Two Total Syntheses of Trigoxyphins K and L

Two total syntheses are presented for trigoxyphins K and L, tricyclic terpenoids from Trigonostemon xyphophylloides. The first proceeds via electrophlic cyclization in A/C-ring substrates to close the B ring at C4–C5 and then 1O2-mediated hydroxybutenolide formation to trigoxyphin L, with Luche reduction leading to trigoxyphin K. The second route develops from tetralone ring expansion to a B/C-ring intermediate that, by one-step O-demethylation–lactonization–isomerization, affords trigoxyphin K and then trigoxyphin L following enolate oxygenation.


General methods
Procedures are presented in the order given in the Schemes except for the natural products which are described at the end of the section.
All solvents for anhydrous reactions were obtained dry from Grubbs solvent dispenser units after being passed through an activated alumina column under argon.THF was additionally distilled from sodium/benzophenone ketyl under argon.
Commercially available reagents were, in general, used as supplied; amines and dipolar aprotic solvents were purified by standard methods before use."Petrol" refers to the fraction of light petroleum ether boiling in the range of 30-40 °C; "ether" refers to diethyl ether.Unless stated otherwise, all reactions were carried out in oven-dried glassware and under an inert atmosphere (N2 or Ar as specified); reactions performed above ambient temperature were heated using a thermostatically-controlled oil bath.Silica gel chromatography was carried out using Geduran Silicagel 60, particle size 40-63 µm.Thin-layer chromatography (TLC) was conducted after all reactions whenever practical, using Merck aluminium-backed Silicagel 60 F254 fluorescent treated silica; visualisation was enabled by UV light (λmax = 254 nm) and staining with potassium permanganate or phosphomolybdic acid solution to give the retention factors (Rf) quoted.
Compound names are as generated by PerkinElmer ChemDraw Professional 22.2.Melting points (mp) were recorded (uncorrected) in degrees Celsius (°C), using a Griffin MFB-700-010U melting point apparatus.IR spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer as a thin film on a diamond ATR module.Only selected absorption maxima (νmax) are reported, in wavenumbers (cm −1 ). 1 H and 13 C NMR spectra were recorded using a Bruker AVIIIHD-400 spectrometer using the solvents specified.Chemical shifts are quoted in ppm downfield of tetramethylsilane (δ = 0) and referenced in MestReNova to the appropriate solvent peak: CDCl3, 7.26/77.16;C6D6, 7.16/128.06;(CD3)2CO, 2.05/29.84,CD3OD, 3.31/49.00.Coupling constants (J) are quoted in Hz, rounded to the nearest 0.5 Hz.All 1 H NMR spectra are reported as follows: ppm (number of protons, multiplicity, coupling constants).High-resolution mass spectra (HRMS) were recorded by the staff at the Chemistry Research Laboratory (University of Oxford) using a Bruker Daltonics MicroTOF spectrometer; mass-to-charge ratios (m/z) are reported in Daltons.
The crude product was purified by flash chromatography (petrol/ether, 9:1 to 4:1) to afford the title compound (6) as a
Iodomethane (1.18 mL, 19.0 mmol) was then added and the mixture was stirred for 14 h.The reaction was quenched with water (10 mL) and the mixture extracted with ether (3 × 20 mL).The combined organic extracts were washed with water (20 mL) and brine (20 mL), and were then dried (Na2SO4), filtered, and concentrated.The crude product was purified by silica gel chromatography (pentane/ethyl acetate, 9:1), affording ketone 20 as a colourless solid (1.05 g, 89%