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.     

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.     

Steric Effects in the Tuning of the Diastereoselectivity of the Intramolecular Free-Radical Cyclization to an Olefin As Exemplified through the Synthesis of a Carba-Pentofuranose Scaffold

Two free-radical cyclization reactions with the radical at the chiral C4 of the pentose sugar and the intramolecularly C1-tethered olefin (on radical precursors 8 and 17) gave a new diastereospecific C4-C8 bond in dimethylbicyclo[2.2.1]heptane 9, whereas the new C4-C7 bond in 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b gave trans and cis diastereomers, in which the chirality of the C4 center is fully retained as that of the starting material. It has been shown how the chemical nature of the fused carba-pentofuranose scaffolds, dimethylbicyclo[2.2.1]heptane 9 vis-a-vis 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b (C7-Me in the former versus 2-O- in the latter), dictates the stereochemical outcome both at the Grignard reaction step as well as in the free-radical ring-closure reaction. The formation of pure 1,8-trans-bicyclo[2.2.1]heptane 9 from 8 suggests that the boat-like transition state is favored due to the absence of steric clash of the bulky 1(S)-O-p-methoxybenzyl (PMB) and 7(R)-Me substituents (both in the α-face) with that of the 8(R)-CH(2)(?) radical in the β-face. The conversion of 17 → 18a-7(S) and 18b-7(R) in 6:4 ratio shows that the participation of both the chair- and the boat-like transition states is likely.     

Mechanistic insights into the opening of epoxides with trimethylsilyl cyanide - zinc iodide

-2,3-Epoxy-1,7,7-trimethylbicyclo[2.2.1]heptane reacted with trimethylsilyl cyanide in the presence of zinc iodide to produce a complex mixture of products. The major product, -7-trimethylsiloxy- -2,3,3-trimethyl- -2-isocyanobicyclo[2.2.1]heptane was obtained in 72% yield. In addition, eight other products were identified in yields ranging from 10% to 1%. All of the products could be rationalized on the basis of initial generation of a carbocationic intermediate.     

Construction of bicyclic systems containing an oxygen bridge by isomerization of cyclic epoxy alcohols

A novel method for constructing a 7-oxabicyclo[2.2.1]heptane skeleton was developed. The substrates, namely cis-3,4-epoxy-1-cyclohexanol derivatives, were prepared from the corresponding 3-cyclohexen-1-ol derivatives via a stereoselective epoxidation reaction using a vanadium catalyst. Upon heating with lithium iodide in propionitrile, the cis-epoxy alcohol was transformed into the 7-oxabicyclo[2.2.1]heptane derivative in high yield. The reaction proceeds through formation of a lithium alkoxide bearing an iodohydrin moiety, followed by an intramolecular S_N2 reaction.     

Interaction between Oxygen Lone-Pair Orbitals of Ether and α,β-Unsaturated Ketone Functions in 3,5,6-Trimethylidene-7-oxabicyclo[2.2.1]heptan-2-one and 3,6-Dimethylidene-7-oxabicyclo[2.2.1]heptane-2,5-dione: A PE-Spectroscopic Investigation

Controlled ozonolysis of 2,3,5,6-tetramethylidene-7-oxabicyclo[2.2.1]heptane ( 1 ) afforded 3,5,6-trimethylidene-7-oxabicyclo[2.2.1]heptan-2-one ( 2 ). Ozonolysis of 2 gave a 1:1 mixture of 3,5-dimethylidene-7-oxa-bicyclo[2.2.1]heptane-2,6-dione ( 3 ) and 3,6-dimethylidene-7-oxabicyclo[2.2.1]heptane-2,5-dione ( 4 ). The He(Iα) photoelectron (PE) spectra of 2 and 4 have been recorded. Comparison with the PE data of related systems, and with the result of ab initio STO-3G calculations, confirm the existence of significant through-bond interactions between the oxygen lone-pair orbitals n(CO) of the carbonyl functions and n(O) of the O(7) ether bridge.     

