Diastereoisomeric Pairs Research Articles

Photolabile precursors of inositol phosphates. Preparation and properties of 1-(2-nitrophenyl)ethyl esters of myo-inositol 1,4,5-trisphosphate.

1-(2-Nitrophenyl)ethyl esters of D-myo-inositol 1,4,5-trisphosphate (InsP3) have been synthesized and shown to have suitable properties for use as photolabile precursors of InsP3. Synthesis was accomplished by treatment of InsP3 with 1-(2-nitrophenyl)diazoethane in a CHCl3/water mixture. This resulted in esterification of each of the three phosphate residues in InsP3, the 1-phosphate being more reactive than the 4- or 5-phosphate. Singly esterified P-1, P-4, and P-5 esters, termed P-1, P-4, and P-5 caged InsP3, were isolated from the reaction mixture by anion-exchange HPLC and characterized by 500-MHz 1H NMR spectroscopy. Each of these caged InsP3 esters exists as a pair of diastereoisomers and was identified by examining the effects of pH and nitrophenyl ring current shielding on the chemical shifts of nonexchangeable inositol protons. 1H NMR spectra of InsP3 were analyzed for comparison. On photolysis the compounds released InsP3 with rate constants of 175 (P-1), 225 (P-4), and 280 s-1 (P-5) as determined by monitoring the aci-nitro decay reaction at pH 7.1, 0.2 M ionic strength, 21 degrees C. Quantum yields determined by steady-state near-UV photolysis were 0.65 +/- 0.08 for each compound. P-4 and P-5 caged InsP3 were the most promising biologically inactive InsP3 precursors since at concentrations up to 50 microM they did not release Ca2+ from smooth muscle sarcoplasmic reticulum (SR) and were not metabolized by vascular smooth muscle InsP3 5-phosphatase or bovine brain InsP3 3-kinase.(ABSTRACT TRUNCATED AT 250 WORDS)

Konkurrenz von Endoperoxid‐ und Hydroperoxid‐Bildung bei der Umsetzung von Singulett‐Sauerstoff mit cyclischen, konjugierten Dienen. Teil I

Competition of Endoperoxide and Hydroperoxide Formation in the Reaction of Singlet Oxygen with Cyclic, Conjugated DienesRose‐bengal‐sensitized photooxygenation of (−)‐(R)‐α‐phellandrene (1) in MeOH at room temperature yielded a complex mixture of products, contrary to previous reports describing cis‐(3S, 6R)‐epidioxy‐p‐menthene (2) and trans‐(3R, 6S)‐epidioxy‐p‐menthene (3) as the only products. The mixture was separated by prep. HPLC (silica gel, pentane/Et2O 9:1). Besides the known endoperoxides 2 (yield 39%) and 3 (26%), all those hydroper‐oxides, which can be deduced from an ene reaction of 1O2 with 1, were isolated, i.e. 4β‐p‐mentha‐2,5‐dien‐1β‐yl hydroperoxide (4) (14%), 4β‐p‐mentha‐2,5‐dien‐1α‐yl hydroperoxide (5) (9%), (2R, 4R)‐p‐mentha‐1(7), 5‐dien‐2‐yl hydroperoxide (6) (2,1%), (2S, 4R)‐p‐mentha‐1(7),5‐dien‐2‐yl hydroperoxide (7) (1,5%) and (1R)‐p‐mentha‐3,6‐dien‐yl hydroperoxide (8; 1,5%; Scheme 1). Furthermore, the constant cis/trans ratio for all diastereoisomeric pairs (2/2, 4/2, 6/2) was striking. With the help of the two possible conformers 1a and 1b of the starting material a model of a common first step for endoperoxide as well as for hydroperoxide formation is developed. A photooxygenation at −50° supports this model. The absolute value of the cis/trans ratio changes in the same way for the endoperoxides and the hydroperoxides.

Chemistry of novel compounds with multifunctional carbon structure. Part 4. Steric and electronic influences on the diastereoisomeric chemical shift differences in 19F n.m.r. spectra by introduction of fluorine, phenyl, and heteroatom groups into acetates

In order to develop reagents more efficient than MTPA for the determination of enantiomeric excess, several fluoroacetic esters (2b)–(7b) have been prepared which have various heteroatom-centred groups or bulky groups at the α position. These compounds have been converted into the corresponding s-butyl ester (8a)–(13a), α-phenylethyl ester (8b)–(13b), and α-phenylethylamide (8c)–(13c) diastereoisomers; the chemical shift differences between each pair of diastereoisomers (Δδ) have been obtained from the 1H and 19F n.m.r. spectra for each derivative. The influence on Δδ values of steric and possible electronic effects which arise upon introduction of a phenyl or a heteroatom group into the fluoroacetate structure are discussed.

