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Solid Phase Synthesis
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Solid Phase Synthesis

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: closed (15 May 2018) | Viewed by 41633

Special Issue Editor

Prof. Dr. Viktor Krchnak

E-Mail Website
Guest Editor
1. Department of Chemistry and Biochemistry, 251 Nieuwland Science Center, University of Notre Dame, Notre Dame, IN 46556, USA
2. Department of Organic Chemistry, Palacký University, 17. Listopadu 12, 771 46 Olomouc, Czech Republic
Interests: solid-phase synthesis; combinatorial chemistry; heterocycles; chiral molecular scaffold; iminium chemistry

Special Issue Information

Dear colleagues,

This Special Issue of Molecules is dedicated to “Solid-Phase Synthesis”. The concept of solid-phase (SP) peptide synthesis was revealed by Bruce Merrifield in 1963 and its potential for general organic chemistry was soon recognized. However, it was not until the onset of combinatorial chemistry in early 1990s when the application of SP organic synthesis started to flourish.

Today, SP synthesis is widely used particularly in the area of drug discovery. Critical advantages of SP synthesis include very efficient isolation of intermediates by washing resin beads. Consequently, high boiling solvents, such as DMF and DMSO, can be used beneficially without the need to evaporate them.

Drug discovery efforts benefited from the time efficient synthesis of compounds decks for high throughput screening as well as dedicated libraries for hit/lead optimization. Diversity oriented synthesis (DOS) that was mainly focused on synthesis of structurally dissimilar compounds has now shifted to biology oriented synthesis (BIOS) focused on the design of structures resembling natural products, including complex chiral molecular scaffolds with three-dimensional architecture.

This Special Issue will provide an opportunity to publish research results dedicated to all aspects of SP synthesis including, but not limited to, development of new chemical transformations, new resins, linkers, methodology, catalyst development, combinatorial synthesis, solid-phase reagents, synthesis of drug-like molecules, peptides, preparation of compound decks for high throughput screening, etc.

Prof. Viktor Krchnak
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • development of new chemical transformations
  • new resins
  • linkers
  • methodology
  • catalyst development
  • combinatorial synthesis
  • solid-phase reagents
  • synthesis of drug-like molecules
  • peptides
  • preparation of compound decks for high throughput screening

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Published Papers (8 papers)

