CHEM01200604012 Dibakar Goswami - Homi Bhabha National ...

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1H), 3.85-3.95 (m, 1H), 4.05-4.16 (m, 2H), 5.10-5.17 (m, 2H), 5.57-5.75 (m, 1H); 13 C NMR: δ 16.2, 23.9, 24.0, 25.1, 33.9, 34.9, 36.5, 42.6, 67.2, 73.9, 76.1, 77.0, 109.6, 117.2, 141.3. Anal. Calcd. for C 15 H 26 O 4 : C, 66.64; H, 9.69%. Found: C, 66.43; H, 9.82%. (4S,5S,6S,7R)-4-Benzoyloxy-6-(tert)-butyldiphenylsilyloxy-7,8-cyclohexylidenedioxy- 5-methyloct-1-ene 136. The alcohol 132 (0.800 g, 1.58 mmol) was benzoylated with PhCOCN (0.484 mL, 4.08 mmol) in CH 2 Cl 2 (15 mL) at 0 o C as described earlier. Work up and column chromatography (silica gel, 0-10% EtOAc/hexane) afforded pure 136, but as a 22 mixture of rotamers. Yield: 0.858 g (90%); light yellow oil; [α] D +13.5 (c 2.52, CHCl3 ); IR: 2935, 2857, 1638 cm -1 ; 1 H NMR: δ 1.16 (overlapping d and s, J = 7.0 Hz, 12H), 1.23- 1.54 (m, 10H), 1.92-2.10 (m, 1H), 2.23-2.31 (m, 2H), 3.75-3.86 (m, 2H), 3.89-3.99 (m, 1H), 4.13-4.21 (m, 1H), 4.87-5.01 (m, 2H), 5.45-5.52 (m, 1H), 5.56-5.77 (m, 1H), 7.29- 7.45 (m, 9H), 7.66-7.92 (m, 5H), 7.98-8.05 (m, 1H) ; 13 C NMR: δ 10.6, 11.0, 19.5, 23.7, 23.8, 25.1, 27.1, 34.7, 34.9, 35.7, 36.1, 36.8, 40.1, 40.5, 64.0, 67.8, 73.5, 73.8, 75.1, 75.5, 76.5, 109.4, 109.6, 116.9, 117.0, 127.4, 127.5, 128.3, 129.1, 129.4, 129.6, 129.7, 129.8, 130.2, 132.1, 132.9, 133.8, 133.9, 134.1, 135.8, 136.0, 136.1, 165.4, 165.5. Anal. Calcd. for C 38 H 48 O 5 Si: C, 74.47; H, 7.89%. Found: C, 74.28; H, 7.68%. (2R,3S,4S,5S)-1,2-Cyclohexylidenedioxy-5-benzoyloxy-4-methyloct-7-en-3-ol 137. Desilylation of 136 (0.800 g, 1.33 mmol) with Bu 4 NF (2.25 mL, 2.25 mmol, 1 M in THF) in THF (20 mL) at 0 o C, followed by work up and purification by column chromatography (silica gel, 0-10% EtOAc/hexane) furnished pure 137. Yield: 0.390 g (79%); colourless oil; 22 [α] D +18.7 (c 1.60, CHCl3 ); IR: 3437, 1720 cm -1 ; 1 H NMR: δ 1.06 (d, J = 7.4 Hz, 3H), 1.20-1.36 (m, 2H), 1.48-1.57 (m, 8H), 2.01-2.13 (m, 1H), 2.35-2.52 (m, 3H), 3.72-3.89 (m, 3H), 4.03-4.21 (m, 1H), 4.97-5.13 (m, 2H), 5.43-5.50 (m, 1H), 5.72-5.93 (m, 1H), 7.35- 193
7.51 (m, 3H), 7.92-8.08 (m, 2H); 13 C NMR: δ 11.4, 23.7, 23.9, 25.1, 34.4, 34.9, 36.0, 38.9, 64.1, 71.7, 74.7, 109.4, 117.5, 128.3, 129.5, 130.5, 132.8, 134.2, 165.9. Anal. Calcd. for C 22 H 30 O 5 : C, 70.56; H, 8.07%. Found: C, 70.35; H, 7.96%. (2R,3R,4S,5S)-1,2-Cyclohexylidenedioxy-5-benzoyloxy-4-methyloct-7-en-3-ol 138. Oxidation of 137 (0.350 g, 0.95 mmol) with PCC (0.334 g, 1.52 mmol) in CH 2 Cl 2 (20 mL), followed by work-up furnished the 3-keto compound. In view of its instability it was directly used for the next step. For this, K-selectride ® (1.31 mL, 1.31 mmol, 1 M in THF) was injected into a cooled (-78 o C) and stirred solution of the above compound (0.290 g, 0.78 mmol) in THF (15 mL). After stirring the mixture at the same temperature till completion of the reaction (cf. TLC, ~ 3 h), the excess hydride was decomposed with MeOH, the supernatant decanted and concentrated in vacuo. The residue was taken in Et 2 O (50 mL), the organic extract washed with H 2 O and brine, and dried. Removal of solvent in vacuo followed by column chromatography of the residue (silica gel, 0-10% 22 EtOAc/hexane) furnished pure 138. Yield: 0.291 g (82%); colourless