Enantioselective de novo synthesis of 14-hydroxy-6-oxomorphinans

The enantioselective de novo synthesis of pharmacologically important 14-hydroxy-6-oxomorphinans is described. 4,5-Desoxynaltrexone and 4,5-desoxynaloxone were prepared using this route and their biological activities against the opioid receptors were measured.


General Information
Reactions.All air-sensitive reactions were carried out under an inert atmosphere using oven-dried apparatus.
Reagents and Solvents.All commercially available reagents were used as received unless otherwise stated.Petroleum ether refers to Sigma-Aldrich product 24587 (petroleum ether boiling point 40-60 °C).
Chromatography.Thin layer chromatography (TLC) was performed on Merck DF-Alufoilien 60F254 0.2 mm precoated plates.Compounds were visualized by exposure to UV light or by dipping the plates into solutions of potassium permanganate followed by gentle heating.Column chromatography was carried out using a Biotage Isolera 4 fitted with Agela Claricep silica gel disposable flash columns.
Melting Points.Melting points were recorded on a Gallenkamp melting point apparatus and are uncorrected.The solvent of recrystallization is reported in parentheses.
IR Spectra.Infrared (IR) spectra were recorded on Bruker platinum alpha FTIR spectrometer on the neat compound using the attenuated total refraction technique.NMR Spectra. 1 H and 13 C NMR spectra were referenced to external tetramethylsilane via the residual protonated solvent ( 1 H) or the solvent itself ( 13 C).All chemical shifts are reported in parts per million (ppm).For CDCl3, the shifts are referenced to 7.26 ppm for 1 H NMR spectroscopy and 77.16 ppm for 13 C NMR spectroscopy.For DMSO-D6, the shifts are referenced to 2.50 ppm for 1 H NMR spectroscopy and 39.52 ppm for 13 C NMR spectroscopy.For CD3OD, the the shifts are referenced to 3.31 ppm for 1 H NMR spectroscopy and 49.00 ppm for 13 C NMR spectroscopy. 13C NMR Assignments were made using the DEPT sequence with secondary pulses at 90° and 135° or using 2D NMR spectroscopy techniques including HSQC and HMBC.Coupling constants (J) are quoted to the nearest 0.1 Hz.

Mass Spectra. Electrospray ionisation (ESI) high-resolution mass spectrometry (HRMS) analyses
were performed on a Bruker micrOTOFII mass spectrometer (Bruker Daltonik, Bremen, Germany), interfaced to an Agilent 1200 HPLC (Agilent Technologies, Santa Clara, USA).Samples were presented in solution for analysis by Flow Injection, 1 μL of solution being injected into the ion source of the instrument along with a flow of 0.2 mL min -1 of 70% MeOH/H2O eluent.The mass spectrometer was operated in electrospray ionisation (ESI) mode at a typical resolving power of 8000.
Control of the analysis was performed through Bruker's Compass Open Access QC automated data acquisition and reporting software (v1.3;Bruker Daltonik, Bremen, Germany).
X-ray Crystallography.Single crystal X-ray diffraction data for compounds 10, 12, and 22 were collected on an Oxford Diffraction GV1000 (TitanS2 CCD area detector, mirror-monochromated Cu-Kα radiation source; λ = 1.54184Å, ω scans).Single crystals were selected, mounted using Fomblin® (YR-1800 perfluoropolyether oil) on a polymer-tipped MiTeGen MicroMount TM , and cooled rapidly to 120 K in a stream of cold N2 using an Oxford Cryosystems open flow cryostat. 1Cell parameters were refined from the observed positions of all strong reflections and absorption corrections were applied using a Gaussian numerical method with beam profile correction (CrysAlisPro). 2 Structures were solved within Olex2 3 by dual space iterative methods (SHELXT) 4 and all non-hydrogen atoms refined by full-matrix least-squares on all unique F2 values with anisotropic displacement parameters (SHELXL). 5Hydrogen atoms were refined both freely and with constrained riding geometries and thermal parameters linked to Uiso of their parent atoms.Structures were checked with checkCIF (http://checkcif.iucr.org).CCDC 2341582-2341584 contain the supplementary data for these compounds.These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to yield the crude title compound S1, which was used directly in the next step without further purification.