Evaluation of the Binding to Fixed Platelets of Agonists and Antagonists of ADP-Induced Aggregation

Steady state binding of eleven different ADP analogues to formaldehyde-fixed platelets has been determined in a competitive binding assay using 3H-ADP. The compounds tested were the inactive analogues L-ADP and L-ATP; the agonists 2-chloroadenosine 5'-diphosphate, adenosine 5'-O-(2-thiodiphosphate) and the diasteroisomeric pair Sp-adenosine 5'-(1-thiodiphosphate) (Sp-ADP-alpha-S) and Rp-adenosine 5'-(1-thiodiphosphate) (Rp-ADP-alpha-S); and the antagonists adenosine 5'-O-thiomonophosphate, 2-chloroadenosine 5'-O-thiomonophosphate, 2-choloroadenosine 5'-triphosphate, and the diastereoisomeric pair 5'-(1-thiotriphosphate) (Sp-ATP-alpha-S) and RP-adenosine 5'-(1-thiotriphosphate) (Rp-ATP-alpha-S). All compounds tested competed at the high affinity binding sites for ADP previously identified (Blood 1988; 71: 110-6) but in some cases competition could not be demonstrated at the low affinity sites because of the high nucleotide concentrations required. As a group, C2-substituted analogues bound less strongly (Ki greater than 2 micro M) than did the analogues without substituents in the purine ring (Ki less than 0.7 microM). With the pair of diastereoisomeric agonists Sp-ADP-alpha-S and Rp-ADP-alpha-S the Ki values at the high affinity site (210 nM and 560 nM) were of the same relative magnitude and in the same direction as their reported potencies as agonists (Ki 4 microM and 20 microM). With the diastereoisomeric antagonists Sp-ATP-alpha-S and Rp-ATP-alpha-S a similar relationship was seen between affinity (17 nM and 156 nM) and inhibitory potency (Ki 4 microM and 20 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Isoxazolinyldioxepins. Part 1. Structure–reactivity studies of the hydrolysis of oxazolinyldioxepin derivatives

The preparation and acid catalysed hydrolysis of a number of isoxazolinyldioxepins is reported. Individual diastereoisomer pairs were isolated by column chromatography and shown to differ significantly in their hydrolytic stability at acidic pH. The crystal structures of one diastereoisomer pair reveal that conformational differences induce a selective stereoelectronic effect at the acetal centre of the more hydrolytically labile isomer, while the less labile isomer shows no such selectivity.

Isoxazolinyldioxepins. Part 1. Structure–reactivity studies of the hydrolysis of oxazolinyldioxepin derivatives

The preparation and acid catalysed hydrolysis of a number of isoxazolinyldioxepins is reported. Individual diastereoisomer pairs were isolated by column chromatography and shown to differ significantly in their hydrolytic stability at acidic pH. The crystal structures of one diastereoisomer pair reveal that conformational differences induce a selective stereoelectronic effect at the acetal centre of the more hydrolytically labile isomer, while the less labile isomer shows no such selectivity.

High-performance liquid chromatographic method for the simultaneous determination of the enantiomers of carvedilol and its O-desmethyl metabolite in human plasma after chiral derivatization

Quantitative methodology for the simultaneous high-performance liquid chromatographic (HPLC) resolution and determination of the enantiomers of carvedilol, a new multiple-action antihypertensive agent exhibiting both vasodilator and beta-blocking activity, and its active metabolite, O-desmethylcarvedilol, in human plasma is described. The method involves reversed-phase solid-phase extraction of the analytes, followed by derivatization of the extract with the chiral reagent, 2,3,4,6,-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate and injection of the resultant diastereoisomers onto a reversed-phase HPLC column coupled to a fluorescence detector. Both pairs of diastereoisomers formed are completely resolved within 12 min (resolution for the respective pairs is 2.26 and 3.32) and the baseline is clean and free from extraneous peaks. The assay is linear over the range 0.6-80 ng/ml of human plasma with a lower limit of detection of approximately 100 pg on-column for each of the enantiomers. The method can be adapted for a number of structural analogues of carvedilol and is currently applied in support of preclinical and clinical studies of the drug.