Control of the Diels-Alder-Addition Regioselectivity by Remote Olefins. Syntheses and Cycloadditions of 2,3,5-Trimethylidenebicyclo[2.2.1]heptane and 2,3,5,6,7-Pentamethylidenebicyclo[2.2.2]octane

The syntheses of 2,3,5-trimethylidenebicyclo[2.2.1]heptane ( 1 ) and 2,3,5,6,7-pentamethylidenebicyclo[2.2.2]-octane ( 2 ) are reported. The Diels-Alder additions of the diene moieties of these polyenes can be regioselective, probably because of a possible transannular interaction between the homoconjugated methylidene and s-cis-buta-diene groups.     

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.     

Barriers to inversion at nitrogen in bicyclic amines and hydrazines

Nitrogen inversion barriers have been measured for 7-chloro-1,7-diazabicyclo-[2.2.1] heptane and [2.2.2]octane; the unusual nature of the bridging nitrogen in bicyclo [2.2.11 systems is discussed.     

Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes. Part 6: synthesis and incorporation into peptides of the first reported 2,3-dihydroxycyclopentanecarboxylic acid

Herein we report the intramolecular alkylation of nitronates of methyl-5-O-benzyl-3,6-deoxy-6-nitro-β-d-glucofuranoside and methyl-5-O-benzyl-3,6-deoxy-6-nitro-α-d-glucofuranoside into the corresponding 2-oxabicyclo[2.2.1]heptane derivatives. Similarly, methyl-3-O-benzyl-5-deoxy-5-nitromethyl-β-d-xylofuranoside and methyl-3-O-benzyl-5-deoxy-5-nitromethyl-α-d-xylofuranoside were cyclized to (1R,3R,4S,5R,7R)-7-benzyloxy-3-methoxy-5-nitro-2-oxabicyclo[2.2.1]heptane and (1R,3S,4S,5R,7R)-7-benzyloxy-3-methoxy-5-nitro-2-oxabicyclo[2.2.1]heptane, respectively. These 2-oxabicyclo[2.2.1]heptane derivatives were eventually transformed into enantiopure methyl (1S,2S,3R,4S,5R)-2-amino-2,3-dihydroxycyclopentanecarboxylate and this novel β-amino acid was incorporated into peptides.     

A New Route to the Synthesis of 7-Functionalised Bicyclo[2.2.1]Heptane Derivatives

A new route to the synthesis of 7-functionalised bicyclo[2.2.1]heptane derivatives having a bridgehead alkoxy group is described involving Wolff rearrangement of α-diazo ketone in a bicyclo[2.2.2]octane derivative.     

Enantiomeric discrimination of cyclic β-amino acids using (18-crown-6)-2,3,11,12-tetracarboxylic acid as a chiral NMR solvating agent

(18-Crown-6)-2,3,11,12-tetracarboxylic acid is an excellent chiral NMR solvating agent for cyclic β-amino acids with cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, bicyclo[2.2.1]heptane, and bicyclo[2.2.1]heptene rings. The crown ether was added to the neutral β-amino acids in methanol-d₄. A neutralization reaction between the crown ether and β-amino acid forms the ammonium ion needed for favorable association. Enantiomeric discrimination of the two hydrogen atoms α to the amine and carboxylic acid moieties of the β-amino acid was observed with every substrate studied. Trends in the order of the enantiomeric discrimination of certain hydrogen atoms for substrates of similar structures correlate with the absolute configuration.     

