Multivalent polyglycerol supported imidazolidin-4-one organocatalysts for enantioselective Friedel–Crafts alkylations

Summary The first immobilization of a MacMillan’s first generation organocatalyst onto dendritic support is described. A modified tyrosine-based imidazolidin-4-one was grafted to a soluble high-loading hyperbranched polyglycerol via a copper-catalyzed alkyne–azide cycloaddition (CuAAC) reaction and readily purified by dialysis. The efficiency of differently functionalized multivalent organocatalysts 4a–c was tested in the asymmetric Friedel–Crafts alkylation of N-methylpyrrole with α,β-unsaturated aldehydes. A variety of substituted enals was investigated to explore the activity of the catalytic system which was also compared with monovalent analogues. The catalyst 4b showed excellent turnover rates and no loss of activity due to immobilization, albeit moderate enantioselectivities were observed. Moreover, easy recovery by selective precipitation allowed the reuse of the catalyst for three cycles.


General methods
Commercial reagents were used as received. All reactions were carried out under magnetic stirring and were monitored by TLC analysis on 0.20 mm silica gel plates (Macherey-Nagel G/UV 254 ). Column chromatography was carried out on silica gel 60 M (0.04-0.063 mm) Macherey-Nagel. Dialysis was performed in benzoylated cellulose tubes from Sigma-Aldrich (D7884-10FT, width: 32 mm, molecular weight cut-off (MWCO) 2000 g•mol −1 . Yields refer to spectroscopically and analytically pure compounds unless otherwise stated. 1 H NMR and 13 C NMR spectra were recorded on Bruker (ECP 400, AC 500, AV 700) or JEOL (ECX 400, Eclipse 500) instruments.

Synthesis of hPG-OMs 2a-c 3,4
General procedure: Mesylation of hyperbranched polyglycerol 1 was carried out under an inert gas atmosphere and exclusion of moisture. In a two-necked 1 L flask, hyperbranched polyglycerol 1 (13.51 mmol OH-groups) was dissolved in anhyd.
pyridine (60 mL). The resulting solution was stirred at 25 °C for 10 min and then cooled to 0 °C in an ice bath. A solution of methanesulfonyl chloride (1.2 equiv, with respect to functionalization degree) in anhyd. pyridine (20 mL) was added dropwise to the reaction mixture and stirring at 25 °C was continued for 16 h. The reaction mixture was then filtered and the solvent was removed under reduced pressure.
The degrees of functionalization were confirmed by 1 H NMR of the crude products correlating the CH 3 -Ms with polyglycerol backbone protons.

Synthesis of hPG-N 3 3a-c 3,4
General procedure: To a homogeneous mixture of O-mesylpolyglycerol 2a-c (1 equiv) in DMF (15 mL), NaN 3 (3 equiv) was added and the resulting suspension was heated at 65 °C for 72 h. After completion of the reaction, the mixture was cooled to room temp. and filtered through Celite ® to remove excess NaN 3 . The filtrate was concentrated under reduced pressure at a temperature below 40 °C and handled with a plastic spatula to avoid a potentially explosive degradation of the polyazide.

hPG-N 3 (30%), 3c
Reaction conditions were as described above, using 2c ( The degrees of functionalization were confirmed by 1 H NMR correlating the aromatic protons with polyglycerol backbone protons.

Synthesis of compound 6
[G1]-N 3 was synthesized according to the earlier reported methods. 6

General procedure for the Friedel-Crafts alkylations
A solution of the catalyst 4a-c or 8 or 16 (x mol %) in the solvent indicated was treated with aq TFA (5 M; x mol %). The mixture was stirred at room temp. for 10 minutes, then the aldehyde 12 or 14a-e (0.25 mmol, 1.0 equiv) was added at the desired temperature T. After 5 minutes of stirring, N-methylpyrrole (11, 111 L, 1.25 mmol, 5.0 equiv) was added and the reaction was stirred at the same temperature T.
Et 2 O (3 mL) was added to the mixture and the catalyst was removed by filtration, washed several time with Et 2 O, then recovered with CH 2 Cl 2 and dried in vacuo for future use. The organic phase was concentrated under reduced pressure and the soobtained residue was purified by silica gel chromatography (pentane/Et 2 O) to afford the corresponding products. MHz):200. 9, 142.5, 133.1, 128.8, 127.7, 126.8, 122.5, 106.7, 106.6, 50.1, 37.7, 33.9 ppm. The enantiomeric excess was determined by chiral GC on a Hydrodex-β-TBDAc column (120 ºC isotherm, 1.1 mL/min He): S isomer t r = 185.45 min and R isomer t r = 191.51 min. The absolute configuration was determined by reduction to the corresponding alcohol and comparison of the optical specific rotation with reported data. 9