Solid-Phase Synthesis and Combinatorial Technologies

630 INDEX

Quality control (QC) of combinatorial libraries (Continued)

automated, 215–223 bead-based, 275 off-bead, 275

FTIR, 275 HPLC/MS, 278, 360 MS, 275, 293 NMR, 275

Quinazolinediones, SP combinatorial libraries of, 242

Quinazolinones, SP combinatorial libraries of, 235

Quinic acid, SP combinatorial libraries from, 155

Quinine macrocycles, solution-phase combinatorial libraries of, 406

Quinolines, solution-phase combinatorial libraries of, 378

Quinolones, solution-phase combinatorial libraries of, 358

Quinolones, SP combinatorial libraries of, 240

Randomization points, 138, 346

Reaction monitoring in SPS, 1, 26–33, 95, 96

off-bead, 27, 80, 102, dimethoxytrityl cation release, 66

on-bead, 27–33, colorimetric/fluorescence, 27, 28

bromophenol blue, 48 disperse red 1 test, 28 Kaiser test, 27, 28, 48

ninhydrin test, see Kaiser test on bead, reaction monitoring in SPS

p-nitrobenzylpyridine test, 28 gel-phase NMR spectroscopy, 3, 4, 28,

29

13C-enriched, 29

IR spectroscopy, 32, 33, 230 attenuated total reflection (ATR), 32 DRIFTS, 32

Fourier Transform IR (FT-IR), 32 near IR, 32

photoacoustic FT-IR, 32 mass spectrometry, 29–31 analytical constructs, 31 MALDI-TOF, 29, 82

TOF-SIMS, 29 Raman spectroscopy, 32

Reaction monitoring of combinatorial library synthesis, 274, 347

in solution, 340 chiral GC, 475 by NMR, 399 by TLC, 399

on SP, off-bead, 274

Fmoc reading, 274, 316 UV quantitation, 274

on-bead, 168, 214 colorimetric techniques, 214

Kaiser test, 274

Reaction optimization, combinatorial, 456–460

parallel reaction libraries, 456–460 reagent-outcome relationship (ROR), 458,

459

Reactions in solution for combinatorial library synthesis

acylations, 342, 357, 480–484 aldol condensations, 433 alkylations, 357, 395

C-H insertions, 461, 462 cyclizations, 351 cycloadditions, 1,3-dipolar, 395 cyclocondensations, 350 Diels-Alder, 350, 550

Flugi, 365 Fluginelli, 365 Grignard, 393

Hantsch condensations, 435 Henry, 395

Hoffman eliminations, 391 hydrosilylation, 462–466 metathesis, ring opening cross-, 391 Michael additions, 386, 435 Mitsunobu, 381

reductions, 406 asymmetric, 471–473

reductive aminations, 371, 386 Robinson annulations, 435 Sonogashira coupling, 342, 350 Stille coupling, 344, 367, 394

transesterifications/cyclizations, 408, 410 Reactions on solid phase

acylations, 51, 232, 236, 308, 459, 460

alkylations, 308 N-, 277, 279 brominations, 443

cycloadditions, 121, 122 Dess-Martin oxidation, 129 Diels-Alder, 7, 234, 275 electrophilic iodinations, 116 Grignard, 235

Heck couplings, 466–471 Horner-Emmons, 235 macrocyclizations, 35, 56 metathesis, 279, 342

intramolecular, 275 Michael addition, 51 Mitsunobu, 277

nucleophilic substitutions, 456–459 aromatic, 234

Pauson-Khand cyclizations, 98, 101, 102 Pictet-Spengler, 214, 234

reductions, 317, 342, 443

reductive aminations, 228, 230, 231, 236, 459

Sonogashira couplings, 116, 321, Suzuki coupling, 128, 240, 243, 245, 279 Tsuge, 240

