Dendrobatid Alkaloids Research Articles

Stereodivergent Synthesis of Alkaloid (±)-223A and (±)-6-epi-223A via Rh-Catalyzed Hydroformylation Double Cyclization.

A stereodivergent approach toward total syntheses of Dendrobatid alkaloids 223A and 6-epi-223A is described. The approach features a concise construction of an indolizidine skeleton by Rh-catalyzed domino hydroformylation double cyclization and sequential stereocontrolled transformations such as reductive alkylation or anti-selective α-alkylation of the 5-oxoindolizidine. These stereoselective reactions afford the desired stereochemistry in the targets.

Rh-Catalyzed Hydroformylation-Initiated Bicyclization: Construction of Azabicyclic Systems.

Here, we describe the recent progress toward construction of 1-azabicyclic structures using a domino hydroformylation double cyclization strategy of an amide bearing the trisubstituted alkene functionality. The method provides a rapid and atom-economic access to alkaloid structures under mild conditions, especially for quinolizidine and pyrrolidine-fused azepane skeletons with yields up to 82% and good diastereoselectivity. Subsequent oxidative cleavage conditions are developed for the synthesis of Dendrobatid alkaloid epi-epiquinamide.

Synthesis of dendrobatid alkaloid (+)-167B and (+)-209D and the investigation of diastereoselectivity using DFT calculations

The synthesis of dendrobatid alkaloid (+)-167B and (+)-209D has been developed on the basis of the effective preparation of chiral tropinone 7-azabicyclo[3.2.1]octan-6-ol.

ChemInform Abstract: Synthesis of (‐)‐Epibatidine.

An asymmetric synthesis to the dendrobatid alkaloid (−)-epibatidine has been described, featuring chiral resolution of both optically pure 7-azabicyclo[2.2.1]heptanecarboxylic acid, and subsequent transformations to (−)-epibatidine. The methodology provides a flexible access to various substituted chiral epibatidine analogues.

Synthesis of (−)-epibatidine

An asymmetric synthesis to the dendrobatid alkaloid (−)-epibatidine has been described, featuring chiral resolution of both optically pure 7-azabicyclo[2.2.1]heptanecarboxylic acid, and subsequent transformations to (−)-epibatidine.

ChemInform Abstract: Enantioselective Synthesis of (-)-Pumiliotoxin C from a Chiral Amino Ester and an Acetylenic Sulfone that Acts as an Alkene Dipole Equivalent.

A new synthesis of the naturally occurring (−)-enantiomer of the dendrobatid alkaloid pumiliotoxin C (1) was achieved by the conjugate addition of methyl (−)-cis-2-amino-trans-6-methylcyclohexanecarboxylate (3) to 1-(p-toluenesulfonyl)-1-pentyne (4), followed by intramolecular acylation to afford (4aS,5R,8aR)-4a,5,6,7,8,8a-hexahydro-5-methyl-2-propyl-3-(p-toluenesulfonyl)-4-quinolinone (2). The acetylenic sulfone thus acts as the synthetic equivalent of an alkene dipole species. The required enantiopure amino ester 3 was obtained by an approach based on pig liver esterase (PLE)-mediated hydrolysis. Thus, the (−)- and (+)-enantiomers of racemic dimethyl trans-3-methylcyclohexane-cis,cis-1,2-dicarboxylate (6) afforded the corresponding half-esters 7 and 8, respectively, when treated with PLE. The desired half-ester 7 was recovered intact after selective conversion of the free carboxylic acid group of the byproduct 8 into its benzyl ester. Half-ester 7 was converted into enantiopure (−)-6 with diazomethane, ...

ChemInform Abstract: Development of New Synthetic Methods and Strategies for the Total Syntheses of Pumiliotoxin A Class Alkaloids

New strategies for the syntheses of the pumiliotoxin (PTX) A dendrobatid alkaloids have been developed which are based on palladium-catalyzed carbonylation, palladium-catalyzed cross-coupling reaction, and nickel-chromium-mediated cyclization. Application of these methodologies to the asymmetric total syntheses of (-) -PTX 209F, (-) - PTX 225F, (+) -PTX A, (+) -allo-PTX 267A, (+) -allo-PTX 339A, and (+) -homo-PTX 223G is described.

