Download Methods in Enzymology, Vol. 369: Combinatorial Chemistry, Part B PDF

TitleMethods in Enzymology, Vol. 369: Combinatorial Chemistry, Part B
TagsChemistry
LanguageEnglish
File Size7.4 MB
Total Pages566
Table of Contents
                            01.pdf
		High-Throughput Parallel LC/UV/MS Analysis of Combinatorial Libraries
			Introduction
			System Optimization
				Standards and Flow Monitoring
				The T-Joint Position
				LC Conditions
			An Efficient Rerun Protocol
			Combinatorial Library Analysis
				Evaluation of Representative Library Compounds
				Library Analysis
			Comparison of the Eight-Channel LC/UV/MS (MUX-LCT) System with a Conventional Single-Channel LC/UV/MS System
				UV and TIC Chromatograms
				Data Acquisition Using Positive and Negative Ionization
				Sample Rerun
				Operation and Maintenance
			Conclusion
			Acknowledgments
02.pdf
	Qualitative Colorimetric Tests for Solid Phase Synthesis
		Introduction
		General Experimental Procedures
			Aliphatic Amines
			Thiols
			Carboxylic Acids
			Aldehydes
		Conclusions and Summary
		Acknowledgments
03.pdf
	A Review of Solid-Phase Organic Synthesis on SynPhase Lanterns and SynPhase Crowns
		Introduction
		Heterocycles
			Benzodiazepines
			Purines
			Quinazolines
			Arylaminobenzimidazoles
			Pyridin-2-ones
			Oxazoles
			Hydantoin/Isoxazolines
			Quinoxalines
			Perhydro-1,4-diazepine-2,5-diones
		Carbohydrates
		Functionalized Peptide Libraries
		Cyclic Peptides
		Other Small Molecules
			Amines
			Ureas and Their Chalogen Analogs
		Future Perspectives
		Addendum
04.pdf
	Directed Sorting Approach for the Synthesis of Large Combinatorial Libraries of Discrete Compounds
		Introduction
		Directed Sorting Approach
			Principle
			Equipment
			Application
			Piperazine Carboxamide Libraries
		Combining Directed Sorting with Parallel Synthesis-Benzothiazepine Library
		Conclusion
		Experimental Section
			General Information
			Resin Bound Amines 8
			Resin Bound Amides 9
			Removal of Fmoc Protecting Group from 9
			Acylation with Carboxylic Acids to Produce 10 or 11 or 20
			Acylation with Chloroformates to Produce 10 or 11 or 20
			Urea Formation with Isocyanates to Produce 10 or 11
			Sulfonamide Formation to Produce 10 or 11 or 20
			Removal of Alloc Protecting Group from Resin 10 or 19
			Preparation of Resin 16 by the Yamaguchi Method
			Preparation of Resin 16 from Acid Chlorides
			Preparation of Resin 16 from Amino Acids
			Preparation of Resin 16 from Symmetrical Diamines
			Alkylation with Piperazine-2-Carboxamide Scaffold to Produce 18
			Amide Bond Formation to Produce 19
			Cleavage
			Cysteine Carbamate Resin 26
			Halo-Nitrobenzene Coupling 28
			Reduction of Nitro Group to Prepare 29
			Cyclization to Benzothiazepine 30
			Oxidation to Sulfone 31b
			Alkylation Reaction to 32
			Archiving, Cleaving, and Free Basing of Resin 33
			TFP Resin Loading 35
			Reaction with TFP Resin to Prepare 36
05.pdf
	Split-Mix Synthesis Using Macroscopic Solid Support Units
		Introduction
		Principle
		String Synthesis: Support Units and Strings
		Manual Device for Redistribution
		Redistribution Pattern
		Software
		Synthesis of a Library of 125 Tripeptides
			Coupling
			Sorting of the Crowns
			Cleavage
			Product Distribution
			Verification of Product Distribution
		Acknowledgments
06.pdf
	The Encore Technique: A Novel Approach to Directed Split-and-Pool Combinatorial Synthesis
		Introduction
		Directed Split-and-Pool Method
		Solid Support
		Encoding
		Process Integration/Automation
		Description of the Encore Method
		Description of the Encore Instrument
			Arraying Tool
			Magazine
			Lapis Tool
			Lantern Dispensing Tool
			Lantern Leveling Tool
		Synthetic Protocol
		Conclusion
07.pdf
