Heptane Derivatives Research Articles

Novel Tricyclo[4.2.1]nonane and Bicyclo[2.2.1]heptane Derivatives: Synthesis, in vitro Biological Activities and in Silico Studies.

The target compounds benzothiazole derivatives (8a-g) were synthesized starting from the norbornene. The antiproliferative activities of the compounds 6a-g and 8a-g were determined against C6 (rat brain tumor) and HeLa (human cervical carcinoma cells) cell lines using BrdU cell proliferation ELISA assay using 5-fluorouracil (5-FU) as standard. In both series, when compared with 5-FU (IC50=<5 µM for C6 and 16.33µM for HeLa), the most active compounds against C6 cells were 6a and 8g with IC50 values of 14.13 µM and 29.99 µM, respectively, while 6a, 6e, 6f and 8b were the most active compounds against HeLa cells with IC50 values of <5, <5, 19.33 and 1813 µM, respectively. Addition, to predict the physicochemical and AMDE properties of the tested compounds, SwissADME online web tool was used. The results showed that all compounds possess promising predicted physiochemical and pharmacokinetic properties, and they complied with Lipinski's rule of 5 indicating that they are predicted to be orally bioavailable, and they possess a predicted bioavailability score of 0.55. Furthermore, in SwissADME Boiled-Egg chart, all compounds showed high predicted GIT absorption, and while compounds 6a-g showed blood brain barrier (BBB) permeation, the compounds 8a-g did not. Moreover, all compounds are not p-glycoprotein (P-gp) substrates.

Recent Progress in (3+3) Cycloadditions of Bicyclobutanes to Access Bicyclo[3.1.1]heptane Derivatives

AbstractThe synthesis of bicyclo[3.1.1]heptane (BCHeps) derivatives, which serve as three-dimensional (3D) bioisosteres of benzenes and are the core skeleton of several terpene natural products, is garnering growing interest. The (3+3) cycloadditions of bicyclobutanes (BCBs) represent an attractive method for efficiently accessing (hetero)BCHep skeletons with 100% atom economy. Herein, we give a brief summary of recent achievements in this approach for the synthesis of diverse BCHep derivatives, emphasizing our recent progress in the initial palladium-catalyzed (3+3) cycloadditions of bicyclobutanes with vinyl oxiranes.1 Introduction2 Radical (3+3) Cycloaddition Reaction3 Polar (3+3) Cycloaddition Reaction4 Palladium-Catalyzed Enantioselective (3+3) Cycloaddition Reaction5 Conclusion

C60–bicyclo[2.2.1]heptanes: new hybrid mono- and hexakis-adducts of the C60 fullerene

New fullerene derivatives keep attracting attention of chemists due to their possible applications. Fullerene adducts with saturated polycyclic hydrocarbons represent one of the promising classes of fullerene compounds but still have rare examples. To enhance molecular diversity of fullerene derivatives in this direction, we have synthesized the representatives of C60–bicyclo[2.2.1]heptanes. For this purpose, we first produced the unsubstituted organic hydrazones from various bicyclo[2.2.1]heptane derivatives and then used the organic precursors in the reactions with C60. New homofullerenes and methanofullerenes with one bicyclo[2.2.1]heptane fragment have been obtained under metal-complex catalysis conditions at the fullerene C60:hydrazone molar ratio equal to 1:1.5. If fullerene C60:hydrazone ratio was 1:10, homofullerenes with six bicyclo[2.2.1]heptane fragments were synthesized, which can be isomerized into methanofullerenes when boiling in o-dichlorobenzene.

Formal [2σ + 2σ]-Cycloaddition of Aziridines with Bicyclo[1.1.0]butanes: Access to Enantiopure 2-Azabicyclo[3.1.1]heptane Derivatives.

Saturated nitrogen heterocycles are among the most significant structural components in small-molecule pharmaceuticals. Herein, a protocol for the construction of enantiopure 2-azabicyclo[3.1.1]heptane derivatives by a stereospecific intermolecular formal cycloaddition of aziridines with bicyclo[1.1.0]butanes is described. The reaction is run by using B(C6F5)3 as a catalytic additive to give access to a library of enantiopure 2-azabicyclo[3.1.1]heptane derivatives (37 examples) under mild and operationally simple conditions. Successful scale-up reactions, mechanistic experiments, density functional theory (DFT) calculations and synthetic applications are presented.

