Direction of Kinetically versus Thermodynamically Controlled Organocatalysis and Its Application in Chemoenzymatic Synthesis

Abstract

Recent developments in the field of (enantioselective) organocatalysis have established it as a broadly applicable and efficient synthetic tool for the preparation of many types of enantiomerically enriched and enantiomerically pure molecules.[1] In these syntheses, organocatalysts are typically used in amounts of 1 to 20 mol %. [1,2] In general it is assumed that the enantioselective reactions proceed under kinetic control when the amount of catalyst used is within this range. Accordingly, the applied amount of catalyst indicates the degree of catalyst activity, and the catalyst amount can be adjusted in order to optimize the reaction rate and the overall conversion. Although organocatalytic reactions are in general assumed to be kinetically controlled within this range of catalyst loadings, it is in principle possible to switch from a kinetically controlled to a thermodynamically controlled regime even within this narrow range of catalyst loadings and within typical reaction times. Herein we report such an example in which the switch from kinetic to thermodynamic control occurs through a variation of catalyst loading in a narrow range between 0.5 and 10 mol %. Since the transformations reported here can be carried out in water, this also allows new efficient applications for chemoenzymatic one-pot multistep syntheses in aqueous reaction media. [3] As a model reaction we chose the aldol reaction of acetone (2) with 3-chlorobenzaldehyde (1) in the presence of the organocatalyst 3, which was developed by Singh et al. [4] In previous work, we conducted such reactions at room temperature as we had aimed at a combination with enzymatic syntheses, and in this connection we used a loading of 5 mol % of the organocatalyst 3.[5] Under these reaction conditions the aldol reaction of 2 (9 equiv) with 1 proceeded with an enantioselectivity of 70 % ee (Scheme 1). [6] With a view toward chemoenzymatic one-pot syntheses in aqueous medium we also have been interested in conducting the aldol reaction in this reaction medium. Accordingly we tested this transformation in aqueous NaCl. We observed that with the same catalyst amount (5 mol %), the reaction gave significantly lower enantioselectivity after 48 h, leading to the formation of the desired product (S)-4 with only 47 % ee (Figure 1). An even more surprising result was obtained in an experiment with 10 mol % of the organocatalyst (R,R)-3, which led to a complete loss of enantioselectivity (0 % ee). To determine the reasons for this drastic decrease of enantioselectivity, we first studied the effect of lower catalyst amounts. Interestingly, when the catalyst amount was lowered to 1.0 mol %, the enantioselectivity of the reaction continuously improved (Figure 1). For example, in the presence of 1.0 mol % of the catalyst a high, greatly improved enantioselectivity of 91 % ee was achieved at a product-based conversion of 90 % (95 % overall conversion). A further increase of the enantioselectivity up to 93 % ee at a product-based conversion of 92 % (95 % overall conversion) was...

Opportunities and challenges for combining chemo- and biocatalysis

“…It is noteworthy that the reaction spectrum of asymmetric organo-and biocatalysis is complementary, thus enabling a range of unique synthetic cascades when combined. The potential of such chiral organocatalysts to be used in chemoenzymatic one-pot processes has been demonstrated, for example, for an asymmetric organocatalytic C-C bond-forming reaction with subsequent biotransformations with redox enzymes [34][35][36][37] . When an initial enantioselective aldol reaction catalysed by a readily accessible β -amino alcohol-derivative is 'merged' with a subsequent diastereoselective biocatalytic reduction, 1,3-diols are obtained with high conversion as well as excellent diastereo-and enantioselectivity (diastereometric ratio (d.r.)…”

“…3a) 35 . Interestingly, one-pot processes proceeding in aqueous medium based on this synthetic sequence have been realized for the sequential as well as the concurrently running tandem mode [34][35][36] . Besides aldol reactions, asymmetric organocatalytic Mannich-type reactions have …”

Iron(III) chloride catalyzed glycosylation of peracylated sugars with allyl/alkynyl alcohols

“…This is due to the catalyst concentration which plays a fundamental role in this glycosylation reaction. 17 Also, catalyst loadings 7 and 5 mol% gave the corresponding product in low yield as compared with the use of 10 mol% (Table 3, entries 3-5). In all cases, the uncharacterizad polymerization products or side products were also observed, whereas using 10 mol% FeCl 3 , comparative low amounts of byproduct formation was observed.…”

β- and σ-Amino acids (2,3- and 3,4-trans-CHA) as catalysts in Knoevenagel condensation and asymmetric aldol reactions

“…A similar dependency of the enantiomeric excess on reaction time (or catalyst loading) has recently been described by Gröger, Berkessel and co-workers. 47 No product formation was detected when the aldol reaction was carried out using 2,3-trans-CHA (2) or 3,4-trans-CHA (4) in the pure forms. Also, the condensation product (elimination of water with formation of the ,β-unsaturated ketone) was not observed.…”