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

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Chapter 3 81substituents are the most important factors governing the enantioselectionof the reduction. It is in fact possible that, due to the presence of the orthosubstituent, the prochiral benzophenone presents the two aromatic moietiesin different planes. The ketone can be almost coplanar with theunsubstituted aromatic ring to form a flat moiety while the aromatic ringbearing the ortho substituent is out of the plane (Fig 3.1).ROFig.3.1: Conformation of ortho substituted benzophenones.2-Bromo-(4'phenyl) benzophenone 25c, reduced under identicalexperimental conditions as used for 2-bromobenzophenone 25b gave (+)-2-bromo-4'phenyl-benzhydrol (+)-27c with an enantiomeric excess of higherthan 95% e.e. (scheme 3.10; table 3.4) and with 98% of chemical yield. It isinteresting to note that in this substrate two substituents are present on thetwo aromatic rings. The presence of a phenyl ring in the para position didnot lead to any loss of stereoselectivity in the chiral reduction probablybecause this did not change the overall geometry of the prochiral ketone.The enantiomeric excess was determinated by examining the carbinolicproton in the 1 H-NMR spectrum (200 MHz) in the presence of the chiralshift reagent tris [3-(heptafluoropropylhydroxy methylen)] camphoratoeuropium 3 [Eu(hfc) 3 ], and also confirmed by chiral HPLC ( Chiracel OD).The procedure was repeated for 4'-phenyl benzophenone 25a and ledto the racemic 4'-phenyl benzhydrole (±)-27a in 98% of chemical yield(scheme 3.10; table 3.4). 2-Fluoro-4'-phenyl benzophenone 25d wasreduced to (+) 2-fluoro 4'-phenyl benzhydrole (+)-27d with 80%enantiomeric excess and 98% of chemical yield (scheme 3.10; table 3.4).The loss of enantiomeric excess could be attributed to the reduced sterichindrance of the fluorine atom in comparison to the bromine. Theenantiomeric excess was determined by chiral HPLC (Chiracel OD), whileall attempts to examine the carbinolic proton in the 1 H-NMR spectrumrecorded in presence of the above chiral shift reagent failed.
Chapter 3 82Product X R Yield % e.e. % [α D ](±)-27a H Ph 95 0 0(+)-27b Br H 97 >95 + 46.6(+)-27c Br Ph 98 >93 + 65.6(+)-27d F H 98 80 + 57.5Table 3.4.: Enantioselective reduction of prochiral ketones 25a-d.Enantioselective reduction of 25a with DIP-chloride was also tried inorder to obtain directly the enantiopure benzhydrol 27a. However thisreduction only led to the racemic alcohol (±)-27a.3.4.3. Synthesis of enantiomerically enriched 2[benzo(b)furan]phenones by asymmetric reduction.To the best of our knowledge no examples for the asymmetricreduction of 2 [benzo(b)furan] phenones are reported in literature, and nosynthetic strategies for the preparation of the 2-[benzo(b)furan]-arylmethanols in enantiopure form are known.Asymmetric reductions of these types of prochiral ketones wereinvestigated using the above chiral complexes as reducing reagents. It wasexpected that the difference between the two aromatic systems would berecognized by the chiral reducing reagent (scheme 3.11), in the hope that thebenzo(b)furane oxygen could be coordinated by the aluminium of thereducing agent.R'LiAlH 4R'OOR26a R=R'=H26c R=R'=ClN(-)-24Dry etherOHOHOHR27g R=R'=H27i R=R'=ClScheme 3.11 : Asymmetric reduction of prochiral ketones 26a and 26c.This hypothetical coordination should give a stereofacialdiscrimination in the ketone 26a. Another hypothesis is that the repulsionbetween the oxygen of the ketone and the oxygen of the benzofuran
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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
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 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 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
Page 142 and 143: Chapter 5 127experiments. But it wa
Page 144 and 145: 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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