Lactone Core Research Articles

Asymmetric syntheses of the lactone core of tetrahydrolipstatin and tetrahydroesterastin and of the oriental hornet Vespa Orientalis pheromone

A synthetic approach to the lactone core of the anti-obesity drugs tetrahydrolipstatin and tetrahydroesterastin has been developed starting from readily accessible methyl (5S)-5-{[tert-butyl(dimethyl)silyl]-oxy}-3-oxohexadecanoate. (6S)-6-Undecyltetrahydro-2H-pyran-2-one, the oriental hornet Vespa Orientalis pheromone, has also been synthesized. A formal synthesis of (3S,4R,6S)-dihydroxy-6-undecyltetrahydro-2H-pyran-2-one (metabolite of a fungus separated from mangrove seeds) has been proposed.

Asymmetric total syntheses of megacerotonic acid and shimobashiric acid A.

The asymmetric total syntheses of the α-benzylidene-γ-butyrolactone natural products megacerotonic acid and shimobashiric acid A have been accomplished in nine and 11 steps, respectively, from simple, commercially available starting materials. The key step for each synthesis is the (arene)RuCl(monosulfonamide)-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenation (DKR-ATH) of racemic α,δ-diketo-β-aryl esters to establish the absolute stereochemistry. Intramolecular diastereoselective Dieckmann cyclization forms the lactone core, and ketone reduction/alcohol elimination installs the α-arylidene.

Synthetic variants of mycolactone bind and activate Wiskott-Aldrich syndrome proteins.

Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of skin lesions called Buruli ulcers. Mycolactone-mediated activation of neural (N) Wiskott-Aldrich syndrome proteins (WASP) induces defects in cell adhesion underpinning cytotoxicity and disease pathogenesis. We describe the chemical synthesis of 23 novel mycolactone analogues that differ in structure and modular assembly of the lactone core with its northern and southern polyketide side chains. The lactone core linked to southern chain was the minimal structure binding N-WASP and hematopoietic homolog WASP, where the number and configuration of hydroxyl groups on the acyl side chain impacted the degree of binding. A fluorescent derivative of this compound showed time-dependent accumulation in target cells. Furthermore, a simplified version of mycolactone mimicked the natural toxin for activation of WASP in vitro and induced comparable alterations of epithelial cell adhesion. Therefore, it constitutes a structural and functional surrogate of mycolactone for WASP/N-WASP-dependent effects.

Asymmetric synthesis of (+)-stagonolide C and (−)-aspinolide A via organocatalysis

A new enantioselective synthesis of two important fungal metabolites, (+)-stagonolide C and (−)-aspinolide A, has been described from readily available raw materials. Proline catalyzed asymmetric α-aminooxylation and Jorgensen’s epoxidation of aldehydes are the key reactions employed in the introduction of chirality. The formation of the 10-membered lactone core structure was finally accomplished via Steglich esterification and ring closing metathesis reactions.

A novel approach toward the synthesis of strigolactones through intramolecular [2+2] cycloaddition of ketenes and ketene-iminiums to olefins. Application to the asymmetric synthesis of GR-24

An intramolecular [2+2] cycloaddition of ketenes and ketene-iminium was developed for the preparation of GR-24, a synthetic analogue of the family of strigolactone plant hormones. Excellent levels of regioselectivity and of chiral induction were obtained using a bulky chiral amine for the formation of the cyclobutanone and a subsequent regioselective Baeyer–Villiger afforded the tricyclic lactone core of (+)-GR-24.

Stereoselective Total Synthesis of Polyrhacitides A and B

AbstractTwo aliphatic polyketide natural products, polyrhacitides A and B, have been synthesized in a concise and highly stereoselective manner. The synthesis involved an auxiliary‐based acetate aldol reaction to generate the initial stereogenic center and an iterative Wittig reaction, intramolecular oxa‐Michael addition, and chelation‐controlled reduction reaction as the key steps to generate additional stereocenters. One‐pot acid‐mediated global deprotection and cyclization reactions shape the final bicyclic lactone core.

Synthesis and Structure–Activity Relationships of Constrained Heterocyclic Analogues of Combretastatin A4

A series of combretastatin A4 (CA4) analogues with a lactam or lactone ring fused to the trimethoxyphenyl or the B-phenyl moiety were synthesized in an efficient and stereoselective manner by using a domino Heck-Suzuki-Miyaura coupling reaction. The vascular-disrupting potential of these conformationally restricted CA4 analogues was assessed by various in vitro assays: inhibition of tubulin polymerization, modification of endothelial cell morphology, and disruption of endothelial cell cords. Compounds were also evaluated for their growth inhibitory effects against murine and human tumor cells. B-ring-constrained derivatives that contain an oxindole ring (in contrast to compounds with a benzofuranone ring) as well as analogues bearing a six-membered lactone core fused to the trimethoxyphenyl ring are endowed with significant biological activity. The most potent compound of this series (oxindole 9 b) is of particular interest, as it combines chemical stability and a biological activity profile characteristic of a vascular-disrupting agent.

