RESUMO
Development of novel anti-cancer therapeutics based on Golgi α-mannosidase II (GMII) inhibition is considerably impeded by an undesired co-inhibition of lysosomal α-mannosidase leading to severe side-effects. In this contribution, we describe a fully stereoselective synthesis of (5S)-5-[4-(halo)benzyl]swainsonines as highly potent and selective inhibitors of GMII. The synthesis starts from a previously reported aldehyde readily available from l-ribose, and the key features include an intramolecular reductive amination with substrate-controlled stereoselectivity and a late-stage derivatisation of the benzyl group via ipso-substitution. These novel swainsonine analogues were found to be nanomolar inhibitors of the Golgi-type α-mannosidase AMAN-2 (Ki = 23-75 nM) with excellent selectivity (selectivity index = 205-870) over the lysosomal-type Jack bean α-mannosidase. Finally, molecular docking and pKa calculations were performed to provide more insight into the structure of the inhibitor:enzyme complexes, and a pair interaction energy analysis (FMO-PIEDA) was carried out to rationalise the observed potency and selectivity of the inhibitors.
Assuntos
Inibidores Enzimáticos , Swainsonina , Humanos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Manosidases/antagonistas & inibidores , Manosidases/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Swainsonina/farmacologia , Swainsonina/síntese química , Swainsonina/química , Compostos de Benzil/química , Compostos de Benzil/farmacologiaRESUMO
Epimerization of C5 of an N-hydroxypyrrolidine ring by regioselective oxidation to a nitrone followed by diastereoselective reduction provides a new approach to the synthesis of swainsonine and related compounds. The only protection in the synthesis of the potent mannosidase inhibitor DIM (1,4-dideoxy-1,4-imino-d-mannitol) was the acetonation of d-mannose.
Assuntos
Pirrolidinas/química , Açúcares/química , Açúcares/síntese química , Swainsonina/química , Swainsonina/síntese química , Configuração de Carboidratos , Técnicas de Química Sintética , Modelos Moleculares , EstereoisomerismoRESUMO
The total syntheses of two fluorinated alkaloids, 6-(R)-fluoroswainsonine and 5-(R)-fluorofebrifugine, are described. Both encompass (4aS,7R,8aR)-7-fluoro-5-tosylhexahydro-4H-[1,3]dioxino[5,4-b]pyridine as a key synthon which is obtained through a further optimized palladium-catalyzed aminofluorination of alkenes with high diastereoselectivity. 6-(R)-Fluoroswainsonine is synthesized from the key synthon in 14 steps, and 5-(R)-fluorofebrifugine requires a sequential 15-step transformation.
Assuntos
Alcaloides/síntese química , Alcenos/química , Paládio/química , Piperidinas/síntese química , Quinazolinas/síntese química , Swainsonina/análogos & derivados , Alcaloides/química , Catálise , Estrutura Molecular , Piperidinas/química , Piridinas/química , Quinazolinas/química , Estereoisomerismo , Swainsonina/síntese química , Swainsonina/químicaRESUMO
An efficient diastereoselective approach to access trans-5-hydroxy-6-alkynyl/alkenyl-2-piperidinones has been developed through nucleophilic addition of α-chiral aldimines using alkynyl/alkenyl Grignard reagents. The diastereoselectivity of alkenyl in C-6 position of 2-piperidinone was controlled by α-alkoxy substitution, while the alkynyl was controlled by the coordination of the α-alkoxy substitution and stereochemistry of sulfinamide. The utility of this straightforward cascade process is demonstrated by the asymmetric synthesis of the (-)-epiquinamide and (+)-swainsonine.
Assuntos
Alcenos/química , Alcinos/química , Piperidonas/química , Quinolizinas/síntese química , Swainsonina/síntese química , Catálise , Estrutura Molecular , Quinolizinas/química , Swainsonina/químicaRESUMO
A short synthesis of hydroxyalkyl dihydropyrroles has been developed that involves the coupling of propargylamines with α-chloroaldehydes, followed by Lindlar reduction and a one-pot epoxide formation/opening sequence. The application of this process to the synthesis of unnatural iminosugars and a formal synthesis of (-)-swainsonine is described.
Assuntos
Alcaloides/síntese química , Swainsonina/síntese química , Alcaloides/química , Compostos de Epóxi/química , Estrutura Molecular , Estereoisomerismo , Swainsonina/químicaRESUMO
Nucleophilic addition of Grignard reagents and organolithium species to a 3-silyloxy-3,4,5,6-tetrahydropyridine N-oxide provides trans-2,3-disubstituted N-hydroxypiperidines exclusively. The application of this methodology to the preparation of a diversity of useful trans-2-substituted-3-hydroxypiperidines, a concise synthesis of (+)-swainsonine, and an enantiopure 1-substituted quinolizidine of utility in target-directed synthesis is reported.
