Slide 1:1


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


Slide 3:3 Callipeltosides A, B & C


Slide 4:4 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.


Slide 5:5 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


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


Slide 7:7 Retrosynthetic analysis of Callipeltoside C


Slide 8:8 Callipeltoside C


Slide 9:9 Callipeltoside C Synthesis:


Slide 10:10 Callipeltoside C Synthesis:


Slide 11:11 Callipeltoside C Retrosynthesis of Fragment 2:


Slide 12:12 Callipeltoside C Steps in Synthesis of Fragment 2: 12


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


Slide 14:14 Callipeltoside C


Slide 15:15 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.


Slide 16:16 Callipeltoside C Barbier Allylation Reaction


Slide 17:17 Callipeltoside C


Slide 18:18 Callipeltoside C


Slide 19:19 Callipeltoside C Protection of secondary hydroxyl group:


Slide 20:20 Callipeltoside C Mechanism:


Slide 21:21 Callipeltoside C Deprotection of PMB group:


Slide 22:22 Callipeltoside C Mechanism:


Slide 23:23 Callipeltoside C Parikh-Doering Oxidation:


Slide 24:24 Callipeltoside C Mechanism:


Slide 25:25 Callipeltoside C


Slide 26:26 Negishi carbometalation-iodination: Callipeltoside C


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


Slide 28:28 Swern Oxidation Callipeltoside C


Slide 29:29 Callipeltoside C Mechanism:


Slide 30:30 Callipeltoside C 30


Slide 31:31 Callipeltoside C 31


Slide 32:32 Callipeltoside C


Slide 33:33 Callipeltoside C 33


Slide 34:34 Callipeltoside C


Slide 35:35 Callipeltoside C


Slide 36:36 Callipeltoside C


Slide 37:37 Callipeltoside C 37


Slide 38:38 Callipeltoside C


Slide 39:39 Callipeltoside C


Slide 40:40 Callipeltoside C Synthesis of fragment 5:


Slide 41:41 Callipeltoside C Retrosynthetic analysis:


Slide 42:42 Callipeltoside C Mechanism:


Slide 43:43 Callipeltoside C Takai Olefination Reaction


Slide 44:44 Callipeltoside C Bestman Ohira Homolgation 44


Slide 45:45 Callipeltoside C


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


Slide 47:47 Callipeltoside C Hydroboration/ chlorination


Slide 48:48 Callipeltoside C Hydroboration/ chlorination


Slide 49:49 Callipeltoside C Synthesis of fragment 5a: 49


Slide 50:50 Callipeltoside C


Slide 51:51 Callipeltoside C Synthesis of fragment 5a:


Slide 52:52 Callipeltoside C Synthesis of fragment 5a:


Slide 53:53 Callipeltoside C Roush Modification


Slide 54:54 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


Slide 55:55 Callipeltoside C Synthesis of fragment 5:


Slide 56:56 Callipeltoside C


Slide 57:57 Callipeltoside C


Slide 58:58 Callipeltoside C Horner-wadsworth-Emmons Olefination


Slide 59:59 Callipeltoside C


Slide 60:60 Callipeltoside C


Slide 61:61 Callipeltoside C Yamaguchi Lactonization:


Slide 62:62 Callipeltoside C


Slide 63:63 Callipeltoside C Synthesis of Carbohydrate moiety


Slide 64:64 Callipeltoside C 64


Slide 65:65 Callipeltoside C Mechanism:


Slide 66:66 Callipeltoside C


Slide 67:67 Callipeltoside C


Slide 68:68 Callipeltoside C Barton-McCombie Protocol:


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


Slide 70:70 Callipeltoside C 71


Slide 71:71 Callipeltoside C


Slide 72:72 Callipeltoside C


Slide 73:73 Callipeltoside C 73


Slide 74:74 Callipeltoside C


Slide 75:75 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


Slide 76:76 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


Slide 77:77 THANK YOU