Exo Compound Research Articles

Synthesis and Leishmanicidal Evaluation of Novel 4-Substituted-2,2-Dimethyl-7-(prop-2-ynyloxy)Chromenes

Substituted 4-chromenes were synthesized via the Grignard coupling reaction of various substituted phenyl- and benzylmagnesium chlorides with 2,2-dimethyl-7-(prop-2-ynyloxy)chroman-4-one (1) in relatively good yield (60%-85%). The benzylic-substituted derivatives were a mixture of 2 exo and endo regioisomers, and the exo compounds were a mixture of E and Z isomers. Structural analysis of the exo and endo isomers, as well as E and Z of exo isomers were based on H-NMR, ^{13}C-NMR, and NOESY experiments. The synthetic compounds were examined for in vitro activity against Leishmania major and compound 9 (a, b) was the most active, with inhibitory activity of 36%.

Unsubstituted Bicyclo[1.1.0]but-2-ylcarbinyl Cations

A synthesis for the unsubstituted bicyclo[1.1.0]but-2-ylmethanols (endo- and exo-9) from 1,3-butadiene has been developed. Solvolyses of their sulfonates 10 and 11 took entirely different courses, as the endo compound 10 gave rise exclusively to rearranged products such as cyclopent-3-en-1-ol (14), while the exo compound 11 underwent only the substitution of the tosylate group with complete retention of the exo-bicyclo[1.1.0]but-2-ylmethyl skeleton. Under solvolytic conditions, 10 reacted at very similar rates to the corresponding monocyclic substrate, that is, cyclopropylcarbinyl mesylate (19); in contrast, 11 reacted only three times as fast as n-butyl tosylate and about 1000-fold slower than 10. The nature of the bicyclo[1.1.0]but-2-ylcarbinyl cations has been probed by quantum chemical calculations. Whereas, the exo isomer (exo-18) corresponds to a local energy minimum, the endo isomer is only a transition state [endo-18(TS)] for an automerization of the nonclassical cyclopent-3-en-1-yl cation (13) and converts into 13 by a Wagner-Meerwein rearrangement. The most favorable isomerization of exo-18 also leads to 13 but via a transition state resembling the 2-vinylcycloprop-1-yl cation [25(TS)]. On the introduction of methyl groups at positions 1 and 3 of exo-18, the cation is no longer an energy minimum and it becomes a transition state [27(TS)] for an automerization of the nonclassical 1,3-dimethylcyclopent-3-en-1-yl cation (28). The large effect of the methyl substitution rationalizes the puzzling results of the previous product and rate studies, which utilized various substituted derivatives of bicyclo[1.1.0]but-2-ylcarbinyl sulfonates as substrates.

Synthesis of Enantiopure 9‐Oxabicyclononanediol Derivatives by Lipase‐Catalyzed Transformations and Determination of Their Absolute Configuration

AbstractMixtures of endo,endo‐9‐oxabicyclo[4.2.1]nonane‐2,5‐diol (meso‐2) and endo,endo‐9‐oxabicyclo[3.3.1]nonane‐2,6‐diol [(±)‐3] were prepared from cycloocta‐1,5‐diene (1) upon treatment with peracids by transannular O‐heterocyclization and subsequent saponification of the formed diol monoesters such as (±)‐4 and (±)‐5. The corresponding diacetates, meso‐6 and (±)‐7, were formed by acetylation of either meso‐2 and (±)‐3 or (±)‐4 and (±)‐5 with acetic anhydride/pyridine. These diacetates were enantioselectively hydrolyzed by microbial enzymes such as the lipases from Candida antarctica (CAL) or Candida rugosa (CRL). The corresponding enantiomers were formed by lipase‐catalyzed acetylation of the diols meso‐2 and (±)‐3 with vinyl acetate. The skeletal isomers can also be separated in this way because the enantiopure monoacetates 4 were formed from the meso‐compounds 2 or 6, while one enantiomer of the racemic diacetate (±)‐7 [or the diol (±)‐3] was transformed into the enantiopure diol 3 (or the enantiopure diacetate 7, respectively) via the corresponding enantiomers of the monoacetate 5. The other enantiomer remained untouched in both cases. The lipases reacted enantioselectively to give the R isomer. Cycloocta‐1,5‐diene (1) was also used to synthesize 2‐oxa‐6‐thiatricyclo[3.3.1.13,7]decane‐4,8‐diol [(±)‐11] in a four‐step sequence. This racemic diol was also acetylated selectively (R isomer) with vinyl acetate and CRL. Reductive desulfuration of (±)‐11 gave exo,exo‐9‐oxabicyclo[3.3.1]nonane‐2,6‐diol [(±)‐12], which was acetylated selectively (S isomer) with CRL under the same conditions. The similarity in size and particularly in shape is responsible for the observed stereoselectivity of the lipases for the racemic endo,endo compounds (±)‐3 and (±)‐7 on the one hand and the exo,exo compound (±)‐12 on the other hand. The absolute configuration and crystal packing of the products was determined by X‐ray structural analysis. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