Assuntos
Piperidinas/química , Quinolizidinas/química , Swainsonina/síntese química , Estrutura Molecular , Estereoisomerismo , Swainsonina/químicaRESUMO
Ring closure of a 3,5-di-O-triflate derived from D-altrose with benzylamine allowed the formation of both monocyclic and bicyclic azetidine analogues of swainsonine.
Assuntos
Azetidinas/síntese química , Hexoses/química , Manitol/análogos & derivados , Polímeros/síntese química , Swainsonina/análogos & derivados , Swainsonina/síntese química , Azetidinas/química , Ciclização , Imino Furanoses/síntese química , Imino Furanoses/química , Manitol/síntese química , Manitol/química , Manosidases/antagonistas & inibidores , Estrutura Molecular , Polímeros/química , Sorbitol/análogos & derivados , Relação Estrutura-Atividade , Swainsonina/químicaRESUMO
The asymmetric synthesis of (-)-swainsonine and (-)-8-epi-swainsonine is reported through the addition of either the allenylzinc or the allenyl lithio cyanocuprate reagents derived from [3-(methoxymethoxy)prop-1-ynyl]trimethylsilane to enantiopure α,ß-dialkoxy N-tert-butanesulfinylimines derived from d-erythronolactone.
Assuntos
Swainsonina/análogos & derivados , Swainsonina/síntese química , Álcoois/química , Iminas/química , Estrutura Molecular , Estereoisomerismo , Ácidos Sulfínicos/química , Swainsonina/químicaRESUMO
The total synthesis of (-)-swainsonine from 2,3-O-isopropylidene-D-erythrose in 12 steps and an overall yield of 28% is reported. The pivotal transformation in our route to this indolizidine alkaloid is the formation of the pyrrolidine ring and C-8a/8 stereodiad through the diastereoselective, bis-cyclofunctionalization of an γ,δ-unsaturated O-alkyl hydroxamate. This transformation is believed to proceed via the intramolecular capture of an N-acyl-N-alkoxyaziridinium ion generated by the diastereoselective addition of a singlet acylnitrenium ion to the pendant alkene.
Assuntos
Alcenos/química , Compostos de Nitrogênio/química , Swainsonina/síntese química , Cátions/química , Ciclização , Estrutura Molecular , OxirreduçãoRESUMO
A concise asymmetric synthesis of (+)-swainsonine (ent-1) is described starting from 2, which was readily prepared from commercially available l-glutamic acid. The method features installation of the indolizidine ring via an intramolecular cyclisation of α-sulfinyl carbanion as a key step. (+)-Swainsonine was obtained in 11.8% overall yield in 10 steps.
Assuntos
Swainsonina/síntese química , Ácido Glutâmico/química , Estrutura Molecular , Oxirredução , EstereoisomerismoRESUMO
A formal synthesis of swainsonine has been achieved using a highly efficient and diastereoselective gold(III)-catalyzed allene cyclization.
Assuntos
Compostos de Ouro/química , Swainsonina/síntese química , Catálise , Ciclização , Estrutura Molecular , Swainsonina/químicaRESUMO
We report a new asymmetric synthetic method for (-)-swainsonine utilizing a chiral oxazoline precursor. The key features in this strategy are the diastereoselective oxazoline formation reaction catalyzed by palladium(0), diasteroselective dihydroxylation, and the stereocontrolled allylation reaction with TiCl(4).
Assuntos
Swainsonina/síntese química , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Oxazóis/química , Estereoisomerismo , Especificidade por Substrato , Swainsonina/químicaRESUMO
The total synthesis of 8a-epi-swainsonine has been achieved in 20% overall yield from R-glyceraldehyde dimethylacetonide 3 through epoxidation with the achiral furyl-substituted sulfonium ylide 2d as one of the key steps.
Assuntos
Compostos de Enxofre/química , Swainsonina/síntese química , Aldeídos/química , Catálise , Estrutura Molecular , Estereoisomerismo , Swainsonina/química , Tiofenos/químicaRESUMO
An enantioselective and diastereocontrolled approach to 8a-epi-d-swainsonine has been developed from achiral furfural. The key step to this synthesis was a one-pot procedure for the hydrogenolytic removal of two protecting groups and two intramolecular reductive amination reactions. The absolute stereochemistry was introduced by asymmetric Noyori reduction of furfuryl ketone. This route relies on diastereoselective palladium-catalyzed glycosylation to install the anomeric bond, and Luche reduction, diastereoselective dihydroxylation to set up the manno-stereochemistry of the indolizidine precursor.
