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

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Chapter 6 133HCuSO 4 .5H 2 O,NH 4 OHCuOR(±)-58a R = H(±)-60a R = AcH 2 O, THF, EtOHORR = H, AcScheme 6.1: Attempts to form the copper (I) acetylide using Castro's procedure.The experimental conditions allowed the synthesis of copper (I)acetylide in presence of 2-iodophenol in situ. The reaction was carried outin dry pyridine as solvent under reflux in an Argon atmosphere, thecopper source was Cu2O, and the molar ratio between Cu2O/2-iodophenol/1-phenyl-2-propyn-1-ol (±)-58a was 0.7:1:1 (Scheme 6.2).HOH2-Iodophenol, Cu 2 OPy, reflux, argonOOH(±)-58a(±)-27gScheme 6.2: Synthesis of Aryl-2-Benzo[b]Furanyl carbinol (±)-27g using Owen'sprocedure.Aryl-2-Benzo[b]Furanyl carbinol (±)-27g was obtained only with alow chemical yield of ca. 10%. Identical reaction conditions were appliedto the enantiopure (-)-(R)-1-phenyl-2-propyn-1-ol (-)-(R)-58a. Theharsh experimental conditions and the long reaction time (18h) led topartial racemization of both the unreacted starting material and theproduct. The reaction was followed by chiral HPLC and it was clear thatthe amount of racemization was proportional to the reaction time.Futhermore, the product was much more prone to racemization than thestarting material. Both attempts demonstrated that Castro's procedure andits modification are not useful for the synthesis of enantiopure aryl-2-benzo[b]furanyl carbinoles 27.6.2 Application of Kundu's procedure to cyclize racemic (±)-58a and enantiopure 1-phenyl-2-propyn-1-ol (-)-(R)-58awith 2-iodophenol in presence of a Pd catalyst.
Chapter 6 1341-Phenyl-2-propyl-1-ol (±)-58a was one of the substrates thatKundu 2 has used in his paper. The experimental conditions were: 1-phenyl-2-propyn-1-ol (±)-58a, o-iodophenol, PdCl2[P(Ph)3]2, CuI, TEAin the ratio of 2:1:0.035:0.13:2 at 80°C for 24 h: the chemical yield ofphenylbenzo[b]furane carbinol (±)-27g was calculated to be 66% basedon 2-iodophenol (Scheme 6.3).HOH(±)58a2-Iodophenol, CuITEA, Ar, 80°PdCl 2 [P(Ph) 3 ] 2OOH(±)27gScheme 6.3: Synthesis of phenylbenzo[b]furanecarbinol (±)-27g using Kundu'sprocedure.Unfortunately, the procedure proved to be not completelyreproducible and the best result obtained in our hands was 50% chemicalyield based on 2-iodophenol corresponding to 25% yield starting from thepropargylic alcohol. The method was therefore unacceptable because ofthe low chemical yield and expecially since an excess of arylpropargylicalcohols 58 was required. These are not commercially available neitherin racemic nor enantiopure forms, and are therefore synthetically mostdemanding as described in chapter 5. Nevertheless the reaction wascarried out also with the chiral substrate (-)-(R)-58a in order to studythe stereochemical outcome. Indeed no racemization occurred when chiral1-phenyl-2-propyn-1-ole (-)-(R)-58a was used as a substrate. Thisdiscovery was considered a real breakthrough for the synthesis ofenantiopure aryl benzofurane carbinoles. Therefore, considerable timewas dedicated to the modification of the reaction conditions in order toachieve our requirements. Several parameters were changed:1) the base2) the ratio of reactants3) the temperature4) the molar percentage of the Pd catalyst and CuIIt was the strategy for the optimization of Kundu's procedure tochange only one parameter at a time and mantaining all other parametersconstant.
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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
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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 146 and 147: Chapter 5 131OHOXHOHRHK 2 CO 3 ; Me
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
Page 196 and 197: 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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