CHEM01200604012 Dibakar Goswami - Homi Bhabha National ...

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suited for the Barbier type reactions. Also the metal mediated allylation reactions of achiral aldehydes and ketones were most efficient in [bmim][Br] (Chapter II), and hence this was choosen as RTIL for carrying out allylation reactions with the chiral aldehyde 1. Table III.2.1. Reaction course of allylation of 1 a Entry Allyl bromide (equiv.) Metal (equiv.) Solvent Additive Time (h) Yield b (%) Product ratio c 68a:68b 1 4 In (2.5) H 2 O -- 5 58 24.2 : 75.8 2 3.5 In (2.5) THF KI+ LiCl 7 69 2.0 : 98.0 3 1.2 In (1.0) [bmim][Br] -- 3 78 29.8 : 70.2 4 4 Ga (2.5) H 2 O -- 6 48 21.9 : 78.1 5 3.5 Ga (2.5) THF KI+ LiCl 16 NR d -- 6 1.2 Ga (1.0) [Bmim][Br] -- 4 73 5.0 : 95.0 7 4 Bi (2.5) H 2 O -- 8 62 23.2 : 76.8 8 3.5 Bi (2.5) THF KI+ LiCl 16 NR d -- 9 1.2 Bi (1.0) [bmim][Br] -- 4 75 31.6 : 68.4 a The reactions were carried out at 2 mmol scale. b The yields refer to those of isolated pure isomers. c The isomeric ratios were determined from the isolated yields. d NR: no reaction. The stereochemical outcome of the metal mediated allylation of 1 was found to be highly dependent on the metal, as well as on the reaction media. In general, for all the metals, reactions could be accomplished in [bmim][Br] with stoichiometric amount of the metal and allyl bromide in a much lesser time with appreciably higher yields of the products (entries 3, 6 and 9, Table III.2.1). In H 2 O, even after using activators, the yields 112
of the products were modest (48-62%). More importantly, a large excess of metal and allyl bromide was required for the completion of the reaction. All the reactions in H 2 O proceeded with a modest diastereoselectivity for the anti-isomer 68b (entries 1, 4 and 7, Table III.2.1). Surprisingly, the Ga- and Bi-mediated allylations in THF did not take place at room temperature (entries 5 and 8, Table III.2.1). However, the In-mediated allylation in THF proceeded with excellent anti-selectivity (entry 2, Table III.2.1). Although the Inand Bi-mediated allylation in [bmim][Br] proceeded with modest anti-selectivity, use of Ga for the allylation in [bmim][Br] yielded the anti-isomer 68b with 90% diastereoselective excess (entry 6, Table III.2.1). In all the cases, the predominant formation of the anti-isomer indicated that all the reaction took place via the Felkin-Anh model. 24b,112 In case of crotylation (Scheme III.2.1), we also used two additional metals, Mg and Sb. In this case also the diastereoselectivity could be tuned by changing the metals, and solvents. 117 The results are summarized in Table III.2.2. With Mg in ethereal solvents, practically no selectivity was obtained, and the diastereomers 69a-c were produced in almost equal amounts (entries 1, 2, Table III.2.2). Use of Sb in aqueous THF or H 2 O gave a similar diastereoselectivity, but poor yields, and required an additional metal activator (KF) (entries 3, 4, Table III.2.2). The In-mediated reaction proceeded well in H 2 O, but not in THF (entries 5-8, Table III.2.2), resulting in preferential formation of 69b and 69c in ~1:1 ratio, as the major products. On the other hand, the Ga-mediated reaction in THF produced the products in poor yields even under metal activation and resulted in modest 69b/69c selectivity (entry 10, Table III.2.2). A similar stereoselectivity was earlier observed using Zn metal (Table III.1.2, Chapter III.1.2). The inability of Ga to carry out 113
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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
Page 103 and 104: Fig. II.3.10. 13 C NMR spectrum of
Page 105 and 106: fragmentation peak at m/z 138 (19%)
Page 107 and 108: Fig. II.3.13. 13 C NMR spectrum of
Page 109 and 110: 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: stereochemistry of allylation of β
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 and 162: III.3 EXPERIMENTAL SECTION: General
Page 163 and 164: (2R,3R)-1,2-Cyclohexylidenedioxy-5-
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-
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IIV. .33: : SSYNTHESSIISS OFF 33' '
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For the actual synthesis, (Scheme I
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Fig. IV.3.1. 1 H NMR spectrum of 14
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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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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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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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