CHEM01200604012 Dibakar Goswami - Homi Bhabha National ...

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(m, 12H), 1.61-1.72 (m, 2H), 3.36-3.48 (m, 2H), 3.62 (t, J=7.2Hz, 1H), 3.71 (dd, J = 2.2 and 6.4 Hz, 1H), 3.86-3.93 (m, 1H), 4.09-4.16 (m, 1H), 7.25-7.47 (m, 6H), 7.66-7.73 (m, 4H); 13 C NMR: δ 15.2, 19.3, 23.7, 23.8, 25.0, 26.9, 33.8, 34.5, 35.2, 35.9, 60.7, 67.4, 75.6, 77.5, 108.9, 127.3, 127.4, 129.5, 129.6, 133.4, 133.5, 135.8. Anal. Calcd. for C 29 H 42 O 4 Si: C, 72.15; H, 8.77%. Found: C, 72.34; H, 8.52%. (2R,3S,4S)-1,2-O-Cyclohexylidene-3-O-(tert)-butyldiphenylsilyl-4-Methyl-6- benzyloxyhexane 178. Reaction of 177 (2.80 g, 5.81 mmol) with BzCN (0.83 mL, 6.97 mmol) and Et 3 N (1.2 mL, 8.71 mmol) in CH 2 Cl 2 (15 mL), followed by work up, isolation and purification by column chromatography (silica gel, 0-10% EtOAc/hexane) furnished 24 pure 178. Yield: 3.06 g (90%); light yellow oil; [α] D -8.7 (c 1.2, CHCl3 ); IR: 1719, 909 cm -1 ; 1 H NMR: δ 1.04 (d merged with s, 12H), 1.31-1.49 (m, 10H), 1.59-1.65 (m, 1H), 1.85-1.93 (m, 2H), 3.54-3.62 (m, 1H), 3.70 (dd, J = 1.8 and 7.0 Hz, 1H), 3.87-3.95 (m, 1H), 4.09-4.20 (m, 3H), 7.25-7.38 (m, 9H), 7.50-7.66 (m, 4H), 7.90-7.99 (m, 2H); 13 C NMR: δ 14.7, 19.3, 23.7, 25.0, 26.7, 26.9, 31.3, 34.4, 34.6, 35.9, 63.2, 67.6, 75.4, 77.3, 190.0, 127.4, 128.1, 129.4, 129.6, 130.3, 132.5, 133.3, 133.5, 135.8, 166.2. (2R,3S,4S)-3-O-(tert)-butyldiphenylsilyl-4-Methyl-6-O-benzoyl-1,2,3,6-tetrahydroxyhexane 179. A mixture of 178 (2.8 g, 4.78 mmol) in CH 2 Cl 2 (25 mL) and aqueous 80% TFA (10 mL) was stirred for 3 h at 0 °C. The mixture was diluted with water (50 mL) and extracted with CHCl 3 (50 mL), the organic layer separated and the aqueous layer extracted with CHCl 3 (20 mL). The organic extract was washed successively with aqueous 2% NaHCO 3 (10 mL), H 2 O (20 mL) and brine, and dried. Solvent removal in vacuo followed by column chromatography of the residue (silica gel, 0-5% MeOH/CHCl 3 ) furnished pure 205
24 179. Yield: 1.49 g (77.5%); colouless oil; [α] D +6.72 (c 1.61, CHCl 3); IR: 3448, 1717 cm -1 ; 1 H NMR: δ 1.03 (d, J = 6.98 Hz, 3H), 1.09 (s, 9H), 1.61-1.66 (m, 1H), 1.9-2.0 (m, 2H), 2.42 (broad s, 2H), 3.53-3.61 (m, 1H), 3.69-3.80 (m, 3H), 4.13-4.19 (m, 2H), 7.25- 7.45 (m, 9H), 7.65-7.71 (m, 4H), 7.92-7.97 (m, 2H); 13 C NMR: δ 15.1, 19.4, 27.0, 31.3, 34.0, 63.4, 63.9, 72.8, 77.4, 127.4, 127.6, 128.1, 129.3, 129.7, 130.1, 132.6, 133.2, 135.8, 166.5. Anal. Calcd. for C 30 H 38 O 5 Si: C, 71.11; H, 7.56%. Found: C, 71.33; H, 7.39%. (3S,4S)-1-O-Benzoyl-3-methyl-4-O-tert-butyldiphenylsilyl-oct-5-ene 181. To a stirred solution of 179 (1.37 g, 2.7 mmol) in 60% aquous acetonitrile (25 mL) at room temperature was added NaIO 4 (1.16 g, 5.4 mmol). The mixture was stirred for ~2 h (cf. TLC), filtered, washed with EtOAc, and the organic layer was washed with water, brine and dried. Solvent was removed under reduced pressure to afford crude aldehyde 180. 24 Yield: 1.15 g (91%); [α] D +30.50 (c 0.8, CHCl3 ); IR: 1723 cm -1 ; 1 H NMR: δ 1.16 (s merged with d, 12H), 1.68-1.72 (m, 1H), 1.90-2.12 (m, 2H), 3.98-4.02 (m, 1H), 4.24-4.32 (m, 2H), 7.33-7.42 (m, 8H), 7.63-7.98 (m, 5H), 7.97-7.99 (m, 2H), 9.61-9.66 (m, 1H); 13 C NMR: δ 15.3, 19.3, 26.9, 30.4, 34.9, 62.7, 81.1, 127.7, 128.2, 129.4, 129.9, 132.7, 135.6, 166.2, 204.0. To a cooled (-60 o C) suspension of n-C 3 H 7 PPh 3 Br (1.4 g. 3.6 mmol) in THF (50 mL) was added n-BuLi (3.6 mL of 1 M in hexane). The resultant orange mixture was stirred for an additional 1 h. To it was added a solution of the aldehyde 180 (1.0 g, 2.12 mmol) in THF (20 mL) over a period of 45 min. The mixture was stirred for an additional 2 h at -60 o C, gradually brought to 0 o C and stirred further for 30 min. The reaction was quenched by adding aqueous saturated NH 4 Cl and extracted with EtOAc (50 mL). The 206
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
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IV.1.3: Present work Although sever
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O O C 6 H 13 i O C 6 H 13 ii OH C 6
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Fig. IV.1.4. 1 H NMR spectrum of 10
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the unit-C contribute positively to
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tartrate, Ti(O-i-Pr) 4 , CH 2 Cl 2
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Based on this hypothesis, the alcoh
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Page 199 and 200: (OH). Oxidative cleavage of its α-
Page 201 and 202: Fig. IV.2.2. 1 H NMR spectrum of 13
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 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: Water and EtOAc was added to the mi
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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