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1H), 5.22-5.14 (m, 2H), 4.21 (d, J = 14.6 Hz, 1H), 3.85 (s, 3H), 3.63 (d, J = 14.6 Hz, 1H), 2.14 (s, 1H), 1.75 (s, 9H); 13 C NMR (75 MHz, CDCl3): δ 207.8, 171.4, 171.2, 149.6, 135.5, 135.1, 131.6, 130.4, 128.3, 127.2, 125.6, 124.3, 122.6, 119.6, 115.0, 114.8, 91.1, 83.6, 80.5, 79.5, 72.7, 68.8, 52.4, 39.1, 28.9, 28.2; IR (thin film): ν 3291, 2980, 2116, 1957, 1735, 1642, 1369 cm -1 ; MS (EI) m/z (%) 498 (6), 398 (20), 339 (32), 293 (63), 105 (100); ESI-HRMS calcd for C30H30N2O5Na m/z [M+23] + 521.2052; found 521.2076. BzN MeO 2C Bn 75a 2-(Benzoylbut-2-enylamino)-2-benzylhexa-3,4-dienoic acid methyl ester (75a). Prepared by following the general procedure F, using: 58a (92 mg, 0.27 mmol), NaH (60% dispersion in mineral oil, 22 mg, 0.55 mmol), crotyl bromide (57 µL, 0.55 mmol). Purification by flash chromatography (hexanes-EtOAc, 9 : 1, v/v) afforded 75a (60 mg, 56%). 1 H NMR (300 MHz, CDCl3): δ 7.39-7.27 (m, 10H), 5.62-5.56 (m, 1H), 5.55-5.21 (m, 2H), 4.96- 4.88 (m, 1H), 4.00 (d, J = 13.5 Hz, 0.63H), 3.97 (d, J = 13.5 Hz, 0.37H), 3.77 (s, 3H), 3.61-3.53 (m, 1H), 3.44-3.36 (m, 1H), 3.35 (d, J = 13.5 Hz, 1H), 1.80 (dd, J = 7.1, 3.3 Hz, 1.9H), 1.74 (dd, J = 7.1, 3.2 Hz, 1.1H), 1.53 (m, 3H); 13 C NMR (CDCl3, 75 MHz): δ 204.7, 173.0, 172.1, 137.3, 137.0, 131.5, 131.5, 129.7, 129.0, 128.6, 128.5, 128.3, 127.7, 127.2, 127.1, 127.0, 126.8, 91.6, 91.5, 90.7, 90.4, 69.2, 52.6, 52.5, 50.4, 50.3, 39.5, 39.4, 18.0, 14.2, 13.9; IR (thin film): ν 2947, 1968, 1744, 1637, 1444 cm -1 ; MS m/z (%) 388 (6), 358 (5), 330 (33), 298 (84), 244 (60), 105 (100); EI-HRMS calcd for [M-1] + , m/z C25H26NO3 388.1913, found 388.1912. 182 • H
BzN MeO 2C Bn 75b 2-(Allylbenzoylamino)-2-benzylhexa-3,4-dienoic acid methyl ester (75b). Prepared by following the general procedure F, using: 58a (100mg, 0.297 mmol), NaH (60% dispersion in mineral oil, 24 mg, 0.59 mmol), allyl bromide (40 µL, 0.45 mmol). Purification by flash chromatography (hexanes-EtOAc, 9 : 1, v/v) afforded 75b (80 mg, 71%). 1 H NMR (300 MHz, CDCl3): δ 7.42-7.26 (m, 10H), 5.58 (dq, J = 9.7, 3.2 Hz, 1H), 5.52-5.41 (m, 2H), 5.25-5.14 (m, 1H), 5.06-5.03 (m, 1H), 3.99 (d, J = 13.5 Hz, 0.73H), 3.95 (d, J = 13.5 Hz, 0.37H), 3.78 (s, 1.1H), 3.77 (s, 1.9H), 3.65-3.57 (m, 1H), 3.39 (d, J = 13.5 Hz, 1H), 3.41-3.28 (m, 1H), 1.80 (dd, J = 7.1, 3.3 Hz, 1.9H), 1.74 (dd, J = 7.0, 3.2 Hz, 1.1H); 13 C NMR (CDCl3, 75 MHz): δ 204.6, 204.5, 172.8, 171.8, 171.7, 136.6, 136.6, 136.5, 136.2, 136.1, 131.1, 131.0, 129.5, 128.0, 126.9, 126.4, 116.6, 116.5, 91.1, 91.0, 90.6, 90.3, 68.7, 52.3, 50.6, 50.5, 38.9, 38.7, 13.8, 13.5; IR (thin film): ν 3028, 2947, 1968, 1743, 1639, 1444, 1393, 1266, 1225 cm -1 ; MS m/z (%) 374 (26), 344 (9), 316 (10), 284 (52), 105 (100); EI-HRMS calcd for C24H24NO3 [M-1] + , m/z 374.1756, found 374.1761. CbzN MeO 2C 75c 2-(Benzyloxycarbonylbut-2-enylamino)-2-methyl-hexa-3,4-dienoic acid methyl ester (75c). Prepared by following the general procedure F, using: 65d (66 mg, 0.23 mmol), NaH (60% dispersion in mineral oil) (14 mg, 0.34 mmol), crotyl bromide (50 µL, 0.45 mmol). Purification by flash chromatography (hexanes-EtOAc, 9 : 1, v/v) afforded 75c (52mg, 66%). 1 H NMR (300 MHz, CDCl3): δ 7.36-7.30 (m, 5H), 5.64 (dq, J = 14.5, 6.3 Hz, 1H), 5.51-5.46 (m, 183 • • H H
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TRANSITION METAL-CATALYZED REACTION
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Transition Metal-Catalyzed Reaction
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List of Abbreviations Ac acetyl AcO
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Table of Contents 1.0 Introduction.
