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

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Presentation on theme: "Zaragozic Acids: Synthesis of Core, Side Chains and Total Synthesis of the Zaragozic Acid A and C Literature Meeting Presented by Kimberly-Ann Laberge."— Presentation transcript:

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, >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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

26 Carreira’s Retrosythesis Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 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, , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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

29 Synthesis of C6 O-Acyl Side Chain Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, >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, , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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

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

33 Functionalization Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

34 Ketalizaton Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

35 Functionalization Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

36 Towards Zaragozic Acid C Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

37 1 st Method Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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

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

40 2 nd Method Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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

42 Towards Zaragozic Acid C Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

43 Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 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, , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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

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

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, >10:1

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

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35,

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, Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, , Nadin, A.; Nicolaou, K.C. Angew. Chem. Int. Ed. Engl. 1996, 35, 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


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