Pinnaic Acid Research Articles

Asymmetric total synthesis strategies of halichlorine and pinnaic acid.

Halichlorine and pinnaic acid are structurally related natural alkaloids isolated from different marine organisms. These two marine alkaloids bearing a 6-azaspiro[4.5]decane skeleton demonstrate a wide range of biological effects. It is this kind of unique structure and potentially valuable biological activity that have prompted strong synthetic interest, making it a research focus in recent years. Since the first total synthesis of halichlorine and pinnaic acid completed by Danishefsky's group, many groups have reported their outstanding synthesis methods especially the asymmetric synthesis strategies. This review summarizes the asymmetric synthesis strategies of halichlorine and pinnaic acid using a 6-azaspiro[4.5]decane skeleton as the key intermediate, which can provide some guidance for related work.

Chemical synthesis of a library of natural product-like derivatives based on pinnaic acid and initial evaluation of their anti-cancer activity.

Halichlorine and pinnaic acid have been shown previously to be potent inhibitors of the inflammatory enzymes cPLA2 and VCAM-1 and have also demonstrated some anti-cancer activity. They possess an almost identical azaspirocyclic core consisting of a unique 3-dimensional geometry with four stereocentres, making them compounds of interest for further study to reveal any bioactivity not yet discovered. The azaspirocyclic core was synthesised from an established protocol, from which a small library of novel analogues were synthesised and tested for activity against two cancer cell lines, HeLa and CaCo-2, along with the non-cancerous cell line HaCaT. Eleven compounds were found to be selective for CaCo-2 cells.

Enantioselective Total Synthesis of Pinnaic Acid and Halichlorine

The enantioselective total synthesis of the bioactive marine natural products pinnaic acid and halichlorine is reported in detail. Our total synthesis features the construction of the five-membered ring and C9 and C13 stereogenic centers through a palladium-catalyzed trimethylenemethane [3+2] cyclization; the installation of the nitrogen atom through a regioselective Beckmann rearrangement of a poorly reactive ketone; the stereoselective cyclization of the spiro ring through a four-step, one-pot hydrogenation-cyclization; and efficient connection of the sterically hindered lower chain through a reduced-pressure cross olefin metathesis reaction.

Stereocontrol in a Combined Allylic Azide Rearrangement and Intramolecular Schmidt Reaction

Pre-equilibration of an interconverting set of isomeric allylic azides is coupled with an intramolecular Schmidt reaction to afford substituted lactams stereoselectively. The effect of substitution and a preliminary mechanistic study are reported. The synthetic potential of this method is demonstrated in the context of an enantioselective synthesis of an advanced intermediate leading toward pinnaic acid.

Divergent approach to the polymaxenolide and pinnaic acid cores

The divergent syntheses of the spirocyclic pyran core of polymaxenolide and the spirocyclic piperidine core of pinnaic acid have been achieved. Our divergent approach takes advantage of highly efficient Achmatowicz and aza-Achmatowicz rearrangements to generate the highly functionalised cores, which are then regioselectively modified.

Pinnarine, Another Member of the Halichlorine Family. Isolation and Preparation from Pinnaic Acid

Pinnarine (1), a new macrocyclic alkaloid, was isolated from the black marine sponge Halichondria okadai. The structure was elucidated on the basis of 2D NMR and comparison with the spectra of the co-isolated known halichlorine. Further confirmation of the structure and the absolute configuration was validated by a synthetic method from authentic pinnaic acid and CD analysis. The isolation of pinnarine also suggested a biogenetic pathway from pinnaic acid to halichlorine.

ChemInform Abstract: Studies on the Synthesis of Pinnaic Acid and Halichlorine. Stereoselective Preparation of a (Z)-δ-Chloro-γ,δ-unsaturated-β-keto Phosphonate as a Side Chain Synthon.

ChemInform Abstract: Studies on the Synthesis of Pinnaic Acid and Halichlorine. Stereoselective Preparation of a (Z)-δ-Chloro-γ,δ-unsaturated-β-keto Phosphonate as a Side Chain Synthon.

Expedient Route to an Amine Precursor of Halichlorine and Pinnaic Acid from Nitrocyclopent-1-ene

Diastereoselective addition of n-propanal to nitrocyclopent-1-ene, aldehyde protection, 1,6-conjugate addition, and cross metathesis provides a facile route to key amine precursors of halichlorine and pinnaic acid.

