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198. Umpolung refers to reversal of the normal reactivity of a functional group. For some references, see: (a) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239. (b) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205. (c) Fischer, C.; Smith, S. W.; Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 1472. 199. (a) Stetter, H.; Schreckenberg, M.; Angew. Chem. Int. Ed. Engl. 1973, 12, 81. (b) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639. (c) Stetter, H.; Kuhlman, H., In Organic Reactions, 1991, Vol 40, 408. (d) Stetter, H.; Haese, W. Chem. Ber. 1984, 117, 682. 200. For recent advances in the Stetter reaction area, see: (a) Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298. (b) de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284. (c) Nahm, M. R.; Linghu, X.; Potnick, J. R.; Yates, C. M.; White, P. S.; Johnson, J. S. Angew. Chem. Int. Ed. 2005, 44, 2377. 201. For Paal-Knorr synthesis of furans, see: (a) Nowlin, G.; J. Am. Chem. Soc. 1950, 72, 5754. (b) Traylelis, V. J.; Hergennother, W L.; Hanson, H. T.; Valicenti, J. A. J. Org. Chem. 1964, 29, 123. (c) Scott, L.; Naples, J. O. Synthesis, 1973, 209. (d) Yuguchi, M.; Tokuda, M.; Orito, K. J. Org. Chem. 2004, 69, 908-914. (e) Minetto, G.; Raveglia, L. F.; Taddei, M. Org. Lett. 2004, 6, 389. 202. (a) Knorr, L. Chem. Ber. 1884, 17, 1635. (b) Bishop, W. S. J. Am. Chem.. Soc. 1945, 67, 2261. (c) Josey, A. D. Org. Synth., Coll. Vol. V, 1973, 716. (d) Alongi, M.; Minetto, G.; Taddei, M. Tetrahedron Lett. 2005, 46, 7069. 203. Piers, E.; Renaud, J. J. Org. Chem. 1993, 58, 11. 204. (a) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465. (b) Braun, R. U.; Zeitler, K.; Müller, T. J. J. Org. Lett. 2001, 3, 3297. 205 (a) Gribble, G. W. In Comprehensive Heterocyclic Chemistry II. Katrizky, A. R., Rees, C. W., Scriven, E. F., Eds.; Pergamon Press: Oxford, 1996; Vol. 2, p 207. (b) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435. (c) Fürstner, A. Angew. Chem. Int. Ed. 2003, 42, 3582. (d) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Org. Chem. 1988, 53, 4570. (e) 330
Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54. (f) Cozzi, P.; Mongelli, N. Curr. Pharm. Des. 1998, 4, 181. (g) Huffman, J. W. Curr. Med. Chem. 1999, 6, 705-720. 206. Harrington, P. E.; Tius, M. A. J. Am. Chem. Soc. 2001, 123, 8509 207. It was noticed that the success of this reaction was dependent on the purity of the starting enone, presumably caused by sulfur containing impurities from the Stetter reaction poisoning the Pd catalyst. 208. Stetter, H., Skobel, H. Chem. Ber. 1987, 120, 643. 209. Suzuki, M.; Kimura, Y.; Terashima, S.; Bull. Chem. Soc. Japan 1986, 59, 3559. 210. (a) Aoyama, H.; Hasegawa, T.; Watanabe, M.; Shiraishi, H.; Omote, Y. J. Org. Chem. 1978, 43, 419. (b) Hashizume, D.; Kogo, H.; Sekine, A.; Ohashi, Y.; Miyamoto, H.; Toda, F. J. Chem. Soc. Perkin Trans. 2 1996, 61. (c) Youn S. W.; Kim, Y. H.; Hwang, J.-W.; Do, Y. Chem. Commun. 2001, 996. 211. (a) Wada, C. K.; Frey, R. R.; Ji, Z.; Curtin, M. L.; Garland, R. B.; Holms, J. H.; Li, J.; Pease, L. J.; Guo, J.; Glaser, K. B.; Marcotte, P. A.; Richardson, P. L.; Murphy, S. S.; Bouska, J. J.; Tapang, P.; Magoc, T. J.; Albert, D. H.; Davidsen, S. K.; Michaelides, M. R. Bioorg. Med. Chem. Lett. 2003, 13, 3331. (b) Wasserman, H. H.; Petersen, A. K.; Xia, M. Tetrahedron 2003, 59, 6771. (c) Otto, H. H.; Schirmeister, T. Chem. Rev. 1997, 97, 133. (d) Han, W.; Hu, Z.; Jiang, X.; Decicco, C. P. Bioorg. Med.Chem. Lett. 2000, 10, 711. 212. (a) Meth-Cohn, O.; Wang, M. –X. Tetrahedron Lett. 1995, 36, 9561. (b) Jousseaume, B.; Kwon, H.; Verlhac, J. –B.; Denat, F.; Dubac, J. Synlett, 1993, 117. (c) Martyn, D. C.; Vernall, A. J.; Clark, B. M.; Abell, A. D. Org. Biomol. Chem. 2003, 1, 2103. 213. Werner, S.; Iyer, P. S.; Fodor, M. D.; Coleman, C. M.; Twining, L. A.; Mitasev, B.; Brummond, K. M. J. Comb. Chem. 2006, 8, 368. 214. Werner, S.; Iyer, P. S. Synlett, 2005, 1405. 331
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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,
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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
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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
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 and 344: 149. (a) Hicks, F. A.; Buchwald, S.
Page 345 and 346: Maiese, W. M. J. Antibiot. 2000, 53
Page 347: 192. The mechanism of decomposition
Page 351: Generated Inhibitors of Human Mitog
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