Design and synthesis of some biologically interesting natural and unnatural products based on organosulfur and selenium chemistry

Organosulfur and selenium chemistry has provided fertile ground for the discovery of novel synthetic methodology and for the design of bioactive molecules with potential therapeutic applications. Thus, acetylenic sulfones have been employed in novel strategies for the synthesis of nitrogen heterocycles, including several biologically active alkaloids. The conjugate addition of nitrogen nucleophiles containing ester or chloroalkyl substituents to acetylenic sulfones was followed by base-mediated intramolecular alkylation or acylation to afford variously substituted piperidines, pyrrolizidines, indolizidines, quinolizidines, decahydroquinolines, and 4-quinolones. The products include the dendrobatid alkaloids (–)-pumiliotoxin C, indolizidines (–)-167B, 207A, 209B, and 209D, as well as (–)-(ent)-julifloridine, (–)-lasubine II, myrtine, and two recently discovered alkaloids from the medicinal plant Ruta chalepensis , which had not been previously synthesized. Acetylenic sulfones were also incorporated on solid supports and employed in the types of cyclizations mentioned above, as well as for Diels–Alder reactions and a large variety of 1,3-dipolar cycloadditions. Conjugate additions of tertiary cyclic α-vinyl amines to acetylenic sulfones generated zwitterions that underwent exceptionally facile formal aza-Cope rearrangements to afford ring-expanded macrocyclic amines. An iterative version was developed and used in the synthesis of motuporamine A and B. With respect to organoselenium chemistry, two classes of compounds are described that function as novel mimetics of the selenoenzyme glutathione peroxidase (GPx), which protects cells from oxidative stress caused by the formation of peroxides during aerobic metabolism. They include cyclic seleninates and spirodioxyselenuranes, both of which efficiently catalyze the reduction of peroxides with thiols and are of potential value in the mitigation of oxidative stress. Their aromatic derivatives are generally less effective catalysts, but substituent effects can be used to modulate their activities. The mechanism of their catalytic cycles has been elucidated and Hammett plots indicate that the oxidation of Se(II) to Se(IV) is the rate-determining step for both classes. A methoxy-substituted aromatic spirodioxyselenurane provided the fastest rate for a small-molecule selenium compound that we have observed to date for the reduction of hydrogen peroxide with benzyl thiol.

A Biomimetic Enantioselective Approach to the Decahydroquinoline Class of Dendrobatid Alkaloids

Der vermutete Schlüsselschritt in der Biosynthese von Dendrobates-Decahydrochinolinalkaloiden, wie dem in Fröschen gefundenen cis-195 A, aus 1,5-Polycarbonylderivaten wurde imitiert. In einer doppelten Cyclokondensation schlüpfte (R)-Phenylglycinol in die Rolle eines chiralen Äquivalents für Ammoniak. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2008/z705888_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 Biomimetic Enantioselective Approach to the Decahydroquinoline Class of Dendrobatid Alkaloids

A Biomimetic Enantioselective Approach to the Decahydroquinoline Class of Dendrobatid Alkaloids

