Bridgehead Methyl Research Articles

Effect of Bridgehead Methyl Substituents on the Gas Permeability of Tröger's-Base Derived Polymers of Intrinsic Microporosity.

A detailed comparison of the gas permeability of four Polymers of Intrinsic Microporosity containing Tröger’s base (TB-PIMs) is reported. In particular, we present the results of a systematic study of the differences between four related polymers, highlighting the importance of the role of methyl groups positioned at the bridgehead of ethanoanthracene (EA) and triptycene (Trip) components. The PIMs show BET surface areas between 845–1028 m2 g−1 and complete solubility in chloroform, which allowed for the casting of robust films that provided excellent permselectivities for O2/N2, CO2/N2, CO2/CH4 and H2/CH4 gas pairs so that some data surpass the 2008 Robeson upper bounds. Their interesting gas transport properties were mostly ascribed to a combination of high permeability and very strong size-selectivity of the polymers. Time lag measurements and determination of the gas diffusion coefficient of all polymers revealed that physical ageing strongly increased the size-selectivity, making them suitable for the preparation of thin film composite membranes.

Ring-opening carbonyl-olefin metathesis of norbornenes.

A computational and experimental study of the hydrazine-catalyzed ring-opening carbonyl–olefin metathesis of norbornenes is described. Detailed theoretical investigation of the energetic landscape for the full reaction pathway with six different hydrazines revealed several crucial aspects for the design of next-generation hydrazine catalysts. This study indicated that a [2.2.2]-bicyclic hydrazine should offer substantially increased reactivity versus the previously reported [2.2.1]-hydrazine due to a lowered activation barrier for the rate-determining cycloreversion step, a prediction which was verified experimentally. Optimized conditions for both cycloaddition and cycloreversion steps were identified, and a brief substrate scope study for each was conducted. A complication for catalysis was found to be the slow hydrolysis of the ring-opened hydrazonium intermediates, which were shown to suffer from a competitive and irreversible cycloaddition with a second equivalent of norbornene. This problem was overcome by the strategic incorporation of a bridgehead methyl group on the norbornene ring, leading to the first demonstrated catalytic carbonyl–olefin metathesis of norbornene rings.

In,in-Cyclophanes with Bridgehead Methyl Groups.

Two in,in-cyclophanes that contain methyl groups in their central cavities have been synthesized, and their X-ray structures have been determined. One of these molecules contains a very short nonbonded contact between a hydrogen atom and a methyl group, and the other is the first example of a macrobicyclic compound that contains two inwardly directed methyl groups.

Identification of 15-nor-cleroda-3,12-diene in a Dominican amber

An unknown compound dominant in the aliphatic hydrocarbon fraction of the solvent extract of a Dominican amber sample was isolated and purified using column chromatography and preparative gas chromatography. 1D and 2D NMR analyses allowed its structure to be assigned as 15-nor-cleroda-3,12-diene. The bridgehead methyl group (CH3 at C-19) has a 13C chemical shift of 19.6ppm, typical for a trans-decalin framework (Nogueira, 2001), indicating the diterpenoid has a trans A/B ring structure. ROESY correlations indicate that the methyl groups at C-19, C-20 were axial and the C-17 methyl group was equatorial, while the H-10 and H-8 were axial and on the other side of Ring B. Taken together, a 5R,8R,9S,10R-configuration for the new nor-clerodadiene can be established. The absolute configuration of 5R,8R,9S,10R was further confirmed by comparing the experimental and calculated electronic circular dichroism (ECD) spectra of this diterpenoid. The identified diene appears to originate from a Hymenaea species (Fabaceae). Non-oxidative decarboxylation of cleroda-3,13-diene-15-oic acid (kovalenic acid) present in Hymenaea species or oxidative decarboxylation of 3-cleroden-15-oic acid in Dominican amber are considered to be the two viable pathways leading to the formation of the identified 15-nor-cleroda-3,12-diene, although the former pathway is more likely.

Enantioselective Approach to the Right‐Hand Substructure of Solanoeclepin A

An enantioselective synthesis of the right‐hand substructure of solanoeclepin A has been developed. The key step was an intramolecular [2+2] photocycloaddition between an allene and a butenolide providing a methylenecyclobutane with three quaternary carbon atoms in a complex tetracyclic framework. Other crucial steps included an enantioselective Noyori transfer hydrogenation of a ketone, a diastereoselective silver‐mediated silyl dienolate allylation, and a diastereoselective cyclopropanation of an allylic alcohol. The installation of the bridgehead methyl group by reduction of the lactone moiety proved to be troublesome.

