Diversity-Oriented Organic Synthesis Research Articles

Interrupted Nef and Meyer Reactions: A Growing Point for Diversity-Oriented Synthesis Based on Nitro Compounds.

The Nef reaction (nitro to carbonyl group conversion) and related Meyer reaction are among the key transformations of aliphatic nitro compounds. The interrupted versions of these reactions in which the normal pathway is redirected to a different end product by an external nucleophile are much less common, albeit these processes substantially increase the synthetic potential of nitro compounds. In this review, examples of interrupted Nef and Meyer reactions are summarized, and the prospects of this methodology in diversity-oriented organic synthesis are analyzed. The bibliography contains 90 references.

Biosynthetically Inspired Transformation of Iboga to Monomeric Post-iboga Alkaloids

Summary Organisms have evolved to produce various natural products from a common precursor as a means of maximizing the number of secondary metabolites, thus acquiring selectional advantages. By adopting nature's divergent biosynthetic strategy, we transformed (+)-catharanthine to various iboga and post-iboga alkaloids, including (−)-conodusine A, (+)-conodusines B and C, (−)-voatinggine, (−)-tabertinggine, and (+)-dippinine B. Well-orchestrated oxidations and reorganizations of catharanthine derivatives enabled chemical access to these natural products.

Synthesis of 5-pentafluorosulfanyl indazoles

An efficient method for the synthesis of 5-SF5 substituted indazoles from commercially available 4-nitro-(pentafluorosulfanyl)benzene through vicarious nucleophilic substitution of hydrogen (VNS) reaction, reduction of nitro group and cyclization of resulting anilines were described. Transformations of 5-SF5-indazoles led to a variety of SF5-substiuted heteroarenes that can serve as a versatile building block for diversity-oriented organic synthesis.

ChemInform Abstract: Target- and Diversity-Oriented Organic Synthesis in Drug Discovery

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Diversity-Oriented Synthesis and Solid-Phase Organic Synthesis Under Controlled Microwave Heating

Diversity-oriented organic synthesis (DOS) and solid-phase organic synthesis (SPOS) are proven technologies for generating small molecule libraries for chemical genetics studies. Integration of controlled microwave heating with DOS and SPOS not only speeds up the library preparation process but also offers unique opportunities in tackling issues which are hardly addressed by thermal heating. Microwave-assisted synthesis is illustrated for (a) highly regioselective Wittig olefination of cycloalkanones by accurate regulation of temperature; (b) tandem Wittig-IMDA sequence toward stereochemical diversity of gamma-butyrolactones; (c) one-pot alkylation-amidation approach toward appendage diversity through use of building blocks; and (d) one-pot U-4CR-annulation strategy toward skeletal diversity via careful reaction design. Microwave-assisted solid-phase organic synthesis (MASPOS) is highlighted by incorporating with split-pool combinatorial synthesis (SPCS) of indole sulfonamides via a key on-resin Cu(II)- or Pd(II)-catalyzed heteroannulation under microwave heating. Design and fabrication of a novel diglycine-derived catlinker are described and its role in facilitating on-resin reaction is evaluated. A traceless synthesis of indole sulfonamides via microwave-assisted Cu(II)-catalyzed heteroannulation of the catlinker-tethered substrates is also given.

Diversity-Oriented Synthetic Approach to Naturally Abundant S-Amino Acid Based Benzannulated Enantiomerically Pure Medium Ring Heterocyclic Scaffolds Employing Inter- and Intramolecular Mitsunobu Reactions

The diversity-oriented organic synthesis of enantiomerically pure benzannulated oxazepine, diazepine, thiazepine, oxazocine, and diazocine scaffolds is described from easily accessible naturally occurring S-amino acids as chiral synthons. Inter- and intramolecular Mitsunobu reactions for the formation of carbon-nitrogen, carbon-oxygen, and carbon-sulfur bonds have been used as key transformations to construct these biologically important privileged heterocycles. This is the first example where the Mitsunobu approach has been utilized for the construction of S-amino acid based seven- and eight-membered ring systems.

