One‐pot Chemoenzymatic Synthesis of Chiral 1,3‐Diols Using an Enantioselective Aldol Reaction with Chiral Zn²⁺ Complex Catalysts and Enzymatic Reduction Using Oxidoreductases with Cofactor Regeneration

Abstract

We previously reported on enantioselective aldol reactions of acetone and some aldehydes catalyzed by chiral Zn(2+) complexes of L-prolyl-pendant [12]aneN(4) (L-ZnL(1)) and L-valyl-pendant [12]aneN(4) (L-ZnL(2)) in aqueous solution. Here, we report on the one-pot chemoenzymatic synthesis of chiral 1,3-diols in an aqueous solvent system at room temperature by a combination of enantioselective aldol reactions catalyzed by Zn(2+) complexes of L- and D-phenylalanyl-pendant [12]aneN(4) (L-ZnL(3) and D-ZnL(3) ) and the successive enantioselective reduction of the aldol products using oxidoreductases with the regeneration of the NADH (reduced form of nicotinamine adenine dinucleotide) cofactor. The findings indicate that all four stereoisomers of 1,3-diols can be produced by appropriate selection of a chiral Zn(2+)-complex and an oxidoreductase commercially available from the "Chiralscreen OH" kit.

Design and Synthesis of Chiral Zn2+ Complexes Mimicking Natural Aldolases for Catalytic C–C Bond Forming Reactions in Aqueous Solution

“…Among the nine enzymes of “Chiralscreen ® OH” tested (E001, 021, 031, 039, 041, 051, 057, 092, and 119), four enzymes such as E001, E031, E039, and E092, were found to be effective for the reduction of 7a (entries 4–7) [34]. In general, E001 and E039 gave better chemical yields than E031 and E092 (entries 4 and 6 versus entries 5 and 7).…”

“…aNumbers in parentheses are the concentrations of catalysts in solvent;bSolvent ratio: DMSO/acetone = 4/1 (entries 1–3), acetone/H 2 O = 4/1 (entries 4–16);cIsolated yield;dCatalytic Turnover Number (=yield/equivalents of catalyst);eDetermined by HPLC analysis using a chiral column (references [31,34]);fZn 2+ complexes, l -CdL 4 , and l -CuL 4 were formed in situ ;gIsolated Zn 2+ complexes were used;h l -L 4 was extracted with CHCl 3 from aq. NaOH (pH > 12) prior to use.…”

“…Zn 2+ complexes were formed in situ ;bIsolated yield;cCatalytic turnover number (=chemical yield/equivalents of catalyst);dDetermined by HPLC analysis using a chiral column (references [31,34]).…”

One-Pot Combination of Metal- and Bio-Catalysis in Water for the Synthesis of Chiral Molecules

“…In this sense, this section covers the combination of: (i) Pd-catalyzed Suzuki coupling with bioreductions [100], bioaminations [101] or enzymatic halogenations [102,103]; and (ii) Pd-catalyzed Heck reaction and bioreduction [104]. Furthermore, and in the final part of this section, we review the combination of indium-mediated Barbier-type coupling [105] or Zn-catalyzed aldol reactions [106] with enzymatic oxidations or bioreductions, respectively. Pd-catalyzed Suzuki cross-coupling of aryl, vinyl or alkyl halides (or pseudohalides) with organoboron reagents is one of the most efficient and selective methodologies for the construction of C-C bonds [97,107,108].…”

“…However, and even under the best catalytic conditions (10 equiv. of the To finish this section, we would like to point out that Aoki and co-workers [106] have reported the combination of an enantioselective Zn-catalyzed aldol reaction (between different aromatic aldehydes and acetone) with the subsequent enantioselective bioreduction of the aldol products promoted by commercially-available NADH-dependent oxidoreductases (i.e., from baker's yeast, S. cerevisiae, L. kefir or Daicel Co. Ltd., Tokyo, Japan) employing a phosphate buffer (pH 7.2) as reaction media. All four possible stereoisomers of the obtained optically-active 1,3-diols could be selectively produced by employing this chemoenzymatic methodology.…”