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Research

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13 pages, 1862 KiB  
Article
Solid-Phase Synthesis and Circular Dichroism Study of β-ABpeptoids
by Ganesh A. Sable, Kang Ju Lee and Hyun-Suk Lim
Molecules 2019, 24(1), 178; https://doi.org/10.3390/molecules24010178 - 5 Jan 2019
Cited by 8 | Viewed by 4130
Abstract
The development of peptidomimetic foldamers that can form well-defined folded structures is highly desirable yet challenging. We previously reported on α-ABpeptoids, oligomers of N-alkylated β2-homoalanines and found that due to the presence of chiral methyl groups at α-positions, α-ABpeptoids were [...] Read more.
The development of peptidomimetic foldamers that can form well-defined folded structures is highly desirable yet challenging. We previously reported on α-ABpeptoids, oligomers of N-alkylated β2-homoalanines and found that due to the presence of chiral methyl groups at α-positions, α-ABpeptoids were shown to adopt folding conformations. Here, we report β-ABpeptoids having chiral methyl group at β-positions rather than α-positions as a different class of peptoids with backbone chirality. We developed a facile solid-phase synthetic route that enables the synthesis of β-ABpeptoid oligomers ranging from 2-mer to 8-mer in excellent yields. These oligomers were shown to adopt ordered folding conformations based on circular dichroism (CD) and NMR studies. Overall, these results suggest that β-ABpeptoids represent a novel class of peptidomimetic foldamers that will find a wide range of applications in biomedical and material sciences. Full article
(This article belongs to the Special Issue Solid Phase Synthesis)
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30 pages, 8711 KiB  
Article
Preparation and Use of a General Solid-Phase Intermediate to Biomimetic Scaffolds and Peptide Condensations
by J. Geno Samaritoni, Jacek G. Martynow, Martin J. O’Donnell and William L. Scott
Molecules 2018, 23(7), 1762; https://doi.org/10.3390/molecules23071762 - 18 Jul 2018
Cited by 2 | Viewed by 4324
Abstract
The Distributed Drug Discovery (D3) program develops simple, powerful, and reproducible procedures to enable the distributed synthesis of large numbers of potential drugs for neglected diseases. The synthetic protocols are solid-phase based and inspired by published work. One promising article reported that many [...] Read more.
The Distributed Drug Discovery (D3) program develops simple, powerful, and reproducible procedures to enable the distributed synthesis of large numbers of potential drugs for neglected diseases. The synthetic protocols are solid-phase based and inspired by published work. One promising article reported that many biomimetic molecules based on diverse scaffolds with three or more sites of variable substitution can be synthesized in one or two steps from a common key aldehyde intermediate. This intermediate was prepared by the ozonolysis of a precursor functionalized at two variable sites, restricting their presence in the subsequently formed scaffolds to ozone compatible functional groups. To broaden the scope of the groups available at one of these variable sites, we developed a synthetic route to an alternative, orthogonally protected key intermediate that allows the incorporation of ozone sensitive groups after the ozonolysis step. The utility of this orthogonally protected intermediate is demonstrated in the synthesis of several representative biomimetic scaffolds containing ozonolytically labile functional groups. It is compatible with traditional Fmoc peptide chemistry, permitting it to incorporate peptide fragments for use in fragment condensations with peptides containing cysteine at the N-terminus. Overall yields for its synthesis and utilization (as many as 13 steps) indicate good conversions at each step. Full article
(This article belongs to the Special Issue Solid Phase Synthesis)
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13 pages, 1643 KiB  
Article
Preparation of Enzyme-Activated Thapsigargin Prodrugs by Solid-Phase Synthesis
by Tomas Zimmermann, Søren Brøgger Christensen and Henrik Franzyk
Molecules 2018, 23(6), 1463; https://doi.org/10.3390/molecules23061463 - 15 Jun 2018
Cited by 8 | Viewed by 4607
Abstract
Since cells in solid tumors divide less rapidly than cells in the bone marrow or cells of the immune system, mitotic inhibitors often cause severe side effects when used for treatment of diseases like prostate cancer and breast cancer. One approach to overcome [...] Read more.
Since cells in solid tumors divide less rapidly than cells in the bone marrow or cells of the immune system, mitotic inhibitors often cause severe side effects when used for treatment of diseases like prostate cancer and breast cancer. One approach to overcome this problem involves attempts at developing drugs based on general cytotoxins, like calicheamicin and thapsigargin, which kill cells at all phases of the cell cycle. However, such toxins can only be used when efficient targeting to the malignant tissue is possible. In the case of thapsigargin, selectivity for tumor-associated cells is achieved by conjugating the drug to a peptide that is only cleaved in the vicinity of tumors to release the cytotoxic drug or an analog with retained activity. Solid-phase synthesis protocols were developed for preparation of three already validated prodrugs of thapsigargin: one prodrug cleavable by human kallikrein 2, one prodrug cleavable by prostate-specific antigen, and one prodrug cleavable by prostate-specific membrane antigen. Full article
(This article belongs to the Special Issue Solid Phase Synthesis)
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15 pages, 8032 KiB  
Article
Molecular Diversity by Olefin Cross-Metathesis on Solid Support. Generation of Libraries of Biologically Promising β-Lactam Derivatives
by Luciana Méndez, Andrés A. Poeylaut-Palena and Ernesto G. Mata
Molecules 2018, 23(5), 1193; https://doi.org/10.3390/molecules23051193 - 16 May 2018
Cited by 7 | Viewed by 3930
Abstract
The application of the reagent-based diversification strategy for generation of libraries of biologically promising β-lactam derivatives is described. Key features are the versatility of the linker used and the cross-metathesis functionalization at the cleavage step. From an immobilized primary library, diversity was expanded [...] Read more.
The application of the reagent-based diversification strategy for generation of libraries of biologically promising β-lactam derivatives is described. Key features are the versatility of the linker used and the cross-metathesis functionalization at the cleavage step. From an immobilized primary library, diversity was expanded by applying different cleavage conditions, leading to a series of cholesterol absorption inhibitor analogues together with interesting hybrid compounds through incorporation of a chalcone moiety. Full article
(This article belongs to the Special Issue Solid Phase Synthesis)
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12 pages, 1382 KiB  
Article
Traceless Solid-Phase Synthesis of [6,7,8 + 5,6,7]-Fused Molecular Frameworks
by Vanesa Giménez-Navarro and Viktor Krchňák
Molecules 2018, 23(5), 1090; https://doi.org/10.3390/molecules23051090 - 4 May 2018
Cited by 4 | Viewed by 4103
Abstract
We report two synthetic strategies for traceless solid-phase synthesis of molecular scaffolds comprising 6- to 8-membered rings fused with 5- to 7-membered rings. Traceless synthesis facilitated preparation of target molecules without any trace of polymer-supported linkers. The cyclization proceeded via acid-mediated tandem N [...] Read more.
We report two synthetic strategies for traceless solid-phase synthesis of molecular scaffolds comprising 6- to 8-membered rings fused with 5- to 7-membered rings. Traceless synthesis facilitated preparation of target molecules without any trace of polymer-supported linkers. The cyclization proceeded via acid-mediated tandem N-acylium ion formation followed by the nucleophilic addition of O- and C-nucleophiles. The presented synthetic strategy enabled, through the use of simple building blocks without any conformational preferences, the evaluation of the predisposition of different combinations of ring sizes to form fused ring molecular scaffolds. Compounds with any combination of [6,7 + 5,6,7] ring sizes were accessible with excellent crude purity. The 8-membered cyclic iminium was successfully fused only with the 5-membered cycle and larger fused ring systems were not formed, probably due to their instability. Full article
(This article belongs to the Special Issue Solid Phase Synthesis)
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12 pages, 6522 KiB  
Article
Solid-Phase Synthesis of Azole-Comprising Peptidomimetics and Coordination of a Designed Analog to Zn2+
by Aanchal Mohan, Allyson H. M. Koh, Gregory Gate, Anna L. Calkins, Kyra N. McComas and Amelia A. Fuller
Molecules 2018, 23(5), 1035; https://doi.org/10.3390/molecules23051035 - 28 Apr 2018
Cited by 7 | Viewed by 4007
Abstract
Peptidomimetics that can coordinate transition metals have a variety of potential applications as catalysts, sensors, or materials. A new modular peptidomimetic scaffold, the “azole peptoid”, is introduced here. We report methods for the solid-phase synthesis of eleven examples of trimeric N-substituted oligoamides [...] Read more.
Peptidomimetics that can coordinate transition metals have a variety of potential applications as catalysts, sensors, or materials. A new modular peptidomimetic scaffold, the “azole peptoid”, is introduced here. We report methods for the solid-phase synthesis of eleven examples of trimeric N-substituted oligoamides that include oxazole- or thiazole-functionalized backbones. The products prepared comprise a diversity of functionality, including a metal-coordinating terpyridine group. The modular synthetic approach enables ready preparation of analogs for specific applications. To highlight a potential use of this new synthetic scaffold, a trimeric azole peptoid functionalized with a terpyridine residue was prepared and studied. The characteristic 2:1 ligand:metal binding of this terpyridine-functionalized azole peptoid to Zn2+ in aqueous solution was observed. These studies introduce azole peptoids as a useful class of biomimetic molecules for further study and application. Full article
(This article belongs to the Special Issue Solid Phase Synthesis)
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8 pages, 1526 KiB  
Article
Convenient Synthesis of Thiohydantoins, Imidazole-2-thiones and Imidazo[2,1-b]thiazol-4-iums from Polymer-Supported α-Acylamino Ketones
by Petra Králová, Michal Maloň, Hiroyuki Koshino and Miroslav Soural
Molecules 2018, 23(4), 976; https://doi.org/10.3390/molecules23040976 - 23 Apr 2018
Cited by 7 | Viewed by 4844
Abstract
The preparation of 5-methylene-thiohydantoins using solid-phase synthesis is reported in this paper. After sulfonylation of immobilized Ser (t-Bu)-OH with 4-nitrobenzenesulfonyl chloride followed by alkylation with various bromoketones, the 4-Nos group was removed and the resulting polymer-supported α-acylamino ketones reacted with Fmoc-isothiocyanate. [...] Read more.
The preparation of 5-methylene-thiohydantoins using solid-phase synthesis is reported in this paper. After sulfonylation of immobilized Ser (t-Bu)-OH with 4-nitrobenzenesulfonyl chloride followed by alkylation with various bromoketones, the 4-Nos group was removed and the resulting polymer-supported α-acylamino ketones reacted with Fmoc-isothiocyanate. Cleavage of the Fmoc protecting group was followed by the spontaneous cyclative cleavage releasing the 5-methylene-thiohydantoin derivatives from the polymer support. Reduction with triethylsilane (TES) yielded the corresponding 5-methyl-thiohydantoins. When Fmoc-isothiocyanate was replaced with alkyl isothiocyanates, the trifluoroacetic acid (TFA) mediated cleavage from the polymer support, which was followed by the cyclization reaction and the imidazo[2,1-b]thiazol-4-iums were obtained. Their conversion in deuterated dimethylsulfoxide led to imidazole-2-thiones. Full article
(This article belongs to the Special Issue Solid Phase Synthesis)
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Review