Theoretical insights into structure, bonding, reactivity and importance of ion-pair interactions in Kirby's tetrafluoroboric acid salts of twisted amides

The hydrolysis of amide 1 is more exothermic and is more favorable than amides 2 and 3 with bridgehead methyl.

Chemoenzymatic Synthesis and Application of Bicyclo[2.2.2]octadiene Ligands: Increased Efficiency in Rhodium‐Catalyzed Asymmetric Conjugate Additions by Electronic Tuning

On your bi(cycle)ke! A series of 1,4-dimethyl bicyclic [2.2.2] diene ligands with tunable substitution at the bridge positions was accessed using a lipase resolution and a high yielding six step sequence (see scheme). The bridgehead methyl groups improve efficiency allowing less aryl boronic acid to be used in the title reaction. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Discovery of novel dihydro-9,10-ethano-anthracene carboxamides as glucocorticoid receptor modulators

A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities. 17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays. A hypothetical binding mode is provided which accounts for the induction of functional activity by a bridgehead methyl group.

Rearrangement of 4,5-Epoxy-9-trimethylsilyldecalines. Application to the Synthesis of the Natural Eremophilane (−)-Aristolochene

Several 4,5-epoxy-9-trimethylsilyl-eudesmanes and 15-nor-eudesmanes, having different relative stereochemistry and substitution at the oxirane ring, have been prepared starting from (-)-carvone and subjected to acid-promoted rearrangement. The presence of the silicon at C9 favors two different main reaction pathways involving C14-methyl or C1-methylene migration through the stabilization of a C10 carbocation intermediate. Selective 1,2-migration of the bridgehead methyl group takes place with trisubstituted beta-epoxide and tetrasubstituted alpha-epoxide, yielding 4-hydroxy-eremophilane and 15-nor-eremophilane compounds, while the trisubstituted alpha-epoxide suffers successive rearrangements to give a 1-hydroxy-15-nor-eremophilane through a pathway involving the initial migration of the C1 methylene. The synthetic utility of these rearrangements is shown by the synthesis of natural (-)-aristolochene.

Influence of methyl substituents on the stability of 1‐aza‐2‐adamantanone, Kirby's most twisted amide

AbstractHydrolysis and carbonyl hydration of adamantane‐based twisted amide 1 were studied computationally. The importance of the bridgehead methyl substituents on these reactions was determined. The carbonyl hydration of 1 is structurally and energetically much like the hydration of a transition state to amide CN bond rotation. However, hydrolysis of 1 to the amino acid is dependent on the bridgehead methyl substituents and less like hydrolysis of an amide transition state. Copyright © 2004 John Wiley & Sons, Ltd.

Comparative Cyclotrimerisation of Enantiopure vic‐Bromo(trimethylstannyl)bicycloalkenes Derived from (+)‐Camphor, (+)‐Fenchocamphorone and (−)‐Epicamphor: Effect of the Bridgehead Methyl Group on the syn/anti Product Ratios

AbstractThe influence of the bridgehead methyl group on syn/anti diastereoselectivity in the cyclotrimerisation of polycyclic alkenes was investigated. To this end, three different enantiopure vic‐bromo(trimethylstannyl)‐substituted bicyclic olefins were prepared and used as probes. The effects of different copper(II) or ‐(I) salts were studied, and most dimeric intermediates were independently synthesised and characterised. Some indications of the mechanism of cyclotrimerisation were furnished by experiments aimed at determining the relative rates of dimerisation. The results gave useful indications of how to achieve highly effective syn‐cyclotrimerisation reactions. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Synthesis, structure, and greatly improved reversible O2 binding in a structurally modulated micro-eta 2:eta 2-peroxodicopper(II) complex with room-temperature stability.

Facile O2 release from an oxyhemocyanin model has been achieved for the first time, with the new room-temperature-stable μ-η2:η2-peroxodicopper complex [Cu2O2(L2)]2+ (1). X-ray structural and spectroscopic studies on 1 show that elongation of the CuO bonds, induced by the bridgehead methyl groups of L2, is responsible for the ease of O2 release. CO/O2 binding by 1, monitored by UV/Vis spectroscopy (see picture), is completely reversible.

Comprehensive study of the methyl effect on the solvolysis rates of bridgehead derivatives.