	Multifunctional Linkers as an Efficient Tool for the Synthesis of Diverse Small Molecule Libraries: The Triazene Anchors
		Introduction
		Triazenes as Linkers
		Traceless Linkers
		Multifunctional Cleavage
		Concept for Heterocycle Synthesis
		Triazene T2 Linker
		Summary and Conclusion
		Experimental Section
			Chemicals, Solvents, Reagents
			T1 Linker: Synthesis of Benzylaminomethyl Polystyrene
			Representative Procedure for the Synthesis of Triazene T1 Resins
			General Procedure for the Traceless Cleavage of the T1 Linker
			The T2 Linker: 3-Aminophenyl-1-oxymethylpolystyrene (55)
			Preparation of Diazonium Salt 56 on the Resin
			Preparation of Triazene Resin 4
			Manual Preparation of Ureas
			Automated Preparation of Amides
			Synthesis of Guanidines Using the T2* Linker
		Acknowledgments
08.pdf
	The Development and Application of Tetrafluorophenol-Activated Resins for Rapid Amine Derivatization
		Introduction
		Background
		Synthesis of Polymeric TFP
		Synthesis of TFP-Activated Resins
		Quality Control of TFP-Activated Resins
		Reaction of TFP Reagents with N-Nucleophiles
		Experimental Protocols
			Preparation of TFP Resin (Scheme 1)
			Preparation of TFP-Activated Carboxylic Acid Esters (Scheme 2)
			Preparation of TFP-Activated Sulfonic Acid Esters (Scheme 2)
			Loading Determination (Chemical Type)
			Amine Derivatization with TFP-Activated Esters
09.pdf
	The Traceless Solid-Phase Synthesis of Organic Molecules
		Introduction
		Traceless Solid-Phase Synthesis of Benzimidazoles
			Background
			Development of the Traceless Route
			Library Rehearsal
			Final Improved Reaction Route
			Conclusion
			Experimental
				Reagents and General Methods
				General Procedure for Coupling of o-Fluoro/Chloro-Nitroarenes
				Procedures for Reduction of the Aromatic Nitro Group
				General Procedure for Quaternization with Alkyl/benzyl Bromides
				Preparation of Resin 7
				Preparation of Resin 10
		Traceless Syntheses Using a Novel Triflate-Type Linker
			Background
			Perfluoroalkylsulfonyl (PFS) Linker/Resin
			Cleavage of the Resin-Bound Phenols Using the Suzuki Coupling Reaction
			Cleavage of the Resin-Bound Phenols Using Catalytic Reductive Elimination
			Cleavage of the Resin-Bound Phenols Using Catalytic Amination
			Conclusion
			Experimental
				Reagents and General Methods
				General Procedure for Attachment of Phenols to Resin 13 (to form 14, 15, 19, 21, 23, or 28)
				General Procedure for Cleavage of Phenols Using the Suzuki Coupling Reaction: Preparation of Resins 15-17 and Compounds 1
				General Procedure for Cleavage of Phenols by a Reductive Elimination Reaction: Preparation of Compounds 20 and 22
10.pdf
	Unnatural Diamino Acid Derivatives as Scaffolds for Creating Diversity and as Linkers for Simplifying Screening in Chemical Lib
		Introduction
		Methodology for the Use of the Protected Aromatic Scaffold 16
		Methodology for the Use of Dpr(Phoc) Linker
		Experimental Protocols
			General
			Chemicals
			Use of AmAbz Building Blocks in the Solid-Phase Synthesis of Peptidomimetics: The Typical Example of Heptapeptide 1925
			Preparation and Use of Dpr(Phoc) Linker
			Boc Protocol
			Fmoc Protocol
11.pdf
	Building Dihydropyrimidine Libraries via Microwave-Assisted Biginelli Multicomponent Reactions
		Introduction
		Previous Dihydropyrimidine Libraries
		Microwave-Assisted Organic Synthesis
		Microwave-Assisted Biginelli Reactions
		Microwave Chemistry Utilizing the Emrys Synthesizer
		Synthesis Criteria for Dihydropyrimidine Library
		Reaction Optimization in the Emrys Synthesizer
			Step 1: Choice of Solvent
			Step 2: Selection of Catalyst
			Step 3: Optimization of Time and Temperature
			Step 4: Optimization for Troublesome Building Blocks
		Automated Sequential Library Production
