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

Racemisation has a large impact upon the biological properties of molecules but the chemical scope of compounds with known rate constants for racemisation in aqueous conditions was hitherto limited. To address this remarkable blind spot, we have measured the kinetics for racemisation of 28 compounds using circular dichroism and 1H NMR spectroscopy. We show that rate constants for racemisation (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-base-catalyzed racemisation that are usefully accurate. When applied to recent publications describing the stereoselective synthesis of compounds of purported biological value, the calculations reveal that racemisation would be sufficiently fast to render these expensive syntheses pointless

Aspects of some alkylation reactions

Friedel-Crafts reactions of the (-)-8-phenylmenthyl and (+ )-trans-2-(acumyl) cycJohexyl aryl hydroxy acetates catalysed by trimethylsilyl triflate (TMSOTf) and equivalents in the presence of electron rich heterocycles gave the expected diarylacetates in high de 88%, via a planar cation. The interaction of trifluoromethanesulfonic (triflic) acid (TfOH) with either bistrimethylsilyl -acetamide (BSA) or -urea (BSU) can be used to generate stoichiometric amounts of trimethylsilyl triflate (TMSOTf) "in situ" , the system can be used efficiently to remove triflic acid from TMSOTf and to generate catalytic amounts of TMSOTf from TfOH for use in a range of trimethylsilyl triflate (TMSOTf) catalysed reactions. Similarly the interaction of fluorosulfonic acid (FSA) with either bis-trimethylsilyl -acetamide (BSA) or -urea (BSU) can be used to generate catalytic amounts of trimethylsilylfluorosulfonate (TMSOFs) "in situ" for use in a wide range of reactions as an alternative to trimethylsilyltriflate (TMSOTf) Scandium(III) trifluoromethanesulfonate and copper(II) trifluoromethanesulfonate can be used to catalyse aromatic alkylation with arylhydroxyacetates. Scandium(III) trifluoromethanesulfonate also proved to be a recyclable catalyst for these reactions. A number of Pictet-Spengler cyclisation reactions were also catalysed by Scandium(III) trifluoromethanesulfonate and copper(II) trifluoromethanesulfonate. Mannich reactions of a number of caJix[4jresorcinarene derivatives with (R)-(+)-amethylbenzylamine under alkaline conditions lead to the formation of single diastereomeric tetrakis(l,3-dihydrobenzoxazine) derivatives in high yields; the reactions using the (S)-(-)-a-methylbenzylamine afford the enantiomers. The products react with protic acids to afford equilibrium mixtures of diastereomers

Highly diastereoselective functionalisation of calix[4]resorcinarene derivatives and acid catalysed epimerisation reactions

Mannich reactions of a number of calix[4]resorcinarene derivatives with (R)-(+)-α-methylbenzylamine under alkaline conditions lead to the formation of single diastereomeric tetrakis(1,3-dihydrobenzoxazine) derivatives in high yields; the reactions using the (S)-(-)-α-methylbenzylamine afford the enantiomers. The products react with protic acids to afford equilibrium mixtures of diastereomers.</p