Concise Synthesis of Pyrrolidine and Indolizidine Alkaloids by a Highly Convergent Three-Component Reaction

The synthesis of pyrrolidine and indolizidine derivatives through radical carboazidation of alkenes with alpha-iodoketones, followed by reductive amination, is described. When properly substituted, further lactamization afforded pyrrolizidinones in good yield. This carboazidation/reductive amination sequence was efficiently applied to the total synthesis of three different simple alkaloids, including (+/-)-monomorine I.

Total synthesis of (-)-indolizidine 167B via an unusual Wolff rearrangement from an alpha,beta-unsaturated diazoketone

A concise synthesis of the (-)-indolizidine alkaloid 167B and two formal syntheses of (-)-indolizidine 209D and (-)-coniceine are described in just three steps from an alpha,beta-unsaturated diazoketone, via an unusual photochemical Wolff rearrangement. Preparation of the unsaturated diazoketone is straightforward from N-Cbz-prolinal and a 3-diazo-2-oxopropylphosphonate, employing a Horner-Wadsworth-Emmons reaction. The strategy should be feasible and easily adaptable to the synthesis of other indolizidine alkaloids and analogues. (C) 2011 Elsevier Ltd. All rights reserved.

alpha,beta-Unsaturated Diazoketones as Platforms in the Asymmetric Synthesis of Hydroxylated Alkaloids. Total Synthesis of 1-Deoxy-8,8a-diepicastanospermine and 1,6-Dideoxyepicastanospermine and Formal Synthesis of Pumiliotoxin 251D

A versatile and concise approach for the stereoselective synthesis of mono-, di-, and trihydroxylated indolizidines is presented in four to six steps from Cbz-prolinal and a diazophosphonate. The key steps involved a Wolff rearrangement, followed by a stereoselective dihydroxylation/epoxidation reaction, from an alpha,beta-unsaturated diazoketone. The strategy also permits extension to the synthesis of many natural hydroxylated indolizidine alkaloids as demonstrated in the formal synthesis of pumiliotoxin 251D.

Indolizidine 239Q and quinolizidine 275I. Major alkaloids in two Argentinian bufonid toads (Melanophryniscus)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The occurrence of defensive alkaloids in non-integumentary tissues of the Brazilian red-belly toad Melanophryniscus simplex (Bufonidae)

The red-belly toads (Melanophryniscus) of southern South America secrete defensive alkaloids from dermal granular glands. To date, all information on Melanophryniscus alkaloids has been obtained by extraction from either skins or whole organisms; however, in other amphibians, tetrodotoxins, samandarines, and bufadienolides have been detected in both skin and other organs, which raise the possibility that lipophilic alkaloids may occur in non-integumentary tissues in Melanophryniscus as well. To test this hypothesis, we studied the distribution of alkaloids in the skin, skeletal muscle, liver, and mature oocytes of the red-belly toad M. simplex from three localities in southern Brazil. Gas chromatography and mass spectrometry of skin extracts from 11 individuals of M. simplex resulted in the detection of 47 alkaloids (including isomers), 9 unclassified and 38 from 12 known structural classes. Each alkaloid that was present in the skin of an individual was also present in the same relative proportion in that individual's skeletal muscle, liver, and oocytes. The most abundant and widely distributed alkaloids were the pumiliotoxins 251D, 267C, and 323A, 5,8-disubstituted indolizidines 207A and 223D, 5,6,8-trisubstituted indolizidine 231B, 3,5-disubstituted pyrrolizidines cis-223B and cis- and trans-251K, and izidine 211C. We report the first record of piperidines in Melanophryniscus, bringing the total number of alkaloid classes detected in this genus to 16. Alkaloid composition differed significantly among the three study sites. The functional significance of defensive chemicals in non-integumentary tissues is unknown.

