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

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Chapter 6 1356.2.1 Heteroannullation of Phenyl-2-propyn-1-ol (±)-58a:variation of bases.Four different bases were tested in order to improve the chemicalyield of the product . Only one arylpropynol was used in the study,racemic 1-aryl-2-propyn-1-ol (±)-58a (scheme 6.4).HOH(±)-58a2-Iodophenol, CuITEA, Ar, 80°PdCl 2 [P(Ph) 3 ] 2OOH(±)-27gScheme: 6.4: Effects of different bases on the heteroannulation process of aryl propynol(±)-58a mediated by Pd catalyst.The molar ratio between the reagents was kept as documented in theoriginal paper 2.0 : 1.0 : 0.035 : 0.13 : 2.0 corresponding toarylpropynols : iodophenole : PdCl2[P(Ph)3]2 : CuI. The results are shownin table 6.1.Entry Substrate Base n.Eq. T°C Product Yield1 (±)-58a TEA 2 80 (±)-27g 552 (±)-58a Py 2 80 (±)-27g 353 (±)-58a Py 4 80 (±)-27g 404 (±)-58a TBuA 2 80 (±)-27g 605 (±)-58a TBuA 4 80 (±)-27g 636 (±)-58a TMG 2 80 (±)-27g 837 (±)-58a TMG 3 80 (±)-27g 918 (±)-58a TMG 4 80 (±)-27g 92Table 6.1: effect of the bases and no. of equivalents in the synthesis of (±)-27g.The temperature was always mainteined at 80°C and the solvent usedwas DMF. Chemical yields were calculated based on 2-iodophenol afterpurification by flash chromatography. Pyridine (Py) was the worst base interms of chemical yield, difficulties in work up and purification (entries2,3; Table 6.1). Triethylamine (TEA) gave a low chemical yield (entry1;
Chapter 6 136Table 6.1), tributylamine (TBuA) was somewhat better (entries 4,5; Table6.1). Clearly the best base was tetramethyl guanidine (TMG) whichincreased the chemical yield by more than 35% in comparison to TEAwhich was the base used in Kundu's paper. The result was considered verysatisfactory since almost all of the 2-iodophenole was converted to thecorresponding aryl-benzo [b] furanyl carbinol (±)-27g.6.2.2 Optimization of molar ratio between Phenyl-2-propyn-1-ol (±)-58a and 2-iodophenol.Further optimization was achieved by decreasing the molar ratio of1-phenyl-2-propyn-1-ole (±)-58a and iodophenol from 2:1 to 1:1 withadditional ratios of 1.5:1 and 1.1:1. (Scheme 6.5).HOH(±)-58a2-Iodophenol, CuITMG, Ar, 80°PdCl 2 [P(Ph) 3 ] 2OOH(±)-27gScheme: 6.3: Effects of different ratios between 2-iodophenol and aryl propynol (±)-58aon the heteroannulation process mediated by Pd catalyst.Three equivalents of TMG were used in all of the experiments; Pdcatalyst and CuI were also maintained at the original ratio of 0.035 and0.13 per cent. The results are shown in table 6-2.With great surprise and enthusiasm it was discovered that excess of1-phenyl-2-propyn-1-ol (±)-58a was indeed not necessary. Almostquantitative yields were obtained with all molar ratios.Entry Substrate molar ratio Product Yield1 (±)-58a 2.0:1.0 (±)-27g 95.02 (±)-58a 1.5:1.0 (±)-27g 94.63 (±)-58a 1.1:1.0 (±)-27g 93.44 (±)-58a 1.0:1.0 (±)-27g 90.0Table 6.2: Optimization of the molar ratio between propynol (±)-58a and 2-iodophenol.
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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
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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 148 and 149: Chapter 6 133HCuSO 4 .5H 2 O,NH 4 O
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=
Page 198 and 199: 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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