Synthesis of Chiral Cyclopentenones.

The cyclopentenone unit is a very powerful synthon for the synthesis of a variety of bioactive target molecules. This is due to the broad diversity of chemical modifications available for the enone structural motif. In particular, chiral cyclopentenones are important precursors in the asymmetric synthesis of target chiral molecules. This Review provides an overview of reported methods for enantioselective and asymmetric syntheses of cyclopentenones, including chemical and enzymatic resolution, asymmetric synthesis via Pauson-Khand reaction, Nazarov cyclization and organocatalyzed reactions, asymmetric functionalization of the existing cyclopentenone unit, and functionalization of chiral building blocks.

Chemical transformation of prostaglandin-A2: a novel series of C-10 halogenated, C-12 hydroxylated prostaglandin-A2 analogues.

[reaction: see text] Synthesis of a novel class of C-10 halogenated and C-12 oxygenated prostaglandin-A(2) derivatives (6a-6c) has been accomplished. (15S)-Prostaglandin-A(2) (1), from the gorgonian Plexaura homomalla, served as the starting material for the synthesis. The absolute configuration was determined using NMR.

[Studies on discovery and synthesis of bioactive marine organic molecules].

This paper describes the discovery and total synthesis of bioactive marine natural products conducted in our laboratory. Clavulone, chlorovulone, bromovulone, and iodovulone are antitumor marine prostanoids isolated from the Okinawan soft coral Clavularia viridis. The synthesis of clavulone and chlorovulone was achieved from chiral 4-hydroxy-2-cyclopentenone. Marine prostanoid punaglandins 3 and 4 were synthesized via similar methodology. The chemical structures of punaglandins 3 and 4 were revised by these syntheses. Dollaberane-type diterpenoid stolonidiol and claenone were isolated from Okinawan soft coral Clavularia sp. Stolonidiol showed potent choline acetyltransferase-inducible activity in cultured basal forebrain cells. The synthesis of stolondiol and claenone was conducted via sequential Michael reaction and retro-aldol reaction. Aragusterols, isolated from the Okinawan marine sponge Xestospongia sp., are structurally unique steroids possessing a rare 26,27-cyclo structure in the side chain. Aragusterols express potent in vivo antitumor activity against L1210 leukemia in mice. The synthesis of aragusterols was carried out via steroselective construction of the side chain and stereocontrolled coupling reaction with the steroid skeleton. Kalihinane-type diterpenoid kalihinol A, isolated by Scheuer, has remarkable in vitro antimalarial activity. The absolute configuration of kalihinol A was determined by applying the CD exciton chiral method. Synthesis of kalihinene X, a kalihinane-type diterpenoid, was achieved. This synthesis involves the regioselective coupling reaction of carbanion of alkyl sulfone with epoxyalcohol and construction of cis-decalin by an intramolecular Diels-Alder reaction.

Solid-phase synthesis and biological activity of a combinatorial cross-conjugated dienone library.

The solid-phase synthesis of a combinatorial cross-conjugated dienone library based on the structure of clavulones and their biological activity are reported. Clavulones are a family of marine prostanoids, and are composed of a cross-conjugated dienone system bearing two alkyl side-chains. The cross-conjugated dienone system irreversibly reacted with two nucleophiles. Our strategy for the solid-phase synthesis of the cross-conjugated dienones involves the Sonogashira-coupling reaction of a solid-supported cyclopentenone 10 bearing an acetylene group, followed by aldol condensation with aldehydes. The diphenyl derivative 7 aA was prepared from the solid-supported cyclopentenone 10 in 56% total yield. Combinatorial synthesis of a small library using twelve halides and eight aldehydes resulted in the production of 74 desired compounds from 98 candidates, and were detected by their mass spectra. Antiproliferative effects of the crude compounds against HeLaS3 cells showed that eleven samples showed strong antitumor activity (IC50<0.05 microM). Further biological examination of four purified compounds by using five tumor cell lines (A549, HeLaS3, MCF7, TMF1, and P388) revealed strong cytotoxicity comparable to that of adriamycin.

Formation of prostaglandin A analogues via an allene oxide.

