having different UAAs. Additionally, a macrocyclic peptide containing a proline turn element is transformed via late-stage C—H oxidation to one containing a linear UAA.
Pyrido[1,2-a]indoles are known as medicinally and pharmaceutically important compounds, but there is a lack of efficient methods for their synthesis. We report a convenient and efficient route to these privileged structures starting from easily accessible 2-substituted pyridines and aryne precursors. A small library of compounds has been synthesized utilizing the developed method, affording variously substituted pyrido[1,2-a]indoles in moderate to good yields.
The reaction of 2-aminoaryl ketones and arynes generated by the treatment of various o-(trimethylsilyl)aryl triflates with CsF results in [4 + 2] annulation to afford substituted acridines in good yields.
The reaction of methyl indole-2-carboxylates and arynes affords a very efficient, high yielding synthesis of a novel indole-indolone ring system, which tolerates considerable functionality, is broad in scope and proceeds under mild reaction conditions. KeywordsAryne; Annulation; Indole Nitrogen-containing heterocycles exhibit a diverse array of favorable biological and pharmacological properties. The indole core, in particular, is the foundation for many well known medicinally active compounds. 1 Convenient methods for constructing fused indoles are of great value to medicinal chemists. 1,2 In addition, indolone derivatives possess potent biological activities. Thus, new methodologies for their synthesis contribute significantly to the pursuit of new drugs. 3 Of considerable current interest to medicinal chemists is the synthesis of new drug-like compounds in which two separate biologically interesting scaffolds, both independently known for their favorable activities, are fused. 2,4 Since both indoles and indolones are relevent core structures for pharmaceuticals, a hybrid thereof could potentially lead to a series of biologically active compounds (Fig. 1).Arynes have been used extensively in recent years in the construction of many heteroaromatic structures. 5 The highly electrophilic nature of benzyne is most suitable for cross coupling with various nucleophilic heteroatoms. If the substrate containing the nucleophilic heteroatom is tethered with a neighboring electrophile, such as a carbonyl group, intramolecular annulations often take place. 6 Recently, our group has reported annulations between ortho-heteroatom (N, O, and S) benzoates with arynes, producing a diverse array of medicinally relevant acridones, xanthones, and thioxanthones in good to excellent yields. 7 The proven success and utility of this novel methodology led us to envision a related [3+2] annulation involving the reaction of indole-2-carboxylate esters and arynes. Herein, we report the synthesis of a novel indoleindolone hybrid, a previously unexplored scaffold with respect to biological activity and materials applications, via the annulation of arynes by methyl indole-2-carboxylates (Scheme 1).* Corresponding author. Tel.: +1-515-294-4660; fax: +1-515-294-0105; e-mail: larock@iastate.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Initial experiments began with ethyl indole-2-carboxylate as our test substrate, but little success was realized using conditions similar to those of our previous annulation chemistry. 7 Switching to the methyl ester, however, produced a slight increase...
N-Unsubstituted β-lactams react with a molecule of aryne by insertion into the amide bond to form a 2,3-dihydroquinolin-4-one, which subsequently reacts with another molecule of aryne to form an acridone by extrusion of a molecule of ethylene. 2,3-Dihydroquinolin-4-ones react under the same reaction conditions to afford identical results. This is the first example of ethylene extrusion in aryne chemistry.
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