Total Synthesis of (±)‐Pumiliotoxin C: An Electrochemical Approach

Abstract

The total stereoselective synthesis of the decahydroquinoline alkaloid (±)‐pumiliotoxin C (cis‐195A, 1) is described. The compound was prepared in 15 steps from the commercially available 4‐piperidone ethylene ketal 2, in an overall 5 % yield. New C–C bonds in the α position relative to the nitrogen atom were formed by the metalation of aminonitriles 4 and 15, which were themselves prepared electrochemically. The ease of this synthesis shows that the N‐aryl group is an efficient nitrogen‐protecting group that can be removed in the last step through a Birch dearomatization. In addition, the aryl substituent serves as an efficient activator of the nitrogen atom during the elaboration of aminonitriles 4 and 15. The oxygen atom of the keto carbonyl group in octahydroquinolinone 10 was removed by an unprecedented two‐step method involving a Shapiro reaction and a palladium‐catalyzed reduction of the intermediate alkene 13. Finally, the expected stereospecific alkylation–hydride reduction process of the cis‐fused aminonitrile 15 established the trans relationship between the propyl group at C‐2 and the methyl substituent at C‐5. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Transition metals in organic synthesis: Highlights for the year 2005

“…Michael additions of dimethylcuprate were used in synthesis of hamigeran B [202], (+)-allocyathine B 2 [128], umbrosone [85]. Stereoselective Michael additions of organocopper reagents were used in synthetic applications toward cylindramine [324], pumiliotoxin C [1613], fumagalone analogs [503], tridachiahydropyrone [1614], guanacastepenes [1516] and 5-epi-10-epi-vibsanin E [704].…”

Quinoline, quinazoline and acridone alkaloids

“…cis-Decahydroquinoline 195A (pumiliotoxin C) 154, the best known and most widespread member of the decahydroquinoline family of amphibian skin alkaloids, remains a popular target for synthesis. Among the interesting features in a new route to the racemic compound by Girard et al 73 is the unusual use of an Nphenyl protecting group, which was attached to the commercially available piperidin-4-one ketal 155 by treatment with bromobenzene and the complex superbase prepared from sodium amide and sodium tert-butoxide (Scheme 8). The electrochemical oxidation of intermediate 156 in the presence of a cyanide ion produced the aminonitrile 157, the anion of which was alkylated with 1bromo-3-chloropropane under carefully controlled conditions to give 158 in 94% yield.…”

Electrochemical strategies for C–H functionalization and C–N bond formation

“…Applying a Pictet-Spengler reaction between the electrosynthesized a-methoxyamines and substituted tryptamines afforded the biologically active indole alkaloid nazlinine (88c) and numerous related unnatural congeners (Scheme 20). 238 Other alkaloids that have been prepared include (À)-crispine A 239 and (AE)-pumiliotoxin C. 240 Here, anodic cyanation furnished the desired a-amino nitriles, which upon further manipulations furnished the target alkaloids. The Santos laboratory has also demonstrated the utility of the Shono oxidation in total syntheses of ropivacaine 241 (93, Scheme 21), (À)-quinolactacin B 242 (96,Scheme 22) as well as (+)-lennoxamine 243 (99,Scheme 23).…”