Total Synthesis of Pterosines B and C via a Photochemical Key Step

Abstract

A total synthesis of pterosines B and C is reported. Starting with a fourfold substituted benzene derivative, the introduction of the remaining substituents is mainly based on Sonogashira couplings followed by different transformations of the ethyne moiety. The key step is a photochemical ring-closure of an α-mesyloxy ­ketone forming the 1-indanone skeleton.

total synthesis - photochemistry - arenes - ketones

References and Notes

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12b

4-(Carboxymethyl)-3,5-dimethylbenzoic Acid (10).
Compound 9 (1.00 g, 3.78 mmol) in 10 mL dry THF was cooled to 0 °C and 6.8 mL (6.8 mmol, 1.8 equiv) 1 M BH₃-THF solution was dropped in slowly. After stirring at 0 °C for 2 h a mixture of 10 mL (0.02 mol, 5 equiv) 2 M NaOH and 5 mL (0.06 mol, 15 equiv) aq H₂O₂ solution (30%) was added. After additional stirring for 2 h further 20 mL of 1 M NaOH and 50 mL of Et₂O were added. The phases were separated and the aqueous phase was extracted several times with Et₂O. Then the aqueous phase was acidified to pH 1 with HCl and the product was extracted with several portions of Et₂O. The combined organic phases were dried and evaporated, giving 350 mg (1.68 mmol, 44%) of 10 as a white solid; mp 285 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.29 (s, 6 H, 3,5-Me), 3.65 (s, 2 H, CH₂), 7.59 (s, 2 H, CH_arom). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 19.8 (3,5-Me), 35.2 (CH₂), 128.5 (CH_arom), 128.8, 137.3, 137.9 (C_q), 167.4, 171.8 (COOH). IR (KBr): 2959 (br s), 2923 (s), 2858 (s), 1718 (s), 1667 (s), 1425 (s), 1413 (s), 1303 (s), 1244 (s), 1230 (s), 1182 (m). HRMS (ESI): m/z calcd for C₁₁H₁₃O₄ [MH⁺]: 209.0808. Found: 209.0809.

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17

Irradiation of 17a and 17b.
For solvents, conditions and yields see Table [1] . The irradiation was performed in a 500 mL reactor vessel, equipped with a 150 W high-pressure mercury arc lamp (TQ 150, Heraeus) and monitored by TLC. The solvent was removed in vacuo and the residue was purified by flash chromatography.
Analytical Data for 2-(4,6-Dimethyl-3-oxo-2,3-dihydro-1 H -inden-5-yl)ethyl Acetate ( 18a).
Mp 39-41 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.03 (s, 3 H, CH₃-acetate), 2.42 (s, 3 H, Me-C_arom), 2.60-2.64 (m, 2 H, 2-CH₂), 2.67 (s, 3 H, Me-C_arom), 2.94-2.98 (m, 2 H, 3-CH₂), 3.03 (t, J ³ = 7.7 Hz, 2 H, CH₂CH₂O), 4.12 (t, J ³ = 7.7 Hz, 2 H, CH₂CH₂O), 7.10 (s, 1 H, CH_arom). ¹³C NMR (75 MHz, CDCl₃): δ = 13.6, 21.0 (CH₃-C_arom), 21.1 (CH₃-acetate), 24.6 (3-CH₂), 27.8 (CH₂CH₂O), 37.1 (2-CH₂), 62.7 (CH₂CH₂O), 125.9 (CH_arom), 132.9, 133.8, 137.8, 140.1, 154.6 (C_q), 171.0 (COOR), 207.8 (RCOR).
Analytical Data for 2-{1-[(Pivaloyl)oxy]-4,6-dimethyl-3-oxo-2,3-dihydro-1 H -inden-5-yl}ethyl Pivalate ( 18b).
¹H NMR (300 MHz, CDCl₃): δ = 1.14, 1.17 (s, 9 H, Piv), 2.46 (s, 3H, Me-C_arom), 2.51 (dd, J ³ = 3.0 Hz, J ² = 18.8 Hz, 1 H, CH₂CH), 2.68 (s, 3 H, Me-C_arom), 3.03 (t, J ³ = 7.7 Hz, 2 H, CH₂CH₂O), 3.08 (dd, J ³ = 7.1 Hz, J ² = 18.8 Hz, 1 H, CH₂CH), 4.10 (t, J ³ = 7.7 Hz, 2 H, CH₂CH₂O), 6.15 (dd, J ³ = 3.0 Hz, J ³ = 7.1 Hz, 1 H, CHOPiv), 7.19 (s, 1 H, CH_arom). ¹³C NMR (75 MHz, CDCl₃): δ = 13.8, 21.3 (CH₃-C_arom), 27.0, 27.1 (CH₃, Piv), 28.0 (CH₂CH₂O), 38.6, 38.6 (C_q, Piv), 44.6 (2-CH₂), 62.3 (CH₂CH₂O), 68.5 (3-CH), 73.2 (CH₂O), 125.4 (CH_arom), 132.8, 136.7, 137.5, 145.1, 151.0 (C_q), 178.5, 178.6 (COOR), 202.9 (RCOR). IR (film): 2973 (s), 1717 (vs), 1599 (s), 1478 (s), 1458 (s), 1396 (s), 1281 (s), 1148 (s), 1033 (s), 1010 (s), 984 (m). HRMS (ESI): m/z calcd for C₂₃H₃₃O₅ [MH⁺]: 389.2323; found: 389.2324.

