Advances in the stereoselective synthesis of antifungal agents and ...

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Chapter 8 185[α] 20 D -5.7 (c 1.75, CHCl 3 ), enantiomeric excess 97.66% (ChiracelOD n-hexane/isopropanole), rt= (S)-(+)-27 l 72.90 min., (R)-(-)-27 l 76.29 min.Physical and spectral data were identical to those described above forthe racemate (±) 27 l.(±)-4'-Chlorophenyl-2-benzo[b]furanyl carbinol (±)-27-m:Synthetic procedure 7.3.1.1H NMR (200 MHz, CDCl 3 ) δ = 7.53-7.15 (m 8H), 6.51 (s 1H), 5.91(d1H, 4.4Hz), 2.53 (d 1H, 4.4 Hz).IR (CHCl 3 ): ν cm-1= 3385,1655,1620.GC-MS M + 258(90%), M + -OH 241 (100%).M.P.=77-79°C.(R)-(-)-2-(Isoindonylinyl) butan-1-ol (R)-(-)24:Synthetic procedure 7.4.1H-NMR (200 MHz, CDCl 3 ) δ =7.20 (s 5H), 4.04 (s 4H), 3.76 (d 1H,J = 4.1Hz), 3.71 (d 1H, J = 4.1Hz), 2.78 ( s1H), 170-1.49 (m 2H)0.97 ( t 3H, J= 7.7 Hz).M.P.= 59-60 °C.[α] 20 D -20.01 (c 1.5, CHCl 3 ).1-Methylimidazole-4,5-dicarbonitrile 33aSynthetic method 7.7.1Purified by chromatography (AcOEt) and then recrystallized fromCH 2 Cl 2 /hexane.1H-NMR (200 MHz, CDCl 3 ) δ = 3.85 (s, 3H), 7.70 (s, 1H).IR (CHCl 3 ): ν cm-1= 2260M.P.= 96-98 °C.Elementary Analysis. calcd. for C 6 H 4 N 4 : C, 54.54; H, 3.05; N,42.41. Found: C, 54.70; H, 3.00; N, 42.30.1-(n-Octyl)imidazole-4,5-dicarbonitrile 33bSynthetic method 7.7.1.Purified by flash chromatography (AcOEt).1H-NMR (200 MHz, CDCl 3 ) δ = 1.27 (t, J = 5 Hz, 3H), 1.66 (m,10H), 1.93 (q, J = 5 Hz, 2H), 4.18 (t, J = 6 Hz, 2H), 7.69 (s, 1H).IR (CHCl 3 ): ν cm-1= 2250 cm -1 ;M.P. = Colorless oil.Elementary Analysis. calcd.for C 13 H 18 N 4 : C, 67.79; H, 7.88; N,24.33. Found: C, 68.08; H, 7.73; N, 24.19.
Chapter 8 186(R,S)-(±)-1-(2-Octyl)imidazole-4,5-dicarbonitrile (±)-33cSynthetic method 7.7.1.Purified by preparative TLC (hexanes/AcOEt 3:1).1H-NMR (200 MHz, CDCl 3 ) δ = 0.88 (t, J = 5.7 Hz, 3H), 1.28 (m,8H), 1.65 (d, J = 5.7 Hz, 3H), 1.93 (m, 2H), 4.43 (sextet, J = 5.7 Hz,1H), 7.75 (s, 1H).IR (CHCl 3 ): ν cm-1= 2240 cm -1 .M.P.= Colorless oil.Elementary Analysis. calcd. for C 13 H 18 N 4 : C, 67.79; H, 7.88; N,24.33. Found: C, 67.92; H, 7.93, N, 24.15.(S)-(+)-1-(2-Octyl)imidazole-4,5-dicarbonitrile(S)-(+)-33cSynthetic method 7.7.1:[α] 0 546 +1.1 (c 2.91, CHCl 3 ).Physical and spectral data were identical with those described abovefor the racemate (±)-33c.(R)-(-)-1-(2-Octyl) imidazole-4,5-dicarbonitrile (R)-(-)-33cSynthetic method 7.7.1[α] 20 546 -1.0 (c 2.18, CHCl 3 ).Physical and spectral data were identical with those described abovefor the racemate (±)-33c.(R,S)-(±)-1-(1-Phenyl-2-propyl)imidazole-4,5-dicarbonitrile (±)-33dSynthetic method 7.7.1.Purified by flash chromatography (n-hexane/AcOEt 3:1). Ananalytical sample was prepared by recrystallization frombenzene/cyclohexane.1H-NMR (300 MHz, CDCl 3 ) δ = 1.48 (d, J = 4.3 Hz, 3H), 2.86 (dd, J= 14.1, 4.3 Hz, 2H), 2.93 (dd, J = 14.1, 4.3 Hz, 2H), 4.38 (sextet, J =4.3 Hz, 1H), 6.83 (m, 2H), 7.05 (m, 3H), 7.26 (s, 1H).IR (CHCl 3 ): ν cm-1=2240 cm -1 ;M.P.= 138-140 °C.Elementary Analysis. calcd. for C 14 H 12 N 4 : C, 71.17; H, 5.12; N,23.71. Found: C, 71.33; H, 5.01; N, 23.57.(S)-(+)-1-(1-Phenyl-2-propyl)imidazole-4,5-dicarbonitrile(S)-(+)-33d
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Advances in the stereoselectivesynt
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ACKNOWLEDGMENT:I would like to than
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Summary:Numerous drugs are chiral,
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IndexII2.2 Synthesis of enantiopure
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IndexIV4.4. Stereochemical Assignme
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IndexVImethyl amine 69 1446.6. Stud
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IndexVIII8.23.3.1 Desilylation usin
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Chapter 1 11.Introduction1.1. Chira
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Chapter 1 3The concept of stereoche
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Chapter 1 5switches is in the area