Stereochemical influences upon the opioid ligand activities of 4‐alkyl‐4‐arylpiperidine derivatives

The synthesis and stereochemistry (configuration and preferred solute conformation) of some 4-alkyl (methyl, n-propyl, isobutyl)-4-(3-hydroxy-phenyl)-1-methylpiperidines and corresponding 3-methyl diastereoisomeric pairs are reported, together with their in vivo and in vitro activities as opioid ligands. All potent agonists exhibit a preference for axial 4-aryl chair conformations when protonated, and stereochemical analogies with rigid opioids of the benzomorphan class are discussed. Antagonist properties are found in compounds with preference for equatorial 4-aryl chairs, notably the cis 3,4-dimethyl derivative.

Asymmetric Diels-Alder cycloadditions with acylnitroso dienophiles obtained from L-proline

N-acylnitroso derivatives of L-proline were formed in situ from the corresponding hydroxamic acids. They reacted easily with 1,3-cyclohexadiene to give the corresponding diastereoisomeric pairs of Diels-Alder cycloadducts with d.e. values ranging from 52 to 68 %.

Synthesis and stereochemistry of a helical 2,18-bridged biliverdin

Biliverdin-IIIα dimethyl ester (1) when treated with acidic methanol undergoes ring closure of the exocyclic vinyl groups with consecutive addition of two methoxy groups and oxidation, predominantly affording (3). The four-membered bridge connecting the pyrrolinone rings possesses two chiral centres of equal configuration either (1′R,4′R) or (1′S,4′S). Due to the M/P helicity of the bilatriene backbone, (3) comprises two thermally interconvertible diastereoisomeric pairs of enantiomers, viz. (3a) of configuration [(P,1′R,4′R) and (M,1′S,4′S)] and (3b) of configuration [(M,1′R,4′R) and (P,1′S,4′S)]. Their stereochemistry was assigned by n.m.r. techniques. The flexibility of the bilatriene unit is restricted so the separation of (3a) and (3b) can be seen at moderately low temperatures. Despite geometric contraints the torsional angles of the bilatriene backbones are close to non-bridged helical shaped derivatives. A mechanism for the acid mediated cyclisation reaction is proposed and briefly discussed.

Resolution of chiral interconvertible diastereoisomers of a 2,18-bridged biliverdin mediated by first-order asymmetric transformation

Chiral diastereoisomers of the bridged biliverdin 2,18-(1′,4′-dimethoxybutane-1′,4′-diyl)-8,12-bis(2″-methoxycarbonylethyl)-3,7,13,17-tetramethylbilin-1,19-(21H,24H)-dionerac-(1a) and rac-(1b) have been resolved and isolated from the four-component mixture. Repetitive enrichment of M-helical isomers with (R)-(–)-mandelic acid followed by chromatographic separation afforded one enantiomer of each diastereoisomeric pair, viz. (M-SS)-(1a) and (M-RR)-(1b). The corresponding enantiomorphic species (P-RR)-(1a) and (P-SS)-(1b) were each obtained from their respective diastereoisomeric counterpart by thermal conversion. The enantiomeric purities achieved (>95%) were checked by n.m.r. techniques. The rotational strengths R(absolute values) of the visible c.d. bands exhibited by the diastereoisomers of (1) are close to one another and similar to those reported for open-chain bilatrienes. The influence of chirality centres on helical excess (h.e.) and helicity of the bridged bilatriene moiety and its pronounced solvent dependence is discussed.

Studien zur CH-Aktivierung: IV. Inter- und Intra-molekulare CH-Aktivierung mit Komplexfragmenten des Typs [C 6R 6M(L)] (M = Ru, Os)

