CHEM01200604012 Dibakar Goswami - Homi Bhabha National ...

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IIII. .22 IINTRODUCTIION TO HOMOALLYLIIC ALCOHOLSS: : ALLYLATIION OFF CARBONYLSS Homoallylic alcohols are important building blocks in organic syntheses, since the alkene functionality can be readily transformed into a wide variety of functional groups such as aldehydes (via ozonolysis), δ-lactones, epoxides, and other olefinic compounds (via cross-metathesis). 55 Furthermore, they are widely distributed in many biological active molecules such as macrolides, polyhydroxylated natural products, polyether antibiotics and alkaloids. 56 Various methods e.g. Alder-ene reaction, 57a Hosomi-Sakurai Reaction, 57b Nozaki-Hiyama coupling reaction 57c etc. have been developed for the diastereoselective synthesis of homoallylic alcohols. However, the metal-mediated allylation of aldehydes is the most popular for its efficiency and ease of operation. The reaction generates a stereogenic carbinol centre with unsubstituted allyl halides. More importantly, reactions with the γ-substituted allyl halides (R-CH=CHCH 2 X, R = Aryl, alkyl; X = Cl, Br) generates two stereogenic centres due to the involvement of allylic rearrangement in the allylic-metal reagents (Scheme II.2.1). The reaction is highly efficient in terms of atom economy, as all the carbons form the scaffold of the desired molecules. O R 1 R 2 OH solvent + R 3 X + M R 1 conditions R 2 R 3 R 1 /R 2 = H/alkyl, R 3 = H (allyl halide), Me (crotyl halide), Ph (cinnamyl halide) M = metal (Zn, Sn, In, Ga etc.) Scheme II.2.1 31
Various protocols have been developed for allylation of carbonyls. 58 Amongst these, the Barbier type protocol is convenient since the reactions can be carried out without the need to isolate the active allyl-metal species responsible for allylation. 59a Currently, considerable attention is given to perform the reaction in “green solvents” viz. H 2 O 59b-d and room temperature ionic liquids (RTILs) 59e from environmental concerns. Reeppoorrt teedd meet thhooddss oof f meet taal l meeddi iaat teedd aal llyyl laat tioonn Ever since Luche et al. used Zn metal in moist THF with aqueous saturated NH 4 Cl for allylation, 60 other metals such as Mn, Sn, In, Ga, etc. have also been explored for this purpose. Li et al. studied the Mn mediated allylation of aromatic aldehydes in presence of catalytic amount of Cu metal. 61a Sn has also been used as a metal of choice for carrying out allylation reactions in THF, H 2 O and RTILs. 61b-h Likewise, preformed allyltin 62a,b and crotyltin 62c reagents have also been successfully employed for this reaction. For example, the crotyl stannane 50 was used for diastereoselective crotylation of benzaldehyde in the presence of BF 3 .Et 2 O (Scheme II.2.2). 62d CHO + Me SnBu 3 OH 49 50 51 i Me syn : anti 82 : 18 (i) BF 3 .Et 2 O, CH 2 Cl 2 . Scheme II.2.2 Other metals viz. Cd, 63a Bi with KF as metal activator 63b and Sb 63c have also been utilized for the allyaltion of carbonyls. Of late, In metal, belonging to group 13 is being used extensively for this reaction. 64 The pioneering work of Araki et al. showed 65a that even α,β-unsaturated aldehydes could be chemoselectively allylated in a 1,2-fashion using 32
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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
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 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: Marshall. 53 More recently, Barbero
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
Page 105 and 106: fragmentation peak at m/z 138 (19%)
Page 107 and 108: Fig. II.3.13. 13 C NMR spectrum of
Page 109 and 110: active catalyst, as suggested for t
Page 111 and 112: 1-(4-Bromophenyl)-but-3-en-1-ol 59b
Page 113 and 114: 1H), 7.90-7.93 (m, 1H); 13 C NMR:
Page 115 and 116: 662, 980, 1079, 1332, 1374 cm -1 .
Page 117 and 118: IIIIII. .11 DIIASSTEREOSSELECTIIVE
Page 119 and 120: cyclohexylideneglyceraldehyde (1) 3
Page 121 and 122: 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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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.;
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L.; Zugay, J. A. J. Med. Chem. 1993
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1. Goswami, D.; Chattopadhyay, A.;
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