Enantiospecific synthesis of annulated nicotine analogues from D-glutamic acid. 7-Azabicyclo[2.2.1]heptano[2.3-c]pyridines

The conformationally restricted nicotinoid (1S,4S)-7-methyl-7-azabicyclo[2.2.1]heptano[2,3-c]pyridine dihydrochloride has been prepared enantiospecifically from D-glutamic acid. The method involved a lithium cis-2,6-dimethylpiperidide-mediated intramolecular anionic cyclization of (2S,5R)-N-(tert-butyloxycarbonyl)-5-[3-(4-N-chloropyridinyl]proline methyl ester in tandem with a standard decarboxylation sequence. Reductive amination afforded the desired N-methylated [2.2.1]bicyclonicotinoid. Cyclization of the corresponding iodopyridinylproline methyl ester, obtained via ultrasound-facilitated chloro-iodo exchange, was also effected.     

Stereocontrolled syntheses of kainoid amino acids from 7-azabicyclo[2.2.1]heptadienes using tandem radical addition-homoallylic radical rearrangement

[reaction; see text] N-Boc syn-7-(2-hydroxyethyl)-4-(alkyl or aryl)sulfonyl-2-azabicyclo[2.2.1]hept-5-enes serve as precursors in syntheses of the neuroexcitants 3-(carboxymethyl)pyrrolidine-2,4-dicarboxylic acid 43, alpha-kainic acid 12, alpha-isokainic acid 14, and alpha-dihydroallokainic acid 77. The key step in these syntheses is the intermolecular radical addition of 2-iodoethanol to a N-Boc 2-(alkyl or aryl)sulfonyl-7-azabicyclo[2.2.1]heptadiene 7 to induce nitrogen-directed homoallylic radical rearrangement. Oxidative cleavage of the resulting 2-azabicyclo[2.2.1]hept-5-enes provide straightforward access to polysubstituted pyrrolidines and, in particular, an efficient entry to the kainoid amino acids.     

Carbocyclic ribosylamines: synthesis of 5-substituted carbocyclic beta-ribofuranosylamines

A synthesis of 5-substituted cyclopentylamine precursors for 5'-substituted carbocyclic nucleoside analogues was developed. We show that the stereochemistry of the OsO4-catalyzed hydroxylation of an apically brominated lactam, 7-bromo-2-azabicyclo[2.2.1]hept-5-en-3-one, can be controlled through the appropriate selection of the lactam N-H protecting group. Sterically large groups direct the hydroxylation to the exo-face of the olefin, yielding hydroxylation products that can be converted into analogues of carbocyclic ribosides. Conversely, a sterically small protecting group permits OsO4 approach from the endo-face, yielding hydroxylation products analogous to carbocyclic lyxosides. A key intermediate for carbocyclic sugar production, (1S,2S,3R, 4R,5S)-1-(tert-butyloxycarbonyl)amino-5-bromo-2,3-(dimethylmethylene)dioxy-4-hydroxymethylcyclopentane, was synthesized starting from a commercially available enantiomerically pure lactam, (1S)-(+)-2-azabicyclo[2.2.1]hept-5-en-3-one, in seven steps in an overall yield of 21%.     

An improved synthesis of(lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane

An improved and efficient method for synthesis of(lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane(1) from trans-4-hydroxy-L-proline was developed. Using benzyloxycarbonyl(Cbz) as protection group of amine, the reactions were inmild conditions, and the title compound 1 was accomplished in six steps in overall yield of 70%.     

