Asymmetric Aldol “Reaction in Water” Using Ferrocene-Amino Acid Conjugates

Abstract

This article reports an array of water-compatible organocatalysts. The precatalysts are based on ferrocene (Fc) conjugates of L-amino acids having the general formula Fc[C(O)− O-aa-OBz] n and Fc[C(O)−NH-Z-Lys-Obz] n ; aa = 4-trans-Z-Hyp, 4-cis-Z-Hyp, and Z-Ser; n = 1, 2; Z = benzyloxy carbonyl, Bz = benzylic; Hyp = hydroxyproline, Ser = Serine, and Lys = Lysine.The Fc is coupled to the amino acids through the functional group that resides in the amino acid side chain, while the α-amine and αcarboxyl groups are protected by Z and Bz moieties, respectively. The removal of protecting groups affords the Fc catalysts. Circular dichroism (CD) of disubstituted Fc-Hyp amino acid precatalysts displays an induced helical chirality at the Fc region of the spectra due to the π−π interactions of the aromatic Z and Bz groups, while disubstituted Fc-precatalysts of Ser and Lys show a positive Cotton effect as a result of intramolecular, interstrand H-bonding, and π−π interactions. The disubstituted Fc catalysts were CD "silent". The studied catalysts promote asymmetric aldol of 4-nitrobenzaldehyde with acetone in water (>70 equiv) at 20 mol % catalyst loading. The catalytic conversion and enantioselectivities (ee) of the control catalysts follow the order Pro ≈ Hyp > Ser > Lys. The monosubstituted Fc catalysts display good conversions (30−90)% and ee (50−80)% and follow a similar decreasing order to their respective control catalysts. The ee of these catalysts outperforms their corresponding control. The disubstituted Fc catalysts express both low conversions and ee. The catalytic behavior of the catalysts is rationalized by both a "hydrophobic" effect and the amino acid propensity to form zwitterions in water at pH ∼ 7.