Synergy, Compatibility, and Innovation: Merging Lewis Acids with Stereoselective Enamine Catalysis

Abstract

In recent years there has been an accelerated rate of development in the field of organocatalysis, with asymmetric organocatalysis now reaching full maturity. The invention of new organocatalytic reactions and the exploration of new concepts now appear in tandem with the application of organocatalytic techniques in the synthesis of natural products and active pharmaceutical ingredients (APIs). After a "golden rush" in organocatalysis, researchers are now starting to combine different methods, thereby taking advantage of the significant benefits of synergy. Metals are used in combination with organocatalytic processes, thus reaching complexity that is found in nature, where enzymes take advantage of the presence of certain metals to increase the arsenal of organic transformations available. In this Focus review, we illustrate the possibility of a "happy marriage" between Lewis acids and organocatalytic stereoselective processes. Questions have been raised about the combination of Lewis acids and organocatalysis owing to the presence of water and/or strong bases in these processes. Some Lewis acids have been shown to be compatible with organocatalysis and concepts relating to their use will be illustrated herein. To summarize the fruitful use of Lewis acids in stereoselective organocatalytic processes, we will draw attention to the advantages and selectivity achieved using this method.

From QCA (Quantum Cellular Automata) to Organocatalytic Reactions with Stabilized Carbenium Ions

“…If the coordinated water is staying on the metal and it is not highly exchanged, activation of a substrate by occupation of a far more coordinative site would be impossible. By selection of the right metals, the merging of enamine catalysis with Lewis acid‐catalyzed reactions would be possible 92. When we were investigating alcohols compatible in our organocatalytic alkylation, we immediately found out that 1,3 diphenyl allylic alcohol was not a reactive substrate, due to its high electrophilicity 93.…”

“…By selection of the right metals, the merging of enamine catalysis with Lewis acid-catalyzed reactions would be possible. [92] When we were investigating alcohols compatible in our organocatalytic alkylation, we immediately found out that 1,3 diphenyl allylic alcohol was not a reactive substrate, due to its high electrophilicity. [93] So, it was not possible to generate the corresponding carbenium ion.…”

A Practical and Stereoselective Organocatalytic Alkylation of Aldehydes with Benzodithiolylium Tetrafluoroborate

“…The organocatalytic stereoselective α‐alkylation of aldehydes represents a challenging area of development in organocatalysis . This reaction has been the source of many innovative breakthroughs in organocatalysis, which has lead to the combination of transition metals with organocatalytic modes of activation . The combination of organocatalysis with photoredox reactions is particularly intriguing, allowing the establishment of a redox cycle by the action of light, which can be captured by a transition metal complex, or by an organic dye …”

Asymmetric γ‐Allylation of α,β‐Unsaturated Aldehydes by Combined Organocatalysis and Transition‐Metal Catalysis

“…With respect to the regioselectivity of allylation reactions,a ccess to av ariety of both linear and branched products has been achieved, although the selectivity is often dependent on the applied substrates and reaction conditions.Achieving selective access to both regioisomers of the products in adivergent fashion is thus no simple task and typically two different methodologies must be developed. [6] Despite the promise of these two branches of organocatalysis,t he combination of vinylogous aminocatalysis with transitionmetal catalysis in individual catalytic cycles is rare. [4] Ar emarkable feature of this mode of catalysis is the ability of aminocatalysts to promote asymmetric reactions by both HOMOraising and LUMO-lowering strategies.I nr ecent years,t wo new exciting fields have emerged in organocatalysis:f irstly, the application of vinylogous aminocatalysis has proven successful in asymmetric functionalization at remote centers of polyunsaturated carbonyl compounds.…”

“…At this point, we set out to develop am ethod for the formation of linear g-allylated products.I tw as envisioned that the regioselectivity could be controlled by exchanging the metal species,a nd given the propensity of palladium-based catalysts to promote the desired regioselectivity, [2,16] our focus turned towards these type of catalysts.T oo ur delight, employment of ap alladium catalyst under otherwise similar reaction conditions (see the Supporting Information for optimization) facilitated the formation of linear products (6) in excellent selectivity (Table 5). Thes cope of the reaction …”