The so‐called “interconversion” of stereoisomeric drugs: An attempt at clarification

Abstract

A variety of reactions can be categorized under the global concept of the "interconversion of stereoisomers." Thus, racemization or epimerization can result from inversion of labile chiral centers. From the examples available, some predictive rules are suggested for a chiral center of the type R"R'RC-H undergoing base-catalyzed inversion and a provisional table of affecting groups is presented. Unimolecular inversion of nonsymmetrical, nonplanar ring systems can also result in racemization or epimerization, but no generalization can yet be offered. Beside these cases of nonenzymatic reactions, a limited variety of enzymatic reactions can operate to interconvert stereoisomers, the outcome rarely being a racemic mixture. An important aspect of stereoisomer interconversion is the time scale in which the phenomenon is observed. Thus, several reactions to nonezymatic racemization or epimerization are fast compared to the duration of action of the drug and therefore have pharmacological significance, while other are slower and are of pharmaceutical relevance only.

Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses

“…Hence, few reports disclose rate constants for racemization under aqueous conditions 1, 15, 16, 17, 18, 19, 20. Chiral centers with certain combinations of substituents have been posited to be prone to general‐base‐catalyzed racemization although with little supporting data 21, 22, 23…”

Supramolecular dynamics of thalidomide and its derivatives in water‐sediment system

“…The chiral interconversions is favored at low pH indicating a mechanism through proton exchange phenomenon as discussed by other authors. [15][16][17][18]24,[25][26][27][28] …”

“…Besides, in vitro pharmacokinetics of thalidomide have also been established in human beings. [15][16][17][18][19][20][21][22] In natural conditions, thalidomide is degraded to more than 20 byproducts because of rapid pH-dependent hydrolysis in aqueous solution. The plasma concentration of thalidomide is 10-15 h depending on the age, race, and sex of the patients.…”

Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses

“…[21][22][23] We therefore classified stereogenic carbon atoms according to their attached substituents.E ach substituent is identified as one of sixty types, [24] which encompass more than 99.95 %ofall such substituents in the GOSTAR database. [25] Thet en most frequently occurring substituents are listed in Figure 1; the Hr equired for general-base-catalyzed racemization is prominent.[24] Groups labelled *w ere selected for experimental study.Based on prevalence,e arlier work, [21][22][23] and chemical intuition, several compounds were selected for detailed kinetic studies. [26][27][28] Ther ate constants for general-basecatalyzed racemization were derived for ar ange of 11 arylglycine derivatives (1, 2 and 3), 12 hydantoins (4, 5 and 6)a nd 5t hiohydantoins (7 and 8).…”

“…[1,[15][16][17][18][19][20] Chiral centers with certain combinations of substituents have been posited to be prone to general-basecatalyzed racemization although with little supporting data. [21][22][23] We therefore classified stereogenic carbon atoms according to their attached substituents.E ach substituent is identified as one of sixty types, [24] which encompass more than 99.95 %ofall such substituents in the GOSTAR database. [25] Thet en most frequently occurring substituents are listed in Figure 1; the Hr equired for general-base-catalyzed racemization is prominent.…”