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UNIVERSITY OF PITTSBURGH FACULTY OF ARTS AND SCIENCES DEPARTMENT OF CHEMISTRY This dissertation was presented by Branko Mitasev It was defended on December 20 th , 2006 and approved by Professor Dennis P. Curran, Department of Chemistry Professor Peter Wipf, Department of Chemistry Professor Billy W. Day, Department of Pharmaceutical Sciences Thesis Director: Professor Kay M. Brummond, Department of Chemistry ii
Transition Metal-Catalyzed Reactions of Allenes in Diversity-Oriented Synthesis Branko Mitasev, Ph.D. University of Pittsburgh, 2006 Abstract Transition metal-catalyzed cyclization reactions involving allenes were demonstrated as useful methods for the synthesis of novel heterocyclic compounds. Multiple scaffolds were accessed from pivotal allenic amino-ester intermediates by varying the reaction conditions. Rhodium(I)-catalyzed allenic Alder-ene reaction of allenynes afforded cross-conjugated trienes in high yields. Double bond selectivity in the allenic cyclocarbonylation reaction of allenynes was accomplished by utilizing either rhodium(I)-catalyzed or molybdenum-mediated conditions, thus gaining access to 4-alkylidene or α-alkylidene cyclopentenones, respectively. In addition, a detailed study of the molybdenum-mediated reaction uncovered an unexpected diastereocontrol element based on the amino acid side chain. Furthermore, replacement of the alkyne with an alkene led to discovery of a novel rhodium(I)-catalyzed cycloisomerization of ene-allenes affording tetrahydroazepines. The novel molecular scaffolds obtained in this manner were studied in complexity generating reactions that were employed in the synthesis of libraries of compounds for biological evaluation. For example, stereoselective sequential Diels-Alder reactions of the cross-conjugated trienes allowed rapid access to polycyclic molecular skeletons. Additionally, a Stetter/Paal-Knorr reaction sequence was developed to gain access to novel tricyclic pyrroles. iii
Page 1: TRANSITION METAL-CATALYZED REACTION
Page 5 and 6: List of Abbreviations Ac acetyl AcO
Page 7 and 8: Table of Contents 1.0 Introduction.
Page 9 and 10: Appendix A : X-ray crystal structur
Page 11 and 12: Table 4.8 Rh(I)-catalyzed cyclocarb
Page 13 and 14: List of Schemes Scheme 1.1 Three fo
Page 15 and 16: Scheme 3.24 Preparation of amide-te
Page 17 and 18: Scheme 4.16 Formation of bicyclo[5.
Page 19 and 20: 1.0 Introduction 1.1 The Role of Di
Page 21 and 22: According to these guidelines, the
Page 23 and 24: Scheme 1.1 Three forms of diversity
Page 25 and 26: Another example from the Schreiber
Page 27 and 28: 1.1.1 Transition Metal-Catalyzed Re
Page 29 and 30: 37, , such reactions include transi
Page 31 and 32: the proximal olefin of allenyne 38
Page 33 and 34: 2.0 Design and Synthesis of the Piv
Page 35 and 36: The allenic amino acid derivatives
Page 37 and 38: This protocol proved particularly u
Page 39 and 40: ZnCl2, which results in a Zn-chelat
Page 41 and 42: Scheme 2.7 Synthesis of trisubstitu
Page 43 and 44: THF), the yield was increased from
Page 45 and 46: the terminus of the alkyne led to d
Page 47 and 48: N-Alkylation of the glycine-derived
Page 49 and 50: circumvent this issue, variants suc
Page 51 and 52: BINAP as a chiral ligand to obtain
Page 53 and 54:
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
Page 237 and 238:
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,
Page 261 and 262:
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.
Page 273 and 274:
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
Page 313 and 314:
1 H and 13 C NMRs of 111a 295
Page 315 and 316:
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
Page 349 and 350:
Boger, D. L.; Boyce, C. W.; Labroli
Page 351:
Generated Inhibitors of Human Mitog
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