The dihydrido ruthenium and osmium complexes C 6H 6RuH 2(PPr i 3), C 6Me 6RuH 2[P(OR) 3] (R = Me, Pr i) and C 6H 6OsH 2(PPr i 3) can be obtained from the corresponding dihalogeno derivatives C 6R 6MX 2(L) (X = Cl, I) and NaBH 4 or Na[AlH 2(OC 2H 4OMe) 2]. Photolysis in presence of benzene and toluene, of C 6H 6RuH 2(PPr i 3) or C 6Me 6RuH 2(PMe 3) gives the hydrido(phenyl) and hydrido(tolyl) complexes, C 2H 2RuH(C 2H 4R)(PPr i 3) or C 6Me 6RuH(C 6H 4R)(PMe 3) (R = H, Me) in 35–63% yield. C 6H 6RuH(C 6H 4Me)(PPr i 3) or C 6Me 6RuH(C 6H 4Me)-(PMe 3) can also be prepared from C 6H 6RuBr(C 6H 4Me)(PPr i 3) or C 6Me 6RuBr(C 6-H 4Me)(PMe 2) and NaBH 4 in ethanol. Photolysis of C 6H 6RuH 2(PPr i 3 in cyclohexane, hexane or mesitylene leads to the formation of the four-membered metallaheterocycle C 6H 6(H)R uCH 2CH(CH 3)P Pr i 2 which can be isolated as a pair of diastereoisomers. It reacts smoothly with C 6H 6, C 6D 6 and C 6H 5Me in the dark to give the corresponding aryl(hydrido)ruthenium compounds C 6H 6RuH(C 6H 4R)(PPr i 3) (R = H, Me) and C 6H 6RuD(C 6D 5)(PPr i 3) in almost quantitative yield. In contrast to C 6H 6RuH 2(PPr i 3), the corresponding osmium complex C 6H 6OsH 2(PPr i 3) is photochemically inert. C 6H 6OsH(C 6H 5)(PPr i 3), C 6H 6OsH(C 6H 5)(PMe 3) and C 6H 6OsD(C 6HD 5)(PMe 3) have been obtained from the reaction of C 6H 6OsI 2(PR 3) (R = Me, Pr i) with NaC 10H 8 in THF/C 6H 6 or C 6D 6, by the classical Chatt route.

Soman-hydrolyzing and -detoxifying properties of an enzyme from a thermophilic bacterium

An enzyme that hydrolyzes soman (1,2,2-trimethylpropyl methylphosphonofluoridate) and two other phosphonofluoridates, but does not hydrolyze DFP (diisopropylphosphorofluoridate), has been partially purified from a rod-shaped spore-forming gram-positive OT (obligate thermophilic) bacterium. The enzyme shows a marked Mn 2+ stimulation, and in this and its substrate preference does not resemble the organophosphorus acid anhydrolase (sometimes termed DFPase) found in squid. Like the squid enzyme, it is not inhibited by mipafox ( N,N′-diisopropylphosphordiamidofluoridate), is not inactivated by ammonium sulfate, and does hydrolyze the acetylcholinesterase-inhibitory pair of diastereoisomers of soman as well as the relatively noninhibitory pair, thus detoxifying soman. In these three properties the OT enzyme does not resemble the ubiquitous organophosphorus acid anhydrolase often purified from mammalian and bacterial sources by cold ethanol fractionation. Thus this phosphono-specific OT enzyme may have a natural substrate and a physiological role distinct from other organophosphorus acid anhydrolases.

Synthesis of pseudo-trehaloses: [(1,2, [formula omitted],5)-2,3,4-trihydroxy-5-hydroxymethyl-1-cyclohexyl] d-glucopyranosides

All the theoretically possible, foru diastereoisomeric pairs, α,α ( 2A and 2B), α,β ( 3A and 3B), β,α ( 4A and 4B), and β,β ( 5A and 5B), of pseudo-trehalose, composed of d-glucopyranose and pseudo- d- or l-glucopyranose, have been synthesised by coupling of the appropriately protected pseudo-α- ( 6) and -β- dl-glucopyranoses ( 9) with d-glucopyranose derivatives ( 10 and 11) in the presence of trimethylsilyl trifluoromethanesulfonate. Elucidation of the structures and absolute configurations of the pseudo-disaccharides was based on the 1H-n.m.r. spectra of their octa-acetates and the optical rotations. None of the pseudo-trehaloses inhibited trehalase.

Non‐covalent interactions in the protonation of diastereoisomeric dipeptides in aqueous solution

New and already reported thermodynamic data concerning the protonation of a series of diastereoisomeric pairs of dipeptides have been compared with the upfield chemical shifts observed in the PMR spectra of some systems as a consequence of alkyl‐aryl interactions. The enthalpy and entropy changes associated with the protonation of the dipeptides, obtained by potentiometric and calorimetric measurements, together with the PMR data, show the importance of the solvophobic and the electrostatic interactions in the stereoselectivity of these systems. The overall agreement and the differences are discussed.

