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

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Chapter 5 115to avoid this side reaction trimethyl silyl acetylene (TMSA) was used togenerate the stable nucleophile lithium trimethyl silyl acetylide. For thisTMSA in dry THF was cooled to -75°C and n-butyllithium was addeddropwise, leading to lithium trimethyl silyl acetylide. The reactionmixture was then cannulated dropwise into a solution of the aryl aldehydein dry THF at -78°C to form the desired 1-aryl-2-propyn-3-trimethylsilyl-1-ols (±)-59a-g (Scheme 5.2).RH1)H SiMe 3nBuLidry THF -78 0 CRSiMe 3O2) dry THF -78/0 0 COH(±)-59 a-gScheme 5.2: Synthesis of 1-aryl-2-propyn-3-trimethylsilyl -1-ols (±)-59a-g.These reactions gave very good chemical yields with seven arylaldehydes as reported in table 5.1.Entry R aldehyde T °C Product Yield %1 H -15 (±)-59a 98.52 4Me -78 / 0 (±)-59b 97.03 4F -78 / 0 (±)-59c 98.04 4Cl -78 / -15 (±)-59d 96.05 4CN -78 (±)-59e 87.06 4NO2 -78 (±)-59f 49.07 3,4 OMe -15 (±)-59g 96.0Table 5.1: Reaction conditions and chemical yields for the synthesis of (±)-59a-f.It is interesting that for the first four compounds (±)-59a-e (entries1-4) the reactions were so clean that purifications were unnecessary. Forcompounds (±)-59e-f, (entries 5,6), it was necessary to keep thetemperature very low (-78°C). Raising the temperature to -15°C causedcomplete degradation of both the starting material and the product. It wasimpossible to recover the materials. Under these conditions, the cyanogroup does not react with the lithium reagent. This procedure led to thedesired ethynyl carbinoles in very good yield with the exception of the
Chapter 5 116product resulting from 4-nitrobenzol aldehyde which led to (±)-59f inonly 49 % yield.5.1.1.Desilylation of Aryl trimethylsilyl propargylic alcohols 59a-d.1-Aryl-2-propyn-3-trimethylsilyl-1-ols (±)-59a-d constitute formallyprotected acetylenes. Various desilylation methods were tried inorder to obtain the acetylenic products (±)-58a-g. No reaction occurredwhen (±)-59a was treated with 1 N HCl in THF at differenttemperatures. Better results were obtained when the alcohols (±)-59a-gwere treated with KF in DMF (scheme 5.3). The results are reported intable 5.2.RSiMe 3KF, DMFRHOH(±)-59a-g25-60°COH(±)-58a-gScheme 5.3: desilylation of (±)-59a-g by KF in DMF.Entry R T °C Product Yield %1 4H 60 (±) - 58a 87.12 4Me 60 (±) - 58b 47.53 4F 60 (±) - 58c 96.94 4Cl 60 (±) - 58d 93.25 4CN RT-60 (±) - 58e 06 4NO2 RT-60 (±) - 58f 07 3,4 OMe RT-60 (±) - 58g 0Table 5.2: Reaction conditions and chemical yields for the desilylation of (±)-59a-g usingKF in DMF.The reaction worked, however, well only for three substrates: (±)-59a,c,d (entries 1,3,4), compounds with an unsubstituted aryl moiety orwith one halogen in the para position.The presence of a methyl group onthe aromatic moiety (±)-59b decreased the yield to 47.5% (entry 2).
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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
Page 80 and 81: Chapter 2 65There are various effec
Page 82 and 83: 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 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 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
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Chapter 8 165Alcohol 27a (0.2 mmol)
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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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