CHEM01200604012 Dibakar Goswami - Homi Bhabha National ...

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Cram rule actually allows the analysis of the stereochemical outcome of such a reaction. On the basis of the nature of the substituents at the chiral centre, two different conformations of the substrate 21 were proposed together with the favored trajectory of the attacking nucleophile to explain the preferential formation of 22 and 23, respectively (Scheme I.3.6). a) Cram-chelate rule : 23 If chelation between the carbonyl group and one of the substituents of the α-stereocentre facilitated by a metal cation can occur, the transition state is locked into the conformation 24, leading to 23 as the major product (Scheme I.3.7). Nu Nu - 24 23 R O S L M Met S R M L OH Cram-chelate or anti-Felkin product Scheme I.3.7 b) Cram rule: 22b If chelation can not occur, 25 was proposed to be the preferred reactive conformation based on steric reasons. Consequently, L is oriented anti to the carbonyl group. A nucleophile will now preferably attack from side of S, leading to 22 as the major product (Scheme I.3.8). L R M S O Nu - L R M Nu S 25 22 OH Cram or Felkin product Scheme I.3.8 14
If a strongly electronegative group, e. g., a halogen atom is present α to the C=O group, a dipolar model is suggested to predict the stereochemical outcome of the reaction. The dipoles of the carbonyl bond and the C-X bond oppose each other and so they are placed anti as in the model 26 so as to minimize the dipolar repulsion. The nucleophile adds from the side of S giving the major product as shown in Scheme I.3.9. Nu X S R M O X R Nu S OH M 26 27 Scheme I.3.9 Desptite correctly predicting the stereochemical course of the reactions, the Cram's models often fails to give a quantitative assessment of the asymmetric induction in terms of steric interactions. A few alternative models have been proposed to predict the stereochemical outcome of the designated reactions in more quantitative terms. Of these the Felkin-Anh model, discussed below has gained consensus. In Felkin-Anh model, 24 In this model, two reactive conformations 28 and 29 (Scheme I.3.10) have been considered in which either the largest (L) or the most electron withdrawing group (which provides the greatest σ*-π* overlap with the carbonyl π* orbital, allowing delocalization of the electron density by hyperconjugation from the reaction centre towards L) at C α is placed at right angle to the C=O double bond. Between the two, the first with M opposing C=O and S gauche to R is usually preferred. The nonbonded interactions which involve R and S (rather than R and M as in 29) are thus minimized. The model predicts the same stereochemistry as Cram’s, but provides a more 15
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 and 22: For the benzylation reaction, the c
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: Models for Asymmetric Synthesis. 21
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
Page 73 and 74: Various protocols have been develop
Page 75 and 76: In the absence of a sterically-bulk
Page 77 and 78: IIII. .33. . PPRESSENT WORK It is w
Page 79 and 80: [pyridinium][Sn 2 Cl 5 ] etc. can b
Page 81 and 82: RCHO 59a-j i R OH 60a-j (i) Allyl b
Page 83 and 84: Fig. II.3.2. 1 H NMR spectrum of 60
Page 85 and 86: in [bmim][BF 4 ] using sub-stoichio
Page 87 and 88: The reaction in THF was also follow
Page 89 and 90: The integration of the signal at δ
Page 91 and 92: The standard reduction potential of
Page 93 and 94: It has also been reported, 83a,b th
Page 95 and 96: IIII. .33. .33 Gaal lliuum meeddi i
Page 97 and 98: 5 3.0 5.0 THF LiCl+KI c 14 d 71 6 1
Page 99 and 100: 3 59d 4-(CH 3 ) 2 CH-C 6 H 4 H 60d
Page 101 and 102: Fig. II.3.8. 13 C NMR spectrum of 6
Page 103 and 104: 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-
Page 201 and 202:
Page 203 and 204:
Page 205 and 206:
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
Page 253 and 254:
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
Page 281 and 282:
1. Goswami, D.; Chattopadhyay, A.;
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