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

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Chapter 5 119Entry R T °C Product Yield1 4H 0 (±)-58a 992 4Me -15 (±)-58b 983 4F 0 (±)-58c 894 4CN -78 (±)-58e 905 3Me 0 (±)-58h 916 3F 0 (±)-58i 787 2Me 0 (±)-58l 988 2,4Cl 0 (±)-58m 98Table 5.4: Reaction conditions and chemical yields for the synthisis of aryl-propynols(±)-58a-c,e,h-m.The chemical yields were very high, the reaction conditions mild andall products could be purified by easy filtration over silica gel. In orderto obtain a colorless liquid it was necessary to distill the crude productsunder high vacuum. The cyano group present in 4-cyano benzaldehydeproved to be unreactive with the Grignard reagent also in presence of aslight excess.5.3 Enzymatic resolution of 2-substituted-2-propynyl-1-oles(±)-58.In the literature several methods for the enzymatic resolution ofacetylenic alcohols by hydrolysis or esterification are reported. O'Hagan 8has reported a very good study of the resolution of tertiary acetyleneacetate esters in presence of a lipase from Candida cylindracea. However,the enantiomeric excesses usually are very low. Much more efficient is theesterification of secondary acetylenic alcohols in presence of Pseudomonas(A.K.) in hexane with vinyl acetate 9 . In these cases e.e.'s higher than 95%were reported both for the alcohol and the acetate. E values are higherthan 200. Unfortunately, the paper describes only one kinetic resolutionof a secondary propynyl alcohol with an internal triple bond. Only oneexample describes a terminal triple bond and this was the worst substrate,leading to only very low enantiomeric excess. In the master thesis ofClaudia Waldinger 6 preliminary results were reported concerning theenzymatic resolution of four different terminal aryl propynoles byhydrolysis or esterification in presence of a lipase from Pseudomonas
Chapter 5 120fluorescens (SAM II). The hydrolysis of the acetates gave better resultsthan the esterification. Only in the case of 1-Phenyl-1-propyn1-ol, the Evalue was higher than 100 and a perfect resolution of the two enantiomerswas achieved. In presence of a methoxy group on the phenyl ring thestereoselectivity decreased dramatically, in fact E values of 1.05 for theortho methoxy, 5.7 for the meta - and 2.2 for the para - methoxycompoundswere found. These preliminary results opened the possibilityof obtaining aryl propynoles in enantiopure form by enzymaticresolution.5.3.1 Kinetic resolution of aryl propynoles (±)-58: screeningfor useful enzymes.Lipases are known to catalyse both the enantioselective esterificationof racemic alcohols and/or the hydrolysis of their corresponding esters. Inorder to identify the most desirable mode of transformation and the bestsuited enzyme for the aryl propynoles, a series of screening experimentswere carried out. Ten different lipases were used in these experiments.5.3.1.1 Enzymatic esterification of racemic aryl propargylicalcohols(±)-58: screening experiments.Transesterification of aryl propynoles in presence of ten lipases[from Hog Pankreas, Porcine Pankreas, Aspergillus Niger, Mucorjavanicus, Candida cylindracea, Candida lipolytica, Penicilliumroquefortii, Mucor miehei (Lipozyme), SAMI and SAMII] were carriedout under the conditions of irreversible acyl transfer. They revealed thatonly two lipases, those derived from Pseudomonas species (SAMI andSAMII) were able to catalyze these reactions, albeit with rather lowenantioselectivities and in preparatively unsatisfactory reaction times.(Scheme 5.6 and table 5.5). The substrate chosen for the screeningexperiments was (±)-58e because: (a) it contains a para-substituent on thearomatic ring and (b) it is the most important precursor for the Menariniaromatase inhibitors.Enzymatic esterifications were carried out in MTBE as solvent. Therelative ratio between substrate (±)-58e : enzyme : vinyl acetate was
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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
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Chapter 2 45PhaxeqP 1MP 2axeqPhP 2M
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Chapter 2 47pyrrolidine ] 20 , LAH-
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Chapter 2 49Enzymatic reactions are
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Chapter 2 51As [ES] in equation 4 c
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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
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
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 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
Page 160 and 161: Chapter 6 145afforded the benzo[b]f
Page 162 and 163: Chapter 6 147RR[P(Ph) 3 ]Pd°OHOPh
Page 164 and 165: Chapter 6 149H2-IodophenolOHOH(±)-
Page 166 and 167: Chapter 6 151presence of base as de
Page 168 and 169: Chapter 7 153A chiral lithium alumi
Page 170 and 171: Chapter 7 155derivatives were tried
Page 172 and 173: Chapter 7 157Finally an hypothesis
Page 174 and 175: Chapter 8 159were washed with a sat
Page 176 and 177: Chapter 8 16145 min, the mixture wa
Page 178 and 179: Chapter 8 1638.9 Decarboxylation of
Page 180 and 181: Chapter 8 165Alcohol 27a (0.2 mmol)
Page 182 and 183: 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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