A. Condensations to prepare amides, esters, ureas, imines, and phosphorous compounds.

I. Amide bond formation:

1. General points of interest for amide bond formation on solid support.
2. A comparison of different coupling procedures with methodological implications.

3. Amide bond formation with amino acid halides.

4. Azabenzotriazole-based coupling reagents HOAt and HATU for solid-phase peptide synthesis.

5. Alternative procedures for amide bond formation during cleavage from resin.

II. Esterification reactions on solid support:

1. First amino acid loading by ester bond formation.

III. Imine formation on solid support:

1. Solid-phase imine formation with trimethylorthoformate.
2. Other examples of imine formation on solid support.

IV. Urea formation on solid support:

1. A strategy for combinatorial solid-phase synthesis of urea linked diamine libraries.

V. Condensations with phosphorous compounds on solid support:

1. The preparation of phosphodiesters in solid-phase oligonucleotide synthesis.
2. A combinatorial method for the solid phase synthesis of a-amino phosphonates and phosphonic acids.

3. A combinatorial method for the solid phase synthesis of a-hydroxy phosphonates.

4. Other examples of condensations involving phosphorous compounds.

B. Carbon-carbon bond formation on solid support.

I. Suzuki reactions on solid support:

1. Biaryl synthesis via Suzuki coupling on solid support. 2. Suzuki coupling for carbon-carbon bond formation on solid support. 3. Additional examples of solid-phase Suzuki coupling reactions.

II. Organozinc reactions on solid support:

1. Zinc organic reagents in aryl-aryl cross coupling on solid support.

III. Stille coupling reactions on solid support:

1. Application of the Stille coupling reaction with a support-bound aryl iodide and a range of stannanes in solution.
2. Stille coupling reaction between support-bound amino aryl stannane and acid chloride in solution in the solid-phase synthesis of 1,4-benzodiazepines.

3. Additional examples of solid-phase Stille coupling reactions.

IV. Heck reactions on solid support:

1. Heck reactions in solid-phase synthesis.
2. Solid-phase synthesis using the Heck reaction under phase transfer conditions at 37 °C.

3. Additional examples of solid-phase Heck reactions.

V. Enolate alkylation for carbon-carbon bond formation on solid-support:

1. Enolate alkylation on Kenner’s acylsulfonamide linker.
2. Aldol and imine reactions with support-bound silyl enol ethers.

3. Other examples of carbon-carbon bond formation with support-bound enolates.

VI. Solid-phase Wittig reactions:

1. Solid-phase synthesis of alkenes using the Horner-Wadsworth-Emmons reaction.
2. The preparation of a hydroxystillbene library with a solid-phase Wittig reaction.

3. Other examples of solid-phase Wittig reactions.

VII. Metathesis reactions on solid support:

1. Ruthenium-catalyzed metathesis of polymer-bound olefins.

VIII. Other examples of carbon-carbon bond formation on solid support.

C. Mitsunobu reactions on solid support.

1. An efficient solid phase Mitsunobu reaction in the presence of a tertiary amine.
2. Solid phase synthesis of aryl ethers via the Mitsunobu reaction.

3. Polymer-supported Mitsunobu ether formation and its use in combinatorial chemistry.

4. Mitsunobu functionalization of biphenyl phenols.

5. The solid-phase synthesis of phosphonic acid esters under modified Mitsunobu conditions.

6. Mitsunobu coupling with a support-bound trifluoroanilide.

7. Additional studies of Mitsunobu reactions on solid support.

D. Substitution and addition reactions on solid support.

1. Nucleophilic displacement of support-bound a-bromoamides in the submonomer preparation of peptoids.
2. Thiol alkylation in the solid phase synthesis of beta-turn mimetics.
Anilide alkylation with primary alkyl halides in the solid-phase synthesis of 1,4-benzodiazepines.
4. One pot cyclization and anilide alkylation in the solid-phase synthesis of 1,4-benzodiazepine-2,5-diones.

5. Successive amide alkylations: libraries from libraries.

6. Benzophenone imine a-carbon alkylation in solid-phase unnatural peptide synthesis.

7. Alkylation or sulfonylation of a support-bound phenol.

8. Enolate monoalkylation for carbon-carbon bond formation on solid support.

9. Alkylation of support-bound 1,3-diketones in the solid-phase synthesis of pyrazoles and isoxazoles.

10. Tosyl displacement with primary or secondary amines on solid support.

11. Grignard additions to support-bound esters.

12. SNAr reaction on solid-support.

13. The palladium catalyzed amination of resin-bound aromatic bromides has been reported.

14. 1,4-Michael addition of thiols to support-bound enones.

