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

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Chapter 4 95the products with ethyl acetate was necessary since after acidification noprecipitation of the products occured. In all cases the chemical yields werehigh.In table 4.3 the structures and chemical yields of the products of thehydrolysis are reported.Entry Substrate R1 R2 Produc (Yield t%)1 (±)-33c Me nC 6 H 13 (±)-34a(77)2 (+)-(S)-33c Me nC 6 H 13 (+)-(S)-34a(65)3 (±)-33d Me Bn (±)-34b (79)4 (+)-(S)-33d Me Bn (+)-(S)-34b(76)5 (±)-33e Et Ph (±)-34c (73)6 (-)-(S)-33e Et Ph (-)-(S)-34c(73)7 33f Ph Ph 34d (97)8 (±)-33g Ph 4PhC 6 H 4 (±)-34e (85)Table 4.3: Hydrolysis of the N-Alkyl-4,5-dicyanoimidazoles 33c-g.At this stage the enantiomeric excess of the diacids was not measuredbecause of their low solubility in CDCl 3 (the normal solvent used with theshift reagents). Attempts with other solvents like pyridine-d 6 and DMSO-d 6were unsuccessful. After the addition of the chiral shift reagentprecipitations always occured and it was not possible to perform the 1 H-NMR experiment. Thus the synthesis was carried on to the desired finalimidazole derivatives.Some of the diacids 34a-e were used to synthesize separablediasteroisomers by reacting them with enantiopure amines or alcohols asdescribed in paragraph 4.5.4.2.1. Decarboxylation of N-Alkyl-4,5-imidazol dicarboxylic acids34a-e.Three different methods were tried for the decarboxylation of the N-Alkyl-4,5-imidazoldicarboxylic acids 34a-e. The first method involvedchinoline and copper powder at 120 °C. Almost all of the unreactedstarting material was recovered from the reaction mixture. The secondmethod used copper carbonate in DMF under reflux. This reaction did notgive any desired product, only decomposition products and starting
Chapter 4 96material. The third method was purely thermal and was carried out indiphenyl ether at reflux in an inert atmosphere. The desired product wasobtained in only 10 minutes and purification was carried out by silica gelfiltration with two different solvents: n-hexane to remove the the diphenylether and ethyl acetate to recover the product.The chemical yields were moderate to very high. For these compoundsit was again possible to calculate the enantiomeric excess using 300 MHz1H-NMR analysis in presence of the chiral shift reagent Eu(hfc) 3 {europium(III) tris[3-((heptafluoropropyl) hydroxymethylene)-(+)champhorato} for (+)-(S)-35a and europium(III) {tris(d,ddicampholylmethanate)}for (+)-(S)-35b and (±)-35c.In table 4.4 the chemical yields, the enantiomeric excess and theabsolute configurations of the obtained products are reported.Entry Substrate R 1 R 2 Product (yield %) Con. (% e.e.)1 (±)-34a Me nC 6 H 13 (±)-35a (81) -2 (+)-(S)-34a Me nC 6 H 13 (+)-35a (77) S (97)3 (±)-34b Me Bn (±)-35b (55) -4 (+)-(S)-34b Me Bn (+)-35b (53) S (98)5 (±)-34c Et Ph (±)-35c (33) -6 (-)-(S)-34c Et Ph (±)-35c (38) R,S (0)7 34d Ph Ph 35d (90) -8 (±)-34e Ph 4PhC 6 H 4 (±)-6a (98) -Table 4.4: Decarboxylation products of N-Alkyl-4,5-imidazoldicarboxylic acid 34a-e.300 MHz 1 H-NMR analysis in presence of chiral shift reagents revealedan enantiomeric excess higher than 97% e.e. for (+)-(S)-35a and (+)-(S)-35b. Therefore no racemization occurs during the final steps. Only in thehydrolysis and the decarboxylation of (-)-(S)-33e the product (±)-35c wasproduced in racemic form.In order to establish where racemization took place in the hydrolysisand decarboxylation sequence, the intermediate diacid (±)-34c and (-)-(S)-34c were methylated by an excess of diazomethane to obtain the dimethylesters (±)-36 and (-)-(S)-36 (Scheme 4.3).
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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
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 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 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
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
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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
Page 218 and 219:
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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