CHEM01200604012 Dibakar Goswami - Homi Bhabha National ...

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5 CH 3 Zn/aq NH 4 Cl 1 : 3.5 : - 5 74 7 2.4:32.5:65.1 6 CH 3 Zn/FeCl 3 1: 2.0 : 2.0 0.2 86.9 7 1.5: 48.4: 50.1 7 CH 3 Zn/CuCl 2 .2H 2 O 1: 2.5 : 2.0 15 78.7 7 4.2: 29.5:66.3 8 CH 3 Zn/CoCl 2 .8H 2 O 1: 2.5 : 2.0 24 77.8 7 3.8: 47.5:48.7 9 CH 3 Zn/SnCl 2 1: 2.0 : 2.0 0.75 80.4 7 7.1: 78.2:14.7 10 cis-C 6 H 13 Zn/aq NH 4 Cl 1 : 3.5 : - 4 77.5 9 2.7:51.9:45.4 11 cis-C 6 H 13 Zn/FeCl 3 1 : 3: 3 3 84 9 3.1:28.4:68.5 12 cis-C 6 H 13 Zn/CuCl 2 .2H 2 O 1: 3.5 : 3.5 4 77 9 1.0:48.0:51.0 13 cis-C 6 H 13 Zn/CoCl 2 .8H 2 O 1 : 4.5 : 4 15 NR -- -- 14 trans-C 6 H 13 Zn/aq NH 4 Cl 1 : 3.5 : - 4 77.9 9 4.5:55.5:40.0 15 trans-C 6 H 13 Zn/FeCl 3 1 : 4.5 : 4 15 NR -- -- 16 trans-C 6 H 13 Zn/CuCl 2 .2H 2 O 1 : 3: 3 3.5 83 9 15.1:40.9:44.0 17 trans-C 6 H 13 Zn/CoCl 2 .8H 2 O 1: 3.5 : 3.5 4 78.7 9 7.0:62.0:31.0 a The reactions were carried out at 2 mmol scale. The yields refer to those of isolated pure isomers. The isomeric ratios were determined from the isolated yields. NR: no reaction. While the reaction of 6 with 3 (Scheme 4, Table 3, entries 5-9) using low valent Cu yielded 7d as the major product, the Co and Fe mediated reactions produced 7c and 7d in comparable proportions. In contrast, low valent Sn mediated reaction yielded 7c as the major product. The effect of the olefin geometry on the stereoselectivity of the above allylation reactions was examined using the individual cis and trans isomers of the bromide 8. The combination of Zn/FeCl 3 provided the best results. For a given bimetallic combination, both 3,4-syn 9c and 3,4-anti 9d were produced in almost similar proportions in all the reactions, irrespective of the olefin geometry in 8. The preponderance of the 4,5- anti products in these reactions suggested that the addition followed the Felkin Anh model. x
For the benzylation reaction, the combinations of Zn/CuCl 2. 2H 2 O and Zn/FeCl 3 were unsuccessful. To our delight, the reaction between benzyl bromide and different aldehydes 10a-g took place successfully with the Mg/CuCl 2 .2H 2 O combination affording the homobenzylic alcohols 11a-g in acceptable yields that varied from ~58-74% (Scheme 5, Table 4). The protocol was effective for both aliphatic and aromatic aldehydes, although it was slightly slower with aliphatic substrates. Interestingly, benzylation of 3 produced 12 in better yield (68.4%) and much improved syn selectivity [syn-12a: anti-12b:: 80 : 20] compared to Grignard addition (56% yield and ~1:1 isomeric ratio). The predominant formation of syn-12a suggested the intermediacy of an α-chelate cyclic transition state that would be possible via the involvement of a nucleophilic attack by the organocopper reagent to 3. RCHO 10a-g + PhCH 2 Br i R OH Ph 11a-g i O + PhCH 2 Br O CHO 3 i) Mg, CuCl 2 , 2H 2 O / moist THF/ rt O O 12a OH + Ph O O OH 12b Ph Scheme 5 xi
Page 1: ASYMMETRIC STRATEGIES FOR THE SYNTH
Page 6 and 7: ACKNOWLEDGEMENTS First of all, I wa
Page 8 and 9: CONTENTS SYNOPSIS LIST OF FIGURES L
Page 10: SYNOPSIS
Page 13 and 14: models (e. g. Cram’s model, Felki
Page 15 and 16: 4 1d 4-(CH 3 ) 2 CH-C 6 H 4 1 : 1.5
Page 17 and 18: 14. 1n C 6 H 5 CO C 6 H 5 2n 8 77 1
Page 19: imetallic systems. In all the cases
Page 23 and 24: O O 3 CHO i O O + OH 13a O O OH O O
Page 25 and 26: 10 3.5 Ga (2.5) THF KI+LiCl 10 55 5
Page 27 and 28: multidrug-resistant (MDR) cancer ce
Page 29 and 30: directly afforded the furanose, whi
Page 31 and 32: References 1. Stephenson, G. R. Adv
Page 33 and 34: LIST OF FIGURES
Page 35 and 36: II.3.13 III.1.1 III.1.2 III.1.3 III
Page 37 and 38: IV.5.2 IV.5.3 IV.5.4 IV.5.5 1 H NMR
Page 39 and 40: Table Title Page No. II.3.1 II.3.2
Page 41 and 42: II. .11 PPREAMBLE Demand for specia
Page 43 and 44: II. .22 IINTRODUCTIION TO CHIIRALII
Page 45 and 46: The most dramatic example in this a
Page 47 and 48: H H 2 N OH COOH i PhH 2 CO O H N H
Page 49 and 50: Methods of Asymmetric Synthesis: 15
Page 51 and 52: O O O O i, ii iii iv HO HO N N OH O
Page 53 and 54: Models for Asymmetric Synthesis. 21
Page 55 and 56: If a strongly electronegative group
Page 57 and 58: enantiomeric products are formed at
Page 59 and 60: vi) The balance between chiral auxi
Page 61 and 62: IIII. .11 IINTRODUCTIION TO CHIIRAL
Page 63 and 64: Scheme II.1.2 However, availability
Page 65 and 66: Prof. R. Noyori received the Nobel
Page 67 and 68: Apart from the cinchona alkaloids,
Page 69 and 70: 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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OR 3 O R 1 R 2 NaBH 4 H H R 1 R 1 +
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(OH). Oxidative cleavage of its α-
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Page 203 and 204:
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IIV. .33: : SSYNTHESSIISS OFF 33' '
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For the actual synthesis, (Scheme I
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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
Page 271 and 272:
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.;
Page 279 and 280:
L.; Zugay, J. A. J. Med. Chem. 1993
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1. Goswami, D.; Chattopadhyay, A.;
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