		Concluding Remarks
		Experimental Section
			Reagents and General Methods
			Microwave Irradiation Experiments
			Spectral Data for DHPM Library
12.pdf
	Microwave-Assisted Solid-Phase Organic Synthesis (MA-SPOS) of Oxazolidinone Antimicrobials
		Introduction
		Instrumentation
		Solid-Phase Biaryloxazolidinones
		Conclusion
		Reagents and General Methods
		Experimental Section
			Coupling of Iodoaryloxazolidinone to BAL Resin
			Acylation of Solid-Supported Iodoaryloxazolidinone
			Microwave-Assisted Solid-Phase Suzuki Coupling
			Cleavage of Biaryloxazolidinone from the Solid Support
13.pdf
	Automated Synthesis of Polysaccharides
		Introduction
		Background
		Overview
		Detailed Description
		State of the Art
		Experimental Procedures
			Materials and Methods
			F-Tag Protocols
14.pdf
	Solid-Phase Oligosaccharide Chemistry and Its Application to Library Synthesis
		Introduction
		Solid-Phase Oligosaccharide Synthesis (SPOS)
		Combinatorial Solid-Phase Oligosaccharide Synthesis (CSPOS)
		Conclusion
		Acknowledgments
15.pdf
	Design, Synthesis, Screening, and Decoding of Encoded One-Bead One-Compound Peptidomimetic and Small Molecule Combinatorial Lib
		Introduction
		General Synthetic Procedures for Encoded Peptidomimetic and Small Molecule Libraries
		On-Bead Screening of Encoded Peptidomimetic and Small Molecule Libraries
		Decoding of Peptidomimetic and Small Molecule Libraries
		Materials and Methods
			Preparation of Topologically Segregated Bifunctional Beads with 70% Fmoc Outside and 30% Free NH2 Inside
			Synthesis of an Encoded Peptidomimetic Library, an Example
			Screening of an Encoded Peptidomimetic Library with Streptavidin-Alkaline Phosphatase Conjugate
		Acknowledgments
16.pdf
	Intelligent Design in Combinatorial Chemistry: Use of Designed Peptide Libraries to Explore Secondary and Tertiary Structures i
		Introduction
		Background
		Exploration of Antimicrobial Peptides Using Combinatorial Chemistry
		Design Strategies in Combinatorial Libraries of Peptides
		Protein Design
		Cyclization
		Hinges in Peptide Libraries
		Conclusion
17.pdf
	Synthesis and Screening of "One-Bead One-Compound" Combinatorial Peptide Libraries
		Introduction
		Synthesis of Linear and Cyclic Peptide Libraries
			Preparation of the Amino Acid Solutions
			Monitor Coupling Reaction
			Synthesis of a Linear Heptapeptide Library with 19 Eukaryotic Amino Acids (Cysteine Excluded)
			Synthesis of a Disulfide Cyclic Peptide Library
			On-Resin Synthesis of a Cyclic Peptide Library Using Lys and Glu Side-Chains
			The Synthesis of "Fluorescence-Quench" Combinatorial Library for Protease Substrate Determination
		Library Screening
			Enzyme-Linked Colorimetric Assay
			Whole Cell Binding Assay
			Screening for Protease Substrates
			COPAS Screening
			Protein Kinase Substrate Assay
		Microsequencing of Peptide Beads
			Edman Sequencing
		Acknowledgments
18.pdf
	Synthetic Combinatorial Libraries as an Alternative Strategy for the Development of Novel Treatments for Infectious Diseases
		Background
		Mixture-Based Combinatorial Libraries
		Development of Antifungal Agents Using the PS-SCL Approach
			Screening of a PS-SCL for Antifungal Activity
			Deconvolution Process
		Development of Antibacterial Agents Using the PS-SCL Approach
		Development of HIV-1 Antagonists Using the SCL Approach
			Determination of Inhibition of HIV-1 Mediated Fusion
			Identification of Inhibitors of HIV-1-Mediated Fusion from PS-SCLs
			Inhibition of HIV-1 Replication
		Novel Strategies toward the Development of Vaccines against Infectious Diseases
			Identification of Epitope Mimics
			Identification of Natural Epitopes in Protein Databases
		Conclusions
		Acknowledgments
19.pdf
