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mL) and treated with 1M HCl (50 mL). The aqueous layer was extracted with Et2O (2 x 50 mL), and the organic layers were combined, washed with 1M HCl (50 mL), dried over MgSO4, and concentrated under vacuum to afford a yellow oil. Step 2. Methyl ester formation: The yellow oil was dissolved in DMF (5 mL). Pulverized KHCO3 (515 mg, 5.09 mmol) was added at rt, followed by addition of MeI (256 µL, 4.08 mmol) via a syringe. The reaction mixture was stirred for 2 h, and then diluted with water (100 mL). The cloudy mixture was extracted with EtOAc (3 x 75 mL), the organic layers were combined, washed with brine, dried over MgSO4 and concentrated under vacuum. Purification of the crude residue by flash chromatography (gradient elution; hexanes-EtOAc, 10 : 0 to 4 : 1, v/v) afforded 65b (555 mg, 73%). 65b : 1 H NMR (300 MHz, CDCl3): δ 7.42-7.28 (m, 5H), 5.78 (bs, 1H), 5.49 (dt, J = 7.0, 3.5 Hz, 1H), 5.13 (d, J = 12.4 Hz, 1H), 5.07 (d, J = 12.3 Hz, 1H), 3.70 (s, 3H), 2.37 (sex, J = 6.3 Hz, 1H). 1.92-1.86 (m, 2H), 1.70 (s, 3H), 1.36-1.27 (m, 4H), 1.05 (s, 3H), 1.03 (s, 3H), 0.88 (t, J = 7.2 Hz, 1H); 13 C NMR (75 MHz, CDCl3): δ 198.7, 173.5, 154.8, 137.0, 128.7, 128.2, 108.0, 105.8, 77.5, 66.7, 60.9, 52.9, 30.4, 28.9, 27.0, 22.7, 22.6, 14.2; IR (thin film): ν 3416, 2958, 1728, 1493, 1273 cm -1 ; MS m/z (%) 373 (11), 314 (9), 183 (21), 91 (100); EI-HRMS calcd for C22H31NO4 m/z [M] + 373.2253; found 373.2268. MeO 2C • H C6H13 Bn NHBoc 65a 2-Benzyl-2-tert-butoxycarbonylamino-3-methylundeca-3,4-dienoic acid methyl ester (65a). Prepared by following general procedure D, using: LDA (1.58 mmol), 64a (265 mg, 0.661 mmol), ZnCl2 (158 µL of a 0.5 M solution in THF, 0.793 mmol), KHCO3 (62 mg, 0.62 mmol), 158
MeI (38 µL, 0.62 mmol). Yield 65a (60 mg, 22%). Note: The intermediate carboxylic acid after the Claisen rearrangement step was purified by silica gel flash chromatography (hexanes-EtOAc, 4 : 1 to 1 : 1, v/v) and obtained in 41% yield. 1 H NMR (300 MHz, CDCl3): δ 7.27-7.23 (m, 3H), 7.08-7.06 (m, 2H), 5.27 (bs, 1H), 5.16 (bs, 1H), 3.78 (s, 3H), 3.55-3.43 (m, 2H), 2.04 (bs, 2H), 1.72 (d, J = 2.7 Hz, 3H), 1.48 (s, 9H), 1.48- 1.28 (m, 8H), 0.88 (t, J = 6.7 Hz, 1H). 13 C NMR (75 MHz, CDCl3): δ 201.6, 172.8, 153.8, 137.0, 130.3, 127.9, 126.6, 99.6, 95.7, 64.5, 52.8, 37.9, 31.8, 29.1, 28.8, 28.5, 22.7, 15.5, 14.2. MS m/z (%) 416 (27), 359 (25), 324 (30), 268 (100), 57 (100); EI-HRMS calcd for C21H29NO4 m/z [M- 57] + 359.2097; found 359.2110. MeO 2C • 65c H NHCbz 2-Benzyloxycarbonylamino-2-methylhexa-3,4-dienoic acid methyl ester (65c). Prepared by following general procedure D, using: LDA (7.15 mmol), 64c (820 mg, 2.98 mmol), ZnCl2 (7.1 mL of a 0.5 M solution in THF, 3.6 mmol), KHCO3 (752 mg, 7.45 mmol), MeI (460 µL, 7.45 mmol). Purification by flash chromatography (hexanes-EtOAc, 9 : 1, v/v) afforded 65c (618 mg, 70%) as a 1 : 1 mixture of diastereomers. 65c : 1 H NMR (300 MHz, C6D6): δ 7.21-7.02 (m, 5H), 5.39 (m, 2H), 5.09-4.98 (m, 3H), 3.32 (s, 3H), 1.74 (s, 1.5H), 1.70 (s, 1.5H), 1.37-1.32 (m, 3H). 159
