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Synlett 2009(11): 1852-1858  
DOI: 10.1055/s-0029-1217510
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Synthesis-Driven Structure Revision of ‘Plagiochin E’, a Highly Bioactive Bisbibenzyl

Andreas Speicher*a, Matthias Groha, Josef Zappb, Anu Schaumlöffelc, Michael Knauerc, Gerhard Bringmannc
a FR 8.1 Chemistry, Organic Chemistry, Saarland University, 66041 Saarbrücken, Germany
Fax: +49(681)3022029; e-Mail: anspeich@mx.uni-saarland.de;
b FR 8.2 Pharmacy, NMR Department, Saarland University, 66041 Saarbrücken, Germany
c Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
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Publication History

Received 9 March 2009
Publication Date:
16 June 2009 (online)

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Abstract

Recently, a bisbibenzyl named plagiochin E showing remarkable antifungal and antitumor activities was isolated from Marchantia polymorpha, a liverwort. The total synthesis of the proposed structure for plagiochin E and of two structurally and biosynthetically related bisbibenzyls and comparison of the NMR data of the synthetic compounds with those of the isolated bisbibenzyls necessitates a structure revision for plagiochin E. Exemplarily for this metabolite, the stereostructure was investigated, by racemate resolution on a chiral Lux Cellulose-1 phase with HPLC-CD coupling and quantum chemical CD calculations, clearly assigning the P-configuration for the faster and the M-configuration to the slower enantiomer.

Key words

plagiochin E - bisbibenzyl - axially chiral biaryl - total synthesis - natural products - circular dichroism

23

General Procedure for the McMurry Macrocyclization: A mixture of zinc dust (2.12 g, 32.4 mmol) and TiCl3(DME)2 (3.00 g, 8.76 mmol) in anhyd DME (80 mL) was heated to reflux for 1.5 h under an argon atmosphere. A solution of the dialdehyde (560 mg, 1.13 mmol) in anhyd DME (100 mL) was added dropwise over 5 h. The black mixture was heated to reflux for 48 h. After cooling to r.t. the reaction mixture was filtered through a short pad of silica gel eluting with EtOAc. The colorless filtrate was then concentrated and purified by flash chromatography (silica gel; hexane-EtOAc, 3:1).

26

Resolution of the enantiomers of 4 was carried out on a Lux Cellulose-1 phase (4.6 mm × 250 mm, 5 µm, Phenomenex); flow rate: 0.5 mL/min using an i-PrOH-n-hexane gradient (20:80, 60:40 for 16.5 min, 95:5 for 9.5 min, 20:80 for 2 min, 20:80 for 12 min).

30

A solution of 37 (2.50 g, 5.03 mmol) and Ph3P˙HBr (1.81 g, 5.27 mmol) in MeCN (60 mL) was refluxed for 12 h. The solvent was removed in vacuo and the crude phosphonium salt was dissolved in anhyd CH2Cl2 (250 mL). This solution was added dropwise over 6 h to a mixture of NaOMe (1.50 g, 27.8 mmol) in anhyd CH2Cl2 (350 mL), and stirring was continued for 12 h. After filtration and evaporation of the solvent the residue was purified by column chromatography (silica gel, CH2Cl2) and 38 was obtained as a colorless solid (1.60 g, 3.44 mmol, 68%).