Heptane Derivatives Research Articles

ChemInform Abstract: Rh(II)-Catalyzed Skeletal Reorganization of 1,6- and 1,7-Enynes Through Electrophilic Activation of Alkynes.

The skeletal reorganization of 1,6- and 1,7-enynes leading to 1-vinylcycloalkenes using Rh(II) as a catalyst is reported. Two possible isomers of 1-vinylcycloalkenes, type I and type II, can be obtained, the ratio of which are highly dependent on the substitution pattern of the enynes used. Formation of type I compounds involves a single cleavage of a C-C double bond, the product of which is identical to that of enyne metathesis. In contrast, the formation of type II compounds involves the double cleavage of both the C-C double and triple bonds, which has an anomalous bond connection. The presence of both a phenyl group at the alkyne carbon and a methyl group at the internal alkene carbon facilitates the formation of type II compounds. The electronic and steric nature of the substituents on the aromatic ring also affects the ratio of type I and type II. The nature of a tether also has a significant effect on the course of the reaction. Experimental evidence for the intermediacy of a cyclopropyl rhodium carbenoid, a key intermediate in the skeletal reorganization of enynes, is also reported. In addition to the skeletal reorganization of enynes, Rh(II) complexes were found to have a high catalytic activity for some cycloisomerization reactions of alkyne derivatives, including the bicyclization of enynes to bicyclo[4.1.0]heptene derivatives and the cyclization of alkynylfurans to phenol derivatives.

Enantiomeric Differentiation of Oxygenated Bicyclo[2.2.1]heptane Derivatives by 13C NMR Spectroscopy Using Yb(hfc)3

ABSTRACT The 13C NMR behavior of 10 oxygenated compounds (ketones, alcohols, acetates) bearing the bicyclo[2.2.1]heptane skeleton was examined in the presence of a chiral lanthanide shift reagent (Yb(hfc)3). For each compound, we measured the lanthanide-induced shift (LIS) on the signals of the carbons and the splitting of signals, enabling the enantiomeric differentiation. The enantiomeric splitting was observed for the majority of signals in the spectrum of each compound.

Photosensitized intramolecular cyclization of furan and non-activated alkene: pathway switching by the substituent on the furan ring

A photosensitized reaction of furan with a non-activated simple alkene was investigated. Intramolecular Diels–Alder-type cycloaddition reactions between furan and a trisubstituted alkene were found to proceed in high yield in the presence of 9,10-dicyanoanthracene under UV irradiation to afford oxabicyclo[2.2.1]heptane derivatives in high stereoselectivity when the furan was alkyl substituted. On the other hand, the aryl-substituted furan cyclized via a completely different pathway to give spirocyclic and tricyclic products.

Studies on the stereocontrolled transformation of nitrohexofuranoses into 2-oxabicyclo[2.2.1]heptanes. V: Synthesis of enantiopure methyl (1 R,2 R,4 S)-2-amino-4-hydroxycyclopentanecarboxylate

The first total synthesis of enantiopure methyl (1 R,2 R,4 S)-2-amino-4-hydroxycyclopentanecarboxylate was carried out according to our recent novel strategy for the transformation of nitrohexofuranoses into cyclopentylamines, which is based on an intramolecular cyclisation leading to 2-oxabicyclo[2.2.1]heptane derivatives. It was observed that one of the substrate anomers produces an elimination rather than a cyclisation reaction. These and other differences in the reaction paths for this key step were rationalised by means of molecular mechanism based calculations.

First synthesis of 2,6-diazabicyclo[3.2.0]heptane derivatives

The first synthesis of 6-phenyl-2,6-diazabicyclo[3.2.0]heptane 1 and its orthogonally protected precursor 2 is herein reported. Our strategy enables to chemically address the two nitrogen atoms of 2,6-diazabicyclo[3.2.0]heptane core individually and selectively, thus allowing rapid access to several subsets of widely substituted fused azetidines.

Rh(II)-Catalyzed Skeletal Reorganization of 1,6- and 1,7-Enynes through Electrophilic Activation of Alkynes

The skeletal reorganization of 1,6- and 1,7-enynes leading to 1-vinylcycloalkenes using Rh(II) as a catalyst is reported. Two possible isomers of 1-vinylcycloalkenes, type I and type II, can be obtained, the ratio of which are highly dependent on the substitution pattern of the enynes used. Formation of type I compounds involves a single cleavage of a C-C double bond, the product of which is identical to that of enyne metathesis. In contrast, the formation of type II compounds involves the double cleavage of both the C-C double and triple bonds, which has an anomalous bond connection. The presence of both a phenyl group at the alkyne carbon and a methyl group at the internal alkene carbon facilitates the formation of type II compounds. The electronic and steric nature of the substituents on the aromatic ring also affects the ratio of type I and type II. The nature of a tether also has a significant effect on the course of the reaction. Experimental evidence for the intermediacy of a cyclopropyl rhodium carbenoid, a key intermediate in the skeletal reorganization of enynes, is also reported. In addition to the skeletal reorganization of enynes, Rh(II) complexes were found to have a high catalytic activity for some cycloisomerization reactions of alkyne derivatives, including the bicyclization of enynes to bicyclo[4.1.0]heptene derivatives and the cyclization of alkynylfurans to phenol derivatives.

