Mass spectrometric screening of chiral catalysts by monitoring the back reaction : palladium-catalysed allylic substitution

摘要

The principle of microscopic reversibility serves as the basis of a novel screening method forudthe evaluation of chiral catalysts within asymmetric allylic substitution reactions. Monitoringudthe back reaction of quasienantiomeric products 142a and 142b by electrospray ionisationudmass spectrometry (ESI-MS) reveals the intrinsic enantioselectivity of palladium catalysts inudthe nucleophilic addition step and thus in the overall substitution process.udIn this manner, an equimolar mixture of mass-labelled quasienantiomers 142a and 142b wasudsubjected to typical reaction conditions and the ratio of the resulting cationic allyl-palladiumudcomplexes A and B, which are the only species visible in the mass spectrum, was determinedudwith high accuracy.udA series of linear diaryl allylation products with commonly used nucleophiles as leavingudgroups were initially analysed with respect to their leaving group ability, which correlatesudwell with the pKa values of the respective nucleophiles. Based on these results, screeningudprocedures for allylic alkylations and aminations using substrates derived from acetyl acetoneudand phthalimide were developed. In both cases, the ratios of allyl intermediates A/B closelyudmatch with the enantiomeric product ratios of corresponding preparative reactions asuddetermined by HPLC analysis of the products. The methodology is fast, reliable, and enablesudthe simultaneous screening of catalyst mixtures, as long as the catalysts possess differentududmolecular masses. Three palladium complexes were tested in a single reaction vessel and theudmost powerful derivative was readily identified.udAfter having established a protocol for the evaluation of chiral palladium catalysts in allylicudsubstitutions of linear diaryl substrates, the methodology was extended to the moreuddemanding carbocyclic substrates. An efficient screening for the kinetic resolution ofudcyclohexenyl benzoate was developed by the use of cyclic allyl esters 65a and 65b.udMoreover, analysis of the back reaction starting from the allylation products 90a and 90budallowed for determining the efficiency of the catalysts in the overall substitution process. Theudobserved data were in good agreement with the corresponding preparative reactions.udIn an additional project, new pyridyl-phosphite 208, bis(N-sulfonylamino)phosphine 209, andudphosphinooxazoline ligands 133 were successfully synthesised and evaluated by the ESI-MSudprocedures and conventional preparative catalytic reactions.udThe back reaction screening method was further extended to the mass spectrometricudevaluation of racemic catalysts. Using a scalemic mixture of quasienantiomers 142a and 142budenabled to determine the enantioselectivities of chiral catalysts by testing their racemates.udThis approach was used to study phosphinooxazoline ligands 143, which possess aududstereogenic phosphorus atom as the only source of chirality, because the synthesis of theudenantiomerically pure compounds is not straightforward.udA series of derivatives was synthesised and evaluated by ESI-MS. Conventional preparativeudreactions of the separated enantiomers were performed as well. Ligands derived from dialkyl,udalkylaryl, and diaryl phosphines induced only low to moderate selectivities in allylicudsubstitutions and the results are not competitive with the established phox ligands derivedudfrom chiral aminoalcohols. The screening methodology was successfully used to determineudthese selectivities without the time-consuming preparation of the enantiomerically pureudcompounds.udFinally, the ESI-MS analysis of iridium-catalysed allylic substitution reactions proved theudactual existence of a previously postulated allyl-iridium intermediate. Preliminary results areudpromising and provide information which is in accordance with the suggested reactionudmechanism.