B. Macchia

New methods for the preparation of 1-phenyl-trans-cyclohexane-1,2-diol

Abstract In contrast with previous reports, it was found that the reaction of 1-phenylcyclohexene with peroxyformic acid is not entirely stereospecific, but gives some trans -1-phenylcyclohexane-1, 2-diol (IV) beside the cis -isomer (III). The reaction of 1-phenylcyclohexene oxide (II) with formic acid yielded a similar mixture of III and IV, while addition of trichloroacetic acid in benzene was entirely cis -stereospecific. Reaction of the epoxide II with potassium hydroxide took place only under very drastic conditions to give a small yield of III, while sodium 2-dimethylaminoethoxide added exclusively in a trans way, leading to the amino ether X, which was easily transformed into the trans -glycol IV. The latter compound was also the main product of the borohydride reduction of 2-hydroxy-2-phenylcyclohexanone (IX). Possible explanations of the observed stereochemical results are discussed.

Preparation and stereochemical characterization of the diastereoisomeric 1-phenyl-4-t-butylcyclohexene oxides and 1-phenyl-4-t-butylcyclohexane-1,2-diols

Abstract The cis and trans forms of 1-phenyl-4-t-butylcyclohexene oxide were prepared and their conversion into the corresponding glycols was investigated. Several methods, some of which highly stereospecific, were found for the preparation of all four possible diastereoisomeric glycols 5-8, as shown in Chart I. Dimethyl sulphoxide proved to be a good solvent for the diaxial cleavage of epoxides by alkali, while hydrolysis in the same solvent under acidic conditions led to the diaxial glycol 7 from the trans epoxide 3, and to the diequatorial one 8 from the cis expoxide 2. Relative configurations of all exposides and glycols were deduced from their methods of preparation, their reactions and NMR spectra.

3-(4-iodomethyl-2-oxo-1-azetidinyl)propynoic acidt-butyl ester: a new β-lactam derivative, synthesis of an ynamide by reaction of 4-iodomethylazetidin-2-one with the t-butyl ester of propiolic acid in the presence of copper(i)

Abstract The reaction of 4-iodomethylazetidin-2-one (2) with the t-butyl ester of propiolic acid (4) in the presence both of equimolar amounts of copper(I) and oxygen results unexpectedly in the fomation of the β-lactam ynamide 5. Its structure was suggested by spectroscopic data and confirmed by single-crystal X-ray analysis.

Synthesis and antimicrobial properties of substituted 3-aminoxy-(E)-2-methoxyiminopropionyl penicillins and cephalosporins☆

Abstract The 3-aminoxy-( E )-2-methoxyiminopropionyl penicillins 13 and cephalosporins 14 and 15 were synthesized and assayed for their antimicrobial activity on Gram-positive and Gram-negative bacteria whether producers of β-lactamases or otherwise. Compounds 13 , 14 , and 15 exhibited an activity which was generally lower than that of the corresponding phenylacetyl derivative: penicillin G ( 4 ), cephaloram ( 5 ), and phenylacetamidodesacetoxycephalosporanic acid ( 6 ). Furthermore, the comparison of the minimum inhibitory concentration values of some of the new 2-methoxyimino 3-aminoxypropionyl derivatives 13–15 with those of the corresponding ones 1–3 lacking the 2-methoxyimino substituent showed that the introduction of the 2-methoxyimino group of E configuration on the aminoxypropionamido side chain of 1–3 gives compounds ( 13–15 ) which do not generally possess better antimicrobial properties.

Stereochemistry of the ring opening of some stilbazole oxides

Abstract The trans and cis forms of 3- and 4-stillbazole oxide and trans -2-( p -methoxystyryl)pyridine oxide have been prepared from the corresponding stilbazoles, by addition of HClO and HBrO, followed by dehydrohalogenation of the halohydrins with base. The configurations of the epoxides have been confirmed by their NMR spectra. The stereochemistry of the ring opening of the above mentioned compounds with HCl, HBr and CCl 3 COOH has been investigated and compared with that of the similar reactions of the stilbene oxides, very pronounced differences in steric course being observed. The reactions of the stilbazole oxides with the hydrogen halides take place with complete inversion, those with CCl 3 COOH with decreasing degrees of inversion in going from the 2- to the 3- and to the 4-pyridyl derivatives.

