Intramolecular hydrogen abstraction promoted by N-radicals: synthesis of chiral 7-oxa-2-azabicyclo[2.2.1]heptane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems

Homochiral 7-oxa-2-azabicyclo[2.2.1]heptane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems can be synthesized by reaction of specifically protected phosphoramidate derivatives of carbohydrates with (diacetoxyiodo)benzene or iodosylbenzene and iodine. The reaction mechanism goes through homolytic fragmentation of a hypothetical iodoamide intermediate. The N-radicals so generated participate in an intramolecular hydrogen abstraction reaction (IHA) to give the aforementioned bicycles.     

Stereocontrolled approach to 1-azabicyclo[4.1.0]heptanes: application to the synthesis of trans-2,6-disubstituted piperidines

Stereocontrolled synthesis of a 1-azabicyclo[4.1.0]heptane is achieved by formation of an NH aziridine from the corresponding 1,2-azido alcohol and subsequent intramolecular conjugate addition onto a tethered α,β-unsaturated ester. Regioselective ring opening of the product at C-7 by heteroatom based nucleophiles yields trans-2,6-disubstituted piperidines in moderate to good yields.     

Intramolecular hydrogen abstraction reaction promoted by N-radicals in carbohydrates. Synthesis of chiral 7-oxa-2-azabicyclo[2.2.1]heptane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems

The reaction of phenyl and benzyl amidophosphates and alkyl and benzyl carbamate derivatives of aminoalditols with (diacetoxyiodo)benzene or iodosylbenzene and iodine is a mild and selective procedure for the synthesis of chiral 7-oxa-2-azabicyclo[2.2.1]heptane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems under neutral conditions. This reaction can be considered to be an intramolecular N-glycosidation that goes through an intramolecular 1,5-hydrogen abstraction promoted by an N-amido radical followed by oxidation of the transient C-radical intermediate to an oxycarbenium ion. This methodology proved to be useful not only as a suitable strategy for the preparation of these bicyclic arrays but also for the selective oxidation of specific carbons of the carbohydrate skeleton, constituting a good procedure for the synthesis of protected N,O-uloses.     

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%.     

N-Arylmethyl-7-azabicyclo[2.2.1]heptane derivatives: synthesis and reaction mechanisms

N-Arylmethyl-7-azabicyclo[2.2.1]heptane (I) derivatives have been synthesized by deprotection of N-protected, N-(arylmethyl)cyclohex-3-enamines, bromination of the resulting secondary cyclohex-3-enamines, followed by base-promoted cyclization (route a), or by bromination of N-protected, N-(arylmethyl)cyclohex-3-enamines followed by deprotection and base-mediated cyclization (route b). In these protocols we have observed that the bromination of the key intermediates (12, 13, and 19) is stereoselective leading to major trans-3-cis-4-dibromides (14, 17, and 20), whose mild base-mediated heterocyclization (on compound 14), or the two-step acid hydrolysis plus base-promoted cyclization (on compounds 17 and 20), gave products 6 and 7 in good yield. A mechanistic investigation using DFT has been carried out to explain the results observed in this work.     

The synthesis and stereochemical assignment of exo-7-phenyl-2,5-dioxabicyclo[4.1.0]heptane

The synthesis and stereochemical assignment of exo-7-phenyl-2,5-dioxabicyclo[4.1.0]heptane is reported. The stereochemical assignment was made based on data obtained from variable temperature nmr spectra.     

Efficient synthesis of a 7-azabicyclo[2.2.1]heptane based GlyT1 uptake inhibitor

An efficient synthetic route based on generation and subsequent electrophilic reaction of a Boc-protected azabicyclo[2.2.1]heptane anion to prepare a potent GlyT1 uptake inhibitor (1) is described.     

Total synthesis of (+)-trans- dihydronarciclasine from (+)-7-azabicyclo[2.2.1]heptanone

A concise asymmetric total synthesis of Amaryllidaceae alkaloid (+)-trans-dihydronarciclasine is accomplished starting from optically pure 7-azabicyclo[2.2.1]heptanone scaffold in 13 linear steps. Key features of the strategy include substrate-directed stereoselective installation of the trans B-C ring junction and regioselective Wacker-type internal olefin oxidation to provide a rapid access to all hydroxyl functionalities over the key cyclohexane ring in a stereocontrolled manner.     

Exploiting the regioselectivity of pyroglutamate alkylations for the synthesis of 6-azabicyclo[3.2.1]octanes and 4-azabicyclo[3.3.0]octanes

Depending on the N-protecting group of pyroglutamates, the reactivity can be directed to the formation of 6-azabicyclo[3.2.1]octanes or 4-azabicyclo[3.3.0]octanes, which are conformationally restricted glutamate analogues.     

The synthesis of potential Neramexane metabolites: cis- and trans-3-amino-1,3,5,5-tetramethylcyclohexanecarboxylic acids

A seven step synthetic route toward potential Neramexane metabolites cis- and trans-3-amino-1,3,5,5-tetramethylcyclohexanecarboxylic acids, cis-1 and trans-1, has been developed from isophorone. The synthetic procedure represents a useful method for the preparation of γ-amino acids with both amino and carboxyl groups situated at tertiary carbon atoms.     

Synthesis and conformational analysis of exo-and endo-7-substituted-3-azabicyclo[3.3.1]nonanes

The synthesis of some 7-substituted-3-azabicyclo[3.3.1]nonanes is described. Routes followed were the debenzoylation of the 7-benzoyl derivative 7 and the decarboxylation of the 7-carboxy compounds 21 and 27. The so-obtained 7-oxo-N-tosyl-3-azabicyclo[3.3.1]nonanes 8and 11 show an extremely low reactivity towards a series of nucleophilic reagents. From analysis of the ¹H NMR spectral data of a series of derivatives, the twin-chain conformation for the 7-exo compounds and the chair-boat conformation for the 7-endo compounds is indicated.     

