Download (3249Kb) - D-Scholarship@Pitt - University of Pittsburgh

More documents

Recommendations

Info

1 H NMR (300 MHz, CDCl3): δ 7.68-7.64 (m, 2H), 7.46-7.38 (m, 3H), 7.33-7.21 (m, 5H), 5.83- 5.80 (m, 1H), 5.57-5.41 (m, 1H), 3.98-3.91 (m, 1H), 3.76 (s, 1.9H), 3.75 (s, 1.1H), 3.67-3.65 (m, 1H), 3.52-3.41 (m, 2H), 1.81 (dd, J = 7.2, 3.1 Hz, 1.9H), 1.77 (dd, J = 7.1, 3.1 Hz, 1.1H), 0.16 (s, 5.7H), 0.15 (s, 3.3H); 13 C NMR (75 MHz, CDCl3): δ 204.6, 172.6, 171.5, 136.4, 136.3, 135.8, 130.9, 130.3, 128.2, 128.0, 127.3, 126.8, 103.2, 90.9, 90.4, 89.4, 68.8, 52.4, 39.8, 38.8, 38.5, 13.9, 13.7, -0.3; IR (thin film): ν 2952, 2177, 1967, 1745, 1649 cm -1 ; MS m/z (%) 445 (21), 444 (36), 354 (50), 244 (74), 105 (100); EI-HRMS calcd for C27H30NO3Si m/z [M-1] + 444.1995; found 444.1984. BzN MeO 2C Bn 73d 2-[Benzoyl(3-phenylprop-2-ynyl)amino]-2-benzylhexa-3,4-dienoic acid methyl ester (73d). Prepared by following general procedure F, using: 58a (72 mg, 0.21 mmol), NaH (17 mg of 60% dispersion in mineral oil, 0.43 mmol), (3-bromoprop-1-ynyl)-benzene (66 mg, 0.34 mmol). Purification by flash chromatography (hexanes-EtOAc, 9 : 1, v/v) afforded 73d (86 mg, 89%) as a mixture of diastereomers in a ~1.6 : 1 ratio determined by integration of the methyl group resonances in the 1 H NMR. 1 H NMR (300 MHz, CDCl3): δ 7.79-7.77 (m, 2H), 7.57-7.51 (m, 4H), 7.41-7.23 (m, 9H), 5.98 (sept, J = 3.1 Hz, 1H), 5.65-5.50 (m, 1H), 4.11 (d, J = 13.6 Hz, 0.61H), 4.11-4.01 (m, 2H), 3.87 (s, 1.2H), 3.85 (s, 1.8H), 3.83-3.77 (m, 1H), 3.54 (d, J = 13.5 Hz, 1H), 1.89 (dd, J = 7.2, 3.2 Hz, 1.8H), 1.83 (dd, J = 7.1, 3.2 Hz, 1.2H); 13 C NMR (75 MHz, CDCl3): δ 204.6, 172.7, 172.6, 171.7, 171.6, 136.4, 136.3, 131.6, 131.5, 131.0, 130.4, 128.4, 128.3, 128.2, 128.0, 127.3, 126.9, 122.6, 90.9, 90.8, 90.4, 86.4, 86.3, 84.2, 69.0, 68.9, 52.4, 39.8, 39.0, 38.7, 13.9, 13.7; IR (thin film): ν 2948, 1967, 1743, 1645, 1392 cm -1 ; MS m/z (%) 448 (7), 390 (78), 358 (25), 105 (100); 170 • Ph H
EI-HRMS calcd for C30H26NO3 m/z [M-1] + 448.1913; found 448.1929. BzN MeO 2C TBSO 73e 2-(Benzoylbut-2-ynylamino)-2-(tert-butyldimethylsilyloxymethyl)-hexa-3,4-dienoic acid methyl ester (73e). Prepared by following general procedure F, using: 58i (245 mg, 0.629 mmol), NaH (50 mg of a 60% dispersion in mineral oil, 1.3 mmol), 1-bromo-2-butyne (88 µL, 1.1 mmol). Purification by flash chromatography (gradient elution; hexanes-EtOAc, 19 : 1 to 9 : 1, v/v) afforded 73e (237 mg, 85%) as a mixture of diastereomers. 1 H NMR (300 MHz, CDCl3): δ 7.71-7.65 (m, 2H), 7.46-7.37 (m, 3H), 5.90-5.86 (m, 1H), 5.41- 5.31 (m, 1H), 4.45 (d, J = 10.1 Hz, 0.66H), 4.44 (d, J = 10.1 Hz, 0.33H), 4.31-4.16 (m, 2H), 3.99 (dq, J = 18.5, 2.3 Hz, 1H), 3.74 (s, 1H), 3.73 (s, 2H), 1.90-1.87 (m, 3H), 1.71 (dd, J = 7.1, 3.2 Hz, 1H), 1.71 (dd, J = 7.1, 3.2 Hz, 2H), 0.87 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13 C NMR (75 MHz, CDCl3): δ 205.1, 205.0, 172.3, 172.2, 170.6, 136.1, 130.1, 128.1, 127.3, 127.3, 89.9, 89.8, 89.7, 79.8, 79.7, 77.2, 68.3, 68.2, 64.0, 63.9, 52.2, 52.1, 39.4, 39.3, 25.8, 25.7, 18.1, 14.0, 13.7, 3.6, -5.5, -5.6, -5.6, -5.7; IR (thin film): ν 2952, 1968, 1744, 1644 cm -1 ; MS m/z (%) 384 (35), 296 (31), 84 (100); EI-HRMS calcd for C21H26NO4Si m/z [M-57] + 384.1631; found 384.1630. CbzN MeO 2C Me 73f 2-(Benzyloxycarbonylbut-2-ynylamino)-2-methylhexa-3,4-dienoic acid, methyl ester (73f). Prepared by following general procedure F, using: 65d (400 mg, 1.38 mmol), NaH (110 mg of 60% dispersion in mineral oil, 2.76 mmol), 1-bromo-2-butyne (157 µL, 1.79 mmol). Flash chromatography (hexanes-EtOAc, 9 : 1, v/v) afforded 73f (390 mg, 84%). 171 • • H H
