Combinatorial Chemistry A Practical Approach

by Fenniri, Hicham

• ISBN13: 9780199637577
• ISBN10: 0199637571
• Edition: 1st
• Format: Hardcover
• Copyright: 2000-12-28
• Publisher: Oxford University Press

Summary

Combinatorial Chemistry is a genuine practical guide covering all the major areas of combinatorial chemistry from an experimental and conceptual point of view. Being one of the most powerful of modern technologies, combinatorial chemistry has had implications to many areas of chemistry and biology and the current approaches to drug, catalyst, receptor, and materials development and discovery are all included in this volume. It also contains protocols on solid, liquid, and solution phase synthesis and expedient methods of library screening and evaluation. The use of automation and robotics is also explained. It is written at a level easily accessible to novices and will enable readers to use combinatorial techniques to the best advantage.

Table of Contents

Preface	v
List of protocols	xxiii
Abbreviations	xxvii
Synthesis of combinatorial libraries using the portioning-mixing procedure	1	(32)
Arpad Furka
Linda K. Hamaker
Mark L. Peterson
Introduction	1	(1)
The portioning-mixing (split-mix) synthesis	1	(4)
Basic principles	1	(2)
Important features of the synthesis	3	(2)
Manual and automated synthesis	5	(7)
Manual synthesis	5	(3)
Automated synthesis	8	(4)
Preliminary considerations for library design	12	(1)
The weight of the libraries	12	(1)
The weight of the solid support	12	(1)
The significance of the number of resin beads	13	(1)
Synthetic strategies for library construction	13	(16)
Soluble libraries	14	(1)
Tethered libraries	15	(14)
Summary	29	(4)
Acknowledgements	29	(1)
References	29	(4)
One-bead one-compound combinatorial library method	33	(18)
Gang Liu
Kit S. Lam
Introduction	33	(1)
Synthesis of the peptide library	34	(8)
Preparation of the amino acid solutions	34	(1)
Synthesis of a linear peptide library on solid phase using TentaGel resin with 19 eukaryotic amino acids (cysteine excluded)	35	(3)
Synthesis of disulfide cyclic peptide library	38	(1)
Synthesis of Dpr-Dpr cyclic peptide (oxime bond) library	39	(1)
On-resin synthesis of a cyclic peptide library using Lys and Glu side-chains	40	(2)
Library screening	42	(9)
References	48	(3)
Synthesis and screening of positional scanning synthetic combinatorial libraries	51	(24)
Clemencia Pinilla
Jon R. Appel
Sylvie E. Blondelle
Colette T. Dooley
Jutta Eichler
Adel Nefzi
John M. Ostresh
Roland Martin
Darcy B. Wilson
Richard A. Houghten
Introduction	51	(1)
Mixture-based synthetic combinatorial libraries	51	(10)
Positional scanning concept	52	(2)
Synthesis of a tripeptide PS-SCL	54	(2)
Alkylation of peptide PS-SCL	56	(3)
PS-SCL reduction	59	(1)
From peptides to small organic and heterocyclic compounds	60	(1)
Screening mixture-based libraries	61	(3)
PS-SCL deconvolution	62	(1)
Assay optimization	63	(1)
Library screening using ELISA	64	(3)
Identification of T cell-specific ligands	67	(2)
Identification of antimicrobial and antifungal compounds	69	(1)
Library screening using a radioreceptor assay	70	(1)
Identification of enzyme inhibitors using PS-SCLs	71	(4)
References	72	(3)
High-throughput combinatorial synthesis of discrete compounds in multimilligram quantities: non-chemical encoding and directed sorting	75	(20)
Xiao-Yi Xiao
K.C. Nicolaou
Introduction	75	(1)
Non-chemical encoding and directed sorting	76	(3)