Asymmetric synthesis of inositol derivatives

Both the enantiomers of racemic 4-O-tosyl-6-O-benzyl-myo-inositol-1,3,5-orthoformate (2) were isolated by preferential crystallization and used to synthesize several enantiomeric myo-inositol derivatives - natural ononitol, natural laminitol, precursors for myo-inositol phosphates and an oxabicyclo [2.2.1] heptane derivative. This work demonstrates the potential of the enantiomeric tosylates D2 and L2 to serve as versatile starting materials for the absolute asymmetric synthesis of inositol derivatives and other natural products from symmetric myo-inositol since no optically active molecular entity was required for the resolution of 2.

Gold(I)-Mediated Isomerization of Spring-loaded 1,7-Enynes seen through the Lens of Density Functional Theory.

We propose a mechanism for the previously reported formation of benzobicyclo[3.2.0]heptane derivatives from 1,7-enyne derivatives bearing a terminal cyclopropane. -> A mechanism for the previously reported formation of benzobicyclo[3.2.0]heptane derivatives from 1,7-enyne derivatives bearing a terminal cyclopropane is proposed.

Selective [2σ + 2σ] Cycloaddition Enabled by Boronyl Radical Catalysis: Synthesis of Highly Substituted Bicyclo[3.1.1]heptanes.

In contrast to the traditional and widely-used cycloaddition reactions involving at least a π bond component, a [2σ + 2σ] radical cycloaddition between bicyclo[1.1.0]butanes (BCBs) and cyclopropyl ketones has been developed to provide a modular, concise, and atom-economical synthetic route to substituted bicyclo[3.1.1]heptane (BCH) derivatives that are 3D bioisosteres of benzenes and core skeleton of a number of terpene natural products. The reaction was catalyzed by a combination of simple tetraalkoxydiboron(4) compound B2pin2 and 3-pentyl isonicotinate. The broad substrate scope has been demonstrated by synthesizing a series of new highly functionalized BCHs with up to six substituents on the core with up to 99% isolated yield. Computational mechanistic investigations supported a pyridine-assisted boronyl radical catalytic cycle.

Catalytic Enantioselective Desymmetrization of meso-Cyclopropane-Fused Cyclohexene-1,4-diones by a Formal C(sp2)–H Alkylation

AbstractA bicyclo[4.1.0]heptane framework consisting of cis-fused cyclopropane and cyclohexane rings is found in several bioactive compounds. Given the symmetry of this core, catalytic desymmetrization can be considered as the most straightforward strategy for its enantioselective synthesis. Known desymmetrization reactions of meso-bicyclo[4.1.0]heptane derivatives proceed with opening of the cyclopropane ring. We now report the first ring-retentive desymmetrization of bicyclo[4.1.0]heptane derivatives, namely meso-cyclopropane-fused cyclohexene-1,4-diones, through a formal C(sp2)-H alkylation using a nitroalkane as the alkylating agent. This reaction is catalyzed by a dihydroquinine-derived bifunctional tertiary aminosquaramide and generates the products with up to 97:3 er. An application of this reaction is demonstrated by the first catalytic enantioselective synthesis of the natural product (–)-car-3-ene-2,5-dione.

Ketoreductase-Catalyzed Access to Axially Chiral 2,6-Disubstituted Spiro[3.3]heptane Derivatives.

The desymmetrization of a prochiral 6-oxaspiro[3.3]heptane-2-carboxylic acid derivative via biocatalytic ketoreductase-mediated reduction has provided access to both enantiomers in high ee. The axially chiral alcohol was converted to the corresponding ester alcohol, amino acid, and amino alcohol building blocks while high enantiopurity was maintained.

Selective synthesis of multifunctionalized cyclopent-3-ene-1-carboxamides and 2-oxabicyclo[2.2.1]heptane derivatives

Triethylamine promoted cycloaddition reaction of phenacylmalononitrile with o-hydroxychalcones or chalcone o-enolates to selectively give cyclopent-3-ene-1-carboxamides and 2-oxabicyclo[2.2.1]heptanes.

Synthesis of a Bicyclo[2.2.1]heptane Skeleton with Two Oxy-Functionalized Bridgehead Carbons via the Diels-Alder Reaction.

