Combinatorial Chemistry & High Throughput Screening, Vol. 5, No. 3, 2002

Development and Applications of Polymer-Supported Reagents and Ion Exchange Resins in Organic Synthesis and Combinatorial Chemistry

Guest Editor: Stephen J. Shuttleworth

Synthesis of Trifluoromethyl Ketones Using Polymer-Supported Reagents Pp.197-199

I.R. Baxendale, S.V. Ley, W. Lumeras and M. Nesi

[Abstract] [Purchase Issue/Articles]

Optimisation of Polystyrene Resin-supported Pt Catalysts in Room Temperature, Solvent-less, Oct-l-ene Hydrosilylation using Methyldichlorosilane Pp.201-209

R. Drake, R. Dunn, D.C. Sherrington and S.J. Thomson

[Abstract] [Purchase Issue/Articles]

The Use of a Supported Base and Strong Cation Exchange (SCX) Chromatography to Prepare a Variety of Structurally-Diverse Molecular Libraries Prepared by Solution-Phase Methods Pp.211-218

M.G. Organ, C.E. Dixon, D. Mayhew, D.J. Parks and E.A. Arvanitis

[Abstract] [Purchase Issue/Articles]

Parallel Synthesis of Tri- and Tetrasubstituted Ureas from Carbamoyl Imidazolium Salts Pp.219-232

Robert A. Batey, Ming Shen, V. Santhakumar and Chiaki Yoshina-Ishii

[Abstract] [Purchase Issue/Articles]

Developing Soluble Polymers for High-Throughput Synthetic Chemistry Pp.233-240

Carsten Spanka, Paul Wentworth Jr. and Kim D. Janda

[Abstract] [Purchase Issue/Articles]

Synthesis of Combinatorial Libraries Based On Terpenoid Scaffolds Pp.241-248

A. Pathak, S.K. Singh, M.A. Farooq Biabani, D.K. Kulshreshtha, S.K. Puri, S. Srivastava and B. Kundu

[Abstract] [Purchase Issue/Articles]

Automated Parallel Solid-Phase Synthesis of Non-Peptide CCR1 Receptor Antagonists Pp.249-251

Brad O. Buckman, Ameen Ghannam, Angela Li, Meina Liang, Raju Mohan and Howard P. Ng

[Abstract] [Purchase Issue/Articles]

Parallel Synthesis of PNA-Peptide Conjugate Libraries Pp.253-259

Satish Kumar Awasthi and Peter E. Nielsen

[Abstract] [Purchase Issue/Articles]

Abstracts

[Back to top] [Purchase Issue/Articles]
Synthesis of Trifluoromethyl Ketones Using Polymer-Supported Reagents

I.R. Baxendale, S.V. Ley, W. Lumeras and M. Nesi

A two step synthesis of trifluoromethyl ketones from aldehydes is reported. A combination of polymer-supported reagents and sequestering agents were employed to effect the transformation without the need for chromatographic purification.

[Back to top] [Purchase Issue/Articles]
Optimisation of Polystyrene Resin-supported Pt Catalysts in Room Temperature, Solvent-less, Oct-l-ene Hydrosilylation using Methyldichlorosilane

R. Drake, R. Dunn, D.C. Sherrington and S.J. Thomson

Six precursor resins with systematic variation of porous parameters were prepared by suspension polymerisation using specific compositions of divinylbenzene, styrene vinylbenzyl chloride (VBC) and 2- ethylhexan-l-ol (a porogen). Surface areas from N2 sorption and BET analysis were ~ 2-170 m2g-1. The VBC content in each case was 38 mol% and these groups were aminated using the sodium salt of trimethylethylene diamine. Pt was introduced onto each resin at three different loadings (~0.03, ~ 0.2 and ~ 0.4 mmol g-1) by appropriate manipulation of K2PtCl6.

The matrix of 18 resin-supported Pt complexes was then assessed for catalytic activity in the room temperature, solvent-less, hydrosilylation of oct-l-ene using methyldichlorosilane such that alkene: silane: Pt ratio was fixed at 2:1:1x10-3. Though all the catalysts showed activity lower than that of homogeneous Speier’s catalyst, most were sufficiently active to be potentially valuable heterogeneous catalysts in the laboratory, and indeed the plant. The most lightly loaded resins proved to be the least active. The remainder were recycled 5 times, and the best performers, the most highly loaded species, a further 5 times making 10 consecutive uses in all. A strong dependence on the porous structure of the resins was demonstrated with the activity rising systemically with the surface area. The two highest surface area highest loaded species displayed good activity even when used for the tenth time. The level of concurrent alkene isomerisation observed was very low throughout (<1%) making these heterogeneous species very selective as well as highly active. Overall the derived catalysts are excellent candidates for use in the research laboratory, and with further development could also be valuable in continuous processes.

