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127.8, 126.5, 98.9, 84.6, 78.9, 64.0, 52.4, 40.0, 28.4, 13.3, -0.3; IR (thin film): ν 3426, 2977, 1938, 1723, 1487 cm -1 ; MS m/z (%) 403 (5), 347 (7), 256 (100), 178 (49); EI-HRMS calcd for C22H33NO4Si m/z [M] + 403.2179; found 403.2196. TMS BocHN tert-Butoxycarbonylaminoacetic acid 1-methyl-3-trimethylsilylprop-2-ynyl ester (69). To a solution of 4-trimethylsilyl-3-yn-2-ol (1.17 g, 8.27 mmol), in CH2Cl2 (10 mL), was added DMAP (81 mg, 0.66 mmol), DCC (1.38 g, 6.71 mmol) and N-Boc-Glycine 68 (954 mg, 6.71 mmol) all at rt. The reaction mixture was stirred for 1 h at rt, then filtered through a plug of silica gel eluting with hexanes/EtOAc (1 : 1), and the filtrate was concentrated under vacuum. Purification of the crude oily residue by flash chromatography (hexanes-EtOAc, 4 : 1, v/v) afforded 69 (1.92 g, 92%). 1 H NMR (300 MHz, CDCl3): δ 5.50 (q, J = 6.7 Hz, 1H), 5.06 (br s, 1H), 3.91 (d, J = 5.4 Hz, 2H), 1.48 (d, J = 6.7 Hz, 1H), 1.44 (s, 9H), 0.15 (s, 9H); 13 C NMR (75 MHz, CDCl3): δ 169.4, 155.8, 102.9, 90.3, 80.1, 61.8, 42.7, 28.4, 21.6, -0.2; IR (thin film): ν 3379, 2978, 1756, 1721, 1169 cm - 1 ; MS m/z (%) 299 (10), 243 (100); EI-HRMS calcd for C14H25NO4Si m/z [M] + 299.1553; found 299.1547. O 69 164 O
TMS MeO 2C • 70 H H NHBoc 2-tert-Butoxycarbonylamino-3-trimethylsilylhexa-3,4-dienoic acid methyl ester (70). Ester- enolate Claisen rearrangement. To a freshly prepared solution of LDA ii (20.4 mmol) in THF (10 mL) was added 69 (1.6 g, 5.1 mmol) in THF (10 mL) at -78 °C. After 10 min of stirring ZnCl2 (20 mL of a 0.5 M solution in THF, 9.8 mmol) was added at -78 °C. The reaction mixture was allowed to warm to rt over 12 h. Upon completion the reaction mixture was diluted with Et2O (100 mL), and treated with 1M HCl (100 mL). The aqueous layer was extracted with Et2O (2 x 100 mL), and the organic layers were combined and washed with brine. Concentration under vacuum afforded a oily residue which was dissolved in DMF (10 mL). Pulverized KHCO3 (1.08 g, 1.07 mmol) was added at rt, followed by MeI (530 µL, 8.24 mmol). The reaction mixture was left stirring for 2h at rt, and then diluted with water (100 mL). The cloudy mixture was extracted (benzene-EtOAc, 1 : 9, v/v) (3 x 75 mL), the organic layers were combined, washed with brine (2 x 50 mL) and concentrated in vacuo. Purification by flash chromatography (gradient elution: hexanes-EtOAc, 32 : 1 to 19 : 1, v/v), afforded 70 (740 mg, 44%). 1 H NMR (300 MHz, CDCl3): δ 5.10-5.03 (m, 2H), 4.75 (d, J = 8.3 Hz, 1H), 3.72 (s, 3H), 1.63 (d, J = 7.1 Hz, 1H), 1.45 (s, 9H), 0.15 (s, 9H); 13 C NMR (75 MHz, CDCl3): δ 207.2, 172.1, 155.0, 95.4, 84.5, 80.0, 53.4, 52.1, 28.4, 13.2, -1.1; IR (thin film): ν 3373, 2955, 1943, 1749, 1720 cm -1 ; MS m/z (%) 314 (6), 257 (43), 242 (45), 198 (100); EI-HRMS calcd for C11H19NO4Si m/z [M- 56] + 257.1083; found 257.1080. ii LDA was prepared as outlined in general procedure E. 165
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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
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 and 176: Boc TMS N H Bn 64f tert-Butyl-1-((4
Page 177 and 178: MeI (38 µL, 0.62 mmol). Yield 65a
Page 179 and 180: with brine and concentrated under v
Page 181: H MeO 2C • H Bn NHBoc tert-Butyl-
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,
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,
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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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