C-25 epimeric 26-haloponasterone A: synthesis, absolute configuration and moulting activity

A convenient synthesis of inokosterone has been accomplished. Inokosterone exists as two C-25 epimers, which could be separated from each other through their diacetonide derivatives. The absolute configuration of these compounds was determined. Two C-25 epimers of 26-chloroponasterone A were synthesized from the respective C-25 epimeric inokosterone. Two epimeric 26-bromo and 26-iodoponasterone A compounds were also synthesized. Moulting activity of these compounds was evaluated using the Musca bioassay, and it was found that the (25S)-26-halo analogues were more active than the corresponding (25R)-26-halo analogues. Among the 25S series, an increase in activity with an increase in size of the halogen atom was observed, indicating that the steric factor was more important than the electronic factor in binding of these ecdysteroid analogues to the receptor. On the other hand, a decrease in activity with an increase in size of the halogen atom was noted in the 25R series, suggesting that the steric factor was less important than the electronic factor. The results indicated that the configuration at C-25 and the substituent at C-26 have significant influences on the interaction of ecdysteroids with their receptor.     

Stereospecific synthesis and absolute configuration of mexiletine

Data on the absolute configuration of mexiletine (MEX) do not appear to have been published, although in several published reports the configuration is referred to as (?)-(R) and (+)-(S), based on information from manufactures providing the drug stereoisomers. We demonstrate that (?)-MEX has the (R)-configuration by mean of a new stereospecific synthesis. X-Ray analysis of an optical active sample of (+)-MEX as its hydrobromide salt, obtained from chemical resolution of the racemic mixture, was carried out in order to obtain precise information on bond lengths and angles, useful for studies on structure–activity relationships. We also report the NMR analysis in presence of Eu(hfc)₃ as shift reagent, which represents a simple method for the determination of enantiomeric excess (ee) in addition to the well-known chiral HPLC methods. © 1994 Wiley-Liss, Inc.     

NMR determination of the absolute configuration of an alpha-exo-methylene-gamma-lactone

Both the enantiomers of the axially chiral reagent, 2'-methoxy-1,1'-binaphthalene-2-carbohydroximoyl chloride (MBCC), were used to convert igalan, an alpha-exo-methylene-gamma-lactone, to yield 4,5-dihydroisoxazoles. The absolute configuration of igalan was determined to be (3aR,5R,6R,7aR)-6-ethenylhexahydro-6-methyl-3-methylen e-5-(1-methylethenyl)-2(3H)-benzofuranone (IUPAC name) on the basis of NOE correlations in these derivatives. The absolute configurations of other alpha-exo-methylene-gamma-lactones can be determined by the same method.     

NMR assignment of the absolute configuration of C-25 in furostanol steroidal saponins

The chemical shifts of the geminal proton resonances of H(2)-26 (δa and δb) are a widely used predictor of C-25 stereochemistry in furostanol steroidal saponins, being in general more resolved in 25S than 25R compounds. Unexpectedly, we found that application of this empirical rule in different solvents led to conflicting assignments of stereochemistry. An experimental survey revealed that, while the chemical shifts of H(2)-26 exhibit a dependence on C-25 configuration, it is less pronounced in methanol-d4 than pyridine-d5 solvent, and thus the general rule derived for pyridine-d5 fails when NMR spectra are acquired in methanol-d4. We propose a modified empirical method for the direct assignment of C-25 stereochemistry in furostanol saponins in methanol-d4 (Δ(ab)=0.45-0.48 ppm for 25S; Δ(ab)=0.33-0.35 ppm for 25R), and provide several detailed examples. In addition, the absolute configuration of compound 8, a steroidal saponin isolated in previous work from Ruscus colchicus, is corrected from 25R to 25S stereochemistry.     

Total synthesis and determination of the absolute configuration of FD-838, a naturally occurring azaspirobicyclic product

The first asymmetric total synthesis of FD-838, a naturally occurring azaspirobicyclic product, has been accomplished allowing determination of its absolute stereochemistry.     