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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
Page 125 and 126: proximal double bond to give α-alk
Page 127 and 128: the methyl ester and Ha are syn. Sc
Page 129 and 130: that the major diastereomer in the
Page 131 and 132: We were motivated to first examine
Page 133 and 134: Scheme 4.42 Synthesis of pyrrole 29
Page 135 and 136: periodic acid (H5IO6). 209 These hi
Page 137 and 138: eaction failed to go to completion,
Page 139 and 140: 4.5.2 Synthesis of a Library of Tri
Page 141 and 142: diketones 312{1-3,1-2} in yields ra
Page 143 and 144: Figure 4.2 Distribution for physico
Page 145 and 146: tricyclic pyrrole 314{3,2,26} (Figu
Page 147 and 148: 4.6 Synthesis of α-Alkylidene Cycl
Page 149 and 150: anched and linear carboxylic acid i
Page 151 and 152: eactivity of the species prepared i
Page 153 and 154: considerably lower than the ratio o
Page 155 and 156: diastereomer. Next, allenyne 328 wa
Page 157 and 158: Conclusions In summary, we have dem
Page 159 and 160: Experimental Section General Method
Page 161 and 162: General procedure A for esterificat
Page 163 and 164: F Bz N H 56f 2-Benzoylamino-3-(4-fl
Page 165 and 166: MeO2C Bz N H 58c 2-Benzoylamino-2-m
Page 167 and 168: MeO MeO2C Bz N H 58e 2-Benzoylamino
Page 169 and 170: mL) and MeOH (10 mL) instead of sat
Page 171 and 172: hexanes-EtOAc, 19 : 1 to 4 : 1, v/v
Page 173 and 174: which was immediately used in the C
Page 175: Boc TMS N H Bn 64f tert-Butyl-1-((4
Page 179 and 180: with brine and concentrated under v
Page 181 and 182: H MeO 2C • H Bn NHBoc tert-Butyl-
Page 183 and 184: TMS MeO 2C • 70 H H NHBoc 2-tert-
Page 185 and 186: 185 (10), 141 (21), 57 (100); EI-HR
Page 187 and 188: dispersion in mineral oil, 1.0 mmol
Page 189 and 190: EI-HRMS calcd for C30H26NO3 m/z [M-
Page 191 and 192: CbzN MeO 2C Me 73h 2-[Benzyloxycarb
Page 193 and 194: CbzN MeO 2C Me 2-(Benzyloxycarbonyl
Page 195 and 196: dispersion in mineral oil, 3.85 mmo
Page 197 and 198: completion of the addition, the rea
Page 199 and 200: BzN MeO 2C S 74h 2-(Benzoylprop-2-y
Page 201 and 202: BzN MeO 2C Bn 75b 2-(Allylbenzoylam
Page 203 and 204: BzN MeO 2C TBSO 75e 2-(Benzoylbut-2
Page 205 and 206: Hz, 1H), 5.85 (s, 1H), 5.52 (dd, J
Page 207 and 208: 1H), 3.69 (s, 3H), 1.58 (d, J = 7.1
Page 209 and 210: µmol), [Rh(CO)2Cl]2 (1 mg, 3 µmol
Page 211 and 212: 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,
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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
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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
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1 H and 13 C NMRs of 111a 295
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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
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Boger, D. L.; Boyce, C. W.; Labroli
Page 351:
Generated Inhibitors of Human Mitog
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