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Me methyl min minutes MAPK mitogen activated protein kinase MKP mitogen activated protein kinase phosphatase µw microwave nbd norbornadiene NBS N-bromosuccinimide NMR nuclear magnetic resonance nOe nuclear Overhauser effect NOESY nuclear Overhauser effect spectroscopy Ph phenyl PPTS pyridinum p-toluenesulfonate PS polymer supported PTSA p-toluenesulfonic acid RI refractive index sat’d saturated TBAF tetrabutylammonium fluoride TBS or TBDMS tert-butyldimethylsilyl Tf trifluoromethanesulfonyl TFA trifluoroacetic acid TFE trifluoroethanol THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl Tol toluene Tos toluenesulfonyl UPCMLD University of Pittsburgh Center for Chemical Methodologies and Library Development wt. weight vi
Table of Contents 1.0 Introduction.................................................................................................................... 1 1.1 The Role of Diversity-Oriented Synthesis in Modern Biomedical Research... 1 1.1.1 Transition Metal-Catalyzed Reactions in Diversity-Oriented Synthesis.9 2.0 Design and Synthesis of the Pivotal Intermediates ................................................... 15 2.1 Design of the Pivotal Intermediates................................................................... 15 2.2 Synthesis of the Pivotal Intermediates .............................................................. 17 2.2.1 Synthesis of Allenic Amino Esters............................................................. 17 2.2.1.1 Claisen Rearrangement via an Oxazole............................................ 17 2.2.1.2 Ester-enolate Claisen Rearrangement .............................................. 20 2.2.2 N-Alkylation of Allenic Amino Esters....................................................... 26 3.0 Synthesis and Use of Cross-Conjugated Trienes....................................................... 30 3.1 Transition Metal-Catalyzed Ene-type Cycloisomerization Reactions ........... 30 3.1.1 Allenic Cycloisomerization Reaction......................................................... 33 3.2 Rhodium(I)-Catalyzed Allenic Cycloisomerization Reaction of Amino-Ester Tethered Allenynes ............................................................................................. 37 3.2.1 Preparation of Enol-ether Trienes via an Allenic Cycloisomerization Reaction ...................................................................................................... 41 3.3 Diversification of Cross-Conjugated Trienes via Diels-Alder Reaction ........ 46 vii
Page 1 and 2: TRANSITION METAL-CATALYZED REACTION
Page 3 and 4: Transition Metal-Catalyzed Reaction
Page 5: List of Abbreviations Ac acetyl AcO
Page 9 and 10: Appendix A : X-ray crystal structur
Page 11 and 12: Table 4.8 Rh(I)-catalyzed cyclocarb
Page 13 and 14: List of Schemes Scheme 1.1 Three fo
Page 15 and 16: Scheme 3.24 Preparation of amide-te
Page 17 and 18: Scheme 4.16 Formation of bicyclo[5.
Page 19 and 20: 1.0 Introduction 1.1 The Role of Di
Page 21 and 22: According to these guidelines, the
Page 23 and 24: Scheme 1.1 Three forms of diversity
Page 25 and 26: Another example from the Schreiber
Page 27 and 28: 1.1.1 Transition Metal-Catalyzed Re
Page 29 and 30: 37, , such reactions include transi
Page 31 and 32: the proximal olefin of allenyne 38
Page 33 and 34: 2.0 Design and Synthesis of the Piv
Page 35 and 36: The allenic amino acid derivatives
Page 37 and 38: This protocol proved particularly u
Page 39 and 40: ZnCl2, which results in a Zn-chelat
Page 41 and 42: Scheme 2.7 Synthesis of trisubstitu
Page 43 and 44: THF), the yield was increased from
Page 45 and 46: the terminus of the alkyne led to d
Page 47 and 48: N-Alkylation of the glycine-derived
Page 49 and 50: circumvent this issue, variants suc
Page 51 and 52: BINAP as a chiral ligand to obtain
Page 53 and 54: stereochemistry of the exocyclic ol
Page 55 and 56: 3.2 Rhodium(I)-Catalyzed Allenic Cy
Page 57 and 58:
exocyclic olefin geometry is not re
Page 59 and 60:
3.2.1 Preparation of Enol-ether Tri
Page 61 and 62:
Scheme 3.15 Synthesis of cycloisome
Page 63 and 64:
Scheme 3.17 Cycloisomerization of a
Page 65 and 66:
Scheme 3.19 Tandem cycloadditions o
Page 67 and 68:
Scheme 3.21 Intermolecular Diels-Al
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attractive, since additional functi
Page 71 and 72:
increased yield of the triene (47%)
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as an isobutyl-amide 155b was prepa
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group) demonstrated that this cyclo
Page 77 and 78:
in 1M HCl/dioxane (1 : 1) for 1h, t
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ppm (dd, J = 7.1, 4.6 Hz, 1H) assig
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http://ccc.chem.pitt.edu/). Using f
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Notably, exclusive cycloisomerizati
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intermediate in the reaction we sou
Page 87 and 88:
epulsive dipole interactions (Schem
Page 89 and 90:
Table 3.4 Diels-Alder reactions of
Page 91 and 92:
allenic Alder-ene reaction, ene-all
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Figure 3.4 Examples of natural prod
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species onto the proximal double bo
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Scheme 3.49 Rh(I)-catalyzed ene rea
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y Magnus 144 and it involves the in
Page 101 and 102:
usually is DMSO. Heating to 100 ºC
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that require high pressures of CO.