Simultaneous accumulation of both skeletal and appendage-based diversities on tandem Ugi/Diels–Alder products

Diversity-oriented organic synthesis (DOS) is a key concept for construction of skeletally diverse small molecule libraries to discover drug-like small molecules. Here, we describe a DOS class to transform a complex 7-oxanorbornene skeleton, which is readily accessible by a tandem Ugi/Diels–Alder reaction, into two heterotricycle skeletons selectively by using tandem ROM/CM/RCM reaction. In the present study, the mode of cyclization is pre-encoded by building blocks used in the complexity-generating tandem Ugi/Diels–Alder reaction. Since variable alkenes can be used in the CM reaction, our approach can be extended to construct both skeleton- and appendage-diverse small molecule libraries.

The site-selective functionalization of halogen-bearing phenols: an exercise in diversity-oriented organometallic synthesis

The organometallic approach to diversity-oriented organic synthesis was subjected to a further test, this time in the phenol series. The model compounds selected were 2,3,6-trifluorophenol, the three isomers of (trifluoromethoxy)phenol and the three isomers of chlorophenol. A combination of optionally site selective metalations and protective group-controlled metalations enabled the selective generation of several isomeric intermediates in each case and their subsequent conversion into functionalized derivatives, in particular hydroxybenzoic acids.

1-Isocyano-2-dimethylamino-alkenes: Versatile Reagents in Diversity-Oriented Organic Synthesis

1-Isocyano-2-dimethylamino-alkenes are versatile and multifunctional reagents in organic synthesis. Two useful protocols are given for multicomponent reactions (MCRs) for the assembly of a 6-oxo-1,4,5,6-tetrahydropyrazine-2- carboxylic acid methyl ester derivative and a highly substituted thiazole. The procedures, in a modified set-up, are useful for array synthesis.

Rapid diversity-oriented synthesis in microtiter plates for in situ screening of HIV protease inhibitors.

Since the early days of the discovery of HIV-1 protease (HIV-1 PR), this enzyme has been selected as an important target for the inhibition of viral replication. The enormous effort over the past two decades to develop effective molecules that inhibit the HIV1 PR has resulted in the discovery of drugs that have dramatically improved the quality of life and survival of the patients infected with HIV-1. To date there are six different HIV-1 PR inhibitors (PI) that are commercially available. These drugs are administered in combination with the reverse transcriptase inhibitors in what is called TMhighly active anti-retroviral therapy (HAART)∫. Unfortunately, many drug-resistant and cross-resistant mutant HIV-1 PRs have been identified, thus hampering long term suppression of the virus and resulting in return of AIDS symptoms. Therefore, the development of new protease inhibitors, which are efficacious against both the wild type and drug resistant HIV-1 PR and less prone to development of resistance, is urgently needed. During the last decade, the number and throughput of biological assays of protease activity has notably increased. However, the high rates of HIV-1 PR mutation still outpace conventional drug discovery efforts, mostly because of limitations associated with identification of the lead structures and, to a greater extent, slow structure ± activity profiling. While the former can be improved by rational design and computational studies, rapid synthesis of diverse analogues and their optimization still remains a challenge. We have recently developed a new strategy to facilitate the drug discovery process: diversityoriented organic synthesis in microtiter plates followed by in situ screening without product isolation and protecting group manipulation. This strategy was demonstrated with the use of amide-forming reaction in a rapid identification of new potent HIV protease inhibitors. Click chemistry has emerged as a strategy for the rapid and efficient assembly of molecules with diverse functionality on both laboratory and production scales. Enabled by a few nearly perfect reactions, it guarantees reliable synthesis of the desired products in high yield and purity. Modularity, selectivity, and wide scope make click chemistry ideal for achieving diversity in just a few steps and with no need for further purification. Advantages of click chemistry in biological studies have recently been demonstrated in several applications: construction of fluorescent oligonucleotides for DNA sequencing, in situ assembly of acetylcholinesterase inhibitors, chemically orthogonal high fidelity bioconjugation, and activity-based protein profiling in whole proteomes. In principle, this type of chemistry is well suited for microscale synthesis and for biological screening in situ. To demonstrate its feasibility we have used the copper(I)-catalysed triazole formation for the synthesis of sugar arrays in the above mentioned microtiter plate format, followed by in situ screening of glycosyltransferase inhibitors and enzyme glycosylation. Herein, we report an expedient approach to the discovery of novel HIV-1 PR inhibitors based on the latest advance in the copper(I)-catalyzed 1,2,3-triazole synthesis. 11] This highly reliable process, which proceeds well in aqueous solvents and tolerates virtually all functional groups without the need for protection, made it possible to quickly generate the desired libraries of potential inhibitors and to screen them directly in microtiter plates, without any purification, against HIV-1 PR and its mutants. The efficacy of hydroxyethylamine isosteres as transition-state mimics and as backbone replacements of amide bonds in the P1/P1 position of aspartyl protease inhibitors has been well documented, most notably in incorporation in the structures of three commercially available drugs, amprenavir, nelfinavir, and saquinavir. We, therefore, envisioned a library of compounds which retained this core, while diversifying the P2/P2 residues to generate new inhibitors. Starting from the optically active epoxy amine 1, two different azide cores were prepared as summarized in Scheme 1. Epoxy amine 1 in H2O/EtOH was

