CHEM01200604012 Dibakar Goswami - Homi Bhabha National ...

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General procedure for Barbier type allylation/crotylation of 1 in H 2 O or THF. Finely divided metal powder (In, Sb, Ga or Bi) was added to a mixture of 1 (5.0 g, 0.029 mol) and allyl /crotyl bromide (equivalents specified in Table III.2.1 and Table III.2.2) in H 2 O (30 mL) or THF (30 mL). After stirring the mixture for the time specified in Table III.2.1 and Table III.2.2, it was filtered and worked-up as above to isolate the pure products. For the reaction with Sb, an aqueous solution of KF (5-6 mL, 2M) was also added in the reaction mixture. The In-mediated reaction was also carried out in the presence of LiCl and KI (1.0 equiv. each). Procedure for allylation/crotylation in [bmim][Br]. A mixture of the metal (In, Ga or Bi) and allyl/crotyl bromide (quantities specified in Table III.2.1 and Table III.2.2) in [bmim][Br] (3 mL/mmol) was stirred at room temperature for 0.5 h, followed by addition of the aldehyde 1. The reaction mixture was stirred at room temperature for 4-5 h. After completion of the reaction (cf. TLC), the mixture was extracted with Et 2 O (30 mL), the ether extract evaporated in vacuo and the residue purified by column chromatography (silica gel, 0-15% EtOAc/hexane) to give the respective products as colourless oils. Crotylation of 1 via the Grignard route. To a stirred solution of 1 (1.70 g, 0.01 mol) in THF (25 mL) was slowly injected the Grignard reagent [prepared from crotyl bromide (4.10 g, 0.03 mol) and Mg-turnings (1.20 g, 0.05 mol)] in Et 2 O or THF (40 mL). After stirring for 12 h, the reaction was quenched with aqueous saturated NH 4 Cl (2 mL). The organic layer was separated and the aqueous portion extracted with Et 2 O (30 mL). The combined organic extracts were washed with brine (5 mL), and dried. Solvent removal in vacuo and column chromatography of the residue afforded the pure homoallylic alcohols 69a-c. 120
(2R,3R)-1,2-Cyclohexylidenedioxy-5-hexene-3-ol 68a. colourless oil; R f = 0.80 (20% 24 EtOAc/hexane); [α] D +5.3 (c 1.24, CHCl3 ); IR: 3451, 1640, 1098, 1042 cm -1 ; 1 H NMR: δ 1.25-1.37 (m, 2H), 1.56-1.61 (m, 8H), 2.22 (t, J = 6.5 Hz, 2H), 2.31(d, J = 4.8 Hz, D 2 O exchangeable, 1H), 3.52-3.58 (m, 1H), 3.68-3.76 (m, 1H), 3.93-4.02 (m, 2H), 5.06-5.16 (m, 2H), 5.77-5.91 (m, 1H); 13 C NMR: δ 23.5, 23.7, 24.8, 34.5, 35.9, 37.9, 65.4, 71.3, 77.8, 109.6, 117.4, 133.8. (2R,3S)-1,2-Cyclohexylidenedioxy-5-hexene-3-ol 68b. colourless oil; R f = 0.73 (20% 24 EtOAc/hexane; [α] D +10.2 (c 1.38, CHCl3 ); IR: 3453, 1642, 1101, 1044 cm -1 ; 1 H NMR: δ 1.36-1.38 (m, 2H), 1.55-1.59 (m, 8H), 2.13-2.33 (m overlapped with broad s, 3H), 3.71- 3.79 (m, 1H), 3.88-4.01 (m, 3H), 5.13-5.16 (m, 2H), 5.75-5.88 (m,1H); 13 C NMR: δ 24.1, 24.3, 25.5, 35.2, 36.6, 38.0, 65.2, 71.0, 78.0, 110.0, 118.6, 134.4. (2R,3R,4R)-1,2-Cyclohexylidenedioxy-4-methyl-5-hexen-3-ol 69a. colourless oil; R f = 24 0.83 (20% EtOAc/hexane); [α] D +47.1 (c 1.41, CHCl3 ); IR: 3408, 1648, 990 cm -1 ; 1 H NMR: δ 1.09 (d, J = 6.8 Hz, 3H), 1.33-1.58 (m, 10H), 2.22-2.30 (m, 1H), 2.68 (broad s, 1H), 3.31-3.39 (m, 1H), 3.71-3.76 (m, 1H), 3.93-4.15 (m, 2H), 4.98-5.08 (m, 2H), 5.68- 5.84 (m, 1H); 13 C NMR: δ 12.4, 16.9, 23.9, 25.1, 35.0, 36.2, 41.3, 65.7, 74.6, 75.4, 109.6, 112.8, 139.6. (2R,3S,4R)-1,2-Cyclohexylidenedioxy-4-methyl-5-hexen-3-ol 69b. colourless oil; R f = 24 0.75 (20% EtOAc/hexane); [α] D +29.7 (c 1.45, CHCl3 ); IR: 3400, 1651, 995 cm -1 ; 1 H NMR: δ 1.09 (d, J = 6.8 Hz, 3H), 1.39-1.61 (m, 10H), 1.81 (broad s, 1H), 2.19-2.29 (m, 1H), 3.63-3.69 (m, 1H), 3.83-3.99 (m, 2H), 4.06-4.15 (m, 1H), 5.02-5.09 (m, 2H), 5.65- 5.82 (m, 1H); 13 C NMR: δ 12.5, 17.4, 24.1, 25.4, 35.3, 35.8, 41.2, 65.4, 74.7, 75.6, 109.2, 114.1, 138.8. 121
Page 1:
ASYMMETRIC STRATEGIES FOR THE SYNTH
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ACKNOWLEDGEMENTS First of all, I wa
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CONTENTS SYNOPSIS LIST OF FIGURES L
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SYNOPSIS
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models (e. g. Cram’s model, Felki
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4 1d 4-(CH 3 ) 2 CH-C 6 H 4 1 : 1.5
