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

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Chapter 4 109reverse addition in the Mitsunobu reaction. The results using this procedureare shown in table 4.6.entry substrate R1 R2 product yield% [α]1 (±)-27a Ph 4Ph C6H4 (±)-55a 53.8 02 (±)-27c 2 BrPh 4Ph C6H4 (±)-55b 57.5 03 (+)-27c 2 BrPh 4Ph C6H4 (±)-55b 68.5 04 (±)-27g 2 benzo[b]furane Ph (±)-55c 15.0 05 (±)-27m 2 benzo[b]furane 2,4 C6H3 (±)-55d 13.3 06 (+)-27m 2 benzo[b]furane 2,4 C6H3 (+)-55d 10.8 0Table 4.6: Synthesis of azide 55a-d via Mitsunobu reaction with DPPA.All reactions were carried out in dry THF overnight with an excess ofreagents. In the case of compounds 27g-m (entries 4-6, table 4.6) largeamounts of starting material were always recovered. With benzhydroles27a-c (entries 1-3, table 4.6) products were obtained, however, due topartial decomposition during chromatography yields were low. Thebenzhydroles (entries 1-3, table 4.6) led to better results regarding chemicalyields than the benzo[b]furan aryl methanols (entries 4-6). The results are ingood agreement with those obtained in the Mitsunobu reaction with 4,5dicyanoimidazole using the same substrates. None of the products showeda specific rotation neither at the sodium line nor at all Hg lines. This led tothe conclusion that all compounds were racemic. All attempts to measurethe enantiomeric excess directly by chiral HPLC or by NMR in thepresence of shift reagents failed.4.5.2.2. Direct conversion of alcohols to azides usingdiphenylphosphoroazidate and DBU.These reactions were carried out by dissolving the alcohols and DPPAin dry toluene to a final alcohol concentration of about c.a. 0.5-1.0 M. Tothe reaction mixture a slight excess of DBU was added (Scheme 4.13). Theprocedure was applied to the alcohols reported in table 4.7.
Chapter 4 110R R 1N 3OH27a,c,g,mDPPADBUR R 155a-dScheme 4.13: Synthesis of azides 55a-d by DPPA-DBU.entry substrate R1 R2 product yield% [α]1 (±)-27a Ph 4 PhC6H4 (±)-55a 0 02 (±)-27c 2 BrPh 4 PhC6H4 (±)-55b 5.8 03 (+)-27c 2 BrPh 4 PhC6H4 (±)-55b 5.2 04 (±)-27g 2benzo[b]furane Ph (±)-55c 54.3 05 (±)-27m 2benzo[b]furane 2,4ClC6H3 (±)-55d 67.2 06 (+)-27m 2benzo[b]furane 2,4ClC6H3 (+)-55d 69.8 +0.5Table 4.7: Synthesis of azides 55a-d by DPPA-DBU.The results were quite opposite to those obtained by the Mitsunobureaction described in chapter 4.2.2.1. In fact, the benzo[b]furanes (entries4-6) reacted better than the benzhydroles (entries 1-3) without anyapparent reason. The reaction takes place in two discrete steps, the firstone being the phosphate formation, followed by azide displacement(Scheme 4.14).H+R RR R 1 N1 (PhO) R R 2 PN 31ONOH N 327a,c,g,m DBUO P OPh -N 3 55a-dOPhScheme 4.14: reaction mechanism for azide synthesis by DPPA-DBU.The mechanism was proposed by Thompson 13 The reaction hasconsiderable advantages as compared to the Mitsunobu reaction withDPPA. The only by-product of the reaction is the DBU salt ofdiphenylphosphate. This salt is water soluble and can be removed duringaqueous work up. The other two contaminants were: (a) excess of DBUwhich was eliminated by acidic work up and (b) a slight excess of DPPA
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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
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Chapter 1 31Enantioselective synthe
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Chapter 1 33+R,S DRUG ANCHOR R MOLE
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Chapter 1 35solubilized in hot etha
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Chapter 2 37RsORmRmRsRLRL RRRLH - A
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Chapter 2 39The stereochemistry and
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Chapter 2 41An asymmetric reducing
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Chapter 2 43This approach clearly e
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Chapter 2 45PhaxeqP 1MP 2axeqPhP 2M
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Chapter 2 47pyrrolidine ] 20 , LAH-
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Chapter 2 49Enzymatic reactions are
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Chapter 2 51As [ES] in equation 4 c
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Chapter 2 53E+AK 1AK -1AEAK 2AE+PE+
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Chapter 2 552.2.4 Lipases.Most lipa
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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
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 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
Page 146 and 147: Chapter 5 131OHOXHOHRHK 2 CO 3 ; Me
Page 148 and 149: Chapter 6 133HCuSO 4 .5H 2 O,NH 4 O
Page 150 and 151: Chapter 6 1356.2.1 Heteroannullatio
Page 152 and 153: Chapter 6 137This discovery allowed
Page 154 and 155: Chapter 6 139OH(±)-62OHFigure 6.1
Page 156 and 157: Chapter 6 141Entry Substrate R Time
Page 158 and 159: Chapter 6 143HOH58-a-c,e,h-lRPdCl 2
Page 160 and 161: Chapter 6 145afforded the benzo[b]f
Page 162 and 163: Chapter 6 147RR[P(Ph) 3 ]Pd°OHOPh
Page 164 and 165: Chapter 6 149H2-IodophenolOHOH(±)-
Page 166 and 167: Chapter 6 151presence of base as de
Page 168 and 169: Chapter 7 153A chiral lithium alumi
Page 170 and 171: Chapter 7 155derivatives were tried
Page 172 and 173: 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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