Volume 3, Number 2, 2000: Contents

Polymer-Supported Reagents and Catalysts: Recent Advances in Synthetic Applications

Sukanta Bhattacharyya*. Pp.65-92 .
[Abstract]

Organic Synthesis Using Chemical Tags: The ôThird Legö of Parallel Synthesis

The Use of Polymer-Bound Triphenylphosphine in the Stereochemical Inversion of Secondary Alcohols

Functionalized Porous Silica Microspheres as Scavengers in Parallel Synthesis

Titanium(IV) Isopropoxide Mediated Solution Phase Reductive Amination on an Automated Platform: Application in the Generation of Urea and Amide Libraries

Sukanta Bhattacharyya*, Lisa Fan, Lanchi Vo and Jeff Labadie. Pp.117-124 .
[Abstract]

Chemoselective High-Throughput Purification Mediated by Solid-Supported Reagents: Its Application to the First 6,9-Disubstituted Purine Library Synthesis

Kyungjin Kim* and Warren McComas. Pp.125-129 .
[Abstract]

Chromatography-Free Synthesis of 1,2,4-Oxadiazoles Using ROMPGEL-Supported Acylating Reagents

A. G. M. Barrett,*^, S. M. Cramp, R. S. Roberts  and F. J. ZΘcri . Pp. 131-138.
[Abstract]

Multi-Step Polymer-Assisted Solution-Phase (PASP) Library Synthesis of Functionalized Diaminobenzamides

Michael S. South*, Brenda L. Case, Thomas A. Dice, Gary W. Franklin, Michael J. Hayes, Darin E. Jones, Richard J. Lindmark, Qingping Zeng and John J. Parlow. Pp. 139-151.
[Abstract]

Fluorous-Phase Soluble Polymeric Supports

David E. Bergbreiter*, Justine G. Franchina, Brenda L. Case, La Kenya Williams, Jonathon D. Frels and Nirmal Koshti. Pp.153-164 .
[Abstract]

Abstracts

Sukanta Bhattacharyya*

Argonaut Technologies, 887 Industrial Road, Suite G, San Carlos, CA 94070, USA

Abstract: The current surge in parallel array synthesis for the production of small molecule libraries has generated keen interest in the application of solid-supported reagents and catalysts in solution-phase chemistry. The strategy assimilates the advantages of product isolation and purification of solid-phase organic synthesis with the flexible choice of chemistry from the vast repertoire of solution-phase organic reactions. This review summarizes the significant recent advances in the application of polymer-bound reagents and catalysts in solution-phase synthesis of organic molecules. Multi-step reaction sequences employing sequential use of polymer-supported reagents are also discussed. In view of the earlier review publications on this topic, only the recent literature covering 1998 and 1999 is included.

[Back to top]Organic Synthesis Using Chemical Tags: The ôThird Legö of Parallel Synthesis

John A. Porco, Jr.*

Department of Chemistry and Center for Streamlined Synthesis, Metcalf Center for Science and Engineering, Boston University, 590 Commonwealth Avenue, Boston Massachusetts 02215, USA

Abstract: Increasing emphasis has recently been placed on the development of synthetic methods which effectively couple chemical synthesis and purification. For example, new formats for parallel synthesis are being developed which involve attachment of chemical tags to both reagents, reactants, and substrates to permit their chemoselective removal from reaction mixtures. The driving force for the development of tagged organic reagents is the ability to use standard solution-phase chemistry methods and reaction monitoring techniques (e.g. TLC and HPLC). In this mini-review, we will outline recent developments on the growing class of chemically tagged reagents, reactants, and substrates and highlight examples of their use in multistep synthesis.

[Back to top]The Use of Polymer-Bound Triphenylphosphine in the Stereochemical Inversion of Secondary Alcohols

J. M. White, A. R. Tunoori, D. Dutta and G. I. Georg*

Department of Medicinal Chemistry and The Drug Discovery Program, Higuchi Biosciences Center, University of Kansas, Lawrence, KS 66045, USA

Abstract: Polymer-bound triphenylphosphine can replace triphenylphosphine in the Mitsunobu reaction to generate stereochemically inverted secondary alcohols. This method is comparable with the standard Mitsunobu reaction in terms of inversion of stereochemistry, yield, and reaction time, even for sterically very hindered secondary alcohols. The special merit of this reaction is that the excess polymer-bound triphenylphosphine and its by-products are easily removed by filtration from the reaction products.

[Back to top]Functionalized Porous Silica Microspheres as Scavengers in Parallel Synthesis

Lorin A. Thompson^a*, Andrew P. Combs^a, George L. Trainor^a, Qunjie Wang^b, Timothy J. Langlois^b and Joseph J. Kirkland^b

^aDuPont Pharmaceuticals Company, Experimental Station, Wilmington, DE 19880-0500 USA

^bAgilent Technologies, 2850 Centerville Road, Wilmington, DE 19808, USA

Abstract: The use of solid scavengers in parallel solution-phase organic synthesis is an effective method for work-up and purification. Functionalized macroreticular or gel-form polystyrene particles are generally used for scavenging applications, how ever these materials have some limitations. We have developed new scavenging reagents based on ultrapure silica microspheres displaying a variety of functional groups useful for sequestering impurities from reaction products. These materials are easy to handle, have excellent mass-transfer properties, and are efficient scavengers in both polar and nonpolar organic solvents. The properties of these materials were tailored specifically to fit the needs of a medicinal chemist employing parallel synthesis techniques in current commercial equipment. Results are presented from head-to-head comparisons with conventional scavengers in tests designed to demonstrate the versatility of these new materials.