Synthesis of exo-3-amino-10-hydroxy-hexacyclo[10.2.1.0.0.0.0]pentadecane-5,7-diene-endo-3-carboxyclic acid and endo-3-amino-10-hydroxy-hexacyclo[10.2.1.0.0.0.0]pentadecane-5,7-diene-exo-3-carboxylic acid

Treatment of hexacyclo[7.4.2.0^1,9.0^3,7.0^4,14.0^6,15]pentadecane-10,12-diene-2,8-dione with aqueous sodium cyanide produced 2,8-dihydroxy-hexacyclo[7.4.2.0^1,9.0^3,7.0^4,14.0^6,15]pentadecane-10,12-diene-2,8-lactam and with sodium cyanide, ammonium chloride and ammonium hydroxide, 2-amino-8-hydroxy-hexacyclo [7.4.2.0^1,9.0^3,7.0^4,14.0^6,15]pentadecane-10,12-diene-2,8-lactam was obtained. 10-Hydroxy-hexacyclo [10.2.1.0^2,11.0^4,10.0^4,14.0^9,13]pentadecane-5,7-diene-3-one was converted into the corresponding aminonitrile and hexacyclo[10.2.1.0^2,11.0^4,10.0^4,14.0^9,13]pentadecane-5,7-diene-10-hydroxy-3-spiro-5′-hydantoin. Treatment of the latter with barium hydroxide produced exo-3-amino-10-hydroxy-hexacyclo [10.2.1.0^2,11.0^4,10.0^4,14.0^9,13]pentadecane-5,7-diene-endo-3-carboxylic acid. The isomeric endo-3-amino-10-hydroxy-hexacyclo[10.2.1.0^2,11.0^4,10.0^4,14.0^9,13]pentadecane-5,7-diene-exo-3-carboxylic acid was obtained from 3-cyano-3-ureido-hexacyclo[10.2.1.0^2,11.0^4,10.0^4,14.0^9,13]pentadecane-5,7-diene-10-ol.     

Studies on the ring opening reactions of 3-oxa-1-azabicyclo[3.1.0]hexan-2-ones. Synthesis of aminomethyl oxazolidinones and aziridinyl ureas

The reaction of fused ring aziridines, 3-oxa-1-azabicyclo[3.1.0]hexan-2-ones, with amine nucleophiles can provide either an aminomethyl oxazolidinone or an aziridinyl urea. The amine, reaction solvent, and aziridine substitution have been examined with the aid of computational studies to identify reaction conditions that provide a single product. Polar solvents provided only the aminomethyl oxazolidinone products. Formation of aziridinyl ureas required control of aziridine substitution, solvent, and reactant stoichiometry.     

Short diastereoselective synthesis of cis- and trans-hexahydropyrido[2,1-a]isoindole derivatives

A new and highly stereoselective access to 4,10b-trans or 4,10b-cis hexahydropyrido[2,1-a]isoindole derivatives is reported, both requiring an intramolecular Mannich-type reaction as key step. The cis diastereoisomer is obtained in three steps from a 2-alkyl benzaldehyde through the stereoselective formation of a 2,6-cis-disubstituted piperidine, while the trans stereomer is efficiently obtained, in a single step, if a 2-formyl benzoic acid is involved in the Mannich cyclization process.     

Conformational equilibria of 7-benzyl-2-iodo-9-oxa-7-azabicyclo[4.3.0]nonan-8-one in solution. Correlations between conformational distribution and solvent solvatochromic parameters

A quantitative study of the variation of the conformational equilibria of 7-benzyl-2-iodo-9-oxa-7-azabicyclo[4.3.0]nonan-8-one 1 in 10 solvents has been carried out. The experimental composition in each solvent has been obtained from experimental NMR vicinal H-H coupling constants together with molecular modeling. The solvent properties, particularly polarity and hydrogen bonding ability, were described according to Kamlet and Taft using experimental parameters. Very good linear relationships were obtained between the equilibrium constants of each single conformational equilibrium and the polarity and hydrogen bonding parameters of the solvent. These linear relationships allow an accurate prediction of the conformational composition in any solvent as well as a thorough understanding of the influence of each separate parameter on the conformational equilibrium composition.     

Synthesis and stereochemistry of new 1,3-thiazolidine systems based on 2-amino-2-(mercaptomethyl)propane-1,3-diol: 4,4-bis(hydroxymethyl)-1,3-thiazolidines and c-5-hydroxymethyl-3-oxa-7-thia-r-1-azabicyclo[3.3.0]octanes

The thiaminalisation of 2-amino-2-(mercaptomethyl)propane-1,3-diol [‘2-(hydroxymethyl)cysteinol’] with aryl(di)aldehydes is reported. The resulting new class of 2-aryl-4,4-bis(hydroxymethyl)-1,3-thiazolidines is investigated by NMR and IR spectroscopy in tandem with DFT calculations, permitting structural assignments that are discussed in terms of conformational analysis, anomeric effects and ring-chain tautomerism. These acquired data are subsequently exploited. After treatment with formaldehyde, the subsequent (double) regio- and diastereoselective oxaminalisation of the 1,3-thiazolidine building-block affords the first non-symmetric series of a thiazolidin-oxazolidine fused system singly functionalised at the C-5 position. An unexpected rearrangement, which consists of the partial relocation of the Ar ligand from the 1,3-thiazolidine to the 1,3-oxazolidine ring, is observed as a major influence on the substitution of the Ar ring. The first single crystal X-ray analysis of the title bicyclic system, which discloses the homo- and/or heterochiral non-bonding interactions, is also presented.