Synlett
DOI: 10.1055/s-0039-1690216
letter
© Georg Thieme Verlag Stuttgart · New York

A Chemoenzymatic Formal Synthesis of Epoxyquinols A and B

a  Department of Chemistry, Whitman College, 345 Boyer Ave., Walla Walla, WA 99362, USA   Email: collinja@whitman.edu
,
b  Department of Chemistry, Amherst College, A205 Science Center, 25 East Drive, Amherst, MA 01002, USA
,
Madeleine M. Duncan
a  Department of Chemistry, Whitman College, 345 Boyer Ave., Walla Walla, WA 99362, USA   Email: collinja@whitman.edu
› Author Affiliations
Further Information

Publication History

Received: 20 August 2019

Accepted after revision: 08 October 2019

Publication Date:
23 October 2019 (eFirst)

Abstract

A formal synthesis of epoxyquinols A and B was completed in nine steps starting from benzoic acid. Enantioselectivity was established through an enzymatic arene dihydroxylation reaction performed by whole cells of Ralstonia eutropha B9 expressing benzoate dioxygenase. Subsequent formation of the enone core was facilitated by a Dauben–Michno-type oxidative transposition of an allylic tertiary alcohol.

Supporting Information

 
  • References and Notes

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  • 34 Methyl (1S,2R,3S,6S)-3-(Acetoxy)-2-{[tert-butyl(dimethyl) silyl]oxy}-7-oxabicyclo[4.1.0]hept-4-ene-3-carboxylate (11) and Methyl (1R,2S,3R,6R)-2-(Acetoxy)-3-{[tert-butyl (dimethyl)silyl]oxy}-7-oxabicyclo[4.1.0]hept-4-ene-2-carboxylate (12) Preparation of DMDO solution: DMDO was prepared by the procedure reported by Taber et al.40 (CAUTION! DMDO is a volatile peroxide and should be handled with care: the preparation and reactions of DMDO should be carried out behind a safety shield under a hood; see Ref. 40 for details). The preparation was repeated four times to produce sufficient DMDO solution (~100 mL, 60 mM in acetone). The DMDO solution was stored in a sealed round-bottomed flask at –15 °C until use. Epoxidation: Acetate 10 (0.660 g, 2.02 mmol) was cooled in an ice bath and a solution of DMDO in acetone (84 mL, 5.05 mmol, ~60 mM) was added in one portion. The mixture was swirled to dissolve the substrate and the flask was stoppered and placed in a freezer at –15 °C for 2 d until the reaction was complete (TLC). The solution was then concentrated under reduced pressure to give epoxides 11 and 12 [yield: 0.678 g (98%)] in a ratio of 4.5:1 (NMR). Flash column chromatography [silica gel, hexane–EtOAc (5:1) + 2% Et3N] gave an enriched mixture of 11 and 12 as a clear colorless oil [yield: 0.574 g (83%)] in a ratio of 6.5:1.0. 11 Rf  = 0.45 (EtOAc–hexane, 1:3). 1H NMR (400 MHz, CDCl3): δ = 6.36 (dd, J = 9.8, 0.7 Hz, 1 H), 6.14 (ddd, J = 9.8, 2.6, 0.6 Hz, 1 H), 4.19 (d, J = 2.0 Hz, 1 H), 3.74 (s, 3 H), 3.44 (ddd, J = 4.2, m2.1, 0.6 Hz, 1 H), 3.40 (dd, J = 4.1, 2.7 Hz, 1 H), 2.11 (s, 3 H), 0.93 (s, 9 H), 0.17 (s, 3 H), 0.08 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 169.95, 169.73, 134.01, 126.61, 78.97, 72.29, 56.74, 52.68, 47.36, 25.59, 20.89, 18.01, –4.78, –5.24. 12 Rf  = 0.45 (EtOAc–hexane, 1:3). IR (neat): 2955, 2931, 2895, 2858, 1768, 1741, 1234, 1123, 1055 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.03 (ddd, J = 10.0, 3.7, 2.8 Hz, 1 H), 5.79 (ddd, J = 10.0, 1.7, 1.7 Hz, 1 H), 4.65 (dd, J = 2.7, 1.7 Hz, 1 H), 4.35 (d, J = 3.8 Hz, 1 H), 3.85 (s, 3 H), 3.40 (m, 1 H), 2.11 (s, 3 H), 0.90 (s, 9 H), 0.07 (s, 3 H), 0.01 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.68, 169.27, 136.89, 122.89, 80.69, 69.14, 53.64, 52.80, 47.69, 25.59, 21.02, 17.90, –4.65, –5.33. HRMS (ESI+): m/z [M + H]+ calcd for C16H27O6Si: 343.1571; found: 343.1572
