Synthesis of Ring-A-Substituted Tryptophan by a Palladium-Catalyzed Heteroannulation Reaction

Abstract

Coupling of substituted o-iodoanilines with methyl (S)-2-N,N-di-tert-butoxycarbonyl-5-oxo-pentanoate, derived from glutamic acid, in DMF in the presence of palladium acetate and DABCO provides substituted tryptophans in good to excellent yields.

palladium-catalyzed heteroannulation - indole synthesis - substituted tryptophan

References

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l-Try was isolated in 10% yield under Baran’s modified conditions.

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26 Typical Experimental Procedure. A solution of o-iodoaniline 3a (73.0 mg, 0.33 mmol), aldehyde 6 (104.0 mg, 0.30 mmol), and DABCO (101.0 mg, 0.9 mmol) and Pd(OAc)₂ (3.4 mg, 0.015 mmol) in dry DMF (1.5 mL) was degassed. The reaction mixture was heated to 85 °C until the reaction was complete (usually 8-12 h). The reaction mixture was cooled to r.t. and was diluted with H₂O. The aqueous phase was extracted with EtOAc and the combined organic phase was washed with brine, dried (Na₂SO₄), and evaporated to dryness under reduced pressure. Purification of crude product by flash column chromatography (silica gel, 20% EtOAc in heptane) provided the desired product 7 (101 mg, 81%; yellow oil). [α]_D ²³ -60.0 (c 1.00, CHCl₃). IR (CHCl₃): 3348, 2980, 2359, 1782, 1741, 1457, 1369, 1273, 1140, 1092, 852 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.45 (br s, 1 H), 7.58 (d, 1 H, J = 7.7 Hz), 7.34 (d, 1 H, J = 7.9 Hz), 7.15 (dt, 1 H, J = 1.2, 7.7 Hz), 7.09 (dt, 1 H, J = 1.2, 7.9 Hz), 6.98 (d, 1 H, J = 2.1 Hz), 5.20 (dd, 1 H, J = 4.7, 10.3 Hz), 3.77 (s, 3 H), 3.62 (dd, 1 H, J = 4.7, 14.9 Hz), 3.40 (dd, 1 H, J = 10.3, 14.9 Hz), 1.28 (s, 18 H). ¹³C NMR (75 MHz, CDCl₃): δ = 171.1, 151.5, 136.3, 127.5, 123.2, 121.7, 119.2, 118.5, 111.2, 82.8, 58.9, 52.1, 27.6 (6 C), 25.8. MS (ESI): m/z = 441 [M + Na]. HRMS (ESI): m/z calcd for C₂₂H₃₀N₂O₆Na [M + Na]: 441.2002; found: 441.1975.

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