CHEM01200604012 Dibakar Goswami - Homi Bhabha National ...

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(2R,3S,4S)-3-(tert)-Butyldiphenylsilyloxy-1,2-cyclohexylidenedioxy-4-methylhex-5-ene 128. To a solution of 69c (1.44 g, 6.37 mmol) and imidazole (0.828 g, 12.18 mmol) in CH 2 Cl 2 (30 mL) was added TBDPSCl (2.51 g, 9.15 mmol), and the mixture stirred for 12 h at room temp. After completion of the reaction (cf. TLC), it was poured into water (20 mL) and extracted with CHCl 3 (15 mL). The organic extract was washed with water and brine, dried, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-5% EtOAc/hexane) to give pure 128. Yield: 2.75 g (93%); colourless oil; 23 [α] D +31.8 (c 2.31, CHCl 3 ); IR: 1586, 998, 909 cm -1 ; 1 H NMR: δ 0.93 (d, J = 7.0 Hz, 3H), 1.05 (s, 9H), 1.23-1.51 (m, 10H), 2.28-2.37 (m, 1H), 3.70-3.86 (m, 3H), 4.01-4.10 (m, 1H), 4.96-5.01 (m, 2H), 5.81-5.98 (m, 1H), 7.22-7.26 (m, 6H), 7.68-7.77 (m, 4H); 13 C NMR: δ 14.2, 19.6, 23.9, 24.0, 25.3, 26.9, 27.2, 34.7, 36.2, 40.9, 66.6, 76.1, 77.8, 108.9, 114.7, 127.5, 127.6, 129.7, 129.8, 133.8, 133.9, 135.6, 136.2, 140.4. Anal. Calcd. for C 29 H 40 O 3 Si: C, 74.95; H, 8.68%. Found: C, 75.10; H, 8.56%. (2R,3S,4R)-3-(tert)-Butyldiphenylsilyloxy-4,5-cyclohexylidenedioxy-2-methylpentanal 129. Ozone was bubbled through a cooled (-78 °C) solution of 128 (2.55 g, 5.49 mmol) in CH 2 Cl 2 (20 mL) till the solution turned blue. After 0.5 h, the excess O 3 was removed by purging with N 2 (gas), the mixture treated with Ph 3 P (6.0 g, 22.89 mmol), and stirred for 16 h at room temperature. Most of solvent was removed in vacuo, the residue was dissolved in hexane (30 mL) and chormatographed (silica gel, 0-10% EtOAc/hexane) to 22 furnish pure 129. Yield: 2.08 g (81%); colourless oil; [α] D +8.2 (c 1.00, CHCl3 ); IR: 1726 cm -1 ; 1 H NMR: δ 1.01 (s, 9H), 1.16-1.28 (m containing a d at δ 1.26, J = 7.0 Hz, 5H), 1.41-1.48 (m, 8H), 2.68-2.71 (m, 1H), 3.42-3.48 (m, 1H), 3.74-3.81 (m, 1H), 4.12-4.22 (m, 2H), 7.32-7.42 (m, 6H), 7.56-7.71 (m, 4H), 9.55 (d, J = 1.2 Hz, 1H); 13 C NMR: δ 7.4, 187
19.5, 23.8, 23.9, 25.1, 26.9, 34.6, 36.2, 49.9, 67.6, 73.9, 76.1, 109.6, 127.6, 127.9, 129.9, 130.2, 132.2, 133.4, 135.9, 136.2, 204.8. Anal. Calcd. for C 28 H 38 O 4 Si: C, 72.06; H, 8.21%. Found: C, 71.85; H, 8.45%. (4R/S,5S,6S,7R)-6-(tert)-Butyldiphenylsilyloxy-7,8-cyclohexylidenedioxy-5-methyloct- 1-en-4-ol 130. To a cooled (10 °C) and stirred mixture of 129 (1.95 g, 4.17 mmol), Zn dust (0.543 g, 8.34 mmol) and allyl bromide (1.01 g, 8.34 mmol) in THF (25 mL) was dropwise added aqueous saturated NH 4 Cl (8 mL) in 30 min. The mixture was stirred for 4 h at ambient temperature until the aldehyde was totally consumed (TLC). The mixture was filtered, the precipitate thoroughly washed with EtOAc, the aqueous layer separated, acidified with 5% aqueous HCl, and the clear solution extracted with EtOAc (30 mL). The organic extract was washed successively with aqueous 10% NaHCO 3 , H 2 O and brine, and dried. Solvent removal in vacuo gave a residue which was column chromatographed (silica gel, 0-25% EtOAc/ hexane) to isolate 130 as an inseparable diastereomeric mixture. Yield: 1.61 g (76%); colourless oil; IR: 3443 cm -1 ; 1 H NMR: δ 1.06 ( overlapping s and d, J = 7.2 Hz, 12H), 1.29-1.43 (m, 10H), 1.54-1.85 (m, 3H), 1.98-2.21 (m, 1H), 3.47-3.62 (m, 3H), 4.04-4.17 (m, 2H), 4.87-4.99 (m, 2H), 5.80-5.96 (m, 1H), 7.26-7.45 (m, 6H), 7.61-7.70 (m, 4H); 13 C NMR: δ 6.3, 11.1, 19.3, 23.8, 24.9, 27.1, 34.9, 35.0, 35.8, 39.6, 42.4, 43.5, 68.3, 68.7, 71.8, 72.7, 74.1, 74.5, 74.6, 79.9, 109.9, 110.2, 116.7, 127.6, 129.0, 133.2, 133.5, 133.6, 134.9, 135.3, 135.4, 136.0. Anal. Calcd. for C 31 H 44 O 4 Si: C, 73.18; H, 8.72%. Found: C, 72.93; H, 8.63%. (5R,6S,7R)-6-(tert)-Butyldiphenylsilyloxy-7,8-cyclohexylidenedioxy-5-methyloct-1-en- 4-one 131. To a cooled (0 °C) and stirred suspension of PCC (1.02 g, 4.68 mmol) and NaOAc (0.09 g, 1.11 mmol) in CH 2 Cl 2 (20 mL) was added the alcohol 130 (1.59 g, 3.12 188
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
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) )-
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: As described earlier, compound 108
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.
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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