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4.0 Synthesis and Use of Amino-Acid Derived Cyclopentenones 4.1 Transition Metal Catalyzed Cyclocarbonylation – Pauson-Khand Reaction The cocyclization of an alkyne, alkene and carbon monoxide to form a cyclopentenone (217) constitutes a formal [2+2+1] cycloaddition and was first described by Pauson and Khand in 1973 (Scheme 4.1). 142 Since then, the Pauson-Khand reaction has become one of the most convenient methods for synthesis of cyclopentenones, which are synthetically important class of molecules. 143 The initial reaction conditions utilized a stoichiometric amount of dicobaltoctacarbonyl (Co2(CO)8) to effect the intermolecular reaction of an alkyne and an alkene. Scheme 4.1 Intermolecular Co2(CO)8-mediated Pauson-Khand reaction. 218 R 2 R 1 OC CO OC Co Co CO OC CO R 2 R 2 R 2 R 2 O 217 R 1 R 2 C O R 1 - CO Co 2(CO) 4 Co 2(CO) 8 R 2 R 2 O 217 R2 R2 OC OC Co OC CO Co CO R1 R2 R2 OC CO OC Co R OC Co OC 1 219 220 OC heat R2 R2 Co O OC OC Co OC 222 R 1 R 1 OC R2 R2 OC Co OC Co OC A widely accepted mechanism for this Co-mediated cyclocarbonylation reaction was proposed 80 221 O R 1
y Magnus 144 and it involves the intermediacy of the cobalt complex 218, formed by complexation of Co2(CO)8 to the alkyne, which was later firmly established by Krafft (Scheme 1.1). 145 These conditions, however, were limited to promoting the reaction of strained olefins (e.g., norbornadiene), typically with low efficiency. Furthermore, use of unsymmetrical olefins generally led to formation of regioisomers. Despite these initial disadvantages, the potential application of this transformation to complex molecule synthesis was apparent, and wealth of research in the past three decades has resulted in improved methods for effecting related Co- mediated cyclocarbonylation reactions. In the intramolecular version of the reaction, first reported by Schore in 1981, enyne 223 was converted to a fused bicyclic cyclopentenone 224 (Scheme 4.2). 146 Tethering of the alkyne and alkene gives the advantage of exclusive regioselectivity and increased reactivity. Scheme 4.2 Intramolecular Pauson-Khand reaction of a tethered enyne. ( ) n 223 Co Co2(CO) 2(CO) 8 95 o 95 C oC ( ) n 224 O n = 1, 31% n = 2, 40% Extensive efforts in the past have been aimed at improving the efficiency of the Co-mediated reaction by using various additives. 147 Silica gel is believed to accelerate the reaction by acting as a polar surface to facilitate CO ligand exchange. Primary amines (e.g., cyclohexylamine) are more effective additives and are believed to act by stabilizing certain coordinatively unsaturated intermediates in the reaction pathway. Thioethers and phosphines have similar effect on accelerating the reaction. Amine oxides are another class of effective additives, which generally act by oxidizing a coordinated CO ligand to CO2 thereby creating a vacant site on the metal. Although the use of stoichiometric amount of Co2(CO)8 to promote the Pauson-Khand reaction is still widely used today, there has been a significant progress in developing a catalytic reaction 81
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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
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
Page 55 and 56: 3.2 Rhodium(I)-Catalyzed Allenic Cy
Page 57 and 58: exocyclic olefin geometry is not re
Page 59 and 60: 3.2.1 Preparation of Enol-ether Tri
Page 61 and 62: Scheme 3.15 Synthesis of cycloisome
Page 63 and 64: Scheme 3.17 Cycloisomerization of a
Page 65 and 66: 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: Scheme 3.49 Rh(I)-catalyzed ene rea
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 and 118: Scheme 4.22 Cyclocarbonylation reac
Page 119 and 120: neat or in solution. This decomposi
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
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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
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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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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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