Pyrrolizidine Skeleton Research Articles

Direct enantioselective synthesis of pyrrolizidines

Stereoselective synthesis of natural and unnatural compounds containing the pyrrolizidine skeleton is of immense interest to synthetic organic chemists due to their enormous biological importance. In addition to the numerous total synthetic approaches, the development of direct synthetic strategies for the enantioselective preparation of pyrrolizidines has shown rapid progress in the last decade. The 1,3-dipolar cycloaddition reaction of a dipole and a dipolarophile has been found to be the most useful tool for the direct asymmetric synthesis of pyrrolizidines, and Michael addition followed by cyclisation is implicated for the preparation of pyrrolizidinones. In this digest review, we discuss the direct approaches for the preparation of optically active pyrrolizidines and pyrrolizidinones.

New alkaloids from the diversity-enhanced extracts of an endophytic fungus Aspergillus flavus GZWMJZ-288

Three new alkaloids (1–3) together with four previously reported compounds (4–7) were identified from the extracts and the diversity-enhanced extracts of the fermentation broth of the endophytic fungus, Aspergillus flavus GZWMJZ-288 associated with Garcinia multiflora. The structures of new compounds were respectively determined as 19-amino-19-dehydroxy 5-epi-α-cyclopiazonic acid (1), 2-hydroxymethyl-5-(3-oxobutan-2-yl)aminopyran-4(4H)-one (2) and 4-amino-2-hydroxymethylpyridin-5-ol (3) by spectroscopic analysis, ECD calculation and X-ray single crystal diffraction. Compounds 1 and 4 with 19-enamine were dynamic equilibrium of Z- and E- isomers in the solution but favored in Z- isomers in the solid state, while compound 7 with 19-enol was favored in Z- isomer in the solution but a mixture of Z- and E- isomers in solid state. This phenomenon could be explained by the quantum–mechanical energies calculations. Among the isolated compounds 1–7, compounds 1, 4 and 7 with a rare 1,3,4,5-tetrahydro-1-azaacenaphtho[3,4-c]pyrrolizidine skeleton showed α-glucosidase inhibitory activity with the IC50 values of 41.97 ± 0.97, 232.57 ± 11.45 and 243.95 ± 3.36 μM, respectively, and the binding modes were performed by silico docking studies.

Status of content analysis of pyrrolizidine alkaloids in food and herbs

Pyrrolizidine alkaloids(PAs) are a group of naturally occurring alkaloids with a pyrrolizidine skeleton which can be found in about 3% of the world's flowering plants. It is notorious that PAs are cause the hepatoxic and genotoxic-carcinogenic effects by taking PA-containing herbs, food and dietary supplements. In order to control the poisoning caused by PAs, European Medicines Agency has set a limit of intake of PAs from herbal medicinal products at 0.007 μg of 1,2-unsaturated PAs/kg body weight. Nonetheless, a systematic overview of the amount of PAs in the herb has not been provided. Therefore, this paper is to systematically review the current status of PAs content analysis of herbal medicines and foods reported in the literature, and to provide theoretical and experimental support for the safety risk assessment and control of PAs in Chinese herbal medicines.

Asymmetric synthesis of epohelmins A, B and 3-epi ent-epohelmin A

An efficient method for asymmetric synthesis of epohelmins A (3), B (4) and their isomer 24 is detailed in this report. The key feature in this divergent synthesis includes the SmI2-induced cross-coupling of N-tert-butanesulfinyl imine 10 with chiral aldehyde 9 derived from d-malic acid. A cascade cyclization to the pyrrolizidine skeleton is achieved in our synthetic route for epohelmins. In addition, an interesting intramolecular oxa-Michael addition was observed for epohelmin A (3).

Stereoselective synthesis of (+)-loline alkaloid skeleton.

The loline alkaloids present a compact polycyclic pyrrolizidine skeleton and contain a strained five-membered ethereal bridge, structural features that have proven challenging for synthetic chemists to incorporate since the discovery of this natural product family more than 100 years ago. These alkaloids are produced by mutualistic fungal symbionts (endophytes) living on certain species of pasture grasses and protect the host plant from insect herbivory. The asymmetric total synthesis of loline alkaloids is reported and extends our first-generation (racemic) synthesis of this alkaloid family. Key to the synthesis is a diastereoselective tethered aminohydroxylation of a homoallylic carbamate function and a Petasis Borono-Mannich addition.