Assuntos
Swainsonina/síntese química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Espectrofotometria Infravermelho , Swainsonina/químicaRESUMO
The utility of a D-glucose-derived aziridine carboxylate was demonstrated for the synthesis of polyhydroxylated quinolizidine and indolizidine alkaloids. The chemoselective reduction of 1 followed by two-carbon homologation by the Wittig reaction afforded gamma,delta-aziridino-alpha,beta-unsaturated ester 9, which on regioselective nucleophilic aziridine ring opening either by using water as a nucleophile or hydrogenation afforded delta-lactams 11/16--true synthons for the synthesis of four structurally different iminosugars, namely quinolizidine alkaloids 5b/5c, swainsonine 6b and lentiginosine 7b analogues. Glycosidase inhibitory activities of these iminosugars were investigated.
Assuntos
Alcaloides/síntese química , Alcaloides/farmacologia , Aziridinas/química , Glucose/análogos & derivados , Glicosídeo Hidrolases/antagonistas & inibidores , Indolizinas/síntese química , Indolizinas/farmacologia , Quinolizidinas/síntese química , Quinolizidinas/farmacologia , Swainsonina/síntese química , Swainsonina/farmacologia , Alcaloides/metabolismo , Glicosídeo Hidrolases/metabolismo , Indolizinas/metabolismo , Concentração Inibidora 50 , Quinolizidinas/metabolismo , Estereoisomerismo , Especificidade por Substrato , Swainsonina/metabolismoRESUMO
The previously developed enantioselective iodocyclization of gamma-hydroxy-cis-alkenes required 30 mol% of (R,R)-salen-Co(II) complex as chiral catalyst and 0.75 equivalent of N-chlorosuccinimide (NCS) as activator to produce 2-substituted tetrahydrofurans with 61 to 90% ee. Due to the considerable loading amount of the Co(II) complex, another more effective catalyst was pursued by screening (R,R)-salen-transition metal complexes. When 10 mol% of the catalysts were applied with 0.5 equivalent of NCS, a higher level of stereoselectivity was attained with the corresponding Cr(III)Cl (84% ee), Mn(II)Cl (52% ee) and Co(II) complexes (66% ee). Refinement of the conditions established a novel catalytic enantioselective iodocyclization protocol using iodine in the presence of 7 mol% of (R,R)-salen-Cr(III)Cl complex activated by 0.7 equivalent of NCS in toluene to induce 74 to 93% ee.
Assuntos
Cloretos/química , Cromo/química , Etilenodiaminas/química , Iodo/química , Compostos Organometálicos/química , Swainsonina/síntese química , Catálise , Ciclização , Conformação Molecular , Estereoisomerismo , Swainsonina/químicaRESUMO
[reaction: see text] An asymmetric total synthesis of (-)-swainsonine and (+)-6-epicastanospermine is described from a common intermediate, which is obtained through diastereoselective [2 + 2] cycloaddition of dichloroketene to a chiral enol ether.
Assuntos
Indolizinas/síntese química , Swainsonina/síntese química , Indolizinas/química , Estrutura Molecular , Estereoisomerismo , Swainsonina/químicaRESUMO
Enantiopure alpha,beta-unsaturated delta-lactams 1 and 2 react stereoselectively with carbon-, nitrogen-, sulfur-, and oxygen-centered nucleophiles. The synthetic potential of these conjugate additions is demonstrated through the synthesis of two new substituted indolizidines: (7R)-7-amino-8-deoxyswainsonine 3 and (7R)-7-acetylaminoswainsonine 4.
Assuntos
Carbono/química , Indolizinas/química , Nitrogênio/química , Oxigênio/química , Enxofre/química , Swainsonina/química , Hidroxilação , Estrutura Molecular , Estereoisomerismo , Swainsonina/análogos & derivados , Swainsonina/síntese químicaRESUMO
Chiral alpha-hydroxy aldehydes generated in situ by the ADH reaction of vinyl sulfones undergo a borono-Mannich reaction with beta-styrenyl boronic acid and primary amines to give anti-1,2-amino alcohols in high enantiomeric purities (83-95% ee). This new method allows much more rapid access to these valuable chiral building blocks that has been used in a short formal synthesis (10 synthetic steps from 4-penten-1-ol) of (-)-swainsonine.
Assuntos
Amino Álcoois/síntese química , Química Orgânica/métodos , Swainsonina/síntese química , Amino Álcoois/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Estereoisomerismo , Swainsonina/químicaRESUMO
The synthesis of a bicyclic sulfonium-ion analogue of a naturally occurring glycosidase inhibitor, swainsonine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, has been achieved by a multi-step synthesis starting from 1,4-anhydro-2,3-di-O-benzyl-4-thio-D-lyxitol. The synthetic strategy relies on the intramolecular displacement of a leaving group on a pendant acyclic chain by a cyclic thioether. This bicyclic sulfonium salt will serve as a candidate to test the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective glycosidase inhibitor.