Enantiodivergent Chemoenzymatic Dynamic Kinetic Resolution: Conversion of Racemic Propargyl Alcohols into Both Enantiomers

Abstract

Natural lipases typically recognize enantiomers of alcohols based on the size differences of substituents near the carbinol moiety and selectively react with the R enantiomers of secondary alcohols. Therefore, lipase-catalyzed dynamic kinetic resolution (DKR) of racemic secondary alcohols produces only R enantiomers. We report herein a method for obtaining S enantiomers by DKR of secondary 3-(trialkylsilyl)propargyl alcohols by using a well-known Rselective Pseudomonas fluorescens lipase in combination with a racemization catalyst VMPS4, in which the silyl group reverses the size relationship of substituents near the carbinol moiety. We have already reported R-selective DKR of the corresponding propargyl alcohols without substituents on the ethynyl terminal carbon, and the presence of an easily removable silyl group has enabled us to produce both enantiomers of propargyl alcohols in high chemical yields and with high enantiomeric excess. In addition, immobilization of the lipase on Celite was found to be important for achieving a high efficiency of the DKR.

Lipase/H2SO4‐Cocatalyzed Dynamic Kinetic Resolution of Alcohols in Pickering Emulsion

“…Compartmentalization by immobilizing racemization catalysts and/or lipases inside mesoporous materials has also been reported, [24–26] including our original mesoporous silica‐supported oxovanadium catalyst (V‐MPS4), in which an oxovanadium species was covalently bound to the surface of the 4‐nm‐sized pores in mesoporous silica [27–29] . However, although highly compatible with lipases, V‐MPS4 is prone to side reactions such as ether formation during the racemization process [30–33] . In addition, its racemization profile is limited by the electronic nature of the substrates, with slow racemization observed for simple 1‐phenylethanol ( 1 a : R 1 =Ph, R 2 =Me, Table S2).…”

“…[27][28][29] However, although highly compatible with lipases, V-MPS4 is prone to side reactions such as ether formation during the racemization process. [30][31][32][33] In addition, its racemization profile is limited by the electronic nature of the substrates, with slow racemization observed for simple 1-phenylethanol (1 a: R 1 = Ph, R 2 = Me, Table S2).…”

“…Although the processes described above address the low compatibility of lipases and racemization catalysts, the side reactions during racemization remain a considerable challenge. [22,23,[30][31][32][33] To solve this problem, we envisioned a new strategy using an oil/water biphasic medium for chemoenzymatic DKR (Scheme 1b). In this biphasic DKR, lipase-catalyzed KR of (�)-1 proceeds in the oil phase (A) while Brønsted acidcatalyzed racemization occurs in the aqueous phase (B).…”

“…Although the processes described above address the low compatibility of lipases and racemization catalysts, the side reactions during racemization remain a considerable challenge [22,23,30–33] . To solve this problem, we envisioned a new strategy using an oil/water biphasic medium for chemoenzymatic DKR (Scheme 1b).…”

Expanding the Synthetic Toolbox through Metal–Enzyme Cascade Reactions

“…However, the combination of both worlds must be employed in a reasonable way, taking advantage of both catalysis but also being aware of existing limitations to advance, and therefore considering solutions in the reaction setups. − There is no more powerful technique than organometallic chemistry for C–C or C–X bond formation, while enzymes can provide unique possibilities for chiral induction, so their cooperative work in one-pot multistep transformations undoubtedly constitutes one of the most straightforward manners to design controlled complexity. Gladly, this is an area in continuous evolution, and remarkable examples have recently appeared in the literature including valuable chemoenzymatic cascades. − …”