Heptane Ring System Research Articles

Synthesis of a Novel Conformationally Locked Carbocyclic Nucleoside Ring System.

A fast and efficient synthetic route to novel Northern locked carbocyclic nucleosides (as precursors of carbocyclic locked nucleic acids or cLNAs) is described. The target nucleoside with a oxabicyclo[2.2.1]heptane ring system was prepared from a simple starting material, diethyl malonate. Ring closure by intramolecular O-alkylation provided the target ring system as the major isomer over the [3.2.0] oxetane system. The adenine moiety was introduced through a reactive triflate after inversion of the stereochemistry of the corresponding alcohol by oxidation and reduction.

Synthesis and biological activity of various derivatives of a novel class of potent, selective, and orally active prostaglandin D2 receptor antagonists. 2. 6,6-Dimethylbicyclo[3.1.1]heptane derivatives.

In an earlier paper, we reported that novel prostaglandin D(2) (PGD(2)) receptor antagonists having the bicyclo[2.2.1]heptane ring system as a prostaglandin skeleton were a potent new class of antiallergic agents and suppressed various allergic inflammatory responses such as those observed in conjunctivitis and asthma models. In the present study, we synthesized PGD(2) receptor antagonists having the 6,6-dimethylbicyclo[3.1.1]heptane ring system. These derivatives have the amide moiety, in contrast to those with the bicyclo[2.2.1]heptane ring system, which have the sulfonamide group. The derivatives having the 6,6-dimethylbicyclo[3.1.1]heptane ring also exhibited strong activity in PGD(2) receptor binding and cAMP formation assays. In in vivo assays such as allergic rhinitis, conjunctivitis, and asthma models, these series of derivatives showed excellent pharmacological profiles. In particular, compound 45 also effectively suppressed eosinophil infiltration in allergic rhinitis and asthma models. This compound (45, S-5751) is now being developed as a promising alternative antiallergic drug candidate.

Synthesis and biological activity of various derivatives of a novel class of potent, selective, and orally active prostaglandin D2 receptor antagonists. 1. Bicyclo[2.2.1]heptane derivatives.

Novel prostaglandin D(2) (PGD(2)) receptor antagonists were synthesized as a potential new class of antiallergic agents having a bicyclo[2.2.1]heptane ring system with sulfonamide groups. Some of them exhibit extremely potent antagonism of the PGD(2) receptor in radioligand binding and cAMP formation assays with IC(50) values below 50 nM and much less antagonism of TXA(2) and PGI(2) receptors. These potent PGD(2) receptor antagonists, when given orally, dramatically suppress various allergic inflammatory responses such as increased vascular permeability in allergic rhinitis, conjunctivitis, and asthma models. The excellent pharmacological profiles of PGD(2) receptor antagonists, originally synthesized in our laboratories, are of potentially great clinical significance. This study also provides experimental evidence suggesting that PGD(2) plays an important role in the pathogenesis of allergic diseases.

Synthesis of a novel conformationally locked carbocyclic nucleoside ring system.

[reaction: see text] A fast and efficient synthetic route to novel Northern locked carbocyclic nucleosides (as precursors of carbocyclic locked nucleic acids or cLNAs) is described. The target nucleoside with a oxabicyclo[2.2.1]heptane ring system was prepared from a simple starting material, diethyl malonate. Ring closure by intramolecular O-alkylation provided the target ring system as the major isomer over the [3.2.0] oxetane system. The adenine moiety was introduced through a reactive triflate after inversion of the stereochemistry of the corresponding alcohol by oxidation and reduction.

Intramolecular Hydrogen Abstraction Reaction Promoted by Alkoxy Radicals in Carbohydrates. Synthesis of Chiral 2,7‐Dioxabicyclo[2.2.1]heptane and 6,8‐Dioxabicyclo[3.2.1]octane Ring Systems.

AbstractFor Abstract see ChemInform Abstract in Full Text.

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

The reaction of specifically protected anhydroalditols with (diacetoxyiodo)benzene or iodosylbenzene and iodine is a mild and selective procedure for the synthesis of chiral 6,8-dioxabicyclo[3.2.1]octane and 2,7-dioxabicyclo[2.2.1]heptane ring systems under neutral conditions. This reaction can be considered to be an intramolecular glycosidation that goes through an intramolecular hydrogen abstraction promoted by an alkoxy radical followed by oxidation of the transient C-radical intermediate to an oxycarbenium ion. This methodology is useful not only for the preparation of chiral synthons but also for the selective oxidation of specific carbons of the carbohydrate skeleton, constituting a good procedure for the synthesis of protected uloses.

ChemInform Abstract: Intramolecular Hydrogen Abstraction Reaction in Carbohydrate Chemistry. Synthesis of Chiral 2,7-Dioxabicyclo[2.2.1]heptane and 6,8-Dioxabicyclo[3.2.1]octane Ring Systems

Abstract The reaction of specifically protected alditols with (diacetoxyiodo)benzene or iodosylbenzene and iodine is a mild and selective procedure for the synthesis of chiral 6,8-dioxabicyclo[3.2.1]octane and 2,7-dioxabicyclo[2.2.1]heptane ring systems under neutral conditions. This methodology can be useful not only for the preparation of chiral synthons but also for the selective oxidation of specific carbons of the carbohydrate skeleton, constituting a good procedure for the synthesis of protected uloses. This reaction could be considered to be an intramolecular glycosidation that proceeds through an oxycarbenium ion.