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Appendix A : X-ray crystal structur
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Table 4.8 Rh(I)-catalyzed cyclocarb
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List of Schemes Scheme 1.1 Three fo
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Scheme 3.24 Preparation of amide-te
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Scheme 4.16 Formation of bicyclo[5.
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1.0 Introduction 1.1 The Role of Di
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According to these guidelines, the
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Scheme 1.1 Three forms of diversity
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Another example from the Schreiber
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1.1.1 Transition Metal-Catalyzed Re
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37, , such reactions include transi
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the proximal olefin of allenyne 38
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2.0 Design and Synthesis of the Piv
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The allenic amino acid derivatives
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This protocol proved particularly u
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ZnCl2, which results in a Zn-chelat
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Scheme 2.7 Synthesis of trisubstitu
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THF), the yield was increased from
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the terminus of the alkyne led to d
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N-Alkylation of the glycine-derived
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circumvent this issue, variants suc
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BINAP as a chiral ligand to obtain
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stereochemistry of the exocyclic ol
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3.2 Rhodium(I)-Catalyzed Allenic Cy
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exocyclic olefin geometry is not re
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3.2.1 Preparation of Enol-ether Tri
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Scheme 3.15 Synthesis of cycloisome
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Scheme 3.17 Cycloisomerization of a
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Scheme 3.19 Tandem cycloadditions o
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Scheme 3.21 Intermolecular Diels-Al
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attractive, since additional functi
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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
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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
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epulsive dipole interactions (Schem
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Table 3.4 Diels-Alder reactions of
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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
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usually is DMSO. Heating to 100 ºC
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that require high pressures of CO.
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In contrast to the Mo(CO)6-mediated
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Scheme 4.15 Rh(I)-catalyzed allenic
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4.2 Rhodium(I)-Catalyzed Cyclocarbo
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lack of double bond selectivity, si
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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
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proximal double bond to give α-alk
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the methyl ester and Ha are syn. Sc
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that the major diastereomer in the
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We were motivated to first examine
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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
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 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
Page 197 and 198: completion of the addition, the rea
Page 199: BzN MeO 2C S 74h 2-(Benzoylprop-2-y
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 =
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4.98 (dt, J = 7.7, 5.1 Hz, 1H), 4.1
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N Bz MeO2C OTBS 214 1-Benzoyl-2-(te
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270a (major diastereomer-eluting fi
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CDCl3): δ 7.42-7.17 (m, 13H), 7.04
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18.6 Hz, 1H), 4.34 (d, J = 18.0 Hz,
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Bz N MeO2C 2-Benzoyl-3,7-dimethyl-6
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v/v) afforded a mixture of compound
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(435 mg, 1.21 mmol), DMSO (429 µL,
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4.02 (s, 1H), 3.88 (s, 3H), 1.82 (s
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(207 mg, 96%) consisting of 287e (7
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procedure O, using: 74f (110 mg, 0.
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Bz N O H CO2Me BocN 287i 3-(2-Benzo
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4.17 (d, J = 15.0 Hz, 1H), 4.10 (d,
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137.1, 136.9, 130.4, 129.8, 128.5,
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H BzN MeO2C Bn H N C3H7 298b CO 2Me
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NMR (75 MHz, CDCl3): δ 172.3, 169.
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following the general procedure Q,
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H BzN MeO2C Bn H 5-Benzoyl-1,4-dibe
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119.9, 114.1, 109.9, 108.6, 73.0, 5
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4.11 (m, 1H), 4.07-3.98 (m, 1H), 3.
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126.8, 126.2, 109.0, 72.9, 58.7, 56
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NMR (75 MHz, CDCl3): δ 172.2, 169.
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3.0 Hz, 1H), 5.82-5.80 (m, 1H), 5.2
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87%). The diastereomeric ratio (288
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APPENDIX A: X-ray crystal structure
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APPENDIX B: X-ray crystal structure
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APPENDIX C: X-ray crystal structure
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APPENDIX D: X-ray crystal structure
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APPENDIX E: X-ray crystal structure
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APPENDIX F: QikProp property predic
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1 H and 13 C NMRs of 74b 293
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1 H and 13 C NMRs of 111a 295
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1 H and 13 C NMRs of 270h 303
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1 H and 13 C NMRs of 307 307
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1 H and 13 C NMRs of 308n 309
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10. (a) Burke, M. D.; Schreiber, S.
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Hu, Y. J. Comb. Chem. 2006, 8, 286.
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49. For reviews on reactions of all
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69. (a) Trost, B. M.; Lautens, M.;
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containing cross-conjugated trienes
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Vaillancourt, J.; Rasper, D. M.; Ta
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130. Oppolzer, W.; Snieckus, V. Ang
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149. (a) Hicks, F. A.; Buchwald, S.
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Maiese, W. M. J. Antibiot. 2000, 53
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192. The mechanism of decomposition
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Boger, D. L.; Boyce, C. W.; Labroli
Page 351:
Generated Inhibitors of Human Mitog
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