piperidines and norsecurinine

A consecutive synthetic strategy was developed toward the total synthesis of securinega alkaloids. (-)-Norsecurinine was concisely assembled by addition of a methoxyallene to a ketone for efficient side-chain installation. Ring-closing metathesis was also utilized as a key step. The first total synthesis of (-)-niruroidine was achieved from (-)-norsecurinine in three steps, while the route to (-)-flueggine A featured a 1,3-dipolar cycloaddition to forge the core structure.

Topics: Alkaloids; Azepines; Cycloaddition Reaction; Euphorbiaceae; Indolizines; Piperidines

The most representative securinega alkaloids have been synthesized through a new strategy involving the palladium-catalyzed enantioselective allylation of a cyclic imide, a vinylogous Mannich reaction, and a ring-closing metathesis process, as the key steps. The diastereoselectivity of the vinylogous Mannich reaction was in partial agreement with DFT theoretical calculations performed in a model system. The synthesis of (-)-norsecurine has been accomplished in nine steps from succinimide and 14% overall yield and that of securinine in 10 steps from glutarimide and 20% overall yield. Both syntheses compare favorably with those previously described. The three key transformations have been performed in a synthetically useful scale (more than 500 mg). Moreover, since the enantioselectivity was originated by a chiral phosphine ligand, the antipode of which is readily available, the same route is expected to give access to (+)-norsecurinine and virosecurinine.

Topics: Alkaloids; Azepines; Catalysis; Euphorbiaceae; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Imides; Lactones; Palladium; Piperidines; Quantum Theory; Stereoisomerism; Substrate Specificity

[structure: see text] Two unprecedented C,C-linked dimeric indolizidine alkaloids, flueggenines A (1) and B (2), as well as their biosynthetic precursor (-)-norsecurinine, were isolated from the roots of Flueggea virosa. Their structures and absolute configurations were elucidated by spectroscopic methods, especially 2D NMR and CD spectral analyses, and supported by their unique biosynthetic pathway as proposed. Both 1 and 2 were tested against two tumor cell lines, and alkaloid 1 showed weak activity against the P-388 cell line.

Topics: Alkaloids; Animals; Azepines; Drug Screening Assays, Antitumor; Euphorbiaceae; Humans; Indolizines; Leukemia P388; Mice; Molecular Structure; Piperidines; Plant Roots; Plants, Medicinal

[reaction: see text] A highly versatile approach to the enantioselective synthesis of securinega alkaloids is presented. Crucial steps are a palladium-catalyzed enantioselective imide alkylation, a vinylogous Mannich reaction, and a ring-closing metathesis process. Through this strategy, the synthesis of (-)-norsecurinine has been accomplished in nine steps and 11% overall yield.

Topics: Alkaloids; Azepines; Euphorbiaceae; Molecular Structure; Piperidines; Stereoisomerism

A new strategy for enantiospecific construction of the Securinega alkaloids has been developed and applied in total syntheses of (+)-14,15-dihydronorsecurinine (8), (-)-norsecurinine (6), and phyllanthine (2). The B-ring and C7 absolute stereochemistry of these biologically active alkaloids originated from trans-4-hydroxy-L-proline (10), which was converted to ketonitrile 13 via a high-yielding eight-step sequence. Treatment of this ketonitrile with SmI2 afforded the 6-azabicyclo[3.2.1]octane B/C-ring system 14, which is a key advanced intermediate for all three synthetic targets. Annulation of the A-ring of (-)-norsecurinine (6) with the required C2 configuration via an N-acyliminium ion alkylation was accomplished using radical-based amide oxidation methodology developed in these laboratories as a key step, providing tricycle 33. Annulation of the D-ring onto alpha-hydroxyketone 33 with the Bestmann ylide 45 at 12 kbar gave (+)-14,15-dihydronorsecurinine (8). In the securinine series, the D-ring was incorporated using an intramolecular Wadsworth-Horner-Emmons olefination of phenylselenylated alpha-hydroxyketone 47. The C14,15 unsaturation was installed late in the synthesis by an oxidative elimination of the selenoxide derived from tetracyclic butenolide 50 to give (-)-norsecurinine (6). The A-ring of phyllanthine (2) was formed from hydroxyketone 14 using a stereoselective Yb(OTf)3-promoted hetero Diels-Alder reaction of the derived imine 34 with Danishefsky's diene, affording adduct 35. Conjugate reduction and stereoselective equatorial ketone reduction of vinylogous amide 35 provided tricyclic intermediate 36, which could then be elaborated in a few steps to stable hydroxyenone 53 via alpha-selenophenylenone intermediate 52. The D-ring was then constructed, again using an intramolecular Wadsworth-Horner-Emmons olefination reaction to give phyllanthine (2).

Topics: Alkaloids; Azepines; Euphorbiaceae; Lactones; Piperidines; Stereoisomerism

Topics: Alkaloids; Azepines; Chemistry Techniques, Analytical; Chemistry, Pharmaceutical; Piperidines; Research

Topics: Alkaloids; Azepines; Chemistry Techniques, Analytical; Euphorbiaceae; Phenethylamines; Piperidines; Plants, Medicinal; Research; Spectrum Analysis; Tyramine