The Crystal Structure and Mechanism of an Unusual Oxidoreductase, GilR, Involved in Gilvocarcin V Biosynthesis

GilR is a recently identified oxidoreductase that catalyzes the terminal step of gilvocarcin V biosynthesis and is a unique enzyme that establishes the lactone core of the polyketide-derived gilvocarcin chromophore. Gilvocarcin-type compounds form a small distinct family of anticancer agents that are involved in both photo-activated DNA-alkylation and histone H3 cross-linking. High resolution crystal structures of apoGilR and GilR in complex with its substrate pregilvocarcin V reveals that GilR belongs to the small group of a relatively new type of the vanillyl-alcohol oxidase flavoprotein family characterized by bicovalently tethered cofactors. GilR was found as a dimer, with the bicovalently attached FAD cofactor mediated through His-65 and Cys-125. Subsequent mutagenesis and functional assays indicate that Tyr-445 may be involved in reaction catalysis and in mediating the covalent attachment of FAD, whereas Tyr-448 serves as an essential residue initiating the catalysis by swinging away from the active site to accommodate binding of the 6R-configured substrate and consequently abstracting the proton of the hydroxyl residue of the substrate hemiacetal 6-OH group. These studies lay the groundwork for future enzyme engineering to broaden the substrate specificity of this bottleneck enzyme of the gilvocarcin biosynthetic pathway for the development of novel anti-cancer therapeutics.

Silver-Catalyzed One-Pot Synthesis of Arylnaphthalene Lactone Natural Products

Naturally occurring arylnaphthalene lactone lignans have demonstrated a variety of valuable medicinal chemistry properties and have therefore been of continued interest to drug discovery research. Our group has demonstrated a silver-catalyzed one-pot synthesis of the arylnaphthalene lactone core using carbon dioxide, phenylpropargyl chloride, and phenylacetylene. This new approach has been employed in the synthesis of six arylnaphthalene lactone natural products: retrochinensin (1), justicidin B (2), retrojusticidin B (3), chinensin (4), justicidin E (5), and taiwanin C (6). Additionally, an arylnaphthalene lactone regioisomer was isolated (9), which we refer to as isoretrojusticidin B.

Total Synthesis of 2‐Hydroxytetracosanolide and 2‐Hydroxy‐24‐oxooctacosanolide By Using an Effective Lactonization

We have developed effective methods for the total synthesis of 2-hydroxytetracosanolide and 2-hydroxy-24-oxooctacosanolide, the defensive salivary secretions of termites. The former natural product isolated from Armitermes neotenicus, a species of termite that inhabits Guyana, contains a 25-membered lactone backbone, and the latter, extracted from Pseudacanthoterme springer, an African termite, includes a 29-membered lactone moiety. The key cyclization to produce the 25- or 29-membered lactone core is performed by using 2-methyl-6-nitrobenzoic anhydride (MNBA) with a stoichiometric amount of 4-(dimethylamino)pyridine (DMAP) or a catalytic amount of 4-(dimethylamino)pyridine N-oxide (DMAPO).

Mycolactones: immunosuppressive and cytotoxic polyketides produced by aquatic mycobacteria.

Mycolactones are a family of highly related macrocyclic polyketides that exhibit immunosuppressive and cytotoxic properties. First discovered in 1999, they are the primary virulence factors produced by the environmental human pathogen Mycobacterium ulcerans, the causative agent of Buruli ulcer, and by some closely-related aquatic mycobacteria that cause disease in fish and frogs. Mycolactones are characterized by a common 12-membered lactone core to which is appended an unsaturated fatty acyl side-chain of variable length and oxidation state. This Highlight summarizes recent progress in understanding the structural diversity of the mycolactones, their biological activity and mode of action in mammalian cells, and the genetics, evolution, and enzymology of their biosynthesis.

The First Total Synthesis of (−) and (+)-2-Hydroxy-24-oxooctacosanolide Using an Effective Lactonization

[structure: see text] An effective method for the total synthesis of 2-hydroxy-24-oxooctacosanolide, a defensive salivary secretion of the African termite Pseudacanthotermes spiniger, has been developed. The key lactonization to form a 29-membered ring lactone core is performed using 2-methyl-6-nitrobenzoic anhydride with a catalytic amount of 4-(dimethylamino)pyridine N-oxide.

Synthesis of the floresolide B hydroquinone lactone core using ring-closing metathesis

The hydroquinone lactone core of the floresolides was synthesized through a ring-closing metathesis (RCM) approach. Optimal RCM efficiency was obtained at higher reaction concentration. An unexpected Lewis acid-promoted rearrangement of the hydroquinone and other observations relevant to on-going total synthesis efforts are discussed.

