1. Zaragozic Acids: Synthesis of Core, Side Chains and Total Synthesis of the Zaragozic Acid A and C Literature Meeting Presented by Kimberly-Ann Laberge April 17, 2007

2. Zaragozic Acids -Characterized by a 4,6,7-trihydroxy-2,8-dioxabicyclo[3,2,1]octane-3,4,5-tricarboxylic acid core with an array of six stereogenic centers including contiguous quaterny ones, with various C1 alkyl and the C6 O-acyl side chains. -Zaragozic Acid A was extracted from an unidentified sterile fungal culture, Sporormiella intermedia, and Zaragozic Acid B and C from a fungal strain, Leptodontium elatius. -Class of Natural Products that have been shown to be potent inhibitor of both squalene synthase, an enzyme found in the cholestrol biosynthetic pathway, and farnesyl-protein transferase(FPTase), a potential target enzyme in the treatment of cancer. Sooty Blotch = Leptodontium elastius

3. Family of Zaragozic Acids.Nicolaou (Dihydroxylation Strategy).Carreira (Carbonyladdition Strategy).Evans (Tartrate-Derived Aldol Strategy)

4. Outline -Total Synthesis of Zaragozic Acid:.A: Nicolaou -Synthesis of the Side Chains.C. Carreira -Synthesis of the Side Chains.C: Evans

5. Nicolaou’s Retrosynthesis Addition of the C6 O-Acyl Side Chain Addition of the C1 Akyl Side Chain Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

6. Nicolaou’s Retrosynthesis Dihydroxylation Stille Coupling Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

7. Synthesis of the C1 Akyl Side Chain Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

8. Synthesis of the C1 Akyl Side Chain Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656. >95:5

9. Synthesis of the C1 Akyl Side Chain Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

10. Synthesis of the C1 Akyl Side Chain Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656. C1 Alkyl Side Chain 8% overall yield in 10 steps from 4 (allylic alcohol) Recrystallisation for cyclohexane to give 95% ee

11. Synthesis of C6 O-Acyl Side Chain Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656. C6 O-Acyl Side Chain 92% de

12. Stille Coupling Organostannate R-Halide Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

13. Stille Coupling Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

14. 1 st Assymetric Dihydroxylation β-face α-face Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

15. 2 nd Assymetric Dihydroxylation Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

16. Functionalization Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

17. Functionalization Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

18. Dithiane Addition – 1 st Attempt Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656. Undesired Product

19. Dithiane Addition – 2 nd Attempt Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

20. Rearrangement Cascade Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

21. Dithiane Addition – 3 rd Attempt Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

22. Rearrangement Cascade Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

23. Coupling of the Side Chain Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

24. Completion of the Total Synthesis Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656. Zaragozic Acid A

25. Nicolaou’s Total Synthesis Summary Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

26. Carreira’s Retrosythesis Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656. Addition of C6 side chain Ketalisation Addition of C1 side chain

27. Synthesis of the C1 Akyl Side Chain Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

28. Synthesis of the C1 akyl chain C1 Akyl Chain Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

29. Synthesis of C6 O-Acyl Side Chain Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656. >95% ee 60:40 mixture

30. Synthesis of C6 O-Acyl Side Chain C6 O-Acyl Side Chain Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

31. Carbonyl Addition 20:1 Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

32. Addition of the C1 Alkyl Chain Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

33. Functionalization Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

34. Ketalizaton Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

35. Functionalization Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

36. Towards Zaragozic Acid C Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

37. 1 st Method Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

38. 1 st Method Cont’d Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

39. 1 st Method Cont’d Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

40. 2 nd Method Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

41. 2 nd Method Cont’d Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

42. Towards Zaragozic Acid C Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

43. Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656. Addition of the C6 O-Acyl Side Chain (+)-Zaragozic Acid C If coupling of the C6 side chain was done on 50, the hydroxyl groups free at C6 and C7 position, a 1:3 mixture of C6:C7

44. Carreira’s Total Synthesis Summary Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826., Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656. -Highly diastereoselective addition of the Grignard to an unsaturated ketone: + effect of Cosolvant and additive -Use of [Cr(OAc) 2.H 2 O] 2 for stereoselective reduction -Regiselective protection of the C7 carbinol vs the C6 OH -Installation of 3 aldehydes simultaneously (more efficient)

45. Evans’s Retrosynthesis Esterification Ketalisation Addition Zaragozic Acid C Barrow, J. C.; Leighton, J. L.; Robichaud, A. J.; Sefkow, M.; Evans, D. A. J. Am. Chem. Soc. 1994, 116, 12111-12112. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

46. Evans’s Retrosynthesis Mukaiyama Aldol Reaction Evan’s Aldol Reaction Barrow, J. C.; Leighton, J. L.; Robichaud, A. J.; Sefkow, M.; Evans, D. A. J. Am. Chem. Soc. 1994, 116, 12111-12112. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

47. Evans Aldol Reaction Barrow, J. C.; Leighton, J. L.; Robichaud, A. J.; Sefkow, M.; Evans, D. A. J. Am. Chem. Soc. 1994, 116, 12111-12112. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

48. Mukaiyama Aldol Reaction Barrow, J. C.; Leighton, J. L.; Robichaud, A. J.; Sefkow, M.; Evans, D. A. J. Am. Chem. Soc. 1994, 116, 12111-12112. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

49. Functionalization Correct C5 Dia Barrow, J. C.; Leighton, J. L.; Robichaud, A. J.; Sefkow, M.; Evans, D. A. J. Am. Chem. Soc. 1994, 116, 12111-12112. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656. >10:1

50. Functionalization Barrow, J. C.; Leighton, J. L.; Robichaud, A. J.; Sefkow, M.; Evans, D. A. J. Am. Chem. Soc. 1994, 116, 12111-12112. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

51. Coupling of the Side Chain Barrow, J. C.; Leighton, J. L.; Robichaud, A. J.; Sefkow, M.; Evans, D. A. J. Am. Chem. Soc. 1994, 116, 12111-12112. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

52. Completion of the Total Synthesis (+)-Zaragozic Acid C Barrow, J. C.; Leighton, J. L.; Robichaud, A. J.; Sefkow, M.; Evans, D. A. J. Am. Chem. Soc. 1994, 116, 12111-12112. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656.

53. Evan’s Total Synthesis Summary Barrow, J. C.; Leighton, J. L.; Robichaud, A. J.; Sefkow, M.; Evans, D. A. J. Am. Chem. Soc. 1994, 116, 12111-12112. Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 1622-1656. - Efficient Total Synthesis:.Convergent.Late coupling of the 2 side chains - Complete control exerted over each newly formed chiral center

54. Total Synthesis Summary Carreira (Carbonyladdition Strategy) Nicolaou (Dihydroxylation Strategy) Evans (Tartrate-Derived Aldol Strategy)

55. Retrosynthetic Analysis