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

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Chapter 4 93hydroxy or amine groups, that would allow the synthesis of Mosher ormandelate esters, amides or generally diasteroisomers which are easilyanalyzed by HPLC, GC or 1 H-NMR. All attempts using chiral HPLC wereunsuccessful.The only method that gave reasonable results was the analysis by 1 H-NMR in presence of the chiral shift reagent 2 Eu(hfc) 3 { europium(III) tris[3-((heptafluoropropyl)hydroxymethylene)-(+) champhorato}.Figure 4.1.: 1 H-NMR spectrum of (±)-33d (above) and (+)-(S)-33d (below) in presence ofchiral shift reagent.A CDCl 3 solution of Eu(hfc) 3 of known concentration was preparedand added to the NMR tube containing the sample in CDCl 3 solution.Various amounts of shift regent were added until the splitting of the desiredsignals were observed. The best results were obtained with a molar ratio ofthe sample and the chiral shift reagent of 1:1.2 to 1.6.
Chapter 4 94The first measurements were carried out with the racemic product inorder to obtain a reference spectrum. The experiment was then repeatedwith the chiral product. Two points are of importance to note with thismethod. First, the sample purity must be high in order to avoid the presenceof signals that could be coincident with those of the sample. Second, thesignal to be integrated must be completely resolved and as sharp aspossible, in order to allow a perfect integration. It would be best to havemore than one signal for integration and take an average of all values.The measurements were performed for all racemic and chiral productsreported in table 4.1. In some cases it was not possible to detect any signalresulting from the minor enantiomer, in these cases the enantiomeric excesswas assigned to be 98% e.e. In figure 4.1 the 1 H NMR spectra (300 MHz)of (±)-33d and (+)-(S)-33d in presence of the chiral shift reagent Eu(hfc) 3are shown the selected signals corresponding to the proton of theimidazole (10.28 and 10.70 ppm), the aromatic groups (7.40-7.55 and 7.65-7.80 ppm), chloroform (7.23 ppm), methylen (3.75-3.95 and 4.0-4.15 ppm)and methyl moieties (2.25-2.35 ppm) respectively; the spectrum above isracemic (±)33d and the one below from the enantiopure (ee 98%) (+)-(S)-33d. The Imidazole proton betweeen 10 and 11 ppm were used for theintegration.4.2. Hydrolysis and Decarboxylation of N-Alkyl-4,5-dicyanoimidazoles 33c-g.As reported in scheme 4.2. of the synthetic pathway the alkylation ofthe 4,5-dicyanoimidazole via Mitsunobu reaction is followed by twoadditional synthetic steps: hydrolysis and decarboxylation. The cyanogroup is transformed into a carboxylic acid by hydrolysis with 10N NaOHin ethanol under reflux. These harsh conditions were needed for completeconversion. Less concentrated NaOH solution resulted in only partialhydrolysis to the corresponding amide.The N-Alkyl-4,5-dicyanoimidazoles 33c-g were treated with 10NNaOH in ethanol under reflux for 16-24 h. After acidification with 3NHCl the N-Alkyl-4,5-imidazoledicarboxylic acids 34a-e precipitated out,(entries 1-4,7-8 Table 4.3) and were recovered by filtration. Only for theisolation of (±)-33e and (-)-(S)-33e (entries 5,6 Table 4.3) extraction of
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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
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 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 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
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
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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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