Diastereomeric analysis

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

Excellent diastereomeric ratios were achieved with terpene-derived auxiliaries. The pentacarbonyl[(-)-menthyloxycarbene]chromium complex 39 reacted with the sterically hindered 3,3-dimethylbut-l-yne to give tricarbonyl chromium naphthohydroquinone complex 40 in 81% de as the major diastereomer which was also characterised by X-ray analysis [41] (Scheme 25). Surprisingly, the application of other even more sterically demanding terpene auxiliaries or a variation of the alkyne did not improve the diastereomeric ratio [42]. 

The complex 65 was synthesized by reaction of the imidazolinium salt with the precursor ruthenium complex 67 (catalytically inactive) in the presence of silver carbonate (Scheme 42). The complex being air-stable and stable on silicagel was isolated in 52% yield after chromatography. The diastereomeric and enantiomeric purity of 65 was determined by HPLC analysis and found to be above 98% (de and ee). The molecular structure was determined by X-ray analysis and showed the unusual twist geometry of this complex. 

In considering the retrosynthetic analysis of juvabione, two factors draw special attention to the bond between C(4) and C(7). First, this bond establishes the stereochemistry of the molecule. The C(4) and C(7) carbons are stereogenic centers and their relative configuration determines the diastereomeric structure. In a stereocontrolled synthesis, it is necessary to establish the desired stereochemistry at C(4) and C(7). The C(4)-C(7) bond also connects the side chain to the cyclohexene ring. As a cyclohexane derivative is a logical candidate for one key intermediate, the C(4)-C(7) bond is a potential bond disconnection. 

On a capillary GC analysis, the separation of positional isomers of epoxy compounds is generally well accomplished by a high polar column, such as DB-23, rather than by a low polar column, such as DB-1. For the positional isomers, a different elution order depending on the kinds of column has not been reported. In the case of two mono epoxides derived from Z6,Z9-dienes, 6,7-epoxides elute slightly faster than 9,10-epoxides [72,170],but the separation is insufficient even on the high polar column. Three monoepoxides derived from Z3,Z6,Z9-trienes elute in the order of 6,7-, 3,4-, and 9,10-epoxides [9]. The former two isomers are sufficiently separated on the high polar column, while the elution of the latter two isomers overlaps [71]. For each positional isomer of diepoxides derived from the Z3,Z6,Z9-trienes, two diastereomeric... 

Conformational analysis of diastereomeric pyrido[ 1,2-/ ][ 1,3 oxazin-l -ones 91 and 92 revealed that 91 adopted an O-inside m-fused conformation, whereas 92 existed in a /ram-fused form <1996SL100>. Both isomers contained the C-8 substituent in an axial position to avoid A<1,3) strain, which would be present in alternative conformations. 

Our efforts to concretely determine the relative stereochemistry of this dimer have been met by failure. We have made attempts to resolve several of the monomeric tetracyclic aminoaldehydes of type 100 by HPLC using chiral stationary phase, in order to know for sure the structure of the homodimer. The poor solubility of these compounds in typical HPLC solvents hampered these efforts to access enantiopure monomer. A few attempts at diastereomeric salt formation from compounds of type 101 using chiral carboxylic acids were also unsuccessful. Computational analysis corroborates the assumption that the homodimer should be formed preferentially. 

Like Still s reagent, tributyl[(methoxymethoxy)methyl)etannane incorporates an alcohol protective group that can be conveniently unmasked under mild acidic conditions. However, an advantageous feature of this MOM ether derivative is that, in contrast to Still s reagent, it is achiral. In many applications the introduction of an additional chiral center into synthetic intermediates is undesirable because of the complications associated with the manipulation, analysis, and purification of diastereomeric mixtures. 