We describe a synthetic method for a bicyclo[2.2.1]heptane skeleton with two oxy-functionalized bridgehead carbons. This method involves an intermolecular Diels-Alder reaction using 5,5-disubstituted 1,4-bis(silyloxy)-1,3-cyclopentadienes, the diene structure of which has never been synthesized. Furthermore, the intramolecular Diels-Alder reaction using a diene bearing a dienophile moiety at the C-5 position can provide a tricyclic carbon framework that includes the bicyclo[2.2.1]heptane skeleton. The novel bicyclo[2.2.1]heptane derivatives could be utilized as versatile building blocks for organic synthetic chemistry.

Highly Efficient Visible-Light-Driven [2+2] Cycloaddition of Maleimides to Alkenes and Alkynes for the Synthesis of 3-Aza­bicyclo[3.2.0]heptane-Fused Scaffolds

AbstractA highly efficient [2+2] cycloaddition between maleimides and unsaturated moieties, utilizing a visible-light triplet sensitization mode, has been developed for the direct synthesis of multifunctional 3-azabicyclo[3.2.0]heptane derivatives. This reaction relies on selective activation of the maleimide functionality upon energy transfer from a new photosensitizer that outperforms diverse well-established photosensitizers. The strategy developed herein overcomes previous obstacles such as limited substrate scope and undesired reaction pathways under harsh UV irradiation.

Design, synthesis, and optimization of a series of 2-azaspiro[3.3]heptane derivatives as orally bioavailable fetal hemoglobin inducers

Pharmacological reactivation of the γ-globin gene for the production of fetal hemoglobin (HbF) is a promising approach for the management of β-thalassemia and sickle cell disease (SCD). We conducted a phenotypic screen in human erythroid progenitor cells to identify molecules that could induce HbF, which resulted in identification of the hit compound 1. Exploration of structure–activity relationships and optimization of ADME properties led to 2-azaspiro[3.3]heptane derivative 18, which is more rigid and has a unique structure. In vivo using cynomolgus monkeys, compound 18 induced a significant dose-dependent increase in globin switching, with developable properties. Moreover, compound 18 showed no genotoxic effects and was much safer than hydroxyurea. These findings could facilitate the development of effective new therapies for the treatment of β-hemoglobinopathies, including SCD.

GABA Analogues and Related Mono‐/Bifunctional Building Blocks Derived from the Fluorocyclobutane Scaffold

A series of GABA analogs and related mono‐ and bifunctional building blocks based on the monofluorinated 1,3‐disubstituted cyclobutane scaffold was designed and synthesized. The synthetic approaches included desilylative deoxyfluorination of TMS‐protected cyanohydrin and iodofluorination of methylenecyclobutane carboxylate as the key steps. Both approaches were highly efficient for the multigram synthesis of γ‐ and δ‐amino acids, monoprotected diamines, amino alcohols, and hydroxy acids. The first method was diastereoselective (dr 3:1) but it failed to produce the target products as pure, separable diastereomers. On the contrary, the second approach lacked diastereoselectivity but provided pure cis and trans isomers of the corresponding fluorocyclobutanes by separation of diastereomers; the products were obtained on up to 100 g scale in a single run. Moreover, the method was applied for the preparation of 3‐azabicyclo[3.1.1]heptane derivatives. X‐ray diffraction studies showed that the synthesized building blocks are appropriate analogs of GABA with either somewhat larger or smaller size as compared to the parent amino acid.

Reaction of Tricyclo[4.1.0.02,7]heptane with 1-(Arenesulfonyl)-2-phenyldiazenes

Tricyclo[4.1.0.02,7]heptane reacted with 1-(arenesulfonyl)-2-phenyldiazenes by radical mechanism to give bicyclo[3.1.1]heptane derivatives. Unlike analogous reactions with alkenes, the addition of diazenes occurs readily without a catalyst and yields mainly arylazosulfonation products at the C1–C7 bond of tricyclo-[4.1.0.02,7]heptane. The addition products are capable of undergoing thermal prototropic isomerization to 7-endo-(arenesulfonyl)bicyclo[3.1.1]heptan-6-one phenylhydrazones.

Radical Reactions of Tricyclo[4.1.0.02,7]heptane Derivatives with Arenesulfonylethynyl(trimethyl)silanes

Photochemically or thermally initiated reactions of arenesulfonylethynyl(trimethyl)silanes ArSO2C≡CSiMe3 (Ar = Ph, 4-MeC6H4) with 1-R-tricyclo[4.1.0.02,7]heptanes (R = H, Me, Ph) involve addition to the C1–C7 central bicyclobutane bond of the latter with the formation of bicyclo[3.1.1]heptane (norpinane) derivatives with endo(anti)-oriented arenesulfonyl group. A plausible reaction mechanism is discussed.

