Synthesis and Enantioselective Baeyer-Villiger Oxidation of Prochiral Perhydro-pyranones with Recombinant E. coli Producing Cyclohexanone Monooxygenase

Marko D. Mihovilovic; Florian Rudroff; Wolfgang Kandioller; Birgit Grötzl; Peter Stanetty; Helmut Spreitzer

doi:10.1055/s-2003-42035

LETTER

Synthesis and Enantioselective Baeyer-Villiger Oxidation of Prochiral Perhydro-pyranones with Recombinant E. coli Producing Cyclohexanone Monooxygenase

Marko D. Mihovilovic*^a, Florian Rudroff^a, Wolfgang Kandioller^a, Birgit Grötzl^a, Peter Stanetty^a, Helmut Spreitzer^b
^a Vienna University of Technology, Institute for Applied Synthetic Chemistry, Getreidemarkt 9/163, 1060 Vienna, Austria
Fax: +43(1)5880115499; e-Mail: mmihovil@pop.tuwien.ac.at;
^b Vienna University, Institute of Pharmaceutical Chemistry, Vienna, Austria

Abstract

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Abstract

Recombinant whole cells of Escherichia coli overexpressing Acinetobacter sp. NCIMB 9871 cyclohexanone monooxygenase (E.C. 1.14.13.22) have been utilized for the Baeyer-Villiger oxidation of prochiral perhydro-pyranones. The spatial limitations of the enzyme’s active site have been estimated by increasing the chain length of cis-substituents in positions 2 and 6. A diastereoselective synthetic sequence to the required substrate ketones has been developed utilizing high pressure hydrogenation.

Key words

biocatalysis - recombinant whole-cell biotransformation - cyclohexanone monooxygenase - Baeyer-Villiger oxidation - enantioselectivity

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References

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Typical procedure for the high pressure hydrogenation:
Precursor 5 dissolved in anhyd MeOH was hydrogenated with Pd/C (10%, 300 mg) in a Büchi steel autoclave under H₂ atmosphere (20 bar) for 2 d. The solution was filtered through a bed of Celite^® and MeOH was evaporated. In the case of partial ketal formation (6), the crude material was treated with a 5:1 mixture of THF and 0.1 N HCl at r.t. overnight. The solution was washed with NaHCO₃, extracted with CH₂Cl₂, dried over Na₂SO₄, filtered, and concentrated in vacuo. Pure 1 was obtained after Kugelrohr distillation or flash column chromatography.
cis -Tetrahydro-2,6-dimethyl-4 H -pyran-4-one (1a): 42% yield, colorless liquid, bp 50 °C/12mbar (Kugelrohr),
¹H NMR (200 MHz, CDCl₃): δ = 1.35 (d, J = 6 Hz, 6 H), 2.10-2.45 (m, 4 H), 3.61-3.80 (m, 2 H),
¹³C NMR(50 MHz, CDCl₃): δ = 21.9 (q), 48.8 (t), 72.9 (d), 207.2 (s).
cis -Tetrahydro-2,6-diethyl-4 H -pyran-4-one ( 1b): 57% yield, colorless liquid, bp 81-83 °C/11mbar (Kugelrohr).
¹H NMR (200 MHz, CDCl₃): δ = 1.00 (t, J = 7 Hz, 6 H), 1.43-1.81 (m, 4 H), 2.11-2.45 (m, 4 H), 3.39-3.55 (m, 2 H).
¹³C NMR (50 MHz, CDCl₃): δ = 9.6 (q), 29.3 (t), 47.5 (t), 78.2 (d), 207.7 (s).
cis -Tetrahydro-2,6-dipropyl-4 H -pyran-4-one ( 1c): 56% yield, beige oil.
¹H NMR (200 MHz, CDCl₃): δ = 0.90 (t, J = 6 Hz, 6 H), 1.30-1.80 (m, 8 H), 2.15-2.40 (m, 4 H), 3.60-3.75 (m, 2 H).
¹³C NMR (50M Hz, CDCl₃): δ = 14.3 (q), 19.0 (t), 38.9 (t), 48.4 (t), 77.1 (d), 207.9 (s).
cis -Tetrahydro-2,6-bis-(1-methylethyl)-4 H -pyran-4-one ( 1d): 71% yield, colorless oil, bp: 90-95 °C/0.1 mbar (Kugelrohr).
¹H NMR (200 MHz, CDCl₃): δ = 0.90, 0.95 (2 × d, J = 6 Hz, 2 × 6 H), 1.75 (oct, J = 6 Hz, 2 H), 2.10-2.45 (m, 4 H), 3.20-3.30 (m, 2 H).
¹³C NMR (50 MHz, CDCl₃): δ = 18.2 (t), 33.4 (d), 45.3 (t), 81.7 (d), 208.9 (s).
cis -Tetrahydro-2,6-dibutyl-4 H -pyran-4-one ( 1e): 35% yield, beige oil.
¹H NMR (200 MHz, CDCl₃): δ = 0.90-1.00 (m, 6 H), 1.20-1.80 (m, 12 H), 2.10-2.40 (m, 4 H), 3.40-3.55 (m, 2 H).
¹³C NMR (50 MHz, CDCl₃): δ = 14.4 (q), 22.9 (t), 27.9 (t), 36.5 (t), 48.8 (t), 77.4 (d), 208.4 (s).

