Other 2-substituted Pyrrolidines as Asymmetric Organocatalysts

Even though the use of (S)-proline (1) for the synthesis of the Wieland- Miescher ketone, a transformation now known as the Hajos–Parrish– Eder–Sauer–Wiechert reaction, was reported in the early 1970s,1 aminocatalysis – namely the catalysis promoted by the use of chiral secondary amines – was rediscovered only thirty years later. The renaissance of aminocatalysis was prompted by two independent reports by List et al. on the asymmetric intermolecular aldol addition catalysed by (S)-proline (1)2 and by MacMillan et al. on the asymmetric Diels–Alder cycloaddition catalysed by a phenylalanine-derived imidazolidinone 2.3 These two reactions represented the archetypical examples of asymmetric carbonyl compound activation, via enamine (Figure 11.1A) and iminium-ion (Figure 11.1B), respectively. In the following fifteen years a huge number of reactions had been reported for the asymmetric construction of carbon–carbon and carbon– heteroatom bonds using small organic molecules as catalysts, with pyrrolidine derivatives undoubtedly having the most important role.4 Since the first seminal reports by Stork5 on the use of secondary amines for the generation of enamines with carbonyl compounds, it was soon recognised that enamines derived from pyrrolidine were among the most reactive ones (pyrrolidine4piperidine4morpholine), and more recently this trend was confirmed by Mayr et al. with the calculation of the relative rate constants for the reaction of a series of enamines commonly employed in organocatalytic transformations with different electrophiles.6 The highest reactivity of pyrrolidine- derived enamines can be directly related to the spn character of the nitrogen atom, which affects the p–p orbital interaction determining the electron density on the nucleophilic enamine b-carbon.7 Thus, in the cyclic amine series, pyrrolidine-derived enamines display the highest reactivity since an almost pure sp2 nitrogen can be accommodated in a 5-member ring without significant angular strains. The relative reactivity of organocatalytic relevant iminium ions was also recently rationalised byMayr et al.8 Since in the case of iminium-ions the positive nitrogen is naturally nearly sp2-hybridised, the reactivity trend determined by the secondary amine used is in this case dictated mainly by the presence of inductive electron-withdrawing effects, raising the positive charge density on the unsaturated system. The most active compound of the series analysed was the iminium ion derived from MacMillan’s catalyst 2, immediately followed by the one deriving from Jørgensen–Hayashi silylated (S)-a,a-diphenyl-prolinol (3a, Ar¼Ph, R¼Si(CH3)3 Figure 11.2),9 easily prepared starting from (S)-proline (1).10 In view of these considerations, it should not be surprising that among the natural chiral pyrrolidines available, (S)-proline 1 and its derivatives, as well as the nonproteinogenic (2S,4R)-4-hydroxy-proline (4, Figure 11.2) and its derivatives, have played a major role in the recent tremendous development of aminocatalysis. The properties and applications of these organocatalysts are the subject of Chapters 5 and 10 of this book. In this chapter, differently substituted pyrrolidine-derived organocatalysts will be further analysed and discussed.