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The preparation of several new analogues of the natural dihydropyrone pironetin is described. They differ from the natural product mainly in the nature of the side chain and the lactone ring. Their cytotoxic activity has been measured. In addition, their interaction with tubulin, their ability to inhibit the secretion of the vascular endothelial growth factor (VEGF) and the expression of angiogenesis and telomerase-related genes have been determined. Unexpectedly, and unlike pironetin, the lactones studied in this work do not interact with tubulin. Two of the compounds have been found to downregulate the expression of the hTERT and VEGF genes. Furthermore, one of them causes an appreciably decrease in the secretion of the VEGF protein.

A convergent synthesis of the structure proposed for the naturally occurring lactone stagonolide G is described. All three stereocenters were created with the aid of asymmetric Brown allylations. The lactone ring was built by means of a ring-closing metathesis (RCM). The synthetic and the natural compound differed in their spectral properties. A new structure is now proposed for stagonolide G and demonstrated by means of a chemical transformation.

A stereoselective synthesis of the cytotoxic 14-membered macrolide aspergillide A has been performed. The preparation of a cis-2,6-disubstituted tetrahydropyran ring via stereoselective reduction of an intermediate cyclic hemiacetal was one key feature of the synthesis. The macrocyclic lactone ring was created by means of a ring-closing metathesis (RCM), whereby the new C=C bond displayed exclusively the undesired Z configuration. Conversion to the required E configuration was achieved via photochemical isomerization.

The total synthesis of the proposed structure of feigrisolide A is reported. Ethyl (S)-3-hydroxybutyrate was the chiral starting material. A Brown asymmetric allylation and an Evans aldol reaction were key steps of the synthesis. The NMR data of the synthetic product are different from those of the natural product. The published structure of feigrisolide A is therefore erroneous. A subsequent comparison of spectral data strongly suggests that feigrisolides A and B are identical with (-)-nonactic acid and (+)-homononactic acid, respectively.

The naturally occurring gamma-lactones (+)-goniofufurone 1 and (+)-cardiobutanolide 2, two pharmacologically active products from Goniothalamus species (Annonaceae), have been synthesized in enantiopure form using l-erythrulose as the chiral starting material. Key steps of these syntheses were a stereoselective anti boron aldol reaction and an asymmetric allylboration.

The conjugated delta-lactone passifloricin A, a natural product with antiprotozoal activity, and seven isomers thereof have been synthesized in enantiopure form. It has been shown in this way that the proposed structure for the natural compound was erroneous. The correct structure is now evidenced. Key steps of the syntheses were asymmetric Brown-type aldehyde allylations and ring-closing metatheses.

Stereoselective syntheses of the naturally occurring, cytotoxic lactone spicigerolide and three nonnatural stereoisomers thereof are described. The commercially available sugar l-rhamnose was in all cases the chiral starting material. Key steps in each of these syntheses were asymmetric Brown allylations and ring-closing metatheses. The cytotoxic activities of the four lactones against a range of tumoral lines were then determined.

Stereoselective syntheses of the delta-lactone of (2Z,5S,7R,9S,11S)-tetrahydroxyhexacos-2-enoic acid, the structure reported for passifloricin A, and of its (5R)-epimer are described. The creation of all stereogenic centers relied upon Brown's asymmetric allylation methodology. The lactone ring was created via ring-closing metathesis. The NMR data of both synthetic products, however, were different from those of the natural product. The published structure of passifloricin A is thus erroneous and will require further synthetic work to be unambiguously assigned. [structure: see text]

The delta-lactone boronolide (+)-1, a pharmacologically active, naturally occurring product, has been synthesized in enantiopure form with L-erythrulose as the chiral starting material. The key steps of the synthesis were a highly stereoselective aldol-reduction one-pot sequence, an indium-mediated diastereoselective aldehyde allylation, and a ring-closing metathesis.

Nucleophilic C-vinylation and C-allylation of aldehydes and ketones followed by O-allylation of the obtained carbinols gave the corresponding allyl or homoallyl ethers, respectively. Ring-closing metathesis of these compounds afforded in many cases cyclic ethers (dihydrofurans and dihydropyrans, respectively) bearing disubstituted and trisubstituted C&z.dbnd;C bonds. These were then subjected to allylic oxidation to yield conjugated γ- and δ-lactones. Reasons for the observed failures are presented and discussed. [Copyright &y& Elsevier]

The stereoselective syntheses of the naturally occurring δ-lactones (+)-tanikolide and (−)-malyngolide as well as of the unnatural (+)-enantiomer of the latter are described. Key steps in each of these syntheses were stereoselective additions of organometallic reagents to α-oxygenated ketones and olefin ring-closing metatheses. [Copyright &y& Elsevier]

Abstract: The first stereoselective syntheses of the naturally occurring, α,β-unsaturated lactone hyptolide 1 and of its nonnatural epimer at C-6 are described. Ethyl l-lactate was the chiral starting material. Key steps of these syntheses were a Brown''s asymmetric allylation, a Carreira''s asymmetric ethynylation and a ring closing metathesis. [Copyright &y& Elsevier]

The structure reported in the literature for the pharmacologically active, natural lactone passifloricin A (δ-lactone of 2Z,5R*S*,7R*,9S*,11S*-tetrahydroxyhexacos-2-enoic acid) is incorrect not only as regards stereochemical issues, but also in the placement of one of the hydroxyl groups of the side chain. By means of an unambiguous synthesis, passifloricin A is shown to be the δ-lactone of 2Z,5R,7S,9S,12S-tetrahydroxyhexacos-2-enoic acid. All of the stereogenic centres were created with the aid of Brown''s asymmetric allylation methodology. The lactone ring was made via ring-closing metathesis. [Copyright &y& Elsevier]

The first total synthesis of the naturally occurring lactone (+)-hyptolide is described. Ethyl l-lactate was the chiral starting material. Key steps of this 15-step synthesis were a Brown''s asymmetric allylation, a Carreira''s asymmetric ethynylation and a ring closing metathesis. [Copyright &y& Elsevier]

The first total synthesis of the naturally occurring, cytotoxic lactone spicigerolide is described. The commercially available sugar l-rhamnose was the chiral starting materal. Key steps in the synthesis were an aldehyde two-carbon homologation via the Corey–Fuchs protocol, an asymmetric Brown-type aldehyde allylation and a ring-closing metathesis. [Copyright &y& Elsevier]

Convergent, stereoselective syntheses of the pharmacologically active, naturally occurring lactones (-)-microcarpalide and (+)-lethaloxin have been achieved from the commercially available, chiral reagents (R)-glycidol, (S,S)-tartaric acid, and D-ribose as the starting materials. These syntheses have further served to establish the hitherto unknown absolute configuration of (+)-lethaloxin and to show its identity with (+)-pinolidoxin. [ABSTRACT FROM AUTHOR]

A stereoselective synthesis of the naturally occurring, α,β-unsaturated lactone anamarine is described. The key step was a highly stereoselective aldol reaction of a protected erythrulose derivative with a chiral aldehyde. Another relevant step was an asymmetric aldehyde allylation with a chiral allylborane. The lactone ring was made by means of a ring-closing metathesis. [Copyright &y& Elsevier]

Abstract: A total, stereoselective synthesis of the cytotoxic macrolide aspergillide B has been performed. A cross metathesis and a C-glycosidation via a Mukaiyama-type aldol reaction were key features of the synthesis. The macrocyclic lactone ring was created by means of the Yamaguchi procedure. [Copyright &y& Elsevier]