CHEM01200604012 Dibakar Goswami - Homi Bhabha National ...

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Table 4. Reaction course of Mg/CuCl 2 .2H 2 O-mediated benzylation of aldehydes a Entry R Time (h) product Yield (%) 1 n-C 6 H 13 (10a) 18 11a 61.8 2 n-C 9 H 19 (10b) 16 11b 64.4 2 n-C 13 H 27 (10c) 16 11c 57.8 4 C 6 H 5 (10d) 9 11d 71.7 5 3-MeOC 6 H 5 (10e) 8 11e 73.8 6 4-Et-C 6 H 5 (10f) 7 11f 70.7 7 4-Cl-C 6 H 5 (10g) 11 11g 68.9 8 (R)-2,3-Cyclohexylideneglyceral (3) b 20 12a + 12b 68.4 a The reactions were carried out at 2 mmol scale. The yields refer to those of isolated pure products. b In this case the isomers 12a and 12b were isolated in 80:20 ratio. The diastereoselectivity of the substrate-controlled asymmetric allylation is known to be governed by the nature of the metal and reaction medium. 8 In view of this, in an alternate approach, this aspect was investigated by carrying out the allylation of 3 with different allylic bromides using different metal-solvent combinations. For this, both Grignard and Barbier-type protocols were explored using different metals (Mg, Sb, In, Ga and Bi) and solvents (H 2 O, THF, and [bmim][Br]) (Scheme 6), and the results are summarized in Tables 5-7. xii
O O 3 CHO i O O + OH 13a O O OH O O OH 13b + O O OH + O O OH + O O OH 7a. R = CH 3 9a. R = C 6 H 13 7b. R = CH 3 7c. R = CH 3 7d. R = CH 3 9b. R = C 6 H 13 9c. R = C 6 H 13 9d. R = C 6 H 13 i) Allyl bromide/g-alkylated allyl bromide, metal (Mg/Sb/In/Ga/Bi), solvent (H 2 O/THF/[bmim][Br]) Scheme 6 The In-mediated allylation (Scheme 6, Table 5) produced best yield (78%) of the allylated products (13a/b) in [bmim][Br], while excellent syn:anti diastereoselectivity (2:98) was achieved in THF. Surprisingly, Ga was ineffective in THF and proceeded with modest yield and diastereoselectivity` in H 2 O. Table 5. Reaction course of allylation of 3 using different metals in different solvents a Entry Allyl Metal Solvent Additive Time (h) Yield 13a:13b c bromide (equiv.) (%) (equiv.) 1 4 In (2.5) H 2 O -- 5 58 24.2 : 75.8 2 3.5 In (2.5) THF KI + LiCl 7 69 2.0 : 98.0 3 1.2 In (1.0) [bmim][Br] -- 3 78 29.8 : 70.2 4 4 Ga (2.5) H 2 O -- 6 48 21.9 : 78.1 5 3.5 Ga (2.5) THF KI + LiCl 16 NR -- 6 1.2 Ga (1.0) [Bmim][Br] -- 4 73 5.0 : 95.0 xiii
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 and 20: imetallic systems. In all the cases
Page 21: For the benzylation reaction, the c
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
Page 71 and 72: 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
Page 151 and 152:
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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
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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.;
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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