Pteridine-, thymidine-, choline- and imidazole-derived alkaloids from the Australian ascidian, Leptoclinides durus

Four new acylated pteridine alkaloids, duramidines A-D, two new acylated thymidine alkaloids, leptoclinidines A and B, two new 1-acylglyceryl-3-(O- carboxyhydroxymethylcholine) alkaloids, durabetaines A and B, three new 1,3-dimethyl-5-methylsulfanylimidazole alkaloids, leptoclinidamines D-F, and the known alkaloids leptoclinidamines B and C and 6-bromo-1H-indolo-3-yl-oxoacetic acid methyl ester were isolated from the Australian ascidian Leptoclinides durus. The duramidines are the first pteridine alkaloids, possessing a three carbon side chain esterified at C-1′ with a 4-hydroxy-2′- methoxycinnamic acid, and are either hydroxylated or sulfated at C-2′. The leptoclinidines are the first 3′-indole-3-carboxylic acid ester derivatives of thymidine to be reported in the literature. The durabetaines are the first glyceryl-3-(O-carboxyhydroxymethylcholine) alkaloids to be reported from an animal source and are also the only known derivatives from this class to be acylated with aromatic carboxylic acids. MS and NMR data analysis established the structures of the new compounds. All compounds were shown to be inactive when tested for cytotoxic activity against prostate (LNCaP) and breast (MDA-MB-231) cancer cell lines and antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus.

Isolation, structure determination and cytotoxicity studies of tryptophan alkaloids from an Australian marine sponge Hyrtios sp

Mass-guided fractionation of the MeOH extract from a specimen of the Australian marine sponge Hyrtios sp. resulted in the isolation of two new tryptophan alkaloids, 6-oxofascaplysin (2), and secofascaplysic acid (3), in addition to the known metabolites fascaplysin (1) and reticulatate (4). The structures of all molecules were determined following NMR and MS data analysis. Structural ambiguities in 2 were addressed through comparison of experimental and DFT-generated theoretical NMR spectral values. Compounds 1–4 were evaluated for their cytotoxicity against a prostate cancer cell line (LNCaP) and were shown to display IC50 values ranging from 0.54 to 44.9 μM.

Ecionines A and B, two new cytotoxic pyridoacridine alkaloids from the Australian marine sponge, Ecionemia geodides

Chemical investigations of the Australian marine sponge Ecionemia geodides resulted in the isolation of two new pyridoacridine alkaloids, ecionines A (1) and B (2), along with the previously isolated marine natural products, biemnadin (3) and meridine (4). Compounds 1 and 2 both contain an imine moiety, which is rare for the pyridoacridine structure class. The chemical structures of 1 and 2 were determined by extensive 1D and 2D NMR and MS data analyses. All compounds were tested against a panel of human bladder cancer cell lines, the increasingly metastatic TSU-Pr1 series (TSU-Pr1, TSU-Pr1-B1 and TSU-Pr1- B2) and the superficial bladder cancer cell line 5637. Ecionine A (1) displayed cytotoxicity against all cell lines, with IC50 values ranging from 3 to 7 mM. This is the first report of chemistry from the sponge genus Ecionemia.

Cytotoxic C20 diterpenoid alkaloids from the Australian endemic rainforest plant Anopterus macleayanus

In order to identify new anticancer compounds from nature, a prefractionated library derived from Australian endemic plants was generated and screened against the prostate cancer cell line LNCaP using a metabolic assay. Fractions from the seeds, leaves, and wood of Anopterus macleayanus showed cytotoxic activity and were subsequently investigated using a combination of bioassay-guided fractionation and mass-directed isolation. This led to the identification of four new diterpenoid alkaloids, 6α-acetoxyanopterine (1), 4′-hydroxy-6α-acetoxyanopterine (2), 4′-hydroxyanopterine (3), and 11α-benzoylanopterine (4), along with four known compounds, anopterine (5), 7β-hydroxyanopterine (6), 7β,4′-dihydroxyanopterine (7), and 7β-hydroxy-11α-benzoylanopterine (8); all compounds were purified as their trifluoroacetate salt. The chemical structures of 1–8 were elucidated after analysis of 1D/2D NMR and MS data. Compounds 1–8 were evaluated for cytotoxic activity against a panel of human prostate cancer cells (LNCaP, C4-2B, and DuCaP) and nonmalignant cell lines (BPH-1 and WPMY-1), using a live-cell imaging system and a metabolic assay. All compounds showed potent cytotoxicity with IC50 values of <400 nM; compound 1 was the most active natural product from this series, with an IC50 value of 3.1 nM toward the LNCaP cell line. The live-cell imaging assay on 1–8 showed a concentration- and time-dependent effect on the cell morphology and proliferation of LNCaP cells.