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14. 1n C 6 H 5 CO C 6 H 5 2n 8 77 1
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imetallic systems. In all the cases
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For the benzylation reaction, the c
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O O 3 CHO i O O + OH 13a O O OH O O
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10 3.5 Ga (2.5) THF KI+LiCl 10 55 5
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multidrug-resistant (MDR) cancer ce
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directly afforded the furanose, whi
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References 1. Stephenson, G. R. Adv
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LIST OF FIGURES
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II.3.13 III.1.1 III.1.2 III.1.3 III
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IV.5.2 IV.5.3 IV.5.4 IV.5.5 1 H NMR
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Table Title Page No. II.3.1 II.3.2
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II. .11 PPREAMBLE Demand for specia
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II. .22 IINTRODUCTIION TO CHIIRALII
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The most dramatic example in this a
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H H 2 N OH COOH i PhH 2 CO O H N H
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Methods of Asymmetric Synthesis: 15
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O O O O i, ii iii iv HO HO N N OH O
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Models for Asymmetric Synthesis. 21
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If a strongly electronegative group
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enantiomeric products are formed at
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vi) The balance between chiral auxi
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IIII. .11 IINTRODUCTIION TO CHIIRAL
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Scheme II.1.2 However, availability
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Prof. R. Noyori received the Nobel
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Apart from the cinchona alkaloids,
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ligand, it assumes a tetrahedral co
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Marshall. 53 More recently, Barbero
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Various protocols have been develop
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In the absence of a sterically-bulk
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IIII. .33. . PPRESSENT WORK It is w
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[pyridinium][Sn 2 Cl 5 ] etc. can b
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RCHO 59a-j i R OH 60a-j (i) Allyl b
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Fig. II.3.2. 1 H NMR spectrum of 60
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in [bmim][BF 4 ] using sub-stoichio
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The reaction in THF was also follow
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The integration of the signal at δ
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The standard reduction potential of
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It has also been reported, 83a,b th
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IIII. .33. .33 Gaal lliuum meeddi i
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5 3.0 5.0 THF LiCl+KI c 14 d 71 6 1
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3 59d 4-(CH 3 ) 2 CH-C 6 H 4 H 60d
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Fig. II.3.8. 13 C NMR spectrum of 6
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Fig. II.3.10. 13 C NMR spectrum of
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fragmentation peak at m/z 138 (19%)
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Fig. II.3.13. 13 C NMR spectrum of
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active catalyst, as suggested for t
Page 111 and 112: 1-(4-Bromophenyl)-but-3-en-1-ol 59b
Page 113 and 114: 1H), 7.90-7.93 (m, 1H); 13 C NMR:
Page 115 and 116: 662, 980, 1079, 1332, 1374 cm -1 .