Page 105 and 106:
In contrast to the Mo(CO)6-mediated
Page 107 and 108:
Scheme 4.15 Rh(I)-catalyzed allenic
Page 109 and 110:
4.2 Rhodium(I)-Catalyzed Cyclocarbo
Page 111 and 112:
lack of double bond selectivity, si
Page 113 and 114:
Table 4.2 Cyclocarbonylation reacti
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Notably, the allenic cyclocarbonyla
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Scheme 4.22 Cyclocarbonylation reac
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neat or in solution. This decomposi
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the newly synthesized fulvenes (e.g
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stereocenters and mixture of E/Z is
Page 125 and 126:
proximal double bond to give α-alk
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the methyl ester and Ha are syn. Sc
Page 129 and 130:
that the major diastereomer in the
Page 131 and 132:
We were motivated to first examine
Page 133 and 134:
Scheme 4.42 Synthesis of pyrrole 29
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periodic acid (H5IO6). 209 These hi
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eaction failed to go to completion,
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4.5.2 Synthesis of a Library of Tri
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diketones 312{1-3,1-2} in yields ra
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Figure 4.2 Distribution for physico
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tricyclic pyrrole 314{3,2,26} (Figu
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4.6 Synthesis of α-Alkylidene Cycl
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anched and linear carboxylic acid i
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eactivity of the species prepared i
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considerably lower than the ratio o
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diastereomer. Next, allenyne 328 wa
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Conclusions In summary, we have dem
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Experimental Section General Method
Page 161 and 162:
General procedure A for esterificat
Page 163 and 164:
F Bz N H 56f 2-Benzoylamino-3-(4-fl
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MeO2C Bz N H 58c 2-Benzoylamino-2-m
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MeO MeO2C Bz N H 58e 2-Benzoylamino
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mL) and MeOH (10 mL) instead of sat
Page 171 and 172:
hexanes-EtOAc, 19 : 1 to 4 : 1, v/v
Page 173 and 174:
which was immediately used in the C
Page 175 and 176:
Boc TMS N H Bn 64f tert-Butyl-1-((4
Page 177 and 178:
MeI (38 µL, 0.62 mmol). Yield 65a
Page 179 and 180:
with brine and concentrated under v
Page 181 and 182:
H MeO 2C • H Bn NHBoc tert-Butyl-
Page 183 and 184:
TMS MeO 2C • 70 H H NHBoc 2-tert-
Page 185 and 186:
185 (10), 141 (21), 57 (100); EI-HR
Page 187 and 188:
dispersion in mineral oil, 1.0 mmol
Page 189 and 190:
EI-HRMS calcd for C30H26NO3 m/z [M-
Page 191 and 192:
CbzN MeO 2C Me 73h 2-[Benzyloxycarb
Page 193 and 194:
CbzN MeO 2C Me 2-(Benzyloxycarbonyl
Page 195 and 196:
dispersion in mineral oil, 3.85 mmo
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completion of the addition, the rea
Page 199 and 200:
BzN MeO 2C S 74h 2-(Benzoylprop-2-y
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BzN MeO 2C Bn 75b 2-(Allylbenzoylam
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BzN MeO 2C TBSO 75e 2-(Benzoylbut-2
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Hz, 1H), 5.85 (s, 1H), 5.52 (dd, J
Page 207 and 208:
1H), 3.69 (s, 3H), 1.58 (d, J = 7.1
Page 209 and 210:
µmol), [Rh(CO)2Cl]2 (1 mg, 3 µmol
Page 211 and 212:
1.25 (m, 6H), 0.88 (t, J = 6.9 Hz,
Page 213 and 214:
6.72 (d, J = 7.6 Hz, 0.5H), 6.68 (d
Page 215 and 216:
BzN MeO2C Bn 122a Methyl-2-(N-(but-
Page 217 and 218:
Bz N MeO2C Bn 1-Benzoyl-2-benzyl-4-
Page 219 and 220:
13.9, 5.3 Hz, 1H), 2.51-2.47 (m, 1H
Page 221 and 222:
15 min the solvent was removed unde
Page 223 and 224:
Benzoyl chloride (0.169 mL, 1.46 mm
Page 225 and 226:
mg, 0.11 mmol), [Rh(CO)2Cl]2 (4 mg,
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mL). kk The aqueous layer was extra
Page 229 and 230:
ºC. After quenching the reaction b
Page 231 and 232:
129.8, 129.0, 128.7, 128.4, 126.2,
Page 233 and 234:
MeO 2C O O O N H N R 1 O N Ph [10c-
Page 235 and 236:
The crude residue was purified by f
Page 237 and 238:
