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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

2-azatricyclo[2.2.1.01,6]heptane: Synthesis and conversion to 2-azabicyclo[2.2.1]heptanes

A facile route to 6-substituted 2-azabicyclo[2.2.1]heptanes via the novel tricyclic system, 2-azatricyclo[2.2.1.0^1,6]heptane (2), is described. The key intermediate (2) was prepared by oxidation of 4-aminomethylcyclopentene with lead tetra-acetate, and the bicyclic system was obtained by reaction of acetate with 2.MeI. Equilibration of exo- and endo-6-hydroxy-1-methyl-2-azabicyclo[2.2.1]heptane afforded an exo-endo isomeric ratio close to that of norborneol, and on this basis it is suggested that the steric requirements of the nitrogen lone pair are similar to that of CH.     

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 conformationally constrained spirodihydrofuropyridine analogues of epibatidine

Conformationally constrained spirofuropyridine analogues of epibatidine, syn-2 and anti-2, in which the 7-azabicyclo[2.2.1]heptane system and the 2-chloropyridine ring are held rigidly with the shorter and longer N-N distances, respectively, were synthesized from N-Boc-7-azabicyclo[2.2.1]heptan-2-one. The preliminary binding studies suggested that syn-2 has stronger binding affinity for nAChRs than anti-2.     

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.     

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.     

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.     

A novel entry to dispiropyrrolo-bicyclo[2.2.1]heptanes through sequential 1,3-dipolar and Diels-Alder cycloaddition reactions

The synthesis of novel dispiroheterocycles containing a bicyclo[2.2.1]heptane ring system through sequential [3+2] and [4+2] cycloadditions is described.     

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.     

Halogenation of 2-alkyl-2-azabicycloalkenes as a method for the synthesis of stable aziridinium salts of a new class

Addition of bromine and potassium dihaloiodates(i) to 2-alkyl-2-azabicyclo[2.2.1]hept-5-enes and 2-alkyl-2-azabicyclo[2.2.2]oct-5-enes affords quaternary ammonium salts containing the aziridine ring and the polyhalide anion. The possibility of using these salts for the synthesis of 6-substituted 2-alkyl-2-azabicyclo[2.2.1]heptanes has been shown.