Page 117 and 118: IIIIII. .11 DIIASSTEREOSSELECTIIVE
Page 119 and 120: cyclohexylideneglyceraldehyde (1) 3
Page 121 and 122: mixture of Zn dust, allyl or γ-sub
Page 123 and 124: Fig. III.1.2. 13 C NMR spectrum of
Page 125 and 126: Reaction with crotyl bromide: In ca
Page 127 and 128: Fig. III.1.5. 1 H NMR spectrum of 6
Page 129 and 130: The formation of the 2,3-anti addit
Page 131 and 132: To establish the C-4 configuration
Page 133 and 134: Allylation with (E) and (Z)-1-bromo
Page 135 and 136: (i) Zn, aqueous satd. NH 4 Cl, THF,
Page 137 and 138: Fig. III.1.12. 1 H NMR spectrum of
Page 139 and 140: Allylation with 1-Bromo-4-(tert)-bu
Page 141 and 142: fast and gave a significantly bette
Page 143 and 144: espectively) due to the cyclohexyli
Page 147 and 148: was treated with excess amount of b
Page 149 and 150: Fig. III.1.20. 1 H NMR spectrum of
Page 153 and 154: stereochemistry of allylation of β
Page 155 and 156: of the products were modest (48-62%
Page 157 and 158: 6 1.2 In (2.0) H 2 O LiCl+ KI 14 72
Page 159 and 160: are consistent with our previous re
Page 161: III.3 EXPERIMENTAL SECTION: General
Page 165 and 166: for an additional 2 h, gradually br
Page 167 and 168: (m, 2H), 5.82-5.98 (m, 1H), 7.25-7.
Page 169 and 170: 31.6, 32.2, 63.4, 128.8, 133.0. Ana
Page 171 and 172: 23 (2R,3S,4R)-1,2-Cyclohexylidenedi
Page 173 and 174: (2R,3S,4S)-1,2-Cyclohexylidenedioxy
Page 175 and 176: (m, 1H), 3.50-4.02 (m, 5H), 4.10-4.
Page 177 and 178: and dried. Removal of solvent in va
Page 179 and 180: ine, and dried. Solvent removal und
Page 181 and 182: IIV. .11 SSYNTHESSIISS OFF ENANTIIO
Page 183 and 184: Scheme IV.1.1 The same group also d
Page 185 and 186: IV.1.3: Present work Although sever
Page 187 and 188: O O C 6 H 13 i O C 6 H 13 ii OH C 6
Page 189 and 190: Fig. IV.1.4. 1 H NMR spectrum of 10
Page 191 and 192: the unit-C contribute positively to
Page 193 and 194: tartrate, Ti(O-i-Pr) 4 , CH 2 Cl 2
Page 195 and 196: Based on this hypothesis, the alcoh
Page 197 and 198: OR 3 O R 1 R 2 NaBH 4 H H R 1 R 1 +
Page 199 and 200: (OH). Oxidative cleavage of its α-
Page 205 and 206: IIV. .33: : SSYNTHESSIISS OFF 33' '
Page 207 and 208: For the actual synthesis, (Scheme I
Page 211 and 212: IV.4: SSYNTHESSIISS OFF 22( (SS) )-
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(i) PhCHO, triethyl orthoformate, M
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O N 3 II Ph HO OH b1 N 3 Ph O O Ben
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Fig. IV.4.2. 1 H NMR spectrum of 91
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Thus, easily accessible 1 has been
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167 and subsequent reduction gave 1
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from the appearance of 13 C NMR pea
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Fig. IV.5.2. 1 H NMR spectrum of 17
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IV.6 EXPERIMENTAL SECTION (2R,3S,4R
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As described earlier, compound 108
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19.5, 23.8, 23.9, 25.1, 26.9, 34.6,
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74.2, 74.4, 110.1, 116.7, 127.6, 12
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mmol) in MeOH (10 mL), work up, fol
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7.51 (m, 3H), 7.92-8.08 (m, 2H); 13
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subsequent isolation afforded rotam
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4.18 (t, J = 3.4 Hz, 1H), 4.75-4.84
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-4.21 (c 1.2, CHCl 3 ); IR: 3466, 1
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(3R)- 3,4-O-Cyclohexylidene-2-oxo-1
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Water and EtOAc was added to the mi
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24 179. Yield: 1.49 g (77.5%); colo
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24 furnished pure 183. Yield: 0.37
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1. Wender, P. A. Chem. Rev. 1996, 9
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17. Hanessian, S.; Maji, D. K.; Gov
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32. For some selective references s
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43. (a) Cleare, M. J.; Hydes, P. C.
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54. Barbero, A.; Pulido, F. J.; Rin
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2008, 1681. (d) Fargeas, V.; Zammat
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72. Karodia, N.; Guise, S.; Newland
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Kaminski, J.; Millhauser, G.; Ortiz
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Böhm, V. P. W.; Reisinger, C. J. O
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119. Wender, P. A.; Holt, D. A.; Si
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140. (a) Chemler, S. R.; Roush, W.
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Lett. 1996, 107, 53. (c) Smith, C.
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158. Mitsuya, H.; Weinhold, K. J.;
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L.; Zugay, J. A. J. Med. Chem. 1993
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1. Goswami, D.; Chattopadhyay, A.;
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