Unusually high pyramidal geometry of the bicyclic amide nitrogen in a complex 7-azabicyclo[2.2.1]heptane derivative: Theoretical analysis using a bottom-up strategy

The high pyramidalization of the bicyclic amide nitrogen found in the crystal structure of a dipeptide incorporating (1S,2S,4R)-N-benzoyl-2-phenyl-7-azabicyclo[2.2.1]heptane-1-carboxylic acid has been investigated using quantum mechanical calculations. More specifically, a bottom-up strategy based on the study of model molecules of progressive complexity has been used. First, an appropriate quantum mechanical method has been selected by examining the distortion of the amide bond in three simple model molecules. Next, the amide distortion induced by the norbornane ring has been evaluated by considering three different 7-azabicyclo[2.2.1]heptane amides. After this, the suitability of quantum mechanical calculations to predict the effect of the substituents on the pyramidalization of the bicyclic amide nitrogen has been investigated by comparing experimental and theoretical parameters for a number of compounds. Finally, the factors responsible for amide distortion in the (1S,2S,4R)-N-benzoyl-2-phenyl-7-azabicyclo[2.2.1]heptane-1-carboxylic acid derivative have been elucidated using a hierarchical approach. For this purpose, several derivatives were generated by removing or modifying the substituents attached to the 7-azanorbornane system. Results have been discussed in terms of intramolecular specific interactions.     

Synthesis of alpha-kainic acid from a 7-azabicyclo[2.2.1]heptadiene by tandem radical addition-homoallylic radical rearrangement

Reductive radical addition of 2-iodoethanol to N-Boc 2-tosyl-7-azabicyclo[2.2.1]heptadiene gives N-Boc syn-7-(2-hydroxyethyl)-4-tosyl-2-azabicyclo[2.2.1]hept-5-ene, which is converted into the neuroexcitants 3-(carboxymethyl)pyrrolidine-2,4-dicarboxylic acid and alpha-kainic acid. [structure: see text]     

Synthesis of 7-azabicyclo[2.2.1]heptane and 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives by base-promoted heterocyclization of alkyl N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides

We have studied the base-promoted heterocyclization of alkyl N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides, investigating the effect of the nitrogen protecting group and the relative configuration of the leaving group at C3 and C4 on the outcome of this reaction. We have observed that the sodium hydride-promoted heterocyclization of alkyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamates (10, 12, 14, 16, 18) is a convenient method for the synthesis of 7-azabicyclo[2.2.1]heptane derivatives. For instance, the reaction of tert-butyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamate (10) with sodium hydride in DMF at room temperature provides 2-bromo-7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]heptane (2) (52% yield), whose t-BuOK-promoted hydrogen bromide elimination affords 7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]hept-2-ene (31) in 78% yield, an intermediate in the total synthesis of epibatidine (1). However, the NaH/DMF-mediated heterocyclization of alkyl N-(trans-3,cis-4-dibromocyclohex-1-yl)carbamates (11, 13) is a more structure dependent reaction, where the nucleophilic attack of the oxygen atom of the protecting group controls the outcome of the reaction, giving rise to benzooxazolone and 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives, respectively, from low to moderate yields, in complex reaction mixtures. Conversely, the NaH/DMF heterocyclizations of N-(cis-3,trans-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (40) or N-(trans-3,cis-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (42) are very clean reactions giving 7-azabicyclo[2.2.1]heptane or 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives, respectively, in good yields. Finally, a mechanistic investigation, based on DFT calculations, has been carried out to rationalize the formation of the different adducts.     

Synthesis of bicyclic tertiary alpha-amino acids

Novel bicyclic alpha-amino acids, exo and endo-1-azabicyclo[2.2.1]heptane-2-carboxylic acid, 1-azabicyclo[2.2.1]heptane-7-carboxylic acid, and 1-azabicyclo[3.2.2]nonane-2-carboxylic acid have been readily synthesized for the generation of neuronal nicotinic receptor ligands. Alkylation of glycine-derived Schiff bases or nitroacetates with cyclic ether electrophiles, followed by acid-induced ring opening and cyclization in NH4OH, allowed for the preparation of substantial quantities of the three tertiary bicyclic alpha-amino acids.     

