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eaction. 159 It was shown that Jeong’s Mo(CO)6 conditions applied to allenyne 242 containing a terminally unsubstituted allene selectively afford the α-alkylidene cyclopentenone 243 arising from reaction with the proximal double bond of the allene (Scheme 4.10). Scheme 4.10 Mo(CO)6-mediated cyclocarbonylation reaction of 242. • TMS Mo(CO) 6, DMSO 100 o C, toluene, 68% 242 243 Subsequent detailed studies by Brummond established that the double bond selectivity is substrate dependent (Scheme 4.11). 160 In addition to terminally unsubstituted allenes (242), substrates possessing one or two substituents on the terminal allenic position were found to react selectively with the proximal double bond to give α-alkylidene cyclopentenones. In the case of terminally monosubstituted allenes, the products are obtained as mixtures of E and Z isomers of the exocyclic olefin. For example, reaction of allenyne 244 gives 245 as a 2 : 1 mixture of diastereomers. The terminally disubstituted allene in 246 also reacts to give α-alkylidene cyclopentenone 247 as a single product in 59% yield. In contrast, placing an additional substituent on the proximal carbon of the allene as in 248, leads exclusively to formation of 4- alkylidene cyclopentenone 249. These trends were proven general by subjecting variety of additional substrates to the reaction conditions. 160b-c Scheme 4.11 Mo-mediated allenic cyclocarbonylation reactions. • C7H15 244 • Mo(CO) 6, DMSO 100 o C, toluene, 75% E / Z = 2 : 1 Mo(CO) 6, DMSO 100 o C, toluene, 59% 245 246 247 O C 7H 15 O 86 C4H9 • 248 TMS O Mo(CO) 6, DMSO 100 o C, toluene, 60% C 4H 9 249 O
In contrast to the Mo(CO)6-mediated cyclocarbonylation reaction, which exhibits excellent double bond selectivity, the standard Pauson-Khand promoter Co2(CO)8 proved largely unselective by giving mixtures of constitutional group isomers. Subsequently, Cazes reported low selectivity in more examples of Co-mediated allenic Pauson-Khand reaction. 161 The substrate-controlled selectivity observed in the Mo-mediated reaction by Brummond has been exploited towards the synthesis of the potent antitumor agent hydroxymethylacylfulvene (HMAF) (250). Due to the presence of a methyl group at the proximal allenic position, the cyclocarbonylation reaction of allenyne 251 proceeds to give exclusively the 4-alkylidene cyclopentenone 252 desired for the synthesis of HMAF (Scheme 4.12). 162 Scheme 4.12 Application of the allenic cyclocarbonylation reaction to the synthesis of HMAF. Me HO Me • OTBS Mo(CO) 6, DMSO toluene, 110 o C 10 min, 69% Me HO Me OTBS 251 252 250 (HMAF) The alternative pathway, selective for the proximal double bond of the allene, was employed in the synthesis of 5-deoxy-∆ 12,14 -prostaglandin J2 (253) by utilizing a cleavable silicon tether in the allenyne 254 which gave 38 % yield of α-alkylidene cyclopentenones 255a and 255b (Scheme 4.13). 163 Scheme 4.13 Application of the allenic cyclocarbonylation reaction to the synthesis of 5-deoxy- ∆ 12,14 -PGJ2 (253). Ph 2 Si • 254 H C 5H 11 Mo(CO) 6, DMSO toluene, 100 o C 38% Ph 2Si O C 5H 11 Ph 2Si O 255a 255b 2 : 1 87 O Me C 5H 11 HO Me O O OH Me 253 C 5H 11 COOH
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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
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 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: that require high pressures of CO.
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
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
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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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Page 317 and 318:
Page 319 and 320:
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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
Page 349 and 350:
Boger, D. L.; Boyce, C. W.; Labroli
Page 351:
Generated Inhibitors of Human Mitog
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