Wittig, 51, 240

Reactivity prediction models, 180 Receptors, see Molecular recognition

combinatorial libraries artificial, 484

Recombinant DNA techniques, 508 Reducing agents, polymer combinatorial

libraries of, 604, 605 Redundancy, 269, 270

Resin capture, 391–394 Ribosomes, 535 Ribozymes, 141, 156, 424

Scaffolds, 102, 106, 115, 138, 148, 150, 151, 159, 167, 169, 170, 172, 176, 178, 180, 224, 228, 282, 325, 342, 430, 433, 448, 485, 521, 604, 606

natural products as, 152, 154 polycyclic, 319, 342

rigid, 118, 119, 154, 170 Screening of combinatorial libraries,

high-throughput , 136, 137, 140, 223, 280, 429, 433, 437, 514

INDEX 631

adsorption, distribution, metabolism, excretion (ADME), 452, 453

in vitro, 453

artificial membranes, 453 in vivo, 453

cassette dosing, 453 assays for, 428–430,

cytoblot, 425

miniaturized, see Miniaturization whole plant, 456

automation for, 429, 430 robustness, 429

bead-based, 271, 466, 468, 469, 475, 478, 482, 483

for catalysis, 139, 461–484 chiral HPLC-based, 471, 473

colorimetric, 462–465, 475, 478 fluorescent, 466, 468, 469, 594, 595 GC, 586, 593

MS, 588, 591–593 resonance-enhanced multiphoton

ionization (REMPI), 588, 590 time-resolved IR thermographic

screening, 465, 482–484, 588, 589, 593

for chiral selection, 486

circular dichroism (CD)-based, 486 differential scanning calorimetry

(DSC), 486

for materials science, 139, 579, 580, 588–600

dielectric materials from, 599 scanning-tip microwave near-field mi-

croscope (STMNM), 599 magnetoresistant materials from, 142,

161

photoluminescent materials from, 142, 595–599

visual imaging for, 597 superconductor materials from, 142

metabolic, 422, 453 miniaturized, see Miniaturization

on-bead, 147, 252, 284–290, 303, 304, 306, 469, 485, 486, 490

binding assays, 284 detection methods for,

colorimetric, 284, 285, 494 dual color, 285

fluorescent, 284, 485, 486–489

632 INDEX

Screening of combinatorial libraries, high-throughput (Continued)

radioisotopic, 284 functional assays, 284

on-phage, 510, 514, 518, 528, 530 on-thread, 252

for pharmaceutical applications, 139 physicochemical, 422, 430, 454

blood brain barrier (BBB) penetration, 454

chromatography hydrophobicity index (CHI), 454

lipophilicity, 454 solubility, 454

pooling strategies for, 430 for polymers, 140, 604, 606 by fluorescence, 614, 615

by HPLC, 612

for separations, 612 in vivo, 609

positives from, 140, 154, 284, 288, 306, 430

false, 215, 285, 292, 293, 301, 588 target-assisted, see Direct, structure

determination of combinatorial libraries

toxicity, 430, 453, 454 in silico, 454

virtual, 177, 182, 189 Sequestration-enabling reagents, 382, 383,

385, 386 Similarity, 137, 171, 187

indices, 183 Tanimoto, 183

Solid-phase assisted solution-phase synthesis, 339, 372–396

dendritic supports for TADDOL, 377

ion exchange-supported in, 373, 374, 381, 386, 391, 395, 459, 460 N-phenylmaleimide/organotin chlorides

in, 377 poly(4-vinylpyridine) in, 373

poly(4-vinylpyridinium dichromate) in, 374

PS-supported, 111

catalysts in, 224, 372, 376–378 aluminium-based, 378 cobalt-based, 378

osmium tetroxide, 377 palladium-based, 378 piperidine, 378 ruthenium, Grubbs, 378 scandium-based, 378

reagents in, 372–376, 395 benzotriazole, 373, 374 bicyclic guanidines, 373 borohydride, 373 cyanoborohydride, 374

cyclopentadienyl phosphazine, 373 di(acyloxy)halogenates, 373, 374 diazidohalogenates, 373 distannane, 373

DMAP, 374, 376, 386 EDC, 373, 386 guanidines, 395 iodoso diacetate, 373 lithium amides, 373

Mukayama’s reagent, 373 nitroacetate, 373 perruthenate, 373, 395 phosphazene, 395

