An evaluation of amide group planarity in 7-azabicyclo[2.2.1]heptane amides. Low amide bond rotation barrier in solution

Here we show that amides of bicyclic 7-azabicyclo[2.2.1]heptane are intrinsically nitrogen-pyramidal. Single-crystal X-ray diffraction structures of some relevant bicyclic amides, including the prototype N-benzoyl-7-azabicyclo[2.2.1]heptane, exhibited nitrogen-pyramidalization in the solid state. We evaluated the rotational barriers about the amide bonds of various N-benzoyl-7-azabicyclo[2.2.1]heptanes in solution. The observed reduction of the rotational barriers of the bicyclic amides, as compared with those of the monocyclic pyrrolidine amides, is consistent with a nitrogen-pyramidal structure of 7-azabicyclo[2.2.1]heptane amides in solution. A good correlation was found between the magnitudes of the rotational barrier of N-benzoyl-7-azabicyclo[2.2.1]heptanes bearing para-substituents on the benzoyl group and the Hammett's sigma(p)(+) constants, and this is consistent with the similarity of the solution structures. Calculations with the density functional theory reproduced the nitrogen-pyramidal structures of these bicyclic amides as energy minima. The calculated magnitudes of electron delocalization from the nitrogen nonbonding n(N) orbital to the carbonyl pi orbital of the amide group evaluated by application of the bond model theory correlated well with the rotational barriers of a variety of amides, including amides of 7-azabicyclo[2.2.1]heptane. The nonplanarity of the amide nitrogen of 7-azabicyclo[2.2.1]heptanes would be derived from nitrogen-pyramidalization due to the CNC angle strain and twisting of the amide bond due to the allylic strain.     

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.     

Structural features of aliphatic N-nitrosamines of 7-azabicyclo[2.2.1]heptanes that facilitate N-NO bond cleavage

N-Nitrosamines can be considered as potential nitric oxide (NO)/nitrosonium ion (NO(+)) donors. However, the relation of the structures of N-nitrosamines, in particular of aliphatic N-nitrosamines, to the characteristics of release of NO or NO(+) remains unclear. Here we show that aliphatic N-nitrosoamines of 7-azabicyclo[2.2.1]heptanes can undergo heterolytic N-NO bond cleavage. On the basis of the observation of reduced rotational barriers of the N-NO bonds in solution and nitrogen-pyramidal structures of the N-nitroso group in the solid state, we postulate that N-NO bond cleavage of N-nitrosamines is enhanced by a reduction of the resonance in the N-NO group. Computational studies suggest that these structural features of the N-nitrosamines of 7-azabicyclo[2.2.1]heptane are derived from angle strain imposed on the CNC angles.     

Approaches to syn-7-substituted 2-azanorbornanes as potential nicotinic agonists; synthesis of syn- and anti-isoepibatidine

[reaction: see text] Coupling of N-Boc-7-bromo-2-azabicyclo[2.2.1]heptane with aryl and pyridyl boronic acids incorporates aryl and heterocyclic substituents at the 7-position and leads to a preference for syn over anti stereoisomers. Incorporation of a chloropyridyl group followed by N-deprotection gives syn-isoepibatidine. Facial selectivity in attack on 7-keto-2-azanorbornanes depends heavily on the N-protecting group leading to the first syn-7-hydroxy-2-azabicyclo[2.2.1]heptane derivative.     

Synthesis of n-heteroaryl-7-azabicyclo[2.2.1]heptane derivatives via palladium-bisimidazol-2-ylidene complex catalyzed amination reactions

[reaction in text] A one-step approach to novel N-heteroaryl-substituted-7-azabicyclo[2.2.1]heptanes from readily available heteroaryl halides and 7-azabicyclo[2.2.1]heptane has been achieved. The cross-coupling amination reaction employs palladium-bisimidazol-2-ylidene complexes as catalysts to give good to moderate yields over a wide variety of substrates.     