[Back to top] [Purchase Issue/Articles]
The Use of a Supported Base and Strong Cation Exchange (SCX) Chromatography to Prepare a Variety of Structurally-Diverse Molecular Libraries Prepared by Solution-Phase Methods

M.G. Organ, C.E. Dixon, D. Mayhew, D.J. Parks and E.A. Arvanitis

The preparation of molecular libraries of aminomethylbiaryls, allylic amines, and ethanolamines using solution-phase methodology is described. In particular, the use of a solid-supported base reagent (PTBD resin) and strong cation exchange(SCX) resin to effect 'catch and release' purification across these diverse libraries is highlighted.

[Back to top] [Purchase Issue/Articles]
Parallel Synthesis of Tri- and Tetrasubstituted Ureas from Carbamoyl Imidazolium Salts

Robert A. Batey, Ming Shen, V. Santhakumar and Chiaki Yoshina-Ishii

A method for producing tri- and tetrasubstituted ureas from carbamoyl imidazolium salts is presented. Carbamoyl imidazolium salts are prepared from the reaction of N,N’–carbonyldiimidazole (CDI) with secondary amines, followed by alkylation with iodomethane. These stable salts can be stored for extended periods and are effective electrophilic carbamoylation reagents. Primary and secondary amines add to carbamoyl imidazolium salts at room temperature to give tri- and tetrasubstituted ureas in excellent yields. This reaction was used to synthesize ureas using both liquid-liquid extraction and solid-phase extraction (cation exchange) purification techniques. Liquid-liquid extraction affords the product ureas more cleanly than cationic exchange. A series of urea compounds were synthesized using parallel synthesis techniques in high yields and with suitable purity for routine in vitro biological tests. These studies validate the utility of carbamoyl imidazolium salts as useful “building blocks” for combinatorial library synthesis.

[Back to top] [Purchase Issue/Articles]
Developing Soluble Polymers for High-Throughput Synthetic Chemistry

Carsten Spanka, Paul Wentworth Jr. and Kim D. Janda

Soluble polymers have emerged as viable alternatives to resin supports across the broad spectrum of high-throughput organic chemistry. As the application of these supports become more widespread, issues such as broad-spectrum solubility and loading are becoming limiting factors and therefore new polymers are required to overcome such limitations. This article details the approach made within our group to new soluble polymer supports and specifically focuses on parallel libraries of block copolymers, de novo poly(styrene-cochloromethylstyrene), PEG-‘stealth’ stars, and substituted poly(norbornylene)s.

[Back to top] [Purchase Issue/Articles]
Synthesis of Combinatorial Libraries Based On Terpenoid Scaffolds

A. Pathak, S.K. Singh, M.A. Farooq Biabani, D.K. Kulshreshtha, S.K. Puri, S. Srivastava and B. Kundu

Triterpenoid-based scaffolds betulinic acid (1a) and ursolic acid (1b), have been used for the generation of combinatorial libraries in parallel format using solid phase organic synthesis method. These templates have the potential for the synthesis and amplification of triterpenoid-based compounds with one and two-point diversity. This has been demonstrated by the synthesis of two small libraries comprising 18 derivatives each of betulinic acid and ursolic acid with structural diversity at C-3 and C-28 positions. The primary screening of antimalarial activity of these libraries against P. falciparum in vitro led to the identification of four compounds with 5 fold increase in the activity compared to betulinic and ursolic acids.

[Back to top] [Purchase Issue/Articles]
Automated Parallel Solid-Phase Synthesis of Non-Peptide CCR1 Receptor Antagonists

Brad O. Buckman, Ameen Ghannam, Angela Li, Meina Liang, Raju Mohan and Howard P.Ng

An automated, parallel, solid-phase synthesis and screening strategy using commercially available aryl acetic acids as starting materials has discovered novel, non-peptide CCR1 antagonists (Ki < 100 nM).

[Back to top] [Purchase Issue/Articles]
Parallel Synthesis of PNA-Peptide Conjugate Libraries

Satish Kumar Awasthi and Peter E. Nielsen

An optimized semi-automatic protocol for parallel synthesis of up to 96 peptide nucleic acids (PNA) or PNA-peptide conjugates using Boc-protection strategy has been developed using a robotic system. The approach is illustrated by synthesizing PNA and PNA-peptide libraries varying between 15 and 27 “amino acid” units. The peptides (NLS (nuclear localization signal) or Tat-peptide) were attached to N-terminus of the PNA. The method was found to be far superior to that based on the SPOT/Fmoc protocol by which PNAoligomers are synthesized on a modified cellulose membrane. On a 0.5 micromole scale the method typically yielded 2 mg product of 90% purity by HPLC/MALDI-TOF analysis. This approach is suitable for screening of a large number of PNA and/or peptide sequences for biochemical and biological studies.