- An efficient asymmetric synthesis of (-)-lupinine
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The asymmetric synthesis of (-)-lupinine was achieved in 8 steps, 15% overall yield and >99:1 dr from commercially available starting materials. The strategy used for the construction of the quinolizidine scaffold involved reaction of an enantiopure terti
- Davies, Stephen G.,Fletcher, Ai M.,Foster, Emma M.,Houlsby, Ian T. T.,Roberts, Paul M.,Schofield, Thomas M.,Thomson, James E.
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p. 8309 - 8311
(2014/07/22)
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- Synthesis and comparison of antiplasmodial activity of (+), (-) and racemic 7-chloro-4-(N-lupinyl)aminoquinoline
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Recently the N-(-)-lupinyl-derivative of 7-chloro-4-aminoquinoline ((-)-AM-1; 7-chloro-4-{N-[(1S,9aR)(octahydro-2H-quinolizin-1-yl)methyl]amino} quinoline) showed potent in vitro and in vivo activity against both Chloroquine susceptible and resistant strains of Plasmodium falciparum. However, (-)-AM-1 is synthesized starting from (-)-lupinine, an expensive alkaloid isolated from Lupinus luteus whose worldwide production is not sufficient, at present, for large market purposes. To overcome this issue, the corresponding racemic compound, derived from synthetic (±)-lupinine was considered a cheaper alternative for the development of a novel antimalarial agent. Therefore, the racemic and the 7-chloro-4-(N-(+)-lupinyl)aminoquinoline ((±)-AM-1; (+)-AM-1) were synthesized and their in vitro antimalarial activity and cytotoxicity compared with those of (-)-AM-1. The (+)-lupinine required for the synthesis of (+)-AM-1 was obtained through a not previously described lipase catalyzed kinetic resolution of (±)-lupinine. In terms of antimalarial activity, (±)-AM1 and (+)-AM1 demonstrated very good activity in vitro against both CQ-R and CQ-S strains of P. falciparum (range IC50 16-35 nM), and low toxicity against human normal cell lines (therapeutic index >1000), comparable with that of (-)-AM1. These results confirm that the racemate (±)-AM1 could be considered as a potential antimalarial agent, ensuring a decrease of costs of synthesis compared to (-)-AM1.
- Rusconi, Chiara,Vaiana, Nadia,Casagrande, Manolo,Basilico, Nicoletta,Parapini, Silvia,Taramelli, Donatella,Romeo, Sergio,Sparatore, Anna
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p. 5980 - 5985
(2012/11/06)
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- Organocatalytic enantioselective synthesis of quinolizidine alkaloids (+)-myrtine, (-)-lupinine, and (+)-epiepiquinamide
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The organocatalytic synthesis of quinolizidine alkaloids (+)-myrtine, (-)-lupinine, and (+)-epiepiquinamide is described. It involved, as the key step, an enantioselective intramolecular aza-Michael reaction (IMAMR) catalyzed by J?rgensen catalyst I, affording the common precursor with high enantioselectivity. This compound was subsequently transformed into the three alkaloids in a highly diastereoselective manner.
- Fustero, Santos,Moscardó, Javier,Sánchez-Roselló, María,Flores, Sonia,Guerola, Marta,Pozo, Carlos Del
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p. 7412 - 7417
(2011/10/09)
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- Short total synthesis of (-)-lupinine and (-)-epiquinamide by double Mitsunobu reaction
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Alternative total syntheses of (-)-lupinine (1) and (-)-epiquinamide (2) have been described via the key intermediate 3 obtained from the addition of 2-trialkylsilyloxyfuran 5 to N-acyliminium intermediate derived from 4. The major R,R-isomer 8 obtained from the Mannich reaction was converted into its R,S-isomer through Mitsunobu reaction. Then, a second Mitsunobu reaction of 3 led to cyano 9 and azido 11 derivatives, which were converted into 1 and 2 in 33 and 36% overall yield from 4, respectively. The synthetic route is amenable for the generation of several quinolizidine alkaloids. Georg Thieme Verlag Stuttgart · New York.
- Santos, Leonardo Silva,Mirabal-Gallardo, Yaneris,Shankaraiah, Nagula,Simirgiotis, Mario J.
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experimental part
p. 51 - 56
(2011/02/26)
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- Convenient one-pot synthesis of chiral tetrahydropyridines via a multicomponent reaction
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The multicomponent condensation of various β-dicarbonyl compounds, acrolein and (S)-2-phenylglycinol was found to provide a one-pot access to chiral 6-carbonyl-3-phenyl-2,3,8,8a-tet-rahydro-7H-[l,3]oxazolo[3,2-a]pyridines. The value of this methodology is illustrated by the short and efficient synthesis of (-)-lupinine.