The effect of a bridgehead methyl group on the hydride ion affinity in the gas phase of bicyclo[1.1.1]pent-1-yl (1+), 1-norbornyl (3+), cubyl (5+), 1-adamantyl (7+), bicyclo[2.2.2]oct-1-yl (9+),and bicyclo[3.1.1]hept-1-yl (11+) cations has been studied using density functional theory and ab initio methods. It is concluded that the methyl group always increases the stability of the substituted cations. The effect of the solvent on the stability of methyl-substituted cations in relation to the unsubstituted cations has been studied using the polarizable continuum model of the self-consistent reaction field theory. In the case of rearranging cations, the nucleophilic assistance of the solvent is determined by means of the interaction energy of the corresponding water complexes. It is concluded that the solvent causes the relative stabilization of the parent cations. As a consequence, most of the methyl-substituted bridgehead derivatives show a lower solvolysis rate than the corresponding unsubstituted compounds. A nonqualitative explanation of the methyl effect on the relative stability of bridgehead cations in both gas phase and solution is given for the first time. The ratios of solvolysis products in the case of rearranging bridgehead cations have also been computed from the relative stability of the intermediate water complexes.

Twisted Amides: Synthesis and Structure of 1,6-Dipivaloyl-3,4,7,8- tetramethyl-2,5-dithioglycoluril

[structure: see text] The 1,6-dipivaloyl derivative of 3,4,7,8-tetramethyl-2,5-dithioglycoluril (6) was prepared and the crystal structure determined by X-ray diffraction; 6 is a twisted amide in which severe ring strain and nonbonded interactions compel both pivaloyl groups to twist dramatically out of the ring plane. The amide oxygen atoms point in opposite directions with respect to the mean plane through the glycoluril core, and the bridgehead methyl groups are forced out of the symmetric syn geometry (eta = 30.5 degrees ). The structure of 7, a rearrangement product generated during synthesis of 6, was also determined by single-crystal X-ray diffraction.

Total Synthesis of 9-Isocyanoneopupukeanane.

Sponges elaborate the largest number of bioactive marine natural products, which often possess fascinating structures of great varieties. Our involvement in this area of chemistry has resulted in the synthesis of curcuphenol and curcudiol,1 (-)-furodysin,2 (-)-furodysinin,3 the enantiomer of herbasolide,4 and tavacpallescensin.5 More recently, efforts in attaining the isocyanopupukeananes also bore fruit;6 we now describe our approach to 9-isocyanoneopupukeanane (1), which is a constituent of a Ciocalypta sp.7 Besides the syntheses of 2-isocyanopupukeanane (2a, Chart 1)8 and 9-isocyanopupukeanane (2b),9,10 formal syntheses of the latter that terminated at 9-pupukeanone11-13 have also been reported. On the other hand, we are not aware of 1, which possesses a rearranged skeleton, having been yielded to synthesis. This work stemmed from our general interest in synthesis design related to molecular symmetry.14 In a retrosynthetic analysis of isocyanoneopupukeanane, the disconnection of the isopropyl group and functional group interchange at the isocyano-substituted center led to the symmetrical ketone 10. Further tracking indicated the tricyclic olefin 8, and the cyclohexadiene 7 to be useful synthetic precursors. To secure these compounds, we started from 3, which is readily available15 from a reaction sequence consisting of Birch reduction of p-cresyl methyl ether, Diels-Alder reaction with methyl acrylate (after in situ conjugation), and Grignard reaction with MeMgCl. Treatment of 3 with HClO4 led to enone 4 (63%), which was epoxidized at the side chain with hydrogen peroxide-urea in acetic anhydride to give 5 in 70% yield (75% by using m-CPBA). Reduction of the epoxy enone with lithium aluminum hydride afforded the diol 6a (62%, inseparable diastereomers), which was acetylated (Ac2O, py, DMAP) to provide diacetate 6b (92%, inseparable diastereomers). Pyrolysis of 6b in a sealed tube at 450 °C for 1 h furnished directly the desired tricyclic olefin 8 (54%), indicating the generation of 7 as an intermediate. With the acquisition of 8 the functionalization of its double bond was in order. We expected that hydroboration-oxidation would give rise to 9 predominantly because the formation of the regioisomeric alcohol 9a is less favorable due to steric hindrance from the bridgehead methyl substituents. Indeed, a separable mixture was produced in 52% and 10% yield, respectively. By PCC oxidation of the major alcohol 9 to afford ketone 10 (85%) the work entered its last stage. Thus, after exposure of 10 to i-PrMgBr/CeCl3 (91%) and then Me3SiCN/H2SO4, the formamide 12 was obtained in 42.5% yield. Completion of our synthesis was attained by subjecting 12 to TsCl-py at room temperature. 9-Isocyanoneopupukeanane was isolated in 83% yield. The final product showed spectral data in good agreement with the reported values. In conclusion, this report delineates the first total synthesis of isocyanoneopupukeanane. It is interesting that we did not isolate the dimethyltwistene isomer from the pyrolysate of 6b.

