Erstmals gelang die enantioselektive Totalsynthese der cytotoxischenM eroterpenoide Terreumol Au nd Ca us dem Gemeinen Erd-Ritterling Tricholoma terreum. Schlüsselschritt ist der Aufbau des zehngliedrigen Rings durchO lefinmetathese zur trisubstituierten Z-Doppelbindung des [8.4.0]-Bicyclus,d ie nur in Abwesenheit freier Hydroxygruppen gelang.( À)-Terreumol Cw urde vollständig diastereoselektiv in das Bisepoxid( À)-Terreumol Aü berführt, das somit ausgehend von 2-Brom-3,4-dimethoxybenzaldehyd in 14 Stufen und einer Gesamtausbeute von 23 %erhalten wurde. Eine Rçntgenstrukturanalyse des p-Benzochinon-Analogons von (À)-Terreumol Abestätigt die absolute Konfiguration der Naturstoffe.Schema 4. Ringschlussmetathesezu(À)-Terreumol C(2). IBX = o-Iodoxybenzoesäure.Schema 5. Oxidation von (À)-Terreumol C(2)zu(À)-Terreumol A(1) und zum p-Benzochinon 25 mit Molekülstruktur im Kristall. mCPBA = meta-Chlorperbenzoesäure.
The cytotoxic meroterpenoids terreumol A and C from the grey knight mushroom Tricholoma terreum were synthesized for the first time. The key step of the enantioselective total synthesis of terreumol C is a ring-closing metathesis to form a trisubstituted Z double bond embedded in the 10-membered ring of the [8.4.0] bicycle. Interestingly, the presence of a free hydroxy group in the metathesis precursor prevents cyclization and favors cross metathesis. (-)-Terreumol C was converted into (-)-terreumol A by diastereoselective epoxidation. Starting from 2-bromo-3,5-dimethoxybenzaldehyde, 14 steps with an overall yield of 23 % are needed for the synthesis of (-)-terreumol A. X-ray analysis of the benzoquinone analogue of terreumol A provides independent proof of the absolute configuration.
Aiming at the discovery of new cytotoxic meroterpenoids, the chemical reactivity of the natural product (-)-terreumol C from the edible mushroom Tricholoma terreum was investigated. A series of high-yielding oxygenations and brominations at the 10-membered ring were discovered. The regioselectivity of hydroxylation could be guided by installing protecting groups at the hydroquinone section. Dihydroxylation led to the stereoselective formation of a novel tricycle containing an 11-oxabicyclo[5.3.1]undecane system. Several of the compounds proved to be as cytotoxic against cancer cell lines as the natural products terreumols A and C in the single-digit micromolar range. Interestingly, functionalization of the southern rim formed by carbons C5-C6-C7-C8 is tolerated without much loss of cytotoxicity.
The first synthesis of diterpenoid eunicellane skeletons incorporating a 1,3-cyclohexadiene moiety is presented. Key step is a low-valent titanium-induced pinacol cyclization that proved to be perfectly diastereoselective. Determination of the relative configuration of the diol was aided by the conversion to the diastereomer by oxidation and reduction. Conformational analysis of some of the resulting diols obtained under McMurry conditions was complicated by the presence of several conformers of similar energy. The pinacol coupling appears to start at the ketone, as indicated by the selective reduction of non-cyclizing cyclohexane systems that were synthesized from limonene oxide. The title compounds and their synthetic precursors are prone to aromatization on contact with air oxygen. Attempted synthesis of cyclohexene-containing eunicellane bicycles by elimination of water from tertiary alkynyl carbinols afforded novel allene systems. Our study may be of help towards the total synthesis of solenopodin or klysimplexin derivatives.
The first enantioselective total synthesis of the cytotoxic meroterpenoids terreumol A (I) and C (II), originally isolated from the grey knight mushroom Tricholoma terreum, is described.
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