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

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Chapter 9 219112) Brodie, A. M. H.; Hendrickson, J. R.; Tsai-Morris, C. H.; Garret,W. M.; Marcotte, P.A. and Robinson, C. H. Steroids 1981, 38,693-702.113) Sjoerdsma, A. Clin. Pharmac. Ther. 1981, 30, 3-22.114) Brueggemeier, R. W.; Li, P. K.; Snider, C. E.; Darby, M. V. andKatlic, N. E. Steroids 1987, 50, 163-178.115) Brueggemeier, R. W.; Li, P. K.; Chen, H. H.; Moh, P. P. andKatlic, N. E. J. Steroid Biochem. 1990, 37, 379-385.116) Metcalf, B.W.; Wright,C. L.; Burkhart, J. P.; Johonston, J. O. J.Am. Chem. Soc. 1981,103, 3221-3222117) Zaccheo, T.; Giudici, D.; Ornati, G.; Panzeri, A. and Di Salle, E.Eur. J. Cancer 1991, 27, 1145-1150.118) Giudici, D.; Ornati, G.; Briatico, G.; Buzzetti, F.; Lombardi, P.and Salle, E. D. J. Steroid Biochem. 1988, 30, 391-394.119) Drugs of the future 1993,18, 510-512120) Lonning,P. E.; Kuinnsland, S. Drugs 1988, 35, 684.121) Santen, R.J. and Misbin, R. Pharmacotherapy 1981, 1, 95-120.122) Santen, R.J.; Worgul, T.J. and Lipton, A. Ann. Intern. Med. 1982,96, 94-101.123) Cash, R.; Brough, A.J.; Cohen, M.N.P. and Satoh, P.S. J.Clin.Endocrinol. Metab. 1967, 27, 1239-1248.124) Graves, P.E.; Salhanick, H.A. Endocrinology 1979, 105, 52.125) Chakraborty, J.; Hopkins, R.;Parke, D. V. Biochem. J. 1972, 130,19.126) Camacho, A. M.; Cash, R.; Brough, A. J.; Wilory, R. J. J. Am.Med. Assoc. 1967, 202, 20.127) Foster, A. B.; Jarman, M.; Leung, C.S.; Rowlands, M.G.; Taylor,G. N.; Plevey, R. G.; Sampson, P. J. J. Med.Chem. 1985,28, 200.128) Foster, A. B.; Jarman, M.; Taylor, G. N.; Leung, C.S. U.K. Patent2151226A, 1985.129) Hartmann, R.W.; Batzl, C.; Pongratz, T.; Mannscheck, A. J. Med.Chem. 1992, 35, 2210.130) Stanek, J.; Alder, A.; Bellus, D.; Bhatnagar, A.S.; Haeusler, A.;Schieweck, K. J. Med. Chem. 1991, 34, 1329.131) Harvey,H. A.; Santen, R. J.; Deners,D.; Gaber, J.E.; Henderson, I.C.; Navari, R. M.; Miller, A.A.; Mulagha, M.; Hanagan, J. In
Chapter 9 220Clinical use of Aromatase Inhibitors: Current Data and FuturePerspectives. Ed. Edimes, Pavia, 1992.132) Bhatnagar, A. S.; Schieweck, K.; Hoeusler, A.; Browne, L. J.;Steele, R.E. Proc. R. Soc. Edinburgh 1989, 95B, 293.133) Browne,E., L.J.; Gude, C.; Rodriguez, H.; Steele, R.E. J. Med.Chem. 1994, 74, 725-729.134) Furet, P.; Batzl, C.; Bhatnagar, A.; Francotte, E.; Rihs, E.; Long,M. J. Med. Chem. 1993, 36, 1393-1400.135) Bowmann, R. M.; Steele, R. E.; Browne, L. J. U.S. Patent 4-9377250, 1990.136) See Ref. 21-27 Cancer Research 1993,4563-4566.137) See Ref. 21, 28 Cancer Research 1993,4563-4566.138) Van der Wall, E.; Danker, T.H.; de Frakrijker, E.; Notrtier, H W.R.; Thijssen, J. H. H.; Blankenstein, M. A. Cancer Research 1993,53, 4563-4565.139) PCT WO 94/11364 Janssen Pharmaceuticals 26 May 1995.140) Whomsley, R.; Fernandez, E.; Nicholls, P. J.; Smith, H.J.;Lombardi, P.; Pestellini, V. J. Steroid Biochem. Molec Biol.1993,44,675-676.141a) Lombardi, P.; Pestellini,V.; Personal communication.141b) Pepper, C.; Smith, H.J.;Barrell, K.J.; Hewlins, M.J.E. Chirality1994,6,400142) Furet, P.; Batzl,C.; Bhatnagar, A.; Francotte, E.; Rihs, G.; Lang,M. J. Med. Chem. 1993, 36, 1393-1400.143) Chang, S.; Koh, H.J.; Lee, B.S.; Lee, I. J. Org. Chem. 1995, 60,7760-7768.144) Brown, E., Penfornis, A.; Bayma, J.; Touet, J. Tetrahedron:Asymmetry. 1991, 2, 339-342.145) Brown, E., Leze, A.; Touet, J. Tetrahedron: Asymmetry.1992, 2, 841-844.2.5. References Chapter 21) Cram,D. J.; Abd Elhafez, F. A. J. Am. Chem. Soc. 1952, 74,5828.2) Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. Soc.1959,112.3) Cram,D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81,2748.
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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
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
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Chapter 1 19HOHODesmolaseHOCholeste
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Chapter 1 21formic acid results in
Page 38 and 39:
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
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
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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+
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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
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
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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
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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
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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
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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
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Chapter 6 143HOH58-a-c,e,h-lRPdCl 2
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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
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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
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Chapter 8 1638.9 Decarboxylation of
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Chapter 8 165Alcohol 27a (0.2 mmol)
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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 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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