Combination of Olefin Metathesis and Enzymatic Ester Hydrolysis in Aqueous Media in a One‐Pot Synthesis

Abstract

A new synthetic method for the preparation of cyclic malonic acid monoesters in aqueous media was developed based on the combination of a metathesis reaction and subsequent biocatalytic hydrolysis with a pig liver esterase in a one-pot synthesis. Both reaction steps proceed smoothly under optimized conditions in aqueous media requiring only a low amount of the metal catalyst for the metathesis reaction. Notably, the applied biocatalyst turned out to be highly compatible with the metal catalyst showing no significant influence on the enzyme activity.

Synthesis of substituted cycloalkene-1,1-dicarboxylates via olefin metathesis in water

“…However, when comparing this reaction shown in Scheme 3 with the analogous one using the less sterically hindered, non-substituted substrate of type 1 with n = 1 (98% and 100% conversion, see reference 14), it also has to be stated that 3a is less reactive, which can be attributed to the presence of an additional substituent at the alkene moiety and the resulting steric hindrance in the metathesis step.…”

“…Metathesis reactions in water have gained increasing interest in the last years, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] and provide a range of advantages such as a high potential for the development of sustainable syntheses. Our interest in this field also resulted from the goal to combine metathesis as a metal-catalyzed reaction with enzymatic reactions, which typically require water as the solvent of choice, towards one-pot processes running in the same (aqueous) solvent.…”

“…14,15 In general, several successful examples of one-pot processes through combination of chemo-and bio-catalytic transformations have been established recently. [14][15][16][17][18][19][20][21] A prerequisite and challenge in this field of chemoenzymatic one-pot processes is to find conditions, which make the chemocatalytic step compatible with the enzymatic one. Recently, we reported the proof of concept for such an one-pot process combining metathesis and enzymatic hydrolysis reactions exemplified for the synthesis of cycloalkene-1,1-dicarboxylate monoesters starting from readily available bis-substituted malonates (Scheme 1).…”

“…Recently, we reported the proof of concept for such an one-pot process combining metathesis and enzymatic hydrolysis reactions exemplified for the synthesis of cycloalkene-1,1-dicarboxylate monoesters starting from readily available bis-substituted malonates (Scheme 1). 14 Notably, water turned out to represent an excellent solvent for the metathesis transformation even though the substrate is poorly soluble in water. The resulting cyclic malonate diesters have then be transformed via a selective hydrolysis by means of a biocatalyst (esterase) into their monoesters.…”

“…14 These monoesters are an interesting product class due to their application potential in organic synthesis, for example, in terms of conversion into the corresponding cyclic non-natural α-amino acids bearing a quaternary stereogenic center through amide formation and subsequent Hofmann degradation. 22 However, since our earlier study (reported in a short communication) 14 only covered unsubstituted examples of type 1, there remained an open question, with respect to the synthesis of cyclic malonates via metathesis in water, whether this method is general in terms of substrate scope, and if so, whether other sterically more complex prochiral substituted cycloalkene-1,1-dicarboxylates of type 2 could be prepared efficiently in a similar fashion.…”