Copper-catalysed asymmetric allylic alkylation of alkylzirconocenes to racemic 3,6-dihydro-2H-pyrans

Summary Asymmetric allylic alkylation is a powerful reaction that allows the enantioselective formation of C–C bonds. Here we describe the asymmetric alkylation of alkylzirconium species to racemic 3,6-dihydro-2H-pyrans. Two systems were examined: 3-chloro-3,6-dihydro-2H-pyran using linear optimization (45–93% ee, up to 33% yield, 5 examples) and 3,6-dihydro-2H-pyran-3-yl diethyl phosphate with the assistance of a design of experiments statistical approach (83% ee, 12% yield). 1H NMR spectroscopy was used to gain insight into the reaction mechanisms.


IV.
General Procedures S1 Procedures of enantioenriched products from 2a S11 Procedures of enantioenriched products from 2d S12 Procedures of racemic products from 2a S12 Procedures of racemic products from 2d S13 Derivatisation of products to the corresponding epoxides for GC analysis S13

I. General Information
All reactions involving oxygen/moisture sensitive reagents were performed with anhydrous solvents in flame-dried glassware under a positive pressure of anhydrous argon, using standard Schlenk techniques. Cooling of reaction mixtures to -78 ºC was effected using an acetone/dry ice bath; to 0 °C using an ice/water bath; to other temperatures using a Julabo FT902 immersion cooler. Heating was performed using Drysyn® heating blocks.
In the cases where silver salts were used, the resulting solutions were filtered using syringe filters PTFE (0.2 μm, 13 mm diameter) from Camlab.
Nuclear magnetic resonance spectra were acquired in deuterated solvents at room temperature on Bruker: AVIIIHD 400 nanobay, AVIIIHD 500, AVII 500, AVII 500 with cryoprobe spectrometers. Chemical shifts (δ) are reported in ppm from the residual solvent. Coupling constants (J) are quoted in Hertz (Hz) and are recorded to the nearest 0.1 Hz. Resonances are descried as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), doublet of doublets (dd), doublet of doublets of doublets (ddd), doublet of triplets (dt), multiplet (m) and broad (br.). Labels Hb and Ha refer to diastereotopic protons attached to the same carbon and impart no stereochemical information. Assignments were made with the assistance of gCOSY, DEPT-Q, gHSQC and gHMBC NMR spectra.
Low resolution (LRMS) and high resolution (HRMS) mass spectral analyses were acquired by electrospray ionisation (ESI), electron impact (EI), Field Ionisation (FI). Low resolution ESI were recorded using an Agilent 6120 quadrupol LC/MS. High resolution accurate ESI were recorded using a Thermo Exactive 1.1 SP5 Benchtop orbitrap MS and EI/FI on a Waters GTC Temperature programmed solid probe inlet within the department of chemistry, University of Oxford.
Infrared spectroscopy (IR) measurements (neat, thin film) were carried out using a Bruker Tensor 27 FT-IR with internal calibration in the range of 4000-600 cm −1 . Absorption maxima are reported as wavenumbers (cm -1 ).
Optical rotations were recorded using a Schmidt Haensch Unipol L 2000 Polarimeter.
Chiral HPLC separations were achieved using an Agilent 1260 Infinity series normal phase HPLC unit and HP Chemstation software. Chiralpak ® columns (250 × 4.6 mm), fitted with matching Chiralpak ® Guard Cartridges (10 × 4 mm), were used as specified. Solvents used were of HPLC grade (Fisher Scientific, Sigma Alrich or Rathburn). All eluent systems were isocratic.
TMSCl was distilled before use and stored in Schlenk flasks under an argon atmosphere containing CaCl2. Schwartz reagent was prepared according to a literature procedure [1] from Cp2ZrCl2 provided by Strem Chemicals. (CuOTf)2.PhH was synthesised using a modified literature [2] procedure and carefully maintained under inter atmosphere. (CuOTf)2.PhH should be a white or off-white powder. Phosphoramidite ligands were synthesised according to in-house procedures. [3] III.
Synthesis of starting materials

S7
Based on a modified procedure [4] , PCl3 (1.6 mL, 18.5 mmol, 0.37 equiv) was added dropwise to a mixture of 3,6-dihydro-2H-pyran-3-ol (5.0 g, 49.9 mmol, 1 equiv) and pyridine (0.4 mL, 5.0 mmol, 0.1 equiv) at 0 °C. After stirring for 30 min at 0 °C, the reaction mixture was allowed to warm up to room temperature and stirred overnight. The non-viscous organic layer of the resulting mixture was removed by pipette and the bottom layer was rinsed with pentane (3 × 1 mL). The combined organic material was concentrated under reduced pressure and purified by Kugelrohr distillation (20 mbar, 100 °C) to afford the title product as a very pale yellow liquid (

S8
Spectral data was in accordance with literature [4] .

