Programmed serial stereochemical relay and its application in the synthesis of morphinans

A rationally designed, serial point-to-axial and axial-to-point stereoinduction and its integration into a multi-step and target-oriented organic synthesis was demonstrated in a novel chemical method to access morphinans and it is potentially applicable to other structurally related alkaloids.

chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F254) using UV light as visualizing agent and an ethanolic solution of ammonium molybdate, anisaldehyde or potassium permanganate, and heat as developing agents. E. Merck silica gel (60, particle size 0.0400.063 mm) was used for flash column chromatography. NMR spectra were recorded on an Agilent 400-MR DD2 Magnetic Resonance System or Varian/Oxford As-500 instrument and calibrated using residue undeuterated solvent as internal reference.
The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. IR spectra were recorded on a Thermo Scientific Nicolet 6700 spectrometer. High-resolution mass spectra (HRMS) were recorded on a Bruker (compact) Ultra High Resolution ESI Q-TOF mass spectrometer.
The resulting mixture was warmed to reflux and stirred for 16 h before it was cooled to room temperature, and evaporated to approximately half of its original volume. The resulting mixture was diluted with water (200 mL) and extracted with Et 2 O (3 × 100 mL), the combined organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure to afford dimethyl ether 2b (74.7 g, 87%) as a white solid. The crude material was sufficiently pure based on thin-layer-chromatography and 1 H NMR analysis for the subsequent reaction.

Alcohol 2c
To a stirred solution of aldehyde 2b (33.1 g, 135 mmol) in THF (250 mL) at 0 °C was added NaBH 4 (13.0 g, 344 mmol) in portions. The resulting mixture was warmed to 40 °C and stirred for 2 h before it was cooled to room temperature and quenched with water (200 mL).

Atropisomer Thermal Stability Studies:
NMR samples of atropisomerically pure (obtained through silica-gel flash column chromatography and purity confirmed by 1 H NMR analysis) compounds 5a, 5a', 5b, 5b', 5c, 5c', 5d and 5d' in C 6 D 6 were subjected to heating (oil bath) and held at temperatures 40 °C , 70 °C , 90 °C , 100 °C , 110 °C , 120 °C for 1 hour intervals. The samples were then cooled to room temperature after each incremental heating, and degree of atropisomerization analyzed by 1 H NMR analysis. Finally, all samples were further heated at 120 °C until atropisomeric ratio remained constant.

TBS Ethers 6d and 6d'
To a stirred solution of bis-TBS ethers TBS-6d and TBS-6d' (13.0 g, 23.3 mmol) in MeCN/H 2 O (10:1, 75.0 mL) at room temperature was added DBU (3.30 mL, 22.1 mmol). The resulting mixture was warmed to 45 °C and stirred for 24 h before it was cooled to room temperature and quenched with NH 4 Cl (40 mL, sat. aq.) and water (40 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL), the combined organic layer was washed with water (40 mL), brine (40 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. Flash column chromatography (silica gel, hexanes:EtOAc 13:1) afforded TBS ethers 6d and 6d' (9.00 g, 87% combined yield) as an amorphous solid. Small amount of analytically pure isomers 6d and 6d' were obtained through column chromatography. All physical data of TBS ethers 6d and 6d' are identical to those obtained from mono-silylation of alcohols 5d and 5d'.

Biaryl Ether 2g
(i) To a stirred solution of dibromide 2d (450 mg, 1.45 mmol) in acetone (150 mL) at room temperature was added K 2 CO 3 (602 mg, 4.36 mmol) followed by catechol (192 mg, 1.74 mmol). The resulting mixture was warmed to reflux and stirred for 16 h before it was cooled to room temperature and diluted with water (100 mL). The resulting mixture was extracted with Et 2 O (3 × 75 mL), the combined organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure. Flash column chromatography (silica gel, hexanes:EtOAc 4:1) afforded biaryl ether 2f (433 mg, 88%) as an amorphous white solid.

Atropisomer Thermal Stability Studies:
NMR samples of atropisomerically pure 6e and 6e' in C 6 D 6 were subjected to heating (oil bath) at temperatures 40 °C , 70 °C , 90 °C , 100 °C, 110 °C , 120 °C over 1 hour intervals. The samples were then cooled to room temperature after each incremental heating, and degree of atropisomerization analyzed by 1 H NMR analysis. Finally, heating was maintained at 120 °C until atropisomeric ratio remained constant.

Allylic Alcohols 6f and 6f'
(i) To a stirred solution of lactone 3b (40.0 mg, 0.13 mmol) in THF (3 mL) at 78 °C was added DIBAL-H (1.0 M in hexane, 0.27 mL, 0.27 mmol). The resulting mixture was stirred for 7 min before it was quenched with sodium potassium tartrate (5 mL, sat. aq.) and diluted with EtOAc (5 mL), and stirred vigorously for 1 h. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 × 8 mL), the combined organic layer was washed with water (15 mL), brine (15 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure to afford a crude mixture of hydroxy aldehyde 4b and hemiacetal 4b' (18 mg, 45%) as an amorphous white solid, which was used directly in the subsequent step without further purification.

