RESUMEN
Despite a wealth of information on cocaine-like compounds, there is no information on cocaine analogs with substitutions at C-1. Here, we report on (R)-(-)-cocaine analogs with various C-1 substituents: methyl (2), ethyl (3), n-propyl (4), n-pentyl (5), and phenyl (6). Analog 2 was equipotent to cocaine as an inhibitor of the dopamine transporter (DAT), whereas 3 and 6 were 3- and 10-fold more potent, respectively. None of the analogs, however, stimulated mouse locomotor activity, in contrast to cocaine. Pharmacokinetic assays showed compound 2 occupied mouse brain rapidly, as cocaine itself; moreover, 2 and 6 were behaviorally active in mice in the forced-swim test model of depression and the conditioned place preference test. Analog 2 was a weaker inhibitor of voltage-dependent Na+ channels than cocaine, although 6 was more potent than cocaine, highlighting the need to assay future C-1 analogs for this activity. Receptorome screening indicated few significant binding targets other than the monoamine transporters. Benztropine-like "atypical" DAT inhibitors are known to display reduced cocaine-like locomotor stimulation, presumably by their propensity to interact with an inward-facing transporter conformation. However, 2 and 6, like cocaine, but unlike benztropine, exhibited preferential interaction with an outward-facing conformation upon docking in our DAT homology model. In summary, C-1 cocaine analogs are not cocaine-like in that they are not stimulatory in vivo. However, they are not benztropine-like in binding mechanism and seem to interact with the DAT similarly to cocaine. The present data warrant further consideration of these novel cocaine analogs for antidepressant or cocaine substitution potential.
Asunto(s)
Benzotropina/farmacología , Cocaína/análogos & derivados , Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Condicionamiento Operante/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Femenino , Indicadores y Reactivos , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Neocórtex/citología , Neocórtex/efectos de los fármacos , Neocórtex/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Embarazo , Unión Proteica , Conformación Proteica , Ensayo de Unión Radioligante , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Sodio/metabolismo , Canales de Sodio/metabolismo , Relación Estructura-Actividad , Natación/psicología , Veratridina/farmacologíaRESUMEN
This short perspective reports on the synthesis and applications of a class of chiral amino carbonyl compounds, masked oxo-sulfinamides where the amine is protected with an N-sulfinyl moiety and the carbonyl group is protected as the ketal or 1,3-dithiane. These polyfunctionalized chiral building blocks are prepared by addition of organometallic reagents to masked oxo-sulfinimines (N-sulfinyl imines) or the addition of oxo-organometallic reagents and lithio-1,3-dithianes to sulfinimines. Because unmasking of the amino and carbonyl groups results in cyclic imines, these chiral building blocks are particularly useful for the asymmetric synthesis of functionalized nitrogen heterocycles, including prolines, pipecolic acids, pyrrolidines, homotropinones, tropinones, and tropane alkaloids such as cocaine and C-1 cocaine analogues.
Asunto(s)
Amidas/química , Aminas/química , Técnicas de Química Sintética/métodos , Compuestos Heterocíclicos/química , Iminas/química , Compuestos de Sulfonio/química , Amidas/síntesis química , Aminas/síntesis química , Aminoácidos/síntesis química , Aminoácidos/química , Amino Alcoholes/síntesis química , Amino Alcoholes/química , Cocaína/análogos & derivados , Cocaína/síntesis química , Compuestos Heterocíclicos/síntesis química , Iminas/síntesis química , Organofosfonatos/síntesis química , Organofosfonatos/química , Ácidos Pipecólicos/síntesis química , Ácidos Pipecólicos/química , Prolina/síntesis química , Prolina/química , Pirrolidinas/síntesis química , Pirrolidinas/química , Compuestos de Sulfonio/síntesis química , Tropanos/síntesis química , Tropanos/química , beta-Lactamas/síntesis química , beta-Lactamas/químicaRESUMEN
The first examples of cocaine analogues having substituents (methyl, ethyl, n-propyl, n-pentyl, and phenyl) at the C-1 position of the cocaine tropane skeleton were prepared by heating sulfinimine-derived α,ß-unsaturated pyrrolidine nitrones. In the presence of the Lewis acid Al(O(t)Bu)(3) the nitrones undergo an intramolecular [3 + 2] cycloaddition to give tricyclic isoxazolidines that were transformed in three steps to the cocaine analogues. In the absence of the Lewis acid, lactams were formed resulting from rearrangement of the nitrone to an oxaziridine. A novel Pd- and base-promoted rearrangement of methanesulfonate salts of isoxazolidine to bridge bicyclic[4.2.1]isoxazolidines was discovered.