Article

The crystal structure of 3,4,7,8-tetramethylglycoluril (5) was determined by X-ray diffraction. The structure reveals a hydrogen-bonding motif in the crystal lattice that differs from that present in related glycolurils. The two sides of each molecule form part of two independent, but parallel, infinite helical chains. These chains are formed by the NH donor and C==O acceptor on one side of a glycoluril molecule, forming H-bonds to two different molecules at adjacent positions within the helix. On the other side of the same molecule, a similar motif generates another helix of opposite helicity to the first. The molecule has a crystallographic plane of symmetry through the two bridgehead carbon atoms and the two bridgehead methyl groups, which are syn-periplanar. Thus, 5 is similar to 3,4-dimethylglycoluril (3), but differs from some glycolurils, where there is a significant dihedral angle between the two bridgehead-to-bridgehead substituent bonds. Bond lengths and angles in 5 resemble those reported for 3, but bond lengths around the bridgehead positions are slightly lengthened relative to 3.Key words: glycoluril, 1,2,5,8-tetramethyl-2,6,7,8-tetraazabicyclo[3.3.0]octane-3,7-dione, X-ray diffraction, crystal structure, hydrogen-bond array.

The crystal structure of 3,4,7,8-tetramethylglycoluril

The crystal structure of 3,4,7,8-tetramethylglycoluril (5) was determined by X-ray diffraction. The structure reveals a hydrogen-bonding motif in the crystal lattice that differs from that present in related glycolurils. The two sides of each molecule form part of two independent, but parallel, infinite helical chains. These chains are formed by the NH donor and CTO acceptor on one side of a glycoluril molecule, forming H-bonds to two different molecules at adjacent positions within the helix. On the other side of the same molecule, a similar motif generates another helix of opposite helicity to the first. The molecule has a crystallographic plane of symmetry through the two bridgehead carbon atoms and the two bridgehead methyl groups, which are syn-periplanar. Thus, 5 is similar to 3,4-dimethylglycoluril (3), but differs from some glycolurils, where there is a significant dihedral angle between the two bridgehead-to-bridgehead substituent bonds. Bond lengths and angles in 5 resemble those reported for 3, but bond lengths around the bridgehead positions are slightly lengthened relative to 3.

ChemInform Abstract: Radical Induced Cyclopropane Fragmentation‐H‐Abstraction‐Cyclization Cascade: Synthesis of Carbocyclic Systems Containing Bridgehead Methyl Groups.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Radical Induced Cyclopropane Fragmentation—H-Abstraction—Cyclization Cascade: Synthesis of Carbocyclic Systems Containing Bridgehead Methyl Groups

The intramolecular hydrogen abstraction by an alkyl radical has been exploited for the first time in a synthetically useful tandem sequence that gives rise to cis-fused bicyclic systems carrying bridgehead methyl groups, a structural feature found in numerous natural products. © 1997 Elsevier Science Ltd.

Theoretical Insights Regarding the Cycloaddition Behavior of Push-Pull Stabilized Carbonyl Ylides.

A series of diazoamido keto esters were prepared by the reaction of N-substituted 3-carbethoxy-2-piperidone with n-butylmagnesium chloride followed by the addition of ethyl 2-diazomalonyl chloride. Treatment of these diazo amides with rhodium(II) acetate afforded transient push-pull carbonyl ylide dipoles which could be readily trapped with electron deficient dipolarophiles. All attempts to induce the dipolar cycloaddition to occur across tethered alkenyl pi-bonds failed to give internal cycloadducts. However, placing a sp(2) center on the tethered side chain was found to result in the formation of a tricyclic adduct in 95% yield. The stereochemistry of the cycloadduct was firmly established by an X-ray crystallographic study and occurred endo with respect to the amido carbonyl ylide dipole. A detailed computational study was undertaken to provide better insight into the factors that influence the intramolecular cycloaddition process. The calculations indicate that a severe cross-ring 1,3-diaxial interaction caused by the bridgehead methyl group promotes a boat or twist-boat conformation in the piperidine ring fused to the newly forming one. The presence of a carbonyl group in the dipolarophile tether helps to relieve the steric congestion by virtue of favoring a second boat in the latter ring. Without the C=O group, both nascent and piperidine rings are in the chair conformation at lowest energy, and the reaction barrier is disadvantaged by 5.6 kcal/mol, allowing other competing processes to intervene.