Enantioselective Synthesis of the Sporolide Quinone Acid Fragment

Abstract

The sporolide quinone acid is a key fragment in the biosynthesis of the complex heptacyclic marine metabolite sporolide. We report a concise enantioselective route to this fragment, which is obtained in seven steps with 65% overall yield from trimethoxybenzene. The enantioselective transfer reduction is achieved by Ipc₂BCl, and the absolute configuration of the product secured by X-ray analysis of its cinchonine salt. The target fragment is then obtained by methylation and oxidation to the quinone by AgO.

Key words

asymmetric synthesis - natural products - biosynthesis - transfer hydrogenation - quinones

References and Notes

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10

Preparation and Selected Data for Compound 4
A solution of 2-oxo-2-(2,4,5-trimethoxy-3-methylphenyl)-acetic acid (300 mg, 1.18 mmol, 1.0 equiv) in THF (6 mL) at -40 ˚C was treated with Et₃N (164 mL, 1.18 mmol, 1.0 equiv) and stirred for 5 min followed by the slow addition of (-)-Ipc₂BCl (417 mg, 1.30 mmol, 1.1 equiv) in THF (2 mL). The reaction mixture was gradually warmed up to r.t. and stirred at r.t. for 3 h. The reaction was quenched with H₂O, treated with NaOH (10%) to pH >12, extracted with Et₂O, and the organic layers were combined and washed with H₂O (25 mL). The aqueous layers were then combined and acidified with 1 N HCl to pH 2 and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na₂SO₄. Once concentrated, the crude hydroxy acid was purified by recrystallization from hot EtOH as its cyclohexylammonium salt. The title compound was then obtained (233 mg, 0.909 mmol, 77%) as a white crystalline solid by extraction with Et₂O of the aqueous acid solution of the salt. R _f  = 0.21 (CH₂Cl₂-MeOH-AcOH = 9:1:0.05); [α]_D ^²5 -81.6 (c 0.2325, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 6.89 (s, 1 H), 5.36 (s, 1 H), 3.84 (s, 6 H), 3.80 (s, 3 H), 2.24 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃):
δ = 193.66, 174.75, 150.16, 148.35, 125.78, 125.41, 107.98, 68.61, 61.33, 60.33, 55.99, 9.71. ESI-HRMS (TOF): m/z calcd for C₁₂H₁₆O₆ [M + Na]⁺: 279.0845; found: 279.0834. IR: ν = 3429 (br m), 2994 (m), 2940 (m), 2858 (w), 1728 (s), 1597 (w), 1489 (s), 1462 (m), 1420 (m), 1335 (m), 1242 (s), 1123 (s), 1084 (s), 1007 (m) cm^-¹.

11

Preparation and Selected Data for Compound 1
To a stirred solution of (R)-methyl 2-methoxy-2-(2,4,5-trimethoxy-3-methylphenyl)acetate (5, 250 mg, 0.879 mmol, 1.0 equiv) in dioxane (4 mL) was added AgO (545 mg, 4.397 mmol, 5.0 equiv) followed by 4 N HNO₃ until the silver oxide was completely dissolved. The resulting solution was stirred for 30 min and then diluted with CH₂Cl₂. The organic layer was washed with H₂O, brine, dried over Na₂SO₄, and the solvent was evaporated under reduced pressure to afford the crude product, which was purified by chromatography using hexane-EtOAc (8:2) as eluent. The analytically pure product (188 mg, 0.782 mmol, 89%) was obtained as a red viscous oil. R _f  = 0.50 (hexane-EtOAc = 1:1); [α]_D ^²5 -33.0 (c 0.36, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 6.85 (d, J = 1.3 Hz, 1 H), 4.90 (d, J = 1.3 Hz, 1 H), 3.77 (s, 3 H), 3.51 (s, 3 H), 1.96 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 186.63, 183.06, 169.48, 151.73, 146.22, 128.88, 118.02, 76.81, 59.37, 53.25, 1.45. IR: ν = 3352 (w), 2955 (m), 2920 (s), 2851 (m), 1744 (s), 1659 (s), 1643 (s), 1620 (m), 1458 (w), 1393 (m), 1346 (m), 1269 (m), 1196 (s), 1157 (m), 1107 (m), 1045 (w), 1011 (w) cm^-¹.

12

Preparation and Selected Data for Compound 6
To a solution of (R)-methyl 2-(4-chloro-5-methyl-3,6-dioxocyclohexa-1,4-dienyl)-2-methoxyacetate (1, 46 mg, 0.193 mmol, 1.0 equiv) in dry CH₂Cl₂ (1.9 mL) at 0 ˚C was added oxalyl chloride (33 µL, 0.387 mmol, 2.0 equiv) followed by one drop of DMF. The reaction mixture was stirred for 1 h at 0 ˚C and 16 h at r.t. The reaction was quenched with H₂O (3 mL), and the aqueous layer was extracted with CH₂Cl₂. The combined organic layers were dried over Na₂SO₄ and concentrated to afford the crude product, which was purified by chromatography using hexane-EtOAc (9:1) as eluent. The analytically pure product (42 mg, 0.162 mmol, 84%) was obtained as a red viscous oil. R _f  = 0.71 (hexane-EtOAc = 1:1); [α]_D ^²5 -48.0 (c 0.27, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.00 (d, J = 1.2 Hz, 1 H), 4.88 (d, J = 1.2 Hz, 1 H), 3.80 (s, 3 H), 3.54 (s, 3 H), 2.24 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 183.56, 178.92, 173.23, 168.85, 143.69, 142.41, 132.61, 76.27, 59.05, 52.88, 13.75. ESI-HRMS (TOF): m/z calcd for C₁₁H₁₁ClO₅ [M + Na]⁺: 281.0187; found: 281.0189. IR: ν = 2955 (w), 2924 (w), 2847 (w), 2361 (w), 2338 (w), 1748 (s), 1670 (s), 1605 (w), 1439 (w), 1373 (w), 1277 (m), 1246 (m), 1204 (m), 1165 (w), 1111 (m), 1015 (w) cm^-¹.