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25 pages, 10907 KiB  
Review
Recent Reports of Solid-Phase Cyclohexapeptide Synthesis and Applications
by Allan M. Prior, Taylor Hori, Ashriel Fishman and Dianqing Sun
Molecules 2018, 23(6), 1475; https://doi.org/10.3390/molecules23061475 - 18 Jun 2018
Cited by 11 | Viewed by 10553
Abstract
Macrocyclic peptides are privileged scaffolds for drug development and constitute a significant portion of macrocyclic drugs on the market today in fields spanning from infectious disease to oncology. Developing orally bioavailable peptide-based drugs remains a challenging task; however, macrocyclization of linear peptides can [...] Read more.
Macrocyclic peptides are privileged scaffolds for drug development and constitute a significant portion of macrocyclic drugs on the market today in fields spanning from infectious disease to oncology. Developing orally bioavailable peptide-based drugs remains a challenging task; however, macrocyclization of linear peptides can be an effective strategy to improve membrane permeability, proteolytic stability, oral bioavailability, and overall drug-like characteristics for this class. Significant advances in solid-phase peptide synthesis (SPPS) have enabled the efficient construction of macrocyclic peptide and peptidomimetic libraries with macrolactamization being performed on-resin or in solution phase. The primary goal of this review is to summarize solid-phase cyclohexapeptide synthesis using the on-resin and solution-phase macrocyclization methodologies published since 2013. We also highlight their broad applications ranging from natural product total synthesis, synthetic methodology development, and medicinal chemistry, to drug development and analyses of conformational and physiochemical properties. Full article
(This article belongs to the Special Issue Solid Phase Synthesis)
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