IR Study of p–π Conjugation in 2-Substituted 4-Methylene-1,3-dioxolanes and 4-Methyl-1,3-dioxoles

Selected group frequencies of the IR spectra of a number of 2-substituted 4-methylene-1,3-dioxolanes (a) and their endocyclic isomers, 2-substituted 4-methyl-1,3-dioxoles (b), have been studied to establish their usefulness as a measure of the strength of p–π conjugation in the O—C=C moieties of the title compounds. In the exo compounds (a), the C=C stretching frequencies νC=C and the in-phase, out-of-plane bending (wagging) frequencies δCH2 w of the =CH2 group were found to be linearly related, besides to each other, also to the electron-donating character of the substituents and the 13C NMR chemical shift of the C atom of the exocyclic CH2 group. This suggests that the two IR group frequencies of the exo isomers are linearly related to the strength of p–π conjugation in the O—C=C moiety. The C=C stretching absorption of the exo compounds in the 1600–1700 cm−1 region appeared as a doublet, shown to arise from Fermi resonance of the νC=C fundamental with the δCH2 w overtone. The νC=C frequencies of the endo compounds support some previous findings of an unexpected strength of p–π conjugation in the 2-alkoxy derivatives. Finally, DFT calculations at the B3LYP/6-31G* level of theory are shown to give accurate predictions of the effect of 2-substituents on the group frequencies.

Synthesis and pharmacology of site-specific cocaine abuse treatment agents: 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane dopamine uptake inhibitors.

As part of a program to develop site-specific medications for cocaine abuse, a series of 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Selected compounds were tested for their ability to substitute for cocaine in rat drug discrimination tests. Synthesis was accomplished by a series of Diels-Alder reactions, using cis- and trans-cinnamic acid derivatives (nitrile, acid, acid chloride) with cyclohexadiene and cyclopentadiene. Standard manipulations produced the aminomethyl side chain. Many of the compounds bound with high affinity (median IC50 = 223 nM) to the cocaine binding site as marked by [3H]WIN 35,428. Potency in the binding assay was strongly enhanced by chlorine atoms in the 3- and/or 4-position on the aromatic ring and was little affected by corresponding methoxy groups. In the [2.2.2] series there was little difference in potency between cis and trans compounds or between N, N-dimethylamines and primary amines. In the [2.2.1] series the trans exo compounds tended to be least potent against binding, whereas the cis exo compounds were the most potent (4-Cl cis exo: IC50 = 7.7 nM, 27-fold more potent than 4-Cl trans-exo). Although the potencies of the bicyclic derivatives in the binding and uptake assays were highly correlated, some of the compounds were 5-7-fold less potent at inhibiting [3H]dopamine uptake than [3H]WIN 35,428 binding (for comparison, cocaine has a lower discrimination ratio (DR) of 2.5). The DR values were higher for almost all primary amines and for the trans-[2.2.2] series as compared to the cis-[2.2.2]. Most of the compounds had Hill coefficients approaching unity, except for the [2. 2.2] 3,4-dichloro derivatives, which all had nH values of about 2.0. Two of the compounds were shown to fully substitute for cocaine in drug discrimination tests in rats, and one had a very long duration of action.

Diastereoselective synthesis of 3,6-dihydro-2 H-1,3,4-thiadiazines

Thionation of the benzil hydrazones 3 with Lawesson's reagent afforded the 3,6-dihydro-2 H-1,3,4-thiadiazines 4 by an intramolecular cyclisation. This reaction was shown to be diastereospecific and allowed the formation of the exo compounds 4b– e. When the homochiral SAMP–hydrazone 3f was used, the reaction afforded enantiomerically pure (4 R,6 R,9 S)- 4f.

