Recyclable organocatalysts: The first chiral DMAP analogue immobilized on magnetic nanoparticles is a highly active catalyst that is capable of the acylation of racemic sec-alcohols under convenient, process-scale friendly conditions (room temperature, 5 mol % loading, with acetic anhydride as the acylating agent) with excellent enantiodiscrimination. The catalyst is easily recovered and possesses unprecedented recyclability-in this study it was demonstrated to retain excellent activity and selectivity over 32 iterative cycles.
A systematic study concerning the immobilisation onto magnetic nanoparticles of three useful classes of chiral organocatalyst which rely on a confluence of weak, easily perturbed van der Waals and hydrogen bonding interactions to promote enantioselective reactions has been undertaken for the first time. The catalysts were evaluated in three different synthetically useful reaction classes: the kinetic resolution of sec-alcohols, the conjugate addition of dimethyl malonate to a nitroolefin and the desymmetrisation of meso anhydrides. A chiral bifunctional 4-N,N-dialkylaminopyridine derivative could be readily immobilised; the resulting heterogeneous catalyst is highly active and is capable of promoting the kinetic resolution of sec-alcohols with synthetically useful selectivity under process-scale friendly conditions and has been demonstrated to be reusable in a minimum of 32 consecutive cycles. The immobilisation of a cinchona alkaloid-derived urea-substituted catalyst proved considerably less successful in terms of both catalyst stability and product levels of enantiomeric excess. An immobilised cinchona alkaloid-derived sulfonamide catalyst was also prepared, with mixed results: the catalyst exhibits outstanding recyclability on a par with that associated with the successful N,N-dialkylaminopyridine analogue, however product enantiomeric excess is consistently lower than that obtained using the corresponding homogeneous catalyst. While no physical deterioration of the heterogeneous catalysts was detected on analysis after multiple recycles, in the cases of both the conjugate addition to nitroolefins and the desymmetrisation of meso anhydrides, significant levels of background catalysis by the nanoparticles in the absence of the organocatalyst was detected, which explains in part the poor performance of the immobilised organocatalysts in these reactions from a stereoselectivity standpoint. It seems clear that the immobilisation of sensitive chiral organocatalysts onto magnetite nanoparticles does not always result in heterogeneous catalysts with acceptable activity and selectivity profiles, and that consequently the applicability of the strategy must be ascertained (until more data is available) on a case-by-case basis.
A systematic preliminary study has identified a suite of catalysts, all readily prepared and derived from (S)-proline, which differ by a remote substituent only. If this substituent is capable of hydrogen-bond donation the catalyst will promote the resolution of secondary alcohols with the opposite sense of enantiodiscrimination to that observed when the substituent is capable of accepting hydrogen bonds.Enantioenriched secondary alcohols are arguably one of the most important broad classes of building block available to those interested in asymmetric synthesis. Among the most straightforward methodologies for accessing these compounds is the acylative kinetic resolution (KR) of the corresponding racemic materials. While enzymatic catalysis-based protocols have been available for some time, 1 the development of artificial small-molecule catalysts for these reactions has emerged as a powerful alternative tool over the past two decades. 2 A variety of catalytic systems for the acylative KR of secondary alcohols have been developed which were recently categorised by Schreiner and Müller 2e as belonging to one of five distinct groups: phosphines 3 and phosphinites, 4 4-N,N-dialkylaminopyridines, 5 N-alkylimidazoles, 6 amidines, 7 vicinal diamines 8 and N-heterocyclic carbenes. 9 Our group has been engaged in the development of organocatalysts for the acylative KR of secondary alcohols 10 and thiols. 11 The 3-substituted 4-N,N-dialkylaminopyridine analogues 1 and 2 (Figure 1) 10 were designed to circumvent the traditional activity-selectivity conundrum associated with DMAP-based catalyst systems (i.e. installation of the chiral information at C-2 of the pyridine ring leads to an inactive catalyst) by undergoing a conformational change upon acylation in the acylative KR of secondary alcohol substrates (an 'induced-fit'-type mechanism pioneered by Fuji some years earlier 5b ) which allows the chiral information to influence the stereochemical outcome without retarding the rate of catalyst acylation to an impractical extent.This strategy was a qualified success: the optimum catalysts 1a 10a,b and 1d 10c are readily prepared from (S)-proline and were capable of synthetically useful enantioselective acylation (s >10, maximum of 30) 12 of a variety of secondary alcohols (including challenging sp 2 -sp 2 carbinol substrates 10c ). Leigh et al. have subsequently utilised 1a as a tool in the operation of a molecular ratchet. 13 However, with the exception of their ability to resolve sp 2 -sp 2 carbinols, these catalysts are easily outperformed by the benchmark literature systems in the KR of all other classes of secondary alcohols. In addition, the factors which are responsible for enantiodiscrimination are numerous and subtle. For instance, a combination of catalyst screening, 1 H NMR spectroscopic, X-ray crystallographic and computational studies 10a,b provided evidence that four characteristics of the acylated catalyst (for a representation see 3, Figure 1) are crucial: A: More enantioselective acylation occurs using substr...
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