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 enantiomerically pure 1,2-diamine derivatives of 7-azabicyclo[2.2.1]heptane. New leads as glycosidase inhibitors and rigid scaffolds for the preparation of peptide analogues

Enantiomerically pure alcohols (-)- and (+)-7-tert-butoxycarbonyl-6-endo-p-toluenesulfonyl-7-azabicyclo[2.2.1]hept-2-en-5-endo-ol ((-)-11 and (+)-11) have been obtained from the Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrroel and 2-bromo-1-p-toluenesulfonylacetylene, including a resolution method. These two alcohols were converted into (+)- and (-)-5-exo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-18 and (-)-18) and (+)- and (-)-5-endo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-19 and (-)-19) after adequate functionalization and desulfonylation steps. The corresponding conformationally constrained bicyclic 1,2-diamines (+)-4, (-)-4, (+/-)-5, (+/-)-6, (+)-7, and (-)-7 were obtained from the protected precursors 18 and 19 and evaluated as glycosidase inhibitors. Diamines (+)-4, (-)-4, (+)-6, and (-)-6 can be seen as new nonpeptide molecular scaffolds for the design of peptide analogues.     

An analysis of the through-bond interaction using the localized molecular orbitals with ab initio calculations—II : Lone-pair orbital energies in bicyclo compounds: 7-azabicyclo[2.2.1]heptane and 2-azabicyclo[2.2.2]octane,and their n-methyl derivatives

Ab intio SCF MO calculations using STO-3G basis set were performed on 7-azabicyclo[2.2.1]heptane, N-methyl-7-azabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.2)octane, N-methyl-2-azabicyclo[2.2.2)octane, and their model molecules. The orbital energies obtained by these calculations were compared with the experimental ionization potentials The canonical MOs obtained for the model molecules were then transformed into the localized Mos. With the use of the localized MOs thus obtained, the lone-pair orbital energies were pursued in the light of the through-space and/or the through-bond interactions between thw specified localized MOs. As a result of this analysis, it was found that the effects of the inner shell orbitals, 1s electrons of the N atom, and of the neighbouring N-C bonds of the skeleton (through-bond interaction) play a dominant role in the interaction with the lone-pair orbitals. It was also found that the effect of the N-Me group on the lone-pair orbital energy is considerably important.     

7-substituted 2-azabicyclo[2.2.1]heptanes as key intermediates for the synthesis of novel epibatidine analogues; synthesis of syn-and anti-isoepiboxidine

Neighboring group participation by the 2-nitrogen in anti-7-bromo-2-benzyl-2-azabicyclo[2.2.1]heptane allows ready nucleophilic substitution at the 7-position by C, N, O, and halogen nucleophiles and opens the way to a range of novel 7-substituted 2-azabicyclo[2.2.1]heptanes. Conversion of an anti-7-ethoxycarbonyl group into a methylisoxazole ring provides anti-isoepiboxidine, a conversion that is possible even without protection of the secondary bicyclic nitrogen. Successful base-induced epimerization alpha to the carbonyl of the anti-7-ethoxycarbonyl derivative gives the syn-stereoisomer and hence syn-isoepiboxidine.     

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.     

aza-Prins-pinacol approach to 7-azabicyclo[2.2.1]heptanes and ring expansion to [3.2.1]tropanes

[reaction: see text] The 7-azabicyclo[2.2.1]heptane ring system can be rapidly accessed from 5-(1-hydroxyallyl)-2-alkoxy-N-tosylpyrrolidines via an unusual aza-Prins-pinacol reaction mediated by Lewis acid. The products can undergo ring expansion to isomeric tropanones. These reactions show promise for a concise entry to biologically relevant azabicyclic targets.     

A new class of bicyclic dicationic salts based on the 7-azoniabicyclo[2.2.1]heptane scaffold

A new class of dicationic ionic salts has been developed based on two 7-azoniabicyclo[2.2.1]heptane moieties and a variable spacer. The construction of the 7-azabicyclo[2.2.1]heptane skeleton and introduction of the two- to ten-atom spacer occurred concurrently in a one-pot reaction. Quaternization and subsequent metathesis afforded the dicationic salts consisting of two linked quaternized bicyclic moieties and bis(trifluoromethylsulfonyl)imide or dicyanamide as counterions. These salts are liquids at room temperature if the spacer length was larger than seven atoms. X-ray diffraction analysis revealed a linear conformation of the spacer and RS/SR stereochemistry of the quaternized nitrogens.     

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.     

