A Catalytic Asymmetric Ene Reaction for Direct Preparation of α-Hydroxy 1,4-Diketones as Intermediates in Natural Product Synthesis

Abstract

Asymmetric access to α-hydroxy-1,4-diketones has been achieved by direct ene coupling of silyl enol ethers with glyoxal electrophiles, mediated by a chiral N,N′-dioxide–nickel(II) complex catalyst. Successful union of a polyketide silyl enol ether with an α-quaternary glyoxal, generated by dioxirane oxidation of an α-diazo ketone, models a proposed C₅–C₆ disconnection of the polyketide and spirocyclic imine domains of the marine natural product, portimine.

Key words

ene reaction - glyoxal - N,N′-dioxide–nickel(II) complex - natural product synthesis - Leighton crotylation - portimine

• References and Notes

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Some methods for asymmetric synthesis of simple derivatives have been reported:
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• 15 Preparation of Glyoxal (6) To stirred diazoketone 22 (104 mg, 0.400 mmol), dimethyldioxirane (69 mM in acetone, 6.7 mL, 0.466 mmol) was added rapidly. The mixture was vigorously stirred for 2 min, then concentrated under a stream of nitrogen. The resultant crude oil was used in the next step without further purification. An analytical sample gave the following data. IR (film): 2972, 1716, 1452, 1316, 1274, 1113, 1026, 712 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.20 (s, 1 H), 7.91–7.86 (m, 2 H), 7.59–7.52 (m, 1 H), 7.47–7.40 (m, 2 H), 4.36 (t, J = 6.1 Hz, 2 H), 2.31 (t, J = 6.1 Hz, 2 H), 1.35 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 202.3, 188.7, 166.4, 133.3, 129.7, 129.6, 128.6, 61.5, 44.3, 37.8, 24.0. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₆NaO₄: 271.0941; found: 271.0935.
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• 21 To a solution of ketone 5 (40 mg, 0.142 mmol) in dichloromethane (1 mL) at –10 °C triethylamine (97 μL, 0.71 mmol) was added, followed by tert-butyldimethylsilyl trifluoromethanesulfonate (65 μL, 0.28 mmol). After 1 h the reaction was quenched with saturated aqueous sodium hydrogen carbonate (2 mL) and extracted with dichloromethane (3 × 3 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated, then dissolved in petroleum ether (10 mL), filtered through a plug of cotton wool and concentrated again, to give the crude silyl enol ether. To a solution of diamine-N-dioxide (8.7 mg, 0.015 mmol) in dichloromethane (1 mL) at 30 °C, nickel tetrafluoroborate hexahydrate (4.8 mg, 0.014 mmol) was added, the mixture was stirred vigorously for 30 min, and then concentrated and dried in vacuo for 5 h. A solution of freshly prepared crude glyoxal (6, ca. 0.142 mmol) and the previously prepared silyl enol ether in dichloromethane (1 mL) was then added, and the mixture warmed to 30 °C. After 2 h, further glyoxal 6 (ca. 0.142 mmol) in dichloromethane (0.5 mL) was added dropwise, followed after a further 2 h by another solution of glyoxal 6 (ca. 0.142 mmol) in dichloromethane (0.5 mL). The reaction was then stirred for 18 h and quenched with aqueous citric acid (0.5 M, 3 mL), stirred for 30 min, and then extracted with dichloromethane (3 × 3 mL). The combined organic layers were washed with brine (6 mL), dried over sodium sulfate, filtered, and concentrated. The resultant oil was allowed to stand in chloroform for 14 h, then concentrated in vacuo. Chromatography (petroleum ether/ethyl acetate, 15:1) afforded (7, 24 mg, 32%) as a colorless oil and returned starting material ketone (5, 22 mg, 55%); [α]_D ²⁰ 2.2 (c 2.4, CHCl₃). IR (film): 3480, 2958, 2857, 1716, 1275, 1113, 1027, 837, 776, 713 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.01–7.97 (m, 2 H), 7.59–7.53 (m, 1 H), 7.46–7.40 (m, 2 H), 4.90–4.83 (m, 1 H), 4.39–4.27 (m, 2 H), 3.71–3.67 (m, 1 H), 3.60–3.56 (m, 1 H), 2.65–2.57 (m, 2 H), 2.58–2.36 (m, 2 H), 2.28 (ddd, J = 16.6, 5.8, 2.6 Hz, 1 H), 2.23–1.98 (m, 3 H), 1.95 (dd, J = 3.0, 2.6 Hz, 1 H), 1.80–1.62 (m, 3 H), 1.33 (s, 3 H), 1.33 (s, 3 H), 0.96 (d, J = 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 214.4, 209.4, 166.7, 133.2, 130.3, 129.7, 128.5, 83.9, 73.4, 70.6, 69.2, 61.9, 46.0, 45.8, 40.2, 38.3, 37.9, 26.9, 26.0, 25.4, 24.6, 21.9, 18.2, 14.4, –4.1, –4.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₄₆NaO₆Si: 553.2956; found: 553.2957.