oil; [α] D +38.8 (c 1.06, CHCl 3 ); IR: 3477, 1724 cm -1 ; 1 H NMR: δ 1.03 (d, J = 7.2 Hz, 3H), 1.32-1.36 (m, 2H), 1.37-1.57 (m, 8H), 2.09-2.21 (m, 1H), 2.26-2.34 (m, 2H), 3.50-3.54 (m, 1H), 3.87- 3.94 (m, 2H), 4.13-4.18 (m, 1H), 4.34-4.45 (m, 1H), 5.03-5.12 (m, 2H), 5.25-5.32 (m, 1H), 5.78-5.93 (m, 1H), 7.39-7.53 (m, 3H), 7.99-8.06 (m, 2H); 13 C NMR: δ 15.0, 23.7, 23.8, 25.0, 34.7, 36.1, 40.6, 64.4, 73.8, 76.2, 79.1, 109.1, 114.9, 129.4, 130.3, 133.2, 136.7, 140.4, 167.7. Anal. Calcd. for C 22 H 30 O 5 : C, 70.56; H, 8.07%. Found: C, 70.71; H, 8.15%. (2R,3R,4S,5S)-1,2-Cyclohexylidenedioxy-4-methyloct-7-en-3,5-diol 138a. A mixture of 138 (0.100 g, 0.267 mmol) and anhydrous K 2 CO 3 (0.062 g, 0.454 mmol) in MeOH (10 mL) was stirred at 0 o C. After consumption of the starting material (cf. TLC, ~2 h), the 194
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
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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
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are consistent with our previous re
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III.3 EXPERIMENTAL SECTION: General
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(2R,3R)-1,2-Cyclohexylidenedioxy-5-
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for an additional 2 h, gradually br
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(m, 2H), 5.82-5.98 (m, 1H), 7.25-7.
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31.6, 32.2, 63.4, 128.8, 133.0. Ana
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23 (2R,3S,4R)-1,2-Cyclohexylidenedi
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(2R,3S,4S)-1,2-Cyclohexylidenedioxy
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(m, 1H), 3.50-4.02 (m, 5H), 4.10-4.
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and dried. Removal of solvent in va
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ine, and dried. Solvent removal und
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IIV. .11 SSYNTHESSIISS OFF ENANTIIO
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Scheme IV.1.1 The same group also d
Page 185 and 186: IV.1.3: Present work Although sever
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Page 189 and 190: Fig. IV.1.4. 1 H NMR spectrum of 10
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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) )-
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: mmol) in MeOH (10 mL), work up, fol
Page 239 and 240: subsequent isolation afforded rotam
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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.
Page 261 and 262: 54. Barbero, A.; Pulido, F. J.; Rin
Page 263 and 264: 2008, 1681. (d) Fargeas, V.; Zammat
Page 265 and 266: 72. Karodia, N.; Guise, S.; Newland
Page 267 and 268: Kaminski, J.; Millhauser, G.; Ortiz
Page 269 and 270: Böhm, V. P. W.; Reisinger, C. J. O
Page 271 and 272: 119. Wender, P. A.; Holt, D. A.; Si
Page 273 and 274: 140. (a) Chemler, S. R.; Roush, W.
Page 275 and 276: Lett. 1996, 107, 53. (c) Smith, C.
Page 277 and 278: 158. Mitsuya, H.; Weinhold, K. J.;
Page 279 and 280: L.; Zugay, J. A. J. Med. Chem. 1993
Page 281 and 282: 1. Goswami, D.; Chattopadhyay, A.;
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