Tropinone Derivatives Research Articles

Convenient synthesis of thiolated 2,7-disubstituted tropones via double C-N bond cleavage of tropinone derivatives.

A range of 2,4-dialkylidenetropinone-derived quaternary ammonium salts smoothly reacted with thiols in the presence of tributylamine, delivering structurally diverse thiolated 2,7-disubstituted tropones in moderate to excellent yields with high site selectivity. The reaction employs readily available feedstocks and reagents, is free of transition metals, tolerates various functional groups, and can be easily scaled up.

A Study on N-Substituted Nortropinone Synthesis using Acetone Equivalents

Robinson′s synthesis has long been a classic in organic chemistry due to its simplicity and impact in the industry. Various modifications have been made to improve the system. Among them, replacing acetone with more acidic chemical equivalents such as calcium dicarboxylic acid or ethyl dicarboxylic acetone improved the yield. In line with this trend, our group previously reported the synthesis of mono- and di-N-substituted tropinone derivatives from the one-pot reaction of 2,5-dimethoxy tetrahydrofuran and various amines with acetonedicarboxylic acid in the presence of HCl and water at room temperature. In this study, the synthesis with acetone instead of acetone-dicarboxylic acid was examined. Mono- and di-N-substituted nortropinones were prepared in higher yields in all cases although there were extent to which yields increased depending on the nature of substituents

Synthesis and Cytotoxicity Evaluation of Tropinone Derivatives

Sixteen tropinone derivatives were prepared, and their antitumor activities against five human cancer cells (HL-60, A-549, SMMC-7721, MCF-7 and SW480) were evaluated with MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy methoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium] assay. Most of the derivatives exhibited better activities compared with tropinone at the concentration of 40 μM. Particularly, derivative 6 showed significant activities with IC50 values of 3.39, 13.59, 6.65, 13.09 and 12.38 μM respectively against HL-60, A-549, SMMC-7721, MCF-7 and SW480 cells, which suggested more potent activities than that of cis-dichlorodiamineplatinum (DDP).Graphical

ChemInform Abstract: Acid‐Catalyzed [4 + 3] Cycloaddition Reaction of N‐Nosyl Pyrroles.

Abstract An acid-catalyzed [4+3] cycloaddition reaction of N-nosyl pyrroles with 2-(tert-butyldimethylsilyloxy)acrolein has been developed. The reaction of 2-(silyloxy)acrolein with N-nosyl pyrrole was catalyzed by Tf2NH, and a regio- and stereoselective reaction with 2-substituted N-nosyl pyrroles leading to tropinone derivatives possessing tetra-substituted carbon centers was also achieved. High regioselectivities were obtained by using Cu(OTf)2 or Sc(OTf)3 as a catalyst in nitromethane, and the reaction was applicable to various 2-substituted N-nosyl pyrroles in good yields and with high regioselectivities.

Acid-catalyzed [4+3] cycloaddition reaction of N-nosyl pyrroles

An acid-catalyzed [4+3] cycloaddition reaction of N-nosyl pyrroles with 2-(tert-butyldimethylsilyloxy)acrolein has been developed. The reaction of 2-(silyloxy)acrolein with N-nosyl pyrrole was catalyzed by Tf2NH, and a regio- and stereoselective reaction with 2-substituted N-nosyl pyrroles leading to tropinone derivatives possessing tetra-substituted carbon centers was also achieved. High regioselectivities were obtained by using Cu(OTf)2 or Sc(OTf)3 as a catalyst in nitromethane, and the reaction was applicable to various 2-substituted N-nosyl pyrroles in good yields and with high regioselectivities.

