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CDCl3): δ 206.7, 172.0, 166.6, 163.5, 160.3, 134.4, 131.7, 131.5, 128.6, 128.6, 126.8, 115.1, 114.8, 92.9, 80.4, 62.6, 53.0, 38.8; IR (thin film): ν 3412, 2951, 1958, 1741, 1655, 1510 cm -1 ; MS m/z (%) 338 (28), 230 (57), 198 (19), 105 (100); EI-HRMS calcd for C20H18NO3F m/z [M] + 339.1259; found 339.1258. S Bz N H CO2Me • 58g 2-Benzoylamino-2-thiophen-2-ylmethylpenta-3,4-dienoic acid methyl ester (58g). Prepared by following general procedure B with: 56g (270 mg, 0.863 mmol), Et3N (504 µL, 3.62 mmol), CCl4 (291 µL, 3.02 mmol), PPh3 (700 mg, 2.67 mmol). Yield of 58g (235 mg, 83%). 1 H NMR (300 MHz, CDCl3): δ 7.75-7.72 (m, 2H), 7.52-7.38 (m, 3H), 7.13-7.11 (m, 1H), 7.01 (s, 1H), 6.89-6.86 (m, 1H), 6.79-6.78 (m, 1H), 5.61 (t, J = 6.6 Hz, 1H), 5.04 (dd, J = 11.4, 6.6 Hz, 1H), 4.99 (dd, J = 11.3, 6.6 Hz, 1H), 4.05 (d, J = 14.7 Hz, 1H), 3.83 (s, 3H), 3.80 (d, J = 14.7 Hz, 1H); 13 C NMR (75 MHz, CDCl3): δ 207.0, 171.7, 166.4, 137.1, 134.5, 131.5, 128.4, 127.4, 126.8, 126.5, 124.7, 92.6, 80.2, 62.6, 52.9, 34.2; IR (thin film): ν 3410, 2950, 1957, 1740, 1655, 1521 cm -1 ; MS m/z (%) 327 (10), 230 (40), 206 (47), 147 (31), 105 (100); EI-HRMS calcd for C18H17NO3S m/z [M] + 327.0929; found 327.0937. Boc N Bz N H CO 2Me 3-(2-Benzoylamino-2-methoxycarbonylpenta-3,4-dienyl)-indole-1-carboxylic acid tert-butyl ester (58h). Prepared by following general procedure B with these modifications: (a) the reaction mixture was heated to 50 °C for 2 h. (b) methanolysis was performed by addition of Et3N (0.1 150 58h •
mL) and MeOH (10 mL) instead of sat’d solution of HCl in MeOH and stirred for 12 h (it was reasoned that addition of HCl/MeOH may result in cleavage of the Boc group). After concentrating the reaction mixture under vacuum the viscous brown paste was immediately purified by flash chromatography (hexanes/EtOAc, 9 : 1 to 4 : 1, v/v) to afford 58h. Starting reagents used: 56h (239 mg, 0.535 mmol), Et3N (312 µL, 2.25 mmol), CCl4 (181 µL, 1.87 mmol), PPh3 (434 mg, 1.66 mmol). Yield of 58h (157 mg, 64%). 1 H NMR (300 MHz, CDCl3): δ 8.24-8.23 (m, 1H), 7.78-7.19 (m, 9H), 7.06 (s, 1H), 5.80 (t, J = 6.6 Hz, 1H), 5.11 (dd, J = 11.2, 6.7 Hz, 1H), 5.03 (dd, J = 11.2, 6.6 Hz, 1H), 4.01 (d, J = 14.5 Hz, 1H), 3.87 (s, 3H), 3.74 (d, J = 14.6 Hz, 1H), 1.65 (s, 9H); 13 C NMR (75 MHz, CDCl3): δ 207.1, 172.2, 166.7, 149.4, 135.0, 134.6, 131.5, 130.9, 128.5, 126.9, 125.0, 124.2, 122.4, 119.1, 115.0, 114.6, 93.1, 83.4, 80.2, 62.6, 53.0, 29.8, 28.0; IR (thin film): ν 3411, 2979, 1959, 1735, 1666, 1369 cm -1 ; ESI-HRMS calcd for C27H28N2O5Na m/z [M+23] + 483.1896; found 483.1893. 2-tert-Butoxycarbonylamino-3-(tert-butyldimethylsilyloxy)propionic acid (59) was prepared from N-Boc-serine according to a previously reported procedure. hh TBDMSO Boc O NH O 60 2-tert-Butoxycarbonylamino-3-(tert-butyldimethylsilyloxy)propionic acid 1-methylprop-2- ynyl ester (60). To a solution of 3-butyne-2-ol (53 µL, 0.72 mmol) in CH2Cl2 (2 mL) were added DCC (149 mg, 0.724 mmol) and DMAP (8 mg, 7 µmol) at rt. Then, a solution of carboxylic acid 59 (220 mg, 0.69 mmol) in CH2Cl2 (4 mL) was added via a syringe. After 1 h at rt, the reaction hh Yoo, D.; Oh J. S.; Lee, D. -W.; Kim, Y. G. J. Org. Chem. 2003, 68, 2979. 151
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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
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: MeO MeO2C Bz N H 58e 2-Benzoylamino
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 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-
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13.9, 5.3 Hz, 1H), 2.51-2.47 (m, 1H
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15 min the solvent was removed unde
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Benzoyl chloride (0.169 mL, 1.46 mm
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mg, 0.11 mmol), [Rh(CO)2Cl]2 (4 mg,
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mL). kk The aqueous layer was extra
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ºC. After quenching the reaction b
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129.8, 129.0, 128.7, 128.4, 126.2,
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MeO 2C O O O N H N R 1 O N Ph [10c-
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The crude residue was purified by f
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14.4 Hz, 1H), 3.49-3.39 (m, 2H), 3.
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1H), 5.49 (dd, J = 17.3, 1.8 Hz, 1H
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was stirred at rt for 1 h when it w
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BzN HOOC 2-(N-(but-2-ynyl)benzamido
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°C and DIBAL-H (0.440 mL of a 1.0M
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129 (62), 91 (100); EI-HRMS calcula
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(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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Page 317 and 318:
Page 319 and 320:
Page 321 and 322:
1 H and 13 C NMRs of 270h 303
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Page 325 and 326:
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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