A concise approach to the core structures of pinnaic acid and halichlorine

An efficient and flexible synthetic approach to the core structures of pinnaic acid and halichlorine is described using spirocyclic nitrone 4 as a key intermediate. 1,3-Dipolar cycloaddition of 4 with dipolarophile 8 provides access to the azaspirocyclic core of pinnaic acid 5 while the spiroquinolizidine core of halichlorine 6 has been synthesised via cycloaddition of 4 with dipolarophile 29. Nitrone 4 is accessed by oxidative ring opening of isoxazolidine 9. The utility of this synthetic strategy in the synthesis of C5 substituted analogues of pinnaic acid is also demonstrated.

Synthesis of Pinnaic Acid

Pinnaic acid, isolated from the Okinawan bivalve Pinna muricata, inhibits activity of cytosolic 85 kDa phospholipase (cPLA2) and therefore has anti-inflammatory potential. Markworthy steps of the synthesis are: (1) a Pd-catalyzed trimethylenemethane [3+2] cyclization (B→D) and (2) a tandem hydrogenation-cyclization (I→J).

Asymmetric Total Synthesis of Pinnaic Acid.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

An Enantioselective Total Synthesis of Pinnaic Acid.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Asymmetric Total Synthesis of Pinnaic Acid

Asymmetric Total Synthesis of Pinnaic Acid

Asymmetric Total Synthesis of Pinnaic Acid

Zusammengebastelt: Die asymmetrische Totalsynthese von Pinnasäure gelang auf einem stereospezifischen Weg, wobei Schlüsselschritte eine Pd-katalysierte Trimethylenmethan(TMM)-[3+2]-Cyclisierung, eine vierstufige Tandem-Hydrierung-Cyclisierung und Kreuz-Olefinmetathesereaktionen waren (siehe Schema). Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2007/z701581_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

A Concise and Flexible Synthesis of the Core Structure of Pinnaic Acid

An efficient and flexible approach to the core structure of pinnaic acid has been developed that centres on the microwave-induced 1,3-dipolar cycloaddition of a novel spirocyclic nitrone 5 with alkene 7. The application of this nitrone to the synthesis of a diverse set of C5-substituted analogues of pinnaic acid is also de-monstrated.

An enantioselective total synthesis of pinnaic acid

An enantioselective and convergent total synthesis of marine natural product pinnaic acid has been achieved. Our general synthetic approach is featured with an asymmetric hydrogenation of racemic γ-keto ester 3, a diastereoselective methylation on the α-methylene of the (1 R,5 R)-lactone 4, and a diastereoselective Michael addition of the tertiary nitro cyclopentane. The central azaspiro[4.5]decane was constructed utilizing reductive cyclization of the δ-nitroketone followed by highly stereoselective reduction of the cyclic imine with NaBH 4. Ultimately, successive use of triethyl-2-phosphonopropionate and Heathcock's phosphorane 18 to elaborate C5 and C13 side chains completed the total synthesis of pinnaic acid.

Formal syntheses of (+/-)-pinnaic acid and (+/-)-halichlorine.

[chemical reaction: see text]. Concise formal syntheses of marine alkaloids (+/-)-pinnaic acid (1) and (+/-)-halichlorine (2) have been accomplished from a common intermediate. The syntheses illustrate the utility of selective olefin cross metathesis methodologies for the elaboration of advanced synthetic intermediates in complex molecule synthesis.

An Efficient and Enantioselective Approach to the Azaspirocyclic Core of Alkaloids: Formal Synthesis of Halichlorine and Pinnaic Acid

A novel, highly stereoselective synthesis of an azaspirocyclic core, which contains four stereogenic carbons consistent with structures of natural halichlorine and pinnaic acid, is presented. Lipase PS-catalyzed selective acylation, asymmetric methylation on the alpha-methylene of the bicyclic lactone, and an asymmetric Michael addition of the tertiary nitro cyclopentane were concisely used to conquer the challenging problem of successfully constructing the C9 quarternary carbon center with complete stereocontrol. The spiropiperidine ring was formed by reduction of the delta-nitroketone, intramolecular condensation, and then highly stereoselective reduction of the cyclic nitrone with NaBH(4). This spirocyclic core is a key intermediate in Danishefsky's synthesis of pinnaic acid and halichlorine.

A diastereoselective approach for an asymmetric synthesis in pinnaic acid series

An enantiopure spiran-bearing advanced intermediate in pinnaic acid series was obtained in 11 steps starting with CN( R, S) building block.

A Chiral Base Desymmetrization—Ring‐Closing Metathesis Route to Chiral Azaspirocycles: Synthesis of Core Structures Related to Pinnaic Acid and Halichlorine.

AbstractFor Abstract see ChemInform Abstract in Full Text.