Pathway Development and Pilot Library Realization in Diversity‐Oriented Synthesis. Exploring Ferrier and Pauson—Khand Reactions on a Glycal Template

AbstractFor Abstract see ChemInform Abstract in Full Text.

An Alkynylboronic Ester Annulation: Development of Synthetic Methods for Application to Diversity-Oriented Organic Synthesis

An Alkynylboronic Ester Annulation: Development of Synthetic Methods for Application to Diversity-Oriented Organic Synthesis

An alkynylboronic ester annulation: development of synthetic methods for application to diversity-oriented organic synthesis.

An alkynylboronic ester annulation: development of synthetic methods for application to diversity-oriented organic synthesis.

A Chemical Approach Towards Understanding the Mechanism and Reversal of Drug Resistance in Plasmodium falciparum: Is it Viable?

Genetic and biochemical approaches to studies of drug resistance mechanisms in Plasmodium falciparum have raised controversies and contradictions over the past several years. A different and novel chemical approach to this important problem is desirable at this point in time. Recently, the molecular basis of drug resistance in P. falciparum has been associated with mutations in the resistance genes, Chloroquine Resistance Transporter (PfCRT) and the P-glycoprotein homologue (Pgh1). Although not the determinant of chloroquine resistance in P. falciparum, mutations in Pgh1 have important implications for resistance to other antimalarial drugs. Because it is mutations in the aforementioned resistance genes rather than overexpression that has been associated with drug resistance in malaria, studies on mechanisms of drug resistance and its reversal by chemosensitisers should benefit from a chemical approach. Target-oriented organic synthesis of chemosensitisers against proteins implicated in drug resistance in malaria should shed light on mechanism of drug resistance and its reversal in this area. The effect of structurally diverse chemosensitisers should be examined on several putative resistance genes in P. falciparum to deal with antimalarial drug resistance in the broadest sense. Therefore, generating random mutations of these resistance proteins and subsequent screening in search of a specific phenotype followed by a search for mutations and/or chemosensitisers that affect a specific drug resistance pathway might be a viable strategy. This diversity-oriented organic synthesis approach should offer the means to simultaneously identify resistance proteins that can serve as targets for therapeutic intervention (therapeutic target validation) and chemosensitisers that modulate the functions of these proteins (chemical target validation).

Pathway Development and Pilot Library Realization in Diversity-Oriented Synthesis: Exploring Ferrier and Pauson-Khand Reactions on a Glycal Template

Through a correlation of the ability of small molecules to bind biological macromolecules and their ability to modulate cellular and organismal processes, chemistry can inform biology and vice versa. Diversity-oriented organic synthesis (DOS), which aims to provide structurally complex and diverse small molecules efficiently, can play a key role in such chemical genetic studies. Here we illustrate the trial-and-error experimentation that can refine an initial pathway-planning exercise and result eventually in an effective diversity pathway. By exploring Ferrier and Pauson-Khand reactions on a glycal template, we have developed efficient and stereoselective syntheses of tricyclic compounds. In this pathway, diversity results from the substituents and their spatial relationships about the tricyclic rings. A pilot split-pool library synthesis of 2500 tricyclic compounds highlights the use of planning considerations in DOS and a “one-bead, one-stock solution” technology platform. Additionally, it illustrates a promising synthetic pathway for future chemical genetic studies.

