Two- and three dimensional combinatorial chemistry from multicomponent Grignard reagents

The conjugate addition of five component Grignard reagents to methyl ecgonidine was used to create libraries of 3-substituted tropanes. By variation in the reagent combination in 10 such 5-membered sublibraries, a library of 25 compounds was made in a two-dimensional format. Screening of this library led to identification of two new potent monoamine transporter ligands that were subsequently synthesized. The most potent compound in this library was (1R,2S,3S,5S)-3-(3,4-dimethylphenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester, which inhibited dopamine transporter (hDAT) binding and reuptake with a K(i) of 26 and 20 nM, respectively. The conjugate addition to a 5-membered library of methyl ecgonidine analogues with variation of nitrogen substituent was also carried out and used to create 15 sublibraries of 25 compounds, which displayed 125 compounds in a three-dimensional format. From this 3D library, several potent dopamine transport inhibitors were likewise identified and synthesized. The most potent hDAT inhibitor discovered was (1R,2S,3S,5S)-3-(3,4-dimethylphenyl)-8-pentyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester. The study also showed that 3-alkyltropanes were poor inhibitors of monoamine transporters.     

Stereoselective synthesis of 2,4-methanoproline homologues

The stereoselective synthesis of 2-azabicyclo[2.2.1]heptane-1-carboxylic acid and 6-azabicyclo[3.2.1]octane-5-carboxylic acid, novel rigid bicyclic proline analogues, is reported. The synthesis was performed in five steps from the corresponding 2-cycloalken-1-ones. A known approach to 2,4-methanoproline is improved. The three amino acids constitute a library of conformationally constrained proline analogues, which can be used for the design of peptidomimetics and peptide models.     

An efficient route to all stereoisomeric enantiopure 6-amino-3-alkyl-3- azabicyclo[3.2.1]octane-6-carboxylic acids

A single-step synthesis on a gram scale of four pure stereoisomers of the 6-amino-3-azabicyclo[3.2.1]octane-6-carboxylic acid was carried out using (R)-1-phenylethylamine to confer chirality. The phenylethyl group, and the p-methoxy group linked to the N-atom, are easily removed by hydrogenolysis to afford the corresponding NH-3 derivatives. A series of N-3-alkyl compounds were prepared by way of a "one-pot" deprotection-alkylation procedure starting from the above key compounds. Their biological activity has been evaluated on the GABA receptor.     

A new constrained proline analogue with an 8-azabicyclo[3.2.1]octane skeleton

A straightforward synthesis of 8-azabicyclo[3.2.1]octane-1-carboxylic acid, a new proline analogue with a bicyclic structure, is described. The procedure makes use of readily available starting materials and involves simple, high-yielding transformations.     

Synthesis of potential metabolites of the brain imaging agents methyl (1R,2S,3S,5S)-3-(4-Iodophenyl)-8-alkyl-8-azabicyclo[3.2.1]octane-2-carboxylate

The synthesis of potential hydroxy metabolites of the brain imaging agents methyl (1R,2S,3S,5S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate and methyl (1R,2S,3S,5S)-3-(4-iodophenyl)-8-(3-fluoropropyl)-8-azabicyclo[3.2.1]octane-2-carboxylate are reported. The nitration of iodophenyltropanes 1 or 2 with nitronium tetrafluoroborate afforded the nitro compounds 3 or 4 which were reduced with iron powder to the corresponding amino compounds 5 and 6 . The final hydroxylated products 7 and 8 were obtained via a modified Sandmeyer reaction.     

Alpha,gamma-diamino acids: asymmetric synthesis of new constrained 6-amino-3-azabicyclo[3.2.1]octane-6-carboxylic acids

The synthesis of two new diastereomeric 6-amino-3-azabicyclo[3.2.1]octane-6-carboxylic acids exo- and endo-8,9 is reported using exo- and endo-norbornene amino acids as chiral building blocks. This method provides a fast access to optically pure amino acids 8 and 9 which can be considered both alpha,gamma- and alpha,delta-diamino acids containing sterical constraints and characterized by alpha,alpha-disubstitution.     

