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1H), 6.52 (dd, J = 8.2, 1.8 Hz, 1H), 6.22 (s, 1H), 5.34 (d, J = 15.1 Hz, 1H), 5.11 (d, J = 15.1 Hz, 1H), 4.23 (d, J = 13.6 Hz, 1H), 3.87 (d, J = 7.3 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.62 (s, 3H), 3.59-3.55 (m, 4H), 3.39 (d, J = 13.7 Hz, 1H), 3.36-3.30 (m, 1H), 3.18-3.12 (m, 1H), 2.42 (dd, J = 15.1, 6.9 Hz, 1H), 2.33-2.23 (m, 1H), 2.13 (d, J = 15.6 Hz, 1H), 1.82-1.92 (m, 4H); 13 C NMR (75 MHz, CDCl3): δ 172.3, 169.9, 162.2, 149.0, 148.2, 141.0, 137.7, 137.2, 131.3, 131.1, 129.8, 129.7, 128.5, 128.3, 126.9, 126.4, 122.9, 119.3, 110.9, 110.5, 108.8, 73.1, 56.5, 56.0, 55.9, 52.2, 49.8, 48.0, 45.7, 39.4, 28.8, 25.5; IR (thin film): ν 2949, 1734, 1638, 1605, 1445, 1400 cm -1 ; MS m/z (%) 647 (51), 556 (42), 381 (27), 151 (100), 105 (65); EI-HRMS calcd for C39H41N3O6 m/z [M] + 647.2995; found 647.2991. H BzN MeO2C Bn H 5-Benzoyl-4-benzyl-1-(4-hydroxy-3-methoxybenzyl)-2-(pyrrolidine-1-carbonyl)- MeO 308c 3b,4,5,6,6a,7-hexahydro-1H-1,5-diazacyclopenta[a]pentalene-4-carboxylic acid methyl ester (308c). Prepared by following general procedure T with: 307 (35 mg, 0.068 mmol), 4- aminomethyl-2-methoxyphenol hydrochloride (39 mg, 0.20 mmol), AcOH (80 µL). Yield 308c (31 mg, 72%). 1 H NMR (300 MHz, CDCl3): δ 7.41-7.27 (m, 10H), 6.75 (d, J = 8.1 Hz, 1H), 6.64 (s, 1H), 6.44 (d, J = 8.1 Hz, 1H), 6.21 (s, 1H), 5.72 (bs, 1H), 5.31 (d, J = 15.0 Hz, 1H), 5.07 (d, J = 15.0 Hz, 1H), 4.22 (d, J = 13.6 Hz, 1H), 3.86 (d, J = 7.2 Hz, 1H), 3.79 (s, 3H), 3.61 (s, 3H), 3.61-3.50 (m, 4H), 3.44-3.29 (m, 2H), 3.18-3.11 (m, 1H), 2.42 (dd, J = 15.2, 7.0 Hz, 1H), 2.33-2.22 (m, 1H), 2.13 (d, J = 15.4 Hz, 1H), 1.93-1.80 (m, 4H); 13 C NMR (75 MHz, CDCl3): δ 172.2, 169.8, 162.1, 146.5, 144.8, 140.8, 137.5, 137.0, 130.9, 130.5, 129.7, 129.6, 128.4, 128.2, 126.8, 126.2, 122.7, 268 N OH O N
119.9, 114.1, 109.9, 108.6, 73.0, 56.4, 55.8, 52.0, 49.7, 45.5, 39.2, 28.7; IR (thin film): ν 3253, 2949, 1734, 1602, 1447, 1401 cm -1 ; ESI-HRMS calcd for C38H40N3O6 m/z [M+1] + 634.2917; found 634.2938. H BzN MeO2C Bn H 308d 5-Benzoyl-4-benzyl-1-(5-methylfuran-2-ylmethyl)-2-(pyrrolidine-1-carbonyl)-3b,4,5,6,6a,7- hexahydro-1H-1,5-diazacyclopenta[a]pentalene-4-carboxylic acid methyl ester (308d). Prepared by following general procedure T with: 307 (35 mg, 0.068 mmol), C-(5-Methylfuran-2- yl)-methylamine (23 µL, 0.20 mmol), AcOH (90 µL). Yield 308d (34 mg, 85%). 1 H NMR (300 MHz, CDCl3): δ 7.45-7.27 (m, 10H), 6.18 (s, 1H), 6.01 (d, J = 3.0 Hz, 1H), 5.81 (d, J = 2.2 Hz, 1H), 5.35 (d, J = 15.5 Hz, 1H), 5.06 (d, J = 15.5 Hz, 1H), 4.22 (d, J = 13.6 Hz, 1H), 3.85 (d, J = 7.3 Hz, 1H), 3.65-3.55 (m, 4H), 3.57 (s, 3H), 3.39 (d, J = 13.6 Hz, 1H), 3.35- 3.29 (m, 1H), 3.21-3.16 (m 1H), 2.53 (dd, J = 15.1, 7.3 Hz, 1H), 2.33-2.20 (m, 2H), 2.17 (s, 3H), 1.97-1.86 (m, 4H); 13 C NMR (75 MHz, CDCl3): δ 172.2, 169.7, 162.1, 151.6, 149.5, 140.7, 137.6, 137.0, 130.9, 129.5, 129.4, 128.3, 128.1, 126.7, 126.2, 122.5, 108.6, 106.2, 72.9, 56.3, 52.1, 52.0, 48.7, 45.4, 42.9, 39.2, 28.6, 13.5; IR (thin film): ν 2949, 1734, 1638, 1605, 1445, 1400 cm -1 ; MS m/z (%) 591 (30), 500 (16), 406 (10), 105 (88), 95 (100); EI-HRMS calcd for C36H37N3O5 m/z [M] + 591.2733; found 591.2735. 269 O N O 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
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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
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We were motivated to first examine
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Scheme 4.42 Synthesis of pyrrole 29
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periodic acid (H5IO6). 209 These hi
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eaction failed to go to completion,
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4.5.2 Synthesis of a Library of Tri
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diketones 312{1-3,1-2} in yields ra
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Figure 4.2 Distribution for physico
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tricyclic pyrrole 314{3,2,26} (Figu
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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-
Page 235 and 236: The crude residue was purified by f
Page 237 and 238: 14.4 Hz, 1H), 3.49-3.39 (m, 2H), 3.