pyridinium bromide perbromide, 374 quaternary ammonium salts, 395 selenium, 373

silyl cyanide, 374 silyl triflate, 373 sulfonylhydrazine, 393 tosic acid, 393

trifluoromethyl aryl ketones, 373 triphenylphosphine, 374

Wittig, 374

scavengers in, 351, 372, 374, 381, 395 acyl chlorides,382

aldehydes, 382 amines, 382, 386, 395 isocyanates, 382 morpholines, 382

ROMPGEL supported, 373, 377 silica-supported, 377, 378

Solid-phase linkers, 9–26, 94, 223 acid-labile, 10–14, 47, 48

acid-sensitive methoxy benzaldehyde (AMEBA), 224

backbone amide linkage (BAL), 48, 53, 54

carbazate linker, 13 diethanolamine linker, 13

halide linker, 12

p-hydroxymethyl benzoic acid (HMB), 403

hypersensitive linker, 10, 11 indole linker, 12

Knorr linker, 315 PAL linker, 11, 52

Rink amide linker, 11, 35, 234, 293, 391, 442

Rink ester linker, 11, 243 silicon-based linkers, 12, 78

super-acid sensitive resin (SASRIN), 10 THP linker, 11, 12, 116, 400

trityl linkers, 12

Wang linker, 10, 101, 102, 241, 277, 475

base-labile, 10, 14, 59–63 acetyldimedone linker, 14 carbamate linker, 61 disulfide linker, 61

ester linkers, 60, 61 fluorene linker, 14

oxime linker, 14, 244, 245 silicon-based linkers, 14 squarate linker, 80 p-thiophenol linker, 14, 78, 230

cleavage of

cyclative, 10, 24–26, 48, 51, 79, 80, 94, 120, 121, 123, 235, 293, 351, 393, 394, 399

multiple options, 113

photolabile, 10, 14–17, 148, 306, 318, 320 carbamate linker, 31

o-nitrobenzyl linkers, 16, 17, 78 pivaloylglycolic linker, 17

safety-catch, 10, 17–20 acetal linker, 18 acid-labile, 17

imidazole hydroxyl linker, 18 Kenner sulfonamide linker, 17 phenol-sulfide linker, 17 redox linker, 20 sulfide-based linker, 18 thioketal hydroxyl linker, 18

traceless, 10, 20–24, 93 carboxyl-based linker, 22 chromium carbonyl linkers, 21 cobalt carbonyl linkers, 21 germanium-based linkers, 20

INDEX 633

hydrazide linker, 23 phosphorus-based linkers, 20 quinodimethane linker, 20 regenerated Michael (REM) linker, 20 selenium-based linkers, 24, 113 silicon-based linkers, 20, 24, 128

Solid-phase synthesis, 1–135 accessibility of reaction sites, 285 automated, 91, 96, 141 combinatorial exploitation of, 91, 92,

102–107, 113, 117, 118, 123–125, 132–134, 173

by decoration, 96–98, 106 continuous-flow, 5, 6, 48, 58, 71, 95 design of, 93–95, 99–101, 115, 116, 120,

121, 127, 128 purification in, 7, 96

rationale for, 108, 114, 115, 125 reaction conditions in,

chemistry assessment, 5, 7, 8, 95–97, 101, 102, 111, 116, 117, 121–123, 128–131, 167, 212, 226, 230, 236, 241, 269, 320, 340, 443

optimization of, see Chemistry assessment, reaction conditions in, solid-phase synthesis

validation in solution, 93, 98, 99, 109–112

validation on SP, see Chemistry assessment, reaction conditions in, solid-phase synthesis

transfer from solution synthesis, see Chemistry assessment, reaction conditions in, solid-phase synthesis

reaction kinetics in, 6, 7, 95 retrosynthetic studies in, see Target

selection, reaction conditions in, solid-phase synthesis

side products in, 96

site isolation, see Site-site interactions, reaction conditions in, solid-phase synthesis