Intramolecular hydrogen abstraction reaction in carbohydrate chemistry. Synthesis of chiral 2,7-dioxabicyclo[2.2.1]heptane and 6,8-dioxabicyclo[3.2.1]octane ring systems

The reaction of specifically protected alditols with (diacetoxyiodo)benzene or iodosylbenzene and iodine is a mild and selective procedure for the synthesis of chiral 6,8-dioxabicyclo[3.2.1]octane and 2,7-dioxabicyclo[2.2.1]heptane ring systems under neutral conditions. This methodology can be useful not only for the preparation of chiral synthons but also for the selective oxidation of specific carbons of the carbohydrate skeleton, constituting a good procedure for the synthesis of protected uloses. This reaction could be considered to be an intramolecular glycosidation that proceeds through an oxycarbenium ion.

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 conformationally locked C-nucleosides having a 2,5-dioxabicyclo[2.2.1]heptane ring system

Some novel C-nucleosides having a 2,5-dioxabicyclo[2.2.1]heptane ring system were successfully synthesized via the coupling reaction of tetrahydrofurancarbaldehyde 1 with the lithium and the magnesium derivatives of aromatic heterocycles.

Synthesis of 7-azabicyclo[2.2.1]heptanes by anionic cyclization

Cyclizations of α-amino-organolithiums, derived by tin-lithium exchange, which proceed via a stereoselective two-electron process and totally regiospecific 5- exo-trig ring closure, have been extended to the preparation of the 7-azabicyclo[2.2.1]heptane ring system. Cyclization occurs from either the cis or the trans isomer of 5-allyl-2-tri- n-butylstannyl- N-benzylpyrrolidine to give only the exo product as a single diastereomer in isolated yields up to 83%.

Silver acetate catalysed cycloadditions of isocyanoacetates

Silver acetate is an efficient catalyst for the cycloaddition of methyl isocyanoacetate with Michael-acceptors under mild conditions to give Δ 1- or Δ 2-pyrrolines in good yields. In the case of acrolein, novel chemoselectivity was observed. In the absence of a suitable olefin isocyanoacetates undergo silver acetate catalysed cyclodimerisation to give imidazoles in excellent yields. The mechanism of the cycloadditions has been probed. The reaction has been combined with azomethine ylide 1,3-dipolar cycloadditions in a one-pot sequential cascade process to afford the 7-azabicyclo[2.2.1]heptane ring system, a characteristic structural feature of the naturally occurring potent analgesic epibatidine.

Intramolecular anodic olefin coupling reactions: The construction of bridged bicyclic ring skeletons

Intramolecular anodic olefin coupling reactions have been used to construct both bicyclo[3.2.1]octane and bicyclo[2.2.1]heptane ring systems. The effect of substituents on the stereochemistry about the newly generated carbon-carbon bond was examined.

A unified asymmetric approach to substituted hexahydroazepine and 7-azabicyclo[2.2.1]heptane ring systems from D(−)-quinic acid: Application to the formal synthesis of (−)-balanol and (−)-epibatidine

3,4- O-Isopropylidene-3( R),4( S)-dihydroxycyclohexanone 7, a chiron easily prepared through a five step sequence from D(-)-quinic acid 1, has been efficiently utilized as the starting building block for the enantioselective syntheses of (3 R,4 S)- N- p-toluenesulfonyl-3,4-epoxy-hexahydroazepine 17 and (1 R,4 S)- N- tert-butoxycarbonyl-7-azabicyclo[2.2.1]heptan-2-one 43, advanced intermediates already taken to (-)-balanol and (-)-epibatidine respectively. While the nitrogen atom ring-insertion via Beckmann rearrangement was the key step for the construction of the hexahydroazepine ring of 17, a regio- and stereospecific intramolecular nucleophilic ring opening of an intermediate cyclic sulfate featured the approach to the substituted 7-azabicyclo[2.2.1]heptane nucleus of 43.

ChemInform Abstract: Enantioselective Approach to 7‐Azabicyclo(2.2.1)heptane Ring Systems Using D‐(‐)‐Quinic Acid as the Chiral Educt: Application to the Formal Synthesis of (+)‐Epibatidine.

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Enantioselective approach to 7-azabicyclo[2.2.1]heptane ring systems using D-(−)-quinic acid as the chiral educt: Application to the formal synthesis of (+)-epibatidine

By utilizing D-(−)-quinic acid as the chiral starting material the optically pure 7-[(1,1-dimethylethoxy)carbonyl]-7-azabicyclo[2.2.1.]heptan-2-one 2, an advanced intermediate already taken to (+)-epibatidine 1, a non-opioid analgesic isolated from Ecuadorian poison frogs, was synthetized through a facile, regioselective intramolecular nucleophilic ring opening of a cyclic sulfate moiety.

Total synthesis of (±) epibatidine

An efficient total synthesis of the non-opiate antinociceptive alkaloid epibatidine is described. Distinctly different from the previously published approaches it features the novel synthesis of the 7-azabicyclo[2.2.1]heptane ring system by contraction of the tropinone skeleton via Favorskii rearrangement.

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.

A radical cyclisation approach to the 2-oxabicyclo[2.2.1]heptane ring system

Intramolecular cyclisations of radicals generated from the β-substituted tetrahydrofurans 6, 7 and 14c onto suitably positioned alkene functions attached to the α′-position of the heterocycle give good to excellent yields of the 2-oxabicyclo[2.2.1]heptanes 8, 9 and 16.

The tandem Michael-S N2 reaction for the construction of the 3-azabicyclo[3.1.0]hexane ring system

The 3-azabicyclo[3.1.0]-hexane ring system was constructed in a convergent one-pot procedure starting from readily available starting materials, using the intramolecular tandem Michael-S N2 reaction. The methodology was also extended to the synthesis of 3-azabicyclo[4.1.0]heptane ring system.