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2 TOTAL SYNTHESIS AND STRUCTURAL REVISION OF CALLIPELTOSIDE C Angew. chem. Int. Ed. 2008, 47, 3568-3572 SHAZIA KOUSAR

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3 Callipeltosides A, B & C

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4 1- Isolated by Minale and Co- workers in 1996 and 1997. 2- A novel cytotoxic macrolide containing sugar unit. 3- Have antitumor activity , as well as in vitro protection of HIV infected cells. 4- Cytotoxicity, varies among the callipeltosides and their IC50 value range from 11.3 to 30.0 µgml-1 against human bronchopulmonary NSCLC- N6 cell lines. 5 - Block cell proliferation in the G1 phase. 6- Sugar is essential for biological activity while chlorine not.

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5 In term of structure 12-membered macrocycle containing seven stereocentres. A unique dienyne chlorocyclopropane side chain. Differentiated by the composition of saccharides moiety. Callipeltoside A and B are characterized by the presence of two unique deoxyamino sugars, While C incorporates the novel deoxy sugar 2-O- methylevalose. Carbohydrate moities of Callipeltosides B and C exist in opposite enantiomeric series than that found in Callipeltoside A. 5

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6 The unique structure and biological activity of Callipeltoside C have stimulated efforts directed towards the synthesis of this natural product.

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7 Retrosynthetic analysis of Callipeltoside C

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8 Callipeltoside C

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9 Callipeltoside C Synthesis:

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10 Callipeltoside C Synthesis:

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11 Callipeltoside C Retrosynthesis of Fragment 2:

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12 Callipeltoside C Steps in Synthesis of Fragment 2: 12

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13 It is a proline catalyzed transformation that do not require the pregeneration of enolate or enolates equivalents Callipeltoside C

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14 Callipeltoside C

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15 Callipeltoside C Catalytic property of Proline is due to the Bifunctional structure Contains both a nucleophilic secondary amino group and a carboxylic acid moiety functioning as a Bronsted acid. Facilitate a highly pre-organized transition state during the reaction pathway. Available in both enantiomeric forms, which is a definite advantages over enzymatic methods.

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16 Callipeltoside C Barbier Allylation Reaction

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17 Callipeltoside C

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18 Callipeltoside C

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19 Callipeltoside C Protection of secondary hydroxyl group:

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20 Callipeltoside C Mechanism:

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21 Callipeltoside C Deprotection of PMB group:

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22 Callipeltoside C Mechanism:

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23 Callipeltoside C Parikh-Doering Oxidation:

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24 Callipeltoside C Mechanism:

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25 Callipeltoside C

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26 Negishi carbometalation-iodination: Callipeltoside C

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27 Callipeltoside C Zr-assisted carbometallation: Al-assisted carbometallation:

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28 Swern Oxidation Callipeltoside C

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29 Callipeltoside C Mechanism:

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30 Callipeltoside C 30

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31 Callipeltoside C 31

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32 Callipeltoside C

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33 Callipeltoside C 33

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34 Callipeltoside C

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35 Callipeltoside C

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36 Callipeltoside C

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37 Callipeltoside C 37

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38 Callipeltoside C

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39 Callipeltoside C

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40 Callipeltoside C Synthesis of fragment 5:

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41 Callipeltoside C Retrosynthetic analysis:

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42 Callipeltoside C Mechanism:

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43 Callipeltoside C Takai Olefination Reaction

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44 Callipeltoside C Bestman Ohira Homolgation 44

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45 Callipeltoside C

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46 Callipeltoside C 3 Mechanism K-OMe H R H H H H H H 46

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47 Callipeltoside C Hydroboration/ chlorination

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48 Callipeltoside C Hydroboration/ chlorination

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49 Callipeltoside C Synthesis of fragment 5a: 49

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50 Callipeltoside C

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51 Callipeltoside C Synthesis of fragment 5a:

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52 Callipeltoside C Synthesis of fragment 5a:

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53 Callipeltoside C Roush Modification

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54 Angew.Chem.Int.Ed.2008,47,3568-3572 Callipeltoside C 3 R1-X R1 TIOEt Tl-X R1 OEt R2 TIOEt OEt R1 R1-R2 R2 R2

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55 Callipeltoside C Synthesis of fragment 5:

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56 Callipeltoside C

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57 Callipeltoside C

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58 Callipeltoside C Horner-wadsworth-Emmons Olefination

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59 Callipeltoside C

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60 Callipeltoside C

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61 Callipeltoside C Yamaguchi Lactonization:

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62 Callipeltoside C

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63 Callipeltoside C Synthesis of Carbohydrate moiety

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64 Callipeltoside C 64

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65 Callipeltoside C Mechanism:

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66 Callipeltoside C

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67 Callipeltoside C

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68 Callipeltoside C Barton-McCombie Protocol:

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69 Callipeltoside C Mechanism: AIBN + Bu3Sn-H AIBNH +.SnBu3

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70 Callipeltoside C 71

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71 Callipeltoside C

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72 Callipeltoside C

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73 Callipeltoside C 73

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74 Callipeltoside C

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75 Conclusion: It is a first highly efficient enantioselective synthesis of Callipeltoside C. It has been accomplished with longest linear sequence of 20 steps in 11% overall yield from commercially available Roche ester. It also represent the structural revision with respect to the enantioseries of the pendent 2-O-methylevalose carbohydrate. It involve the Proline catalyzed direct aldol reaction & enantioselective a- Oxyamination reaction. Rapid access to the Carbohydrate framework using a de novo synthesis Protocol. 75

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76 Callipeltoside C ABBRIVATIONS TASF: tris( dimethylamino)-sulfonium difluorotrimethyl silicate TBAF: tetra butyl amminium fluoride. AIBN: Azobisisobutyronitrile TMSOTf: Trimethylsilyl trifluoromethanesulfonate MeOTf: Methyl Trifluoromethanesulfonate DMAP: 4-Dimethylaminopyridine HMDS: hexamethyldisilazane

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77 THANK YOU