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

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Chapter 2 45PhaxeqP 1MP 2axeqPhP 2MP 1PhPhTOP VIEWSIDE VIEWFigure 2.5: Orientation of posphophenyl groups in BINAPThus, spatial characteristics exert a significant influence on thesubstrate coordination sites allowing for exceptional efficiency in BINAPcatalysis.A wide variety of functionalized ketones can be converted into theirrespective optically pure alcohols via homogeneous hydrogenation in thepresence of halogen-containing Ru-BINAP catalysts in alcoholic media.The reaction proceeds in a higly enantioselective and predictable fashion. Ageneral mechanism which describes this selective process involves initialcoordination of the carbonyl oxygen and the α or β adjacent heteroatom(such as nitrogen, oxygen or halogen) to create a five to seven memberedmetal chelated ring complex prior to hydrogen transfer.In the BINAP-Ru catalyzed reaction, diverse polar functionalitiesfacilitate the hydrogenation of the neighboring carbonyl group and allow theefficient enantioface differentation. The halogen containing complexes oftype RuX 2 -BINAP, the dimeric triethylamine complex or dicarboxylatecomplex, Ru(OCOR)2-Binap, may be used as catalyst, depending on theketonic substrates. Methanol or ethanol are the solvents of choice.The reaction with a substrate:catalyst molar ratio of 2200:230 proceedswith a reasonable rate at room temperature using an initial hydrogenpressure of 40-100 atm.Noyori, in 1979, reported also the use of optically pure 2,2' dihydroxy-1,1'- binaphthyl as LiAlH 4 chelating agent. The 1,1' Binaphthol itself has anaxial asymmetry and possesses an extremely high ability of chiralrecognition 15 .BINAL-H 21e is prepared by modification of LiAlH 4 with (R)- or (S)-binaphthol and one equivalent of ethanol (Scheme 2.8).
Chapter 2 46LiOHOHLiAlH 4EtOHOOHAlOEtScheme 2.8: Formation of BINAL-H 21e.Complex hydride reagents of the type LiAlH n (OR) 4-n are known toexist in a complicated equilibrium with a variety of disproportionated andaggregated species 16 . However, the stereochemical outcome arising fromthe rigid, unique chiral conformation of this reagent is most economicallyrationalized by the mechanism involving a six membered, chelating transitionstate 17 . For example, in the transition state of the reaction of acetophenoneand (R)-BINAL-H containing an ordinary R' group, the R'O oxygen acts asbridging atom because of its highest basicity among the three oxygensbound to Al. Therefore the chair conformation with axial-methyl andequatorial-phenyl groups 23a is favoured over the diastereomeric transitionstate 23b in accordance with the observed enantioselectivity 16 (Fig.2.6).OOAlH23aOEtFAVOREDMeLiPhOOOAlH23bOEtrepulsionPhLiDISFAVOREDFigure 2.6: BINAL-H transition state 23a/b in the acetophenon reduction.The BINAL-H is one of the best chiral LiAlH 4 complex reported;many other examples are reported in the literature such as: LAH-Darvon-Alc(Alc=2S,3R-(+)-4dimethylamino-3-methyl-1,2-diphenyl-2-butanol) 18a-d , LAH-MEP-ArOH ( MEP = N-Methyl ephedrine; ArOH =3,5-dimethylphenol) 19a-b , LAH-diamine[diamine(S)-2-(2,6xylidimethyl)-MeO
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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
Page 10 and 11: IndexIV4.4. Stereochemical Assignme
Page 12 and 13: IndexVImethyl amine 69 1446.6. Stud
Page 14 and 15: IndexVIII8.23.3.1 Desilylation usin
Page 16 and 17: Chapter 1 11.Introduction1.1. Chira
Page 18 and 19: Chapter 1 3The concept of stereoche
Page 20 and 21: Chapter 1 5switches is in the area
Page 22 and 23: Chapter 1 7-bonds 9 . It is now wid
Page 24 and 25: Chapter 1 914CH 3Cyt P-450 DMOH3O 2
Page 26 and 27: Chapter 1 11piperazine) is also the
Page 28 and 29: Chapter 1 13The four stereoisomers
Page 30 and 31: Chapter 1 15single enantiomers and
Page 32 and 33: Chapter 1 17was synthesized by the
Page 34 and 35: Chapter 1 19HOHODesmolaseHOCholeste
Page 36 and 37: Chapter 1 21formic acid results in
Page 38 and 39: Chapter 1 23inactivation. 113 . Bec
Page 40 and 41: 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 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 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
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Chapter 4 95the products with ethyl
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Chapter 4 97NCO 2 HNCO 2 H(±)34c(-
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Chapter 4 99NNH37CO2EtOH(±)-27a(+)
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Chapter 4 101As already outlined ab
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Chapter 4 103(+)-(S)-2-octylimidazo
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Chapter 4 105CNNH N2 NCN nC 6 H 13N
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Chapter 4 107key step is the conver
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Chapter 4 109reverse addition in th
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Chapter 4 111which was eliminated e
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Chapter 4 113separate (±)-57a and
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Chapter 5 115to avoid this side rea
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Chapter 5 117Complete degradation o
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Chapter 5 119Entry R T °C Product
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Chapter 5 1212:1:3 in weight. All t
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Chapter 5 123reaction conditions we
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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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