Enantioselectivity with pyroglutamate

Figure 15.8 Multidimensional GC-MS separation of urinary acids after derivatization with methyl chloroformate (a) pre-column cliromatogram after splitless injection (h) Main-column selected ion monitoring cliromatogram (mass 84) of pyroglutamic acid methyl ester. Adapted from Journal of Chromatography, B 714, M. Heil et ai, Enantioselective multidimensional gas chromatography-mass spectrometry in the analysis of urinary organic acids , pp. 119-126, copyright 1998, with permission from Elsevier Science.

Several chiral ligands have been developed for use with the rhodium catalysts, among them are pyrrolidinones and imidazolidinones.207 For example, the lactamate of pyroglutamic acid gives enantioselective cyclopropanation reactions. 

In connection with the enantioselective alkylation of Pro or 4-hydroxy-proline, the azabicyclo[3.3.0]octane system 81 was obtained after reaction with pivaldehyde (81HCA2704 85HCA155). In a more complex transformation A-protected L-Pro was transformed into the same bicyclic system (Scheme 49) (81JA1851 84JA4192). The product was prepared as a model substance in the total synthesis of pumiliotoxin. A related compound 82 was prepared from 5-(hydroxymethyl)-2-pyrrolidinone (prepared from L-pyroglutamic acid) by an acid-catalyzed condensation with benzaldehyde (86JOC3140). 

Somfai et al. demonstrated that it is also possible to use A-sulphonyl groups (Somfai and Ahman 1992 Ahman and Somfai 1992 Weinreb 1997) using the same concept for the cyclization step developed by Speckamp with the allylsilanes (Esch et al. 1987). In this case, the starting product was the L-pyroglutamic acid, inside the succinimide (Esch et al. 1987), allowing the enantioselective synthesis of the (+)-anatoxin-a. The key step consisted of an intramolecular cyclization of an 7V-tosyl iminium ion, catalysed by a Lewis acid, TiCl, to set up the desired bicyclic ring system (Somfai and Ahman 1992). 

The ethyl ester of (.S l-pyroglutamic acid (,S)-32 was applied for the preparation of dien-amines used as chiral dienes in enantioselective Diels-Alder reactions (Section D.l.6.1.1.1.1.5.1.). Thus, acrolein or methacrolein reacted with the auxiliary under acidic catalysis to form the corresponding dienamines 31. 

Asymmetric cyclopropanation. The ability to effect ligand exchange between rhodium(II) acetate and various amides has lead to a search for novel, chiral rhodium(II) catalysts for enantioselective cyclopropanation with diazo carbonyl compounds. The most promising to date are prepared from methyl (S)- or (R)-pyroglutamate (1), [dirhodium(ll) tetrakis(methyl 2-pyrrolidone-5-carboxylate)]. Thus these complexes, Rh2[(S)- or (R)-l]4, effect intramolecular cyclopropanation of allylic diazoacetates (2) to give the cyclo-propanated y-lactones 3 in 65 S 94% ee (equation 1). In general, the enantioselectivity is higher in cyclopropanation of (Z)-alkenes. 

Many of the syntheses are lengthy, and most contain some specialized reactions. The following problems emphasize the planning aspect of amino acid-based enantioselective syntheses starting with either L-glutamic acid or (5 )-pyroglutamic acid. The few reactions that are included are either familiar or similar to those covered in earlier chapters. 

In 2008, Ye and coworkers reported that chiral NHCs prepared from l-pyroglutamic acid were efficient catalysts for the enantioselective Staudinger reaction of ketenes with imines. The corresponding c/s-p-lactams 158 were obtained in good yields with good diastereoselectivities and excellent enantioselectivities (up to 99% ee) (Scheme 20.66). In the same year. Smith and coworkers independently reported the NHC-catalysed [2 + 2] cycloaddition of disubstituted ketenes and N-tosylimines. ... 

In 2010, Ye and co-workers [20a] found that the chiral triazolium salts 5 derived from L-pyroglutamic acid could improve the reaction, affording products in up to 99% ee (Scheme 7.5). The substrates were also widely broaded. Connon and coworkers [20b] also explored these reactions by using this series of catalysts but with a pentafluorophenyl substituent to enhance the catalyst efficiency and improve the enantioselectivity. 

Ye and coworkers have since reported a wide range of cycloadditions using different electrophilic partners, all in the presence of pyroglutamic acid-derived triazolium catalysts [120]. A noteworthy example is represented by the enantioselective formal [4-1-2] cycloaddition of ketenes with enones 151 to obtain dihydropyranones... 

---