	Advances in the Applications of Polymer-Supported Reagents for Organic Synthesis
		Introduction
		Acids and Bases
			Synthesis of Dihydropyrimidones (Entry 5)
		Oxidations and Reductions
			Synthesis of Carboxylic Acids (Entry 8)
			Hydrogenation of Alkenes (Entry 10)
		Sulfur and Phosphorous Transfer Reagents
		Carbon Transfers
			Synthesis of Olefins via Wittig Reaction (Entry 17)
		Electrophilic Reagents and Radical Reaction Reagents
			Reaction of Pyrene-Functionalized Tin Hydride with an Alkyl Halide (Entry 20)
		Supported Transition Metal Catalysts
			Synthesis of Arylamines (Entry 24)
			Synthesis of Biphenyls Via Suzuki Coupling (Entry 25)
		Esterification and Amide-Coupling Reagents
		Group Transfer Reagents
			Synthesis of Esters (Entry 28)
			Synthesis of Fmoc-Amino Acids (Entry 31)
			Synthesis of Guanidines (Entry 33)
		Scavengers
			Scavenging of Phosphines and Phosphinoxides (Entry 34)
		Multistep Synthesis Using Polymer-Supported Reagents
20.pdf
	Advanced Polymer Reagents Based on Activated Reactants and Reactive Intermediates: Powerful Novel Tools in Diversity-Oriented S
		Introduction: Current Challenges in Combinatorial Chemistry Research
		Polymer-Assisted Solution Phase (PASP) Synthesis
		A Concept for Advanced Polymer Reagents
		Example 1: Oxidizing Polymers
			Polymer-Supported Heavy-Metal Oxides
			Oxidations with Immobilized Oxoammonium Salts
			Protocol for Oxidations Employing Oxoammonium Resins22
			Oxidations with Immobilized Periodinanes27
			Protocol for Oxidation with and Reactivation of Polymer-Supported Periodinane26
		Example 2. Alkylating Polymers38
			Protocol for the Alkylation of Carboxylic Acids by Use of Alkylating Resins37
		Example 3. Polymer-Supported Carbanion Equivalents
		Example 4. Radical Release from Polymer Gels42
		Example 5. Optimization of the Polymer Support: Highly Loading Resins for Polymer-Supported Reagents44
		Conclusions
21.pdf
	Scavenger Resins in Solution-Phase CombiChem
		Introduction
		Scavenger Resins Synthetic Applications
		Concluding Remarks
		Experimental Section
			Reagents and General Methods
			Resin Preparation
			Solid-Phase Assisted Solution-Phase Synthesis
22.pdf
	Cyclative Cleavage Strategies for the Solid-Phase Synthesis of Heterocycles and Natural Products
		Introduction
		Nitrogen Nucleophile Attacking sp2 or sp3 Carbon: Five-Membered Ring Formation
		Nitrogen Nucleophile Attacking sp2 Carbonyl: Six-Membered Ring Formation
		Nitrogen Nucleophile Attacking sp2 Carbonyl: Seven-Membered and Larger Ring Formation
		Oxygen Nucleophiles
		Carbon Nucleophiles
		Organometallic Reactions
			"Reverse" Cyclative Cleavage
		Summary
		Experimental
			Reagents and General Methods
		Acknowledgments
23.pdf
	Derivatization Reactions of Heterocyclic Scaffolds on Solid Phase: Tools for the Synthesis of Drug-Like Molecule Libraries
		Introduction
		Nucleophilic Aromatic Displacements
		Palladium-Catalyzed Reactions
		Acylations, Alkylations, Reductive Alkylations (Aminations, Alkaminations)
		Name Reactions
		Conclusion
		Experimental
			Substitution of Remaining Chloro Group with Amines via Non-Palladium-Catalyzed Amination Reaction without Base (Fig. 2)15
			Substitution of Remaining Chloro Group with Amines via Non-Palladium-Catalyzed Amination Reaction with KOtBu as Base (Fig. 2)15
			General Reaction Conditions for the Conversions in Fig. 312
			General Procedure for the Synthesis of Rink Resin-Bound 6-Chloro-2-methane sulfenyl pyrimidine (9) (Fig. 3)12
			Cleavage of 4-Amino-6-chloro-2-methanesulfenyl Pyridine from (9) (Fig. 3)12
			Resin-Bound 2-Methylthio-6-piperidinopyrimidine (16) (R2NR2' = Piperidine) (Fig. 3)12
			Cleavage of 2-Methylthio-6-piperidinopyrimidine from Resin 16 (Fig. 3)12
			Oxidation of the Methylthio Group (Fig. 3)12