Variable-Temperature and -Pressure Kinetics and Mechanism of the Cyclopalladation Reaction of Imines in Aprotic Solvent

The cyclometalation reactions of benzylidenebenzylamines, -anilines, and -propylamine with palladium acetate have been studied in toluene solution. The cyclometalated compounds are formed via C−H electrophilic bond activation to produce different types of metallacycles, depending upon the polyfunctional nature of the ligand selected. If a five-membered endo metallacycle is possible, it is formed via aromatic C−H bond activation. Formation of a five-membered exo metallacycle only takes place when endo cyclometalation requires the formation of a six-membered compound via aliphatic C−H bond activation or when the steric hindrance affects the planarity of the imine in an important way. The activation of aliphatic C−H bonds has been achieved for endo six-membered metallacycles only when the alternative aromatic C−H bond activation would produce a four-membered exo compound; no activation of aliphatic C−H bonds to form exo five-membered complexes has been observed. The reactions have been monitored kinetically at different temperatures and pressures in order to establish the mechanism through which these spontaneous reactions occur. Three different sets of activation parameters are apparent from the results obtained: those related to the benzylamines and propylamine (ΔH⧧ = +45/+67 kJ mol-1, ΔS⧧ = −100/−180 J K-1 mol-1, ΔV⧧ = −11/−17 cm3 mol-1), those related to the aniline derivatives (ΔH⧧ = +66/+75 kJ mol-1, ΔS⧧ = −96/−123 J K-1 mol-1, ΔV⧧ = −21/−25 cm3 mol-1), and finally those related to the imines producing aliphatic bond activation (ΔH⧧ = +48/+49 kJ mol-1, ΔS⧧ = −167/−177 J K-1 mol-1, ΔV⧧ = −20/−24 cm3 mol-1). The results are interpreted as the formation of a highly ordered four-center transition state, involving the C−H and Pd−O(acetato) bonds, which is found to be very sensitive to the flexibility and steric hindrance of the imine ligands and very insensitive to electronic changes of the C−H bonds.

Fluorinated acetylenes. Part 15. The reaction of ethyl 4,4,4-trifluorobut-2-ynoate with dienes and cycloheptatriene

Thermal reaction of the acetylenic ester CF 3CCCO 2Et ( 1) with cyclopentadiene ( 4), buta-1,3-diene ( 5) and 1,4-diphenylbuta-1,3-diene ( 6) gave the corresponding Diels-Alder 1:1 cycloadducts 10, 11 and 12, respectively in high yield (73%–97%). With norbornadiene ( 7), the homo Diels-Alder adduct ( 13) was formed. The reaction with 3-carboethoxyfuran gave a mixture (55%) of the isomeric Diels-Alder 1:1 adducts 14 and 15 (ratio 55:45), together with four 2:1 adducts, i.e., the exo,endo compounds 16a (10%) and 16b (9%) and the exo,exo compounds 17a (8%) and 17b (9%), resulting from Diels-Alder cycloaddition of the furan to the least substituted double bond in the 1:1 adducts 14 and 15. The cycloadditions to the 1:1 adducts were regioselective with the two CO 2Et groups on the unsaturated bonds involved in the cycloadditions being 1,4 to each other in the 2:1 adducts. The products from reaction of ester 1 with cycloheptatriene ( 9) were formed via two competing reaction paths; (a) cycloaddition of ester 1 to norcaradiene ( 23) which gave the Diels-Alder adduct 18 (74%) and (b) an initial regioselective ‘ene’ reaction followed by isomerisation of the resulting 1:1 adduct 24 to the corresponding norcaradiene 25, which then underwent both rearrangement to afford 1:1 adduct 19 (15%) and Diels-Alder cycloaddition with ester 1 to give the 2:1 adduct 20 (6%).