Procedures of enantioenriched products from 2a
In a flame-dried flask under inert atmosphere, Cp2ZrHCl (2.0 equiv) was added to a solution of alkene (2.5 equiv) in CH2Cl2 under an argon atmosphere and stirred vigorously until a clear yellow solution was obtained (20-40 min). Simultaneously, in another flask under inert atmosphere, CuCl (0.1 equiv) and (R)-D (0.1 equiv) were dissolved in CH2Cl2 and stirred for 1 h at room temperature. AgClO4 (0.11 equiv Perchlorates are explosive and should be handled with caution) was added to the freshly formed Cu-ligand complex solution and stirred for 15 min. The resulting catalyst complex mixture was filtered into the freshly prepared alkylzirconocene species. After 10 min, 3-chloro-3,6-dihydro-2H-pyran (1.0 equiv) was added dropwise via a microsyringe to the resulting black solution followed by the dropwise addition of B(OiPr)3 (1.0 equiv). The reaction mixture was stirred overnight. The reaction mixture was diluted with Et2O (2 mL) and quenched with NH4Cl (3 mL, 1 M). The mixture was partitioned and the aqueous phase was extracted with Et2O (3 × 10 mL). The combined organic extracts were washed with NaHCO3 (aq., sat., 30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, Et2O 02% in pentane) yielded the enantioenriched products.

Procedures of enantioenriched products from 2d
In a flame-dried flask under inert atmosphere, Cp2ZrHCl (2.0 equiv) was added to a solution of alkene (2.5 equiv) in CH2Cl2 under an argon atmosphere and stirred vigorously until a clear yellow solution was obtained (20-40 min). S13 Simultaneously, in another flask under inert atmosphere, CuCl (0.1 equiv) and (S, S)-A (0.1 equiv) were dissolved in CH2Cl2 and stirred for 1 h at room temperature. AgOTf (0.11 equiv) was added to the freshly formed Cu-ligand complex solution and stirred for 15 min. The resulting catalyst complex mixture was filtered into the freshly prepared alkylzirconocene species. After 10 min, 3,6-dihydro-2H-pyran-3-yl diethyl phosphate (1.0 equiv) was added dropwise via a microsyringe to the resulting black solution and stirred overnight. The reaction mixture was diluted with Et2O (2 mL) and quenched with NH4Cl (3 mL, 1 M). The mixture was partitioned and the aqueous phase was extracted with Et2O (3 × 10 mL). The combined organic extracts were washed with NaHCO3 (aq., sat., 30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, Et2O 02% in pentane) yielded the enantioenriched products.

Procedures of racemic products from 2a
In a flame-dried flask under inert atmosphere, Cp2ZrHCl (2.0 equiv) was added to a solution of alkene (2.5 equiv) in CH2Cl2 under an argon atmosphere and stirred vigorously until a clear yellow solution was obtained (20-40 min). Simultaneously, in another flask under inert atmosphere, CuCl (0.1 equiv) and (S, S, S)-Feringa ligand (0.05 equiv) and (R, R, R)-Feringa ligand (0.05 equiv) were dissolved in CH2Cl2 and stirred for 1 h at room temperature. AgClO4 (0.11 equiv Perchlorates are explosive and should be handled with caution) was added to the freshly formed Cu-ligand complex solution and stirred for 15 min. The resulting catalyst complex mixture was filtered into the freshly prepared alkylzirconocene species. After 10 min, 3-chloro-3,6-dihydro-2H-pyran (1.0 equiv) was added dropwise via a microsyringe to the resulting black solution followed by the dropwise addition of B(OiPr)3 (1.0 equiv). The reaction mixture was stirred overnight. The reaction mixture was diluted with Et2O (2 mL) and quenched with NH4Cl (3 mL, 1 M). The mixture was partitioned and the aqueous phase was extracted with Et2O (3 × 10 mL). The combined organic extracts were washed with NaHCO3 (aq., sat., 30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, Et2O 02% in pentane) yielded the racemic products.

Derivatisation of products to the corresponding epoxides for GC analysis
In a flame-dried flask, the isolated product (1.0 equiv) was dissolved in CH2Cl2 (6 mL, for 0.4 mmol scale reaction) under an argon atmosphere. m-CPBA (2.0 equiv) and Na2HPO4 (3.0 equiv) were added at room temperature and the reaction mixture was stirred arbitrarily for 3 h before being diluted and quenched by addition of Et2O (10 mL) and an aqueous solution of saturated Na2S2O3 (10 mL) . The organic layer was washed with NaOH (1 M aq., 3 × 5mL), dried over Mg2SO4, filtered and concentrated under vacuum. The crude mixture of diastereoisomeric epoxides was directly analyzed by GC chromatography using a chiral non-racemic stationary phase.

