Actinophyllic acid

Actinophyllic acid (3), an indole alkaloid with novel l-azabicyclo-[4.4.2]dodecane and l-azabicyclo[4.2.1]nonane fragments, was isolated from the tree Alstonia actinophylla, collected on the Cape York Peninsula, Queensland, Australia, in 2005 by Quinn, Carroll and coworkers [23]. As a carboxypeptidase U inhibitor (IC50 = 0.84 pM), actinophyllic acid shows potential application for the treatment of cardiovascular disorders [23]. Much effort has been devoted to this unique molecule, including recent synthetic studies by Wood and coworkers [24], but only Overman et al. has accomplished its synthesis [25],... 

This racemic synthesis of actinophyllic acid (3) was accomplished in eight steps with an overall 15% yield from the readily available indole di-ferf-butyl malonate 9. The intramolecular oxidative coupling of ketone and malonate enolates and an aza-Cope-Mannich rearrangement for the construction of the unprecedented actinophyllic acid ring skeleton are the key transformations. 

Scheme 2 Total synthesis of actinophyllic acid (3) by Oveiman and coworkers...

Martin CL, Overman LE, Rohde JM (2008) Total synthesis of ( )-actinophyllic acid. J Am Chem Soc 130 7568-7569... 

A concise synthesis of the indole alkaloid ( )-actinophyllic acid was reported, in which a key step involves a cationic reaction cascade. The indole (163) is treated with TMSOTf to generate the electrophilic carbocation (164), and this reacts with a dihydroazepine to provide the A-acyliminium ion intermediate (166). A Eriedel-Crafts reaction gives the indole product (165) and the framework for actinophyllic acid (Scheme 34). 

The aza-Cope Mannich reaction has observed extensive use in natural product synthesis.One example of its use is in the concise synthesis of the indole alkaloid actinophyl-lic acid 104 (Scheme 17.24). ° Actinophyllic acid was isolated from the leaves of the tree Alstonia actinophylla and shows inhibitory activity toward carboxypeptidase U. Substrate 105 for this sequence is readily obtained from di-tert-butyl malonate in only five steps. Treatment of this material with TFA in CH2CI2 cleaves the A-protecting... 

SCHEME 17.24. Synthesis of actinophyllic acid via aza-Cope-Mannich sequence. 

Procedure for the aza-Cope Mannich sequence from the total synthesis of actinophyllic acid (Scheme 1735). Pentacyclic diester 108 Trifluoroacetic acid (2.0 mL) was added to a 0 C... 

The formation of C—C bonds by oxidative coupling has been used by Overman and co-workers in their total synthesis of the hexacyclic alkaloid actinophyllic acid. This compound was isolated from the tree Alstonia actinophylla,... 

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