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

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Chapter 2 57enzyme intermediate can be transferred also to other nucleophiles such asR''OH leading to new esters RCO 2 R''. The success of such acyl transferreactions largely depends on the nucleophilicity of the acceptor alcoholR''OH. Upon inspection of reaction d (figure 2.10) it is evident that thedesired transfer can be achieved only if the initially eliminated alcohol R'OHis less nucleophilic than R''OH.This enzymatic process, however is reversible and often requires longreaction times and a large excess of ester as acyl doner to form the acylenzymein order to achieve a reasonable degree of conversion 38ac .The application of vinyl or isopropenyl esters as acylating agents forlipase catalyzed esterifications 39ac offers an effective solution of thisproblem because the end side product of the esterification is immediatelyconverted irreversibly into acetaldehyde or acetone, respectively. (scheme2.11):ROH+OAcLipaseROO+OHScheme 2.11: Esterification of alcohol by lipase with vinyl acetateThe only nucleophile present in solution is the alcohol that will beesterified.The enantioselectivity E of lipase catalyzed reactions in aqueoussolution, water organic solvent mixtures, and anhydrous organic solventfollows the classical competitive equation 14 30,39 .2.2.4.1 Active site model for interpreting and predicting thespecificity of lipases.The previous absence of a complete set for X Ray data of lipases hasled to the development of simple models for interpreting and predicting thespecifity of enzymatic kinetic resolutions. On the basis of substituent sizesat the stereocenter, rules, allowing a prediction which enantiomer of asecondary alcohol is favoured in a kinetic enzymatic resolution have beendeveloped by analysis of the data reported in the literature and wereconfirmed by subsequent experiments. This strategy has been applied to
Chapter 2 58three different enzymes 40 (cholesterol esterase CE, Pseudomonas cepaciaPCL, Candida rugosa CRL).A more detailed model has been developed for Pig Liver Esterase(PLE) based on cubic space descriptors that form the active site 41 . For thismodel, approximately 100 methyl esters with representative structures wereidentified and the results of their PLE catalyzed hydrolyses on a preparativescale were analyzed collectively. This has led to a model consisting of fivebinding loci, where the serine region is considered as a sphere with adiameter of 1 Å. The binding regions controlling specificity are representedby two hydrophobic and two more polar pockets. The two hydrophobicsites, which interact with the aliphatic or aromatic hydrocarbon portions ofsubstrate, have a volume of approximately 33 Å 3 , and 5,5 Å 3 respectively.Polar groups, such as hydroxy, amino, carbonyl, nitro funtions etc, areexcluded from this area. The hydrophobic pockets can, however,accommodate less polar groups such as ether or ketal groups, if necessary.The remaining two sites accept groups that are more polar orhydrophilic. They are located at the front and back of the active site.A model accounting for enantioselective esterifications 42 catalyzed byPseudomonas species has been also developed. Also in this case, from theliterature data, a working hypothesis has been developed assuming that thealcohol is resolved most efficiently if it has one small and one relativelylarge group, the latter slightly removed from the asymmetric center (Fig.2.11) carrying the hydroxy group.SmallHOHLargeFigure 2.11:Simple model for predicting the resolution of secondary alcohols via acylationThis study has led to the development of a model for the lipasePseudomonas AK which seems to be effective for the resolution ofmolecules with near planar structure. It is not suitable for the resolution ofsubstrates carrying relatively bulky moieties close to the hydroxymethinecenter, or which are unable to adopt low energy planar conformationsaround the hydroxy group. The active site is envisaged as a near planarpocket with a hydrophilic canopy for the alcohol functionality
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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
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
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 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 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
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Chapter 4 107key step is the conver
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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
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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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