Synthesis and isomer distribution of 2-alkyltropinones and 2-alkylgranatanones

Tropinone (8-methyl-8-azabicyclo[3.2.1]octan-3-one) metal (Li, Na, K, Mg) enolates were used to achieve α-alkylation. The reactions, regardless of the metal or conditions used, were low-yielding. N,N-Dimethylhydrazones of tropinone and granatanone (pseudopelletierine, 9-methyl-9-azabicyclo[3.3.1]nonan-3-one) were prepared and α-alkylated using n-butyllithium as the lithiating reagent. Lithium amides, including a polymer-supported lithium amide, were less effective. The reactions were modelled using DFT calculations at the B3LYP 6-31G(d) level and the CPCM solvent model, revealing that the face-selective alkylations of tropinone and granatanone hydrazones favoured the exo-isomers. Granatanone and α-isopropyl tropinone derivatives resisted typical mild hydrolytic hydrazone cleavage (aqueous trifluoroacetic acid) and required more forceful conditions (p-TsOH, boiling dioxane). Using the hydrazone alkylation strategy, 16 α-alkyl derivatives (benzyl, methyl, propyl, isopropyl, allyl, pentyl, heptyl, p-methoxybenzyl) were prepared in 52–90% yields overall. For the α-alkylated tropinones and granatanones (10 examples), the DFT calculations and experimental thermodynamic distributions in base catalysed equilibrations showed that except for the α-isopropyl derivatives, the endo-isomers were more stable than the exo-isomers and were the major products. For 2-isopropyltropinone, the bulky substituent favoured the exo (axial) position in the bicyclic skeleton. The thermodynamic distribution for the α,α′-dibenzyl tropinone isomers was also evaluated.

ChemInform Abstract: Concise [4 + 3] Cycloaddition Reaction of Pyrroles Leading to Tropinone Derivatives.

Abstract2‐(Silyloxy)allyl cations, stabilized with a methylthio function or geminal methyl groups, are generated in situ from the corresponding allylic alcohols.

Synthesis and Antidiabetic Activity of Tropinone Derivatives

Synthesis and Antidiabetic Activity of Tropinone Derivatives

Concise [4+3] cycloaddition reaction of pyrroles leading to tropinone derivatives

A concise [4+3] cycloaddition reaction of pyrroles with 2-(silyloxy)allyl cations has been developed. The oxyallyl cations stabilized with a methylthio group or geminal methyl groups were generated from the corresponding allylic alcohols under the influence of a Brönsted acid (Tf2NH), respectively. The use of N-nosyl-protected pyrroles as the four-carbon unit was found to give tropinone derivatives in high yield.

Synthesis of new tropinone derivatives by palladium-catalyzed couplings of 8-azabicyclo[3.2.1]oct-2-enyl nonaflates

Whereas tropinone derived nonaflate 3 was no suitable precursor for Heck-reactions, the related carbamate 7 was an excellent substrate for palladium-catalyzed processes. Nonaflate 7 was either isolated in excellent yield by LDA treatment of ketone 5 followed by trapping with NfF (nonafluorobutanesulfonyl fluoride) or generated in situ by fluoride-catalyzed reaction of silyl enol ether 6 with NfF. The desired 1,3-diene 8 was prepared by conventional Heck-reaction of nonaflate 7 with methyl acrylate in almost quantitative yield. Alternatively, the one-pot nonaflation-Heck protocol starting from silyl enol ether 6 provided 8 in good yield. The couplings of acrylonitrile or phenyl vinyl sulfone were also performed with in situ generated 7 and they afforded the expected 1,3-dienes 9 and 10 in good yields. The Sonogashira-reaction with phenylacetylene also started from silyl enol ether 6 and provided enyne 11 via 7 in good yield. A Diels–Alder reaction of 1,3-diene 8 with N-phenyl maleimide at 100 °C furnished tetracyclic adduct 12 in good yield, with excellent diastereofacial selectivity, but with low endo– exo-selectivity. Nonaflate 14 was easily obtained from the corresponding unsaturated bicyclic ketone 13 . It behaved differently in an attempted Heck-reaction and mainly led to fragmentation products 15 and 16 , whereas the expected 1,3-diene 17 was formed only as minor component. However, 14 could successfully be used in a Sonogashira-reaction with phenylacetylene to afford compound 18 . These transformations demonstrate the great potential of tropinone derived alkenyl nonaflates for diversity oriented syntheses of interesting compounds containing an 8-azabicyclo[3.2.1]octane scaffold.

Synthesis of Tropinones by Cyclization of 1,3‐Bis‐Silyl Enol Ethers with Iminium Triflates.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Tropinones by Cyclization of 1,3-Bis-Silyl Enol Ethers with ­Iminium Triflates

Tropinone derivatives were prepared by cyclization of 1,3-bis-silyl enol ethers with iminium salts.

