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, 8806-8809 Speaker： 呂益誌 Date ：2012/8/4

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

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.

Structure of (–)-Alotaketal A

Past synthesis of spiroketals J. Am. Chem. Soc. 1999, 121, 456-457 Emmanuel A. Theodorakis

Past synthesis of spiroketals J. Am. Chem. Soc. 2006, 128, 4936-4937 Micheal T. Crimmins

Past synthesis of spiroketals J. Am. Chem. Soc. 2011, 133, 6114-6117 Thomas R.R. Pettus

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

Family structure of (–)-Alotaketal A

Family structure of (–)-Alotaketal A

Retrosynthetic analysis of (–)-Alotaketal A +

Retrosynthetic analysis of (–)-Alotaketal A

Synthesis of 5β-hydroxycarvone by Mukaiyama reaction

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

Preparation of bicyclic lactone 7

Synthesis of aldehyde 22 by DMP oxidation reaction

Preparation of allyl iodide 8

Combine allyl iodide 8 and bicyclic lactone 18 by Barbier coupling

To obtain spiroketals 29/30 via spiroketalization

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

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

To obtain spiroketals 29/30 via spiroketalization

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

Bioactivity test of (–)-Alotaketal A and analogues

Bioactivity test of (–)-Alotaketal A and analogues 32 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 )

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.

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Mitsunobu reaction

Barbier coupling

Luche reduction