Radiofrequency tags	77	(1)
Radiofrequency tagged MicroKans	78	(1)
Radiofrequency tagged MicroTubes	78	(1)
2D bar codes and bar coded microreactors	78	(1)
Applications in combinatorial synthesis	79	(13)
Rf tagged MicroKans: synthesis of taxoid, epothilone, and muscone libraries	79	(9)
Rf tagged MicroTubes: synthesis of a tyrphostin library	88	(3)
Bar coded microreactors: application to oligonucleotide synthesis	91	(1)
Conclusion	92	(3)
References	92	(3)
Positionally addressable parallel synthesis on continuous membranes	95	(22)
Holger Wenschuh
Heinrich Gausepohl
Lothar Germeroth
Mathias Ulbricht
Heike Matuschewski
Achim Kramer
Rudolf Volkmer-Engert
Niklas Heine
Thomas Ast
Dirk Scharn
Jens Schneider-Mergener
Introduction	95	(1)
SPOT synthesis of peptides on continuous cellulose surfaces	96	(6)
Preparation of the cellulose matrix	96	(2)
Positionally addressable array synthesis on SPOT membrane	98	(1)
The peptide synthesis cycle	99	(2)
Cleavage of the peptides and subsequent handling	101	(1)
Synthesis of PNA arrays using the SPOT technique	102	(4)
Reagents and equipment	102	(1)
Reagents preparation	102	(1)
Linker chemistry	103	(1)
Membrane preparation	104	(1)
Synthesis verification	104	(1)
Final work-up	105	(1)
Quality control	105	(1)
Comments	105	(1)
Preparation of stable polymeric membranes for SPOT synthesis of organic compound libraries	106	(11)
Hydroxy-functionalized PEG acrylate polypropylene membranes (PP-g-P(PEGMA))	106	(4)
Amino-functionalized ester-free PEG methacrylamide polypropylene membranes (PP-g-P(AmPEGMAm))	110	(3)
Comments on the functionalization procedures and applications of the novel polymeric membranes	113	(3)
References	116	(1)
Resins and anchors for solid phase organic synthesis	117	(22)
Martin Winter
Ralf Warrass
Introduction	117	(1)
Why do organic synthesis on a solid support?	117	(1)
The orthogonality principle	117	(1)
The practice of solid phase synthesis	118	(1)
Solid supports	118	(9)
Physical properties of solid supports	118	(3)
Families of solid supports and their specific properties	121	(6)
Linkers and anchors in SPOS	127	(12)
Choosing the right linker	128	(5)
Introduction of the first building block	133	(2)
Determination of the loading of the resin	135	(1)
Cleavage	136	(1)
Acknowledgements	136	(1)
References	136	(3)
Organic reactions on solid support---an overview	139	(124)
William M. Bennett
Introduction	139	(1)
Solid phase organic reactions---1998	140	(58)
Anchoring reactions	140	(5)
Amide bond forming reactions	145	(3)
Aromatic substitution	148	(3)
Condensation reactions	151	(3)
Cycloaddition reactions	154	(1)
Organometallic reactions	155	(2)
Michael addition	157	(1)
Heterocycle forming reactions	158	(3)
Multi-component reactions	161	(1)
Olefin forming reactions	162	(1)
Oxidation reactions	163	(2)
Reduction reactions	165	(2)
Substitution reactions	167	(5)
Protection/deprotection reactions	172	(2)
Other solid phase reactions	174	(4)
Cleavage from supports	178	(7)
Polymer-supported reagents	185	(6)
Scavenger resins	191	(1)
References	192	(6)
Solid phase organic reactions---1999	198	(65)
Anchoring reactions	199	(5)
Amide bond forming reactions	204	(4)
Aromatic substitution	208	(5)
Condensation reactions	213	(3)
Cycloaddition reactions	216	(1)
Organometallic reactions	217	(1)
Michael addition	218	(2)
Heterocycle forming reactions	220	(4)
Multi-component reactions	224	(1)
Olefin forming reactions	225	(1)
Oxidation reactions	226	(1)
Reduction reactions	227	(4)
