Enzymatic Resolution of 3-oxodicyclopentadiene on a Decagram Scale

Abstract

The chiral building block 3-oxodicyclopentadiene (1) can be readily resolved on a decagram scale by a short sequence consisting of (1) reduction to the corresponding endo-alcohol, (2) enzymatic oxidative resolution with a ketoreductase enzyme to give (+)-1 and the (+)-form of the endo-alcohol, and (3) reoxidation of the (+)-endo-alcohol with another ketoreductase to give (–)-1. With a selectivity factor of 310, the enantiomeric ratios of the resolved (+)-endo-alcohol and (+)-ketone are both >99:1. Both enzymatic oxidations could be performed with a at least 300:1 substrate/catalyst ratio (w/w).

Key words

enzymes - oxidation - resolution - alcohols - gram-scale synthesis - tetrahydromethanoindenone

• References and Notes


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capnellene:
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• 7 (±)-endo-Alcohol (±)-4A 1.0 M solution of DIBAL-H in toluene (89 mL, 89 mmol, 1.3 equiv) was added dropwise to a solution of (±)-1 (10.0 g, 68 mmol, 1.0 equiv) in toluene (200 mL) at –78 °C, and the mixture was stirred for 20 min at –78 °C. The reaction was then quenched with MeOH (40 mL), and sat. aq NaK tartrate (120 mL) was added. The mixture was stirred until a clear solution formed, and the layers were then separated. The aqueous layer was extracted with CH₂Cl₂ (2 × 200 mL), and the combined organic layers were dried (Na₂SO₄) and concentrated to give a yellowish crystalline solid; yield: 9.7 g (97%); mp = 54.4–55.5 °C. ¹H NMR (300 MHz, CDCl₃): δ = 6.16 (dd, J = 5.6, 2.3 Hz, 1 H), 5.82 (dd, J = 5.6, 3.1 Hz, 1 H), 5.59 (s, 2 H), 4.67 (d, J = 7.4 Hz, 1 H), 3.30 (dd, J = 7.3, 3.6 Hz, 1 H), 2.99–2.91 (m, 3 H), 1.57 (d, J = 8.0 Hz, 1 H), 1.46 (d, J = 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 135.4, 135.3, 134.8, 133.5, 76.1, 54.2, 52.7, 47.2, 47.0, 44.9.
• 8 CCDC 1827649, 1827648, 1831369, and 1827647 contain the supplementary crystallographic data for compounds (+)-1, (–)-1, (–)-exo-3, and (±)-endo-4, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 9 The distance between the C(3) hydrogen atom and C(9) was measured from the X-ray structure of (–)-exo-3 to be 2.58 Å on average, and the distance between the C(3) oxygen atom and C(9) was in (±)-4 was 2.86 Å on average.
• 10 Another 10.7 g batch of (+)-4 was oxidized under the following conditions: total reaction volume: 75 mL; initial loading of KRED-P1-C01: 27 mg. An additional 10 mg of KRED-P1-C01 added after 73 hours. In this way, the total reaction time was reduced to five days, affording a quantitative yield (10.6 g) of (–)-1.
• 11 Oxidative Enzymatic Kinetic Resolution of (±)-4KRED-P1-B02 (60 mg) in KRED Recycle Mix P (3 mL) was added to a solution of (±)-endo-4 (23.7 g, 160 mmol) in acetone (47 mL) and KRED Recycle Mix P (110 mL). The mixture was stirred for 14 h at r.t., then extracted with Et₂O (2 × 100 mL). The extracts were washed with brine (50 mL), dried (Na₂SO₄), and concentrated. Purification by Combiflash (100% hexane to 20% EtOAc–hexane) gave alcohol (+)-endo-4 [yield: 9.9 g (42%), er > 99:1] and ketone (+)-1 [yield: 9.7 g (41%), er > 99.5:0.5] as white crystalline solids.(+)-endo-4: mp = 66.6–68.2 °C (Lit.³ 81–82.5 °C); [α]_D +120° (c = 1.0, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃): δ = 6.16 (dd, J = 5.6, 2.3 Hz, 1 H), 5.82 (dd, J = 5.6, 3.1 Hz, 1 H), 5.59 (s, 2 H), 4.67 (d, J = 7.4 Hz, 1 H), 3.30 (dd, J = 7.3, 3.6 Hz, 1 H), 2.99–2.91 (m, 3 H), 1.57 (d, J = 8.0 Hz, 1 H), 1.46 (d, J = 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 135.4, 135.3, 134.8, 133.5, 76.1, 54.2, 52.7, 47.2, 47.0, 44.9.Enzymatic Oxidation of Alcohol (+)-4 to Ketone (–)-1:KRED-P1-C01 (34 mg) in KRED Recycle Mix P (1 mL) was added to a solution of the resolved alcohol (+)-4 [9.7 g, 65 mmol, ee >99%, containing <0.5% ketone (+)-1] in acetone (24 mL) and KRED Recycle Mix P (45 mL). The mixture was stirred for 7 days at 30 °C then extracted with Et₂O (2 × ca. 200 mL) washed with brine, dried (Na₂SO₄), and concentrated to give a white crystalline solid; yield: 9.3 g (97%, er > 99:1).