Reaction of 4-Oxocyclohexane-1,1,2,2-tetracarbonitriles and 5-Hydroxy-7-oxo-6-azabicyclo[3.2.1]octane-1,2,2-tricarbonitriles with Amines

New methods have been developed for the synthesis of fused amino-substituted pyrrolidinones and dihydropyrrolones. 4-Oxocyclohexane-1,1,2,2-tetracarbonitriles react with ammonia, hydrazine, and hydroxylamine to give, respectively, 5-amino-, 5-hydrazino-, and 5-hydroxylamino-7-oxo-6-azabicyclo[3.2.1]octane-1,2,2-tricarbonitriles, while with phenylhydrazine, semicarbazide, and thiosemicarbazide, 6-hydrazono-, 6-semicarbazono-, and 6-thiosemicarbazono-3-amino-1-oxo-3a,4,5,6,7,7a-hexahydro-1H-isoindole-3a,7a-dicarbonitriles are formed. The latter can also be obtained under analogous conditions from 5-hydroxy-7-oxo-6-azabicyclo[3.2.1]octane-1,2,2-tricarbonitriles. Reactions of 5-hydroxy-7-oxo-6-azabicyclo[3.2.1]octane-1,2,2-tricarbonitriles with diethylamine or triethylamine give 3-amino-1,6-dioxo-3a,4,5,6,7,7a-hexahydro-1H-isoindole-3a,7a-dicarbonitriles.     

Synthesis and stereochemistry of (3α)-6β,7β-dihydroxy- and 6β-hydroxy-8-alkyl-8-azabicyclo[3.2.1]octane-3-spiro-5′-imidazoline-2′,4′-diones

The synthesis of 6β-hydroxy- and 6β,7β-dihydroxy-8-alkyl-8-azabicyclo[3.2.1]octane-3-spiro-5′-hydantoins was stereoselectively achieved by Bucherer-Bergs reaction of the corresponding ketones. An α configuration on C₃ was proposed for all hydantoins on the basis of spectral data.     

Nitroxydes—LXIII : Oxydation de nitroxydes isoquinuclidiniques par l'oxyde d'argent humide. Preparation de nitroxydes aza-6 bicyclo[3.2.1]octeniques

Moist silver oxide oxidation of three isoquinuclidinic nitroxide ketones is described. 1,3,3-Trimethyl-2-azabicyclo[2.2.2]octane-5-one-2-oxyl 3, and 1,3,3,7-anti-tetramethyl-2-azabicyclo[2.2.2]octane-5-one-2-oxyl 4 lead to 6-aza-bicyclo[3.2.1]oct-3-ene-2-one-7-oxyl derivatives 6, 7, and 1,3,3,7-syn-tetramethyl-2-aza-bicyclo[2,2.2]octane-5-one-2-oxyl 5 to 8-substituted p-menthenones.     

Aspects of the chemistry of 8-azabicyclo[3.2.1]octanes

Mesylation and elimination from dimethyl 3-hydroxy-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate gave a conjugated alkenyl ester. Reduction of the mesyloxy ester by di-isobutylaluminium hydride was also accompanied by elimination giving an unsaturated aldehyde. Treatment of the mesylate of the corresponding monoprotected diol with potassium tert-butoxide gave a 2-unsubstituted alkene via a Grob fragmentation but a different alkene was obtained using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile. Epoxidation of both the protected hydroxy-alkene and the free hydroxy-alkene was stereoselective in favour of epoxidation from the exo-face, and ring-opening of the hydroxy-epoxide using hydrogen bromide gave the diaxial bromohydrin. Treatment of a 2-iodomethyl-3-oxo-8-azabicyclo[3.2.1]octane with tert-butyllithium gave a cyclopropane, whereas the corresponding iodo-alcohol gave the 1-azatricyclo[5.3.0.0^4,10]decan-2-one as the major product.     