Substitution reactions	231	(5)
Protection/deprotection reactions	236	(3)
Other solid phase reactions	239	(6)
Cleavage reactions	245	(7)
Resin-supported reagents	252	(4)
Scavenger resins	256	(1)
References	257	(6)
Analytical methods in combinatorial chemistry	263	(24)
Bing Yan
Yen-Ho Chu
Michael Shapiro
Ramsay Richmond
Jefferson Chin
Lina Liu
Zhiguang Yu
Introduction	263	(1)
Analytical methods in reaction optimization	263	(9)
FTIR methods	264	(3)
Gel phase NMR	267	(1)
Magic angle spinning (MAS) NMR	268	(2)
Spectrophotometric methods	270	(2)
Quality control of libraries from parallel synthesis	272	(3)
MS analysis	272	(2)
MS-guided purification	274	(1)
High-throughput NMR	274	(1)
Analysis of compounds from pooled libraries	275	(3)
MS analysis	276	(1)
Other methods	276	(2)
The screening of pooled combinatorial libraries	278	(6)
On-bead screening	278	(3)
Solution affinity selection methods	281	(3)
Concluding remarks	284	(3)
References	285	(2)
Multi-component reactions (MCRs) of isocyanides and their chemical libraries	287	(16)
Ivar Ugi
Alexander Domling
Introduction	287	(1)
Isocyanide chemistry	288	(2)
MCR chemistry	290	(3)
Stereoselective U-4CRs and their applications in the synthesis of α-amino acids, peptides, and related compounds	293	(3)
Multi-component reactions of five and more reactants	296	(7)
References	299	(4)
Multi-step solution phase combinatorial synthesis	303	(24)
Dale L. Boger
Joel Goldberg
Introduction	303	(1)
Aspects of solution phase combinatorial chemistry	303	(3)
Solution phase versus solid phase combinatorial chemistry	303	(2)
Synthesis of mixtures versus individual compounds	305	(1)
Development of solution phase combinatorial chemistry	305	(1)
Cyclic anhydride chemistry with extractive purification	306	(6)
Higher order libraries	312	(11)
Dimerization, trimerization, or tetramerization of iminodiacetic acid diamide libraries	312	(1)
Dimerization coupling with dicarboxylic acids	313	(3)
Dimerization via olefin metathesis coupling	316	(2)
Tetramerization of iminodiacetic acid diamides	318	(5)
Deconvolution	323	(4)
Introduction to deconvolution	323	(1)
Iterative/recursive deconvolution	323	(1)
Deletion synthesis deconvolution and scanning deconvolution	324	(2)
References	326	(1)
Experimental techniques in fluorous synthesis: a user's guide	327	(26)
Dennis P. Curran
Sabine Hadida
Armido Studer
Mu He
Sun-Young Kim
Zhiyong Luo
Mats Larhed
Anders Hallberg
Bruno Linclau
Introduction	327	(1)
General aspects of fluorous chemistry	328	(5)
Features of fluorous techniques	328	(2)
Reaction and extraction solvents	330	(1)
Fluorous starting materials	331	(1)
Fluorous reverse phase silica gel	331	(2)
Fluorous tin chemistry	333	(10)
Synthesis of representative perfluorohexylethyltin reagents	333	(3)
Parallel synthesis with a fluorous tin hydride	336	(1)
Synthesis and reaction of a fluorous tin azide	336	(2)
Rapid fluorous Stille coupling reactions with microwave heating	338	(2)
Synthesis of `propylene-spaced' fluorous allyltin reagents	340	(1)
Parallel allylation of aldehydes with fluorous allyltins	341	(2)
Fluorous synthesis	343	(4)
Fluorous isoxazoline synthesis without intermediate purification	344	(2)
Fluorous Ugi sequence	346	(1)
Fluorous quenching (scavenging)	347	(4)
Tin hydride quench of alkenes by hydrostannation	347	(2)
Fluorous amine quenching in robotic parallel synthesis of ureas	349	(2)
Conclusions	351	(2)
Acknowledgements	351	(1)
References	351	(2)
