Research (English)
Research of the Brückner Group
Our research interests are the total synthesis of natural products, the synthesis of biologically active analogs thereof, and - in the context of this work - the development of efficient synthetic methodology.
Alkylidenbutenolides
Among the more than 700 natural occuring carotenoids a few contain a butenolide moiety. The most prominent example of such a carotenoid is peridinin (1, Scheme 1) and the runner-up is the closely related pigment pyrrhoxanthin (not shown). These compounds are key-constituents of the light-harvesting complexes of plankton. Striving towards these and related compounds in order to find out what is so special about them, we realized a total synthesis of peridinin in 27 steps (Angew. Chem. Int. Ed. Engl. 2005, 44, 1553-1557; Angew. Chem. Int. Ed. Engl. 2006, 45, 4023-4027).
Scheme 1.
In 1990 the dye “xerulinic acid” (2, Scheme 2) was isolated from the fungus Xerulina melanotricha and reported to have a hypocholesterolemic effect different from that of the statins. Its key structural motifs are the hexaenediyne backbone and the annulated γ-alkylidenebutenolide. Through a modular approach we were able to synthesize xerulinic acid for the first time (Angew. Chem. Int. Ed. Engl. 2004, 43, 4523-4526; Chem. Eur. J. 2005, 11, 1610-1624).
Scheme 2.
Naturally Occuring Lactones with a Five-Membered Ring
Other targets of interest are tetronic acid antibiotics - like iso-gregatin D (3) - and thiotetronic acid antibiotics - like thiolactomycin (4) (Scheme 3). A further-reaching goal in this field is determining the 3D-structure of the tetronic acid derivatives kodaistatin A (5) and C (not shown) through enantioselective synthesis of its four diastereomers. Kodaistatins are inhibitors of the glucose-6-phosphate translocase. Therefore, they spur the hope for a new therapy of diabetes II. As a spin-off-result we have developed broadly applicable accesses to the pulvinone core (6) of this class of compounds.
Scheme 3.
For the enantioselective synthesis of β-hydroxy-γ-lactones we have established a „Sharpless-dihydroxylation / lactonization” approach (Scheme 4). This methodology allows to transform β,γ-unsaturated carboxylic esters 7 in a single step and with usually high enantioselectivities in butyrolactones 9 (Synlett 2005, 1281-1285; Chem. Eur. J. 2005, 11, 2154-2162; Eur. J. Org. Chem. 2006, 2110-2118; ibid. 2119-2133).
Scheme 4.
The β-hydroxy-γ-butyrolactones 9 obtained by this method were converted into naturally occuring lactones of a wide variety of substitution patterns (Scheme 5).
Scheme 5.
Polyol,Polyene Macrolide Antibiotics
The so-called polyol,polyene macrolide antibiotics are knwon for their high activity against Gram-positive bacteria and their complex structures. Our group pursues the total syntheses of four such macrolides plus selected unnatural derivatives thereof, namely mycoticin B (10), roflamycoin (12), amphotericin B, and pentamycin (Scheme 6). The syntheses of the polyol-fragments of the former two molecules were already completed in the form of building-blocks 11 and 13, respectively.
Scheme 6.
During the aforementioned endeavors we have developed several methods for the stereoselective construction of the 1,3-diol subunit. Originally, our “lactone→1,3-diol degradation” played a key-role in this context, more recently, the 4-step transformation of enones 14 shown in Scheme 7 (Synlett 2005, 2905-2910).
Scheme 7.
Further Targets in Natural Product Synthesis
Scheme 8.