6-Azido hyacinthacine A2gives a straightforward access to the first multivalent pyrrolizidine architectures

The synthesis of the first multivalent pyrrolizidine iminosugars is reported. The key azido intermediates 4 and 31 were prepared after suitable synthetic elaboration of the cycloadduct obtained from 1,3-dipolar cycloaddition of D-arabinose derived nitrone to dimethylacrylamide. The key step of the strategy was the stereoselective installation of an azido moiety at C-6 of the pyrrolizidine skeleton. The click reaction with different monovalent and dendrimeric alkyne scaffolds allowed the preparation of a library of new mono- and multivalent pyrrolizidine compounds that were preliminarily assayed as glycosidase inhibitors towards a panel of commercially available glycosyl hydrolases.

Total synthesis of the proposed structure for pochonicine and determination of its absolute configuration

Pochonicine is a polyhydroxylated pyrrolizidine alkaloid with a powerful inhibitory activity against β-N-acetylglucosaminidases. The proposed structure for pochonicine and the three diastereomers concerning its C-1 and/or C-3 positions were synthesized from N-acetyl-d-glucosamine through construction of the pyrrolizidine skeleton by two intramolecular amino cyclizations as key steps. This synthetic study not only revised the structure of the natural product to the corresponding 1,3-di-epi-form but also determined the absolute configuration as 1R, 3S, 5R, 6R, 7S, 7aR.

First Total Synthesis of the Pyrrolizidine Alkaloid Amphorogynine C through Intramolecular Azide–Olefin Cycloaddition

AbstractThe first total synthesis of the natural alkaloid amphorogynine C is reported (2.9 % overall yield in 20 steps). The key steps include a Claisen–Johnson rearrangement and an intramolecular azide–olefin cycloaddition, followed by a reduction of the resulting imine. The construction of the pyrrolizidine skeleton was achieved by an alkoxide‐mediatedlactone ring opening and subsequent cyclization of a conveniently functionalized bicyclic amine. Finally, the proposed structure of amphorogynine C was confirmed by single‐crystal X‐ray diffraction analysis.

Synthesis of (±)-Acetylnorloline via Stereoselective Tethered Aminohydroxylation

Loline alkaloids exhibit a strained ether-bridged pyrrolizidine skeleton and possess insecticidal and insect antifeedant properties. The synthesis of acetylnorloline, a prototypical member of the alkaloid family, is described. Central to the route is a stereoselective tethered aminohydroxylation (TA) of a homoallylic carbamate. Allylic (A1,3) strain is exploited to enforce diastereofacial selectivity during the aminohydroxylation.

Synthesis and evaluation of opioid receptor-binding affinity of elaeocarpenine and its analogs

Both enantiomers of elaeocarpenine ( 1) and its analogs, 21, 22, 25, and 27, were synthesized from bicyclic aldehydes 8– 10 via a flexible route previously established for total synthesis of grandisines, and their binding affinities for μ-, κ- and δ-opioid receptor subtypes were evaluated. We found that (9 R)- 1 exhibited higher affinity than (9 S)- 1 for all the subtypes, but the enantiomers showed little subtype selectivity. Analogs 21 having a pyrrolizidine skeleton and 27 having a stemona-type skeleton in place of the indolizidine unit of (9 S)- 1 showed μ-selective and μ-, κ-selective binding, respectively.

A Stereoselective Domino Reaction Leading to a Pyrrolizidine Skeleton

A Stereoselective Domino Reaction Leading to a Pyrrolizidine Skeleton

New Access to Indolizidine and Pyrrolizidine Alkaloids from an Enantiopure Proline: Total Syntheses of (−)-Lentiginosine and (1R,2R,7aR)-Dihydroxypyrrolizidine

A new approach to the synthesis of indolizidine and pyrrolizidine skeletons is reported. (-)-Lentiginosine and (1R,2R,7aR)-dihydroxypyrrolizidine have both been synthesized in 13 steps from di-O-isopropylidene-d-mannitol. The common key intermediate is (-)-dihydroxyproline benzyl ester 10.

