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

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Chapter 3 79XXOH+ H 2 NDry K 2 CO 3NDry CH 3 CNX = Cl, Br. reflux (-)-24OHScheme 3.9: Synthesis of (R)-(-)-2-(2-isoindolinyl)butan-1-ol (-)-24.Both substrates were used in small scale syntheses (one gram) but 1,2-dichloroxylene was chosen also for the scale up (150 grams) because it ismore safe in comparison with 1,2-dibromoxylene which has very irritatingproperties. The synthesis of (R)-(-)-2-(2-iso indolinyl) butan-1-ol (-)-24 wasperformed at different temperatures and in different solvents such asacetone and acetonitrile. Reactions in acetone were always incomplete evenunder reflux for more than 24 hours. Acetonitrile was found to be thesuperior solvent for the reaction but only under refluxing conditions. In factall experiments carried out at lower temperatures led to mixtures ofproducts, mainly the N-monoalkylated-2-amino-1-butanol (uncyclizedproduct) in mixture with the desired product (-)-24. Generally high dilutionconditions were required in order to favour the intramolecular cyclizationinstead of intermolecular alkylation. Dry potassium carbonate was used asbase in all cases. Purification was achieved via repeated high vacuumdistillation of the crude solid reaction product.3.4.2 Asymmetric reduction of prochiral benzophenones 25 a-dby a complex between (R)-(-)-2-(2-isoindolinyl)-butan-1-ol(-)-24 and LiAlH 4 .The first experiment was performed with 2-bromobenzophenone 25b(scheme 3.10). This substrate was described by Brown in its papers 25,26and was shown to be the best substrate for this kind of asymmetricreduction. The experiment was done in order to validate the reproducibilityof the method.The reaction was carried out under the reported experimentalconditions: a diethyl ether solution of LAH was added to a solution of 2.5equivalents of (R)-(-)-2-(2-isoindolinyl)-butan-1-ol (-)-24 in dry diethyl
Chapter 3 80ether at 0°C, under an inert atmosphere in order to form a complex with thegross formula of LiAl(OR*) 2,5 H 1,5 ; After 45 min. the reaction mixture wascooled to -15°C and a solution of 2-bromobenzophenone 25b in drydiethyl ether was added dropwise. The asymmetric reduction led to theortho-(+)-Bromobenzhydrole (+)-27b (scheme 3.10). After quenching andwork up the optically rotation was compared with the value reported in theliterature and an identical rotation was found ([α] D = +46.6; c=1.3 inacetone), corresponding to an enantiomeric excess of higher than 95 %e.e.(table 3.4.). The reaction was then repeated with the prochiralbenzophenones 25a-d (scheme 3.10).RLiAlH 4RXO25a X=H R=Ph25b X=Br R=H25c X=Br R=Ph25d X=F R=PhN(-)24Dry etherOHXOH(±) 27a X=H R=Ph(+) 27b X=Br R=H(+) 27c X=Br R=Ph(+) 27d X=F R=HScheme 3.10: Synthesis of chiral benzhydroles (+)-27b-d and racemic (±)-27aSome modifications of the original procedure were introduced.Especially regarding the reaction work up a procedure was chosen whichallowed the recyclisation of the chiral auxiliary and the improved recoveryof the pure product. The optimal molar ratio of 2.5 equivalents of (R)-(-)-2-(2-isoindolinyl)-butan-1-ol (-)-24 for one mole of LAH which correspondsto the gross formula LiAl(OR*) 2,5 H 1,5 was not changed. It was assumed tobe the optimal condition also for the prochiral benzophenones 25a-d. Thechiral reducing complex reagent led to very good enantiomeric excessesonly with ortho substituted benzophenones, while meta substitutedbenzophenones gave markedly lower enantiomeric excesses.The reason for this remains unclear. Obviously an o-substituent onthe phenyl ring must be present in order to achieve good enantioselection.Speculations can be based on the results reported by Brown. Due to thechemical nature of the substituents it seems reasonable to exclude thatelectronic effects are involved in the recognition process between thechiral LAH complex and the ketone. Probably the steric effects of the
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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
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
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 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
Page 132 and 133: 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
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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
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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
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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
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Chapter 8 169room temperature for t
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Chapter 8 171in CH 2 Cl 2 and washe
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Chapter 8 1738.26 Screening of lipa
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Chapter 8 175Na 2 SO 4 . After remo
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Chapter 8 177NMR and MS analysis we
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Chapter 8 179Argon was bubbled thru
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Chapter 8 181IR (CHCl 3 ): ν cm-1=
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Chapter 8 183GC-MS: 305 M + (68%),
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Chapter 8 185[α] 20 D -5.7 (c 1.75
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Chapter 8 187Synthetic method 7.7.1
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Chapter 8 189(R,S)-(±)-1-(2-Octyl)
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Chapter 8 191M.P. = oil.Elementary
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Chapter 8 193Synthetic method 7.11.
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Chapter 8 195(±)-N-1-(2-Octyl)-2-t
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Chapter 8 197IR (CHCl 3 ) ν cm-1 =
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Chapter 8 199(±)-1-(4-Fluorophenyl
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Chapter 8 201Physical and spectral
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Chapter 8 203(±)-1-(Phenyl)-2-prop
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Chapter 8 205128.61, 128.87, 130.39
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Chapter 8 207min.Physical and spect
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Chapter 8 20913C J MOD NMR (CDCl 3
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Chapter 8 211(±)-2'-Methylphenyl-2
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Chapter 9 213References chapter 1:1
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Chapter 9 21531) De Felice, R.; Joh
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Chapter 9 21768) Brodie, A.M.H. in
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Chapter 9 219112) Brodie, A. M. H.;
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Chapter 9 2214) Karabatsos, M.C. J.
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Chapter 9 22334c) Blow D. Nature 19
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Chapter 9 22567a) Kundu, N.G.; Pal,
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Chapter 9 22712) Thompson,A.S.; Hum
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