Cytochrome P450 CYP102A1 from Bacillus megaterium is a fatty acid hydroxylase which catalyses the highly regioselective hydroxylation of branched fatty alcohols like (2R,4R,6R,8R)-tetramethyldecanol (4). The product of this reaction (2R,4R,6S,8S)-tetramethyldecane-1,9-diol (3) can be used in synthesis of macrolide antibiotics. For setting up the biooxidation process on a preparative scale a monophasic aqueous reaction system has been established. The system was optimised using an NADHdependent CYP102A1 mutant, dodecanoic acid as a model substrate and takes advantage of randomly methylated beta-cyclodextrins for the solubilisation of hydrophobic substrates. In the reaction with 50 mM of dodecanoic acid a total turnover number of 66,700 and substrate conversion of 66.7 % could be reached. The total turnover number of a CYP102A1 mutant in the reaction with 23.4 mM (2R,4R,6R,8R)-tetramethyldecanol 4 was 17,290 and substrate conversion reached 74 %. The reaction on a preparative scale yielded 420 mg of (2R,4R,6S,8S)-tetramethyldecane-1,9-diol (3) in 60% de. The major diastereomer 3a has the (2R,4R,6S,8S,9R)-configuration. The configuration of 3a was determined by an X-ray single crystal structure analysis of the corresponding bis-dinitrobenzoate 5a.

Unnatural (+)-capensifuranone (+)-2 and its epimer (-)-5-epi-capensifuranone 6 were prepared from enantiopure methyl-branched aldehyde 4, employing cyclisation with 3-bromomethacrylic acid to 4-bromofuranones 5a,b followed by Negishi cross coupling. Compound 4 was obtained from the preen-gland wax-derived ester 3 after ozonolysis and reductive work-up. The configuration of 6 was determined via the X-ray crystal structure analysis of a derivative 10. Compounds (+)-2, 5a,b and 6 showed cytotoxic activity against L-929 mouse fibroblasts, and KB-3-1 HeLa and U-937 lymphoma cells.

Unnatural (-)-pectinatone (-)-3 was prepared in five steps starting from the highly methylbranched wax ester 4 employing bromination of the ester enolate and subsequent baseinduced elimination to the enoate 6 as the key step. Both (-)-pectinatone 3 and the amides 8b,c, which were isolated as by-products in the reaction sequence, displayed antimicrobial activity and cytotoxicity. As a part of our ongoing program on polypropionate-containing natural products and their unnatural enantiomers, we recently reported the "ex chiral pool" synthesis of (-)-siphonarienone (-)-2 starting from the methyl-branched wax ester 4 [5,6] (Scheme 2) which is obtained from preen-gland wax of the domestic goose Anser a. f. domesticus [7]. Herein 3 the results towards the total synthesis of (-)-pectinatone (-)-3 and its biological evaluation are discussed. Scheme 2Results and Discussion. -As shown in Scheme 3, we first reinvestigated the critical α-hydroxylation/elimination step from wax ester 4 to the unsaturated precursor 6 which was ac- The latter were simply heated in pyridine, giving the target ester 6 as the major product in 59% yield. [13] gave lower yields of 6.Having accomplished this elimination, the further synthesis route to the unnatural pectinatone (-)-3 followed our previously described protocol [5] (Scheme 4). The α,β-unsaturated ester 6 was converted into the Weinreb amide 8a in 81% yield by treatment with Me(OMe)NH · HCl, addition of iPrMgCl and final hydrolysis with NH 4 Cl.In the next step, ethyl 2-methyl-3-oxopentanoate 9, which is accessible by Claisen condensation of ethyl propionate in the presence of NaH [14], was deprotonated with LDA in THF at 0°C and then reacted with the Weinreb amide 8a to yield a mixture of the β,δ-diketo ester 10 (22%) and the amides 8b (26%) and 8c (40%). The formation of amide 8c (Table 1). Additionally, the data of both diastereomeric allylic alcohols 11a and 11a' (Scheme 5) and pure siphonarienones (+)-2 and (-)-2 are listed. Table 1 As can be seen from Table 1, among the derivatives investigated amides 8 and pectinatone (-)-3 exhibited the highest cytotoxicity. While the cytotoxicity of 8b against L929 mouse fibroblasts resembles that of 8c, the cytotoxic activity of (-)-pectinatone (-)-3 was only slightly diminished to 15 μg/ml. Unfortunately, a direct comparison with enantiomer (+)-3 is not possible and moreover, detailed information of biological tests are missing in literature. The IC 50 values for both diastereomeric mixture of allylic alcohols 11a and 11a' 6 were identical. However, enantiopure siphonarienone (+)-2 and (-)-2 significantly differ with 25 μg/ml and 40 μg/ml [5], respectively (Table 1).In this series of compounds only the unnatural pectinatone (-)-3 and amide 8c displayed any antimicrobial activity under the used conditions. As reported for natural (+)-3 [3], the congener (-)-3 was active against Gram-positive bacteria Staphylococcus aureus and Micrococcus luteus (zone of inhibition 13 mm and 11 mm, respectively), while amide 8c weakly inhibited the growth of th...

Both optically pure siphonarienal (-)-1 and siphonarienone (-)-2 are accessible from the enantiopure precursor methyl (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoate 5. The latter was converted into the corresponding methyl 2-undecenoate 9 which either provided aldehyde (-)-1 by reduction and subsequent Swern oxidation of the unsaturated alcohol 10 or gave ketone (-)-2 via Weinreb amide 11 and its conversion with EtMgBr. Alternatively, ketone 2 can be obtained from siphonarienal (-)-1 in a two-step reaction.

Other bioactive products U 1300Ex Chiral Pool Synthesis from a Highly Methyl-Branched Wax Ester and Biological Properties of (+)-Capensifuranone. -Title compound (I) and its 5-epimer are prepared starting from a common preen-gland wax-derived precursor. Both compounds show cytotoxic activity against L-929 mouse fibroblasts, and KB-3-1 HeLa and U-937 lymphoma cells. -(GALEYEVA, Y.; MORR, M.; SASSE, F.; DIESTEL, R.; LASCHAT*, S.; BARO, A.; FREY, W.; Z. Naturforsch., B: Chem. Sci. 64 (2009) 6, 639-645; Inst. Org. Chem., Univ. Stuttgart, D-70569 Stuttgart, Germany; Eng.) -H. Haber 44-200