Formal Synthesis of (±)‐Trachelanthamidine via Base‐Induced Formal [3+2] Annulation and Intramolecular Cyclization

AbstractBase‐induced coupling/cyclization stepwise [3+2] annulation of α‐sulfonylacetamide with (Z)‐2‐bromoacrylates yielded polysubstituted pyroglutamates with three contiguous chiral centers with trans‐trans orientation in a one‐pot synthesis. The pyrrolizidine skeleton was obtained via an intramolecular cyclization. This facile strategy was used to synthesize (±)‐trachelanthamidine.

Formal Synthesis of (.+‐.)‐Trachelanthamidine.

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Formal Synthesis of (±)-Trachelanthamidine

Base-induced coupling-cyclization stepwise [3+2] annulation of α-sulfonylacetamide with (Z)-2-bromoacrylate yielded the polysubstituted pyroglutamate with three contiguous chiral centers with trans-trans orientation in a one-pot synthesis. The pyrrolizidine skeleton was obtained via the ring-closing metathesis (RCM) method. This facile strategy was used to synthesize (′)-trachelanthamidine.

Synthesis of psudoheliotridane via formal [3+2] annulation and ring-closing metathesis

Base-induced coupling/cyclization stepwise [3+2] annulation of α-sulfonylacetamide with ( Z)-2-bromoacrylates yielded polysubstituted pyroglutamates with three contiguous chiral centers with trans– trans orientation in a one-pot synthesis. The pyrrolizidine skeleton was obtained via the ring-closing metathesis (RCM) method. This facile strategy was used to synthesize psudoheliotridane.

Synthesis of psudoheliotridane via formal 63+29 annulation and ring-closing metathesis*1, *2

Base-induced coupling/cyclization stepwise [3+2] annulation of α-sulfonylacetamide with ( Z )-2-bromoacrylates yielded polysubstituted pyroglutamates with three contiguous chiral centers with trans – trans orientation in a one-pot synthesis. The pyrrolizidine skeleton was obtained via the ring-closing metathesis (RCM) method. This facile strategy was used to synthesize psudoheliotridane. Graphic

Enantioselective Cyclization of Alkene Radical Cations.

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Enantioselective cyclization of alkene radical cations.

[reaction: see text] Enantiomerically enriched beta-(diphenylphosphatoxy)nitroalkanes undergo radical ionic fragmentation, induced by tributyltin hydride and AIBN in benzene at reflux, to give alkene radical cations in contact radical ion pairs. These contact ion pairs are trapped intramolecularly by amines to give pyrrolidines and piperidines with significant enantioselectivity ( approximately 60% ee), indicative of cyclization competing effectively with equilibration within the ion pairs. Use of an intramolecular N-propargylamine as a nucleophile provides an enantiomerically enriched pyrrolizidine skeleton via a tandem polar/radical crossover sequence.

Silylcyclocarbonylation (SiCCa) of alkynylamines catalyzed by rhodium complexes

Attempted silylcarbocyclization (SiCaC) of 2-allyl-1-propargyltetrahydroisoquinoline with HSiMe 2Ph and carbon monoxide catalyzed by Rh(acac)(CO) 2 unexpectedly gives8- exo-silylmethylene-4,5-benzo-9-indolizidinone, 8-allyl-8-silylmethyl-4,5-benzo-9-indolizidinone, and a hydrosilylation product. Possible mechanisms are proposed for the observed facile N-allyl cleavage and allyl transfer as well as the silylcyclocarbonylation (SiCCa) of the alkynylamine generated in situ. The SiCCa reactions of 1-propargyltetrahydroisoquinoline, ( R)-2-(3-butynyl)pyrrolidine, ( S)-2-[( R)-1-hydroxy-3-butylnyl]pyrrolidine and ( S)-2-[diethynyl-(hydroxy) methyl]pyrrolidine are further investigated. These reactions give the corresponding indolizidine or pyrrolizidine skeletons in one step. The scope and limitation of the SiCCa reaction and related reactions are discussed.