site-site interactions in, 7, 374

target selection in, 92, 93, 98, 115, 120, 127, 230, 319

work-up protocols in, 5, 7, 8 Solid-solid interface reactions, 7

634 INDEX

Solid supports, 1–8, 48, 58, 59, 94, 246–252, 340, 514

bidimensional supports, see Planar supports, solid supports

cotton, 6, 48 cross-linking in, 1, 2 crowns, 6, 77, 94

gelatinous, see Polystyrene resins, solid supports

loading, 3, 5, 236, 341 high, 383

macroporous nonswelling resins, 5–7, 95 Argopore, 5

controlled pore glass (CPG), 5, 58, 70, 77

kieselguhr-based, 5, 48 polyamide-based, 5, 48

microkans, 314 microscope slides, 327 microtubes, 6, 314, 315

monodimensional supports, see Threads, solid supports

pins, 6, 94, 141, 314 planar supports, 246–248

cellulose, 6, 48, 58, 485 laminar, 247 membranes, 6

polymeric colloids, 58, 59 polystyrene discs, 6 polystyrene resins

handling of, 270, 272

hydrophilic PEG, 3, 4, 37, 48, 58, 77, 94, 95, 285, 320

Argogel, 3, 243, 285 polyethylene glycol acrylamide

(PEGA), 4, 285, 286 polytetrahydrofuran, 4

Tentagel, 3, 285, 286, 318, 480, 482, 483

hydrophobic, 1–3, 37, 48, 58, 77, 95 Merrifield, 3, 11, 74, 81, 236

macrobeads, 38, 253

solvation, see Swelling, PS resins, solid supports

swelling of, 2, 4, 5, 7, 129, 340 sepharose, 48, 78, 80

for targets in phage display, 514 tea bags, 141, 235

threads, 251, 252

Soluble supports, 6, 75, 339, 397–404 dendrimers, 6, 400–404, 602

glycopeptide, 52, 402 PEG-derived, high loading, 402 peptide, 52

non-PEG based, 399, 400 isopropylamide/acrylic acid

heteropolymer, 399 non cross-linked PS, 400

polyvinyl alcohol copolymer, 399 styrene/allylic alcohol heteropolymer,

400 PEG, 77, 397–400

as catalysts, 398 high loading, 398 as reagents, 398 as scavengers, 398

synthesis of, 600–603 Solution-phase synthesis, 339–421

design of, 346 reaction conditions

chemistry assessment, 340, 346, 347, 351, 357

validation of, 346 semiautomated, 352 target selection in, 346

work-up protocols in, 340, 361–372, 391, 461

chromatography, 340, 371, 372 concentrations, see Evaporations, Work-up protocols

crystallizations, 397 drying, 340 evaporations, 340, 361 extractions, 340

liquid-liquid, 361–368, 370 two-phase, 361–363 multiphase, fluorous/aqueous/or-

ganic, 363–368 solid-phase (SPE), 368–371

cartridges, prepacked, 370 fluorous reverse-phase silica gel,

370

ion-exchange chromatography, 368–371

reverse-phase silica gel, 369 filtrations, 361

precipitations, 361, 397

size exclusion chromatography, 401, 402

ultrafiltration, 401 Solvation energy, 180

Spiro[pyrrolidine-2,3’-oxindoles], solution-phase combinatorial libraries of, 358–360, 435

Stereoselection, 461, 462

Steroids, SP combinatorial libraries of, 154 Stilbenes, SP combinatorial libraries of,

197, 198, 240 Structure–activity relationships (SAR), 172,

431, 437, 477, 586, 604, 609 Structure determination for combinatorial

libraries, 139, 215, 269, 274, 275 by deconvolution, 139, 264, 290–301

bogus coin, 299 chiral, 236 deletion, 299, 342

HPLC fractionation, 342

iterative, 142, 144, 149, 290–298, 301, 341, 342, 442, 456, 477, 486

mutational synthetic unrandomization of random oligomer fragments (SURF), 299–300

omission libraries, 299 orthogonal, 299

positional scanning, 143, 298, 299, 301, 341, 342

recursive, 290 subtractive, 299, 342

direct, 264, 279–290

off-bead, target-assisted, 280–284, 286, 531

electrospray ionization (ESI)/MS, 280 and affinity chromatography, 280 and capillary isoelectric focusing,

280

and gel filtration, 280

and immunoaffinity extraction and immunoaffinity ultrafiltration,

280

and pulsed ultrafiltration, 280, 281 and size exclusion chromatography

(SEC), 280 FTICR-MS, 281

HPLC and immunoaffinity deletion, 280

INDEX 635

MALDI-MS and size exclusion chromatography (SEC), 280

NMR

NOE pumping, 283

pulsed field gradient (PFG) NMR, 282, 283

SAR by, 282

saturation transfer difference (STD) NMR, 283

transfer NOE (trNOE), 282, 283 on-bead, see On-bead, screening of

combinatorial libraries

by DNA sequencing for display libraries, 514, 515

by encoding, 139, 264, 272, 286, 301–318, 325, 484, 490

chemical, 139, 154, 167, 301–310, 480 binary scheme, 306, 325

decoding

by capillary electrochromatography (CEC), 307

by electron capture GC (ECGC), 306, 310

by HPLC/fluorescence, 306, 307 non-chemical, 139, 310–318

fluorophoric supports, 311 intrinsically labeled supports, 311 MS-encoded, 311

radiofrequency, 148, 155, 311–318, 477

positional, 215, 252

indirect, see Deconvolution, structure determination for combinatorial libraries

Sulfonamides, solution-phase combinatorial libraries of, 375

Supramolecular chemistry, 485 Synthetic protocols for materials science

combinatorial libraries,

in solution, 579, 580, 586, 587, 589, 590, 594

hydrothermal, 587 inkjet deposition, 594 sol-gel, 588

on SP, 579

diffusion barriers, 580 solid-state, 580

classical, 580

636 INDEX

Synthetic protocols for materials science combinatorial libraries (Continued)