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19

Experimental Procedure for 3-Hydroxy-6-(2-hydroxyethyl)-5,7-dimethyl-1-indanone ( 22).
To a solution of 65 mg (0.17 mmol) 18b in 10 mL DMSO was added a mixture of 100 mL 0.01 M aq HEPES buffer solution (pH 7.5, I = 0.1 M NaCl) and 90 mg (2160 units) porcine liver esterase (EC 3.1.1.1, Sigma). The mixture was stirred 2 d at r.t. in which the reaction course was monitored by HPLC analysis (see below). After complete saponification of both ester groups the mixture was treated with 50 mL CH₂Cl₂, filtrated and the phases were separated. The organic phase was dried with MgSO₄, evaporated and purified by FCC (CH₂Cl₂-MeOH, 10:1, R _f = 0.39) affording 20.0 mg (90.8 mol, 54%) 22 as a white solid.
HPLC conditions: column: Eurospher 100 C-18 (Knauer), 5 µm, 250 × 4 mm; mobile phase: gradient MeOH-H₂O (70:30 → 90:10) linear in 20 min, then 90:10 flow: 1 mL/min. peaks: t _R(22) = 2.6 min, t _R(18b) = 31.9 min.
Mp 143-145 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.34 (dd, J ³ = 3.0 Hz, J ² = 18.5 Hz, 1 H, CH₂CH), 2.40, 2.56 (s, 3 H, Me-C_arom), 2.84 (t, J ³ = 7.5 Hz, 2 H, CH₂CH₂OH), 2.90 (dd, J ³ = 7.0 Hz, J ² = 18.5 Hz, 1 H, CH₂CH), 3.41-3.46 (m, 2 H, CH₂CH₂OH), 4.78 (t, J ³ = 5.5 Hz, 1 H, CH₂OH), 5.02-5.06 (m, 1 H, 3-CH), 5.57 (d, J ³ = 6.0 Hz, 1 H, OH), 7.31 (s, 1 H, CH_arom). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 13.3, 21.0 (CH₃-C_arom), 32.1 (CH₂CH₂OH), 47.7 (2-CH₂), 59.8 (CH₂CH₂OH), 65.6 (3-CH), 125.0 (CH_arom), 131.5, 135.6, 137.1, 144.2, 155.6 (C_q), 204.3 (RCOR). IR (KBr): 3391 (br s), 2923 (m), 1687 (vs), 1596 (s), 1408 (m), 1326 (m), 1308 (s), 1260 (m), 1065 (s), 1025 (s), 804 (m). HRMS (ESI): m/z calcd for C₁₃H₁₇O₃ [MH⁺]: 221.1172; found: 221.1173.