Enantioselective Michael Addition/Iminium Ion Cyclization Cascades of Tryptamine-Derived Ureas

A Michael addition/iminium ion cyclization cascade of enones with tryptamine-derived ureas under BINOL phosphoric acid (BPA) catalysis is reported. The cascade reaction tolerates a wide variety of easily synthesized tryptamine-derived ureas, including those bearing substituents on the distal nitrogen atom of the urea moiety, affording polyheterocyclic products in good yields and good to excellent enantioselectivities.

spectroscopy (COSY, HSQC and HMBC) was used to assist in the assignment. The data are not reported.

Mass spectra
Low-resolution mass spectra (ESI) were recorded on a Waters LCT Premier XE Micromass mass spectrometer. High-resolution mass spectra (ESI) were recorded on Bruker Daltonics MicroTOF mass spectrometer. High-resolution mass spectra (EI) were recorded on a Bruker FT-ICR Apex III mass spectrometer.

Infrared spectra
Infrared spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer as a thin film on a sodium chloride plate. Only selected maximum absorbances are reported.

Determination of enantiomeric excesses
Enantiomeric excesses were determined using high performance liquid chromatography (HPLC) performed on Agilent Technologies 1200 Series or 1260 Infinity Series systems (column and solvent conditions are given for each compound).
All atom numbering used in this section is arbitrary and does not follow any particular convention.

General procedure II for the preparation of tryptamine-derived ureas 5j-p
Tryptamine (1.0 eq.) was dissolved in CH 2 Cl 2 at room temperature. Triethylamine (2.0 eq.) was added and the reaction mixture was cooled to 0 °C. Isocyanate (0.90 eq.) was then added dropwise and the reaction mixture was allowed to slowly warm to room temperature over the indicated time. The resulting precipitate was filtered off washing with CH 2 Cl 2 and dried under vacuum to afford the desired ureas 5j-p. The ureas were used in the next step without further purification.

General procedure III for the enantioselective synthesis of products 9
(Thio)urea derivative 5 (1.0 eq.) was suspended in dry PhMe (200 mL/mmol) and enone 6 (5.0 eq.) was added in one portion at room temperature, immediately followed by the addition of catalyst 10a (0.10 eq.) in one portion. The resulting suspension was heated at 110 °C for the indicated time. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel to afford the desired cyclised products 9a-w.
[Racemic samples were synthesised in an analogous manner to general procedure III, replacing catalyst 10a with p-TsOH (0.10 eq.).]

]pyrido[3,4-b]indol-4(12H)-one 9w
The title compound was synthesised according to general procedure III. Urea derivative 5p (68 mg, 0.20 mmol) was reacted with methyl vinyl ketone 6a (81 µL, 1.0 mmol) in PhMe (40 mL) for 15 hours. The residue was purified by flash column chromatography on silica gel (solvent: CH 2 Cl 2 /MeOH 95/5) to afford product 9w in 74% yield (58 mg) as a brown powder.   (6), and a probability that the structure was the correct hand of >99.99% given that the structure is enantiopure or a racemic twin using the Bayesian method.