Stereochemistry of some derivatives of phenylcyclohexane

Abstract 1-Phenylcyclohexene oxide (I) reacted with hydrogen chloride in chloroform to give only 2-phenyl- cis -2-chlorocyclohexanol (V), while in ethanol a mixture of V and its trans diastereoisomer (IV) were formed. The two diastereoisomeric 1-phenylcyclohexane-1,2-diols were transformed by hydrogen chloride in chloroform into IV and V, with entirely stereospecific reactions involving retention. IV and V were oxidized to 2-chloro-2-phenylcyclohexanone (VI); the compound described in the literature and reported to have the latter constitution was found to be instead cis -2-chloro-6-phenylcyclohexanone (XII). It was transformed, through trans -3-phenyl-1,2-epoxycyclohexane (XV) and the corresponding glycols, into 2-phenyladipic acid. The stereochemistry and the possible mechanisms of the reactions are discussed.

Conformationally restrained β-blocking oxime ethers: synthesis and β-adrenergic properties of diastereoisomeric anti and syn 2-(5'-isoxazolidinyl)-ethanolamines

Abstract The diastereoisomeric N -isopropyl- and N-t -butyl-substituted 2-(5′-(3′-phenyl)- and 2-(5′-(3′-isopropyl)isoxazolidinyl)-ethanolamines ( 5–8 ), which can be viewed as conformationally restrained analogs of the corresponding β-blocking oxime ethers 10 and 11 , were synthesized. The relative configurations of 5–8 were assigned by 1 H-NMR studies and by the determination of the solid-state structure of one of the new compounds ( 6a ). The new isoxazoline derivatives ( 5–8 ) were tested both by radioligand binding assays and by functional tests on isolated preparations. Compounds 5a–8a were found to retain, albeit to a lower extent, the β-blocking properties of the corresponding oxime ethers 10a and 11a , thus indicating that these last compounds may prove to be still capable of interacting with the β-receptors, even if their C = NOCH 2 portion is constrained in a conformationally semi-rigid isoxazoline structure. Possible rationalizations of the results were sought by comparing the conformations and the molecular reactivity of model compounds of the isoxazolines 5–8 and of the oxime ethers 10 and 11 .

(E)-[2-(4-Methylsulphonylphenyl)-1-cyclopentenyl-1-methyliden](arylmethyloxy)amines. Methyleneaminoxymethyl (MAOM) analogues of diarylcyclopentenyl cyclooxygenase-2 inhibitors: synthesis and biological properties.

The (E)-[2-(4-Methylsulphonylphenyl)-1-cyclopentenyl-1-methyliden](methyloxy)amine (5) and (arylmethyloxy)amines (6-12) were designed in order to verify the effects on the biological properties of the substitution of an aryl of selective diarylcyclopentenyl cyclooxygenase-2 (COX-2) inhibitors of type 3 with a methyleneaminoxymethyl moiety (MAOMM). Compounds 5-12 were tested in vitro for their inhibitory activity towards COX-1 and COX-2 by measuring prostaglandin E2 (PGE2) production in U937 cell lines and activated J774.2 macrophages, respectively. The compound with the highest in vitro activity towards COX-2 (9) was also assayed in vivo for its antiinflammatory activity by means of the carrageenan-induced paw edema test in rats. Some of the new compounds showed an appreciable in vitro COX-2 inhibitory activity, with IC(50) values in the microM (6,7,9,10,11) range. Compound 9 also exhibited an appreciable in vivo activity (29% inhibition at a dose of 30 mg kg(-1)) when administered intraperitoneally. The structural parameters of 9 were determined by X-ray crystallographic analysis.

Steric inhibition of resonance and regio- and stereoselectivity in the ring opening of 1-arylsubstituted epoxides : Reactions of 1-phenyl-2,2-dimethyl-7-oxabicyclo[4.1.0]heptane under acidic conditions

Abstract The results of the ring opening of 1-phenyl-2,2-dimethyl-7-oxabicyclo[4.1.0]heptane (2) under acidic conditions show a marked diminution in the regioselectivity and in the cis stereoselectivity with respect to the corresponding non-methylated epoxide. The percentage composition of the reaction products of epoxide 2 varies significantly with the solvent medium employed. Possible explanations of the observed stereochemical results, particularly with respect to the steric inhibition of resonance of the intermediate carbocation and to the solvent effects, are discussed.

Stereochemistry of the conversion of the diastereoisomeric epoxides and glycols derived from 1-phenyl-4-t-butylcyclohexene into chlorohydrins

Abstract The rates and steric courses of the title reactions depend very much on the configuration of the substrate and type of solvent. The reactions of the two epoxides and of the diols having equatorial α-hydroxyl with HCl in dry CHCl 3 involve almost complete retention of configuration, while the presence of water or the use of 2-propanol as solvent considerably diminish the stereospecificity. The rate and stereospecificity of the reaction of the trans -diaxial diol are much lower, while the cis -diol with axial α-hydroxyl is completely unreactive. Mechanistic interpretations for these data are discussed.