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.

Synthesis of chiral 2-furyl and 3-nitro-7-oxabicyclo[2.2.1]heptane derivatives from sugars

Asymmetric Diels–Alder reactions between 2-methylfuran and chiral ( E)-1,2-dideoxy-1-nitroalkenes derived from d-mannose and d-galactose were carried out at room temperature, under 13 kbar pressure. The processes were completely regioselective, and only the four adducts with penta- O-acetyl-1′- C-(4-methyl-3-nitro-7-oxabicyclo[2.2.1]hept-5-en-2-yl)pentitols structures were formed in each case. These adducts, as well as those arising from cycloadditions of the same nitroalkenes and furan, have been converted into chiral derivatives, such as 2-furyl substituted 1-nitrosugars, 2-glyco-4-methyl-3-nitro-7-oxabicyclo[2.2.1]heptanes, and 5,6- exo-epoxy-2-glyco-3-nitro-7-oxabicyclo[2.2.1]hept-5-enes.

Mechanistic Analysis of Intramolecular Free Radical Reactions toward Synthesis of 7-Azabicyclo[2.2.1]heptane Derivatives

The mechanisms for the formation of conformationally constrained epibatidine analogues by intramolecular free radical processes have been computationally addressed by means of DFT methods. The mechanism and the critical effect of the 7-nitrogen protecting group on the outcome of these radical-mediated cyclizations are discussed. Theoretical findings account for unexpected experimental results and can assist in the selection of proper precursors for a successful cyclization.

ChemInform Abstract: Cyclopropanation Reactions for the Synthesis of 2‐Azabicyclo[4.1.0]heptane Derivatives with Nitric Oxide Synthase Inhibitory Activity.

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Synthesis of new 7-azabicyclo[2.2.1]heptane derivatives

The synthesis of new 7-azabicyclo[2.2.1]heptane derivatives has been achieved in a four-step synthetic sequence, starting from readily available cyclohex-3-enecarboxylic acid, Curtius reaction, stereoselective bromination leading to major benzyl(cis-3,trans-4-dibromocyclohex-1yl)carbamates (amides or sulfonamides), followed by NaH-mediated intramolecular cyclization. The synthesis and free radical cyclization of precursors 4-7, as well as the synthesis of a conformationally constrained epibatidine analogue 3 exploiting the reactivity of the 7azabicyclo[2.2.1]hept-2-yl radical in intramolecular reactions, are described. The N-sulfonyl functional motif is the only one to afford a cyclized product when incorporated in the radical precursor.

Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes. IV: Synthesis of enantiopure methyl (1 S,2 R,3 R,4 R,5 S)-5-benzyloxycarbonylamino-2,3-isopropylidenedioxy-4-methoxycyclopentanecarboxylate

The first total synthesis of a new enantiopure polyhydroxylated cyclopentyl β-amino acid [methyl (1 S,2 R,3 S,4 R,5 S)-2-benzyloxy-5-benzyloxycarbonylamino-3-hydroxy-4-methoxycyclopentanecarboxylate] was achieved according to our recent novel strategy for the transformation of nitrohexofuranoses into cyclopentylamines. This approach is based on an intramolecular cyclization leading to 2-oxabicyclo[2.2.1]heptane derivatives. Epimerization of this amino acid derivative to methyl (1 S,2 R,3 R,4 R,5 S)-2-benzyloxy-5-benzyloxycarbonylamino-3-hydroxy-4-methoxycyclopentanecarboxylate constitutes the first example of the preparation of one of the members of this family of amino acids with a stereochemistry that is not compatible with the above key cyclization step.

Anomeric effect for a 2,5,7-triazabicyclo[2.2.1]heptane derivative

A new member of the polyazapolycyclic family of compounds, namely N(3),N(6),2,5,7-pentaphenyl-2,5,7-triazabicyclo[2.2.1]heptane-3,6-diamine xylene solvate, C(34)H(31)N(5).C(8)H(10), was synthesized for the first time and the crystal structure is reported. There are no hydrogen bonds joining the molecules. All four chiral C atoms have the same absolute configurations. With regard to the four N-C-N groups, anomeric effects are observed to cause a reduction of C-N bond length and N-atom pyramidality.