Page 1 and 2:
TRANSITION METAL-CATALYZED REACTION
Page 3 and 4:
Transition Metal-Catalyzed Reaction
Page 5 and 6:
List of Abbreviations Ac acetyl AcO
Page 7 and 8:
Table of Contents 1.0 Introduction.
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
Page 69 and 70:
attractive, since additional functi
Page 71 and 72:
increased yield of the triene (47%)
Page 73 and 74:
as an isobutyl-amide 155b was prepa
Page 75 and 76:
group) demonstrated that this cyclo
Page 77 and 78:
in 1M HCl/dioxane (1 : 1) for 1h, t
Page 79 and 80:
ppm (dd, J = 7.1, 4.6 Hz, 1H) assig
Page 81 and 82:
http://ccc.chem.pitt.edu/). Using f
Page 83 and 84:
Notably, exclusive cycloisomerizati
Page 85 and 86:
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
Page 93 and 94:
Figure 3.4 Examples of natural prod
Page 95 and 96:
species onto the proximal double bo
Page 97 and 98:
Scheme 3.49 Rh(I)-catalyzed ene rea
Page 99 and 100:
y Magnus 144 and it involves the in
Page 101 and 102:
usually is DMSO. Heating to 100 ºC
Page 103 and 104:
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
Page 115 and 116:
Notably, the allenic cyclocarbonyla
Page 117 and 118:
Scheme 4.22 Cyclocarbonylation reac
Page 119 and 120:
neat or in solution. This decomposi
Page 121 and 122:
the newly synthesized fulvenes (e.g
Page 123 and 124:
stereocenters and mixture of E/Z is
Page 125 and 126:
proximal double bond to give α-alk
Page 127 and 128:
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
Page 135 and 136:
periodic acid (H5IO6). 209 These hi
Page 137 and 138: eaction failed to go to completion,
Page 139 and 140: 4.5.2 Synthesis of a Library of Tri
Page 141 and 142: diketones 312{1-3,1-2} in yields ra
Page 143 and 144: Figure 4.2 Distribution for physico
Page 145 and 146: tricyclic pyrrole 314{3,2,26} (Figu
Page 147 and 148: 4.6 Synthesis of α-Alkylidene Cycl
Page 149 and 150: anched and linear carboxylic acid i
Page 151 and 152: eactivity of the species prepared i
Page 153 and 154: considerably lower than the ratio o
Page 155 and 156: diastereomer. Next, allenyne 328 wa
Page 157 and 158: Conclusions In summary, we have dem
Page 159 and 160: 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
Page 165 and 166: MeO2C Bz N H 58c 2-Benzoylamino-2-m
Page 167 and 168: MeO MeO2C Bz N H 58e 2-Benzoylamino
Page 169 and 170: 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: dispersion in mineral oil, 1.0 mmol
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
Page 197 and 198: completion of the addition, the rea
Page 199 and 200: BzN MeO 2C S 74h 2-(Benzoylprop-2-y
Page 201 and 202: BzN MeO 2C Bn 75b 2-(Allylbenzoylam
Page 203 and 204: BzN MeO 2C TBSO 75e 2-(Benzoylbut-2
Page 205 and 206: 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,
Page 227 and 228: 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.
Page 333 and 334:
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
show all

Download (3249Kb) - D-Scholarship@Pitt - University of Pittsburgh

Create successful ePaper yourself

Delete template?

Save as template?