			Displacement of Methanesulfinyl (11b) or Methanesulfonyl (11c) Groups (Fig. 3)12
			Cleavage of the Resin 12 (Fig. 3)12
			Synthesis of 2,4,6-Amino-Substituted s-Triazines Using a Partial Solution Phase Approach (Fig. 4)14
			Polymer-Bound Thiol (19) (Fig. 4)14
			Polymer-Bound Triazine Attached via a Thiol Linker (20) (Fig. 4)14
			Displacement of the Remaining ChloroAtom to (21) (Fig. 4)14
			Oxidation of the Thio Group (Fig. 4)14,51
			Cleavage and Release of the 2,4-Bis-(3,5-dichloroanilinyl)-6-pyrrolidinyl-1,3,5-triazine (24) (R1, R2 = 3,5-Dichloroph
			Conversion of a Resin-Bound Quinazolin-4-one (43) into a 4-Chloroquinazoline (44) (Fig. 8)30
			Preparation of Amino-Substituted Quinazoline (45) and Cleavage from  the Resin to Obtain the 2-Unsubstituted 4-Arylaminoquinaz
			Facilitated Arylations via Iron-pi Complex
			Derivatization of Dichloroheterocyclic Scaffolds (Fig. 10)15
			Preparation of 2,6-Disubstituted Purines (65) Using Pd-Mediated Reactions Involving Amines and Boronic Acids (Fig. 11)33
			Stille Coupling on Support-Bound Compounds 67 (Fig. 11)33
			Acylations, Alkylations, Reductive Alkylations (Aminations, Alkaminations)
24.pdf
	Library Generation via Postcondensation Modifications of Isocyanide-Based Multicomponent Reactions
		Introduction
		UDC (Ugi/De-Boc/Cyclize) Methodology
		Miscellaneous Postcondensation Modifications
			TMSN3 Modified Ugi Reactions
			Postcondensation Passerini Reactions
			TMSN3-Modified Passerini Reaction
		Automation
		Conclusion
		Experimental Section
			Typical Experimental Procedure (Plate Production)
			Typical Experimental Procedure (Scale Up)
			Diketopiperazines (50)
			Azepine-tetrazoles (94)
			Ketopiperazine Tetrazoles (96)
			Nor-statines (104)
			Tetrazole-nor-statine Mimetics (110)
25.pdf
	Mixture-Based Combinatorial Libraries: From Peptides and Peptidomimetics to Small Molecule Acyclic and Heterocyclic Compounds
		Introduction
		Preparation of Mixture-Based Synthetic Combinatorial Libraries
			Resin Mixtures
			Reagent Mixtures
			Libraries from Libraries: Generation of Peptidomimetic Libraries
			Chemistry Optimization
			Solid-Phase Synthesis of Heterocyclic Compounds from Resin-Bound Amino Acids, Short Peptides, and Polyamines
			Solid-Phase Synthesis of Bis-Heterocyclic Compounds from Resin-Bound Acylated and Nonacylated Polyamines
			Parallel Synthesis of Combinatorial Libraries
		Experimental Procedure for the Parallel Synthesis of Heterocyclic Positional Scanning Libraries 47 to 51
			General Requirements for the Synthesis
			Coupling of Boc Amino Acids to MBHA Resin to Introduce the First Position of Diversity
			Trityl Protection of the Resin-Bound Amino Acids
			Alkylation of Trityl-Protected Resin-Bound Amino Acids
			Removal of the Trityl Group
			Coupling of Fmoc Amino Acids to Introduce the Second Position of Diversity
			N-Acylation to Introduce the Third Position of Diversity
			Exhaustive Reduction of the Amide Bond
			Parallel Synthesis of Heterocyclic Libraries 47 to 51
			Cleavage of Resin-Bound Heterocyclic Libraries from the MBHA Resin
			Simultaneous Synthesis of Control Teabags
		Conclusion
26.pdf
	New Strategies for the Solid-Phase Synthesis of Highly Functionalized, Small Molecules: Sequential Nucleophilic Substitutions o
		Introduction
		Sequential Nucleophilic Substitutions on Insoluble Supports
		2,3-Dichloropropionic Acid Derivatives as Polyelectrophile
		4,5-Difluoro-2-nitrobenzamides as Polyelectrophile
		Conclusion
		Experimental Section
			Reagents and General Methods
			2-Phenylsulfanyl-3-(piperidin-1-yl)propionic Acid Trifluoroacetate
			1-[5-Benzenesulfonyl-2-(piperidin-1-yl)-4-(pyridin-4-ylmethylamino)benzoyl]piperazine Trifluoroacetate
		Acknowledgments
                        
