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

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Chapter 1 5switches is in the area of analgesics. Thus Menarini (Italy) has collaboratedwith the British Company Chiros, ( Cambridge, England) to develop (S)-(+)-Ketoprofene 1 (Fig 1.4). Discovered by Rhone-Poulenc it was sold inthe U.S. as racemate under the name Orudis, while the enantiomer has beenregistered by Menarini in Spain. The (S)-(+) enantiomer is an analgesic/antiinflammatorydrug whereas the (R)-(-) isomer shows activity against boneloss in periodontal disease 5 .*MeO1CO 2 HFigure 1.4: (±) Ketoprofene 1 (±) 2-(3-benzoylphenyl) propionic acidThe discovery of two different pharmacological effects for oppositeenantiomers is a common driving force for a racemic switch.Nebivolol, producted by Janssen Pharmaceuticals, is an example fordifferent pharmacological actions in two enantiomers. It had beendeveloped as a β-blocker for hypertension. But, whereas (+)-Nebivolol is aβ-blocker, the (-) enantiomer is a vasodilating agent. Thus, by alleviatinghypertension by two different mechanisms of action, the racemate may beconsidered superior to either enantiomer 5 .There is also a hypothetical case of a chiral drug that is degraded bymetabolic reactions at a site distant from the asymmetrically substitutedcarbon atom. This way both enantiomers would be inactivated at the samerate. Therefore, an inactive enantiomer may serve as a sacrifical substratefor degradation of the enzyme, thus prolonging the residence time of theactive enantiomer in the body. To achieve the same therapeutic benefit, thepatient would have to take the same dose of expensive enantiomers as ofthe cheaper racemate.Clearly, all industrial observers believe that if the potency of an activeand inactive enantiomer is such that the dose can be cut in half, the patientwill benefit.Candidates for racemic switches are also antifungal agents, nonsteroidal inhibitors of aromatase (anticancer), cardiovascular drugs, nonsteroidal anti inflammatory drugs (NSAIDs), central nervous system
Chapter 1 6agents, antihystaminica, and prescription drugs being considered foreventual over the counter sale (OTC's).This thesis will focus on the synthesis of antifungal agents and nonsteroidal inhibitors of aromatase.These two classes of drugs share generalchemical structures and mechanisms of action. In fact both inhibit twodifferent cytochrome P-450 dependent enzymes having a protoporphyrinheme as catalytic site. They present (Fig. 1.5) an heterocyclic moiety suchas an imidazole or triazole in a benzylic or benzhydrilic position.Furthermore the asymmetric centre is the benzhydrilic or benzylic carbonwich is the core of the molecules connecting all other parts of the molecule.Aromatic MoietyAromatic MoietyImidazole or TriazoleBenzylic or BenzhydrylicChiral CentreFigure 1.5: General structure of antifungal agents and non steroidal aromatase inhibitors.Even though these classes of drugs have very simple structures, theyhave never been synthesized in enantiopure form.1.2. Enzymes containing the Cofactor Cytochrome P-450.Cytochrome P-450 dependent enzymes constitute a family of enzymeswhich catalyze the oxidation of a large range of biological substrates. TheP-450 dependent enzymes are divided into 10 groups and 18 subgroupsbased on sequence alignment with groups sharing greater than 30%sequence homology and subgroups with homology greater than 46% 6,8 .The enzymes bind dioxygen and through a stepwise cleavage of the O 2double bond incorporate one oxygen atom into non activated C-H
Page 1 and 2: Advances in the stereoselectivesynt
Page 3: ACKNOWLEDGMENT:I would like to than
Page 6 and 7: Summary:Numerous drugs are chiral,
Page 8 and 9: 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 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 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
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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
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Chapter 2 65There are various effec
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Chapter 2 67The reactions were foun
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Chapter 2 69Yamanaka and coworkers
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Chapter 2 71sodium or potassium car
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Chapter 3 73The reaction is quite s
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Chapter 3 75literature as the best
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Chapter 3 77dry solvents and, is ch
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Chapter 3 79XXOH+ H 2 NDry K 2 CO 3
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Chapter 3 81substituents are the mo
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Chapter 3 83induces a rotation of t
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Chapter 3 85very sharp and it was p
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Chapter 3 87Raney NickelOH Br MeOH;
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Chapter 4 8933a-m were hydrolysed t
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Chapter 4 91benzo[b]furane (entries
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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(-
Page 114 and 115:
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
Page 158 and 159:
Chapter 6 143HOH58-a-c,e,h-lRPdCl 2
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Chapter 6 145afforded the benzo[b]f
Page 162 and 163:
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
Page 190 and 191:
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
Page 218 and 219:
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
Page 234 and 235:
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
Page 240 and 241:
Chapter 9 22567a) Kundu, N.G.; Pal,
Page 242:
Chapter 9 22712) Thompson,A.S.; Hum
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