15. The iodoetherification reaction in the solid-phase synthesis of miconazole analogs.

16. Reactions with support-bound alkyl halides in solid-phase peptide and combinatorial synthesis.

E. Oxidations on solid support.

1. Sulfur trioxide-pyridine mediated oxidation.
2. Oxidation of chloromethyl polystyrene resin to formylpolystyrene resin.

3. Other examples of oxidation on solid support.

F. Reductions on solid support.

1. Rapid optimization of oxidation and reduction reactions on solid phase using the multipin approach: synthesis of 4-aminoproline analogues.
2. Reductive alkylation on a solid phase: synthesis of a piperazinedione combinatorial library.

3. Reductive alkylation of Sieber’s Xan Linker.

4. Loading amino esters onto resin via reductive amination.

5. Reductive amination of a support-bound aniline.

6. Solid-phase reductive alkylation of secondary amines using borane-pyridine complex.

7. Reduction of support-bound amides with Red-Al and support-bound esters with DIBAL.

8. Reduction of support-bound ketones to alcohols on PEG-PS.

9. Reduction of a support-bound nitro group to an aniline.

10. Reduction of a support-bound azide to an amine.

11. Solid phase synthesis of (RS)-1-aminophosphinic acids.

12. Additional studies of reductions on solid support.

G. Preparation of heterocyclic compounds.

1a. The synthesis of 1,4-benzodiazepines from support bound 2-aminobenzophenones or aminoarylstananes.
1b. The solid phase synthesis of 1,4-benzodiazepines from support bound amino esters.

2a. The preparation of 1,4-benzodiazepine-2,5-diones from anthranilic acids.

2b. The solid phase synthesis of 1,4-benzodiazepine-2,5-diones from support bound peptoids.

3a. The solid phase synthesis of beta-turn mimetics incorporating side-chains.

3b. Expedient solid-phase synthesis of second generation b-turn mimetics incorporating the i + 1, i + 2, and i + 3 sidechains.

4a. Solid phase synthesis of hydantoins using a carbamate linker and a novel cyclization/cleavage step.
4b. Solution and solid phase synthesis of 5-alkoxyhydantoins.
5a. The solid phase synthesis of pyrazoles and isoxazoles.

5b. Post-modification of peptoid side chains: [3 + 2] cycloaddition of nitrile oxides with alkenes and alkynes on the solid-phase.

5c. The solid-phase synthesis of structurally diverse 1-phenyl-pyrazolone derivatives.

6a. Imidazole libraries on solid support.
6b. Tetrasubstituted imidazoles via a-N-acyl-N-alkylamino-b-ketoamides.
7. Pyrroles derived from a four component condensation.

8a. Reductive alkylation on a solid phase: synthesis of a piperazinedione combinatorial library.

8b. The solid-phase synthesis of diketopiperazines and diketomorpholines.

8c. The solid-phase synthesis of 2-oxopiperazines by intramolecular Michael addition.

9a. A solid-phase synthesis of 1,4-dihydropyridines.

9b. Solid phase synthesis of pyridines and pyrido[2,3-d]pyrimidines.

10a. Solid phase protocol of the Biginelli Dihydropyrimidine Synthesis.

10b. The solid phase synthesis of 5,6-dihydropyrimidine-2,4-diones.

11a. The solid phase synthesis of dihydro- and tetrahydroisoquinolines.

11b. The solid-phase synthesis of highly substituted peptoid 1(2H)-isoquinolines.

11c. Solid phase synthesis of 2,6-disubstituted quinoline derivatives.

11d. Solid-phase synthesis of 1,3-dialkyl quinazoline-2,4-diones.

11e. Solid phase synthesis of 1,3-disubstituted 2,4(1H,3H)-quinazolinediones.

11f. Solid phase synthesis of tetrahydroisoquinolines and tetrahydroimidazopyridines.

11g. A solid phase approach to quinolones.

12a. Solution and polymer-supported synthesis of 4-thiazolidinones and 4-metathiazanones.

12b. Solid-phase synthesis of thiazolidines.

13a. Combinatorial synthesis of highly functionalized pyrrolidines.

13b. Solid-phase synthesis of proline analogs via a three component 1,3-dipolar cycloaddition.

14. Solid-supported combinatorial synthesis of b-lactams.

15. Dihydrobenzopyrans utilizing the split synthesis method and the haloaromatic tag encoding strategy.

16. Bicyclo[2.2.2]octane derivatives via tandem Michael addition reactions.

17. Solid-phase synthesis of tropane derivatives via a palladium-mediated three-component coupling strategy.

18. Solid phase synthesis of Azabicyclo[4.3.0]nonen-8-one amino acid derivatives via intramolecular Pauson-Khand cyclization.

19a. Pictet-Spengler reaction on an Oxime resin: synthesis of 1,2,3,4-tetrahydro-b-carboline libraries.

