A biomimetic approach for the concise total synthesis of greenwaylactams A–C

A concise, racemic total synthesis of three sesquiterpenoid alkaloids (greenwaylactams A–C) exhibiting an unprecedented 8-membered benzolactam is disclosed. Key transformations of this work include the ring expansion through cleavage of an indole via Witkop oxidation, as well as an HFIP mediated cationic cyclisation to build up the pentacyclic carbon skeleton.


Chemicals and solvents
Unless stated otherwise, all chemicals were purchased from commercial suppliers (Sigma-Aldrich, BLDPharm, TCI, abcr, Acros, Fisher, VWR) and used without further purification. Some dry solvents (toluene, CH2Cl2, THF, Et2O) were obtained from a PureSolv SPS system by Innovative Technologies.
MeCN, MeOH, pyridine, MTBE and all other dry solvents were obtained from Acros Organics over molecular sieves and used without further purification. All other solvents used were HPLC grade or p.a. unless stated otherwise.

Glassware and reaction conditions
Reactions were carried out in round bottom flasks, or oven-dried Schlenk flasks under an inert atmosphere (Argon) unless stated otherwise. unambiguous assignments could not be made the candidate positions are indicated by solidus "/". Due to very small quantities of product in late-stage experiments (<1 mg) residual grease or solvent was observed in some of the NMR spectra. Any grease or residual solvent impurity will be indicated in the spectrum.

Chromatography
Analytical thin layer chromatography was performed on pre-coated silica gel aluminium sheets from Merck (TLC Silica Gel 60 F254). Spots were visualized either by the quenching of UV fluorescence or by staining with phosphomolybdic acid/cerium sulfate, potassium permanganate or acidic p-anisaldehyde or vanillin solutions. Preparative column chromatography was carried out using Geduran Silica Gel 60 (40 µm -63 µm) from Merck. In cases where mixtures of solvents were used, the ratios refer to the component volumes. In cases where gradients where used, the start and the end ratio are stated.

X-ray crystallography
Suitable single crystals were preselected under a polarizing microscope, embedded in perfluorinated polyether and mounted on MiTeGen ® loops. The single crystal diffraction measurement was performed on a STOE Stadivari four-circle diffractometer equipped with an Eiger 1M CdTe detector. Intensity data were collected at 100 K using graphite monochromatized Cu Kα radiation (λ = 1.54186 Å). Correction for absorption effects were carried out with the multi-scan approach of LANA [1]. The crystal structure was solved by using the dual-space algorithm in SHELXT [2] and was refined by the full-matrix leastsquares technique on F 2 with SHELXL [3]. H atoms were positioned geometrically (CH = 0.95-1.00 Å) and were refined as riding with Uiso(H) = 1.2Ueq(C) for aromatic and methine H atoms, and with Uiso(H) = 1.5Ueq(C) for methyl H atoms.
CCDC 2271072 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures

High-resolution mass spectrometry
The HR-MS analysis was carried out from methanol or acetonitrile or water or a mixture of these solvents (concentration: 10 μM) by using an Agilent G7167B multi sampler, an Agilent G7120A binary pump with degasser, an Agilent G7116B oven and Agilent 6545 Q-TOF mass spectrometer equipped with a dual AJS ion score.

1-(p-Toluenesulfonyl)indole (10)
In a 250-mL three-necked flask was charged NaH (ca. 60%, 768 mg, 19.2 mmol, 1.5 eq.) followed by 30 mL dry THF. To the suspension indole 9 (1.50 g, 12.8 mmol, 1 eq.) was added as a solution in 30 mL dry THF over 10 minutes. After stirring the resulting solution for 30 minutes tosyl chloride (2.69 g, 14.1 mmol, 1.1 eq.) in 15 mL dry THF was added via syringe and the reaction was allowed to stir for 16 hours at room temperature. Reaction was quenched with 50 mL water and extracted 3x with EtOAc (250 mL total), to give 3.77 g of crude product. This was purified via flash chromatography (40 g SiO2, LP:EA = 10:1) to give 3.40 g (98% yield) of 1-tosylindole 10 as a white solid.
The pooled organic phases were washed with brine, dried over MgSO4 and evaporated. The crude product was purified on 50 g SiO2 using 40% toluene in hexanes to give 1.05 g (63% yield) of farnesyl indole 11 as a colorless oil. Analytical data is in accordance with literature [6].
The signals of the 1 H and 13 C-NMR spectra are in good agreement except for erroneously copied shifts.
All signals match with the synthesized material [8].
At -25 °C there was added 4-DMAP (2.5 mg, 20 mol, 1.5 eq.) followed by a stock solution of Ac2O (4 mg, 41 mol, 3.0 eq.) in CH2Cl2. The mixture was stirred at that temperature for 30 minutes and then slowly allowed to reach room temperature over 4 hours, at which point the reaction was complete by TLC analysis. The reaction mixture was directly applied onto a 0.7 g SiO2 column and eluted with 2% methanol in CH2Cl2 to give 4.5 mg (81% yield) of greenwaylactam C (4) as a colorless solid.  Information of [9] The signals of the 1 H and 13 C-NMR spectra are in good agreement except for erroneously copied shifts.
All signals match with the synthesized material [8].
The signals of the 1 H and 13 C-NMR spectra are in good agreement except for erroneously copied shifts.
All signals match with the synthesized material [8].