Document Text Contents
Page 1

Untitled


Preface
Combinatorial chemistry has matured from a field where efforts initially

focused on peptide-based research to become an indispensable research tool

for molecular recognition, chemical-property optimization, and drug discovery.

Originally used as a method to primarily generate large numbers of molecules,

combinatorial chemistry has been significantly influenced and integrated with

other important fields such as medicinal chemistry, analytical chemistry, syn-

thetic chemistry, robotics, and computational chemistry.

Even though the initial focus of attention was providing larger numbers of

molecules with a ‘‘diversity’’ goal in mind, other factors came into play

depending upon the problem scientists were trying to solve, such as bioactivity,

solubility, permeability properties, PK, ADME, toxicity, and patentability.

One can think of combinatorial chemistry and compound screening as an

iterative Darwinian process of divergence and selection. Particularly in drug

discovery, where time is a critical factor to success, combinatorial chemistry

offers the means to test more molecule hypotheses in parallel.

We will always be limited to a finite number of molecules that we can

economically synthesize and evaluate. Even with all the advances in automa-

tion technologies, combinatorial chemistry, and higher-throughput screens that

improve our ability to rapidly confirm or disprove hypotheses, the synthesis

and screening cycle remains the rate-determining process. Fortunately, we

continue to make great strides forward in the quality and refinement of pre-

dictive algorithms and in the breadth of the training sets amassed to aid in the

drug discovery/compound optimization iterative process.

Anyone who has optimized chemical reactions for combinatorial libraries

or process chemistry knows first hand how much experimentation is required to

identify optimal conditions. Chemical feasibility is at the heart of small mol-

ecule discovery and chemotype prioritization since it essentially defines what

can and cannot be analoged (i.e., analogability). Although analogability is not

the only driving factor, quite often it is overlooked. For example, when com-

mercially-available compounds or complex natural products are screened, the

leads generated are often dropped because of the difficulty to rapidly analog

them in the lead optimization stage.

The desirability of a chemotype is a function of drug-likeness, potency,

novelty, and analogability. A particularly attractive feature of combinatorial

chemistry is that when desirable properties are identified, they can often be
xiii

Page 2

Untitled


xiv preface
optimized through second-generation libraries following optimized synthetic

protocols. If this process of exploring truly synthetically accessible chemical

spaces could be automated, then it would open up the exciting possibility of

modeling the iterative synthesis and screening cycle.