Efficient synthesis of a new pipecolic acid analogue with a bicyclic structure

This report describes the synthesis of 2-azabicyclo[2.2.2]octane-1-carboxylic acid, a constrained pipecolic acid analogue. The route gives a very good total yield starting from cheap and readily available compounds and uses very easy reactions.     

1H nmr structural analysis of azabicyclospirohydantoins

The structure and spatial conformation of 3-alkyl-3-azabicyclo[3.2.1]octane-8-spiro-5′-hydantoins and 8-alkyl-8-azabicyclo[4.3.1]decane-10-spiro-5-hydantoins has been determined on the basis of the data from ¹H nmr. The chair conformation of the piperidine ring and the presence of only one stereoisomer at the spiro carbon atom are corroborated. All these facts have been confirmed by x-ray diffraction methods (2).     

Mass spectra of azabicyclospirohydantoins

The mass spectra of some N-substituted nortropane and granataninespirohydantoins are compared with those of N-substituted 3-azabicyclo[3.2.1]octane-8-spiro-, 3-azabicyclo[3.3.1]nonane-9-spiro-, 8-azabicyclo-[4.3.1]decane-10-spiro- and 3,7-diazabicyclo[3.3.1]nonane-9-spiro-5′-hydantoins. Mass spectra data of monothio- and dithio-tropanespirohydantoins are also included. Mass fragmentation and structure relationships of these molecules have been established.     

1H Nmr stuctural analysis of N3′-dialkylaminoethyl derivatives from azabicyclospirohydantoins

Based on the data from ¹H nmr spectra, the structure and spatial conformation of the N₃′-β-dimethyl and diethylaminoethyl derivatives from 3-alkyl-3-azabicyclo[3.2.1]octane-8-spiro-5′-hydantoins and 3-alkyl-3-azabicyclo[3.3.1]nonane-9-spiro-5′-hydantoins are established. The monosubstitution on the imide nitrogen atom has also been confirmed.     

A Tandem Horner-Emmons Olefination-Conjugate Addition Approach to the Synthesis of 1,5-Disubstituted-6-azabicyclo[3.2.1]octanes Based on the AE Ring Structure of the Norditerpenoid Alkaloid Methyllycaconitine

A novel Horner-Emmons olefination conjugate addition reaction of N-acetylamides to form 1,5-disubstituted-6-azabicyclo[3.2.1]octanes with two bridgehead quarternary carbon centers is reported. This reaction is a key step in an approach to the synthesis of small ring analogues based on the AE ring structure of the Delphinium norditerpenoid, methyllycaconitine (MLA) (1). Initially, 3-(hydroxymethyl)cyclohex-2-en-1-one (10) was selected as the starting material to these structures, but its generation proved inefficient. In contrast, the synthesis of 3-[(phenylthio)methyl]cyclohex-2-en-1-one (6) and 3-(1,3-dithian-2-yl)cyclohex-2-en-1-one (11) proceeded in good yield. Subsequent hydrocyanation, ketalization, reduction, acetylation, deprotection of the acetal, and Horner-Emmons olefination-conjugate addition reaction to form 1-[(phenylthio)methyl]-5-[(ethoxycarbonyl)methyl]-6-acetamido-6-azabicyclo[3.2.1]octane (28), 1-(1,3-dithian-2-yl)-5-[(ethoxycarbonyl)methyl]-6-acetyl-6-azabicyclo[3.2.1]octane (29), respectively, are reported, as well as for readily available 3-methylcyclohex-2-en-1-one (12). Studies on the Pummerer rearrangement of 28 and subsequent desulfurization and reduction to form an hydroxymethyl-substituted azabicyclo[3.2.1.]octane (40) and then selective protection to form a protected hydroxyethyl N-ethyl (hydroxymethyl)azabicyclo[3.2.1]octane (3) are also described.     