Atropisomer Thermal Stability Studies:
NMR samples of atropisomerically pure 6f and 6f' in C 6 D 6 were subjected to heating (oil bath) at temperatures 40 °C , 70 °C , 90 °C , 100 °C , 110 °C , 120 °C over 1 hour intervals. The samples were then cooled to room temperature after each incremental heating, and degree of atropisomerization analyzed by 1 H NMR analysis. Finally, heating was maintained at 120 °C until atropisomeric ratio remained constant.

Ketones 8b and 8b'
To a stirred solution of alkenes 8 and 8' (98.0 mg, 0.21 mmol) in THF (2.0 mL) at 78 °C was added borane tetrahydrofuran complex (1.0 M in THF, 1.03 mL, 1.03 mmol). The resulting mixture was warmed to 70 °C and stirred for 4 h before it was cooled to room temperature and treated with PCC (223 mg, 1.03 mmol). The resulting mixture was stirred for 5 h before it was filtered through Celite ® and concentrated under reduced pressure. Flash column chromatography (silica gel, hexanes:Et 2 O 1:1) afforded ketones 8b and 8b' (42.0 mg, 41%) as an amorphous white solid. All physical data of ketone 8b and 8b' are identical to those obtained from stepwise hydroboration of alkenes 8 and 8' followed by DMP oxidation.

Oxime 10
To a stirred solution of alkene 9 (3.20 g, 8.93 mmol) in MeOH (28.0 mL) at room temperature was added hydroxylamine hydrochloride (1.86 g, 26.8 mmol) and NaOAc (2.20 g, 26.8 mmol). The resulting mixture was warmed to reflux and gradually allow the reaction mixture to evaporate to dryness, and the resulting solid residue was heated for 16 h before it was cooled to room temperature and quenched with NaHCO 3 (40 mL, sat. aq.) and MeOH (40 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL), the combined organic layer was washed with water (50 mL), brine (50 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. Flash column chromatography (silica gel, hexanes:EtOAc 4:1) afforded oxime 10 (3.0 g, 90%) as an amorphous yellow solid.

Optically Active Allylic Alcohol 6j and 6k
To a strirred solution of (S)()2Methyl-CBS-oxazaborolidine ( (ii) To a solution of dienone 7g (obtained above) in toluene (30.0 mL) was added trimethyl borate (0.48 mL, 4.31 mmol). The resulting mixture was stirred for 30 min, warmed to reflux and stirred for 1 h before it was cooled to room temperature and concentrated under reduced pressure. Flash column chromatography (silica gel, hexanes:EtOAc 4:1) afforded tetracycles 8g and 8g' (~5:1 based on 1 H NMR analysis, 172 mg, 56% over two steps) as an amorphous yellow solid. All physical data of tetracycles 8g and 8g' are identical to those obtained from the intramolecular Diels-Alder reaction in the absence of B(OMe) 3 .
The resulting mixture was stirred for 24 h before it was quenched with NH 4 Cl (10 mL, sat. aq.) and water (10 mL). The resulting mixture was extracted with Et 2 O (3 × 20 mL), the combined organic layer was washed with water (50 mL), brine (50 mL

Data Collection
A colorless crystal with approximate dimensions 0.2 × 0.1 × 0.08 mm 3 was selected under oil under ambient conditions and attached to the tip of a MiTeGen MicroMount © . The crystal was mounted in a stream of cold nitrogen at 120 K and centered in the X-ray beam by using a video camera. The crystal evaluation and data collection were performed on a Bruker D8 Venture diffractometer with Mo K α (λ = 0.71073 Å ) radiation and the diffractometer to crystal distance of 4.00 cm. The initial cell constants were obtained from two series of  scans at different starting angles. Each series consisted of 12 frames collected at intervals of 0.5º in a 6º range about  with the exposure time of 10 seconds per frame. The reflections were successfully indexed by an automated indexing routine built in the APEXII program. The final cell constants were calculated from a set of 4218 strong reflections from the actual data collection. The data were collected by using the half sphere data collection routine to survey the reciprocal space to the extent of a full sphere to a resolution of 0.81 Å . A total of 18865 data were harvested by collecting 3 sets of frames with 0.5º scans in  and φ with an exposure time 10 sec per frame. These highly redundant datasets were corrected for Lorentz and polarization effects. The absorption correction was based on fitting a function to the empirical transmission surface as sampled by multiple equivalent measurements. [1]

Structure Solution and Refinement
The systematic absences in the diffraction data were uniquely consistent for the space group P2 1 /c that yielded chemically reasonable and computationally stable results of refinement. [2,3] A successful solution by the direct methods provided most non-hydrogen atoms from the E-map. The remaining non-hydrogen atoms were located in an alternating series of least-squares cycles and difference Fourier maps. All non-hydrogen atoms were refined with anisotropic displacement coefficients. All hydrogen atoms were included in the structure factor calculation at idealized positions and were allowed to ride on the neighboring atoms with relative isotropic displacement coefficients. The final least-squares refinement of 250 parameters against 3815 data resulted in residuals R (based on F 2 for I≥2σ) and wR (based on