The synthesis of disubstituted chiral diene ligands (3aR,6aR)-and (3aS,6aS)-10 with a pentalene backbone from the corresponding bicycloA C H T U N G T R E N N U N G [3.3.0]octa-1,4-diones 7 is described. The latter were accessible by enzymatic resolution of the racemic diol rac-5 and subsequent Swern oxidation. The efficiency of the ligands 10 in the rhodium-catalyzed 1,4-addition of arylboronic acids 12 to cyclic and acyclic enones 11 and 15 could be demonstrated. In the case of cyclic enones 11 the enantiomeric diphenyldienes (3aR,6aR)-and (3aS,6aS)-10a were more selective than the corresponding dibenzyldiene ligands 10b. When acyclic enones 15 were employed this result, however, reversed. Ligands 10a were nearly inactive whereas dibenzyldienes 10b afforded the addition products 16 with enantioselectivities up to 91 %.

To gain insight into the biological properties of tetramic acid lactam cylindramide 1, the analogues 4 a-d bearing a cyclopentane ring instead of the pentalene unit were prepared by tandem conjugate addition/enolate trapping of cyclopentenone 10; a Sonogashira or Stille coupling, followed by a Julia-Kocienski olefination, macrolactamisation and Lacey-Dieckmann cyclisation were the key steps. The previous NMR structure of cylindramide 1, which was based on NOE and J coupling restraints, could be refined by including residual dipolar coupling data measured for a sample of cylindramide that was aligned in polyacrylonitrile (18 %). Biological screening of cylindramide 1 and its analogues 2-epi-1, 20 and 4 revealed promising antiproliferative activity against several tumour cell lines. It turned out that the activity is strongly correlated to the functionalised pentalene system. The configuration of the cyclopentane ring and an intact tetramic acid lactam with the correct configuration seem to play an equal role in the cytotoxicity. The antiproliferative activity was found to be calcium dependent. Phenotypic characterisation of the mode of action showed vacuolisation and vesicle formation in the endoplasmic reticulum.

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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...