One potential biosynthetic route to the prostaglandins involves the participation of lipoxygenase and allene oxide synthase enzymes, giving a hydroxylated allene oxide, which then might cyclize to form prostaglandin A or a close analogue. We have tested a model of this type of transformation using 8-hydroxy-15S-hydroperoxy eicosanoids as substrates for the dehydrase (allene oxide synthase) in flaxseed. Four of these substrates, each with a 9E,11Z,13E-conjugated triene, gave an observable rate of reaction. The two derived from eicosapentaenoic acid reacted more rapidly than the corresponding arachidonic acid analogues. Also, the 8S-hydroxy-15S-hydroperoxy diastereomers reacted more rapidly than their 8R-hydroxy analogues. Products were characterized by high pressure liquid chromatography, UV, gas chromatography-mass specrometry, 1H NMR, and CD. Reaction of the (8S)-hydroxy-(15S)-hydroperoxy-eicosapentaenoic acid gave two alpha-ketols [8S),15-dihydroxy-14-oxoeicosa-5Z,9E,11Z,17Z+ ++-tetraenoic acid and the corresponding 11E isomer in a 2:1 ratio), together with four prostaglandin A3 analogues which differed in the configurations of the side chains. Oxygen 18 labeling fully supported the intermediacy of an allene oxide in the biosynthesis. The corresponding "8R" substrate was converted to the enantiomers of these products plus three 13-hydroxy-14,15-epoxy derivatives. The arachidonate analogues formed the epoxy-hydroxy derivatives, the alpha-ketols, and two prostaglandin A2 analogues with trans configuration of the side chains. These results demonstrate (i) a feasible route of metabolism of lipoxygenase products to hydroxy allene oxide, (ii) the potential for the resulting allene oxide to cyclize to a prostaglandin A analogue, and (iii) the marked influence of the hydroxyl configuration of the rate of reaction and resulting profile of products. Some of these reactions may occur in a natural pathway of prostanoid biosynthesis in corals and other organisms.

Enantioselective synthesis of 12-amino alkylidenecyclopentenone prostaglandins.

An enantioselective synthesis of new 12-amino alkylidenecyclopentenone prostaglandins is reported. The key step of the synthesis involved a [3.3] sigmatropic rearrangement of an asymmetric allylic cyanate to elaborate an asymmetric 5-amino-1,6-diene which was further transformed into cyclopentenone by successive ring-closing metathesis reaction catalyzed by the Grubbs reagent and one-pot oxidation. A palladium-catalyzed cross-coupling reaction on a 5-iodo-1,5-diene allowed the synthesis of prostanoids with variable Rw side chains. These new compounds exhibit high cytotoxic activities.

Effective irreversible alkylating reagents based on the structure of clavulones.

We describe the design and synthesis of alkylating reagents based on the structure of clavulones. They are composed of cross-conjugated dienone system and irreversibly reacted with two nucleophiles under mildly basic conditions via beta-elimination. Hydroxyl derivative 7b showed the highest reactivity toward thiols and showed the strongest cytotoxicity in Hela S3 cells among the three derivatives having a different protecting group at the tert-hydroxyl group.

Prostaglandins and congeners XIII (1). The synthesis of dl-erythro-16-methoxyprostaglandins.

dl-Erythro-16-methoxy-PGE2, PGA2, PGF2alpha, 11-deoxy PGE1, and 11-deoxy PGF1alpha have been prepared via the cuprate conjugate addition procedure. These congeners are less potent than the parent prostaglandins as stimulators of isolated gerbil colon contractions and as bronchodilators in the guinea pig Konzett assay.

Derivados de prostaglandinas partiendo de la prostaglandina A2: I. Estudio de la reacción de reducción del 15-acetato PGA2 metil ester / Prostaglandin derivatives from prostaglandin A2: I. Study of the reaction of the 15 acetate PGA2 methyl ester

Se efectúa el estudio de la reacción de reducción del 15-acetato PGA2 metil éster con borohidruro de sodio, el cual provoca la pérdida del doble enlace C10-C11 al seguir un mecanismo de adición 1,4 de acuerdo con nuestras condiciones de trabajo y se demuestra que es un reactivo no estereoespecífico. Esto se comprueba mediante el análisis espectroscópico IR y UV, así como por cromatografía de capa delgada de los productos obtenidos y verificados por el posterior producto de oxidación