Carbon-13 chemical shifts of bicyclo[3.2.1]octane and bicyclo[2.2.1]heptane derivatives

¹³C chemical shifts of more than fifty bicyclo[3.2.1]octane and bicyclo[2.2.1]heptane derivatives (hydrocarbons, alcohols, ketones and esters) have been determined. The usefulness of ethyl derivatives for the assignment of close ¹³C chemical shifts in bicyclic methyl derivatives is shown both for the bicyclo[3.2.1]octane and bicyclo[2.2.1]heptane series. Comparison of substituent effects on α-, β-, γ- and δ-carbons in both series of compounds shows remarkable differences in steric interactions. In contrast to the rigid bicyclo[2.2.1]heptane system, both chair and boat conformations can be predominant in the bicyclo[3.2.1]octane series with the conformationally flexible 6-membered ring.     

A Convenient Synthesis of Some 1,4-Disubstituted 7-Oxabicyclo[2.2.1]heptanes

An efficient synthesis of a 1,4-disubstituted 7-oxabicyclo[2.2.1]heptane intermediate and its subsequent conversion to a potential PAF antagonist is described.     

Acid-Catalyzed Rearrangements of 5,6-exo-Epoxy-7-oxabicyclo[2.2.1]hept-2-yl Derivatives. Migratory Aptitudes of Acyl vs. Alkyl Groups in Wagner-Meerwein Transpositions

In the presence of HSO₃F/Ac₂O in CH₂CL₂, 2-exo- and 2-endo-cyano-5,6-exo-epoxy-7-oxabicyclo[2.2.1]hept-2-yl acetates ( 6a , b ) gave products derived from the epoxide-ring opening and a 1,2-shift of the unsubstituted alkyl group (σ bond C(3)–C(4)). In contrast, under similar conditions, the 5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptan-2-one ( 6c ) gave 5-oxo-2-oxabicyclo[2.2.1]heptane-3,7-diyl diacetates 20 and 21 arising from the 1,2-shift of the acyl group. Acid treatment of 5,6-exo-epoxy-2,2-dimethoxy-7-oxabicyclo[2.2.1]heptane ( 6d ) and of 5,6-exo-epoxy-2,2-bis(benzyloxy)-7-oxabicyclo[2.2.1]heptane ( 6e ) gave minor products arising from epoxide-ring opening and the 1,2-shift of σ bond C(3)–C(4) and major products ( 25 , 29 ) arising from the 1,3-shift of a methoxy and benzyloxy group, respectively. Under similar conditions, 5,6-exo-epoxy-2,2-ethylenedioxy-7-oxabicyclo[2.2.1]heptane ( 6f ) gave 1,1-(ethylenedioxy)-2-(2-furyl)ethyl acetate ( 32 , major) and a minor product 33 , arising from the 1,2-shift of σ bond C(3)–C(4). The following order of migratory aptitudes for 1,2-shifts toward electron-deficient centers has been established: acyl > alkyl > alkyl α-substituted with inductive electron-withdrawing groups. This order is valid for competitive Wagner-Meerwein rearrangements involving equilibria between carbocation intermediates with similar exothermicities.     

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.     

Molecular design of biologically active compounds based on platelet activating factor (PAF): 7-oxabicyclo[2.2.1]heptane system as a strong antagonist of PAF.

7-Oxabicyclo[2.2.1]heptane system was designed based on the PAF structure. Among four stereoisomers synthesized, the diexo derivative turned out to be a new and strong antagonist of PAF.     

Thromboxane A2 receptor antagonists. I. Synthesis and pharmacological activity of 7-oxabicyclo-[2.2.1]heptane derivatives with the benzenesulfonylamino group

Four stereoisomers of 7-oxabicyclo[2.2.1]heptane derivatives with the benzenesulfonylamino group, 11, 14, 23 and 33, were synthesized and their sodium salts were examined in vitro for inhibitory activity against aggregation of rabbit platelet-rich plasma and of rat washed platelets. The trans-isomer 23 exhibited high potency but showed a partial agonistic effect. Compound 11 did not show a partial agonistic effect, though it was a less active inhibitor. The following trans compounds were synthesized and their IC50 values were measured: homologated trans-isomers with one methylene chain (47 and 53), an olefin derivative (58), and optically active derivatives [-)-11 and (+)-23).