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

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Chapter 9 21531) De Felice, R.; Johnson, D. G. and Galgiani, J. N. AntimicrobAgents Chemother 1981,19, 1073-1074.32) Kraemer, F. B.; Pont, A. Am. J. Med. 1986, 80, 616-622.33) Miettinen, J. A. J. Lipid Res. 1988, 29, 43-51; Gylling, H.;Vanhanen, H.; Miettinen, J. A. Metabolism, 1991, 49, 35-41 andreferences therein.34) For a review, see: Van den Bossche, H.; Janssen, P. A. J. Targetsites of fungicide action; Koller, W., Ed.; Boca Raton, FL, 1992;pp. 227-254.35) Ballard, S. A.; Ladola, A.; Tarbit, M. H. A. Biochem. Pharmacol.1988, 37, 4643-4651.36) Rotstein, D. M.; Kertesz, D. J.; Walker, K. A. M.; Swinney, D. C.J. Med. Chem. 1992, 35, 2818-2825.37) Walker, K. A. M.; Kertesz, D. J.; Rotstein, D. M.; Swinney, D. C.J. Med. Chem. 1993, 36, 2235-2237.38) Camps, P.; Farres, X.; Garcia, M. L.; Ginesta, J.; Pascual, J.;Mauleon, D.; Garganico, G. Tetrahedron : Asymmetry 1995, 6,1283-1294.39) Heeres, J.; Hendrickx, R. and Van Cutsem J. Med. Chem. 1983,26, 611-613.40) Camps, P.; Farres, X.; Garcia, M. L.; Mauleon, D.; Garganico, G.Tetrahedron : Asymmetry 1995, 6, 2365-2368.41) Sakesena, A. K.; Girijavallabham, V. M.; Lovey, R. G.; Pike, R.E.; Desai, J. A.; Hare, G. R. S.; Loendenberg, D.; Cacciapuoti, A.;Parmegiani, M. Biorg. Med. Chem. Lett. 1994, 4, 2023-2028.42) Van Cutsen, J.; Van gerven, F.; Zaman, R. and Janssen, P. A. J.Chemother. 1983, 29, 322-331.43) Godefroi, E. F.; Heeres, J.; Van Cutsem, E. and Janssen, P. A. J. J.Med. Chem. 1969, 12, 784-791.44) Yamaguchi, H.; Hiratani, T. and Plempel, M. Arzneim-Forsch1983, 33, 546-551.45) Schar, G.; Kayser, F. H. and Dupont, M. C. Chemoter. 1976, 22,211-220.46) Hell, R. C.; Brodger, R. N.; Parkers, G. E.; Sperght, T. M.; Avery,G. S. Drug 1980, 19, 7-30.47) Menuier, F.; Cruciani, M.; Klastersky, J. Eur. J. Cancer Clin.Oncol. 1983; 19, 43-48.
Chapter 9 21648) Gip, L. and Forsstrom, S. Mykosen 1982, 27, 231-241.49) Heel, R.C.; Brodgen, R. N.; Speight, T. M. and Avery, G. S. Drugs1978, 16, 177-201.50) Yoshiharu, Y.; Kenzo, F.; Motoo, U.; Heizo, S. Nippon SaikingakuZasshi 1979, 36, 813-825.51) Sud, I. J. and Feingold, D. S. J. Invest. Dermatol. 1981, 76, 438-441.52) Thienpont, D.; Van Cutsem, J. M.; Niemegeers, C. J. E. andMarsboom, R. Arzneim-Forsch 1975, 25, 224-230.53) Kessler, H. J. Arzneim-Forsch 1979, 29, 1344-1351.54) Jevons, S.; Gymer, G. E.; Brammer, K. W.; Cox, D. A. andLemming, M. R. G. Antimicrob. Agents Chemother. 1979, 15, 597-602.55) International Antifungal Symposium: Bifonazole. ExcerptaMedica: Amsterdam 1982, 104-112.56) International Antifungal Symposium: Bifonazole. ExcerptaMedica: Amsterdam 1982, 2-17.57) International Antifungal Symposium: Bifonazole. ExcerptaMedica: Amsterdam 1982, 37-4058) International Antifungal Symposium: Bifonazole. ExcerptaMedica: Amsterdam 1982, 74-76, 88-94,104-112, 120-125, 126-128, 129-135.59) Massa, S.; Stefancich, G.; Corelli, F.; Silvestri, R.; Panico, S.;Artico, M.; Simonetti, N. Il farmaco 1988, 43, 639-704.60) Massa, S.; Di Santo, R.; Artico, M.; Costi, R.; Apuzzo, G.;Simonetti, G.; Artico, M. Med. Chem. Res. 1992, 148-153.61) Buchel, H. D.; Draber, W.; Regal, E. and Plempel, M. Drugs Madein Germany 1972, 15, 79-94.62) Rumler, W. and Heins, S. Mykosen 1983, 26, 293-2297.63) Yamaguchi, H. and Iwata, K. Sabouraudia 1979, 17, 311-322.64) Shadomy, S. Antimicrob. Agents Chemother. 1971, 169-174.65) Burgess, M. A. and Bodey, G. P. Antimicrob. Agents Chemother.1972,2, 423-426.66) Wright, J. C. J. Natl. Med. Ass. 1985, 77, 617.67) Young, J. L.; Percy, C. L.; Asire, A. J. Incidence of mortality data(1973-77), N.I.H., Bethesda.N°81, 2330.