thin-film deposition, 161, 580–584, 595–597

electrochemical, 582

electron beam evaporation, 582 electron guns for, 581,584 emission jets for, 581

physical masking in, 161, 581, 582, 584, 591, 595–599

physical vapor, 582 pulsed laser ablation, 582

radiofrequency sputtering, 582, 591,598, 599

Synthetic protocols for polymer libraries radical polymerizations, 600

Synthetic protocols for solution-phase combinatorial libraries

automated, 341, 352–360 light fluorous synthesis, 367 parallel, 363, 438 semiautomated, 352

Synthetic protocols for SP combinatorial libraries

automated, 161, 169, 265, 341 directed sorting, 311–315

divide and recombine, see Mix-and-split, synthetic protocols for SP combinatorial libraries

many compounds per bead, 266 mix-and-split, 137, 138, 141, 235,

264–270, 288, 290, 298, 301, 302, 308, 311, 318, 323, 341, 404, 475, 486, 488, 490

one compound per bead, see Mix-and- split, synthetic protocols for SP combinatorial libraries

one compound per well, see Parallel, synthetic protocols for SP combinatorial libraries

parallel, 137, 170, 210–212, 226, 265, 293, 313, 438

automated, 165, 170, 210–215, 240–246

manual, 210–214, 224–235 semiautomated, 170, 210–214, 235–240 spatially addressable, 141

VLSIPS, 246, 248

Synthetic receptors, 422. See also Molecular recognition combinatorial libraries

Tags, 137, 301 chemical, 301, 303

electrophoric, 302, 305, 306, 308–310 nucleotides, 303–305

peptides, 303–305 secondary amines, 306, 307

for extraction, 362, 363 fluorous, 364, 365, 367, 368

non chemical, 301 optical, 139 radiofrequency, 139

Taxol, combinatorial biocatalytic libraries from, 567

Taxol derivatives, 519, 520 Template-directed synthesis, see Dynamic

combinatorial libraries Templates, imprinting, 612. See also

Molecularly imprinted polymer combinatorial libraries

Tetrahydroacridines, solution-phase combinatorial libraries of, 341, 342

Tetrahydro-β-carbolines, SP combinatorial libraries of, 214, 234

Tetrahydroisoquinolinones, SP combinatorial libraries of, 242

Tetrahydroquinolines, solution-phase combinatorial libraries of, 342

Tetrahydroquinolines, SP combinatorial libraries of, 224–228

1,2,3-Thiadiazoles, solution-phase combinatorial libraries of, 393

Thiazoles, solution-phase combinatorial libraries of, 342

Thiazolidinones, SP combinatorial libraries of, 234

Thiohydantoins, solution-phase combinatorial libraries of, 350

Thiohydantoins, SP combinatorial libraries of, 279

Thiophenes, SP combinatorial libraries of, 240

3-Thio-1,2,4-triazoles, SP combinatorial libraries of, 240

Toxicity, 171

Transition state analogues (TSA), 525–527 Triazines, solution-phase combinatorial

libraries of, 150, 151, 355–358 Triazines, SP combinatorial libraries of, 271 Tricyclic compounds, solution-phase

combinatorial libraries of, 435 Tricyclic compounds, SP combinatorial

libraries of, 240

Tyrphostins, SP combinatorial libraries of, 315

Unsaturated dicarboxylates, solution-phase combinatorial libraries of, 406

Ureas, solution-phase combinatorial libraries of, 342

INDEX 637

Ureas, SP combinatorial libraries of, 235, 243

Vaccines, 508

96-Wells format, 355 architecture, 211 microdispensers, 250, 272

plates, 215, 223, 224, 232–235, 240, 375 reaction blocks, 212, 241, 359, 375

SPE cartridges for purification, 371

Yohimbinic acid, SP combinatorial libraries from, 153, 154

Zeolites, 587