19b. Pictet-Spengler reaction on a nitrophenylcarbonate resin: solid phase synthesis of 1,2,3,4-tetrahydro-b-carbolines.

19c. Pictet-Spengler reaction on Merrifield resin.

19d. Pictet-Spengler reaction on Wang resin.

20a. Fischer indole synthesis on solid support.

20b. The Heck reaction in the solid-phase synthesis of indole analogs.

21. The solid-phase synthesis of olomoucine (purine) derivatives.

22. Synthesis of aromatic 1,2-diazines by inverse electron demand Diels-Alder reaction of polymer-supported 1,2,4,5-tetrazines.

23. Other examples of the solid-phase synthesis of heterocycles.


AA. Resin derivatization:

1. Bromination and lithiation: two important steps in the functionalization of polystyrene resins.
2. Zinc chloride-catalyzed chloromethylation of resins for solid-phase peptide synthesis.

3. High capacity aminomethyl-polystyrene resin.

A. Linkers for carboxylic acids:

1. Glycolamidic ester linker.
2. Sheppard’s linkers for Fmoc amino acid synthesis.

3. PAM linker: Phenylacetamidomethyl (PAM) resin.

4. t-Butyl resin: 4-(1’,1’-Dimethyl-1’-hydroxypropyl)phenoxyacetyl handle (DHPP).

5. WANG linker: p-Alkoxybenzyl alcohol resin.

6. SASRIN (Super Acid Sensitive ResiN).

7. Hypersensitive Acid-Labile (HAL) Tris(alkoxy)benzyl ester anchor.

8. 2-Chlorotrityl chloride resin.

9. Rink ester and amide resins.

10. SAC (Silyl ACid linker).

11. Barany’s Pbs linker.

12. Ramage’s silyl linkers.

13. The first o-nitrobenzyl resin for solid-phase synthesis of Boc-peptide acids.

14. a-Methylphenacyl ester linker.

15. Oxidative phenol-sulfide safety catch linker.

16. Kenner’s safety catch linker.

17. A highly reactive acylsulfonamide linker.

18. Reductive acidolysis safety-catch linker.

19. Safety-catch linker cleaved by intramolecular activation.

20. Safety-catch linkage for the direct release into aqueous buffers.

21. Allylic linkers.

22. Fluorene derived linker: N-[9-hydroxymethyl-2-fluorenyl] succinamic acid (HMFS handle).

23. Base labile linker: for cleavage via b-elimination.

24. An oxidation-labile linker.

25. Glycolamidic ester linker.

26. Sheppard’s linkers for Fmoc amino acid synthesis.

B. Linkers for amides:

1. Rink ester and amide resins.
2. PAL linker: Fmoc-aminomethyl-3,5-dimethoxyphenoxy-valeric acid (PAL) resin.

3. CHA and CHE linkers.

4. 9-Xanthenyl (Xan) linker: for cleavage of peptide amides by very mild acidolysis.

5. SAL (Silyl Amide Linker).

6. Photolabile amide linkers.

7. A new o-nitrobenzyl photolabile linker for combinatorial synthesis.

8. N-Methyl- and N-ethylamides of peptides.

9. Oxidative phenol-sulfide safety catch linker.

10. Kenner’s safety catch linker.

11. A highly reactive acylsulfonamide linker.

12. SCAL (Safety Catch Acid Labile) linker.

13. Oxime resin.

C. Linkers for alcohols and amines:

1a. Trityl resins: general information.
1b. Original studies: trityl resins for symmetrical, but not a- or b- polyols.

1c. Original studies: trityl and highly crosslinked trityl resins.

2. Tetrahydropyranyl (THP) linker: for alcohols.

3. Ketal and acetal linkers: for diols and alcohols.

4. Linkers for amines: a solid phase CBZ chloride equivalent.

5. Silyl chloride linkers for alcohols.

6. Linker for preparation of C-terminal peptide alcohols (and peptide aldehydes).

7. Sulfonate ester linkage for oligosaccharide synthesis.

8. Linkers for amines: a support bound p-nitrophenylcarbonate.

9. An ADCC-linker for primary amines.

10. REM linker: for the preparation of tertiary amines.

D. Linkers for hydrocarbons and other functional groups:

1a. Silyl traceless linkers: for the preparation of 1,4-benzodiazepines.
1b. Protodetachable arylsilane linker: for the preparation of biaryls.

1c. Silicon directed ipso-substitution of polymer bound arylsilanes.

1d. A silyl ether linker for solid-phase organic synthesis.

2. A novel 3-propyl-3-(benzyl-supported) triazine linkage for the solid-phase synthesis of phenylacetylene oligomers.

3. Thioester linker for the preparation of thioacids.

4. Disulfide linker for solid-phase synthesis.


A. Standard analytical techniques for solid-phase synthesis

1a. Ninhydrin color test for detection of free terminal amino groups in the solid-phase synthesis of peptides. 1b. Quantitative monitoring of solid-phase peptide synthesis by the ninhydrin reaction.
2. Bromophenol blue test for noninvasive, continuous detection of free amines.

