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Hz, 1H), 3.05 (d, J = 20.2 Hz, 1H), 2.93 (d, J = 20.8 Hz, 1H), 1.63 (s, 9H); 13 C NMR (75 MHz, CDCl3): δ 202.5, 177.8, 171.9, 171.2, 161.0, 149.3, 135.6, 135.4, 135.2, 130.8, 130.0, 128.7, 127.5, 126.5, 124.9, 124.7, 123.9, 122.7, 119.6, 115.3, 114.9, 83.9, 65.9, 53.1, 45.5, 37.8, 29.4, 28.2; IR (thin film): ν 2979, 1736, 1717, 1644, 1371 cm -1 ; ESI-HRMS calcd for C31H30N2O6Na m/z [M+23] + 549.2002; found 549.2018. General procedure P for the Stetter reaction with butyraldehyde. BzN Bn MeO 2C H 293a O O C 3H 7 2-Benzoyl-1-benzyl-4-methyl-5-oxo-6-(2-oxopentyl)-1,2,3,5,6,6a- hexahydrocyclopenta[c]pyrrole-1-carboxylic acid methyl ester (293a). To a solution <strong>of</strong> cyclopentenone 287a (163 mg, 0.403 mmol) in 1,4-dioxane (2 mL), were added Et3N (42 µL, 0.30 mmol), butyraldehyde (184 µL, 2.03 mmol) and 3-benzyl-5-(2-hydroxyethyl)-4- methylthiazolium chloride 292 (22 mg, 0.080 mmol). The reaction vessel was sealed with a rubber septum and heated to 70 °C for 6 h. The reaction mixture was then poured into water, and the aqueous layer extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4 and concentrated under vacuum. Hexanes (5 mL) was added and a white precipitate formed. The precipitate was collected by decantation, and purified by flash chromatography (gradient elution; hexanes-EtOAc, 4 : 1 to 2 : 1, v/v) to afford 293a (121 mg, 63%). The decanted liquid was concentrated under vacuum and the crude residue was purified by flash chromatorgraphy (gradient elution; hexanes-EtOAc, 4 : 1 to 2 : 1, v/v) to afford 293b (19 mg, 10%). 293a: 1 H NMR (300 MHz, CDCl3): δ 7.55-7.44 (m, 5H), 7.33-7.27 (m, 3H), 7.17-7.14 (m, 2H), 256
4.17 (d, J = 15.0 Hz, 1H), 4.10 (d, J = 14.2 Hz, 1H), 3.99 (d, J = 15.1 Hz, 1H), 3.75 (s, 3H), 3.44-3.39 (m, 1H), 3.28 (d, J = 14.2 Hz, 1H), 3.03 (dd, J = 18.4, 5.1 Hz, 1H), 2.86 (dd, J = 18.4, 3.9 Hz, 1H), 2.50 (t, J = 7.2 Hz, 2H), 2.13 (dd, J = 8.5, 4.1 Hz, 1H), 1.66 (sex, J = 7.4 Hz, 2H), 1.62 (s, 3H), 0.99 (t, J = 7.4 Hz, 3H); 13 C NMR (75 MHz, CDCl3): δ 208.4, 207.8, 171.6, 171.3, 166.0, 136.1, 136.0, 131.8, 131.2, 131.0, 128.6, 128.4, 128.3, 127.4, 127.2, 71.7, 52.4, 51.7, 50.8, 45.4, 44.5, 40.9, 37.7, 17.1, 13.7, 8.8; IR (thin film): ν 2953, 1740, 1719, 1687, 1638, 1390 cm -1 ; MS m/z (%) 473 (7), 441 (8), 414 (17), 382 (20), 350 (18), 105 (100); EI HRMS calcd for C29H31NO5 m/z [M] + 473.2202, found 473.2181. 293b: 1 H NMR (300 MHz, CDCl3): δ 7.55-7.29 (m, 10H), 4.21 (d, J = 14.8 Hz, 1H), 4.03-3.94 (m, 2H), 3.71 (s, 3H), 3.68 (bs, 1H), 3.34-3.27 (m, 1H), 3.11 (d, J = 14.1 Hz, 1H), 2.91 (dd, J = 19.2, 3.5 Hz, 1H), 2.52 (t, J = 7.4 Hz, 2H), 2.43 (dd, J = 19.2, 11.3 Hz, 1H), 1.73 (sex, J = 7.4 Hz, 2H), 1.62 (s, 3H), 1.00 (t, J = 7.4 Hz, 3H); 13 C NMR (75 MHz, CDCl3): δ 209.0, 208.9, 172.6, 171.6, 168.2, 136.5, 135.8, 131.6, 131.4, 131.2, 128.7, 128.2, 127.6, 127.0, 69.7, 52.4, 50.7, 49.0, 44.1, 42.0, 39.4, 36.3, 17.2, 13.8, 8.5. BzN MeO2C Bn H 2-Benzoyl-1-benzyl-5-oxo-6-(2-oxo-pentyl)-1,2,3,5,6,6a-hexahydrocyclopenta[c]pyrrole-1- 294a carboxylic acid methyl ester (294a). Prepared by using general procedure P, using: 287b (100 mg, 0.258 mmol), Et3N (107 µL, 0.774 mmol), butyraldehyde (117 µL, 1.29 mmol) and 3- benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride 292 (14 mg, 0.052 mmol). Flash chromatography (gradient elution; hexanes-EtOAc, 9 : 1 to 2 : 1, v/v) afforded 294a (major diastereomer) (78 mg, 66%). The minor diastereomer remains in the decanted liquid. 294a (major diastereomer, eluting second, TLC, hexanes-EtOAc) 1 H NMR (300 MHz, CDCl3): δ 257 O O C 3H 7
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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
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 and 264: v/v) afforded a mixture of compound
Page 265 and 266: (435 mg, 1.21 mmol), DMSO (429 µL,
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: Bz N O H CO2Me BocN 287i 3-(2-Benzo
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 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
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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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