Tying a Molecular Overhand Knot of Single Handedness and Asymmetric Catalysis with the Corresponding Pseudo-D3-Symmetric Trefoil Knot

We report the stereoselective synthesis of a left-handed trefoil knot from a tris(2,6-pyridinedicarboxamide) oligomer with six chiral centers using a lanthanide(III) ion template. The oligomer folds around the lanthanide ion to form an overhand knot complex of single handedness. Subsequent joining of the overhand knot end groups by ring-closing olefin metathesis affords a single enantiomer of the trefoil knot in 90% yield. The knot topology and handedness were confirmed by NMR spectroscopy, mass spectrometry, and X-ray crystallography. The pseudo-D3-symmetric knot was employed as an asymmetric catalyst in Mukaiyama aldol reactions, generating enantioselectivities of up to 83:17 er, which are significantly higher than those obtained with a comparable unknotted ligand complex.

Unless stated otherwise, reagents were obtained from commercial sources and used without purification. Anhydrous THF (HPLC grade, Fischer scientific), CH 2 Cl 2 (HPLC grade, Fischer scientific), and CH 3 CN (HPLC grade, Fischer scientific) were obtained by passing the solvent through an activated alumina column on a Phoenix SDS (solvent drying system; JC Meyer Solvent Systems, CA, USA). DMF (Peptide synthesis grade, Merck) was used throughout. 1 H NMR spectra were recorded on a Bruker Avance III instrument with an Oxford AS600 magnet equipped with a cryoprobe [5mm CPDCH 13 C--1 H/D] (600 MHz).
Chemical shifts are reported in parts per million (ppm) from high to low frequency using the residual solvent peak as the internal reference (CDCl 3 = 7.26 ppm, CD 3 OD = 3.31 ppm and CD 3 CN = 1.94). S1,S2 All 1 H resonances are reported to the nearest 0.01 ppm. The multiplicity of 1 H signals are indicated as: s = singlet; d = doublet; t = triplet; q = quartet; sept = septet; m = multiplet; br = broad; app = apparent; or combinations of thereof. Coupling constants (J) are quoted in Hz and reported to the nearest 0.1 Hz. Where appropriate, averages of the signals from peaks displaying multiplicity were used to calculate the value of the coupling constant. 13 C NMR spectra were recorded on the same spectrometer with the central resonance of the solvent peak as the internal reference (CDCl 3 = 77.16 ppm, CD 3 OD = 49.00 ppm and CD 3 CN = 118.26 ppm). S1,S2 13 C resonances are reported to the nearest 0.01 ppm.

Trimethyl(1--phenylpropenyloxy)silane
Propiophenone (1.34 g, 9.99 mmol) in THF (20 mL) was added dropwise to a stirred solution of LiHMDS (1 M in THF, 15 mL) over a period of 30 min at rt. The resulting solution was stirred for another 15 min before the addition of chlorotrimethylsilane (1.62 g, 14.9 mmol) in THF (10 mL). The reaction mixture was concentrated and the residue taken up in CH 2 Cl 2 (50 mL). The resulting suspension was filtered and the filtrate concentrated under reduced pressure to afford the silyl enol ether (1.85 g, 8.69 mmol) as a yellow oil in 87% yield. The product was stored in the freezer and used without further purification. S6 Characterization data was in agreement with the literature. S7

General procedure A
A solution of europium catalyst (10 mol%) and aldehyde (0.066 mmol, 1 equiv.) in a mixture of dry MeOH/CH 3 CN (5:2, 0.7 mL) was cooled to −10 °C. The silyl enol ether (0.066 mmol, 1 equiv.) was added dropwise and the reaction mixture was stirred at the same temperature for 4 d. The reaction mixture was concentrated and the remaining solid taken up in CH 2 Cl 2 .
The suspension was filtered and the solution was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (PET/EtOAc, 5:1) to afford the aldol adduct.

General procedure B
To a dry microwave vial equipped with a stirrer bar, the europium catalyst (10 mol%) was transferred from a stock solution (CH 3 CN) and the solvent removed under reduced pressure.
To this, the aldehyde (0.01 mmol, 1 equiv.) and silyl enol ether (0.015 mmol, 1.5 equiv.) c d e f g S11 were added sequentially from separate stock solutions of dry MeOH/CH 3 CN (5:2, 0.05 mL) at −10 °C. The resulting slurry was stirred at the same temperature for 4 d. The reaction mixture was concentrated and the remaining solid taken up in CH 2 Cl 2 . The suspension was filtered and the solution was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (PET/EtOAc, 5:1) to afford the aldol adduct, which was analyzed by 1 H NMR and chiral HPLC.
Crystal structure determinations and refinements: X--Ray data were processed and reduced using the CrysAlisPro suite of programs. Absorption correction was performed using empirical methods based upon symmetry--equivalent reflections combined with measurements at different azimuthal angles. S12 The crystal structure was solved and refined against all F 2 values using the SHELXL suite of programs and Olex2. S13 Atoms corresponding to the aliphatic chains were refined isotropically due to the high disorder of these moieties.
The disorders in the aliphatic groups were modelled over two positions. The occupancies of the aliphatic chains were set to be 2/3 for the polyethoxy moieties and 1/3 for the ethene group. Hydrogen atoms were placed in calculated positions refined using idealized geometries (riding model) and assigned fixed isotropic displacement parameters. The phenyl groups were restrained to have idealized geometries using AFIX commands. The C--C, C--O, C--F, C--S and S--O distances in the aliphatic chains and triflates ions were restrained using DFIX and SADI command. The atomic displacement parameters (adp) of the ligands have been restrained using RIGU, EADP and SIMU commands.
The crystal of compound Λ--Eu(R 6 )--2(CF 3 SO 3 ) 3 was twinned. The TwinRotMax protocol inside PLATON suites was used to account the twin components. S14 A large number B alerts were found due to high disorder found in the aliphatic chains.