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

Abstract

Racemization has alarge impact upon the biological properties of molecules but the chemical scope of compounds with knownr ate constants for racemization in aqueous conditions was hitherto limited. To address this remarkable blind spot, we have measured the kinetics for racemization of 28 compounds using circular dichroism and 1 HNMR spectroscopy. We show that rate constants for racemization (measured by ourselves and others) correlate well with deprotonation energies from quantum mechanical (QM) and group contribution calculations.Such calculations thus provide predictions of the second-order rate constants for general-basecatalyzedr acemization that are usefully accurate.W hen applied to recent publications describing the stereoselective synthesis of compounds of purported biological value,t he calculations reveal that racemization would be sufficiently fast to render these expensive syntheses pointless.Thalidomide racemizes in am atter of hours and yet it remains ap oster child for enantioselective synthesis which would not have saved its victims.[1] Thes tatus quo in enantioselective synthesis thus ignores the cruel blind spot that we address in this paper:racemization.Although necessary in dynamic kinetic resolution protocols, [2,3] racemization and epimerization can caus es afe compounds to become toxic or lose efficacy, [4][5][6][7][8][9][10][11] lead to misidentification of chiral compounds extracted from natural sources, [12] etc.I gnoring racemization thus leads to wasted material and human resources.Racemization is ap articular problem because its detection requires chiral analytical methods. [13,14] Hence,f ew 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-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.[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). Briefly,a ts everal buffer concentrations,c ircular dichroism spectroscopy (CD) followed the decrease in ellipticity and/or 1 HNMR spectroscopy the incorporation of Dfrom deuterated buffers.T he pseudo- first-order rate constants for these processes were corrected for hydrolysis side reactions if required. [24] Plotting the firstorder rate constants for ...

Generation of Polar Semi‐Saturated Bicyclic Pyrazoles for Fragment‐Based Drug‐Discovery Campaigns.

“…Pd(dppf)Cl 2 ,C s 2 CO 3 in DMF were found to be the most effective reagents fors uch cross-coupling and microwavei rradiation afforded the bicyclic systems(23 a-c)i ne xcellent yields. [20] The most active enantiomer can be identifiedf rom ap rotein-ligand Xray structure derived from the racemic mixture. Ar ecent poll in the Practicalf ragments blog showsaclear preference for using racemates rather than pure enantiomers for fragment screening and this result is consistent with the DDU fragment libraryg eneration.…”

“…Ar ecent poll in the Practicalf ragments blog showsaclear preference for using racemates rather than pure enantiomers for fragment screening and this result is consistent with the DDU fragment libraryg eneration. [20] The most active enantiomer can be identifiedf rom ap rotein-ligand Xray structure derived from the racemic mixture. [21] The Stille reactionb etween 2 and tributyl(vinyl)stannane to generate 24 was effectively catalysed by Pd/P(tBu) 3 and CsF (Scheme 3).…”

Racemisation in Chemistry and Biology

“…Alternatively, the ability to use both non‐deuterated and fully deuterated buffers provides convenient direct access to the solvent kinetic isotope effects. CD has been successfully applied to measure the racemisation of several systems . Analogous to CD spectroscopy, the process of racemization can also be monitored by using the rotation of plane‐polarized light by using polarimeters and measuring, for example, the optical rotatory power [ α ] D …”

“…This mechanism also suggests that the formation of d ‐Asp could be from l ‐Asn, rather than l ‐Asp. Recent results have suggested that anionic intermediates that have the possibility of aromatic character can enhance racemisation liability and it is noteworthy that the keto–enol tautomer of 55 would fall into this category . Other studies have cast doubt on the relevance of cyclic species favouring a homolysis via a radical …”

“…A quantitative approach to rates of general‐base‐catalysed racemisation across compound classes was recently described in which two computational and two practical methods complement one another to provide differing levels of speed and throughput and different levels of accuracy . Measurements of the rate of racemisation exploited NMR spectroscopy to follow deuterium incorporation or circular dichroism to follow racemisation directly.…”