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

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Chapter 5 125Entry Substrate R Time h C% Product Yield e.e. E1 (±)-60a H 4.5 47.3 (-)-(S)-60a 45.2 87.0 1002 H (-)-(R)-58a 30.5 97.03 (±)-60b 4Me 144 60.7 (-)-(S)-60b 57.3 99.5 354 4Me (-)-(R)-58b 33.8 64.85 (±)-60e 4C 52 67.8 (-)-(S)-60e 60.1 86.6 6N6 4CN(-)-(R)-58e 31.0 41.2Table 5.8: Enzymatic hydrolyses of arylpropargylic acetates (±)-60a,b,e.As reported in table 5.8, SAMII worked perfectly with the acetate(±)-60a which does not contain any substituent on the aromatic moiety,the corresponding E value was >100. For the two others esters having apara- substituent (Me for (±)-60b and CN for (±)-60e) the selectivitywas much lower ((±)-60b E=35, and (±)-60e E=6). In theseexperiments (2 mmoles of esters and 10% in weight of lipase Sam II) thesolubility of the substrates became a problem. (±)-60e was insoluble inthe phosphate buffer and appeared as a solid suspension in the reactionmixture. The inhomogeneity of the reaction mixture led tounreproducible results for the three sets of experiments. It is well knownthat the optimal reaction conditions for lipase catalysed reactions arethose in which the substrates are oil emulsions in buffer since the reactionoccurs at the interface between the two phases. For this reason it was triedto keep (±)-60e as an oil in the reaction mixture, however already afterfew minutes under stirring in the buffer it became solid. Theinhomogeneity of the reaction mixture could be one reason for the lowselectivity of the lipase during the hydrolysis. Therefore, the use of acosolvent was considered as a possible solution for this problem (Scheme5.10).OAcH OAcHO HSAM II, cosolventR PH=7; R.T.+R RH H H(±)-60a,b,e (-)-(S)-60a,b,e (-)-(R)-58a,b,eScheme 5.10: Effect of solvent on the enzymatic hydrolyses of (±)-60a,b,e.
Chapter 5 126Three different solvents were considered: MTBE, THF and acetone.THF was found to be the worst solvent; it was impossible to follow thereaction by GC. Solvents were used in different concentrations asreported in table 5.9. For clarity and direct comparison the resultsobtained without cosolvent are incorporated in the same table.Entry Substrate R Cosolvent Product C% Time h e.e E1 (±)-60b 4Me - (S)-60b 60.7 144 >99.5 352 4Me - (R)-58b 64.83 (±)-60b 4Me MTBE 10% (S)-60b 38.1 47 47.3 124 4Me (R)-58b 77.05 (±)-60b 4Me MTBE 25% (S)-60b 41.2 40 38.4 56 4Me (R)-58b 54.77 (±)-60b 4Me Acetone5% (S)-60b 48.2 76 79.5 318 4Me (R)-58b 85.49 (±)-60e 4CN - (S)-60e 61.8 52 86.6 610 4CN (R)-58e 41.211 (±)-60e 4CN MTBE 10% (S)-60e 67.7 36 86.6 612 4CN (R)-58e 41.213 (±)-60e 4CN MTBE 30% (S)-60e 66.0 36 86.8 714 4CN (R)-58e 44.7Table 5.9: Effect of cosolvent in the enzymatic hydrolyses of (±)-60e.All obtained results were really unsatisfactory. The addition ofMTBE as a cosolvent dramatically decreased the enantioselectivity of theenzymatic process for (±)-60b. 10% of MTBE gave E = 12 and 25% ofMTBE gave E value = 5 (entries 3-5; table 5.9). Acetone (entry 7; table5.9) was found to be a much better cosolvent because it did not decreasethe enantioselectivity of the process as compared with the experimentusing no cosolvent (entry1; table5.9).Its presence did in no way improve the process. The addition ofMTBE with 10% and 30% to the reaction mixture containing (±)-60e(entries 11,13; table5.9) did not lead to any change of the selectivity ascompared with the experiment without cosolvent (entry 9; table 5.9). Itled to a homogeneous trend of the reaction and the enzymatic process wasmuch more continuous. The hypothesis that the solid state of (±)-60b,ewas responsible for the low selectivity was not supported by these
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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
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 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 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
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
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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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