Bis(trifluoromethyl)-containing 1-azatricycloheptanes

6-Substituted 7-halo-3,3-bis(trifluoromethyl)-2-azabicyclo[2.2.1]heptanes were synthesized by the addition of water, alcohols, and acetic acid to 3-halo-7,7-bis(trifluoromethyl)-1-azatricyclo[2.2.1.0^2,6]heptanes in the presence of H₂SO₄. 5,6-Disubstituted 3,3-bis(trifluoromethyl)-2-azabicyclo[2.2.1]heptanes were prepared by oxymercuration of 3,3-bis(trifluoromethyl)-2-azabicyclo[2.2.1]hept-5-ene.     

Olefination of methyl (1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo[2.2.1]heptane-1-carboxylate,a synthetic approach to new conformationally constrained prolines

Wittig olefinations of methyl (1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo[2.2.1]heptane-1-carboxylate with several phosphoranes and the Horner–Wittig reaction, using methyl diethylphosphonoacetate, have been tested in order to evaluate their utility in the synthesis of β-substituted conformationally constrained prolines. Subsequent elaboration of the resulting alkenes has provided proline–amino acid chimeras [combinations of proline with other α-amino acids, such as l-norvaline, l-norleucine, l-α-(3-phenylpropyl)glycine or l-homoglutamic acid] with the 7-azabicyclo[2.2.1]heptane skeleton in an enantiomerically pure form.     

Novel catalytic kinetic resolution of racemic epoxides to allylic alcohols

[formula: see text] The kinetic resolution of racemic epoxides via catalytic enantioselective rearrangement to allylic alcohols was investigated. Using the Li-salt of (1S,3R,4R)-3-(pyrrolidinyl)methyl-2-azabicyclo [2.2.1] heptane 1 as catalyst allowed both epoxides and allylic alcohols to be obtained in an enantioenriched form.     

Asymmetric synthesis of conformationally constrained 4-hydroxyprolines and their applications to the formal synthesis of (+)-epibatidine

This report describes the synthesis of enantiomerically pure (1S,3S,4R)- and (1S,3R,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acids, two new conformationally constrained 4-hydroxyprolines, using a straightforward synthetic route and starting from (−)-8-phenylmenthyl 2-acetamidoacrylate. The easy transformation of the pure (1S,3S,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acid into (1R,4S)-N-Boc-7-azabicyclo[2.2.1]heptan-2-one constitutes a new formal synthesis of (+)-epibatidine.     

Asymmetric synthesis of 3,4-diaminocyclohexanol and endo-7-azabicyclo[2.2.1]heptan-2-amine

Hydroboration of (1R,2R)-bis[(S)-1-phenylethylamino]cyclohex-4-ene and its derivatives with several borane reagents gave diastereomeric mixtures of the 3,4-diaminocyclohexanol derivatives. Cyclization of the prevalent diastereomer with the R configuration of the newly formed stereocenter under Mitsunobu conditions, followed by reductive removal of the N-substituents, gave the optically pure endo-7-azabicyclo[2.2.1]heptane-2-amine.     

Synthesis and total 1H- and 13C-NMR assignment of cephem derivatives for use in ADEPT approaches

We report the synthesis and total NMR characterization of 5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid-3-[[[(4'-nitrophenoxy)carbonyl]oxy]-methyl]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (5), a new cephalosporin derivative. This compound can be used as the carrier of a wide range of drugs containing an amino group. The preparation of the intermediate product, 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (6), as well as the synthesis of the antimalarial primaquine prodrug 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]- 5-dioxide (7) are also described, together with their total (1)H- and (13)C-NMR assignments.     

Intramolecular carbolithiation reactions for the preparation of Azabicyclo

Tin-lithium exchange and intramolecular carbolithiation (anionic cyclization) have been used to construct the three nitrogen-positional isomers of the azabicyclo[2.2.1]heptane ring system. The 7-azabicyclo[2.2.1]heptane ring system is accessed from either diastereomer of a 2,5-disubstituted pyrrolidine, via a chiral organolithium intermediate. The 2-azabicyclo[2.2.1]heptane ring system is formed stereoselectively in low yield by a tandem cyclization, together with the product from monocyclization. Better yields of the 2-aza ring system can be obtained using an alternative approach from a 2-tributylstannyl-4-allylpyrrolidine, despite the trans arrangement of the tin (and, hence, lithium) atom and the allyl unit. The 1-azabicyclo[2.2.1]heptane ring system is accessed in just three steps from 4-piperidone.     

