Racemic content

Essentially, the same results are found for reactions in deuterium and hydrogen (Table 1). As double bond migration (racemization) proceeds, the hydrogen content at C2 increases. 

Evidence was further presented that "eventual success [in separating the enantiomers] came only after several failures using known strategies for enantiomer separation" and that it "could be. .. difficult to separate the enantiomers of PC 4099. .. because it would be understood by chemists that the methyl ester substituent in PCR 4099 could make it more susceptible to re-racemizations, and thus resistant to successfully obtaining a separated product [22]." Accordingly, "neither the chemists at Sanofi nor a person of ordinary skill in the art could have reasonably expected that the separate enantiomers of PCR 4099 could be obtained. .. and if obtained, by what method and configuration [22]." Thus, Apotex s contention that separating the enantiomers was obvious was also refuted. 

Studies aimed at the elucidation of reaction mechanisms have been performed by many groups, notably by those of Backvall [28]. In test reactions, typically enantiopure 1-phenylethanol labeled with deuterium at the 1-position (8) is used. The compound is racemized with acetophenone (9) under the influence of the catalyst and after complete racemization of the alcohol, the deuterium content of the racemic alcohol is determined. If deuterium transfer proceeds from the a-carbon atom of the donor to the carbonyl carbon atom of the acceptor the deuterium is retained, but if it is transferred to the oxygen atom of the acceptor it is lost due to subsequent exchange with alcohols in the reaction mixture (Scheme 20.4). 

FIGURE 4.8 Racemization tests employed for acquiring information on stereomutation. Couplings are carried out, and the isomeric content of the products is determined by a variety of techniques. AAA = amino acid analyzer GLC = gas-liquid chromatography. 

A D Aniello, L Petrucelli, C Gardner, G Fisher. Improved method for hydrolyzing proteins and peptides without inducing racemization and for determining their true D-amino acid content. Anal Biochem 213, 290, 1993. 

A similar rearrangement of a racemic a-deuteriated ether 84-rf afforded 70% yield of S5-d (98% D-content) with significantly decreased enantioselectivity (14% ee) (equation 47). This result suggests that the enantioselectivity may be determined substantially at the lithiation step, since the enantioselectivity should be the same as observed with the non-deuteriated substrate, if determined at the post-lithiation step. 

Another example is illustrated in the relationship between the specific rotation and the microstructure of polypropylene oxide reported by Price. Optically active propylene oxide and racemic propylene oxide-a-d were polymerized under otherwise identical conditions by the freeze-dried ZnEt2-H20 (1 0.7) catalyst system containing varying amounts of ZnEt2. A linear relationship was observed between specific rotation of the former polymer and the tail-to-tail dyad content of the latter (Fig. 14). This result proves quantitatively that the decrease in the specific rotation of polymer prepared by several catalysts is due to the presence of head-to-head and tail-to-tail linkages, and also provides supporting evidence for our microstructure analysis. 

This tetranuclear complex was first prepared by Jorgensen (2), and was resolved into optical isomers by Werner (5), who thereby disposed of the vitalist contention that organic carbon is an essential concomitant of optical activity. Werner named the complex hexol after the bridging ligands. The structure of this tetranuclear species has now been established by an X-ray crystal-structure analysis of the racemic salt (52). The complex racemizes fairly readily and rates of racemization depend heavily on pH the first-order rate constants at pH 2.0, 7.0, and 8.1, are respectively, k = 2 x 10 6, 2 x 10 3, and 4 x 10 2 sec-1 at 22"C. Tartrate and selenate decrease the rate of racemization, probably as a result of ion pairing between the hydroxo bridges and the anions (56). 

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