Asunto(s)
Cocaína/síntesis química , Iminas/química , Compuestos de Sulfonio/química , Cocaína/análogos & derivados , Cocaína/química , Estructura Molecular , EstereoisomerismoRESUMEN
Previously unknown, enantiopure, ß-amino ketones were prepared in modest yield by addition of lithium reagents to N-sulfinyl anti-α-substituted ß-amino Weinreb amides. Grignard reagents failed to add to these Weinreb amides in contrast to the syn-α-substituted isomers which did. The anti-α-substituted ß-amino Weinreb amides were prepared by addition of LiN(OMe)Me to the corresponding N-sulfinyl anti-α-substituted ß-amino esters because α-alkylation of N-sulfinyl ß-amino Weinreb amide enolates resulted in poor diastereoselectivities.
Asunto(s)
Iminas/química , Cetonas/química , Cetonas/síntesis química , Estereoisomerismo , Especificidad por SustratoRESUMEN
Sulfinimine-derived α,ß-unsaturated pyrrolidine nitrones, on heating with Al(O-t-Bu)(3), undergo a highly stereoselective intramolecular [3 + 2] cycloaddition to give tricyclic isoxazolidines, which are transformed in three-steps to give C-1 substituted cocaine analogs.
Asunto(s)
Aminas/química , Cocaína/síntesis química , Ésteres/química , Cetonas/química , Compuestos de Sulfonio/química , Estructura Molecular , EstereoisomerismoRESUMEN
Cyclic cis-beta-amino Weinreb amides, valuable building blocks for the asymmetric synthesis of cyclic beta-amino acids derivatives, are readily prepared via ring-closing metathesis of sulfinimine-derived N-sulfinyl beta-amino diene Weinreb amides. These unsaturated cyclic cis-beta-amino Weinreb amides are valuable building blocks for the asymmetric synthesis of cyclic beta-amino acid derivatives.
Asunto(s)
Aminoácidos/síntesis química , Iminas/química , Compuestos de Sulfonio/química , Amidas/química , Aminoácidos/química , CiclizaciónRESUMEN
Sulfinimine-derived N-sulfinyl beta-amino ketone ketals on heating with NH(4)OAc:HOAc undergo a four-step intramolecular Mannich cyclization cascade reaction to give homotropinones, such as (-)-euphococcinine, in excellent yields as single isomers.
Asunto(s)
Alcaloides/síntesis química , Hidrocarburos Aromáticos con Puentes/síntesis química , Cetonas/química , Cetonas/síntesis química , Piperidinas/síntesis química , Alcaloides/química , Hidrocarburos Aromáticos con Puentes/química , Catálisis , Iminas/química , Estructura Molecular , Piperidinas/química , Estereoisomerismo , Compuestos de Sulfonio/químicaRESUMEN
The first total asymmetric synthesis of the poison frog alkaloid (-)-221T, a 5,6,8-trisubstituted indolizidine is described. The key core piperidine ring was constructed via an acid catalyzed intramolecular cascade Mannich cyclization reaction of a N-sulfinyl syn-alpha-methyl beta-amino ketone and crotonaldehyde. The beta-amino ketone was prepared via the reaction of prochiral lithium Weinreb amide enolate with an enantiopure N-2,4,6-triisopropylphenylsulfinyl imine.
Asunto(s)
Indolicidinas/síntesis química , Aminas/química , Iminas/química , Cetonas/química , Compuestos de Sulfonio/químicaRESUMEN
Addition of vinylaluminum NMO reagents to N-(p-toluenesufinyl)- and N-(2-methypropanesulfinyl)-derived sulfinimines gives N-sulfinyl aza-Morita-Baylis-Hillman products (dr = 7:1 to 12:1) that result from addition of the reagent from the least hindered direction. Hydrogenation of the aza-MBH adducts with a Rh(I) catalyst affords anti-alpha-substituted N-sulfinyl-beta-amino esters in good yield and high dr (10:1 to 21:1).
Asunto(s)
Aluminio/química , Aminas/química , Ésteres/síntesis química , Iminas/química , Compuestos de Sulfonio/química , Compuestos de Vinilo/química , Catálisis , Ésteres/química , Hidrógeno/química , Estructura Molecular , EstereoisomerismoRESUMEN
Sulfinimine-derived, enantiopure N-sulfinyl beta-amino ketone ketals on hydrolysis give dehydropyrrolidine ketones that on treatment with (Boc)(2)O/DMAP afford substituted tropinones in good yield.
Asunto(s)
Iminas/química , Cetonas/química , Compuestos de Sulfonio/química , Tropanos/síntesis química , Catálisis , Ciclización , Cetonas/síntesis química , Estructura Molecular , Estereoisomerismo , Tropanos/químicaRESUMEN
A differentially protected C-3 N-sulfinyl, C-2 N,N-(diphenylmethylene) 2,3-diamino ester was employed in the synthesis of the amino piperidine (2S,3R)-(-)-epi-CP-99,994. Key steps in the synthesis included the chemoselective hydrolysis of the C-2 N,N-(diphenylmethylene) group and its reprotection as a dibenzylamino group.
