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159. Kent, J.L.; Wan, H.; Brummond, K.M. Tetrahedron Lett. 1995, 36, 2407. 160. (a) Brummond, K.M. In Advances in Cycloaddition Chemistry, Vol. 6, Harmata, M. ed. JAI Press Inc., Stamford, Connecticut; 1999, pp 211-237. (b) Brummond K.M.; Wan, H. Tetrahedron Lett. 1998, 39, 931. (c) Brummond, K.M.; Wan, H.; Kent, J.L. J. Org. Chem. 1998, 63, 6535. 161. Ahmar, M.; Locatelli, C.; Colombier, D.; Cazes, B. Tetrahedron Lett. 1997, 38, 5281. 162. Brummond, K. M.; Lu, J.; Petersen, J. J. Am. Chem. Soc. 2000, 122, 4915. 163. Brummond, K. M.; Sill, P. C.; Chen. H. Org. Lett. 2004, 6, 149. 164. Brummond, K.M.; Kerekes, A. D.; Wan, H. J. Org. Chem. 2002, 67, 5156. 165. Brummond, K. M.; Chen, H.; Fisher, K. D.; Kerekes, A. D.; Rickards, B.; Sill, P. C.; Geib, S. J. Org. Lett. 2002, 4, 1931. 166. Kobayashi, T.; Koga, Y.; Narasaka, K. J. Organomet. Chem. 2001, 624, 73. 167. Mukai, C.; Nomura, I.; Yamanishi, I.; Hanaoka, M. Org. Lett. 2002, 4, 1755. 168. (a) Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. J. Am. Chem. Soc. 1997, 119, 12976. (b) Manzano, F. L.; Guerra, F. M.; Moreno-Dorado, J. F.; Jorge, Z. D.; Massanet, G. M. Org. Lett. 2006, 8, 2879. (c) Herz, H.; Santhanam, P. S. J. Org. Chem. 1965, 30, 4340. (d) Lansburg, P. T.; Hangauer, D. G., Jr.; Vacca, J. P. J. Am. Chem. Soc. 1980, 102, 3964. (e) Heathcock, C. H.; DelMar, E. G.; Graham, S. L. J. Am. Chem. Soc. 1982, 104, 1907. (f) Grieco, P. A.; Majetich, G. F.; Ohfune, Y. J. Am. Chem. Soc. 1982, 104, 4226. (g) Heathcock, C. H.; Tice, C. M.; Germroth, T. C. J. Am. Chem. Soc. 1982, 104, 6081. 169. Brummond, K. M.; Gao, D. Org. Lett. 2003, 5, 3491. 170. Singh, M. P.; Janso, J. E.; Luckman, S. W.; Brady, S. F.; Clardy, J.; Greenstein, M.; 326
Maiese, W. M. J. Antibiot. 2000, 53, 256. 171. Shibata, T.; Takagi, K. J. Am. Chem. Soc. 2000, 122, 9852. 172. Shibata, T.; Kadowaki, S.; Hirase, M.; Takagi, K. Synlett, 2003, 4, 573. 173. (a) Crabtree, R. H. The Organometallic Chemistry of the Transition Metals, 3rd Ed, John Wiley and Sons, Inc., New York, 2001, pp 53-54, pp 188-190. (b) McDermott, J. X.; White, J. F.; Whitesides, G. M. J. Am. Chem. Soc. 1976, 98, 6521. 174. Cotton, F. A.; Wilkinson, G.; Murillo, C. A.; Bochmann, M. Advanced Inorganic Chemistry, 6th Ed, John Wiley and Sons, Inc., New York, 1999, p 1208-1212. 175. Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. J. Chem. Soc. A 1966, 1711. 176. McCleverty, J. A.; Wilkinson, G. Inorg. Synth. 1966, 8, 214. 177. For an extensive sumary of halide counterion effects, see (a) Fagnou, K.; Lautens, M. Angew. Chem. In. Ed. 2002, 41, 26. For non-cordinating counter-ion effect on the rate of a Rh(I) catalyzed [4+2] cycloaddition, see: (b) O’Mahoney, D. J. R.; Belanger, D. B.; Livinghouse, T. Synlett, 1998, 443. (c) Gilbertson, S. R.; Hoge, G. S. Tetrahedron Lett. 1998, 39, 2075. 178. (a) Koga, Y.; Kobayashi, T.; Narasaka, K. Chem. Lett. 1998, 249. (b) Kobayashi, T.; Koga, Y.; Narasaka, K. J. Organomet. Chem. 2001, 624, 73. 179. a) Ohshita, J.; Furumori, K.; Matsuguchi, A.; Ishikawa, M. J. Org. Chem. 1990, 55, 3277. b) Singer, H.; Wilkinson, G. J. Chem. Soc. A 1968, 849 180. Brummond, K.M.; Kerekes, A. D.; Wan, H. J. Org. Chem. 2002, 67, 5156. 181. (a) MacDonald, J. R.; Muscoplat, C. C.; Dexter, D. L.; Mangold, G. L.; Chen, S.-F.; Kelner, M. J.; McMorris, T. C.; Von Hoff, D. D. Cancer Res. 1997, 57, 279. (b) Kelner, M. J.; McMorris, T. C.; Estes, L. A.; Wang, W.; Samson, K. M.; Taetle, R. Investigational 327
Page 1 and 2:
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,
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6.72 (d, J = 7.6 Hz, 0.5H), 6.68 (d
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BzN MeO2C Bn 122a Methyl-2-(N-(but-
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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
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 321 and 322: 1 H and 13 C NMRs of 270h 303
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: 149. (a) Hicks, F. A.; Buchwald, S.
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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