Molecular mechanics of diastereoisomers with phenyl groups on neighbouring carbon atoms

Results are summarized from systematic studies by the molecular mechanics method of the conformations of diastereoisomeric pairs of 1,2-disubstituted-1,2-diphenylethanes. An overall result in both series is the preference for conformations with the minimal number of synclinal interactions around the C(1)C(2) bond. Special attention is devoted to the performance of the MM2 force field with the 1,2-diarylethane system. With the readjustment of the V 1 parameter for the torsional unit C arC alC alC ar MM2 operates reasonably well in the case of substituents of a moderate size. For the 1,2,3-triphenylpropane system however, where phenyl groups participate in 1,3-parallel interactions, this force field fails completely. A further more substantial revision of the MM2 force field is necessary in order to achieve internal consistency between different energy contributions in such systems.

NMR SPECTRA AND STEREOCHEMISTRY OF DIASTEREOISOMERIC 4,5-DIPHENYL-CYCLOPHOSPHAMIDES

Abstract The conformational distribution and relative configuration of four diastereoisomeric pairs of 4,5-diphenyl-cyclophosphamides and their N-methyl analogues were determined by means of 1H, 13C, 31P NMR and IR spectroscopy.

Intramolekulare Cycloadditionen Mit Azomethin‐Yliden: Synthese und NMR‐Untersuchungen einiger Paracyclophan‐Derivate vom Makrolid‐Typ

Intramolecular Cycloaddition Reactions with Azomethine Ylides: Synthesis and NMR Investigations of Some Macrolide‐Type ParacyclophanesSeveral aziridine derivatives bearing a para‐substituted phenyl group have been prepared as precursors of azomethine ylides for intramolecular 1,3‐dipolar cycloadditions. Upon heating in refluxing toluene, the expected reactions take place resulting in the regioselective formations of the pairs of diastereoisomers 14/15 and 16/17, respectively. As indicated by the sharply decreasing yield in the a‐series (< 5%), a useful application of this method for preparing paracyclophane compounds is restricted to derivatives with more than 11 bridging atoms. The results of detailed 1H‐ and 13C‐NMR investigations with the pyrrolidino‐annulated cyclophanes are discussed with respect to the configuration at the five‐membered heterocycles and to the conformational flexibility of the bridges.

Carboxylic acids as indicators of oil migration—I. Occurrence and geochemical significance of C-22 diastereoisomers of the (17βH,21βH) C 30 hopanoic acid in geological samples

A pair of diastereoisomers of the 17βH,21βHC 30 hopanoic acid were detected in various geological samples such as coals and crude oils. The identifies of the two isomers (22 R and 22 S) were confirmed by comparison of mass spectra and gas chromatographic retention times with those of synthetic reference compounds. Our data indicate, as expected, a faster rate of epimerization at position 22 for the C 30 hopanoic acid of the 17βH,21βH configuration, than for its higher homologues. These C 30 hopanoic acids are well suited as maturation parameters; they may furthermore be good indicators for the migration of crude oils.

Soman-Hydrolyzing and -Detoxifying Properties of an Enzyme from a Thermophilic Bacterium

Soman-Hydrolyzing and -Detoxifying Properties of an Enzyme from a Thermophilic Bacterium. Chettur, G., DeFrank, J. J., Gallo, B. J., Hoskin, F. C. G., Mainer, S., Robbins, F. M., Steinmann, K. E., and Walker, J. E. (1988). Fundam. Appl. Toxicol 11, 373-380. An enzyme that hydrolyzes soman (1,2,2-trimethylpropyl methylphosphonofluoridate) and two other phosphonofluoridates, but does not hydrolyze DFP (diisopropylphosphorofluoridate), has been partially purified from a rod-shaped spore-forming gram-positive OT (obligate thermophilic) bacterium. The enzyme shows a marked Mn 2+ stimulation, and in this and its substrate preference does not resemble the organophosphorus acid anhydrolase (sometimes termed DFPase) found in squid. Like the squid enzyme, it is not inhibited by mipafox (N. N‘-diisopropyl-phosphordiamidofluoridate), is not inactivated by ammonium sulfate, and does hydrolyze the acetylcholinesterase-inhibitory pair of diastereoisomers of soman as well as the relatively nonin-hibitory pair, thus detoxifying soman. In these three properties the OT enzyme does not resemble the ubiquitous organophosphorus acid anhydrolase often purified from mammalian and bacterial sources by cold ethanol fractionation. Thus this phosphono-specific OT enzyme may have a natural substrate and a physiological role distinct from other organophosphorus acid anhydrolases.