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Chapter 1 7-bonds 9 . It is now wid
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Chapter 1 914CH 3Cyt P-450 DMOH3O 2
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Chapter 1 11piperazine) is also the
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Chapter 1 13The four stereoisomers
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Chapter 1 15single enantiomers and
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Chapter 1 17was synthesized by the
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Chapter 1 19HOHODesmolaseHOCholeste
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Chapter 1 21formic acid results in
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Chapter 1 23inactivation. 113 . Bec
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Chapter 1 25Two newer compounds whi
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Chapter 1 2715 is an advanced repre
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Chapter 1 29transformation of the a
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Chapter 1 31Enantioselective synthe
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Chapter 1 33+R,S DRUG ANCHOR R MOLE
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Chapter 1 35solubilized in hot etha
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Chapter 2 37RsORmRmRsRLRL RRRLH - A
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Chapter 2 39The stereochemistry and
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Chapter 2 41An asymmetric reducing
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Chapter 2 43This approach clearly e
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Chapter 2 45PhaxeqP 1MP 2axeqPhP 2M
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Chapter 2 47pyrrolidine ] 20 , LAH-
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Chapter 2 49Enzymatic reactions are
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Chapter 2 51As [ES] in equation 4 c
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Chapter 2 53E+AK 1AK -1AEAK 2AE+PE+
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Chapter 2 552.2.4 Lipases.Most lipa
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Chapter 2 57enzyme intermediate can
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Chapter 2 59projecting above the pl
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Chapter 2 612.3.1.1. Step 1: Adduct
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Chapter 2 63A -+ ROHRO - + AH'RO 2
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Chapter 2 65There are various effec
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Chapter 2 67The reactions were foun
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Chapter 2 69Yamanaka and coworkers
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Chapter 2 71sodium or potassium car
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Chapter 3 73The reaction is quite s
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Chapter 3 75literature as the best
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Chapter 3 77dry solvents and, is ch
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Chapter 3 79XXOH+ H 2 NDry K 2 CO 3
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Chapter 3 81substituents are the mo
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Chapter 3 83induces a rotation of t
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Chapter 3 85very sharp and it was p
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Chapter 3 87Raney NickelOH Br MeOH;
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Chapter 4 8933a-m were hydrolysed t
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Chapter 4 91benzo[b]furane (entries
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Chapter 4 93hydroxy or amine groups
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Chapter 4 95the products with ethyl
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Chapter 4 97NCO 2 HNCO 2 H(±)34c(-