Enantioselective Epoxidation of Alkenes Catalyzed by 2‐Fluoro‐N‐carbethoxytropinone and Related Tropinone Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enantioselective Desymmetrization of Tropinone Derivatives by Hydroboration

N-Protected tropenone derivs. I (R = CO2Me, CBZ, Ts) prepd. from the resp. pyrroles and tetrabromoacetone, were used as starting materials for desymmetrization by hydroboration of the C-C double bond. Hydroboration of I with (-)-(Ipc)2BH followed by oxidn., however, gave the desired 6-hydroxylated product only in low yield due to byproduct formation. After acetalization of the carbonyl group in I, the corresponding acetals were desymmetrized with (Ipc)2BH and oxidative workup to chiral alcs. II in good yields with excellent enantiomeric excesses in most cases.

Enzymatic Resolution of Tropinone Derivatives

The lipase-mediated kinetic resolution of racemic scopoline [(±)-4] and 6-hydroxytropinone [(±)-7] is reported. Whereas (±)-4 is difficult to resolve due to steric hindrance of the hydroxy function, the resolution of (±)-7 with vinyl acetate as acyl donor gave alcohol (+)-7 and the corresponding acetate (-)-9 with high enantiomeric excess. In case of the optimal result of 99% ee for (+)-7 and 80% ee for (-)-9, an E-value of 35 was calculated. The preparative lipase-catalyzed resolution of (±)-7 resulted in almost enantiopure alcohol (+)-7 with >99% ee after one recrystallization.

Enantioselective epoxidation of alkenes catalyzed by 2-fluoro-N-carbethoxytropinone and related tropinone derivatives.

Several alpha-substituted N-carbethoxytropinones have been evaluated as catalysts for asymmetric epoxidation of alkenes with Oxone, via a dioxirane intermediate. alpha-Fluoro-N-carbethoxytropinone (2) has been studied in detail and is an efficient catalyst which does not suffer from Baeyer-Villiger decomposition and can be used in relatively low loadings. This ketone was prepared in enantiomerically pure form using chiral base desymmetrization of N-carbethoxytropinone. Asymmetric epoxidation catalyzed by 2 affords epoxides with up to 83% ee. Among other derivatives tested, the alpha-acetoxy derivative 7 affords the highest enantioselectivities.

Tropinone 유도체의 항경련성 효과 평가

Tropinone 유도체의 항경련성 효과 평가

Two-carbon bridge substituted cocaines: enantioselective synthesis, attribution of the absolute configuration and biological activity of novel 6- and 7-methoxylated cocaines

In an effort to learn more about the general structure–activity relationships of cocaine with the aim to elucidate those structural features that might confer antagonistic properties to such analogues, we describe herein our synthetic efforts to prepare two-carbon bridge functionalized (methoxylated and hydroxylated) analogues. Our approach makes use of a modification of the classical Willstatter synthesis of cocaine: Mannich type cyclization of acetonedicarboxylic acid monomethyl ester with methylamine hydrochloride and 2-methoxysuccindialdehyde in a citrate buffer solution afforded the 6- and 7-substituted 2-carbomethoxy-3-tropinones 3a, b and 4a, b in approximate yields of 64%. Reduction of the (±)-tropinone derivatives was performed with sodium amalgam in a sulfuric acid solution to afford a mixture of (±)-methoxyecgonine and (±)-methoxypseudoecgonine derivatives 5, 11 and 6, 7, 12, 13. Benzoylation of these alcohols yielded the desired cocaine and pseudococaine-like compounds 8, 14 and 9, 10, 15, 16. Additionally, we show that enzymatic hydrolysis of these cocaine analogues using pig liver esterase (PLE) affords a practical means for achieving their chemical resolution. The enantiomers of the methoxycocaine analogues were also prepared starting from chiral (+)- and (−)-6-methoxytropinone. All new analogues were examined for their ability to displace [ 3H]mazindol binding and to inhibit high-affinity uptake of [ 3H]dopamine into striatal nerve ending (synaptosomes). It appeared evident that methoxylation of the cocaine two-carbon bridge provides compounds of particular interest: the K i for the binding of the methoxypseudococaines is about two to four times smaller than the K i for inhibition of dopamine uptake, thus enabling these compounds capable of countering the effects of cocaine to some extent.

Novel Bioactive Tropinone Derivatives from Sesquiterpenoid Unsaturated Dialdehydes via the Robinson-Schöpf Reaction.

Novel Bioactive Tropinone Derivatives from Sesquiterpenoid Unsaturated Dialdehydes via the Robinson-Schöpf Reaction.