Synthesis of 1-azabicyclo[3.3.0]octane derivatives and their effects as piracetam-like nootropics

A useful pharmaceutical intermediate, 5-nitromethyl-1-azabicyclo[3.3.0]octane (1), was prepared in one step from 1,7-dichloro-4-heptanone (4) under mild conditions. Catalytic hydrogenation of 1 over Raney Ni in the presence of sodium hydroxide afforded 5-aminomethyl-1-azabicyclo[3.3.0]octane (2) in high yield. Piracetam analogues 20-23, which were pyrrolidine derivatives involving a 1-azabicyclo[3.3.0]octane ring, were synthesized. Pharmacological tests showed that N-[(1-azabicyclo[3.3.0]octan-5-yl)methyl]-2-oxo-1-pyrrolidineacetamid e (20) improves cerebral function.     

An efficient enzymatic synthesis of benzocispentacin and its new six- and seven-membered homologues

A very efficient enzymatic method was developed for the synthesis of new enantiomeric benzocispentacin and its six- and seven-membered homologues through the Lipolase (lipase B from Candida antarctica) catalyzed enantioselective (E > 200) ring opening of 3,4-benzo-6-azabicyclo[3.2.0]heptan-7-one, 4,5-benzo-7-azabicyclo[4.2.0]octan-8-one, and 5,6-benzo-8-azabicyclo[5.2.0]nonan-9-one with H2O in iPr2O at 60 degrees C. The (1R,2R)-beta-amino acids (ee > or = 96%, yields > or = 40%) and (1S,6S)-, (1S,7S)-, and (1S,8S)-beta-lactams (ee > 99%, yields > or = 44%) produced could be easily separated. The ring opening of racemic and enantiomeric beta-lactams with 18% HCl afforded the corresponding beta-amino acid hydrochlorides.     

Bis(trifluoromethyl)-containing 1-azatricycloheptanes

Methods for the synthesis ofanti-3-halo-7, 7-bis(trifluoromethyl)-1-azatricyclo[2.2.1.0^2,6]heptanes by conjugated halogenation of 3,3-bis(trifluoromethyl)-2-azabicyclo[2.2.1]hept-5-ene have been developed. Hydrohalogenation of the synthesized 1-azatricyclic compounds gives exclusively 6,7-dihalo-3,3-bis(trifluoromethyl)-2-azabicyclo[2.2.1]heptanes. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1649–1653, September, 1997.     

Radical deoxygenation of 3-azatricyclo[2.2.1.0]heptan-5-ols to 2-azabicyclo[2.2.1]hept-5-enes and 1,2-dihydropyridines

Additions of alkyl or aryl Grignard reagents, or pyridin-3-yl-lithiums or lithium alkoxides, to exo-5,6-epoxy-7-(tert-butoxycarbonyl)-2-tosyl-7-azabicyclo[2.2.1]hept-2-ene lead to 7-substituted-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols. Radical deoxygenations of 7-alkyl-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols give 7-alkyl-4-tosyl-2-azabicyclo[2.2.1]hept-5-enes, whereas 7-aryl-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols give 2-(arylmethyl)-5-tosyl-1,2-dihydropyridines.     

(1R,3S,4S)-2-苄氧羰基-2-氮杂双环[2.2.1]庚烷-3-羧酸的合成

以(R)-(+)-α-甲基苄胺为原料,依次经缩合,Diels-Alder反应,还原,Cbz-保护和水解反应,合成了抗丙肝新药HCV NS3/4A蛋白酶拟肽类抑制剂的重要中间体——(1R,3S,4S)-2-苄氧羰基-2-氮杂双环[2.2.1]庚烷-3-羧酸,总收率66%,其结构经1H NMR和ESI-MS确证。