RESUMEN
Stereoselective reduction of acyclic N-sulfinyl beta-amino ketones with (LiEt(3)BH) and Li(t-BuO)(3)AlH, respectively, gave anti- and syn-1,3-amino alcohols with excellent selectivity. A formal asymmetric synthesis of the hydroxy piperidine alkaloids (-)-pinidinol and (+)-epipinidinol from a common N-sulfinyl beta-amino ketone ketal precursor was developed. The pinidinol piperidine ring was formed via a novel acid-catalyzed cascade reaction of a N-sulfinylamino silyl protected alcohol ketal.
Asunto(s)
Amino Alcoholes/síntesis química , Piperidinas/síntesis química , Indicadores y Reactivos , Cetonas/química , Oxidación-Reducción , EstereoisomerismoRESUMEN
Pyrrolidine enones, derived from 3-oxo pyrrolidine 2-phosphonates and a HWE reaction with aldehydes, on Luche reduction give pyrrolidine allylic alcohols. The alcohols on hydrogenation (Pd/H2) give cis-2,5-disubstituted pyrrolidines and on treatment with TFA-NaBH3CN undergo a hydroxy directed reduction to trans-2,5-disubstituted pyrrolidines.
Asunto(s)
Anisomicina/análogos & derivados , Organofosfonatos/química , Pirrolidinas/síntesis química , Anisomicina/síntesis química , Anisomicina/química , Catálisis , Pirrolidinas/química , EstereoisomerismoRESUMEN
Polysubstituted 2-carboxylate and 2-phosphonate pyrroles are prepared by aromatization of the corresponding 3-oxo 2-carboxylate and 2-phosphonate NH-pyrrolidines using air. Reaction of electrophiles with 3-oxo pyrrolidine dianions readily introduces substituents, regioselectively at C-4 in these pyrrolidines.
RESUMEN
Sulfinimine-derived alpha-amino 1,3-dithianes, alpha-amino carbonyl chiral building blocks, are utilized in asymmetric syntheses of (+)-(tetrahydrofuran-2-yl)glycine and the 2,3-disubstituted piperidine (+)-L-733,060.
RESUMEN
Syn-alpha-substituted beta-amino Weinreb amides are new chiral building blocks for asymmetric synthesis of syn-alpha-substituted beta-amino acids, aldehydes, and ketones and are prepared by addition of prochiral lithium enolates of Weinreb amides to sulfinimines (N-sulfinyl imines).
Asunto(s)
Amidas/química , Aminoácidos/química , Iminas/química , Cetonas/síntesis química , Compuestos de Azufre/química , Aldehídos/síntesis química , Aldehídos/química , Amidas/síntesis química , Aminoácidos/síntesis química , Cetonas/química , Litio/química , Estructura Molecular , EstereoisomerismoRESUMEN
[reaction: see text] Dehydrochlorination of methyl 2-chloroaziridine 2-carboxylates generates the first examples of enantiopure 2-substituted 2H-azirine 3-carboxylates which undergo the aza Diels-Alder reaction with dienes to give bicyclic and tricyclic aziridines in good yields.
Asunto(s)
Azirinas/química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntesis química , Estructura Molecular , EstereoisomerismoRESUMEN
Sulfinimine-derived N-sulfinyl delta-amino beta-ketophosphonates are transformed via the enaminones to the phosphoryl dihydropyridones that selectively give trans-2,6-disubstituted 1,2,5,6-tetrahydropyridines on organocuprate addition and dephosphorylation.
Asunto(s)
Organofosfonatos/química , Piperidinas/síntesis química , Quinolizinas/síntesis química , Piridinas/química , Piridonas/químicaRESUMEN
[reaction: see text] In the absence of water, an excess of the lithium enolate of N-(diphenylmethylene)glycine ethyl ester (4) adds to sulfinimines to give syn-2,3-diamino esters 6, and in the presence of water, this enolate gives the anti-2,3-diamino esters 5. These unusual results are interpreted in terms of those factors that inhibit the retro-Mannich fragmentation in the diamino esters.
Asunto(s)
Ésteres/química , Iminas/química , Azufre/química , Agua/química , Aminación , Estructura Molecular , EstereoisomerismoRESUMEN
Sulfinimine-derived, differentially protected, 2,3-diamino esters are useful building blocks for the asymmetric synthesis of heterocycles and is illustrated by an efficient synthesis of amino piperidine (+)-CP-99,994.