3. Quantiation of amines with the picric acid test.

4. NPIT for quantitatively monitoring reactions of amines in combinatorial synthesis.

5. DMT quantitation of free amines or alcohols.

6. Fmoc quantitation.

7. Other analytical techniques for solid-phase synthesis involving chemical modifications.

8a. Application of gel-phase 13C NMR to monitor solid-phase peptide synthesis.

8b. 13C NMR relaxation times of a tripeptide methyl ester and its polymer-bound analogues.

9. Reaction monitoring by gel phase 31P NMR.

10. 19F NMR monitoring of an SNAr reaction on solid support.

11. Examples of solid-phase infrared spectroscopy--standard KBr pellets

B. Sophisticated analytical techniques for solid-phase synthesis:

1. High-resolution 1H NMR in solid-phase organic synthesis.
2. MAS CH correlation in solvent-swollen resin.

3. Utilization of magic angle spinning HMQC and TOCSY NMR spectra in the structure determination of Wang-bound lysine.

4. Use of spin echo magic angle spinning 1H NMR in reaction monitoring in combinatorial organic synthesis.

5. Influence of resin structure, tether, length, and solvent upon the high-resolution 1H NMR spectra of solid-phase-synthesis resins.

6. An NMR method to identify nondestructively chemical compound bound to a single solid-phase-synthesis bead for combinatorial chemistry applications.

7. A comparison of NMR spectra obtained for solid-phase-synthesis resins using conventional high-resolution, magic-angle-spinning, and high-resolution magic-angle-spinning probes.

8. Other applications of NMR spectroscopy to solid-phase synthesis.

9. Infrared spectrum of a single resin bead for real-time monitoring of solid-phase reactions.

10. Progression of organic reactions on solid supports monitored by single bead FTIR microspectroscopy.

11. Other applications of IR spectroscopy to solid-phase synthesis.

12. The application of solid-phase in situ mass spectrometry for reaction analysis with a range of traditional peptide linkers.

13. Direct monitoring by MALDI-TOF MS. A tool for combinatorial chemistry.


A. Solution Libraries:

1. Synthesis and screening procedures for solution libraries on tetrasubstituted templates.
2. A novel solution phase strategy for the synthesis of triamide libraries containing small organic molecules.

3. Solution synthesis and biological evaluation of a library containing potentially 1600 amides/esters.

4. Automated Parallel Solution Phase Synthesis and Purification of Amides.

5. Solution and solid phase synthesis of 5-alkoxyhydantoins.
6. Liquid-phase combinatorial synthesis on polyethylene glycol monomethyl ether (MeO-PEG).
7a. A fluorous tin hydride reagent for liquid phase combinatorial synthesis.

7b. Stille couplings with fluorous tin reactants for liquid-phase combinatorial synthesis.

8. Solution phase combinatorial synthesis of polyazacyclophane scaffolds and tertiary amine libraries.

9. Parallel-compound solution-phase synthesis for lead optimization.

10. Robotic and solution phase derivatization of dichlorotriazines.

11. Multiple-four component condensation (4CC) strategies in solution-phase combinatorial synthesis.

12. Postcondensation modifications of Ugi four-component condensation products.

B. Resin Capture:

1. Solid-phase, parallel synthesis by the Ugi multicomponent condensation.
2. Synthesis of tetrasubstitutued ethylenes on solid support via resin capture.

C. Support-Bound Reagents

1. Support-bound activated nitrophenylesters.
2. Mediator methodology-a two polymeric system.

3. Polymer-bound EDCI: A convenient reagent for formation of an amide bond.
4. A highly reactive acylsulfonamide linker.
5. The use of anion exchange resins for the solution-phase synthesis of combinatorial libraries containing aryl
and heteroaryl ethers.

6. Simultaneous multistep synthesis using polymeric reagents.

7. Polymer-supported phosphonates: olefins from aldehydes, ketones and dioxolans.

8. One pot solution-phase cleavage of a-diols to primary alcohols with polymer-supported antagonistic reagents: periodate and borohydride.

9. Investigations on the Stille reaction with polymer-supported organotin reagents.

10. An improved protocol for solution-phase azole synthesis with PEG-supported Burgess reagent.

11. Support bound nucleophiles and electrophiles for the purification of small molecule libraries.

12. A polymer-supported scandium catalyst for solution-phase synthesis.

13. A new methodology for solution-phase combinatorial synthesis: construction of a quinoline library using a polymer-supported catalyst.

14. Additional examples of support-bound catalysts.