Explorations of [4+2] and [5+2] Cycloadditions of Dienylcyclopropane Derived Enzymatically from Cyclopropylbenzene

Abstract

Fermentation of cyclopropylbenzene with E. coli JM109(pDTG601a) furnished optically pure 1-cyclopropyl-2,3-dihydroxycyclohexa-4,6-diene whose reactivity in [4+2]- and [5+2]-cycloaddition chemistry was explored.

Key words

dienylcyclopropane - cyclopropylbenzene - [4+2] cyclo­additions - [5+2] cycloadditions - enzymatic dihydroxylation of arenes

References and Notes

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23

Selected Experimental Procedures 1-{4-Cyclopropyl-2,2-dimethyl-3a,4,7,7a-tetrahydro-4,7-(epoxyimino)benzo [ d ][1,3]dioxol-8-yl}ethanone (12): To a solution of diol 6 (0.50 g, 3.28 mmol) in 2,2-dimethoxypropane was added a catalytic amount of p-toluenesulfonic acid. After 5 min, the reaction was quenched with the addition of solid NaHCO₃ (100 mg). The reaction mixture was then diluted with MeOH-H₂O (4:1; 30 mL) and sodium periodate (1.70 g, 8.13 mmol) was added in one portion. The resulting solution was then cooled to 0 ˚C and a solution of acetohydroxamic acid (0.61 g, 8.13 mmol) in MeOH (30 mL) was added dropwise over 10 min. The solution was allowed to warm to r.t. and the stirring was continued for 17 h at r.t. After consumption of starting material, the reaction mixture was filtered and concentrated in vacuo. The oily residue was then diluted with EtOAc, and the organic solution was washed with sat. aq. NaHCO₃ followed by brine. The organic solution was dried over MgSO₄. The crude material was then purified by suction column chromatography to yield oxazine 12 (0.65 g, 75%) as an oil which slowly solidified.
Large-Scale Preparation of Oxazine 12: Dimethoxypropane (15 mL) was cooled to 0 ˚C and a crystal of p-TsOH was added. After 2 min diol 6 (5.0 g, 0.033 mol) dissolved in acetone-EtOAc (15 mL) was added dropwise over 5 min. TLC analysis indicated full conversion to acetonide 7 accompanied by 5-10% of 2-cyclopropylphenol resulting from aromatization of diol 6. The solution was diluted with EtOAc (20 mL), washed once with 1 N NaOH (3 mL), and added to a solution of NaIO₄ (17.0 g, 0.081 mol, 2.5 equiv) in MeOH-H₂O (4:1; 250 mL) cooled to 0 ˚C in
1-L Erlenmeyer flask. Acetohydroxamic acid (6.1 g, 0.081 mol, 2.5 equiv) dissolved in MeOH-H₂O (4:1; 100 mL) was added with vigorous stirring over 15 min. A thick white precipitate formed immediately. The reaction mixture was allowed to warm to r.t. over 1 h and the stirring was continued for 1 h at r.t. at which time the mixture was filtered, the precipitate was washed with EtOAc (200 mL) and the solution was washed with brine (2 × 100 mL), sat. NaHCO₃ (2 × 100 mL), dried over Na₂SO₄, and evaporated. The crude product, containing 5-10% of 2-cyclopropyl-phenol, was purified by chromatography (silica, gradient elution, hexane to hexane-EtOAc, 3:1) to furnish oxazine 12 (5.4 g, 64%) as an oil that slowly solidified. Repetition on 10-gram scale gave the oxazine (7.12 g, 57%). Recrystallization from EtOAc-pentane gave white needles. 12: R _f 0.27 (hexane-EtOAc, 4:1); mp 44-46 ˚C (EtOAc-pentane); [α]^²0 _D -20.5 (c = 1.0, CHCl₃). IR (CHCl₃): 3691, 3011, 2419, 1731, 1655, 1618, 1375, 1270, 1088, 1064, 760 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 6.32 (dd, J = 8.0, 6.3 Hz, 1 H), 5.90 (d, J = 8.1 Hz, 1 H), 5.20-5.28 (m, 1 H), 4.32 (dd, J = 6.6, 4.5 Hz, 1 H), 4.13 (d, J = 6.9 Hz, 1 H), 1.79 (s, 3 H), 1.13 (s, 7 H), 0.37-0.59 (m, 4 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 171.2, 131.3, 131.0, 110.6, 79.9, 77.7, 73.3, 49.7, 25.7, 25.4, 21.5, 13.7, 1.1, 0.5. MS (EI+): m/z (%) = 265 (13), 250 (23), 207 (48), 178 (30), 135 (43), 123 (54), 118 (68), 107 (58), 91 (52), 85 (54). HRMS (EI+): m/z calcd for C₁₄H₁₉NO₄: 265.1314; found: 265.1317. Anal. Calcd for C₁₄H₁₉NO₄: C, 63.38; H, 7.22. Found: C, 62.92; H, 7.07.
N -{(3a S ,4 R ,7 S ,7a S )-7-Cyclopropyl-7-hydroxy-2,2-dimethyl-3a,4,7,7a-tetrahydrobenzo[ d ][1,3]dioxol-4-yl}acetamide (16): To a solution of oxazine 12 (248 mg, 0.94 mmol) in MeCN (7.5 mL) and distilled H₂O (0.5 mL) was added molybdenum hexacarbonyl (371 mg, 1.40 mmol) in one portion. The resulting suspension was immersed in an oil bath and heated to reflux. At reflux, the mixture changed from a clear suspension to a black solution, which was allowed to reflux for 2 h. Progress of the reaction was monitored by TLC (EtOAc). After consumption of the starting material was complete, the reaction mixture was removed from the oil bath and allowed to cool to r.t. The reaction mixture was then filtered through a plug of Celite using EtOAc as the eluent and concentrated in vacuo.
The crude material was then purified via flash column chromatography (EtOAc) to yield amido alcohol 16 (138 mg, 55%) as a white powder; R _f 0.29 (EtOAc); mp 189-192 ˚C (EtOAc); [α]^²0 _D -93.8 (c = 1.0, CHCl₃). IR (CHCl₃): 3404, 3009, 2511, 1661, 1512, 1415, 1382, 1243, 1064, 759 cm^-¹. ^¹H NMR (600 MHz, MeOD): δ = 5.79 (d, J = 10.2 Hz, 1 H), 5.75 (dd, J = 10.2, 4.2 Hz, 1 H), 4.45 (td, J = 3.6, 1.2 Hz, 1 H), 4.27 (m, 2 H), 1.97 (s, 3 H), 1.43 (s, 3 H), 1.36 (s, 3 H), 1.19-1.26 (m, 1 H), 0.47-0.53 (m, 1 H), 0.35-0.47 (m, 3 H). ^¹³C NMR (150 MHz, MeOD): δ = 171.2, 133.9, 128.6, 108.3, 81.1, 76.9, 69.8, 48.8, 25.9, 23.8, 21.5, 16.3, -0.4,
-0.9. MS (FAB+): m/z (%) = 268 (5), 250 (85), 192 (49), 150 (98), 105 (26), 69 (70), 43 (100). HRMS (FAB+): m/z calcd for C₁₄H₂₁NO₄: 267.1471; found: 267.1471. Anal. Calcd for C₁₄H₂₁NO₄: C, 62.90; H, 7.92. Found: C, 63.01; H, 7.93.