Predicting, or even just mapping, synthetic feasibility is a sleeping giant;

few people are looking into it, and the ramifications of a breakthrough would

be revolutionary for both chemistry and drug discovery. In-roads to predicting

(or even just mapping) chemical feasibility have the potential to have as large

an impact on drug discovery as computational models of bioavailability and

drugability. These are important questions where scientists are now starting to

generate a large-enough body of information on high-throughput synthetic

chemistry to begin to more globally understand what is cost-effectively pos-

sible. Within the biopharmaceutical industry, significant investments in new

technologies have been made in molecular biology, genomics, and proteomics.

However, with the exception of combinatorial chemistry, relatively little has

been done to advance the fundamental nature of chemistry in drug discovery

from a conceptual perspective.

Now, after having gone through the molecule-generating period where

research institutions have a large historical compound collection and the pro-

liferation of combinatorial chemistry services, the trend is now after making

more targeted-oriented molecular entities also known as ‘‘focused libraries.’’

An important emerging question is: How can one most effectively make the

best possible ‘‘focused libraries’’ to answer very specific research questions,

given all the possible molecules one could theoretically synthesize?

The first installment in this series (Volume 267, 1996) mostly covered

peptide and peptidomimetic based research with just a few examples of small

molecule libraries. In this volume we have compiled cutting-edge research in

combinatorial chemistry, including divergent areas such as novel analytical

techniques, microwave-assisted synthesis, novel linkers, and synthetic ap-

proaches in both solid-phase and polymer-assisted synthesis of peptides, small

molecules, and heterocyclic systems, as well as the application of these tech-

nologies to optimize molecular properties of scientific and commercial interest.

Guillermo A. Morales

Barry A. Bunin

Page 283

TABLE III

Peptidomimetic Ligands for Streptavidin

Aa2

R1

N
H

O

HN

N
H

O

O

R2

Entry Aa2 Structure R1COOH Structure R2COOH Structure

01 d-Arg H2N COOH

N
H

NH2

NH

Isonicotinic acid
N

COOH

3-Thiophene carboxylic

acid
S

COOH

02 d-Arg

H2N COOH

N
H

NH2

NH

Isonicotinic acid
N

COOH
2-Thiophene carboxylic acid

S COOH

03 Ckbp
a

HN N N

O

COOH
Isonicotinic acid

N

COOH
3-Thiophene carboxylic acid

S

COOH

04 d-Arg

H2N COOH

N
H

NH2

NH

Isonicotinic acid
N

COOH
3-Benzoyl-2-pyridine carboxylic

acid N

O

COOH

05 d-Thi
S

H2N COOH

Isonicotinic acid
N

COOH
4-(Dimethylamino)phenylacetic

acid
N

COOH

(continues)

[1
5
]

e
n

c
o

d
e

d
p
e

p
t
i
d

o
m

i
m

e
t
i
c

a
n

d
s
m

a
l

l
m

o
l

e
c

u
l

e
l

i
b

r
a

r
i
e

s
2

8
5

Page 284

06 Cptd
b

N
N

O
HN COOH

Isonicotinic acid
N

COOH
4-(Dimethylamino)phenylacetic

acid
N

COOH

07 Cptd N
N

O
HN

COOH Isonicotinic acid
N

COOH
4-(Dimethylamino)phenylacetic

acid
N

COOH

08 Cptd N
N

O
HN

COOH 2-Pyrazine carboxylic acid
N

N

COOH
4-(Dimethylamino)phenylacetic acid N

COOH

09 �-Phe(4-tBu) COOH
NH2

2-Pyrazine carboxylic acid
N

N

COOH
(S)-(+)-2-Oxo-4-phenyl-3-

oxazolidineacetic acid

N

O O

COOH

10 �-Phe(4-tBu) COOH
NH2

2-Pyrazine carboxylic acid
N

N

COOH
(S)-(+)-2-Oxo-4-phenyl-3-

oxazolidineacetic acid

N

O O

COOH

a
Ckbp, 4-(3-carboxymethyl-2-keto-one-benzimidazolyl)-piperidine.

b Cptd, 3-Carboxymethyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one.

