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

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Chapter 2 47pyrrolidine ] 20 , LAH-aminobutanol [ (S)-4-anilino-3-( methyl amino) -1butanol 21 , LAH-DBP-EtOH[DBP=(S)-(-)10,10'dihydroxy,9,9'biphenylanthranyl]22 , LAH-MEP-NEA (MEP=N-Methylephedrine,NE ANethylaniline)23 , LAH-MEP-EAP ( MEP = N-Methyl ephedrine, EAP = 2-ethylamino aniline 24 .All the classes of chiral reducing agents shown above are used for thereduction of a wide variety of different classes of prochiral ketones.Unfortunally, however, none of them has never been used for the reductionof prochiral benzophenones or diaryl ketones.In these ketones, both moieties linked to the carbonyl group haveroughly the same size. Therefore, the chiral reducing agent fails todiscriminate between the two faces.To the best of our knowledge, only a small number of methods arereported in literature for the synthesis of enantiopure benzhydroles or diarylmethanoles. In particular: (a) asymmetric reduction by Rodoporidiniumtoruloides 25 , (b) resolution of diasteroisomeric acetyl mandelate esters 26 , (c)nucleophilic addition of aryl groups to aromatic aldehydes byorganotitanium chelating agents 27 . A much more interesting approach hasbeen reported by E. Brown in 1991 28 describing the use of the veryinteresting LAH complexing agent, (R)-(-)- (2)- (isoindoliny) butan-1-ol 24 (Fig.2.7) which will be described later.The major advantages of this chiral complexing agent are that the chiralamino alcohol is very cheap and available in both enantiopure forms.NOH24Figure 2.7: (R)-(-)-2-(2-isoindolynil) butan-1-ol 24, Brown's chiral amino alcohol for theasymmetric reduction of benzophenones.An ortho-substituent in one of the aromatic rings seems to be essentialfor a good stereoselection in the asymmetric reduction of prochiralbenzophenones with this chiral LAH complex. The orthobromobenzophenone 25b was reduced to the ortho-bromobenzhydrol 27bwith an enantiomeric excess > 95% e.e.and a chemical yield of 100%(Scheme 2.8).
Chapter 2 48LAH 1,5 (OR) 2,5dry EtherBr OBr OH25b27be.e. > 95%, 100% YieldScheme 2.8: Chiral reduction of ortho bromobenzophenones 25b by the Brown procedure.The best molar ratio between LAH and the chiral ligand 24 is 1 to 2.5;no mechanistic hypothesis regarding the absolute stereochemistry of thealcohol has yet been reported by Brown.2.2 Synthesis of enantiopure alcohols by enzymatic resolution2.2.1. IntroductionEnzymes are proteins, which catalyze numerous biologicaltransformation in vivo . They are constructed from twenty natural aminoacids. The relationship between the amino acid sequence and its catalyticactivity is still impossible to predict. It is clear that enzymes represent avaluable class of catalysts for organic transformations and numerousorganic reactions can be catalyzed in their presence. For organic synthesis ithas to be decided whether an enzymatic approach towards the solution of aparticular synthetic problem is more practical than a non-biologicalapproach. In many instances enzymatic transformations represent only onealternative or improvement as compared to an existing chemicalmethodology. In some cases, however, enzymatic processes are more costeffectivethan non biological methods and thus have clear advantages.Several large scale enzymatic processes used in industry (resolution ofamino acids with acylase, transformation of pig insuline to human insulincatalyzed by trypsin, preparation of penicillin analogues with penicillinacylase, synthesis of optically pure fine chemicals etc) have demonstratedthat enzymatic catalysts can be the best route to fine chemicals.2.2.2. Enzyme kinetics.
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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
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 60 and 61: Chapter 2 45PhaxeqP 1MP 2axeqPhP 2M
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
Page 110 and 111: 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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