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

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Chapter 3 77dry solvents and, is cheap. The general mechanism of the reduction isshown in scheme 2.7 14 :HR OH O H-BH 3O RRO - + HO H + BH 3 OR -Scheme 2.7: General mechanism of ketone reduction by NaBH4The Na+ seems not to participate in the transition state (as does Li+ inLiAlH 4 reductions 15 ) but kinetic evidences showed that an OR group of thesolvent seems to be involved in the reaction and remains attached to theboron 16 .Both classes of prochiral ketones 25a-f and 26a-e were reduced to racemicalcohols 27a-m with NaBH 4 . A 1:1 mixture of ethanol and THF was usedas solvent to achieve a perfect solubilization of the ketones at lowtemperature (scheme 3.8.):'RRNaBH 4'RRO THF/ EtOHOH25 a-f and 26 a-e 27 a-mScheme 3.8: Synthesis of racemic aryl-phenyl methanols (±)27a-f and aryl-2-benzo[b]furanmethanols (±)27g-m.High yields were obtained and no side products were detected neitherduring the reactions nor after the work up. Products, experimentalconditions and chemical yields are reported in table 3.3.(±)-27a-m were used as reference materials for the determination ofthe enantiomeric excess in the enantiomerically enriched products.Furthermore they were used as starting materials in all the new syntheticroutes in order to prove the feasibility of the strategy. Finally also for thesynthesis of separable diasteroisomers.
Chapter 3 78Product R R' T °C Yield %(±)-27a Biphenyl H 0 95(±)-27b Ph 2Br 0 94(±)-27c Biphenyl 2-Br 0 95(±)-27d Biphenyl 2-F 0 94(±)-27e Biphenyl 4-NO 2 -15-0 98(±)-27f Biphenyl 3-NO 2 -15-0 95(±)-27g 2Benzo[b]furan H 0 93(±)-27h 2Benzo[b]furan 4-CN -15-0 97(±)-27i 2Benzo[b]furan 2,4-Cl 0 93(±)-27l 2Benzo[b]furan 4-F 0 94(±)-27m 2Benzo[b]furan 4-Cl 0 95Table 3.3: Reduction of prochiral ketones 25a-f and 26a-e to racemic alcohols (±)-27a-m byNaBH 4.3.4. Asymmetric Reduction of Prochiral Ketons.The most widely used chiral agents for the reduction of prochiralketones to enantiopure alcohols were reported in chapter 2. It was alsoemphasized that the procedure 25,26 described by E. Brown should beconsidered the only promising method for our purpose, since all othermethods work only very well for ketones having two different substituentseither in size (very large-very small) or in structure (aliphatic-aromatic).3.4.1 Synthesis of (R)-(-)-2-(2-isoindolinyl) butan-1-ol (-)-24. Anoptically active ligand for the asymmetric reduction ofprochiral benzophenones.Brown and coworkers did not report the experimental procedure forthe preparation of the (R)-(-)-2-(2-iso indolinyl) butan-1-ol (-)-24. Thesynthesis was achieved by alkylation of 1,2-dichloroxylene or 1,2-dibromoxylene with R-(-) -2-aminobutan-1-ol in presence of dry K 2 CO 3 asbase (scheme 3.9).
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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
Page 42 and 43: Chapter 1 2715 is an advanced repre
Page 44 and 45: Chapter 1 29transformation of the a
Page 46 and 47: Chapter 1 31Enantioselective synthe
Page 48 and 49: Chapter 1 33+R,S DRUG ANCHOR R MOLE
Page 50 and 51: Chapter 1 35solubilized in hot etha
Page 52 and 53: Chapter 2 37RsORmRmRsRLRL RRRLH - A
Page 54 and 55: Chapter 2 39The stereochemistry and
Page 56 and 57: Chapter 2 41An asymmetric reducing
Page 58 and 59: Chapter 2 43This approach clearly e
Page 60 and 61: Chapter 2 45PhaxeqP 1MP 2axeqPhP 2M
Page 62 and 63: Chapter 2 47pyrrolidine ] 20 , LAH-
Page 64 and 65: Chapter 2 49Enzymatic reactions are
Page 66 and 67: Chapter 2 51As [ES] in equation 4 c
Page 68 and 69: Chapter 2 53E+AK 1AK -1AEAK 2AE+PE+
Page 70 and 71: Chapter 2 552.2.4 Lipases.Most lipa
Page 72 and 73: Chapter 2 57enzyme intermediate can
Page 74 and 75: Chapter 2 59projecting above the pl
Page 76 and 77: Chapter 2 612.3.1.1. Step 1: Adduct
Page 78 and 79: 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 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 140 and 141: Chapter 5 125Entry Substrate R Time
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Chapter 5 127experiments. But it wa
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Chapter 5 129OClOSAM IIPH=7; R.T.OH
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Chapter 5 131OHOXHOHRHK 2 CO 3 ; Me
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Chapter 6 133HCuSO 4 .5H 2 O,NH 4 O
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Chapter 6 1356.2.1 Heteroannullatio
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Chapter 6 137This discovery allowed
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Chapter 6 139OH(±)-62OHFigure 6.1
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Chapter 6 141Entry Substrate R Time
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Chapter 6 143HOH58-a-c,e,h-lRPdCl 2
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Chapter 6 145afforded the benzo[b]f
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Chapter 6 147RR[P(Ph) 3 ]Pd°OHOPh
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Chapter 6 149H2-IodophenolOHOH(±)-
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Chapter 6 151presence of base as de
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Chapter 7 153A chiral lithium alumi
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Chapter 7 155derivatives were tried
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Chapter 7 157Finally an hypothesis
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Chapter 8 159were washed with a sat
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Chapter 8 16145 min, the mixture wa
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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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