Pyrrolizidine Alkaloids in Crotalaria Taxa from Northern Australia: Risk to Grazing Livestock.

Crotalaria species containing hepatotoxic pyrrolizidine alkaloids grow widely in pastures in northern Australia and have sporadically poisoned grazing livestock. The diverse Crotalaria taxa present in these pastures include varieties, subspecies, and chemotypes not previously chemically examined. This paper reports the pyrrolizidine alkaloid composition and content of 24 Crotalaria taxa from this region and assesses the risk of poisoning in livestock consuming them. Alkaloids present in C. goreensis, C. aridicola subsp. densifolia, and C. medicaginea var. neglecta lack the esterified 1,2-unsaturated functionality required for pyrrole adduct formation, and these taxa are not hepatotoxic. Taxa with high levels of hepatotoxic alkaloids, abundance, and biomass pose the greatest risk to livestock health, particularly C. novae-hollandiae subsp. novae-hollandiae, C. ramosissima, C. retusa var. retusa, and C. crispata. Other species containing moderate alkaloid levels, C. spectabilis and C. mitchellii, also pose significant risk when locally abundant.

Risks from plants containing pyrrolizidine alkaloids for livestock and meat quality in Northern Australia.

This chapter describes poisoning associated with consumption of pyrrolizidine alkaloid (PA)-containing plants (Crotalaria spp., Heliotropium spp. and Senecio spp.) by cattle and horses in rangelands of northern Australia, as well as the risks for meat quality of PA residues and potential health hazards to consumers.

Synthesis, structure and DNA cleavage studies of coumarin analogues of tetrahydroisoquinoline and protoberberine alkaloids

Novel molecular matrices have been derived from coumarin-4-acetic acids and beta-phenylethylamines using the Bischler-Napieralski protocol which has led to the synthesis of analogues of tetrahydropapaverine in which the dimethoxybenzene moiety has been replaced by substituted coumarins. One carbon homologation has led to cyclization at the C3 position of coumarin generating the protoberberine skeleton. Structures have been confirmed by diffraction studies. The results showed that compounds 6e, 6f, 7e and 7f were found to be very effective against DNA samples of Gram positive bacterium Staphylococcus aureus and fungus Aspergillus niger. (C) 2010 Elsevier Masson SAS. All rights reserved.

Alkaloid synthesis: stereoselective approach towards fawcettimine-serratinine group of lycopodium alkaloids

The concept of carbocycle-heterocycle equivalency has been utilised to assemble the framework of fawcettimine-serratinine group of alkaloids from 1,5-cyclooctadiene through a common tricarbocyclic intermediate 3.

Preparatively useful transformations of steroids and morphine alkaloids byMucor piriformis

A versatile fungus isolated in our laboratory and identified as Mucor piriformis has been shown to effect novel and preparatively useful transformations in steroids and morphine alkaloids. The organism very effectively carries out hydroxylation of various C-19 and C-21 steroids at 7 and 14-positions. Although the organism is capable of catalysing hydroxylation at 6 beta and 11 alpha-positions, these are not the major activities. The 14 alpha-hydroxylase appears to have a broad substrate specificity. However, steroids with a bulky substitution at C-17 alpha-position or without the 4-en-3-one group are not accepted as substrates by the 14 alpha-hydroxylase system. Studies have demonstrated how various C-19 and C-21 steroids can be modified to yield new structures which are either difficult to prepare by traditional methods or hitherto unknown. The organism also very efficiently and selectively carries out the N-dealkylation of thebaine and its N-variants. Interestingly, the nor-compound formed does not get further metabolized. Since thebaine is very often used as a starting material to synthesize various morphine agonists as well as antagonists, and one of the steps involved in their preparation is the N-dealkylation reaction, the microbial process could certainly offer an alternative approach.