V.
Design of experiments using 2d

VIII. Mechanistic experiments
NMR experiments were carried out on Bruker AVB400 (400/100 MHz), DRX500 (500/125 MHz), AVB500 (500/125 MHz) or AVC500 (500/125 MHz) spectrometers. Processing was performed on Topspin 3.2. Kinetic NMR experiments were performed by pre-tuning, locking and shimming the NMR sample before adding the substrate. No re-locking and re-shimming was performed after the addition of the substrate to facilitate fast data collection. Kinetics integrations were calibrated on the assumption that at any tn, the sum of starting material and products was 100%. All solvents were dried and distilled if necessary (CDCl3) as well as degassed under a flow of argon for a minimum of 30 min. The solvents were stored at 0 °C, in a schlenk on molecular sieves, protected from light.

3-chloro-3,6-dihydro-2H-pyran (2a) Kinetic NMR
In a flame-dried flask under inert atmosphere, ethylene gas (1 atm) was bubble through a solution of Cp2ZrHCl (103 mg, 0.4 mmol, 2.0 equiv) in CD2Cl2 (0.4 mL) under an argon atmosphere and stirred vigorously until a clear yellow solution was obtained (15 min). Simultaneously, in another flask under inert atmosphere, CuCl (1.9 mg, 0.02 mmol, 0.1 equiv) and (R)-D (12.0 mg, 0.02 mmol, 0.1 equiv) were dissolved in CD2Cl2 (1.0 mL) and stirred for 1 h at room temperature. AgClO4 (4.6 mg, 0.022 mmol, 0.11 equiv Perchlorates are explosive and should be handled with caution) was added to the freshly formed Cu-ligand complex solution and stirred for 15 min. The resulting catalyst complex mixture was filtered into a flamed dried NMR tube adapted with an NMR septa and parafilmed. Then the freshly prepared alkylzirconocene species was added to the NMR tube and the tube was thoroughly shaken to obtain an homogenous black solution. 3-chloro-3,6-dihydro-2H-pyran 2a (24 mg, 0.2 mmol, 1.0 equiv) was added via a microsyringe to the NMR tube followed by B(OiPr)3 (46 L, 0.2 mmol, 1.0 equiv). The reaction mixture was shaken vigorously (upside-down mixing) and NMRs were recorded at regular intervals.

S31
CH2Cl2 (3.0 mL) and stirred for 1 h at room temperature. AgClO4 (13.8 mg, 0.066 mmol, 0.11 eq Perchlorates are explosive and should be handled with caution) was added to the freshly formed Cu-ligand complex solution and stirred for 15 min. The resulting catalyst complex mixture was filtered into the freshly prepared alkylzirconocene species. After 10 min, 3-chloro-3,6-dihydro-2H-pyran 2a (71 mg, 0.6 mmol, 1.0 equiv) was added dropwise via a microsyringe to the resulting black solution followed by the dropwise addition of B(OiPr)3 (140 L, 0.6 mmol, 1.0 equiv). The reaction mixture was stirred overnight. Aliquots were taken regularly and analysed by HPLC and GC to obtain the ee of product 5 and starting material 2a.

3,6-dihydro-2H-pyran-3-yl diethyl phosphate (2d) Kinetic NMR
In a flame-dried flask under inert atmosphere, ethylene gas (1 atm) was bubble through a solution of Cp2ZrHCl (103 mg, 0.4 mmol, 2.0 equiv) in CD2Cl2 (0.4 mL) under an argon atmosphere and stirred vigorously until a clear yellow solution was obtained (15 min). Simultaneously, in another flask under inert atmosphere, CuCl (1.9 mg, 0.02 mmol, 0.1 equiv) and (S, S)-A (9.9 mg, 0.02 mmol, 0.1 equiv) were dissolved in CD2Cl2 (1.0 mL) and stirred for 1 h at room temperature. AgOTf (5.7 mg, 0.022 mmol, 0.11 equiv) was added to the freshly formed Cu-ligand complex solution and stirred for 15 min. The resulting catalyst complex mixture was filtered into a flamed dried NMR tube adapted with an NMR septa. Then the freshly prepared alkylzirconocene species was added to the NMR tube and the tube was thoroughly shaken to obtain a homogenous black solution. 3,6-dihydro-2H-pyran-3-yl diethyl phosphate 2d (27 L, 0.2 mmol, 1.0 equiv) was added via a microsyringe to the NMR tube. The reaction mixture was shaken vigorously (upside-down mixing) and NMRs were recorded at regular intervals.