The absolute configuration of the acetylenic compound falcarindiol

The absolute configuration of the acetylenic compound falcarindiol is established as (3R,8S) and falcarindiol is thus (+)-(3R,8S)-(Z)-heptadeca-1,9-dien-4,6-diyn-3,8-diol. (R)-Heptadecan-8-ol and (S)-heptadecan-8- ol are synthesized and (3R,8S)-heptadecan-3,8-diol is characterized.     

Gas chromatographic enantiomer separation of C-3 and C-4 synthons: prediction of absolute configuration from elution order and enzymatic resolution

Enantiomers of C-3 secondary alcohols, 3-hydroxybutanoates, and cyclic 1,3-dithioacetals were separated by chiral GLC using CP-Chirasil-Dex CB and Chiraldex G-TA columns. The former was most successful for analysis of n-alkyl esters of secondary alcohols and the separation depended on the chain length of the acyl group and the electronic and steric properties of the other substituents. The Chiraldex G-TA column was efficient for analysis of secondary alcohols, derivatized as their trifluoroacetates. The elution order of the secondary alcohols and the corresponding acetates was always the same with respect to the size of groups connected to the stereocenter. However, when the secondary alcohols were analyzed as their trimethylsilyl derivatives, the elution order was reversed. Elution order on chiral columns and enantiomeric ratios, E-values, obtained in kinetic resolutions catalyzed by lipase B from Candida antarctica (CALB) were evaluated as a method for prediction of absolute configuration. The usefulness of the method was demonstrated using 22 pairs of enantiomers. Copyright 1999 Wiley-Liss, Inc.     

Assignment of the absolute configuration of P-chiral 5' mRNA cap analogues containing phosphorothioate moiety

Enzymatic cleavage of the P-chiral diastereoisomers of the 5' mRNA cap analogue bearing phosphorothioate moiety in alfa position of 5',5'-triphosphate bridge (m(7)Gppp(S)G D1 and D2) was performed by human Decapping Scavenger (DcpS) enzyme. Analysis of the degradation products allowed to estimate the absolute configuration at the asymmetric phosphorus atoms in examined compounds via correlation with the R(P) and S(P) diastereoisomers of guanosine 5'-O-(1-thiodiphosphate) (GDPalphaS).     

Resolution of racemic mixtures of carbocyclic analogues of nucleosides and assignment of their absolute configuration

Racemic trans-6-chloro-9-[2-(hydroxymethyl)cyclopentyl]purine was resolved using HPLC with a chiral column. The absolute configurations of the enantiomers were determined by NMR studies of their (R)- and (S)-methoxyphenylacetates.     

Trans-diaryl epoxides: asymmetric synthesis, ring-opening, and absolute configuration

Anthryl-phenyl, phenanthryl-phenyl, and naphthyl-phenyl trans-epoxides (1, 2, and 3, respectively) having enantiomeric purities of 95%, 99%, and 96% were synthesized from a diastereo and enantiopure sulfonium salt derived from Eliel's oxathiane. The determination of their (1R,2R) absolute configurations was achieved by application of the CD exciton chirality method using a Zn-porphyrin tweezer on the corresponding alcohols obtained after opening of these epoxides with LiAlH(4). The R-configuration at C2 of these epoxides, (-)-1, (+)-2, and (-)-3, is consistent with our previous results concerning asymmetric synthesis of monoaryl epoxides, cyclopropanes, and aziridines. The (1S,2R)-configuration of the cis isomer (when present) was also confirmed. Moreover, the agreement between the negative exciton chirality for conjugates of (S)-configuration predicted by molecular modeling and the observed CD spectra helps to clarify the relative steric size of phenyl and CH(2)-aryl (phenanthryl or anthryl), which is critical when the tweezer method is applied for absolute configurational assignment (phenyl = medium group; anthacenyl CH(2) and phenanthryl CH(2) = large group).     