Synthesis of Thioaldehydes Having Optically Active Alkoxy Moiety and Their Asymmetric Hetero Diels-Alder Reaction

Optically active α-alkoxycarbonylthioaldehydes (2a-g) were prepared using 8-arylmenthols as chiral auxiliaries. Their asymmetric hetero Diels-Alder reactions with cyclopentadiene gave the endo cycloadducts (3 and 4) and exo cycloadducts (5 and 6) with moderate diastereomeric excesses. However, the major endo cycloadducts (3b-g) were isolated in optically pure form. This is the first chiral synthesis of 2-thiabicyclo[2.2.1]hept-5-ene ring system. The absolute configuration of the cyclic carbonate (12), which was prepared from the major endo cycloadduct (3c) via the epimerization, or the minor exo compound (6c), was determined as 1R by X-ray analysis. The cycloadduct (3c) was transformed to a potential intermediate (14) for the synthesis of carbocyclic homonucleosides

14C-labeling of a novel anxiolytic agent tandospirone

N-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]bicyclo-[2.2.1]heptane-2,3-di-exo-carboxyimide dihydrogen citrate (tandospirone), a novel anxiolytic agent, was labeled with carbon-14 individually at the imido carbonyl group and the pyrimidinyl ring. The synthesis of carbonyl-labeled tandospirone was achieved according to the scheme shown in Fig. 3. Diels-Alder reaction of maleic anhydride (2) with cyclopentadiene (3) afforded the endo anhydride (4), which was transformed into the imide (5) by treating with ammonia water. Thermal isomerization of the endo imide (5) and subsequent chromatographic separation gave the pure exo compound (6). Catalytic hydrogenation of 6 followed by alkylation with 1,4-dibromobutane (8) yielded the bromide (9a). Condensation of 9a with N-(2-pyrimidinyl)piperazine (10a) followed by treatment of the resulting disubstituted piperazine (11a) with citric acid afforded [carbonyl-14C]tandospirone (1a). The overall yield of 1a was 22% from 2. The similar method was applied to the synthesis of pyrimidinyl-labeled tandospirone as shown in Fig. 4. Condensation of 2-chloro[2-14C]pyrimidine (12) with anhydrous piperazine gave the pyrimidinylpiperazine (10b). N-alkylation of 10b followed by treatment with citric acid afforded [pyrimidinyl-2-14C]tandospirone (1b). The overall yield of 1b was 68% from 12.

On the stereoselectivity of iodocarbene and -carbenoid additions to cyclic alkenes

Exclusive formation of endo adducts 3d–f, 9, 10, 11 is observed in both carbene and carbenoid CHI additions with eight to twelve membered-ring alkenes. Cyclopentene, in contrast, gives exo compound 4a as only isolable product, whereas cyclohexene and cycloheptene yield both types of product. :CHBr (from HCBr 3 and NaN(SiMe 3) 2) exhibits similar although less pronounced trends: only cyclodecene and cyclododecene lead to pure endo adducts 7e,f..

Synthesis and conformational analysis of exo-and endo-7-substituted-3-azabicyclo[3.3.1]nonanes

The synthesis of some 7-substituted-3-azabicyclo[3.3.1]nonanes is described. Routes followed were the debenzoylation of the 7-benzoyl derivative 7 and the decarboxylation of the 7-carboxy compounds 21 and 27. The so-obtained 7-oxo-N-tosyl-3-azabicyclo[3.3.1]nonanes 8and 11 show an extremely low reactivity towards a series of nucleophilic reagents. From analysis of the 1H NMR spectral data of a series of derivatives, the twin-chain conformation for the 7- exo compounds and the chair-boat conformation for the 7- endo compounds is indicated.

Chemical ionization mass spectra of some 2‐norbornyl derivatives

AbstractChemical ionization mass spectra of exo‐ and endo‐2‐norbornanols and their phenylurethane derivatives have been obtained with several reactant ions. Small differences are noted in the abundances of norbornyl and [M+H]+ ions for the phenylurethane derivatives: more norbornyl ions with the exo compounds. Relative rate constants for decomposition of [M+H]+ ions, kexo/kendo ≅ 1‐2. No evidence was found for s̀‐participation in the decomposition of these ions. The i‐C4H10 chemical ionization spectrum of endo‐2‐norbornanol contains a much greater abundance of [M‐H]+ ions than the i‐C4H10 chemical ionization spectrum of exo‐2‐norbornanol. This difference presumably results from steric hindrance toward attack of the endo hydrogen.