TABLE III (Continued)

Entry Aa2 Structure R1COOH Structure R2COOH Structure

2
8

6
p
e

p
t
i
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568 subject index
Split-and-pool synthesis

advantages, 124

directed synthesis, see also

Encore synthesis
encoding, 115–116

process integration and

automation, 116–117

random synthesis comparison, 113–114

solid supports, 115

peptide libraries, 75–76

Split-mix synthesis

one-bead one-compound

library, 298–299

principles, 99–100

string synthesis
manual redistribution of

crowns, 102–104

overview, 100–101

redistribution pattern, 104–105, 107

software, 107–108

stringing of support units, 101–102

SynPhase‘ Crowns as support
units, 101–102

tripeptide library synthesis

cleavage, 110–111

coupling, 110

overview, 109

product distribution and

verification, 111–112

sorting of crowns, 110
SPS, see Solid-phase synthesis

String synthesis, see Split-mix synthesis

Suzuki reaction

biphenyl synthesis with transition metal

catalysts, 360

microwave-assisted synthesis

of oxazolinidones
optimization, 228–229

solid-phase coupling, 231

perfluoroalkylsulfonyl linker, cleavage of

resin-bound phenols, 177, 181–182

SynPhase‘ Crown
benzimidazole synthesis, 51–53

benzodiazepine synthesis, 43–44

carbohydrate synthesis, 60–63

1,4-diazepine-2,5-dione synthesis, 58–60

diphenylmethylamine library, 70–71

directed synthesis, see Encore synthesis

hydantoin synthesis, 56–58

overview, 41–43
oxazole synthesis, 54–56

peptide synthesis

cyclic peptides, 64–67, 69

muramyl peptide derivatives, 63, 65

rhinovirus protease inhibitors, 63–64

tripeptide library string synthesis
cleavage, 110–111

coupling, 110

overview, 109

product distribution and

verification, 111–112

sorting of crowns, 110
polyamine synthesis, 67–68, 70

prospects, 72–73

purine synthesis, 45–47

pyrin-2-one synthesis, 53–54

string synthesis, see Split-mix synthesis

urea synthesis, 72

SynPhase‘ Lantern
benzimidazole synthesis, 52–53

benzodiazepine synthesis, 44–45

directed synthesis, see Encore synthesis

overview, 40–44

prospects, 73–74

quinazoline synthesis, 47–51

quinoxaline synthesis, 58–59

urea synthesis, 71–72

T

Tetrafluorophenol-activated resins

amine derivatization
applications, 151–152, 154

library synthesis, 158–161, 163

carboxylic acid ester

preparation, 162

loading determination, 163

polymeric tetrafluorophenol

synthesis, 154–155

quality control, 156–158

sulfonic acid ester preparation, 162

synthesis of resins, 155–156, 161–162

TNBS, see Trinitrobenzenesulfonic acid

p-Toluenesulfonyl chloride/

p-nitrobenzylpyridine test, alcohol assay

in solid-phase synthesis, 28–29

Triazene anchors

acidic cleavage, 132–133

applications in solid-phase

synthesis, 129–130

Page 566

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subject index 569
U

Ugi multicomponent condensation reactions,

see Isocyanide-based multicomponent

reactions

Urea library

isocyanide-based multicomponent

reactions, 479–480

synthesis using SynPhase‘ Crowns and
Lanterns, 71–72

synthesis using T2 triazene linkers, 143, 149

W

Wittig reaction, carbon transfer reagents and

olefin synthesis, 354–355
heterocycle derivatization, 443–444,

461–462

heterocycle library synthesis with T1
linkers, 136–140, 147–148

multifunctional cleavage, 135–136, 145

T2 linkers

guanidine library synthesis, 143–145,

149–150

peptide library

synthesis, 142–143

synthesis, 140–142, 148–149

urea library synthesis, 143, 149

traceless cleavage, 132–134, 148

types, 130–132

1,3,5-Trichlorotriazine-(fluorescein, alizarin

R, or fuchsin) test, alcohol assay in

solid-phase synthesis, 29–30

Trinitrobenzenesulfonic acid, amine assay in

solid-phase synthesis, 26

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