Three-Component Synthesis of 1,4-Diazepin-5-ones and the Construction of γ-Turn-like Peptidomimetic Libraries

Fenster, Erik; Rayabarapu, Dinesh Kumar; Zhang, Mianji; Mukherjee, Sampa; Hill, David R.; Neuenswander, Ben; Schoenen, Frank J.; Hanson, Paul R.; Aubé, Jeffrey

doi:10.1021/cc700174c

Cited by 24 publications

(12 citation statements)

References 45 publications

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“…Schmidt reactions related to those shown in panels b and c were first developed during total synthesis efforts toward lepadiformine and cylindricine alkaloids 39,40 . The azido alcohol-mediated Schmidt reaction has been previously used for building a library of γ-turn mimetics 41 . We prepared most of the scaffolds in racemic form as there was no reason to favor a particular enantiomer for broad screening, often in straightforward biochemical assays (in a few cases, we did make scaffolds from L-configured amino-acid derivatives).…”

Section: Resultsmentioning

confidence: 99%

Probing chemical space with alkaloid-inspired libraries

et al. 2014

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Screening of small molecule libraries is an important aspect of probe and drug discovery science. Numerous authors have suggested that bioactive natural products are attractive starting points for such libraries, due to their structural complexity and sp3-rich character. Here, we describe the construction of a screening library based on representative members of four families of biologically active alkaloids (Stemonaceae, the structurally related cyclindricine and lepadiformine families, lupin, and Amaryllidaceae). In each case, scaffolds were based on structures of the naturally occurring compounds or a close derivative. Scaffold preparation was pursued following the development of appropriate enabling chemical methods. Diversification provided 686 new compounds suitable for screening. The libraries thus prepared had structural characteristics, including sp3 content, comparable to a basis set of representative natural products and were highly rule-of-five compliant.

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Section: Resultsmentioning

confidence: 99%

Probing chemical space with alkaloid-inspired libraries

et al. 2014

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“…100 The example shown utilized a sublibrary of differently substituted thiophenols in the ring -opening step. By modestly substituting R 1 , R 2 , and R 3 with four different groups each, libraries containing up to 64 variations of Markush structure 105 were readily generated.…”

Section: Schmidt Rearrangements Of Hydroxyalkyl Azides Toward Biologimentioning

confidence: 99%

Schmidt Rearrangement Reactions with Alkyl Azides

Grecian¹,

Aubé

2009

Organic Azides

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The sobriquet ' Schmidt reaction ' refers to a number of related processes in which hydrazoic acid or an alkyl azide reacts with an electrophile. 1 -6 The product obtained will depend on the reaction partner (carboxylic acids generate amines, aldehydes give nitriles and formamides, and ketones provide amides, respectively) but all of these reactions have certain features in common. They are the initial nucleophilic addition of the azide component to an electrophile (usually promoted by acid) eventually followed by a rearrangement step driven by the energetically favorable loss of nitrogen. The classical Schmidt reaction of hydrazoic acid with ketones is generally considered to involve an intermediate dehydration step. 7,8 Despite the diversity of reactions that comprise the Schmidt family, its single most common variant is shown in Scheme 7.1 . This overall process can be regarded as an insertion of NH between the carbonyl and an α alkyl group. 9 The development of this version of the Schmidt reaction predates the experience of anyone working in organic chemistry today (Schmidt ' s original report was in 1924) but the extension of the concept to nucleophilic alkyl azides is a decidedly contemporary development. For example, if one compares the two reactions shown in Scheme 7.2 , it is clear that the direct insertion of an alkyl azide into cyclohexanone allows for the introduction of additional nitrogen atom substitution and, in the case of an alkyl azide tethered to a carbonyl substrate, the possibility of an intramolecular reaction. The goal of this chapter

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“…24 Benzylation and triazolation are useful diversification reactions in medicinal chemistry, high-throughput chemistry, and diversity-oriented synthesis (DOS). 25 The benzylation of amines and alcohols also serves as one of the most utilized protecting group strategies in organic synthesis due to its easy incorporation and removal. 26 While these uses have spurred development of a number of alternative approaches to benzylation 27 and triazolation, we believe the generation of the analogous silica-oligomeric benzyl phosphate (Si-OBP n ) and triazole phosphate (Si-OTP n ) reagents could find efficient, safe, and cost effective applications in chemical synthesis and library production.…”

Section: Introductionmentioning

confidence: 99%

Silica-Supported Oligomeric Benzyl Phosphate (Si-OBP) and Triazole Phosphate (Si-OTP) Alkylating Reagents

et al. 2015

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The syntheses of silica-supported oligomeric benzyl phosphates (Si-OBPn) and triazole phosphates (Si-OTPn) using ring-opening metathesis polymerization (ROMP) for use as efficient alkylating reagents is reported. Ease of synthesis and grafting onto the surface of norbornenyl-tagged (Nb-tagged) silica particles has been demonstrated for benzyl phosphate and triazole phosphate monomers. It is shown that these silica polymer hybrid reagents, Si-OBPn and Si-OTPn, can be used to carry out alkylation reactions with an array of different nucleophiles to afford the corresponding benzylated and (triazolyl)methylated products in good yield and high purity.

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Three-Component Synthesis of 1,4-Diazepin-5-ones and the Construction of γ-Turn-like Peptidomimetic Libraries

Cited by 24 publications

References 45 publications

Probing chemical space with alkaloid-inspired libraries

Probing chemical space with alkaloid-inspired libraries

Schmidt Rearrangement Reactions with Alkyl Azides

Silica-Supported Oligomeric Benzyl Phosphate (Si-OBP) and Triazole Phosphate (Si-OTP) Alkylating Reagents

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