Page 1 and 2:
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
Page 20 and 21:
Chapter 1 5switches is in the area
Page 22 and 23:
Chapter 1 7-bonds 9 . It is now wid
Page 24 and 25:
Chapter 1 914CH 3Cyt P-450 DMOH3O 2
Page 26 and 27:
Chapter 1 11piperazine) is also the
Page 28 and 29:
Chapter 1 13The four stereoisomers
Page 30 and 31:
Chapter 1 15single enantiomers and
Page 32 and 33:
Chapter 1 17was synthesized by the
Page 34 and 35:
Chapter 1 19HOHODesmolaseHOCholeste
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Chapter 1 21formic acid results in
Page 38 and 39:
Chapter 1 23inactivation. 113 . Bec
Page 40 and 41:
Chapter 1 25Two newer compounds whi
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Chapter 1 2715 is an advanced repre
Page 44 and 45:
Chapter 1 29transformation of the a
Page 46 and 47:
Chapter 1 31Enantioselective synthe
Page 48 and 49:
Chapter 1 33+R,S DRUG ANCHOR R MOLE
Page 50 and 51:
Chapter 1 35solubilized in hot etha
Page 52 and 53:
Chapter 2 37RsORmRmRsRLRL RRRLH - A
Page 54 and 55:
Chapter 2 39The stereochemistry and
Page 56 and 57:
Chapter 2 41An asymmetric reducing
Page 58 and 59:
Chapter 2 43This approach clearly e
Page 60 and 61:
Chapter 2 45PhaxeqP 1MP 2axeqPhP 2M
Page 62 and 63:
Chapter 2 47pyrrolidine ] 20 , LAH-
Page 64 and 65:
Chapter 2 49Enzymatic reactions are
Page 66 and 67:
Chapter 2 51As [ES] in equation 4 c
Page 68 and 69:
Chapter 2 53E+AK 1AK -1AEAK 2AE+PE+
Page 70 and 71:
Chapter 2 552.2.4 Lipases.Most lipa
Page 72 and 73:
Chapter 2 57enzyme intermediate can
Page 74 and 75:
Chapter 2 59projecting above the pl
Page 76 and 77:
Chapter 2 612.3.1.1. Step 1: Adduct
Page 78 and 79:
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
Page 86 and 87:
Chapter 2 71sodium or potassium car
Page 88 and 89:
Chapter 3 73The reaction is quite s
Page 90 and 91:
Chapter 3 75literature as the best
Page 92 and 93:
Chapter 3 77dry solvents and, is ch
Page 94 and 95:
Chapter 3 79XXOH+ H 2 NDry K 2 CO 3
Page 96 and 97:
Chapter 3 81substituents are the mo
Page 98 and 99:
Chapter 3 83induces a rotation of t
Page 100 and 101:
Chapter 3 85very sharp and it was p
Page 102 and 103:
Chapter 3 87Raney NickelOH Br MeOH;
Page 104 and 105:
Chapter 4 8933a-m were hydrolysed t
Page 106 and 107:
Chapter 4 91benzo[b]furane (entries
Page 108 and 109:
Chapter 4 93hydroxy or amine groups
Page 110 and 111:
Chapter 4 95the products with ethyl
Page 112 and 113:
Chapter 4 97NCO 2 HNCO 2 H(±)34c(-
Page 114 and 115:
Chapter 4 99NNH37CO2EtOH(±)-27a(+)
Page 116 and 117:
Chapter 4 101As already outlined ab
Page 118 and 119:
Chapter 4 103(+)-(S)-2-octylimidazo
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Chapter 4 105CNNH N2 NCN nC 6 H 13N
Page 122 and 123:
Chapter 4 107key step is the conver
Page 124 and 125:
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
Page 134 and 135:
Chapter 5 119Entry R T °C Product
Page 136 and 137:
Chapter 5 1212:1:3 in weight. All t
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Chapter 5 123reaction conditions we
Page 140 and 141:
Chapter 5 125Entry Substrate R Time
Page 142 and 143:
Chapter 5 127experiments. But it wa
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Chapter 5 129OClOSAM IIPH=7; R.T.OH
Page 146 and 147:
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
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Chapter 6 137This discovery allowed
Page 154 and 155:
Chapter 6 139OH(±)-62OHFigure 6.1
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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
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Chapter 6 147RR[P(Ph) 3 ]Pd°OHOPh
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Chapter 6 149H2-IodophenolOHOH(±)-
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Chapter 6 151presence of base as de
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Chapter 7 153A chiral lithium alumi
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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
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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 200 and 201: Chapter 8 185[α] 20 D -5.7 (c 1.75
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 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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