Continuous Flow Enantioselective Three-Componentanti-Mannich Reactions Catalyzed by a Polymer-Supported Threonine Derivative

Abstract

A series of primary amino acid-derived polystyrene-supported organocatalysts was tested in anti-selective Mannich reactions. The polystyrene-immobilized threonine derivative showed the best performance in three-component (hydroxyacetone, anilines and aldehydes) Mannich reactions to provide anti-β-amino-α-hydroxycarbonyl compounds (11 examples; up to 95% ee) and its use could be extended to dihydroxyacetone and protected hydroxyacetones (7 examples; up to 90% ee). The high activity depicted by the catalyst has allowed its implementation in continuous flow. Under this operation mode, the supported threonine catalyst 2 produces anti-Mannich adducts with generally higher diastereo-and enantioselectivity than in batch. A family of five different enantioenriched anti-Mannich adducts has been sequentially prepared in flow by passing different combinations of anilines and aromatic aldehydes over the same sample of catalyst. This confirms the suitability of this methodology for the rapid access to small libraries of enantioenriched compounds.

A fully recyclable heterogenized Cu catalyst for the general carbene transfer reaction in batch and flow

“…In addition to their inherent advantages, such as increased safety, straightforward scale-up and highly simplified work-up, continuous flow processes based on supported catalysts offer the additional advantage of allowing the sequential preparation of small libraries of compounds. 16 In the present instance, such a sequential process would not only be a proof of concept for the robustness and high activity of the catalyst, but it would also enable concise access to various carbene insertion products by sequential synthesis in a flow device. Given the high productivities showcased by the [(PS–TTM)Cu(NCMe)][PF 6 ] catalyst either in batch or in a simple flow process (see above), we decided to assess the feasibility of this concept for the different types of carbene transfer reactions from EDA considered in this study.…”

Recent Advances in Continuous‐Flow Enantioselective Catalysis

“…Enantioselective amination and allylation of aldehydes : In 2013 and 2014, Pericàs and co‐workers demonstrated two enantioselective anti‐Mannich reactions in continuous‐flow conditions . The polystyrene‐supported, pyrrolidine‐based catalyst 47 exhibited very high activity (average 97 % ee ) and excellent stereoselectivity ( anti / syn =95:5) for a variety of aldehyde and ketone substrates.…”

Catalytic Enantioselective Flow Processes with Solid‐Supported Chiral Catalysts

“…Primary amino acids have also been shown to make good catalysts, albeit whereas secondary ones (e. g. proline and derivatives) work better with aldehydes, these are more prone to ketone activation . In 2014, we reported on the three‐component Mannich reaction between hydroxyacetone and glyoxylate imines, that gives an aminohydroxylated compound . To promote this transformation, we immobilized six primary amino acids, of which threonine derivative 13 resulted the most promising one.…”

“…[52] In 2014, we reported on the three- D 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 component Mannich reaction between hydroxyacetone and glyoxylate imines, that gives an aminohydroxylated compound. [53] To promote this transformation, we immobilized six primary amino acids, of which threonine derivative 13 resulted the most promising one. Even if the flow rates were rather low, the three-component reaction could be translated to a continuous regime as depicted in Figure 12.…”