CHEM01200604012 Dibakar Goswami - Homi Bhabha National ...

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Fig. IV.3.3. 1 H NMR spectrum of 148 Overall, a very simple, efficient and stereochemically flexible strategy for the synthesis of 3'-C branched 2',3'-dideoxynucleosides was established. To establish the viability of our strategy, compound 150 has been synthesized as a representative target molecule. Employing a similar strategy, the other stereochemical variations at C-3 and C-4 in the sugar units could be introduced starting from the other stereomers of 83. In hindsight, the poor 3,4-stereoselectivity for all these reactions of 1 with 82 was exploited to our advantage to have access to all four diastereomers 83a-d starting from the same combination of substrates, and to achieve a stereodivergent synthesis of dideoxynucleosides. 167
IV.4: SSYNTHESSIISS OFF 22( (SS) )-[11( (SS) )-AZIIDO- -22- -PPHENYLETHYL] ] OXIIRANE IV.4.1: Introduction The inhibition of the enzyme HIV-1 protease, which cleaves the gag and gag-pol polyproteins into the functional proteins of infectious virions, continues to be a major therapeutic target for the treatment of AIDS and related ailments. 166 These HIV-1 protease inhibitors viz. amprenavir, fosamprenavir etc. are important in the most frequently used regimen for the treatment of HIV/ AIDS, the highly active antiretroviral therapy (HAART). 167 Hence, it is anticipated that their demand will increase in the near future. This demand is matched by a need of technologies to produce these compounds economically on an industrial scale. Also, since these HIV protease inhibitors often exhibit complex structures equipped with multiple stereogenic centers, development of an efficient and practical synyhetic route for these inhibitors presents a challenge for synthetic organic chemists. Regarding the synthesis of this class of inhibitors, 168 considerable attention has been focused on the preparation of protected azidoalkyl and aminoalkyl epoxides 169 primarily due to their inevitable role in the construction of ethylene and ethylamine dipeptide isosteres, which are subsequently incorporated into pseudopeptides that are potent inhibitors of HIV-1 proteases. A key epoxide synthon of this category is 2(S)-[1(S)- Azido-2phenylethyl]oxirane (VI), which has been prepared by several groups starting from chiral sources like (D)-isoascorbic acid and D-tartaric acid. 169d,170 However, a general synthetic methodology for the synthesis of VI with required stereochemical control and optical purity is still appreciated, and this prompted us to accomplish a novel and straightforward synthesis using inexpensive reagents and operationally simple procedures. 168
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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
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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
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1-(4-Bromophenyl)-but-3-en-1-ol 59b
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1H), 7.90-7.93 (m, 1H); 13 C NMR:
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662, 980, 1079, 1332, 1374 cm -1 .
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IIIIII. .11 DIIASSTEREOSSELECTIIVE
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cyclohexylideneglyceraldehyde (1) 3
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mixture of Zn dust, allyl or γ-sub
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Fig. III.1.2. 13 C NMR spectrum of
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Reaction with crotyl bromide: In ca
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Fig. III.1.5. 1 H NMR spectrum of 6
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The formation of the 2,3-anti addit
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To establish the C-4 configuration
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Allylation with (E) and (Z)-1-bromo
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(i) Zn, aqueous satd. NH 4 Cl, THF,
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Fig. III.1.12. 1 H NMR spectrum of
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Allylation with 1-Bromo-4-(tert)-bu
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fast and gave a significantly bette
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espectively) due to the cyclohexyli
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was treated with excess amount of b
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Fig. III.1.20. 1 H NMR spectrum of
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stereochemistry of allylation of β
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of the products were modest (48-62%
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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-
Page 205 and 206: IIV. .33: : SSYNTHESSIISS OFF 33' '
Page 207 and 208: For the actual synthesis, (Scheme I
Page 209: Fig. IV.3.1. 1 H NMR spectrum of 14
Page 213 and 214: (i) PhCHO, triethyl orthoformate, M
Page 215 and 216: O N 3 II Ph HO OH b1 N 3 Ph O O Ben
Page 219 and 220: Thus, easily accessible 1 has been
Page 221 and 222: 167 and subsequent reduction gave 1
Page 223 and 224: from the appearance of 13 C NMR pea
Page 227 and 228: IV.6 EXPERIMENTAL SECTION (2R,3S,4R
Page 229 and 230: As described earlier, compound 108
Page 231 and 232: 19.5, 23.8, 23.9, 25.1, 26.9, 34.6,
Page 233 and 234: 74.2, 74.4, 110.1, 116.7, 127.6, 12
Page 235 and 236: mmol) in MeOH (10 mL), work up, fol
Page 237 and 238: 7.51 (m, 3H), 7.92-8.08 (m, 2H); 13
Page 239 and 240: subsequent isolation afforded rotam
Page 241 and 242: 4.18 (t, J = 3.4 Hz, 1H), 4.75-4.84
Page 243 and 244: -4.21 (c 1.2, CHCl 3 ); IR: 3466, 1
Page 245 and 246: (3R)- 3,4-O-Cyclohexylidene-2-oxo-1
Page 247 and 248: Water and EtOAc was added to the mi
Page 249 and 250: 24 179. Yield: 1.49 g (77.5%); colo
Page 251 and 252: 24 furnished pure 183. Yield: 0.37
Page 253 and 254: 1. Wender, P. A. Chem. Rev. 1996, 9
Page 255 and 256: 17. Hanessian, S.; Maji, D. K.; Gov
Page 257 and 258: 32. For some selective references s
Page 259 and 260: 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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