Combinatorial synthesis on multivalent oligomeric supports	353	(20)
Ronald M. Kim
Jiang Chang
Introduction	353	(1)
Use of supports in organic synthesis	353	(2)
Solid phase synthesis	353	(1)
Liquid phase synthesis	354	(1)
Overview of combinatorial synthesis on multivalent oligomeric supports (COSMOS)	355	(1)
Supports for COSMOS	356	(5)
General considerations	356	(1)
PAMAM dendrimers	357	(1)
Polyethylene glycol-armed supports	358	(3)
Organic synthesis in COSMOS	361	(2)
Size-based purification of homogeneous reaction products in COSMOS	363	(10)
General considerations	363	(1)
Ultrafiltration	364	(1)
Size exclusion chromatography	364	(1)
Size exclusion chromatography resins for COSMOS purification	365	(2)
Methods for COSMOS purification via SEC	367	(3)
Automation and parallelization of COSMOS purification by SEC	370	(1)
References	371	(2)
Automated solution phase synthesis and its application in combinatorial chemistry	373	(28)
Tohru Sugawara
David G. Cork
Introduction	373	(1)
Automated synthesis systems and workstations	373	(6)
The automated synthesis hardware	375	(2)
The automated synthesis control software	377	(2)
Applications of automated synthesis systems	379	(12)
Unusual amino acid derivatives	379	(1)
Condensed azole derivatives	380	(4)
Fragment peptide derivatives	384	(4)
β-Lactam derivatives	388	(3)
Applications of automated synthesis workstations	391	(10)
Preparative multigram scale synthesis	391	(5)
Automated synthesis with supported reagents	396	(2)
Catalytic hydrogen transfer	398	(2)
References	400	(1)
Combinatorial discovery and optimization of electrocatalysts	401	(20)
Erik Reddington
Jong-Sung Yu
Benny C. Chan
Anthony Sapienza
Guoying Chen
Thomas E. Mallouk
Bogdan Gurau
Rameshkrishnan Viswanathan
Renxuan Liu
Eugene S. Smotkin
S. Sarangapani
Introduction	401	(2)
Combinatorial materials discovery	401	(1)
Electrocatalysts for the direct methanol fuel cell (DMFC)	402	(1)
Optimization of the catalyst processing conditions	403	(3)
Reduction of metal salts	404	(1)
Optimization of reduction parameters	404	(2)
Preparation of electrode arrays	406	(6)
Selecting a substrate	406	(1)
Mapping the arrays	407	(1)
Automating the synthesis of arrays	407	(3)
General rules	410	(2)
Optimizing the screening and testing conditions	412	(4)
Optimization of screening conditions of anode electrocatalysts	412	(2)
DMFC testing experiments	414	(1)
Testing and screening of methanol-tolerant cathode materials	414	(2)
Results and conclusions	416	(5)
Results	416	(2)
Conclusions	418	(1)
Acknowledgements	419	(1)
References	419	(2)
Combinatorial library synthesis using polymer-supported catalysts	421	(12)
Shu Kobayashi
Introduction	421	(2)
Tetrahydroquinoline library	423	(3)
β-Amino ketone and ester library	426	(3)
α-Amino nitrile library	429	(1)
Conclusion	430	(3)
Acknowledgements	431	(1)
References	431	(2)
Combinatorial approaches to chiral catalyst discovery	433	(24)
Marc L. Snapper
Amir H. Hoveyda
Introduction	433	(2)
Background	434	(1)
Lewis acid catalysis	434	(1)
Catalyst discovery (optimization of reactivity)	435	(7)
Indexed grid	436	(5)
High-throughput screening	441	(1)
Catalyst optimization (optimization of selectivity)	442	(9)
Positional scanning of ligand structure	443	(3)
Positional scanning for optimal ligand structure in Strecker reaction	446	(5)
Discussion	451	(6)
Overview of current status	451	(1)
Future opportunities	452	(1)
Acknowledgements	453	(1)
References	453	(4)
A1 List of suppliers	457	(6)
Index	463