Synthesis of three tricholoma -derived indoles via an ortho -quinone methide

Three Tricholoma -derived indole natural products have been synthesised via an ortho -quinone methide ( o - QM), itself generated from a phenolic Mannich base


Introduction
Tricholoma is a large genus of white-spored, gilled mushrooms notable for their distinctive pungency and bitter taste. 1,24][5][6] Unlike most indole alkaloids, the Tricholoma indoles are not biosynthetically derived from tryptophan, but instead assembled via a biosynthetic pathway that involves lascivol (5), a bitter component isolated from Tricholoma lascivum that likely serves as a predation deterrent. 7Tellingly, lascivol degrades into the natural product 5-methoxy-2,4-dimethylindole (1)  and dimethylglutamate upon treatment with acid in methanol (Figure 1B). 7As part of an ongoing synthetic study towards the bisindole natural product sciodole (4), we required a supply of the 'lower half' of this alkaloid, specifically 5-methoxy-2,4-dimethylindole (1).Although 5-methoxy-2,4-dimethylindole (1) has been synthesized previously, 8 this route starts with a trifluoromethylbenzoquinone that is not readily attainable.Here, we report a synthesis of 1 via an ortho-quinone methide (o-QM) that has enabled access to grams of the natural product.Furthermore, the Tricholoma indoles 2 and 3 were also accessed via the same o-QM.

Result and Discussion
The known 9 5-hydroxy-2-methylindole 6 was subjected to a regioselective aminomethylation to give the phenolic Mannich base 7, 10 which would serve as an o-QM precursor. 11Upon reaction of the o-QM with an appropriate nucleophile, functionalization of the indole C4-site would occur and thus provide access to the targets 1-3 (Scheme 1).Upon treating Mannich base 7 with sodium borohydride in ethanol at reflux, the desired product 8 was isolated.In this instance, thermal generation of the o-QM is followed by reduction/aromatization 12 to give the indole 8 bearing a methyl group at C4. Selective O-methylation of 8 gave the natural product 5-methoxy-2,4-dimethylindole 1, a key intermediate in our ongoing efforts towards the synthesis of sciodole (4).Our next target was the natural product 2, which required the introduction of a methoxymethyl group at C4.In this instance, the dimethylamino group of 7 was quaternized with iodomethane to allow a base-mediated o-QM formation at ambient temperature; 13,14 trapping of the o-QM with methoxide and concomitant phenol alkylation (MeI) occurred to give the natural product 2 in a single-pot from 7. Finally, natural product 3 was targeted, which required introduction of a methoxy group at C7 in 1.This desired transformation aligns perfectly with the iridium-catalyzed C-H borylation reaction, 15 the regiochemical outcome of which is reliably dictated by the directing ability of the indole N-H.Subjecting 1 to an iridium-catalyzed C-H borylation using the 3,4,7,8-tetramethylphenanthroline as (Me4Phen) 16,17 gave the 7-borylindole 9 in good yield.A DMAP-assisted 18 Chan-Evans-Lam coupling of 9 with methanol gave the natural product 5,7-dimethoxy-2,4-dimethylindole (3).The modest yield for this step can be attributed to the instability of the electron-rich indole 3.

Conclusions
The synthesis of three Tricholoma-derived indole natural products has been achieved.The Mannich base 7 served as a precursor to an o-QM that upon reaction with an appropriate nucleophile, led to efficient installation of a methyl group and a methoxymethyl group at the indole C4-position.The utility of the iridium catalyzed C-H borylation reaction for selective functionalization of the indole C7-site has also been demonstrated.

Experimental Section
General.Commercially available reagents were used throughout without purification unless otherwise stated.Anhydrous solvents were used as supplied.All reactions were routinely carried out in oven-dried glassware under a nitrogen atmosphere unless otherwise stated.Analytical thin layer chromatography was performed using silica plates and compounds were visualized at 254 and/or 360 nm ultraviolet irradiation followed by staining with either alkaline permanganate or ethanolic vanillin solution.Infrared spectra were obtained using a Perkin Elmer spectrum One Fourier Transform Infrared spectrometer as thin films between sodium chloride plates.Absorption maxima are expressed in wavenumbers (cm -1 ).Melting points were recorded on an Electrothermal melting point apparatus and are uncorrected.NMR spectra were recorded using either a Bruker DRX300 spectrometer operating at 300 MHz for 1 H nuclei and 75 MHz for 13 C nuclei or a Bruker DRX400 spectrometer operating at 400 MHz for 1 H nuclei and 100 MHz for 13 C nuclei.Chemical shifts are reported in parts per million (ppm) relative to the tetramethylsilane peak recorded as  0.00 ppm in CDCl3/ TMS solvent, or the residual chloroform ( 7.26 ppm) and DMSO ( 2.50 ppm) peaks.The 13 C NMR values were referenced to the residual chloroform ( 77.1 ppm) and DMSO ( 39.5 ppm) peaks. 13C NMR values are reported as chemical shift, , multiplicity and assignment. 1 H NMR shift values are reported as chemical shift, , relative integral, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), and assignment.Assignments are made with the aid of NOESY and HMBC experiments.High resolution mass spectra were obtained by electrospray ionization in positive ion mode at a nominal accelerating voltage of 70 eV on a Bruker micrOTOF-QII mass spectrometer.

5-Hydroxy-4-(dimethylamino)methyl-2-methylindole (7).
Prepared according to the procedure reported by Monti and Johnson, 10 but with changes to purification.The product 7 was not completely characterised in the literature. 10A solution of formaldehyde (37% aqueous, 1.53 mL) and dimethylamine (40% aqueous, 2.84 mL) in EtOH (30 mL) was prepared and warmed to 80 °C for 30 min.This solution was then cooled to rt before 5hydroxy-2-methylindole (6) 9 (3.30g, 22.42 mmol) in EtOH (70 mL) was added.The mixture was stirred under reflux for 1 h, during which time a colour change from yellow to dark red was observed.The reaction mixture was concentrated in vacuo and the resulting crude material was purified by flash column chromatography on silica gel eluting with CH . Sodium metal (101 mg, 4.41 mmol) was added portionwise to MeOH (10 mL) at 0 °C.The resulting solution was allowed to stir for 15 min until the consumption of the sodium was complete.Mannich base 7 (300 mg, 1.47 mmol) was then slowly added, followed by the dropwise addition of MeI (0.275 mL, 4.41 mmol).The resulting solution was allowed to warm to rt and a nitrogen stream was gently bubbled through the solution for 1 h.After this time, an additional portion of MeI (0.460 mL, 7.35 mmol) was added and the resulting reaction was sealed and stirred at rt for 12 h.The mixture was concentrated in vacuo and the crude material purified by flash column chromatography on silica gel eluting with EtOAc/petroleum ether (2:3) to afford the title compound (73 mg, 0.36 mmol, 24%) as a light brown solid, mp 85-88 °C; vmax (neat)/cm