Page 239 and 240: 1H), 5.49 (dd, J = 17.3, 1.8 Hz, 1H
Page 241 and 242: was stirred at rt for 1 h when it w
Page 243 and 244: BzN HOOC 2-(N-(but-2-ynyl)benzamido
Page 245 and 246: °C and DIBAL-H (0.440 mL of a 1.0M
Page 247 and 248: 129 (62), 91 (100); EI-HRMS calcula
Page 249 and 250: (d, J = 18.0 Hz, 1H), 4.14 (d, J =
Page 251 and 252: 4.98 (dt, J = 7.7, 5.1 Hz, 1H), 4.1
Page 253 and 254: N Bz MeO2C OTBS 214 1-Benzoyl-2-(te
Page 255 and 256: 270a (major diastereomer-eluting fi
Page 257 and 258: CDCl3): δ 7.42-7.17 (m, 13H), 7.04
Page 259 and 260: 18.6 Hz, 1H), 4.34 (d, J = 18.0 Hz,
Page 261 and 262: Bz N MeO2C 2-Benzoyl-3,7-dimethyl-6
Page 263 and 264: v/v) afforded a mixture of compound
Page 265 and 266: (435 mg, 1.21 mmol), DMSO (429 µL,
Page 267 and 268: 4.02 (s, 1H), 3.88 (s, 3H), 1.82 (s
Page 269 and 270: (207 mg, 96%) consisting of 287e (7
Page 271 and 272: procedure O, using: 74f (110 mg, 0.
Page 273 and 274: Bz N O H CO2Me BocN 287i 3-(2-Benzo
Page 275 and 276: 4.17 (d, J = 15.0 Hz, 1H), 4.10 (d,
Page 277 and 278: 137.1, 136.9, 130.4, 129.8, 128.5,
Page 279 and 280: H BzN MeO2C Bn H N C3H7 298b CO 2Me
Page 281 and 282: NMR (75 MHz, CDCl3): δ 172.3, 169.
Page 283 and 284: following the general procedure Q,
Page 285: H BzN MeO2C Bn H 5-Benzoyl-1,4-dibe
Page 289 and 290: 4.11 (m, 1H), 4.07-3.98 (m, 1H), 3.
Page 291 and 292: 126.8, 126.2, 109.0, 72.9, 58.7, 56
Page 293 and 294: NMR (75 MHz, CDCl3): δ 172.2, 169.
Page 295 and 296: 3.0 Hz, 1H), 5.82-5.80 (m, 1H), 5.2
Page 297 and 298: 87%). The diastereomeric ratio (288
Page 299 and 300: APPENDIX A: X-ray crystal structure
Page 301 and 302: APPENDIX B: X-ray crystal structure
Page 303 and 304: APPENDIX C: X-ray crystal structure
Page 305 and 306: APPENDIX D: X-ray crystal structure
Page 307 and 308: APPENDIX E: X-ray crystal structure
Page 309 and 310: APPENDIX F: QikProp property predic
Page 311 and 312: 1 H and 13 C NMRs of 74b 293
Page 313 and 314: 1 H and 13 C NMRs of 111a 295
Page 321 and 322: 1 H and 13 C NMRs of 270h 303
Page 325 and 326: 1 H and 13 C NMRs of 307 307
Page 327 and 328: 1 H and 13 C NMRs of 308n 309
Page 329 and 330: 10. (a) Burke, M. D.; Schreiber, S.
Page 331 and 332: Hu, Y. J. Comb. Chem. 2006, 8, 286.
Page 333 and 334: 49. For reviews on reactions of all
Page 335 and 336: 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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