Asymmetric Au(i)-catalyzed synthesis of bicyclo[4.1.0]heptene derivatives via a cycloisomerization process of 1,6-enynes

The enantioselective asymmetric gold-catalyzed cycloisomerization reactions of heteroatom tethered 1,6-enynes are conducted in the presence of a chiral cationic Au(i) catalyst ((R)-4-MeO-3,5-(t-Bu)(2)-MeOBIPHEP-(AuCl)(2)/AgOTf system) in toluene under mild conditions and lead to functionalized bicyclo[4.1.0]heptene derivatives in excellent enantiomeric excesses ranging from 90-98%.

A novel intramolecular Ugi reaction with 7-azabicyclo[2.2.1]heptane derivatives followed by post-condensation acylations: a new entry to azanorbornyl peptidomimetics

beta-amino acids have been employed in the past as bifunctional building blocks in intramolecular Ugi multicomponent reactions to yield beta-lactam derivatives. By using 7-azabicyclo[2.2.1]heptane-2-carboxylic acid, a different outcome has been observed and rationalised. The final compounds are polyfunctionalised azabicyclic peptidomimetics, and further elaboration can be achieved exploiting an additional carboxylic group that is not involved in the multicomponent step.

Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes. III: synthesis of enantiopure methyl (1 S,2 S,3 R,4 S,5 R)-2-amino-3,4,5-trihydroxycyclopentanecarboxylate

The first total synthesis of enantiopure methyl (1 S,2 S,3 R,4 S,5 R)-2-amino-3,4,5-trihydroxycyclopentanecarboxylate was carried out according to our recent novel strategy for the transformation of nitrohexofuranoses into cyclopentylamines, which is based on an intramolecular cyclization leading to 2-oxabicyclo[2.2.1]heptane derivatives. Differences in reactivity for this key step were rationalized by using molecular mechanism-based calculations.

Wagner–Meerwein rearrangement in the course of the ozonolysis of a bornene derivative

The ozonolysis of the bicyclo[2.2.1]heptene derivative 1 or 2 gave the octaline derivative 6 (the structure was confirmed by X-ray crystallographic analysis) or 7. The exo-addition of ozone to the double bond of 1 or 2 was followed by the fragmentation in carbonyl oxide and aldehyde. Then, the strong electrophilic character of the carbonyl oxide induces an unexpected Wagner–Meerwein rearrangement to give zwitterion 4. Finally, a fragmentation reaction with elimination of dioxygen gave the tetrasubstituted C–C double bonds of 6 or 7.

Cyclopropanation Reactions for the Synthesis of 2-Azabicyclo[4.1.0]heptane Derivatives with Nitric Oxide Synthase Inhibitory Activity

Abstract Synthesis of new bicyclic structures containing cyclopropanes, related to selective iNOS inhibitor ONO-1714, is described. We have evaluated the effect of the compounds obtained on the production of nitric oxide in lipopolysaccharide and interferon-gamma stimulated mouse peritoneal macrophages and on in vitro iNOS activity assays.

New Strategy for the Construction of Epoxy-Bridged Tetrahydropyran Frameworks from Trioxane Precursors: Application to a Concise Synthesis of a Riesling Acetal

A simple one-pot method to prepare dioxabicyclo[2.2.1] heptane derivatives, from readily available 1,2,4-trioxane frameworks, under catalytic hydrogenation conditions over a platinum surface is reported. The overall transformation involves the hydrogenation of the double bond and a ring contraction rearrangement that presumably proceeds via a hydrogenolytic cleavage of the O-O bond and subsequent intramolecular ketalization. The strategy was successfully applied to the synthesis of a Riesling acetal.

Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for neuronal nicotinic acetylcholine receptors

Α series of novel 3,6-diazabicyclo[3.1.1]heptane derivatives 4a–f was synthesized and their affinity and selectivity towards α4β2 and α7 nAChR subtypes were evaluated. The results of the current study revealed a number of compounds (4a, 4b and 4c) having a very high affinity for α4β2 (Ki at α4β2 ranging from 0.023 to 0.056nM) versus α7 nAChR subtypes; among these compounds, the 3-(6-bromopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane 4c was found to be the most α7α4β2 selective term in receptor binding assays (α7α4β2=1295). Moreover, compound 4d also had high affinity for the α4β2 nAChR subtype (Ki=1.2nM) with considerably high selectivity (α7/α4β2=23300).