A Boronic Ester Annulation Strategy for Diversity-Oriented Organic Synthesis

In nur ein bis vier Schritten lassen sich komplexe Strukturen mit Ringen, Stereozentren und ungesättigten Einheiten aufbauen. Dies gelingt durch eine neue Anellierung ungesättigter Boronsäuremonoester mit Allyl- oder Propargylalkoholen (siehe Schema).

A boronic ester annulation strategy for diversity-oriented organic synthesis.

A boronic ester annulation strategy for diversity-oriented organic synthesis.

Asymmetric Catalysis in Diversity-Oriented Organic Synthesis: Enantioselective Synthesis of 4320 Encoded and Spatially Segregated Dihydropyrancarboxamides We thank the National Institute of General Medical Sciences (GM-52067) for support of this research, and Dr. John Tallarico and Max Narovlyansky at the ICCB for generously providing resin for the library synthesis. We thank Dr. Helen Blackwell and Lucy Pérez for expert help with

Small molecules have been used to explore many facets of biology for over a century. However, research in biology is not routinely performed using this approach, in the way that it is with biochemical, genetic, and increasingly, genomic approaches. Several problems limit the use of the former approach. Arguably, the primary one is the lack of routine access to structurally complex and diverse small molecules that can be used to modulate biological systems.[1] Diversityoriented organic synthesis, especially when coupled with an economical and efficient technology platform, offers the means to change this situation, as it aims to synthesize complex and diverse small molecules efficiently.[2] Diversityoriented synthesis is central to chemical genetics, which aims to explore biology with small molecules in a systematic way.[3] Although enantioselective catalysis is often used in targetoriented synthesis, it is still relatively underexplored in diversity-oriented synthesis.[4, 5] We have been interested in reactions catalyzed by bis(oxazoline)metal Lewis acid complexes because of their high efficiency, selectivity, and broad substrate tolerance.[6] We chose to concentrate on inverse electron demand heterocycloadditions of vinyl ethers and b,gunsaturated ketoesters (Scheme 1).[7, 8] An account of related cycloadditions on solid support has been described;[9] however, the reported reactions were performed in the presence of achiral catalysts and with the heterodiene bound to the PS solid support through the ester. We initially investigated this mode of cycloaddition and found it to be highly selective when the enantiomerically pure catalysts (S)or (R)-1 were used.[5, 8] However, in the interest of effectively functionalizing the cycloadduct, we found an alternative mode using support-bound vinyl ethers, linked to a macrobead through either carbon or oxygen, to be more effective.

Asymmetric Catalysis in Diversity-Oriented Organic Synthesis: Enantioselective Synthesis of 4320 Encoded and Spatially Segregated Dihydropyrancarboxamides

Die Herstellung von räumlich getrennten Stammlösungen von über 4000 Dihydropyrancarboxamiden 1 gelingt mit einer Diversitäts-orientierten Synthesestrategie unter Verwendung von enantioselektiven Katalysemethoden, Polystyrol-Makroharzkügelchen mit großem Fassungsvermögen, Kodierungen und „Split-Pool“-Verfahren. Supporting information for this article is available on the WWW under http://www.angewandte.com or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Split--pool synthesis of 1,3-dioxanes leading to arrayed stock solutions of single compounds sufficient for multiple phenotypic and protein-binding assays.

Diversity-oriented organic synthesis offers the promise of advancing chemical genetics, where small molecules are used to explore biology. While the split--pool synthetic method is theoretically the most effective approach for the production of large collections of small molecules, it has not been widely adopted due to numerous technical and analytical hurdles. We have developed a split--pool synthesis leading to an array of stock solutions of single 1,3-dioxanes. The quantities of compounds are sufficient for hundreds of phenotypic and protein-binding assays. The average concentration of these stock solutions derived from a single synthesis bead was determined to be 5.4 mM in 5 microL of DMSO. A mass spectrometric strategy to identify the structure of molecules from a split--pool synthesis was shown to be highly accurate. Individual members of the 1,3-dioxane library have activity in a variety of phenotypic and protein-binding assays. The procedure developed in this study allows many assays to be performed with compounds derived from individual synthesis beads. The synthetic compounds identified in these assays should serve as useful probes of cellular and organismal processes.