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Chapter 4 99NNH37CO2EtOH(±)-27a(+)
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Chapter 4 101As already outlined ab
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Chapter 4 103(+)-(S)-2-octylimidazo
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Chapter 4 105CNNH N2 NCN nC 6 H 13N
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Chapter 4 107key step is the conver
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Chapter 4 109reverse addition in th
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Chapter 4 111which was eliminated e
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Chapter 4 113separate (±)-57a and
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Chapter 5 115to avoid this side rea
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Chapter 5 117Complete degradation o
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Chapter 5 119Entry R T °C Product
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Chapter 5 1212:1:3 in weight. All t
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Chapter 5 123reaction conditions we
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Chapter 5 125Entry Substrate R Time
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Chapter 5 127experiments. But it wa
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Chapter 5 129OClOSAM IIPH=7; R.T.OH
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Chapter 5 131OHOXHOHRHK 2 CO 3 ; Me
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Chapter 6 133HCuSO 4 .5H 2 O,NH 4 O
Page 150 and 151: Chapter 6 1356.2.1 Heteroannullatio
Page 152 and 153: Chapter 6 137This discovery allowed
Page 154 and 155: Chapter 6 139OH(±)-62OHFigure 6.1
Page 156 and 157: Chapter 6 141Entry Substrate R Time
Page 158 and 159: Chapter 6 143HOH58-a-c,e,h-lRPdCl 2
Page 160 and 161: Chapter 6 145afforded the benzo[b]f
Page 162 and 163: Chapter 6 147RR[P(Ph) 3 ]Pd°OHOPh
Page 164 and 165: Chapter 6 149H2-IodophenolOHOH(±)-
Page 166 and 167: Chapter 6 151presence of base as de
Page 168 and 169: Chapter 7 153A chiral lithium alumi
Page 170 and 171: Chapter 7 155derivatives were tried
Page 172 and 173: Chapter 7 157Finally an hypothesis
Page 174 and 175: Chapter 8 159were washed with a sat
Page 176 and 177: Chapter 8 16145 min, the mixture wa
Page 178 and 179: Chapter 8 1638.9 Decarboxylation of
Page 180 and 181: Chapter 8 165Alcohol 27a (0.2 mmol)
Page 182 and 183: Chapter 8 167for 48 h. After coolin
Page 184 and 185: Chapter 8 169room temperature for t
Page 186 and 187: Chapter 8 171in CH 2 Cl 2 and washe
Page 188 and 189: Chapter 8 1738.26 Screening of lipa
Page 190 and 191: Chapter 8 175Na 2 SO 4 . After remo
Page 192 and 193: Chapter 8 177NMR and MS analysis we
Page 194 and 195: Chapter 8 179Argon was bubbled thru
Page 196 and 197: Chapter 8 181IR (CHCl 3 ): ν cm-1=
Page 198 and 199: Chapter 8 183GC-MS: 305 M + (68%),
Page 202 and 203: Chapter 8 187Synthetic method 7.7.1
Page 204 and 205: Chapter 8 189(R,S)-(±)-1-(2-Octyl)
Page 206 and 207: Chapter 8 191M.P. = oil.Elementary
Page 208 and 209: Chapter 8 193Synthetic method 7.11.
Page 210 and 211: Chapter 8 195(±)-N-1-(2-Octyl)-2-t
Page 212 and 213: Chapter 8 197IR (CHCl 3 ) ν cm-1 =
Page 214 and 215: Chapter 8 199(±)-1-(4-Fluorophenyl
Page 216 and 217: Chapter 8 201Physical and spectral
Page 218 and 219: Chapter 8 203(±)-1-(Phenyl)-2-prop
Page 220 and 221: Chapter 8 205128.61, 128.87, 130.39
Page 222 and 223: Chapter 8 207min.Physical and spect
Page 224 and 225: Chapter 8 20913C J MOD NMR (CDCl 3
Page 226 and 227: Chapter 8 211(±)-2'-Methylphenyl-2
Page 228 and 229: Chapter 9 213References chapter 1:1
Page 230 and 231: Chapter 9 21531) De Felice, R.; Joh
Page 232 and 233: Chapter 9 21768) Brodie, A.M.H. in
Page 234 and 235: Chapter 9 219112) Brodie, A. M. H.;
Page 236 and 237: Chapter 9 2214) Karabatsos, M.C. J.
Page 238 and 239: Chapter 9 22334c) Blow D. Nature 19
Page 240 and 241: Chapter 9 22567a) Kundu, N.G.; Pal,
Page 242: Chapter 9 22712) Thompson,A.S.; Hum
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