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

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Chapter 1 11piperazine) is also the most extensively documented antifungalimidazole 25,26 .ClOOR'RCl4 a-d4a R= ImidazoleR'=O N N OAc4b R= 1,2,4 Triazole R'= O N N4c R= Imidazole R'= S NH 24d R= BrR'= O OFigure 1.9: Structures of Ketoconazole 4a and its analogues 4b-c, and together with the keyintermediate for the enantioselective synthesis 4d.Ketoconazole 4a has been shown to have in vitro activity against abroad spectrum of fungi including the three genera of dermatophytes,yeasts, dymorphic fungi and a variety of others. In vivo studies withseveral animal species demonstrated a broad spectrum of activities againstsuperficial as well as systemic fungal infections.The United States Food and Drug Administration approved 4a in1981 for the treatment of candidias, chronic mucocutaneous candidias,oral candidias, candiduria, coccidiomycosis, histoplasmosis, chromomycosisand paracoccidiomycosis 27-29 . One of the salient characteristics of
Chapter 1 12Ketoconazole 4a is that it was the first orally active antifungal agent of theimidazole class after clotrimazole.Ketonazole 4a, as compared with amphotericin B and miconazole, iswell tolerated although certain problems in its use in therapy are reported inthe literature (nausea, vomiting or anorexia, abdominal complaints) 30 .Gynecomastia has been reported to occur in 3-8% of patients receivingketoconazole and this may result in a direct effect of the drug on the breasttissue 31. Another adverse reaction associated with ketoconazole is hepatictoxicity. 4a has also been shown to have a similar inhibitory effect on theenzyme responsible for the conversion of lanosterol to cholesterol inmammals and has been demonstrated to lower cholesterol levels inhumans 32,33 . In addition, it inhibits a number of other cytochrome P450enzymes involved in steroidal biosynthesis and drug metabolism. It has alsobeen shown to block adrenal steroidogenesis by inhibition of the corticoid11-β−hydroxylase 34 . For these properties it has been utilized to treatprostate cancer and Cushing's syndrome 35 .Ketoconazole 4a is marketed as racemic mixture of the cis-(2S,4R)and (2R,4S) enantiomers as illustrated in figure 1.9.It is one of the few antifungal agents which has also been synthesizedin enantiopure form. Starting from optically pure (R)- and (S)-solketaltosylate 4e (figure 1.10), by transketalization with apropiate ketones, bothenantiomers of 4a and also the corresponding trans derivatives wereprepared 36 .The same chiral building block has been used to synthesize selectiveinhibitors of the mammalian 14-α-demethylase in order to reduce thecholesterol levels in the humans 37 .The latest stereoselective synthesis of both enantiomers ofKetoconazole 4a has been reported in 1995. Starting from commerciallyavailable (R)- or (S)-epichlorohydrine 38 4f (Fig. 1.10), (+)-or (-)-4aKetoconazole was obtained in nine steps 38 .OOOTsOCl(S)-4e(S)-4fFigure 1.10: (S)-solketal tosylate 4e and (S)-epichlorohydrine 4f.
Page 1 and 2: Advances in the stereoselectivesynt
Page 3: ACKNOWLEDGMENT:I would like to than
Page 6 and 7: Summary:Numerous drugs are chiral,
Page 8 and 9: IndexII2.2 Synthesis of enantiopure
Page 10 and 11: IndexIV4.4. Stereochemical Assignme
Page 12 and 13: IndexVImethyl amine 69 1446.6. Stud
Page 14 and 15: IndexVIII8.23.3.1 Desilylation usin
Page 16 and 17: Chapter 1 11.Introduction1.1. Chira
Page 18 and 19: 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 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
Page 36 and 37: 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
Page 42 and 43: 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
Page 80 and 81:
Chapter 2 65There are various effec
Page 82 and 83:
Chapter 2 67The reactions were foun
Page 84 and 85:
Chapter 2 69Yamanaka and coworkers
Page 86 and 87:
Chapter 2 71sodium or potassium car
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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
Page 120 and 121:
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
Page 126 and 127:
Chapter 4 111which was eliminated e
Page 128 and 129:
Chapter 4 113separate (±)-57a and
Page 130 and 131:
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
Page 138 and 139:
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
Page 144 and 145:
Chapter 5 129OClOSAM IIPH=7; R.T.OH
Page 146 and 147:
Chapter 5 131OHOXHOHRHK 2 CO 3 ; Me
Page 148 and 149:
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 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 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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