Azabicyclo octane-3-carboxylic acid

ABOCA, 2-azabicyclo[3,3,0]octane-3-carboxylic acid. DBOSA, dibenzyloxysuccinic acid anhydride. [S-M-H-H20]+/[S-H]+ value. 

The initial medicinal chemistry route to the azabicyclo[3.3.0]octane-3-carboxylic acid produced the azabicyclo system in a diastereoselective but racemic manner, and required a classical resolution to achieve enantioenriched material (Teetz et al., 1984a, b 1988). Reaction of (R)-methyl 2-acetamido-3-chloropropanoate (43) and 1-cyclopentenylpyrrolidine (44) in DMF followed by an aqueous acidic work-up provided racemic keto ester 45 in 84% yield (Scheme 10.11). Cyclization of 45 in refluxing aqueous hydrochloric acid provided the bicyclic imine, which was immediately reduced under acidic hydrogenation conditions. The desired cis-endo product 46 was obtained upon recrystaUization. The acid was protected as the benzyl ester using thionyl chloride and benzyl alcohol, providing subunit 47 as the racemate. Resolution of 47 was accomplished by crystallization with benzyloxy-carbonyl-L-phenylalanine or L-dibenzoyl-tartaric acid. 

Hoechst has reported an enantioselective approach toward the key azabicyclo[3.3.0] octane-3-carboxylic acid 46 that preserves the stereochemistry of the L-serine-derived starting material (Urbach and Henning, 1991). L-Serine methyl ester (48) was alkylated... 

In an extension to this work, treatment of the template with 5-hexynal under the standard dehydrating conditions furnished the cycloadduct 301 in good yield (68). However, structural analysis of both the product and the azabicyclo[3.3.0]octane-3-carboxylic acid, derived by hydrogenation of the double bond, followed by... 

The preparation of a chiral bicyclic hydrazine, (15,35,5S)-2-amino-3-methoxymethyl-2-azabi-cyclo[3.3.0]octane (SAMBO, 3), was reported32 in 1990. (12 S, 31 S,51 5 )-2-Azabicyclo[3.3.0]-octane-3-carboxylic acid was resolved into its enantiomers. The (lS ,35,55)-enantiomer was converted to the chiral hydrazine 3 in six steps, utilizing Hofmann degradation, which is also employed in the preparation of SAMP. 

Dansyl amino acids (li ,3R,5R)-2-Azabicyclo-[3,3,0]-octane-3-carboxylic acid 115... 

AZABICYCLO(3.2.1)OCTANE-2-CARBOXYLIC ACID, 3-(BENZOYLOXY)-8-METHYL-, PROPYL ESTER,HYDROCHLORIDE (lR-(2-endo.3-exo))-... 

A solution of 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-l,4-benzoxazine-8-carboxylic acid in tetrahydrofuran and dimethylformamide is cooled to below 0°C and triethylamine is added under stirring thereto. Further, ethyl chlorocarbonate is added and the mixture is stirred at room temperature. To the resultant mixture is added 3-amino-8-azabicyclo[3.2.1]octane and the mixture stirred. After completion of the reaction, aqueous sodium hydrogen carbonate and ethyl acetate are added. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off to give 6-chloro-3,4-dihydro-4-methyl-N-(8-azabicyclo[3.2.1]oct-3-yl)-3-oxo-2H-l,4-benzoxazine-8-carboxamide. 

Chemical Name (3S)-2-((2S)-N-((lS)-l-Carboxy-3-phenylpropyl)alanyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid, (1-ethyl ester)... 

Rooke GA, EO Feigl (1982) Work as a correlate of canine left ventricular oxygen consumption, and the problem of catecholamine oxygen wasting. Circ Res 50 273-286 Scholkens BA, Becker RHA, Kaiser J (1984) Cardiovascular and antihypertensive activities of the novel non-sulfhydryl converting enzyme inhibitor 2-[N-[(S)-l-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(lS,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498). Arzneim Forsch Drug Res 34 1417-1425... 

Ifenprodil (= l-Methyl-2-hydroxy-2-(4-hydroxyphenyl) ethyl-1 -(4-benzyl-piperidine)] -(aryl piperidine) [at(/o-3-(Indol-2-yl)-8-methyl-8-azabicyclo-[3.2.1] octane] (indolotropane) [Kynurenic acid (= 4-Hydroxy-2-quinolinecarboxylic acid)] (quinoline carboxylic acid) [Memantine (= 1-Amino-3,5 dimethyladamantane)] (amino adamantane, amino cyclic aliphatic) [Methadone (= 6-Dimethylamino-4,4-diphenyl-3-heptanone)] (aryl tertiary amine) [em/o-3-(l -Methylindol-2-yl)-8-methyl-8-azabicyclo-[3.2.1] octane(indolotropane) exo- 3-( 1 -Methylindol-2-yl)-8-methyl-8-... 

Kolbe reactions of heterocyclic compounds have been studied in only a few cases. Anodic oxidation of l-azabicyclo[2.2.2]octane-2-carboxylic acid under Kolbe conditions produced 2-methoxy-l-azabicyclo[2.2.2]octane [454]. The primary radical, formed by loss of an electron from the carboxylate ion, decarboxylates and is oxidized further to a carboca-tion, which is attacked by a methoxide ion. A similar pseudo-Kolbe reaction is found in the anodic decarboxylation of 1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid derivatives to 3,4-dihydroisoquinolines [455]. 

The four-step synthesis begins with the hydrogenation of PABA using Rh/AliOs to furnish a 92% yield of 77 as an 80 20 cisitrans mixture. Subsequent heating at 250°C in Dowtherm A to effect epimerization-cyclization afforded the bicyclic lactam (78) in 84% yield. Red-Al reduction furnished 2-azabicyclo[2.2.2]octane which was subsequently protected as the tosylate salt (79) in 85% yield. Employment of more concentrated Dowtherm mixtures and a decreased amount of Red-Al increased the yield for the cyclization step to 89% and the tosylate salt to 91% (overall yield 70%) [85]. Earlier, Werner [86] demonstrated that using the carboxylate methyl ester instead of the carboxylic acid allows the cyclization to occur at lower temperatures (190°C). 

Benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid, ethyl ester, [1/ -(exo.exo)] Cocaethylene C18H23NO4 629-38-4 317.381 pr (eth) 109 vs eth, EtOH... 

They immobilized azabicyclo[3.3.0]octane-3-carboxylic acid 7 both by grafting and by polymerization (Fig. 4). The addition of diethyl zinc to ben-zaldehyde in a column was studied. It was found that the monoUthic catalyst prepared by polymerization turned out to be superior (up to 99% ee) compared to the catalyst prepared by grafting (compare with Schemes 7 and 8). Differences in appropriate chiral cavities inside the polymer may be responsible for these results, the other factors being differences in reaction conditions and most probably the avoidance of diffusional problems in the monoUthic catalyst at high flow rates. 

N-(lS-carboethoxy-3-phenylpropyl)-S-alanyl-c8s,endo-2-azabicyclo[3.3.0]octane-3S-carboxylic acid... 

TLC is also used for direct enantiomeric resolution of D,L-arginine, D,L-histidine, D,L-lysine, D,L-valine, and D,L-leucine on silica gel plates impregnated with optically pure (1/ , 3/ , 5/ )-2-azabicyclo[3,3,0]octan-3-carboxylic acid, which serves as a chiral selector in the pharmaceutical industry. To successfully resolve D,L-amino acids, various combinations of acetonitrile-methanol-water were proposed. The spot was detected by ninhydrin (0.2% in acetone). 

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