Stereoselective oxidative phenol coupling in filamentous fungi

MICHAEL MÜLLER
Institut für Pharmazeutische Wissenschaften
Universität Freiburg
Albertstr. 25
D-79104 Freiburg
michael.mueller@pharmazie.uni-freiburg.de
http://www.pharmazie.uni-freiburg.de/chemie/

References
Unselective Phenolic Coupling of Methyl 2-Hydroxy-4-methoxy-6-methylbenzoate - A Valuable Tool for the Total Synthesis of Natural Product Families: D. Drochner, W. Hüttel, M. Nieger, M. Müller, Angew. Chem. 2003, 42, 961-963; Angew. Chem. Int. Ed. 2003, 115, 931-933.
One monomeric orsellinate suffices for the implementation of a highly efficient total synthesis of the dimeric coumarins kotanin, isokotanin A and desertorin C. This is due to the unselective process of its oxidative phenolic coupling, which affords three regioisomeric biaryls as precursors for the desired dimers.

A short and Efficient Total Synthesis of the Naturally Occurring Coumarins Siderin, Kotanin, Isokotanin A and Desertorin C: W. Hüttel, M. Nieger, M. Müller, Synthesis 2003, 1803-1808.
Starting from methyl 2-hydroxy-4-methoxy-6-methylbenzoate and its three regioisomeric dehydrodimers, readily available by an oxidative coupling reaction, the naturally occurring coumarins siderin, kotanin, isokotanin A and desertorin C were synthesized in a novel and highly efficient three-step transformation. In the case of kotanin both atropisomers were prepared.

Chemical Diversity through Biotransformations: M. Müller, Curr. Op. Biotechnol. 2004, 15, 591-598.
Diversity constitutes an intrinsic property of biosynthesis. This inherent property can be exploited and successfully applied in organic synthesis. Recent advances have been made in many areas, including the use of multifunctional enzymes and catalytic promiscuity, the synthesis of diverse products from a single substrate, the use of different biotransformations to make one product, and the use of in vivo biotransformations.

Stereoselective Synthesis of 1,3-Diols: S. E. Bode, M. Wolberg, M. Müller, Synthesis 2006, 557-588.
Many polyketide-derived natural products contain a syn- or anti-1,3-diol unit. No general and simple approach exists for the flexible synthesis of polyols and other polyketide-derived structural units, therefore a multitude of methods for the stereoselective synthesis of 1,3-diols has been developed. Asymmetric homogeneous and heterogeneous hydrogenation and diastereoselective reduction, chain elongation, enzymatic and nonenzymatic desymmetrization, or dynamic kinetic resolution are some of these methods. The development of different methods to synthesize these 1,3-diols stereoselectively is important, as often small structural changes in a molecule result in low yields or low stereoselectivity with a known method. This review article highlights some of the recent developments in this field.

Dimeric Orsellinic Acid Derivatives: Valuable Intermediates for Natural Product Synthesis: D. Drochner, W. Hüttel, S. E. Bode, M. Müller, U. Karl, M. Nieger, W. Steglich, Eur. J. Org. Chem. 2007, 1749-1758.
Herein we report on the synthesis of dimeric orsellinates by the Ullmann reaction as well as by biomimetic oxidative phenolic coupling. The Ullmann reaction gives the 5,5'- and 3,3'-coupled dimeric orsellinates regioselectively. Oxidative phenolic coupling reaction of methyl 2-hydroxy-4-methoxy-6-methylbenzoate affords the regioisomeric dimeric 3,3'?, 5,5'- and 3,5'-orsellinates simultaneously, which can be separated easily by column chromatography. The atropisomers of the 5,5'- and 3,3'-coupled dimers were partially resolved using chiral column chromatography. Additionally, the enantiomers of 3,3'-dimeric biaryl could be obtained in pure form by derivatizing the racemic compound with chiral auxiliaries, separating the diastereomers by column chromatography and cleaving the auxiliary groups. Thereby the absolute configuration of the biaryl axis in (M)-configurated camphanate ester could be determined by X-ray structure analysis. The racemic and (P)-configurated dimeric orsellinates were used for the synthesis of dimeric dihydroanthracenones by a tandemMichael-Dieckmann reaction.

Dimeric Regio- and Stereoselective Intermolecular Oxidative Phenol Coupling in Kotanin Biosynthesis by Aspergillus niger: W. Hüttel, M. Müller, ChemBioChem. 2007, 8, 521-529.
The intermolecular, regio- and stereoselective phenol coupling for the biosynthesis of the bicoumarin kotanin in Aspergillus niger has been investigated. Feeding experiments with singly and doubly 13C-labeled monomeric precursors clearly proved that it is not the coumarin siderin but its hydroxy derivative, demethylsiderin, that undergoes phenol coupling. However, siderin is demethylated regioselectively to demethylsiderin and it is the latter that is coupled to the corresponding dehydrodimer, orlandin. The product is subsequently O-methylated in a stepwise fashion to demethylkotanin and kotanin. Crude extracts were analysed by HPLC with chemically synthesized bicoumarins as reference compounds. This and a stereochemical analysis of the isolated bicoumarins revealed that A. niger produces exclusively the (P)-atropisomers of the three 8,8'-bicoumarins, kotanin, demethylkotanin, and orlandin. The absence of other monomeric or dimeric coumarins strongly suggests an intermolecular, regio- and stereoselective mode for the phenol-coupling step.

Synthesis, Biosynthesis, and Absolute Configuration of Vioxanthin: S. E. Bode, D. Drochner, M. Müller, Angew. Chem. 2007, in press (DOI: 10.1002/anie.200701014).
The biosynthesis of the biarylic compound vioxanthin by regio- and stereoselective intermolecular oxidative phenol coupling is explored in the filamentous fungi Penicillium citreo-viride and the first enantioselective total synthesis of vioxanthin is described. The absolute configuration of the dimeric dihydronaphthopyranone (P,R,R)-vioxanthin and its (M,R,R)-stereoisomer was elucidated by combining synthetic methods and feeding experiments with 13C-labelled substrates.

[back]