Scheloribatid Mites as the Source of Pumiliotoxins in Dendrobatid Frogs†

The strawberry poison frog Dendrobates pumilio (Anura: Dendrobatidae) and related poison frogs contain a variety of dendrobatid alkaloids that are considered to be sequestered through the consumption of alkaloid-containing arthropods microsympatrically distributed in the habitat. In addition to ants, beetles, and millipedes, we found that adults of two species of oribatid mites belonging to the cohort Brachypylina, trophically a lower level of animal than ants and beetles, contain dendrobatid alkaloids. Gas chromatography/mass spectrometry (GC/MS) of hexane extracts of adult Scheloribates azumaensis (Oribatida: Acari) revealed the presence of not only pumiliotoxin 251D (8-hydroxy-8-methyl-6-(2'-methylhexylidene)-1-azabicyclo[4.3.0]nonane), but also precoccinelline 193C and another coccinelline-type alkaloid. From the corresponding extracts of an unidentified Scheloribates sp., pumiliotoxin 237A (8-hydroxy-8-methyl-6-(2'-methylpentylidene)-1-azabicyclo[4.3.0]nonane) was detected as a minor component, and identified by synthesis. The presence of related alkaloids, namely deoxypumiliotoxin 193H, a 6,8-diethyl-5-propenylindolizidine, and tentatively, a 1-ethyl-4-pentenynylquinolizidine, were indicated by the GC/MS fragmentation patterns, along with at least another six unidentified alkaloid components. Thus, one possible origin of pumiliotoxins, coccinellid alkaloids, and certain izidines found in poison frogs may be mites of the genus Scheloribates and perhaps related genera in the suborder Oribatida.

Development of New Synthetic Methods and Its Application to Total Synthesis of Nitrogen-Containing Bioactive Natural Products

A group of naturally occurring substances containing nitrogen is widely distributed in plants as well as in fungi, animal, marine organisms, and insects, and many exhibit significant biological activity. These natural products with a huge variety of chemical structures include antibiotics, antitumor agents, immunostimulants, drugs affecting the cardiovascular and central nervous systems, analgesics etc. The diverse activities and low natural abundance of this group of natural products when coupled with their molecular complexity warrant development of new and efficient synthetic methods and strategy for the total synthesis of these products, in particular alkaloids. The purpose of this review is to describe some of our achievements in the total synthesis of the naturally-occurring bases including the Dendrobatid alkaloids pumiliotoxin B and allopumiliotoxin A, the anitibiotic streptazolin, the tricyclic marine alkaloids isolated from the ascidians such as fasicularin, lepadiformine, and cylindricine C, and the dimeric monoterpene alkaloid incarvillateine as well as the formal total synthesis of the spirocyclic marine alkaloids halichlorine and pinnaic acid, which are isolated from the Japanese marine sponge and the Okinawan bivalve, respectively.

Investigation of conjugate addition/intramolecular nitrone dipolar cycloadditions and their use in the synthesis of dendrobatid alkaloid precursors.

The sequential intramolecular conjugate addition of the oxime 13 followed by intramolecular dipolar cycloaddition of the intermediate nitrone 14 affords a mixture of the isoxazolidines 15, 16 and 17. The tricyclic 6,5,5-adduct 15 is believed to be the product of kinetic control and can be equilibrated with the epimeric tricyclic 6,5,5-isoxazolidine 17 through a beta-elimination/conjugate addition process. Conditions have been developed for the two-step conversion of the ketone 12 under thermodynamic control into the racemic tricyclic 6,6,5-adduct 16 which is the core precursor of all the known histrionicotoxin alkaloids.

Recent Approaches to cis‐Azadecalins: Synthesis of Dendrobatid Alkaloid Pumiliotoxin C

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric Total Synthesis of Dendrobatid Alkaloid 251F.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric total synthesis of dendrobatid alkaloid 251F.

The dendrobatid alkaloid (-)-251F was synthesized. The key steps of the synthesis were (1) an asymmetric Diels-Alder reaction to establish four of the necessary stereocenters in the target, (2) a ring-opening/ring-closing metathesis reaction to establish a key [3.3.0] bicyclic intermediate, and (3) an intramolecular Schmidt reaction.

Stereodivergent process for the synthesis of the decahydroquinoline type of dendrobatid alkaloids.

