Inversion of Diastereoselectivity Depending on Substrate Concentration in ­Baker’s Yeast Catalyzed Reduction of σ-Symmetrical 1,3-Cyclopentadiones and 1,3-Cyclohexadiones

Abstract

Inversion of diastereoselectivity caused by a change in substrate concentration was first observed in baker’s yeast catalyzed reduction of σ-symmetrical 2,2-dialkylated cyclopentan-1,3-diones 1,2 and cyclohexan-1,3-dione 20. The selectivity altered by degrees depending on the substrate concentration from 8 mM to 40 mM. Meanwhile, application of the yeast-catalyzed reduction to the hydrogenated compound (5) of 1 afforded a single diastereomer in good yield when the reaction was conducted in high substrate ­concentration (40 mM).

Key words

baker’s yeast catalyzed asymmetric reduction - σ-symmetrical cyclopentane-1,3-dione - substrate concentration

References and Notes

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• 8b

  Not only baker’s yeast but also Saccharomyces cerevisiae (brewing yeast), Bacillus thuringiensis afforded excellent results:

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9

The stereochemistry of 13b (Scheme [4] , Figure [3] ) and 14b (Scheme [5] , Figure [4] ) was confirmed by X-ray crystallography after deriving to bromonicotinates.
Compound 13b: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 0.98 (s, 3 H), 1.24-1.35 (m, 1 H), 1.39-1.72 (m, 5 H), 1.92-2.00 (m, 1 H), 2.05 (br s, 1 H), 2.15-2.24 (m, 1 H), 2.26-2.37 (m, 3 H), 2.43-2.52 (m, 1 H), 3.67 (s, 3 H), 4.11 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.2, 23.0, 25.3, 27.8, 29.2, 33.4, 33.9, 51.6, 53.2, 77.2, 174.3, 220.8.
Compound 14b: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 0.97, (s, 3 H), 1.44-1.73 (m, 4 H), 2.00-2.07 (m, 1 H), 2.12-2.22 (m, 1 H), 2.27-2.37 (m, 2 H), 2.42-2.53 (m, 2 H), 3.14 (br s, 1 H), 3.69 (s, 3 H), 4.21 (br dt, J = 4.4, 2.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 18.7, 18.9, 27.2, 29.2, 33.1, 34.0, 51.9, 53.8, 76.8, 175.1, 221.3.

10

In order to obtain high reproducibility in the reaction with 8 mM substrate, newly opened baker’s yeast must be used. If long-term-stored yeast (longer than ca. 6 months at 4 °C) is used in the reaction, a reduced de is observed. The repro-duced results were obtained with baker’s yeast (Sigma, type II, lot. No. 125K0062).
Compound 9a: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.03 (s, 3 H), 1.51-1.64 (m, 2 H), 1.76 (br s, 1 H), 1.84-1.93 (m, 1 H), 2.16-2.31 (m, 4 H), 2.44-2.52 (m, 1 H), 3.72 (s, 3 H), 4.17-4.20 (m, 1 H), 5.83 (td, J = 1.6, 15.7 Hz, 1 H), 6.92 (td, J = 6.8, 15.7 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.7, 26.8, 27.9, 33.3, 34.9, 51.5, 52.6, 75.8, 121.2, 148.7, 166.9, 219.6.
Compound 9b: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.02 (s, 3 H), 1.67-1.76 (m, 3 H), 1.90-1.97 (m, 1 H), 2.18-2.35 (m, 4 H), 2.44-2.53 (m, 1 H), 3.72 (s, 3 H), 4.13 (br dt, J = 3.7, 4.1 Hz, 1 H), 5.86 (td, J = 1.6, 15.7 Hz), 6.99 (td, J = 6.8, 15.7 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.2, 26.7, 28.2, 28.4, 33.9, 51.4, 52.7, 77.3, 121.0, 149.2, 167.1, 220.0.

11

Chiral HPLC analysis of 9b was performed with a Shimadzu LC-10A Liquid Chromatograph series using a SHISEIDO Ceramospher Chiral RU-1 (0.46 φ × 250 mm). Two enantiomers of 9b were detected at the retention time of 10.7 and 11.7 min by eluting with MeOH, flow rate: 0.5 mL/min, at 50 °C. The enantiomer predominantly obtained in the reaction (entry 1, Table [1] ) appeared at 11.7 min. Meanwhile, two enantiomers of 9a were detected using Daicel CHIRALCEL OJ-H (0.46 φ × 250 mm) at 43.2 and 47.5 min by eluting with a mixed solvent of n-hexane and 2-PrOH (9:1), flow rate: 0.5 mL/min, at 25 °C. The predominant enantiomer in the reaction (entry 2, Table [1] ) was detected at 47.5 min.

12

Chiral HPLC analyses of 13b and 14b were performed with Daicel CHIRALCEL OD-H (n-hexane-i-PrOH = 96:4).