1. Total Synthesis of the Potent cAMP Signaling Agonist (–)-Alotaketal A
Jinhua Huang,† Jessica R. Yang, ‡ Jin Zhang,*,‡ and Jiong Yang*,†
J. Am. Chem. Soc. 2012, 134,
Speaker： 呂益誌
Date ：2012/8/4

2. What is cAMP ? Nitrogenous bases Pentose
Earl Sutherland discoveries concerning the mechanisms of the action of hormones, especially epinephrine, via second messengers is call cyclic adenosine monophosphate (cAMP).
cAMP is synthesised from ATP by adenylyl cyclase located on the inner side of the plasma membrane.
Nitrogenous bases
Pentose

3. Signaling cAMP in cells
cMAP involved in the activation of protein kinases and regulates the effects of adrenaline and glucagon.
cMAP binds to and regulates the function of ion channels and few other cyclic nucleotide-binding proteins such as Epac1.
Development of new modulators of cAMP signaling has implications for treating heart failure, cancer, and neurodegenerative diseases.

4. Structure of (–)-Alotaketal A

5. Past synthesis of spiroketals
J. Am. Chem. Soc. 1999, 121,
Emmanuel A. Theodorakis

6. Past synthesis of spiroketals
J. Am. Chem. Soc. 2006, 128,
Micheal T. Crimmins

7. Past synthesis of spiroketals
J. Am. Chem. Soc. 2011, 133,
Thomas R.R. Pettus

8. Isolation and Bioactivity of (–)-Alotaketal A
In 2009, Anderson lab describing the isolation of alotaketals A (1) and B (2) from the marine sponge Hamigera sp. Collected in Papua New Guinea
Alotaketals A (1) was found to cause potent activation of cAMP cell signaling in the absence of hormone binding in a cell-based pHTS-CRE luciferase reporter gene assay with halfmaximal effective concentration (EC50 ) values of 18 nM
3μM

9. Family structure of (–)-Alotaketal A

10. Family structure of (–)-Alotaketal A

11. Retrosynthetic analysis of (–)-Alotaketal A+

12. Retrosynthetic analysis of (–)-Alotaketal A

13. Synthesis of 5β-hydroxycarvone by Mukaiyama reaction

14. Mitsunobu reaction Luche reduction Barbier coupling
Construction of lactol 15 through intramolecular Barbier-type allylation
Mitsunobu reaction
Luche reduction
Barbier coupling

15. Preparation of bicyclic lactone 7

16. Synthesis of aldehyde 22 by DMP oxidation reaction

17. Preparation of allyl iodide 8

18. Combine allyl iodide 8 and bicyclic lactone 18 by Barbier coupling

19. To obtain spiroketals 29/30 via spiroketalization

20. Synthesis of 22-deoxyalotaketal A (33) and isomer 34

21. Combine allyl iodide 8 and bicyclic lactone 7 by Barbier coupling+

22. To obtain spiroketals 29/30 via spiroketalization

23. Total Synthesis of (–)-Alotaketal A (1)

24. Bioactivity test of (–)-Alotaketal A and analogues

25. Bioactivity test of (–)-Alotaketal A and analogues32 D E 1
To examine the effects of 1 and its analogues 29, 30, and 32−34 on cAMP/PKA signaling using a genetically encoded A kinase activity reporter (AKAR4).
6.5 ± 0.32% (n = 10 )
4.4 ± 1.1% (n = 6 )
5.3 ± 2.2% (n = 13 )
6.7 ± 2.5% (n = 24 )

26. Conclusion
Tthe first total synthesis of (-)-alotaketal A and confirmed its assigned absolute configuration. The synthesis proceeds in 26 steps and 2.3% overall yield.
The synthesis features two Barbier-type intraand intermolecular SmI2 -mediated reductive allylations.
Hg(OAc)2-mediated selective functionalization of the Δ7,22 alkene and the subtlety of the spiroketalization/isomerization of the unprecedented spiroketal ring system.

27. Thanks for your attendance

29. Mitsunobu reaction

30. Barbier coupling

31. Luche reduction