Enantioselective sulfoxide-directed preparation of 1,2-diols from oxalic compounds: formal synthesis of the 10-membered lactone core of ascidiatrienolides and didemnilactones

The synthesis of diene 17, which is available in both possible absolute configurations is described. This diene constitutes the key intermediate of a previous synthesis of the 10-membered lactone core of the marine natural products ascidiatrienolides and didemnilactones. This intermediate is available via two successive highly diastereoselective sulfoxide-directed reductions of oxalic diamide 18.

An Approach to the Tricyclic Lactone Core of Brasoside and Related Natural Products

A one-pot iodine atom transfer/cyclisation and intermolecular olefination is described for the efficient, stereoselective construction of bicyclic lactone intermediates en route to compound 21, a potential precursor to the brasoside (1) skeleton.

Synthesis and Preliminary Biological Evaluation of Truncated Zoanthenol Analogues.

ChemInformVolume 35, Issue 38 Natural Products Synthesis and Preliminary Biological Evaluation of Truncated Zoanthenol Analogues. Go Hirai, Go Hirai Dep. Chem., Grad. Sch. Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorHiroki Oguri, Hiroki Oguri Dep. Chem., Grad. Sch. Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorMasahiko Hayashi, Masahiko Hayashi Dep. Chem., Grad. Sch. Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorKoji Koyama, Koji Koyama Dep. Chem., Grad. Sch. Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorYuuki Koizumi, Yuuki Koizumi Dep. Chem., Grad. Sch. Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorSameh M. Moharram, Sameh M. Moharram Dep. Chem., Grad. Sch. Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorMasahiro Hirama, Masahiro Hirama Dep. Chem., Grad. Sch. Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this author Go Hirai, Go Hirai Dep. Chem., Grad. Sch. Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorHiroki Oguri, Hiroki Oguri Dep. Chem., Grad. Sch. Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorMasahiko Hayashi, Masahiko Hayashi Dep. Chem., Grad. Sch. Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorKoji Koyama, Koji Koyama Dep. Chem., Grad. Sch. Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorYuuki Koizumi, Yuuki Koizumi Dep. Chem., Grad. Sch. Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorSameh M. Moharram, Sameh M. Moharram Dep. Chem., Grad. Sch. Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this authorMasahiro Hirama, Masahiro Hirama Dep. Chem., Grad. Sch. Sci., Tohoku Univ., Aoba, Sendai 980, JapanSearch for more papers by this author First published: 26 August 2004 https://doi.org/10.1002/chin.200438205Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume35, Issue38September 21, 2004 RelatedInformation

Synthesis in the Plakortone Series: Plakortone E.

A Pd(II)-mediated hydroxycyclisation-carbonylation-lactonisation sequence has operated efficiently with racemic enediol (8) to furnish (four) separable diastereomers of the bicyclic lactone system assigned to the sponge-derived, bioactive plakortone E. All four are cis ring-fused, and one is identical, on the basis of H-1 and C-13 NMR spectroscopic comparisons, with plakortone E, thus confirming its constitution and relative stereochemistry about the bicyclic lactone core. This synthetic approach, when applied to stereoisomer (13), will establish the absolute stereochemistry of plakortone E, likely to be that shown for (14).

Synthesis and preliminary biological evaluation of truncated zoanthenol analogues

Zoanthamines are a family of marine alkaloids that have complex heptacyclic structures and are reported to be interleukin-6 modulators. While the structure of zoanthamines, especially the ABC-ring portion, is similar to that of steroids, the CDEFG-ring portion, composed of aminoacetal and lactone core, is a unique structural element. In this report, we designed and synthesized ABC-ring 6 and CDEFG-ring 7, which are truncated analogues of the northern and southern hemispheres of zoanthenol 5, respectively, and which incorporate all of the functionality of each hemisphere. A preliminary SAR study suggested that the hydrochloride of the CEFG-ring portion is an active pharmacophore for suppressing the growth of interleukin-6-dependent MH60 cells.

Synthesis in the Plakortone Series: Plakortone E

A Pd(II)-mediated hydroxycyclisation-carbonylation-lactonisation sequence has operated efficiently with racemic enediol (8) to furnish (four) separable diastereomers of the bicyclic lactone system assigned to the sponge-derived, bioactive plakortone E. All four are cis ring-fused, and one is identical, on the basis of H-1 and C-13 NMR spectroscopic comparisons, with plakortone E, thus confirming its constitution and relative stereochemistry about the bicyclic lactone core. This synthetic approach, when applied to stereoisomer (13), will establish the absolute stereochemistry of plakortone E, likely to be that shown for (14).

Zinc-Acetic Acid Reductive Cyclisation in a Two-Step Synthesis of the S1-N10 Nine-Membered Lactone Core ofent-Griseoviridin

The synthesis of the S1-N10 nine-membered lactone core 28 of ent-griseoviridin is reported. Starting from cystine derivative 25, encompassing a terminal ynoate, treatment under Zn/ AcOH conditions led to the formation of lactone 28 in 12% yield. Therefore, the lactone moiety of ent-griseoviridin is obtained in 10.7% overall yield for two steps. An access to the corresponding 5-epi-griseoviridin lactone 29 is also described.