A flexible and stereodivergent synthesis of the cis- and trans-fused 2,5-disubstituted octahydroquinolinone ring systems bearing all four stereogenic centers for the synthesis of the decahydroquinoline type of dendrobatid alkaloids has been achieved. The strategy involves stereoselective and stereodivergent construction of 2,3,6-trisubstituted piperidine ring systems using the Michael type of conjugate addition reaction to the enaminoesters 1 and 3, the intramolecular aldol type of cyclization reaction of keto aldehydes 11 and 12, and ring-closing metathesis of 21 as key steps.

A Convenient New Route to Piperidines, Pyrrolizidines, Indolizidines, and Quinolizidines by Cyclization of Acetylenic Sulfones with β- and γ-Chloroamines. Enantioselective Total Synthesis of Indolizidines(−)-167B,(−)-209D,(−)-209B, and(−)-207A

The methyl esters of (L)-phenylalanine and (L)-methionine underwent conjugate additions via their free amino groups to 1-(p-toluenesulfonyl)hexyne, followed by intramolecular acylation of the corresponding enamide anions and tautomerization to afford 2-benzyl-5-n-butyl-3-hydroxy-4-(p-toluenesulfonyl)pyrrole and 5-n-butyl-3-hydroxy-2-(2-methylthioethyl)-4-(p-toluenesulfonyl)pyr role, respectively. The conjugate additions of a series of acyclic and cyclic secondary beta- and gamma-chloroamines to acetylenic sulfones proceeded similarly under mild conditions. The resulting adducts were deprotonated with LDA in THF at -78 degrees C, and the resulting sulfone-stabilized carbanions underwent intramolecular alkylation to afford cyclic enamine sulfones. Thus, acyclic gamma-chloroalkyl-benzylamines afforded the corresponding 2- or 2,6-disubstituted piperidines, while 2-(chloromethyl)pyrrolidines, 2-(2-chloroethyl)pyrrolidines, 2-(chloromethyl)piperidines, and 2-(2-chloroethyl)piperidines produced the corresponding 3-substituted pyrrolizidines, 5- or 3-substituted indolizidines, and 4-substituted quinolizidines, respectively. 8-Methyl-5-substituted indolizidines were also prepared from the appropriate methyl-substituted chloroamine precursor. Enantioselective syntheses were achieved by employing chiral chloroamines derived from amino acids or other enantiopure precursors. Further transformations of several of the products provided concise syntheses of four dendrobatid alkaloids. Thus, reduction of (8aS)-5-n-propyl-6-(p-toluenesulfonyl)-delta5,6-indolizidine with sodium cyanoborohydride in trifluoroacetic acid, followed by reductive desulfonylation, afforded (-)-indolizidine 167B. The corresponding 5-n-hexyl derivative similarly produced (-)-indolizidine 209D, while (-)-(8R, 8aS)-8-methyl-5-n-pentyl-6-(p-toluenesulfonyl)-delta5,6-indo lizidine furnished (-)-indolizidine 209B. Finally, the similar reduction and debenzylation of (-)-(8R,8aS)-5-(2-benzyloxyethyl)-8-methyl-6-(p-toluenesulfo nyl)-delta5,6-indolizidine produced the corresponding 5-hydroxyethyl indolizidine. This was subjected to chlorination of the alcohol group with thionyl chloride and substitution with a higher order allyl cuprate reagent to afford (-)-indolizidine 207A.

Asymmetric synthesis of (-)-indolizidines 167B and 209D based on stereocontrolled allylation of a chiral tricyclic N-acyl-N,O-acetal.

[reaction: see text] The tricyclic N-acyl-N,O-acetal incorporating (S)-2-(1-aminoethyl)phenol as a chiral auxiliary underwent TiCl4-mediated allylation to give the chiral (5S)-allylpyrrolidinone with retention of configuration in high yield and diastereoselectivity. On the bases of this methodology, the asymmetric syntheses of the dendrobatid alkaloids (-)-indolizidines 167B and 209D were achieved.

First Enantioselective Synthesis of Dendrobatid Alkaloids Indolizidine (-)-209I and (-)-223J

First Enantioselective Synthesis of Dendrobatid Alkaloids Indolizidine (-)-209I and (-)-223J