Catalytic Epoxypolyene Cyclization via Radicals: Highly Diastereoselective Formal Synthesis of Puupehedione and 8-epi-Puupehedione

Abstract

A catalytic and highly stereoselective synthesis of a common building block for the marine natural product puupehedione (1) and its biologically more active 8-epimer is described. Our approach features a copper-catalyzed allylic substitution reaction of epoxyfarnesyl acetate and a diastereoselective titanocene-catalyzed epoxypolyene cyclization via radicals. The formal syntheses of 1 and 2 are completed by highly diastereoselective ring closures to the required benzodihydropyran units.

Key words

catalysis - cuprates - epoxypolyene cyclization - natural products

References and Notes

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17

Compound 3: Colorless oil. IR (film): 2924, 1504, 1484, 1436, 1210, 1152, 1042, 988, 938, 856 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 6.70 (s, 1 H), 6.63 (s, 1 H), 5.87 (s, 2 H), 5.86* (s, 2 H), 5.29-5.23 (m, 1 H), 5.22-5.13 (m, 1 H), 5.08 (s, 2 H), 3.48 (s, 3 H), 3.47* (s, 3 H), 3.26 (d, J = 7.2 Hz, 2 H), 2.73-2.67 (m, 1 H), 2.20-2.00 (m, 5 H), 1.73 (q, J = 1.2 Hz, 1 H), 1.69 (br s, 3 H), 1.67-1.55 (m, 3 H), 1.29 (s, 3 H), 1.28 (s, 3 H), 1.25 (s, 3 H), 1.24* (s, 3 H). ¹³C NMR (100 MHz, CDCl₃, DEPT): δ = 149.51 (C), 149.50 (C), 146.05 (C), 146.02 (C), 142.34 (C), 142.33 (C), 136.23 (C), 136.17 (C), 134.41 (C), 134.35 (C), 124.91 (CH), 124.85 (CH), 123.70 (C), 123.62 (C), 123.00 (CH), 122.89 (CH), 109.20 (CH), 109.14 (CH), 101.15 (CH₂), 98.71 (CH), 98.65 (CH), 95.94 (CH₂), 95.93 (CH₂), 64.34 (CH), 64.31 (CH), 58.47 (C), 58.41 (C), 56.13 (CH₃), 56.12 (CH₃), 40.04 (CH₂), 39.80 (CH₂), 36.46 (CH₂), 36.42 (CH₂), 28.69 (CH₂), 28.25 (CH₂), 28.22 (CH₂), 27.60 (CH₂), 27.58 (CH₂), 26.67 (CH₂), 26.51 (CH₂), 25.05 (CH₃), 25.03 (CH₃), 23.59 (CH₃), 23.44 (CH₃), 18.87 (CH₃), 18.83 (CH₃), 16.16 (CH₃), 16.13 (CH₃). HRMS: m/z calcd for C₂₄H₃₄O₅: 402.2406; found: 402.2408.
Compound 7: Colorless oil. IR (film): 3444, 2938, 1505, 1484, 1209, 1151, 1042, 992, 937, 757 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 6.68 (s, 1 H), 6.61 (s, 1 H), 5.85 (s, 2 H), 5.09 (s, 2 H), 4.79 (d, J = 1.3 Hz, 1 H), 4.65 (d, J = 1.1 Hz, 1 H), 3.49 (s, 3 H), 3.28 (dd, J = 11.5, 4.7 Hz, 1 H), 2.70 (d, J = 4.9 Hz, 1 H), 2.69 (s, 1 H), 2.38 (ddd, J = 12.8, 4.3, 2.5 Hz, 1 H), 2.09 (q, J = 4.3 Hz, 1 H), 2.05-1.85 (m, 2 H), 1.78 (sext, J = 2.6 Hz, 1 H), 1.77-1.28 (m, 4 H), 1.17 (dd, J = 12.5, 2.7 Hz, 1 H), 1.01 (s, 3 H), 0.81 (s, 3 H), 0.80 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃, DEPT): δ = 149.73 (C), 147.91 (C), 145.78 (C), 142.15 (C), 123.84 (C), 108.94 (CH), 108.22 (CH₂), 101.11 (CH₂), 98.30 (CH), 95.80 (CH₂), 79.09 (CH), 56.38 (CH₃), 56.28 (CH), 55.05 (CH), 39.94 (C), 39.32 (C), 38.21 (CH₂), 37.32 (CH₂), 28.54 (CH₃), 28.10 (CH₂), 24.11 (CH₂), 23.52 (CH₂), 15.65 (CH₃), 14.76 (CH₃). HRMS: m/z calcd for C₂₄H₃₄O₅: 402.2406; found: 402.2413.
Compound 8: Colorless oil. IR (film): 2933, 1505, 1483, 1208, 1150, 1043, 993, 938, 858 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 6.68 (s, 1 H), 6.63 (s, 1 H), 5.86 (s, 2 H), 5.10 (d, J = 0.7 Hz, 2 H), 4.77 (d, J = 1.5 Hz, 1 H), 4.62 (d, J = 1.3 Hz, 1 H), 3.50 (s, 3 H), 2.71 (d, J = 1.3 Hz, 1 H), 2.70 (s, 1 H), 2.36 (ddd, J = 12.8, 4.2, 2.5 Hz, 1 H), 2.13 (t, J = 6.6 Hz, 1 H), 1.99 (ddd, J = 12.9, 12.9, 5.2 Hz, 1 H), 1.87 (dd, J = 12.7, 1.3 Hz, 1 H), 1.75 (dd, J = 12.7, 2.6 Hz, 1 H), 1.61 (dt, J = 13.6, 3.3 Hz, 1 H), 1.58-1.10 (m, 6 H), 0.90 (s, 3 H), 0.84 (s, 3 H), 0.81 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃, DEPT): δ = 149.73 (C), 148.61 (C), 145.67 (C), 142.13 (C), 124.30 (C), 109.06 (CH), 107.87 (CH₂), 101.09 (CH₂), 98.35 (CH), 95.93 (CH₂), 56.61 (CH₃), 56.24 (CH), 55.96 (CH), 42.41 (CH₂), 40.23 (C), 39.42 (CH₂), 38.47 (CH₂), 33.83 (CH₃), 33.81 (C), 24.61 (CH₂), 23.42 (CH₂), 21.97 (CH₃), 19.68 (CH₂), 14.72 (CH₃). HRMS: m/z calcd for C₂₄H₃₄O₄: 386.2457; found: 386.2455.