piperidines and sedamine

The synthesis of optically active substituted piperidines has been achieved by using four different methodologies. The first one is an intramolecular nucleophilic displacement of activated alcohol moieties that was used to build up the piperidine ring of (-)-prosophylline and (-)-slaframine, and the second one is a ring-closing metathesis of unsaturated amines which was employed in the synthesis of (+)-sedamine and 4a,5-dihydrostreptazoline. The third methodology is the alpha-functionalization of N-Boc piperidines which was particularly useful in the synthesis of argatroban, and the fourth one is a ring expansion of prolinols to 3-chloropiperidines or 3-hydroxypiperidines which was utilized to synthesize (-)-paroxetine, (-)-pseudoconhydrine, the piperidine ring of (-)-velbanamine and (+)-zamifenacin.

Topics: Alkaloids; Arginine; Chemistry; Dioxoles; Paroxetine; Pipecolic Acids; Piperidines; Pyrrolidines; Sulfonamides

Synthesis of β-sulfinamido ketones was accomplished by the addition of silyl enol ethers derived from arylmethyl ketones to chiral sulfinimines in excellent yield and selectivity. Application of the formed β-amino substituted ketones is exemplified in the total synthesis of sphingolipid HPA-12 and the sedamine alkaloids.

Topics: Alkaloids; Amides; Imines; Ketones; Molecular Structure; Piperidines; Sulfonium Compounds

An efficient total synthesis of the natural alkaloid (+)-dumetorine by using flow technology is described. The process entailed five separate steps starting from the enantiopure (S)-2-(piperidin-2-yl)ethanol 4 with 29% overall yield. Most of the reactions were carried out by exploiting solvent superheating and by using packed columns of immobilized reagents or scavengers to minimize handling. New protocols for performing classical reactions under continuous flow are disclosed: the ring-closing metathesis reaction with a novel polyethylene glycol-supported Hoveyda catalyst and the unprecedented flow deprotection/Eschweiler-Clarke methylation sequence. The new protocols developed for the synthesis of (+)-dumetorine were applied to the synthesis of its simplified natural congeners (-)-sedamine and (+)-sedridine.

Topics: Alkaloids; Catalysis; Cyclization; Molecular Structure; Piperidines; Solvents; Stereoisomerism; Technology; Temperature

A convenient method for the generation of (+)-sedamine and (+)-allosedamine in high optical purity has been elaborated. The key steps are the highly stereoselective 1,2-nucleophilic addition to SAMP hydrazones allowing the installation of the stereogenic center at C2 and ring closing metathesis.

Topics: Alkaloids; Catalysis; Cyclization; Epoxy Compounds; Hydrazones; Molecular Structure; Phenylmercury Compounds; Phosphinic Acids; Piperidines; Potassium; Stereoisomerism

The piperidine alkaloid, (+)-sedamine has been synthesised starting from (S)-1-phenyl-3-butenol using a stereoselective, intramolecular palladium-catalysed cyclocarbonylation reaction of a substituted hydroxylamine.

Topics: Alkaloids; Butanols; Catalysis; Copper; Cyclization; Molecular Conformation; Palladium; Piperidines; Stereoisomerism

Alkyl chloroformates induced indirect trapping of the retroconjugate addition reaction intermediate involved in the epimerization of lobeline is described. This strategy was applied to the conversion of (-)-lobeline to (-)-sedamine in high overall yield.

Topics: Alkaloids; Lobeline; Molecular Structure; Piperidines; Stereoisomerism

Kinetic resolution of N-Boc-piperidine-2-ethanol (2), a case of remote stereocenter discrimination, was accomplished by sequential transesterification mediated by two enzymes, Lipase PS and porcine pancreatic lipase, showing opposite enantioselectivity. The gram-scale availability of the two enantiomeric N-Boc alcohols 2a (R) and 2c (S) enlarges their synthetic exploitation for the enantioselective preparation of piperidine alkaloids. As an example, the convenient three-step synthesis of both the enantiomers of sedamine and allosedamine is described.

Topics: Acetylation; Alkaloids; Animals; Kinetics; Lipase; Models, Chemical; Molecular Structure; Piperidines; Stereoisomerism

A highly stereoselective asymmetric synthesis of (--)-sedamine and (--)-lobeline is described from benzaldehyde in 16 and 17 steps with an overall yield of 20% and 14%, respectively. The key intermediate syn-3,4-epoxyalcohol was prepared in a highly diastereomeric fashion (>99% ee, dr) and served as a common intermediate for both alkaloids.

Topics: Alkaloids; Catalysis; Chemistry, Organic; Chromatography, High Pressure Liquid; Lobelia; Lobeline; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Piperidines; Plants, Medicinal; Stereoisomerism

An enantioselective synthesis of the piperidine alkaloids (+)-sedamine and (-)-prosophylline is reported. The synthesis of (+)-sedamine has been achieved in 12 steps with an overall yield of 20% from benzaldehyde, and (-)-prosophylline was obtained in 15 steps with an overall yield of 9.2%, starting from D-glyceraldehyde acetonide 14. The key steps are enantioselective allyltitanation reactions and ring-closing or cross-metathesis reactions.

Topics: Alkaloids; Benzaldehydes; Catalysis; Chemistry, Organic; Chromatography, High Pressure Liquid; Cyclization; Ethers, Cyclic; Glyceraldehyde; Magnetic Resonance Spectroscopy; Molecular Structure; Piperidines; Stereoisomerism

Interactions of pea seedlings amine oxidase (PSAO, EC 1.4.3.6) with sedamine derivatives were studied. All compounds exhibited a competitive inhibition with the inhibition constants in the range 0.03-1.0 mM. The inhibition effect increased in the order allosedamine < sedamine << norallosedamine < norsedamine. The nor-derivatives are about five-fold stronger inhibitors and the allo-isomers are slightly weaker inhibitors than the others. Interestingly, the (-)-diastereomers of the studied sedamines were considerably stronger inhibitors than the (+)-antipodes. Absorption spectroscopy was used to differentiate between two known groups of competitive inhibitors of PSAO. A representative of substrate analogues, 1,5-diamino-3-pentanone, bleached the spectrum of the TPQ cofactor producing a very stable intermediate of the enzyme catalytic cycle that was only slowly converted to the product. On the other hand, the alkaloids did not perturb the spectrum of TPQ so they may interact with some other residue near the active site.

Topics: Alkaloids; Amine Oxidase (Copper-Containing); Binding Sites; Binding, Competitive; Kinetics; Molecular Probes; Piperidines; Pisum sativum; Seeds; Spectrum Analysis; Stereoisomerism; Structure-Activity Relationship

Topics: Alkaloids; Piperidines