ABSTRACT
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.
Subject(s)
Benztropine/pharmacology , Cocaine/analogs & derivatives , Cocaine/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Animals , Brain/drug effects , Brain/metabolism , Conditioning, Operant/drug effects , Dopamine Plasma Membrane Transport Proteins/metabolism , Female , Indicators and Reagents , Male , Mice , Mice, Inbred C57BL , Motor Activity/drug effects , Neocortex/cytology , Neocortex/drug effects , Neocortex/metabolism , Neurons/drug effects , Neurons/metabolism , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Pregnancy , Protein Binding , Protein Conformation , Radioligand Assay , Serotonin Plasma Membrane Transport Proteins/metabolism , Sodium/metabolism , Sodium Channels/metabolism , Structure-Activity Relationship , Swimming/psychology , Veratridine/pharmacologyABSTRACT
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.
Subject(s)
Amides/chemistry , Amines/chemistry , Chemistry Techniques, Synthetic/methods , Heterocyclic Compounds/chemistry , Imines/chemistry , Sulfonium Compounds/chemistry , Amides/chemical synthesis , Amines/chemical synthesis , Amino Acids/chemical synthesis , Amino Acids/chemistry , Amino Alcohols/chemical synthesis , Amino Alcohols/chemistry , Cocaine/analogs & derivatives , Cocaine/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Imines/chemical synthesis , Organophosphonates/chemical synthesis , Organophosphonates/chemistry , Pipecolic Acids/chemical synthesis , Pipecolic Acids/chemistry , Proline/chemical synthesis , Proline/chemistry , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Sulfonium Compounds/chemical synthesis , Tropanes/chemical synthesis , Tropanes/chemistry , beta-Lactams/chemical synthesis , beta-Lactams/chemistryABSTRACT
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.
Subject(s)
Cocaine/chemical synthesis , Imines/chemistry , Sulfonium Compounds/chemistry , Cocaine/analogs & derivatives , Cocaine/chemistry , Molecular Structure , StereoisomerismABSTRACT
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.
Subject(s)
Imines/chemistry , Ketones/chemistry , Ketones/chemical synthesis , Stereoisomerism , Substrate SpecificityABSTRACT
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.
Subject(s)
Amines/chemistry , Cocaine/chemical synthesis , Esters/chemistry , Ketones/chemistry , Sulfonium Compounds/chemistry , Molecular Structure , StereoisomerismABSTRACT
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.
Subject(s)
Amino Acids/chemical synthesis , Imines/chemistry , Sulfonium Compounds/chemistry , Amides/chemistry , Amino Acids/chemistry , CyclizationABSTRACT
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.
Subject(s)
Alkaloids/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Ketones/chemistry , Ketones/chemical synthesis , Piperidines/chemical synthesis , Alkaloids/chemistry , Bridged-Ring Compounds/chemistry , Catalysis , Imines/chemistry , Molecular Structure , Piperidines/chemistry , Stereoisomerism , Sulfonium Compounds/chemistryABSTRACT
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.
Subject(s)
Indolizidines/chemical synthesis , Amines/chemistry , Imines/chemistry , Ketones/chemistry , Sulfonium Compounds/chemistryABSTRACT
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.
Subject(s)
Imines/chemistry , Ketones/chemistry , Sulfonium Compounds/chemistry , Tropanes/chemical synthesis , Catalysis , Cyclization , Ketones/chemical synthesis , Molecular Structure , Stereoisomerism , Tropanes/chemistryABSTRACT
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).
Subject(s)
Aluminum/chemistry , Amines/chemistry , Esters/chemical synthesis , Imines/chemistry , Sulfonium Compounds/chemistry , Vinyl Compounds/chemistry , Catalysis , Esters/chemistry , Hydrogen/chemistry , Molecular Structure , StereoisomerismABSTRACT
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.
ABSTRACT
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.
Subject(s)
Amino Alcohols/chemical synthesis , Piperidines/chemical synthesis , Indicators and Reagents , Ketones/chemistry , Oxidation-Reduction , StereoisomerismABSTRACT
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.
Subject(s)
Anisomycin/analogs & derivatives , Organophosphonates/chemistry , Pyrrolidines/chemical synthesis , Anisomycin/chemical synthesis , Anisomycin/chemistry , Catalysis , Pyrrolidines/chemistry , StereoisomerismABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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).
Subject(s)
Amides/chemistry , Amino Acids/chemistry , Imines/chemistry , Ketones/chemical synthesis , Sulfur Compounds/chemistry , Aldehydes/chemical synthesis , Aldehydes/chemistry , Amides/chemical synthesis , Amino Acids/chemical synthesis , Ketones/chemistry , Lithium/chemistry , Molecular Structure , StereoisomerismABSTRACT
[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.
Subject(s)
Azirines/chemistry , Carboxylic Acids/chemistry , Carboxylic Acids/chemical synthesis , Molecular Structure , StereoisomerismABSTRACT
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.
Subject(s)
Organophosphonates/chemistry , Piperidines/chemical synthesis , Quinolizines/chemical synthesis , Pyridines/chemistry , Pyridones/chemistryABSTRACT
[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.
Subject(s)
Esters/chemistry , Imines/chemistry , Sulfur/chemistry , Water/chemistry , Amination , Molecular Structure , StereoisomerismABSTRACT
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.