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10 H), 6.21 (s, 1H), 5.62 (s, 1H), 4.24 (d, J = 14.6 Hz, 1H), 4.19 (d, J = 14.3 Hz, 1H), 3.99 (d, J = 14.6, 1.2 Hz, 1H), 3.90 (s, 1H), 3.61 (s, 3H), 3.38 (d, J = 14.3 Hz, 1H), 1.69 (s, 3H); 13 C NMR (75 MHz, CDCl3): δ 195.5, 171.0, 170.2, 162.6, 140.6, 136.1, 135.9, 134.7, 131.3, 131.1, 128.7, 128.5, 127.5, 127.3, 117.6, 71.0, 52.2, 50.5, 49.5, 37.9, 8.9; IR (thin film): ν 2950, 1741, 1707, 1644, 1378, 1340 cm -1 ; MS m/z (%) 401 (40), 342 (22), 296 (35), 105 (100); EI-HRMS calcd for C25H23NO4 m/z [M] + 401.1627 found 401.1641. Mixture of 288a and 289a (Rf = 0.2, TLC, hexanes-EtOAc, 3 : 1 v/v). BzN Bn MeO H 2C 288a 288a: 1 H NMR (300 MHz, CDCl3): δ 7.59-7.44 (m, 5H), 7.17-7.10 (m, 3H), 7.01-6.98 (m, 2H), 6.43 (d, J = 1.9 Hz, 1H), 5.66 (d, J = 1.3 Hz, 1H), 4.32 (d, J = 15.7, 1H), 4.01 (bs, 1H), 3.94 (s, 3H), 3.84 (d, J = 14.3 Hz, 1H), 3.59 (d, J = 15.6 Hz, 1H), 3.29 (d, J = 14.3 Hz, 1H), 1.22 (s, 3H). Bz N MeO2C Bn 289a 289a: 1 H NMR (300 MHz, CDCl3): δ 7.46-7.22 (m, 10H), 5.77 (s, 1H), 4.34 (d, J = 17.8 Hz, 1H), 4.15 (d, J = 13.8 Hz, 1H), 3.80 (s, 3H), 3.37 (d, J = 13.7 Hz, 1H), 3.03 (s, 2H), 2.91 (d, J = 17.9 Hz, 1H), 1.45 (s, 3H). BzN Bn MeO H 2C 287b 2-Benzoyl-1-benzyl-6-methylene-5-oxo-1,2,3,5,6,6a-hexahydrocyclopenta[c]pyrrole-1- carboxylic acid methyl ester (287b). Prepared by following general procedure O, using: 74b 246 O O O
(435 mg, 1.21 mmol), DMSO (429 µL, 6.06 mmol), Mo(CO)6 (400 mg, 1.51 mmol). Heated to 90 °C for 20 min. The crude mixture was purified by flash chromatography (gradient elution, hexanes-EtOAc, 19 : 1 to 2 : 1, v/v) to afford 287b (260 mg, 55%). The correct product ratios listed in Scheme 4.30 were determined in a separate experiment by integration of the olefinic resonances in the 1 H NMR spectrum taken after complete removal of all volatiles from a small reaction sample. 287b: 1 H NMR (300 MHz, CDCl3): δ 7.52-7.27 (m, 10H), 6.19 (s, 1H), 6.07 (s, 1H), 5.63 (s, 1H), 4.24 (d, J = 14.9 Hz, 1H), 4.23 (d, J = 14.2 Hz, 1H), 4.03 (d, J = 15.0 Hz, 1H), 3.98 (s, 1H), 3.62 (s, 3H), 3.39 (d, J = 14.3 Hz, 1H); 13 C NMR (75 MHz, CDCl3): δ 195.2, 170.9, 170.2, 170.1, 140.6, 135.7, 135.5, 131.1, 128.6, 128.5, 127.3, 126.2, 118.0, 70.8, 52.3, 51.5, 50.9, 37.7; IR (thin film): ν 3027, 1741, 1710, 1641, 1383 cm -1 ; MS m/z (%) 387 (15), 328 (10), 282 (22), 105 (100); EI-HRMS calcd for C24H21NO4 m/z [M] + 387.1471 found 387.1470. Bz N Bn MeO2C 289b 2-Benzoyl-3-benzyl-6-oxo-2,3,5,6-tetrahydro-1H-[2]pyrindine-3-carboxylic acid methyl ester (289b). 1 H NMR (300 MHz, CDCl3): δ 7.49-7.41 (m, 3H), 7.34-7.27 (m, 5H), 7.21-7.17 (m, 2H), 5.90 (s, 1H), 5.70 (s, 1H), 4.39 (d, J = 18.1 Hz, 1H), 4.15 (d, J = 13.8 Hz, 1H), 3.81 (s, 3H), 3.38 (d, J = 13.8 Hz, 1H), 3.05 (s, 2H), 3.01 (d, J = 18.1 Hz, 1H); 13 C NMR (75 MHz, CDCl3): δ 202.9, 171.3, 171.1, 161.1, 135.8, 135.4, 135.2, 130.3, 129.9, 128.7, 128.3, 127.4, 127.2, 126.3, 123.5, 65.9, 53.0, 45.1, 39.6, 37.7; IR (thin film): ν 2950, 1740, 1710, 1643, 1391 cm -1 ; MS m/z (%) 387 (47), 356 (15), 328 (12), 296 (30), 105 (100); EI-HRMS calcd for C24H21NO4 m/z [M] + 387.1471 found 387.1489. 247 O
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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
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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
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General procedure A for esterificat
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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
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hexanes-EtOAc, 19 : 1 to 4 : 1, v/v
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which was immediately used in the C
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Boc TMS N H Bn 64f tert-Butyl-1-((4
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MeI (38 µL, 0.62 mmol). Yield 65a
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with brine and concentrated under v
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H MeO 2C • H Bn NHBoc tert-Butyl-
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TMS MeO 2C • 70 H H NHBoc 2-tert-
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185 (10), 141 (21), 57 (100); EI-HR
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dispersion in mineral oil, 1.0 mmol
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EI-HRMS calcd for C30H26NO3 m/z [M-
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CbzN MeO 2C Me 73h 2-[Benzyloxycarb
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CbzN MeO 2C Me 2-(Benzyloxycarbonyl
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dispersion in mineral oil, 3.85 mmo
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completion of the addition, the rea
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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
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1H), 3.69 (s, 3H), 1.58 (d, J = 7.1
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µmol), [Rh(CO)2Cl]2 (1 mg, 3 µmol
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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: v/v) afforded a mixture of compound
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:
1 H and 13 C NMRs of 155a 297
Page 317 and 318:
1 H and 13 C NMRs of 156a 299
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1 H and 13 C NMRs of 186b 301
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1 H and 13 C NMRs of 270h 303
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1 H and 13 C NMRs of 287b 305
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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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