Organic Chemistry Portal
Organic Chemistry Highlights

Sunday, March 25, 2007
Vasco D. B. Bonifacio
Technical University of Lisbon

Proline Derivatives in Organic Synthesis

Since the discovery of L-proline-catalysed reactions, this unique amino acid as been extensively studied as an organocatalyst. Proline has a rigid ring structure, which leads to its special role as a bending template in peptide chains. In order to enlarge the scope of proline-catalysed reactions, an extensive research program to explore derivatives has been pursued, namely in the development of proline-based bioactive compounds, ligands, and organocatalysts. In this Highlight, the literature from 2006 to present is reviewed. A general picture of recent developments is presented in Scheme 1; the preparations are discussed in Section 1, and in Section 2, selected examples were chosen to demonstrate the potential of the proline-assisted chemistry using these derivatives as asymmetric catalysts and auxiliaries.

1. Reactivity and synthesis of proline derivatives

Jung and Avery developed a diastereoselective synthesis of (2S,4S)- and (2S,4R)-5-hydroxypipecolic acid through a regioisomeric ring expansion reaction and stereoselective reduction. These fragments can be used in the synthesis of novel cysteine protease inhibitors. (Tetrahedron: Asymmetry 2006, 17, 2479. DOI: 10.1016/j.tetasy.2006.07.035).

A divergent, chemical synthesis of N-protected prolines bearing a fluorocarbon moiety was developed by Ichikawa and co-workers. This protocol combines (i) oxirane ring opening with (trifluoromethyl)vinyllithium and (ii) 5-endo-trig cyclisation of N-(homoallyl)sulphonamides. This method could find wide application in the design of new organocatalysts and the synthesis of the new fluorine-containing peptides (J. Org. Chem. 2006, 71, 8748. DOI: 10.1021/jo061421n).

Brigaud and co-workers successfully developed a straightforward synthetic route for the synthesis of novel highly constrained α-trifluoromethyl α-amino acids in enantiopure form from chiral trifluoropyruvate-based imine or oxazolidines. The key step is a diastereoselective allylation reaction of ethyl trifluoropyruvate and (R)-phenylglycinol-based oxazolidines or imine. The lactone obtained by cyclisation of the resulting hydroxy ester proved to be a valuable intermediate for the synthesis of fluorinated proline derivatives (Org. Lett. 2006, 8, 6123. DOI: 10.1021/ol062593+).

A very rapid, flexible and efficient approach to highly substituted proline derivatives was developed by Knight and Amjad. These authors found that highly substituted α-alkenyl-α-aminoesters underwent smooth 5-endo iodocyclisations, both in the presence or absence of base, in good to excellent yields and with moderate stereoselectivity (Tetrahedron Lett. 2006, 47, 2825. DOI: 10.1016/j.tetlet.2006.02.017).

Gais and co-workers describe the intramolecular substitution of chloride derivatives which allows the enantioselective synthesis of a bicyclic 3,4-unsaturated proline, and the asymmetric synthesis of monocyclic 3,4-unsaturated prolines and 4-methylene prolines through a fluorine ion mediated migratory cyclisation of functionalised vinyl aminosulphoxonium salts (J. Am. Chem. Soc. 2006, 128, 7360. DOI: 10.1021/ja061152i).

2. Proline derivatives in organocatalysis

Ma and co-workers found that CuI-catalysed coupling between aryl iodides and β-ketoesters can be performed at -45 C through a combination of ortho-substitution, and ligand and solvent effects (70-82% yield; in the case of R1= CO2Me a low yield and ee were observed). This represents the lowest reaction temperature for Ullmann-type reactions to date. The excellent enantioselectivity (71-93% ee) provided evidence for the participation of the Cu(I)-amino acid chelate in the transition state of the reaction. Moreover, it was found that trans-4-hydroxy-L-proline was a superior ligand to L-proline (J. Am. Chem. Soc. 2006, 128, 16050. DOI: 10.1021/ja066991j).

Several proline derivatives were tested by Hanessian and co-workers in the organocatalysed conjugate addition of symmetrical 2-nitroalkanes to 2-cycloalkenones. Trans-4,5-methano-L-proline was found to be the best catalyst (>99% ee and excellent chemical yields). The use of 1-nitroalkanes afforded diastereomeric syn/anti products (enantioenrichment favouring the anti-isomer) (Org. Lett. 2006, 8, 4787. DOI: 10.1021/ol0618407).

Tsogoeva and co-workers explored the potential of 4-trans-aminoproline-based di- and tetrapeptides as organocatalysts for Michael and aldol reactions. The authors have successfully applied these chiral catalysts in the enantioselective conjugate addition of nitroalkanes to cyclic enones (with up to 88% ee and up to 100% yield) and to direct aldol reactions with good yields and enantioselectivity (Tetrahedron: Asymmetry 2006, 17, 989. DOI: 10.1016/j.tetasy.2006.03.012).

It was found that new, versatile multifunctional organocatalysts developed by Benaglia and co-workers promoted high enantioselectivity, so that direct aldol condensation between acetone, methoxyacetone or cyclohexanone and different aldehydes could be carried out in very good yields and high enantioselectivity. Preliminary experiments showed that these organocatalysts can also promote the multicomponent Mannich reaction. The organocatalyst can be easily obtained by the condensation of (S)-proline with 1,1’-binaphthyl-2,2’-diamine derivatives in a few steps (Tetrahedron: Asymmetry 2006, 17, 2754. DOI: 10.1016/j.tetasy.2006.10.018).

V. D. B. Bonifacio, Org. Chem. Highlights 2007, March 25.