Chiral sulfonium ylides have been known for some 30 years, and their stereochemistry and properties have been studied.15 Optically active selenonium ylides were obtained by reacting selenoxides with 1,3-cyclohexanedione under asymmetric conditions by Sakaki and Oae in 1976 for the first time,16 and also optically resolved by fractional recrystallization of the diastereomeric mixtures in the early 1990s.17 In 1995, optically active selenonium ylides 6 were obtained in over 99% de by nucleophilic substitution of optically active chloroselenurane or selenoxide with active methylene compounds with retention of configuration.18 The absolute configurations were determined by X-ray analysis of one... 

Similarly, the (—)-menthyl substituted stannyl bromides 51 and 53, whose diastereomeric purity was confirmed by single crystal X-ray structure analysis, were found to slowly equilibrate to nearly 1 1 mixtures of diastereoisomers on standing in solution (equation 13)28. 

The rate law for two diastereomeric catalyst-substrate complexes -symmetric ligands) resulting from Michaelis-Menten kinetics (Eq. (11)) has already been utilized by Halpern et al. for the kinetic analysis of hydrogenations according to Scheme 10.2, and corresponds to Eq. (3) of this study. 

A variety of methods are also available when the compound under investigation can be converted with a chiral reagent to diastereomeric products, which have readily detectable differences in physical properties. If a derivatizing agent is employed, it must be ensured that the reaction with the subject molecule is quantitative and that the derivatization reaction is carried out to completion. This will ensure that unintentional kinetic resolution does not occur before the analysis. The derivatizing agent itself must be enantiomerically pure, and epi-merization should not occur during the entire process of analysis. 

Nuclear Magnetic Resonance Spectroscopy Measured in a Chiral Solvent or with a Chiral Solvating Agent. One method of NMR analysis for enantiomer composition is to record the spectra in a chiral environment, such as a chiral solvent or a chiral solvating agent. This method is based on the diastereomeric interaction between the substrate and the chiral environment applied in the analysis. 

Achiral lanthanide shifting reagents may be used to enhance the anisochrony of diastereomeric mixtures to facilitate their quantitative analysis. Chiral lanthanide shift reagents are much more commonly used to quantitatively analyze enantiomer compositions. Sometimes it may be necessary to chemically convert the enantiomer mixtures to their derivatives in order to get reasonable peak separation with chiral chemical shift reagents. 

One of the most powerful methods for determining enantiomer composition is gas or liquid chromatography, as it allows direct separation of the enantiomers of a chiral substance. Early chromatographic methods required the conversion of an enantiomeric mixture to a diastereomeric mixture, followed by analysis of the mixture by either GC or HPLC. A more convenient chromatographic approach for determining enantiomer compositions involves the application of a chiral environment without derivatization of the enantiomer mixture. Such a separation may be achieved using a chiral solvent as the mobile phase, but applications are limited because the method consumes large quantities of costly chiral solvents. The direct separation of enantiomers on a chiral stationary phase has been used extensively for the determination of enantiomer composition. Materials for the chiral stationary phase are commercially available for both GC and HPLC. 

MgS04, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give the title compound (176 mg, 83%). Its 1H NMR analysis showed that the diastereomeric ratio was >97 3 and that the stereochemistry of the major isomer was IRS,2SR. 

Early studies were based on 13 noncongeneric molecular series of oqA-AR antagonists [65]. The considered series included compounds 1, 3, 9-11, 14, 19 and 32 in Scheme 8.1 and compounds 43 and 45 in Scheme 8.2. Compounds 9 and 32 were considered in both the enantiomeric forms, whereas compound 45, corynanthine, was considered also in its diastereomeric form yohimbine [55]. The natural agonist, norepinephrine, was also considered, for comparative analysis [55],... 

During the early stages of process development it is very unlikely that relevant impurities will have been synthesized in sufficient quantities that a thorough analysis of their eutectic behaviour can be performed. Eutectics should be investigated when possible and are particularly relevant in the purification of stereo-isomers and in classical resolution using diastereomeric salts [5, 24, 25]. 

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