CH₂Cl₂ was required to achieve efficient extraction of lactones 2a-c from the fermentation broth.

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Physical and spectroscopic data of lactones 2:

cis -2,7-Dimethyl-1,4-dioxepan-5-one ( 2a): colorless oil.
¹H NMR (400 MHz, CDCl₃): δ = 1.18 (d, J = 6 Hz, 3 H), 1.29 (d, J = 6 Hz, 3 H), 2.67 (dd, J = 14 Hz, ca 1 Hz, 1 H), 2.92 (dd, J = 14 Hz, 5 Hz, 1 H), 3.79-3.99 (m, 2 H), 4.02 (dd, J = 13 Hz, ca 1 Hz, 1 H), 4.20 (dd, J = 14 Hz, 6 Hz, 1 H).
¹³C NMR (100 MHz, CDCl₃): δ = 18.6 (q), 23.5 (q), 45.6 (t), 71.0 (d), 74.4 (t). 75.5 (d), 173.8 (s).
cis -2,7-Diethyl-1,4-dioxepan-5-one ( 2b): colorless oil.
¹H NMR (400 MHz, CDCl₃): δ = 0.99 (t, J = 9 Hz, 3 H), 1.00 (t, J = 9 Hz, 3 H), 1.40-1.75 (m, 4 H), 2.69 (dd, J = 16 Hz, ca 1 Hz, 1 H), 2.90 (dd, J = 16 Hz, 10 Hz, 1 H), 3.50-3.67 (m, 2 H), 4.08 (dd, J = 13 Hz, ca 1 Hz, 1 H), 4.21 (dd, J = 13 Hz, 6 Hz, 1 H).
¹³C NMR (100 MHz, CDCl₃): δ = 9.8 (q), 9.9 (q), 25.5 (t), 30.0 (t), 43.8 (t), 73.4 (t), 75.5 (d), 80.3 (d), 173.6 (s).
cis -2,7-Dipropyl-1,4-dioxepan-5-one ( 2c): beige colored oil.
¹H NMR (400 MHz, CDCl₃): δ = 0.90 (t, J = 7 Hz, 6 H), 1.20-1.60 (m, 8 H), 2.65 (d, J = 13 Hz, 1 H), 2.90 (dd, J = 13 Hz, 8 Hz, 1 H), 3.55-3.70 (m, 4 H), 4.05 (d, J = 13 Hz, 1 H) 4.25 (dd, J = 13 Hz, 8 Hz, 1 H).
¹³C NMR (100 MHz, CDCl₃): δ = 13.6 (q), 18.6 (t), 34.2 (t), 38.9 (t), 44.2 (t), 73.7 (t), 73.9 (d), 78.7 (d), 173.5 (s).