14.4 Hz, 1H), 3.49-3.39 (m, 2H), 3.
Page 239 and 240:
1H), 5.49 (dd, J = 17.3, 1.8 Hz, 1H
Page 241 and 242:
was stirred at rt for 1 h when it w
Page 243 and 244:
BzN HOOC 2-(N-(but-2-ynyl)benzamido
Page 245 and 246:
°C and DIBAL-H (0.440 mL of a 1.0M
Page 247 and 248:
129 (62), 91 (100); EI-HRMS calcula
Page 249 and 250:
(d, J = 18.0 Hz, 1H), 4.14 (d, J =
Page 251 and 252:
4.98 (dt, J = 7.7, 5.1 Hz, 1H), 4.1
Page 253 and 254:
N Bz MeO2C OTBS 214 1-Benzoyl-2-(te
Page 255 and 256:
270a (major diastereomer-eluting fi
Page 257 and 258:
CDCl3): δ 7.42-7.17 (m, 13H), 7.04
Page 259 and 260:
18.6 Hz, 1H), 4.34 (d, J = 18.0 Hz,
Page 261 and 262:
Bz N MeO2C 2-Benzoyl-3,7-dimethyl-6
Page 263 and 264:
v/v) afforded a mixture of compound
Page 265 and 266:
(435 mg, 1.21 mmol), DMSO (429 µL,
Page 267 and 268:
4.02 (s, 1H), 3.88 (s, 3H), 1.82 (s
Page 269 and 270:
(207 mg, 96%) consisting of 287e (7
Page 271 and 272:
procedure O, using: 74f (110 mg, 0.
Page 273 and 274:
Bz N O H CO2Me BocN 287i 3-(2-Benzo
Page 275 and 276:
4.17 (d, J = 15.0 Hz, 1H), 4.10 (d,
Page 277 and 278:
137.1, 136.9, 130.4, 129.8, 128.5,
Page 279 and 280:
H BzN MeO2C Bn H N C3H7 298b CO 2Me
Page 281 and 282:
NMR (75 MHz, CDCl3): δ 172.3, 169.
Page 283 and 284:
following the general procedure Q,
Page 285 and 286:
H BzN MeO2C Bn H 5-Benzoyl-1,4-dibe
Page 287 and 288:
119.9, 114.1, 109.9, 108.6, 73.0, 5
Page 289 and 290:
4.11 (m, 1H), 4.07-3.98 (m, 1H), 3.
Page 291 and 292:
126.8, 126.2, 109.0, 72.9, 58.7, 56
Page 293 and 294:
NMR (75 MHz, CDCl3): δ 172.2, 169.
Page 295 and 296:
3.0 Hz, 1H), 5.82-5.80 (m, 1H), 5.2
Page 297 and 298:
87%). The diastereomeric ratio (288
Page 299 and 300:
APPENDIX A: X-ray crystal structure
Page 301 and 302:
APPENDIX B: X-ray crystal structure
Page 303 and 304:
APPENDIX C: X-ray crystal structure
Page 305 and 306:
APPENDIX D: X-ray crystal structure
Page 307 and 308:
APPENDIX E: X-ray crystal structure
Page 309 and 310:
APPENDIX F: QikProp property predic
Page 311 and 312:
1 H and 13 C NMRs of 74b 293
Page 313 and 314:
1 H and 13 C NMRs of 111a 295
Page 315 and 316:
Page 317 and 318:
Page 319 and 320:
Page 321 and 322:
1 H and 13 C NMRs of 270h 303
Page 323 and 324:
Page 325 and 326:
1 H and 13 C NMRs of 307 307
Page 327 and 328:
1 H and 13 C NMRs of 308n 309
Page 329 and 330:
10. (a) Burke, M. D.; Schreiber, S.
Page 331 and 332:
Hu, Y. J. Comb. Chem. 2006, 8, 286.
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49. For reviews on reactions of all
Page 335 and 336:
69. (a) Trost, B. M.; Lautens, M.;
Page 337 and 338:
containing cross-conjugated trienes
Page 339 and 340:
Vaillancourt, J.; Rasper, D. M.; Ta
Page 341 and 342:
130. Oppolzer, W.; Snieckus, V. Ang
Page 343 and 344:
149. (a) Hicks, F. A.; Buchwald, S.
Page 345 and 346:
Maiese, W. M. J. Antibiot. 2000, 53
Page 347 and 348:
192. The mechanism of decomposition
Page 349 and 350:
Boger, D. L.; Boyce, C. W.; Labroli
Page 351:
Generated Inhibitors of Human Mitog
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