Cycloadditions of 2-azaallyllithium species with conjugated polyenes

2-Azaallyllithium species [R(1)CH(-)N=C(X)R(2)Li(+), where R(1) and R(2) are alkyl and X = OMe] were generated by tin-lithium exchange of (2-azaallyl)stannanes and underwent [pi4s+pi2s] and [pi6s+pi4s] cycloadditions with cyclic dienes and trienes, respectively, to generate novel bridged azabicyclic compounds in a highly diastereoselective endo fashion. The periselectivity using cycloheptatriene was modest, producing a 1:1 mixture of [pi6s+pi4s] and [pi4s+pi2s] adducts. The reactions of 2-azaallyllithium species with dienes proceeded by a [pi4s+pi2s] pathway. The cycloadducts derived from cyclic 2-azaallyllithium species possess the 7-azabicyclo[2.2.1]heptane (tropane) or 8-azabicyclo[3.2.1]octane ring system and have been elaborated into cocaine-like analogues.     

Nucleophilic Opening of the Aziridine Ring in 1-Alkyl-1-azoniatricyclo[2.2.1.02,6]heptanes

Opening of the aziridine ring in 3-bromo-1-alkyl-1-azoniatricyclo[2.2.1.02,6]heptane bromides by the action of various nucleophiles leads to formation of the corresponding 6-substituted 2-alkyl-2-azabicyclo[2.2.1]heptanes.     

Synthetic studies toward longeracemine: a SmI2-mediated spirocyclization and rearrangement cascade to construct the 2-azabicyclo[2.2.1]heptane framework

Longeracemine, a member of the Daphniphyllum family of alkaloids contains a novel carbon framework featuring a highly functionalized 2-azabicyclo[2.2.1]heptane core as part of an overall 5/6/5/5/6/5 skeleton. A synthetic intermediate containing the core of longeracemine has been efficiently prepared by employing a stereoselective SmI₂-mediated cascade reaction to advance a 7-azabicyclo[2.2.1]heptadiene to a 2-azabicyclo[2.2.1]heptene that is functionally poised for conversion to the natural product.

A synthetic intermediate containing the core of longeracemine, that is functionally poised for conversion to the natural product, has been efficiently prepared by employing a stereoselective SmI₂-mediated cascade reaction.     

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.     

Methyl rotational barriers in amides and thioamides

The methyl rotational barriers for a series of N-methyl-substituted amides and thioamides have been calculated at the MP2/6-311+G** level. A comparison of the N-methylformamide and methyl formate barriers indicates that the H [bond] C(Me) [bond] N [bond] H eclipsed torsional arrangement destabilizes an amide by about 0.8 kcal/mol. A comparison of thioamides and amides showed the importance of steric repulsion between the sulfur and a methyl hydrogen in the Z-forms of the thioamides. The C [bond] N bond rotation transition states of the N,N-dimethyl amides have much larger methyl rotational barriers than found in the ground states. They can be attributed to the smaller CH(3)(-)N [bond] CH(3) bond angles in the transition states.     

Synthesis of heterocyclic analogues of epibatidine via 7-azabicyclo[2.2.1]hept-2-yl radical intermediates. 1. Intermolecular reactions

The synthesis and reactivity of the 7-azabicyclo[2.2.1]hept-2-yl radical has been extensively investigated in inter- and intramolecular reaction processes for the first time. In this work we will present the preparation of the radical and its successful intermolecular reaction with radical acceptors such as tert-butylisocyanide and acrylonitrile. Computational analyses have been carried out to show and explain the mechanisms and stereochemical outcome of these transformations. Overall and from the chemical point of view, a new and convenient synthetic approach has been developed for the synthesis of exo-2-(cyano)alkyl substituted 7-azabicyclo[2.2.1]heptane derivatives, a series of compounds of wide interest for the synthesis of heterocyclic analogues of epibatidine. As a result, we describe here the synthesis of the tetrazoloepibatidines (8 and 15) and the oxadiazoloepibatidine (10).     

Synthesis of (+/-)-Epibatidine and Its Analogues

A nonopiate analgesic, epibatidine (1), isolated from the skin of the Ecuadoran poison frog was synthesized in racemic form starting from tropinone. Distinctly different from the previously published approaches, this synthesis features the novel synthesis of the 7-azabicyclo[2.2.1]heptane ring system by contraction of the tropinone skeleton viaFavorskii rearrangement. Five analogues of 1 were also prepared, and their analgesic activities were evaluated.