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Scheme 4.23 Structure of HMAF and key fulvene synthesis step. HO OTBS O 1. CH 3Li 2. HCl (0.1 M) 96% HO OTBS 252 278 HO O OH 250 hydroxymethylacylfulvene (HMAF) Therefore, cyclopentenone 270a was treated with MeLi/CeCl3 (1.5 equiv.) to afford tertiary alcohol 279a (Scheme 4.24). q Immediate treatment of the crude reaction mixture with aq. HCl and warming to rt led to formation of a bright yellow solution, from which fulvene 280a was isolated in 74% yield (pentafulvenes are generally characterized by yellow color, Lat. fulvus = yellow). 183 Scheme 4.24 Synthesis of novel pentafulvenes. P N MeO2C R1 O 270a, P = Bz, R 1 = Bn 270f, P = Cbz, R = Me MeLi, CeCl3 THF, -78 oC P MeO2C N R1 279a 279f OH 0.3 M aq. HCl, rt P MeO2C N R1 Bz MeO 2C 280a, P = Bz, R 1 = Bn, 74% 280f, P = Cbz, R = Me, ~50% select 1 H NMR signals of 280a N Bn Ha H a 6.29 (s, 1H) three methyl group resonances 1.87 (s, 3H) 1.71 (s, 3H) 1.39 (s, 3H) The structure of 280a was assigned based on the presence of one olefin peak in the 1 H NMR spectrum at 6.29 ppm for Ha and three methyl groups (Scheme 4.24). Similarly, the N-Cbz protected cyclopentenone 270f afforded fulvene 280f in 50% yield. Unfortunately, the newly synthesized fulvenes proved unstable and readily decomposed when kept on the bench-top either q The presumed tertiary alcohol 279 was treated in situ with aq. HCl and was not characterized. 100
neat or in solution. This decomposition was qualitatively assessed by collecting the 1 H NMR spectrum of 280a at different times. A solution of 280a in CDCl3 stored at rt for 5 days resulted in appearance of additional broadened resonances in the upfield region (1.0 – 2.0 ppm). The decomposition was accelerated when 280a was stored neat. In contrast, storing 280a in deoxygenated frozen benzene r at -10 °C proved advantageous in extending its shelf life up to three months. Unfortunately, these observations rendered the newly synthesized fulvenes unsuitable for biological evaluation because the results may be compromised by the presence of impurities. The pathway of decomposition has not been determined, however it is well known that simple alkyl-pentafulvenes readily polymerize in presence of traces of acid (Scheme 4.25). 184 Additionally, polymerization of pentafulvenes has been triggered by reaction with molecular oxygen. 185 Scheme 4.25 Acid catalyzed polymerization of pentafulvenes. R 1 R 2 H + R 1 R 2 + H H R 1 R 2 R 1 R 2 281 282 283 R 1 + R 2 R 1 R 2 The electron density of the fulvene moiety in 270a and 270f is likely responsible for the observed decomposition. Based on the structure of HMAF (252, Scheme 4.23), it was hypothesized that an acyl group may impart greater stability to these compounds by reducing the electron density of the fulvene. To examine this effect we sought to prepare fulvene 286 (Scheme 4.26). To this end, the cyclocarbonylation reaction of amide tethered allenyne 145e was briefly examined. r Benzene was deoxygenated prior to freezing by bubbling nitrogen via a needle. 101 R 1 R 2 284 n
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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
Page 67 and 68: Scheme 3.21 Intermolecular Diels-Al
Page 69 and 70: attractive, since additional functi
Page 71 and 72: increased yield of the triene (47%)
Page 73 and 74: as an isobutyl-amide 155b was prepa
Page 75 and 76: group) demonstrated that this cyclo
Page 77 and 78: in 1M HCl/dioxane (1 : 1) for 1h, t
Page 79 and 80: ppm (dd, J = 7.1, 4.6 Hz, 1H) assig
Page 81 and 82: http://ccc.chem.pitt.edu/). Using f
Page 83 and 84: Notably, exclusive cycloisomerizati
Page 85 and 86: intermediate in the reaction we sou
Page 87 and 88: epulsive dipole interactions (Schem
Page 89 and 90: Table 3.4 Diels-Alder reactions of
Page 91 and 92: allenic Alder-ene reaction, ene-all
Page 93 and 94: Figure 3.4 Examples of natural prod
Page 95 and 96: species onto the proximal double bo
Page 97 and 98: Scheme 3.49 Rh(I)-catalyzed ene rea
Page 99 and 100: y Magnus 144 and it involves the in
Page 101 and 102: usually is DMSO. Heating to 100 ºC
Page 103 and 104: that require high pressures of CO.
Page 105 and 106: In contrast to the Mo(CO)6-mediated
Page 107 and 108: Scheme 4.15 Rh(I)-catalyzed allenic
Page 109 and 110: 4.2 Rhodium(I)-Catalyzed Cyclocarbo
Page 111 and 112: lack of double bond selectivity, si
Page 113 and 114: Table 4.2 Cyclocarbonylation reacti
Page 115 and 116: Notably, the allenic cyclocarbonyla
Page 117: Scheme 4.22 Cyclocarbonylation reac
Page 121 and 122: the newly synthesized fulvenes (e.g
Page 123 and 124: 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
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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
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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 319 and 320:
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1 H and 13 C NMRs of 270h 303
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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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