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

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Chapter 5 131OHOXHOHRHK 2 CO 3 ; MeOH0°CRHX=H, (-)-( S)-60a,b,eX=Cl, (-)-( S)-61b,c,e,h-l(+)-(S)-58a-c,e,h-lScheme 5.14: Hydrolysis of enantiomeric acetates or chloroacetates (-)-(S)-60 and (-)-(S)-61The reaction proceeds smoothly in almost quantitative yield andwithout racemization of the chiral centre; the enantiomeric excess of theproducts is identical with that of the starting materials. Purity andenantiomeric excess were determined by chiral GC. In table 5.13. theresults of the reaction are summarized.Entry Substrate X R Product e.e % Yield1 (-)-(S)-60a H H (+)-(S)-58a 87.0 94.12 (-)-(S)-60b H 4Me (+)-(S)-58b 65.0 93.53 (-)-(S)-61b Cl 4Me (+)-(S)-58b 97.7 98.94 (-)-(S)-61c Cl 4F (+)-(S)-58c 98.8 98.95 (-)-(S)-61e Cl 4CN (+)-(S)-58e 95.9 97.96 (-)-(S)-60e H 4CN (+)-(S)-58e 86.6 95.87 (-)-(S)-61h Cl 3Me (+)-(S)-58h 99.2 99.68 (-)-(S)-61i Cl 3F (+)-(S)-58i 98.8 98.79 (-)-(S)-61l Cl 2Me (+)-(S)-58l 94.0 98.5Table 5.13: Hydrolyses of acetates (-)-(S)-60 and chloroacetates (-)-(S)-61.The low enantiomeric excess for some compounds (entries 1,2,6) wasdue to the low enantiomeric excess of the starting material.
Chapter 6 1326 Synthesis of Aryl-2-Benzo[b]Furanyl and Aryl-2-Indonyl Carbinols 27 and 64-a-g of HighEnantiomeric Purity via Palladium-CatalyzedHeteroannulation of Racemic and Enantiopure 1-Aryl-1-Propargylic Alcohols 58.The synthetic methods reported in chapter 2.4 were applied to synthesizethe Aryl-2-Benzo[b]Furanyl and Aryl-2-Indonyl carbinols 27 and 64-a-gin racemic and enantiopure forms. The synthetic procedures alreadyknown in literature were modified, or in some cases completely changedfrom the original protocol in order to obtain products in high chemicalyield. This work, to the best of our knowledge, is the first application ofpalladium catalysed heteroannulation of enantiopure 1-Aryl-2-Propyl-1-olalcohols 58 to obtain enantiopure aryl-2-benzo[b]furanyl 27 and aryl-2-indolinyl carbinols 64-a-g.6.1 Application of Castro's procedure for the cyclization ofracemic or enantiopure 1-phenyl-2-propyn-1-ol 58a with2-iodophenol.Castro's procedure uses a preformed copper (I) acetylide asalkylating reagent of 2-iodophenol. The synthesis of this reagent isperformed using CuSO4.5H2O and NH4OH in a mixture of ethanol, THFand water in presence of the acetylenic compound. This experimentalprocedure failed when applied to 1-phenyl-2-propyn-1-ol (±)-58a: it wasimpossible to isolate the product from the reaction mixture bycrystallization because of its high solubility in the reaction mixture. Inorder to decrease the solubility of the Copper (I) acetylide of 1-phenyl-2-propyn-1-ol (±)-58a 1-phenyl-2-propyn-1-acetate (±)-60a was usedunder identical reaction conditions as described above. Unfortunately, alsoin this case it was impossible to recover the product by crystallization(Scheme 6.1). For these reasons Castro's procedure was not furtherapplied and it was necessary to use the modified procedure of Owen 1 .
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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
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Chapter 2 69Yamanaka and coworkers
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Chapter 2 71sodium or potassium car
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Chapter 3 73The reaction is quite s
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Chapter 3 75literature as the best
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Chapter 3 77dry solvents and, is ch
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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 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 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
Page 184 and 185: Chapter 8 169room temperature for t
Page 186 and 187: Chapter 8 171in CH 2 Cl 2 and washe
Page 188 and 189: Chapter 8 1738.26 Screening of lipa
Page 190 and 191: Chapter 8 175Na 2 SO 4 . After remo
Page 192 and 193: Chapter 8 177NMR and MS analysis we
Page 194 and 195: 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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