Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aube rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.

Organic Azides: An Exploding Diversity of a Unique Class of Compounds

Virtual screening : an overview

Schiff bases: A short review of their antimicrobial activities

1. Peptoids 419 2. Oligocarbamates 420 3. Oligoureas 420 4. Vinylogous Sulfonyl Peptides 420 5. Peptidosulfonamides 420 6. Azatides 420 7. Ketides 420 D. Small Molecule Libraries 420 1. Acyclic Libraries 422 2. Libraries on Preformed Scaffolds 422 3. Heterocyclic Libraries 423 4. Structurally Heterogeneous Libraries 427 E. Cleavable Linkers 428 1. Single Cleavable Linkers 428 2. Multiply Cleavable Linkers 429 IV. Screening Methods 432 A. On-Bead Screening 432 1. Binding Assay 432 2. Functional Assay 434 B. Solution-Phase Screening 434 1. The 96-Well Two-Stage Releasable Assays 435

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The “One-Bead-One-Compound” Combinatorial Library Method

Synthesis of secondary amines

Combinatorial Organic Synthesis of Highly Functionalized Pyrrolidines: Identification of a Potent Angiotensin Converting Enzyme Inhibitor from a Mercaptoacyl Proline Library

Trimethylorthoformate: A mild and effective dehydrating reagent for solution and solid phase imine formation

Encoded combinatorial organic synthesis has recently emerged as a powerful tool for the discovery of biologically active compounds from complex chemical libraries This report describes a new encoding methodology that uses chemically robust secondary amines as tags These amines are incorporated into an N-[(dialkylcarbamoyl)methyl]glycine-coding oligomer through simple chemistry that is compatible with a wide range of polymer-supported transformations useful in combinatorial synthesis In the decoding process acidic hydrolysis of the tagging polymer regenerates the secondary amines, which after dansylation are resolved and detected at sub-picomole levels by reversed-phase HPLC The versatility of this strategy is demonstrated here by encoded syntheses of members of several representative heterocyclic compound classes, including β-lactams, 4-thiazolidinones, and pyrrolidines

Versatile approach to encoding combinatorial organic syntheses using chemically robust secondary amine tags

The application of a new encoding technology for drug discovery is described. A combinatorial library of mercaptoacyl pyrrolidines has been prepared on a beaded polymeric support. Each polymer bead carries one library constituent in association with an oligomeric “tag,” the structure of which is a record of the specific reagents from which that library member was prepared. After the ligands were solubilized, an array of such beads was screened for angiotensin-converting enzyme inhibitory activity, and the structures of active pyrrolidines were deduced by analysis of the associated tags at sub-picomole levels. Several extremely potent enzyme inhibitors were identified, many from multiple beads. The most potent inhibitor was found to have a Ki of 160 pM, ≈3-fold more active than captopril in the same assay. Direct comparison with iterative deconvolution shows that the encoded screening strategy is a much more efficient means for extracting information from such compound collections, producing more data on a larger number of active structures.

https://www.pnas.org/content/pnas/94/7/2805.full.pdf

Martin M. Murphy

Papers

Combinatorial Organic Synthesis of Highly Functionalized Pyrrolidines: Identification of a Potent Angiotensin Converting Enzyme Inhibitor from a Mercaptoacyl Proline Library

Trimethylorthoformate: A mild and effective dehydrating reagent for solution and solid phase imine formation

Versatile approach to encoding combinatorial organic syntheses using chemically robust secondary amine tags

Encoded combinatorial chemistry: Synthesis and screening of a library of highly functionalized pyrrolidines

Convergent approaches to the Vitamin D skeleton using a transition metal catalyzed carbometalation/capture strategy