Psi[CH2O] pseudodipeptide synthesis. An improved approach which allows absolute configuration determination

An improved way to obtain psi[CH2O] pseudodipeptide units is proposed, involving an intramolecular Williamson's reaction, with displacement of bromine by an alkoxide, instead of the classical intermolecular one. Until now, psi[CH2O] pseudodipeptide synthesis done by this new method, has used a protected form of the amino alcohol hydroxyl group to prepare the acyclic precursor. In the present paper, the use of an active ester of the brominated carboxylic acid avoids this protection step. The pseudodipeptides AcGly psi[CH2O]-D,L-Ala-OH and Ac-Ser(Bzl) psi [CH2O]-D,L-Ala-OH were obtained in high yields, through a delta-lactam intermediate, which furthermore allows the determination of the absolute configuration of compounds using HPLC and appropriate nuclear magnetic resonance (NMR) techniques.     

Chiral doping of nematic phases and its application to the determination of absolute configuration

Doping nematic liquid crystals with nonracemic chiral compounds induces a twisted nematic (cholesteric) phase. The ability of solutes to twist the nematic phase may be related to the overall shape of the chiral dopant and consequently to its absolute configuration. The cholesteric induction is therefore a powerful tool complementary to chiroptical techniques to obtain stereochemical information on chiral molecules.     

Synthesis and bioactivity of C-29 brassinosteroid analogues with different functional groups at C-6

In this paper, we report the synthesis and bioactivity of four synthetic analogues of 28-homobrassinosteroids, in order to evaluate the influence in bioactivity when the C-6 keto group is replaced by different functional groups. The synthetic analogues are 6-deoxo-28-homocastasterone [(22R,23R)-stigmasta-2alpha,3alpha,22,23-tetraol], 6alpha-hydroxy-28-homocastasterone [(22R,23R)-stigmasta-2alpha,3alpha,6alpha,22,23-pentaol], 6beta-hydroxy-28-homocastasterone [(22R,23R)-stigmasta-2alpha,3alpha,6beta,22,23-pentaol], and [(22R,23R)-6alpha-fluorostigmasta-2alpha,3alpha,22,23-tetraol]. Results indicate that replacement of the 6-keto moiety by an beta or alpha hydroxyl group led to a decrease in activity, whereas the 6-deoxo analogue showed a very low activity, confirming the importance of an electronegative moiety at C-6 to observe hormonal potency. The 6alpha-fluorinated analogue elicited a low activity, similar to that of the 6-deoxo analogue.     

The absolute configuration of phaseic and dihydrophaseic acids

A sample of phaseic acid methyl ester (5 mg, isolated from tomato plants fed (±)-abscisic acid, was reduced to a mixture of the epimeric dihydrophaseates which were separated by TLC. The more polar epimer was identical with the dihydrophaseate isolated from beans by Walton et al. [14]. Comparison of the NMR and IR spectra (H-bonding) of the two epimers shows the secondary hydroxyl of the less polar epimer is cis to the oxymethylene group, which is cis to the tertiary hydroxyl group. The absolute configuration of this centre is known so the absolute configuration of phaseic acid can be deduced. Phaseic acid is (−)-3-methyl-5{8[1(R), 5(R)-dimethyl-8(S)-hydroxy-3-oxo-6-oxabicyclo-(3,2,1)-octane]} 2-cis-4-trans-pentadienoic acid and both it and the reduction products exist in chair conformations. The more polar epimer isolated by Walton et al. is (−)-3-methyl-5{8[3(S,8(S)-dihydroxy-1(R,5(R)-dimethyl-6-oxabicyclo-(3,2,1)-octane]}2-cis-4-trans-pentadienoic acid. It is suggested that the less polar epimer should be referred to as epi-dihydrophaseic acid.     

Chiral reagents for the determination of enantiomeric excess and absolute configuration using NMR spectroscopy

Recent advances in the development of chiral derivatizing and solvating agents that facilitate the determination of enantiomeric excess and absolute configuration are reviewed. These include metal-containing species, host-guest systems, donor-acceptor compounds, and liquid crystal discriminating agents. In the aggregate, these reagents can be used to analyze a wide range of compound classes.