Synthesis of Tricyclo[4.4.0.02,7]decane Derivatives from Tricyclo[4.1.0.02,7]heptane Precursors

Tricyclo[4.1.0.02,7]heptane and 1-phenyltricyclo[4.1.0.02,7]heptane reacted with 2,3-bis(benzenesulfonyl)propene in boiling toluene (20–24 h) in the presence of benzoyl peroxide via trans-selective cleavage of the C1–C7 central bicyclobutane bond to give 6(7)-syn-benzenesulfonyl-7(6)-exo-[2-(benzenesulfonyl)prop-2-en-1-yl]bicyclo[3.1.1]heptane derivatives. The latter underwent cyclization to 1,9- and 7,9-bis(benzenesulfonyl)tricyclo[4.4.0.02,7]decane derivatives by the action of potassium tert-butoxide in dioxane at 50°C as a result of intramolecular Michael addition. Heating of the cyclization products in dioxane at 100°C in the presence of potassium tert-butoxide resulted in elimination of benzenesulfinic acid molecule with the formation of mixtures of two isomeric benzenesulfonyl-substituted tricyclo[4.4.0.02,7]dec-3-enes.

Synthesis, structure of 7-oxa-1-azabicyclo[2.2.1]heptane derivative obtained from sugar nitrone and analysis of its conformational variety

Dispiro derivative of 7-oxa-1-azabicyclo [2.2.1]heptane 5 was synthesized as a single stereoisomer from N-(5-allyl-spiro [1,3-dioxan-2,1′-cyclohexane]-5-yl)hydroxylamine 2 and protected d-mannose 3, through intramolecular 1,3-dipolar cycloaddition of in situ formed N-(but-3-en-1-yl)nitrone 4. Structure of product 5 was attributed on the basis of NMR and X-ray analyses. In the solid state, three crystallographically independent molecules of 5 were detected, every exhibiting a different orientation of spiro connected rings. Conformational analysis performed by DFT calculations in the gas phase was performed and revealed that the conformations observed in the crystal correspond to the most stable molecular geometries. Two of them were also found to be dominant in solution.

Stereocontrolled synthesis of polyhydroxylated bicyclic azetidines as a new class of iminosugars.

We report herein the development of a stereodivergent route towards polyhydroxylated bicyclic azetidine scaffolds, namely 6-azabicyclo[3.2.0]heptane derivatives. The strategy hinges on a common bicyclic β-lactam precursor, which is forged by way of a rare example of a cationic Dieckmann-type reaction, followed by IBX-mediated desaturation. Substrate-controlled diastereoselective oxidations then allow the divergent preparation of novel iminosugar mimics.

Computational study of the structure and properties of bicyclo[3.1.1]heptane derivatives for new high-energy density compounds with low impact sensitivity.

To design new high-energy density compounds (HEDCs), a series of new bicyclo[2.2.1]heptane derivatives containing an aza nitrogen atom and nitro substituent were designed and studied theoretically. The density, heat of sublimation and impact sensitivity were estimated by electrostatic potential analysis of the molecular surface. Based on the designed isodesmic reaction, and the reliable heat of formation (HOF) of the reference compounds, HOFs were calculated and compared at B3LYP/6-311G(d,p) and B3P86/6-311G(d,p), respectively. The detonation performances, bond dissociation energies (BDE) and impact sensitivity were calculated to evaluate the designed compounds. The calculated results show that the number of aza nitrogen atoms and NO2 groups are two important factors for improving HOF, density and detonation properties. Thermal stability generally decreases with increasing nitro groups. And the N-NO2 bond is the trigger bond for all designed compounds except B8, whose trigger bond is C-NO2. Importantly, the BDE values are between 86.95 and 179.71kJmol-1 and meet the requirement for HEDCs. Detonation velocity and detonation pressure were found to be 5.77-9.65kms-1 and 12.30-43.64GPa, respectively. After comprehensive consideration of thermal stability, impact sensitivity and detonation properties, A7, A8, B8, C8, D7, E7, F7 and G6 may be considered as potential HEDCs. Especially, A8, B8, C8, and D7 have better detonation properties than the famous caged nitramine CL-20 (D = 9.40km/s, P = 42.00GPa). Besides, all the designed potential HEDCs have reasonable impact sensitivity. Graphical abstract New high-energy density compounds (HEDCs) with low impact sensitivity (A8, B8, C8 and D7 have better detonation properties than CL-20).