Stereochemical identity

When the two partial sequences stemming from the central NH group are chemically and stereochemically identical, Ci symmetric products result. We consider such compoimds as candidates for biological smdies, as well as models of C2 chiral auxiliaries for asymmetric induction (ref. 23), or ligands for metal ions. Syntheses of C2 symmetric compounds requiring the use of chiral auxiliaries have been recently reported (ref. 24). 

S. Hanessian, P. C. Tyler, G. Demailly, and Y. Chapleur, Total synthesis and stereochemical identity of the ClgH3205 degradation product of boromycin, J. Am. Chem. Soc. 103 6243 (1981). 

The cumbersome route in Scheme 269 had been prompted by frustrated attempts to prepare the dianion of acid 32 on the microscale. A reexamination of this reaction on a larger scale showed that warming of a THF solution of 32 with two equivalents of LDA at 50 °C for 2 h led to an orange solution of dianion. Addition of methyl iodide then gave rise to a single diastereomerically pure homologous acid, 41, in nearly quantitative yield (Scheme 3). The stereochemical identity of 41 was reasonably assumed to be erythro from its conversion to the natural product 1. The possibility of epimerization at some stage in this process was ruled out by the clean conversion of threo acid 37 to 9-epiartemisinin 29. 

During preclinical development, the structure, physical and chemical characteristics, and stereochemical identity of the IND/CTA candidate are fully characterized. This information, for example, is required for the chemical manufacture and control (CMC) section of the IND. Appropriate bioanalytical methods are developed for the evaluation of pharmacokinetics, typically a series of studies focusing on absorption, distribution, metabolism, and excretion (ADME) in toxicology species, as well as systemic exposure and metabolism in toxicological and clinical studies. 

Scheme 5.7 Stereochemical identities of starting materials subjected to Sn1 reactions are lost due to the planarity of reactive carbocations. Two products are formed.

Determination of absolute configuration is another important application of the chromatographic separation of diastereomeric derivatives of enantiomers. This can be accomplished in several different ways. Obviously, if a standard of known configuration is available for comparison, the configuration of a compound of unknown stereochemical identity in a given sample can be readily assigned. If an authentic standard of Itnown... 

Dehydroabietyl isocyanate, [39], was used by Falck et al. to determine the absolute configuration of hydroxyeicosatetraenoic acid methyl esters in a study of the enzymatic epoxidahon of arachidonic acid (175). In another study of similar metabolites, the stereochemical identity of 12-hydroxy-5,8,10,14-eicosatetraenoic acid derived from the lesional scale of patients with psoriasis was studied via separation of the enantiomers after derivatization with [39] (176). In these studies (175,176), LC separation of the derivatives was used. CDA [39] can be prepared from commercially available resolved dehydroabietylamine. It would be worthwhile to examine the applicability of this CDA to the resolution of other compounds. 

Certain identity tests intended to establish the stereochemical identity of a drug are known. Their applicability to a specific drug substance may vary depending upon the magnitude of differences between the values to be determined. These are discussed below in the following order (which does not suggest the suitability of the technique for regulatory purposes) ... 

The ultimate stereochemical identity test is, of course, the direct resolution of the enantiomers using chiral liquid or gas chromatography (9). When compared to a reference standard of the racemate, and under experimental conditions that will resolve the peaks of both enantiomers, the occurrence of two equal peaks will identify the racemate, and one peak will signify an enantiopure material. A proof of the stereochemical identity of the analyte can be provided, based on a match of retention times with a reference standard of known stereochemistry. Inequality between the peaks is a measure of enantiomeric enrichment. Therefore, it is conceivable that both stereochemical identity and purity can be established from a single experiment. 

Some chiral drug substances either occur naturally or are synthetic derivatives of natural products. In these cases, the controls on the raw materials are often assumed to guarantee the stereochemical identity of the finished bulk drug substance product without the use of a specific stereochemically sensitive test. Such an assertion is of little significance for regulatory purposes. First, determination of the source species for an... 

For any chiral drug, establishment of its stereochemical identity is not an insurmountable technical problem, even for enantiopure material. The techniques of X-ray crystallography and NMR spectroscopy will, in general, lead to conclusions of high certainty, at least for the material studied. However, for enantiopure material, it is critical that the relevance of conclusions based on these techniques be correlated to larger batches of material through chiral properties, such as optical rotation. Of the thousands of published determinations of absolute configuration based on X-ray studies, most are unsupported by such data on solutions of the specific crop of crystals from which a few were selected for study. 

An important factor that emerged from our studies is that the above method of catalyst identification increases the frequency with which unexpected observations are made. For example, as illustrated in Scheme 6, a subtle alteration in the structure - and not the stereochemical identity - of the peptide hgand leads to inversion of stereochemistry in the epoxide-opening reaction (compare reaction with ligands I and II). These observations validate our choice of individually synthesizing and testing each catalyst, as mixtures of catalysts can lead to racemic products. 

At this point, the stereochemical identity of each diastereomer remained unknown, but for this treatise the less polar of the two is referred to as 45a and the more polar referred to as 45b . Scheme 17 details chemistry for one of the two diastereomers, and an identical sequence was performed on the other without consequence. Dess-Martin periodinane was used to oxidize the Cl hydroxyl group to the corresponding ketone in very high yield. IBX proved to be quite slow in effecting this same transformation and generally the reaction did not go to... 

All these results are in accord with a non-concerted mechanism. An alternative route by which the stereochemical identity of the methane... 

Drewes, S.E., D.G. Roux, H.M. Saayman, S.H. Eggers, and J. Feeney Some Stereochemically Identical Biflavanols from the Bark Tannins of Acacia mearnsii. J. Chem. Soc. (C), 1302 (1967). 

Early efforts to control P/ stereochemical identity with only modest efficiency included enzymatic hydrolysis of C-terminal methyl carboxylates [18] and... 

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