tert-Butyl (R)-1-(2-bromo-4-methoxybenzyl)-6-methoxy-3,4dihydroisoquinoline-2(1H)-carboxylate (18).
To the above crude mixture was added CH2Cl2 (100 mL), Et3N (5.1 mL, 38.1 mmol), di-tert-butyl dicarbonate (4.13 g, 18.9 mmol), and DMAP (154 mg, 1.26 mmol).The reaction was stirred for 18 h and then separated between saturated aqueous NH4Cl solution and CH2Cl2.The aqueous phase was extracted three times with CH2Cl2 and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo.The crude residue was purified by column chromatography (0-20% EtOAc in pentane) to give the title compound 18 as an amorphous white solid (4.11 g, 71% over two steps, 92% ee).Note: Peaks in the  (Note: The solution of DMDO used was prepared by adding H2O to an Oxone-free solution of DMDO in acetone, which was itself prepared according to an existing literature procedure. 6) The mixture was stirred for 18 h and then partially concentrated to remove most of the acetone.The mixture was extracted seven times with CH2Cl2 and the combined organic phases were dried (Na2SO4) and concentrated in vacuo to yield 1.34 g of crude material.The remaining aqueous phase was an emulsion, which was left to stand for 2 days before brine was added.This aqueous mixture was extracted three times with EtOAc, dried (Na2SO4), and concentrated in vacuo to give a further 293 mg of crude material.Each of the above crude mixtures were separately dissolved in CH2Cl2 (10 mL and 5 mL, respectively) and Et3N (0.5 mL and 0.25 mL, respectively) was added at room temperature.
The reaction mixtures were stirred for 45 min and then concentrated in vacuo to yield the crude allyl alcohols 22 and 12 (22:12 = 1:5).The crude mixtures were separately purified by column chromatography (20-80% EtOAc in pentane) to give 22 (172 mg, 11%) followed by 12 (706 mg, 44%) as the combined yields from the two columns, each as off-white amorphous solids.
Data for 22: Note: Peaks in the 1 H and 13 C NMR spectra are broad due to the presence of rotamers.To a solution of 23 (82 mg, 0.21 mmol) in CH2Cl2 (2.1 mL) at 0 °C was added BBr3 (0.06 mL, 0.63 mmol).The mixture was warmed to room temperature, stirred for 1.5 h, and cooled to 0 °C.The reaction was basified with aqueous NH4OH solution (30-33% NH3 in H2O).The mixture was extracted with three times with CHCl3 and the combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo to leave 4,5-desoxynoroxymorphone, which was used directly in the next step without further purification.
The reaction vessel was purged with argon and then placed on a 70 °C heating block for 3 h.Following a further addition of Et3N (0.04 mL, 0.30 mmol), the mixture was stirred at 70 °C for an additional 17 h.The reaction was cooled to room temperature, diluted with toluene and washed three times with a saturated aqueous NaHCO3 solution.The aqueous phase was extracted with toluene and the combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo.To a solution of 23 (47 mg, 0.12 mmol) in CH2Cl2 (1.2 mL) at 0 °C was added BBr3 (0.06 mL, 0.63 mmol).The mixture was warmed to room temperature, stirred for 1.5 h, and cooled to 0 °C.The reaction was basified with aqueous NH4OH solution (30-33% NH3 in H2O).The mixture was extracted with three times with CHCl3 and the combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo to leave 4,5-desoxynoroxymorphone, which was used directly in the next step without further purification.
To a solution of 4,5-desoxynoroxymorphone in NMP/H2O (10:1, 0.39 mL) at room temperature was added was allyl bromide (10.7 µL, 0.124 mmol) followed by Et3N (0.03 mL, 0.22 mmol).The reaction vessel was purged with argon and then placed on a 70 °C heating block for 2 h.Following a further addition of Et3N (0.03 mL, 0.22 mmol), the mixture was stirred at 70 °C for an additional 3 h.The reaction was cooled to room temperature, diluted with CH2Cl2 and washed three times with a saturated aqueous NaHCO3 solution.The aqueous phase was extracted with CH2Cl2 and the combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo.Recrystallization of 10 from EtOAc/pentane using the vapour diffusion method gave crystals that were suitable for X-ray crystallography: [a] Potency (pEC50) and maximal effect (Emax) were measured using a G-protein dissociation assay in HEK293 cells expressing human MOR, DOR, KOR, or NOP.EC50 is expressed in nM and Emax as the % of the response elicited by a maximal concentration of reference compounds (DAMGO for MOR, SNC-80 for DOR, U-50488 for KOR, and nociceptin for NOP).The data show mean  SEM of at least 3 independent experiments performed in duplicate.
chloride 16 (5.00g, 12.60 mmol) in CH2Cl2 (19 mL) at 0 °C was added HCO2H (1.4 mL, 37.1 mmol) and then slowly, Et3N (5.1 mL, 38.1 mmol).The mixture was warmed to warm to room temperature and stirred for 1 h before being warmed to 30 °C.RuCl(p-cymene)[(S,S)-Ts-DPEN] (17, 80 mg, 0.13 mmol) was added and the mixture was evacuated and back-filled with argon three times.After 18 h, the mixture was basified by the addition of saturated aqueous Na2CO3 solution and then extracted three times with CH2Cl2.