CHEM01200604012 Dibakar Goswami - Homi Bhabha National ...

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HO 80 OH i HO 81 OTBDPS ii Br 82 OTBDPS O O H O 1 iii O R O R O R O R O + O + O + O OH OH OH OH 83a 83b 83c 83d R = CH 2 OTBDPS i) TBDPSCl, imidazole, CH 2 Cl 2, 25 o C; (ii) MsCl, Et 3 N, CH 2 Cl 2 , 0 o C; NaBr, acetone, 25 o C.; iii) Zn, aqueous satd. NH 4 Cl, THF, 25 o C; or CuCl 2 , 2H 2 O, Zn, THF, 0 o C-25 o C; or FeCl 3 , Zn, THF, 10 o C-25 o C; or CoCl 2 , 8H 2 O, Zn, THF, 10 o C-25 o C. Scheme III.1.7 Table III.1.4. Reaction course of addition of 82 to 1 a Entry Metal/ salt 1 : bromide : metal time Product ratio b Yield c : metal salt 83a/b: 83c : 83d (%) 1 Zn/ aq NH 4 Cl 1: 3.0 : 3.5 : - 5 h 3 : 52 : 45 73.0 2 Zn / CoCl 2 .8H 2 O 1:3.0: 3.5:3.5 20 h 2 : 70 : 28 72.1 3 Zn/ CuCl 2 .2H 2 O 1:3.0: 3.5:3.5 20 h 2 : 33 : 65 70.0 4 Zn/ FeCl 3 1:3.0: 3.0:3.0 30 min 2 : 50 : 48 83.0 a The reactions were carried out at 5 mmol scale. b Combined yields of isolated pure products. c Based on isolated yields. The overall yields of the products from the Co-, Cu- and Zn-mediated additions were comparable (entries 1-3, Table III.1.4), but the reactions were sluggish requiring extended stirring. The 83c/83d ratio for the Cu- and Co-mediated reactions were reverse. (entries 2-3, Table III.1.4). The Fe-mediated reaction (entry 4, Table III.1.4) was very 98
fast and gave a significantly better yield (83%) of the products. Both Zn- and Fe-mediated reactions produced the alcohols, 83c and 83d in almost 1:1 ratio. In this case also, the observed excellent 2,3-anti selectivity suggested that the reactions followed the Felkin Anh model, 24b,112 irrespective of the metal chosen. Apparently the α-chelate attack was not favored due to hydration of metals in the moist reaction environment. Interestingly, of the four cases, the Cu-mediated addition produced a higher amount of the 3,4-anti product. The formation of significant amounts of both 3,4- syn- and 3,4-anti-products gave ample evidence of a considerable amount of E,Z equilibration of the allylic intermediate during carbon-carbon bond formation. As evident from the above, none of the above protocols were suitable for the preparation of 83a and 83b, which are also useful chiral intermediates, and may be required for the synthesis of suitable target compounds. Since both these compounds possess a β-hydroxy function, in principle, the previously described oxidation-reduction strategy might be suitable for their synthesis. Hence, for their preparation (Scheme III.1.8), compounds 83c and 83d were separately oxidized with PCC to afford the respective ketones 84c and 84d in good yields. Formations of these compounds were confirmed from the appearance of sharp carbonyl IR board band at ~1715 cm -1 in place of the hydroxyl band. Reduction of these ketones with K-selectride ® furnished the desired 2,3-syn products 83b and 83a in good yields, almost exclusively. As expected, the IR spectra of these compounds showed broad bands at ~3500 cm -1 and absence of the CO peak. The mechanistic rationalization of the steric course of the reduction established the 2,3-syn stereochemistry of 83a and 83b, confirming the 2,3-anti relationship in their progenitors, 83c and 83d. Thus, the studies provided efficient routes to prepare all the four 99
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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
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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
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
Page 123 and 124: Fig. III.1.2. 13 C NMR spectrum of
Page 125 and 126: Reaction with crotyl bromide: In ca
Page 127 and 128: Fig. III.1.5. 1 H NMR spectrum of 6
Page 129 and 130: The formation of the 2,3-anti addit
Page 131 and 132: To establish the C-4 configuration
Page 133 and 134: Allylation with (E) and (Z)-1-bromo
Page 135 and 136: (i) Zn, aqueous satd. NH 4 Cl, THF,
Page 137 and 138: Fig. III.1.12. 1 H NMR spectrum of
Page 139: Allylation with 1-Bromo-4-(tert)-bu
Page 143 and 144: espectively) due to the cyclohexyli
Page 147 and 148: was treated with excess amount of b
Page 149 and 150: Fig. III.1.20. 1 H NMR spectrum of
Page 153 and 154: stereochemistry of allylation of β
Page 155 and 156: of the products were modest (48-62%
Page 157 and 158: 6 1.2 In (2.0) H 2 O LiCl+ KI 14 72
Page 159 and 160: are consistent with our previous re
Page 161 and 162: III.3 EXPERIMENTAL SECTION: General
Page 163 and 164: (2R,3R)-1,2-Cyclohexylidenedioxy-5-
Page 165 and 166: for an additional 2 h, gradually br
Page 167 and 168: (m, 2H), 5.82-5.98 (m, 1H), 7.25-7.
Page 169 and 170: 31.6, 32.2, 63.4, 128.8, 133.0. Ana
Page 171 and 172: 23 (2R,3S,4R)-1,2-Cyclohexylidenedi
Page 173 and 174: (2R,3S,4S)-1,2-Cyclohexylidenedioxy
Page 175 and 176: (m, 1H), 3.50-4.02 (m, 5H), 4.10-4.
Page 177 and 178: and dried. Removal of solvent in va
Page 179 and 180: ine, and dried. Solvent removal und
Page 181 and 182: IIV. .11 SSYNTHESSIISS OFF ENANTIIO
Page 183 and 184: Scheme IV.1.1 The same group also d
Page 185 and 186: IV.1.3: Present work Although sever
Page 187 and 188: O O C 6 H 13 i O C 6 H 13 ii OH C 6
Page 189 and 190: 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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Fig. IV.2.2. 1 H NMR spectrum of 13
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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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