Reactions of 6,6-dialkyl-5,7-dioxo-4,8-dioxaspiro[2.5]octane-1,1,2,2-tetracarbonitriles with O-centered nucleophiles

The reactions of 6,6-dialkyl-5,7-dioxo-4,8-dioxaspiro[2.5]octane-1,1,2,2-tetracarbonitriles with primary aliphatic alcohols lead to the formation of alkyl 2,2,3,3-tetracyanocyclopropanecarboxylates; the reactions of the same compounds with ketone oximes give 2-amino-4,4-bis(alkylideneaminooxy)-6-(alkylidene-aminooxycarbonyl)-3-azabicyclo[3.1.0]hex-2-ene-1,5-dicarbonitriles, while with aldehyde oximes 2-amino-2-oxo-1,5-dicyano-3-azabicyclo[3.1.0]hex-2-ene-6-carboxylic acid is formed.     

An efficient high-yield synthesis of D-ribo-phytosphingosine

[Structure: see text] [4R-[4alpha(S),5alpha]]-2,2-Dimethyl-4-(2-oxo-5-vinyl[1,3]dioxolan-4-yl)oxazolidine-3-carboxylic acid tert-butyl ester 5a, obtained in excellent yield and diastereoselectivity by the alpha-hydroxyallylation of the Garner aldehyde (4), is exploited in a novel high-yield synthesis of D-ribo-phytosphingosine (8), using microwave-enhanced cross metathesis as the key step in the chain elongation.     

Synthesis of 8-substituted bicyclo[3.2.1]octane-6-carboxylic acids and anti-convulsant properties of the corresponding amides

Novel 8-substituted bicyclo[3.2.1]octane-6-carboxylic acids have been made via [3+2]cycloaddition to alkyne 2. A number of the corresponding amides are anti-convulsant in mice.     

Synthesis of novel azabicyclo derivatives containing a thiazole moiety and their biological activity against pine-wood nematodes

Abstract

To explore a new skeleton with nematicidal activity, a series of novel azabicyclo derivatives containing a thiazole moiety were designed, synthesized and evaluated for their nematicidal activities. The bioassay results against pine-wood nematodes (Bursaphelenchus xylophilus) showed that most of the title compounds displayed nematicidal activity at a concentration of 40?mg/L. Especially, the title compounds2-((8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-4-(4-chlorophenyl)thiazole (7e), 2-((8-methyl-8-azabicyclo[3.2.1]octan-3-yl)thio)-4-phenylthiazole (10a) and 2-((8-methyl-8-azabicyclo [3.2.1]octan-3-yl)thio)-4-(4-chlorophenyl)thiazole (10e) exhibited more than 90% mortality against Bursaphelenchus xylophilus.     

Ene Reductase Enabled Intramolecular β-C−H Functionalization of Substituted Cyclohexanones for Efficient Synthesis of Bridged Bicyclic Nitrogen Scaffolds

Herein we report that ene reductases (EREDs) can facilitate an unprecedented intramolecular β-C−H functionalization reaction for the synthesis of bridged bicyclic nitrogen heterocycles containing the 6-azabicyclo[3.2.1]octane scaffold. To streamline the synthesis of these privileged motifs, we developed a gram-scale one-pot chemoenzymatic cascade by combining iridium photocatalysis with EREDs, using readily available N-phenylglycines and cyclohexenones that can be obtained from biomass. Further derivatization using enzymatic or chemical methods can convert 6-azabicyclo[3.2.1]octan-3-one into 6-azabicyclo[3.2.1]octan-3α-ols, which can be potentially utilized for the synthesis of azaprophen and its analogues for drug discovery. Mechanistic studies revealed the reaction requires oxygen, presumably to produce oxidized flavin, which can selectively dehydrogenate the 3-substituted cyclohexanone derivatives to form the α,β-unsaturated ketone, which subsequently undergoes spontaneous intramolecular aza-Michael addition under basic conditions.