[Back to top]Titanium(IV) Isopropoxide Mediated Solution Phase Reductive Amination on an Automated Platform: Application in the Generation of Urea and Amide Libraries

Sukanta Bhattacharyya*, Lisa Fan, Lanchi Vo and Jeff Labadie

Argonaut Technologies, 887 Industrial Road, Suite G, San Carlos, CA 94070, USA

Abstract: Amine libraries and their derivatives are important targets for high throughput synthesis because of their versatility as medicinal agents and agrochemicals. As a part of our efforts towards automated chemical library synthesis, a titanium(IV) isopropoxide mediated solution phase reductive amination protocol was successfully translated to automation on the Trident^‰ library synthesizer of Argonaut Technologies. An array of 24 secondary amines was prepared in high yield and  purity  from  4  primary  amines and 6 carbonyl compounds. These secondary amines were further utilized in a split synthesis to generate libraries of ureas, amides and sulfonamides in solution phase on the Trident‰. The automated runs included 192 reactions to synthesize 96 ureas in duplicate and 96 reactions to synthesize 48 amides and 48 sulfonamides. A number of polymer-assisted solution phase protocols were employed for parallel work-up and purification of the products in each step.

[Back to top]Chemoselective High-Throughput Purification Mediated by Solid-Supported Reagents: Its Application to the First 6,9-Disubstituted Purine Library Synthesis

Kyungjin Kim* and Warren McComas

Hoffmann-La Roche, Inc., Roche Research Center, 340 Kingland Street, Nutley, NJ, 07110, USA

[Back to top]Chromatography-Free Synthesis of 1,2,4-Oxadiazoles Using ROMPGEL-Supported Acylating Reagents

A. G. M. Barrett,*^,a S. M. Cramp,^b R. S. Roberts ^a and F. J. ZΘcri ^a

^aDepartment of Chemistry, Imperial College of Science, Technology and Medicine, London, SW7 2AY, UK

^bAventis CorpSciences, Fyfield Road, Ongar, Essex, CM5 0HW, UK

Abstract: 1,2,4-Oxadiazoles were synthesized in solution from aromatic amidoximes and acylating agents supported on a ring opening metathesis polymer (ROMPGEL) backbone. High yields and purities of the 1,2,4-oxadiazoles were obtained with minimal purification.

[Back to top]Multi-Step Polymer-Assisted Solution-Phase (PASP) Library Synthesis of Functionalized Diaminobenzamides

Michael S. South*, Brenda L. Case, Thomas A. Dice, Gary W. Franklin, Michael J. Hayes, Darin E. Jones, Richard J. Lindmark, Qingping Zeng and John J. Parlow

Department of Combinatorial and Parallel Medicinal Chemistry, Searle Discovery Research, Monsanto Company, 800 North Lindbergh Boulevard, St. Louis, MO 63167, USA

Abstract: A parallel solution-phase library synthesis of functionalized diaminobenzamides is described. The four-step library synthesis is accomplished using  polymer-assisted  solution-phase (PASP) synthesis techniques. This high-yielding, multi-step sequence utilizes sequestering resins for the removal of reactants, reactant by-products, and employs a resin capture/release strategy as a key library synthesis step. Step one of the sequence relies on the displacement of an activated fluoro-group from the aromatic ring of 1a, b with a variety of primary amines to introduce the first diversity position. Step two is hydrolysis of the benzoate ester to a benzoic acid which is subsequently captured on a polyamine resin, washed, and released to give 4a, b in pure form. Step three utilizes PASP resins to mediate the amide coupling of a benzoic acid with a variety of primary amines to give the aminonitrobenzamides 5a, b and introduces the second diversity position. Step four is the parallel reduction of the aminonitrobenzamides 5a, b to the functionalized diaminobenzamides 6a, b. This library synthesis proceeds with high overall purities which average 80 % over the 4-step sequence.

[Back to top]Fluorous-Phase Soluble Polymeric Supports

David E. Bergbreiter*, Justine G. Franchina, Brenda L. Case, La Kenya Williams, Jonathon D. Frels and Nirmal Koshti

Department of Chemistry, Texas A&M University, P. O. Box 30012, College Station, TX 77842-3012, USA

Abstract: Fluorous phase soluble polymer supports derived from fluoroacrylate polymers are described. N-Acryloxysuccinimide-containing fluoroacrylate polymers were readily prepared from commercially available monomers. The activated acrylates so prepared were then converted into chelating and non-chelating ligands by amidation of the N-acryloxysuccinimide active ester residues. Phosphine ligands attached to these supports were used to prepare neutral and cationic rhodium(I) hydrogenation catalysts as well as palladium(0) catalysts. Similar substitution of pendant active ester groups to form hydroxamic acid ligands for metal sequestration is also feasible. Liquid/liquid extraction readily separated, recycled and reused these polymer-bound ligands and catalysts. While fluorous phase solubility could be attained with polymers containing only heptafluorobutyryl groups, selective solubility in a fluorous phase in contact with an organic phase was only seen with fluoroacrylates that contained larger fluorinated ester groups.