A new functional polymer where proline is bonded to polystyrene through a 1,2,3-triazole linker depicts characteristics targeted for an artificial aldolase. In spite of the hydrophobicity of the polymer backbone, the resin swells in water with building of an aqueous microenvironment. This property, arising from the formation of a hydrogen-bond network connecting the proline and 1,2,3-triazole fragments, is translated into a very high catalytic activity and enantioselectivity toward direct aldol reactions in water.

The fast and highly stereoselective Mannich reaction of aldehydes and ketones with the N-(p-methoxyphenyl) ethyl glyoxylate imine catalyzed by polystyrene resins functionalized with (2S,4R)-hydroxyproline is reported. The effect of the nature of the linker connecting proline with the polymeric backbone has been studied, and a 1,2,3-triazole linker constructed from azidomethyl polystyrene and O-propargyl hydroxyproline turns out to be optimal for catalytic activity and enantioselectivity. With aldehyde donors, fast reactions leading to complete conversion in 1-3 h are recorded in DMF. With ketone donors, the reactions tend to be slower, but can be efficiently accelerated (six-membered ring cycloalkanones) by low-power microwave irradiation. This approach, which greatly facilitates product isolation since the catalyst is removed by simple filtration, has allowed the implementation of the reactions of aldehyde substrates in a continuous-flow, single-pass system. In this manner, the continuous synthesis of the enantiomerically and diastereomerically pure adducts (syn/anti>97:3; ee>99 %) has been achieved at room temperature with residence times of 6.0 min. This methodology has allowed for the preparation of up to 7.8 mmol of the desired Mannich adduct through the use of 0.46 mmol of catalytic resin (5.9 mol %), in a greatly simplified experimental protocol that avoids purification steps.

A set of six solid-supported diarylprolinol catalysts (varying on the anchoring strategy and the type of polymeric support) has been prepared and applied to the enantioselective cyclopropanation reaction. The selected candidate allows implementation of a long flow experiment (48 h) and generates a library of 12 cyclopropanes by sequential flow experiments. The mildness and utility of the method have enabled a telescoped process in which the outstream is directly used in a Wittig flow reaction.

Polystyrene (PS)-supported diphenylprolinol silyl ethers have been developed as highly active catalysts for the enantioselective a-amination of aldehydes. Understanding the mechanism of catalyst deactivation has led to the development of reaction conditions notably extending catalyst life in repeated recycling (10 cycles; accumulated TON of 480) and has allowed the implementation of a continuous flow a-amination process (6 min residence time, 8 h operation).