Synthesis of (+/-)-Curcumene Ether

Abstract

A 9 step synthesis of (+/-)-curcumene ether is described starting from 5-bromo-2-methyl-2-pentene and 2-amino-5-methylphenol in 7% overall yield using an intramolecular Heck reaction as the key transformation to generate a stereogenic quaternary center.

total synthesis - intramolecular Heck reaction - spiro compounds - lactones - natural products

References

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10

Purchased from the Aldrich Chemical Company.

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15

Experimental procedure for the conversion of 4 to 12 and 13: A mixture of Pd₂(dba)₃ (13 mg, 0.0141 mmol), (+/-)-BINAP (17.0 mg, 0.0273 mmol), and dry DMA (2.5 mL) under N₂ was added after 45 min. via syringe to a 2 dram screw-top vial containing ester 4 (52.3 mg, 0.141 mmol). PMP (127 µL, 0.705 mmol)was added and the mixture was heated in the sealed vial at 100 °C for 4 days. The solution was poured into ether and washed with saturated NaHCO₃ aq (4 ¥ 10 mL) and NaCl aq (4 ¥ 10 mL). The ether extracts were dried over anhydrous MgSO₄, filtered and ether removed under reduced pressure to give a red/black residue. The oil was purified by flash chromatography (20:1, hexanes: EtOAc) to give a mixture1:1 mixture of 12 and 13 (31 mg, 90%). IR (cm^-1) 1814 (ester C=O), 1629 (alkene C=C); ¹H NMR δ 1.35 (br s, 3 H, H-1 or H-2), 1.39 (br s, 3 H, H-10 or H-11), 1.43 (br s, 3 H, H-1 or H-2), 1.49 (br s, 3 H, H-10 or H-11), 2.31 (m, 2 H, H-14), 2.38 (br s, 6 H, H-8 and H-17), 2.44 (m, 2 H, H-3), 5.63 (dt, 1 H, J = 10.1 Hz, J = 2.05 Hz, H-12), 5.89-6.08 (m, 2 H, H-4 and H-5), 6.23 (dt, 1 H, J = 10.3 Hz, J = 4.2 Hz, H-13), 6.87-7.36 (m, 6 H, H-6, H-7, H-9, H-15, H-16, and H-18); ¹³C NMR δ 21.8 (2 ¥ CH₃), 28.6 (CH₃), 29.0 (CH₃) 29.9 (CH₃), 30.1 (CH₃), 30.8 (CH₂), 35.8 (CH₂), 72.9 (C_q), 73.7 (C_q), 74.9 (C_q), 76.9 (C_q), 111.6 (CH), 111.7 (CH), 118.3 (CH), 124.0 (CH), 124.4 (CH), 124.7 (CH), 125.0 (CH), 125.3 (CH), 126.6 (C_q), 127.0 (C_q), 127.4 (CH), 135.6 (CH), 141.1 (C_q), 141.2 (C_q) 153.1 (C_q), 153.4 (C_q), 174.8 (C_q), 175.5 (C_q); Mass spectra: (Compound 12) 244 (1, M⁺), 216 (26, M⁺-CO), 202 (14), 201 (100, M⁺-CO and
-CH₃), 187 (4), 135 (29), 134 (11), 67 (12); (Compound 13) 244 (20, M⁺), 216 (22, M⁺-CO), 202(13), 201 (100, M⁺-CO and -CH₃), 161 (50), 135 (40), 115 (14), 77 (14); Mass calculated for C₁₅H₁₆O₃ (M⁺): 244.10994, found: 244.10954.

16

Attempts to perform the intramolecular Heck reaction on iodide 4 with enantiopure BINAP, BINAPFu,¹⁸ TetFuBINAP¹⁹ or Pfaltz’s phosphinooxazoline ligand²⁰ gave racemic mixtures of double bond isomers 12 and 13.

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