- Noel, Romain,Fargeau-Bellassoued, Marie-Claude,Vanucci-Bacque, Corinne,Lhommet, Gerard
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experimental part
p. 1948 - 1954
(2009/04/04)
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- Epimerization of lupinine to epilupinine and vice versa. Reexamination of the structures of lupinal and epilupinal
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Although the epimerization of lupinine (1) has been largely investigated, a previously not observed compound of formula C10H17NO was now isolated from the mixture of alkaloids that remains after the separation of epilupinine (2). It is insoluble in dry Et2O but soluble in EtOH, from which it is recovered as an Et2O-soluble oil that slowly returns to the Et2O-insoluble solid form. For these characteristics and based on GC/MS, 1H-NMR, and IR data, it is considered as the inner salt 6 of the common enolic form 5 of lupinal (3) and epilupinal (4), with which it is in equilibrium when standing in solution (see Scheme 1). The oily form, but not the solid one, is able to improve the conversion of 1 to 2, establishing the role of the aldehydes in the epimerization process. It was observed that also 2 can be converted to 1. Finally, the solid lupinal described by Zaboev should be considered as being identical to the now isolated inner salt 6, while the oily epilupinal of Wicky and Schumann is, indeed, a mixture of epilupinal (4) with a minor amount of lupinal (3), which, on standing, is converted to the inner salt 6 of the common enolic form 5.
- Sparatore, Anna,Tasso, Bruno,Boido, Vito,Sparatore, Fabio
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p. 245 - 251
(2007/10/03)
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- Enantioselective synthesis of indolizidine and quinolizidine derivatives from chiral non-racemic bicyclic lactams
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Chiral non-racemic bicyclic lactams 2b,c, derived from (R)- and (S)-phenylglycinol, were used in the enantioselective synthesis of (-)-lupinine and 5-epitashiromine, respectively. The efficiency of the synthesis relied on the high diastereoselectivities of formation and reduction of compounds 2b,c.
- Agami, Claude,Dechoux, Luc,Hebbe, Séverine,Ménard, Cécilia
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p. 5433 - 5438
(2007/10/03)
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- Double ring-closing metathesis reaction of nitrogen-containing tetraenes: Efficient construction of bicyclic alkaloid skeletons and synthetic application to four stereoisomers of lupinine and their derivatives
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The double ring-closing metathesis reaction of nitrogen-containing tetraenes was studied. The selectivity of the fused/dumbbell-type products can be controlled by the electronic/steric effects of the substituents attached to the C=C bonds and the s-cis/s-trans conformational ratios of the substrates. This methodology has also been successfully applied to the enantioselective synthesis of four stereoisomers of lupinine and their derivatives.
- Ma, Shengming,Ni, Bukuo
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p. 3286 - 3300
(2007/10/03)
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- Syntheses from chiral heterocyclic β-amino esters. A new versatile access to pyrrolizidine and quinolizidine alkaloids
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Chiral heterocyclic β-amino esters can be easily transformed into bicyclic alkaloids after a diastereoselective alkylation followed by specific chemical transformations.
- Ledoux, Stéphane,Marchalant, Elisabeth,Célérier, Jean-Pierre,Lhommet, Gérard
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p. 5397 - 5399
(2007/10/03)
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- Radical cyclizations of 1,4-dihydropyridines. Synthesis of chiral fused nitrogen heterocycles. Synthesis of lupinine and epilupinine
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Radical cyclizations of 1-(4-iodoalkanoyl)-3-formyl-4-methyl-l,4- dihydropyridines are described and discussed. A regio and diasteroselective reaction is obtained under ultrasonic conditions. An application to the synthesis of lupinine and epilupinine is shown.
- Mangeney, Pierre,Hamon, Louis,Raussou, Sabine,Urbain, Nicolas,Alexakis, Alexandre
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p. 10349 - 10362
(2007/10/03)
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- Asymmetric total synthesis of (-)-lupinine and (+)-epilupinine via α-sulfinyl ketimine. Stereocontrolled reduction of β-sulfinyl enamines
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(-)-Lupinine and (+)-epilupinine [(1R,9aR)- and (1S,9aR)-octahydro-1-hydroxymethyl-2H-quinolizine] were synthesized from (+)-2,3,4,5-tetrahydro-6-[(R)-(4-methylphenyl)sulfinylmethyl]pyridine (4) in five steps. The intermediate, 3,4,6,7,8,9-hexahydro-1-[(R)-(4-methylphenyl)sulfinyl]-2H-quinolizine (7), was stereoselectively reduced with cerium(III) chloride heptahydrate and sodium borohydride to give predominantly C-9a-R isomers, (9aR)-octahydro-1-[(R)-(4-methylphenyl)sulfinyl]-2H-quinolizines.
- Hua,Miao,Bravo,Takemoto
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p. 970 - 974
(2007/10/02)
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- Synthesis of Cadaverine and its Incorporation into five Quinolizidine Alkaloids
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Cadaverine dihydrochloride (13) was synthesised by the sequential introduction of two equivalents of sodium cyanide to a C3 precursor, and it was fed to Lupinus luteus and L. polyphyllus plants.Complete labelling patterns were obtained in five quinolizidine alkaloids by 13C n.m.r. spectroscopy.The 13C-13C doublets observed in the spectra of (-)-lupinine (3), (-)-sparteine (4), (+)-lupanine (5), (+)-13α-hydroxylupanine (6), and (+)-angustifoline (7) derived biosynthetically from the doubly labelled precursor (13) confirm the intact, specific incorporation of two cadaverine units into the tetracyclic quinolizidine alkaloid skeletons.The cadaverine (13) units are incorporated to about the same extent into each part of the quinolizidine alkaloids (3)-(7).Two of the 13C chemical shifts for lupanine (5) have been reassigned.The labelling pattern of the tricyclic alkaloid angustifoline (7) indicates that the allyl group originates by degradation of one ring of a tetracyclic precursor.
- Robins, David J.,Sheldrake, Gary N.
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p. 2101 - 2120
(2007/10/02)
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