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  • 37 Methyl (1S,2S,6R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-5-oxo-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate (14) Preparation of oxidizing solution: Ac2O (1.0 mL, 10.58 mmol) was added to CrO3 (388 mg, 3.88 mmol) under argon, and the mixture was warmed to 75 °C and stirred for 8 min. The resulting dark-brown solution was cooled to r.t. then further cooled in an ice bath before being diluted with CH2Cl2 (3 mL). Oxidative transposition: A solution of tertiary alcohol 13 (800 mg, 2.66 mmol) in CH2Cl2 (6 mL) under argon was chilled in an ice bath. The oxidizing solution was added dropwise over 3 min. The resulting dark-brown mixture was stirred for 5 min and then the reaction was quenched by slow addition of EtOH (6 mL) and solid NaCO3 (1.0 g). The mixture was allowed to warm to r.t. and stirred for 20 min. The dark-brown mixture was then filtered through a pad of Celite and partitioned between Et2O (125 mL) and H2O (40 mL). The phases were separated and the organic layer was washed with H2O (3 × 30 mL), sat. aq NaHCO3 (2 × 30 mL), and brine (1 × 5 mL). The organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure. Flash column chromatography (EtOAc–hexane, 1:10) gave enone 14 as a colorless oil; yield: 640 mg (81%) [α]D 20 +252.18 (c 0.90, EtOAc); Rf  = 0.51 (hexane–EtOAc, 5:1). IR (neat): 3003, 2954, 28889, 1728, 1693, 1246, 1093, 1080, 854, 795 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.69 (d, J = 1.6 Hz, 1 H), 5.20 (s, 1 H), 3.85 (s, 3 H), 3.71 (dd, J = 3.7, 1.6 Hz, 1 H), 3.53 (m, 1 H), 0.88 (s, 9 H), 0.24 (s, 3 H), 0.14 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 194.33, 165.61, 143.63, 130.23, 63.00, 56.86, 52.73, 25.58, 18.00, –4.54, –4.80. HRMS (ESI+): m/z [M + Na]+ calcd for C14H22NaO5Si = 321.1129; found: 321.1129.
  • 38 (1R,5S,6S)-5-{[tert-Butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-oxabicyclo[4.1.0]hept-3-en-2-one (4) Preparation of oxidizing solution: Ac2O (0.27 mL, 2.92 mmol) was added to CrO3 (110 mg, 1.10 mmol) under argon, and the mixture was warmed to 75 °C and stirred for 10 min. The resulting dark-brown solution was then taken off the heat, allowed to cool to r.t., and then further cooled in an ice bath. Once chilled, the solution was diluted with CH2Cl2 (3 mL).Oxidative transposition : A solution of tertiary alcohol 5 (141 mg, 0.36 mmol) in CH2Cl2 (2 mL) under argon was chilled to 0 °C in an ice bath. Once chilled, the solution was treated by dropwise addition of the oxidizing solution (1.5 mL) over 5 min. The resulting dark-brown mixture was stirred for 45 min. The reaction was then quenched by slow addition of MeOH (1 mL), and the mixture was warmed to r.t. and stirred for 10 min. The resulting mixture was partitioned between Et2O (50 mL) and H2O (5 mL). The organic layer was washed with sat. aq NaHCO3 (3 × 5 mL) and brine (1 × 1 mL) then dried (MgSO4), filtered, and concentrated under reduced pressure. Flash column chromatography [silica gel, hexane–EtOAc (100:1)] gave a colorless oil; yield: 108 mg (78%); [α]D 20 +125.71 (c 1.32) [Lit.35 +129.1 (c 1.35, CHCl3)]; Rf  = 0.74 (hexane–EtOAc, 3:1). IR (neat): 2954, 2930, 2886, 2858, 1684, 1472, 1464, 1254, 1082, 832 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.10 (ddd, J = 3.6, 1.7, 0.7 Hz, 1 H), 4.57 (s, 1 H), 4.42 (dd, J = 16.7, 1.9 Hz, 1 H), 4.16 (ddd, J = 16.7, 1.7, 0.5 Hz, 1 H), 3.63 (dd, J = 3.6, 1.3 Hz, 1 H), 3.45 (ddd, J = 3.6, 1.9, 1.0 Hz, 1 H), 0.92 (s, 9 H), 0.92 (s, 9 H), 0.21 (s, 3 H), 0.18 (s, 3 H), 0.08 (s, 6 H). 13C NMR (101 MHz, CDCl3): δ = 193.25, 158.01, 120.25, 63.91, 62.97, 57.34, 52.99, 25.80, 25.57, 18.31, 17.95, –4.13, –4.69, –5.43, –5.54. HRMS (ESI+): m/z [M + H]+ calcd for C19H37O4Si2: 385.2225; found: 385.2229.
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