Stereoselective synthesis and transformation of pinane-based 2-amino-1,3-diols

A library of pinane-based 2-amino-1,3-diols was synthesised in a stereoselective manner. Isopinocarveol prepared from (−)-α-pinene was converted into condensed oxazolidin-2-one in two steps by carbamate formation followed by a stereoselective aminohydroxylation process. The relative stereochemistry of the pinane-fused oxazolidin-2-one was determined by 2D NMR and X-ray spectroscopic techniques. The regioisomeric spiro-oxazolidin-2-one was prepared in a similar way starting from the commercially available (1R)-(−)-myrtenol (10). The reduction or alkaline hydrolysis of the oxazolidines, followed by reductive alkylation resulted in primary and secondary 2-amino-1,3-diols, which underwent a regioselective ring closure with formaldehyde or benzaldehyde delivering pinane-condensed oxazolidines. During the preparation of 2-phenyliminooxazolidine, an interesting ring–ring tautomerism was observed in CDCl3.


General procedure for carbamate formation
Trichloroacetyl isocyanate (6.78 g, 35.99 mmol) was added dropwise to a solution of the allylic alcohol (4.50 g, 29.56 mmol) in dry DCM (50 mL) at 0 °C. After stirring for 2 h, the mixture was concentrated under reduced pressure and the residue was dissolved in MeOH (60 mL). An aqueous solution of K2CO3 (4.30 g in 15 mL of H2O) was added to the solution at 0 °C and the mixture was allowed to stir for 4 h (TLC monitoring). The MeOH was evaporated under reduced pressure and the aqueous residue was extracted with DCM (3 × 50 mL). The combined organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the crude carbamate, which was purified by column chromatography on silica gel (nhexane/EtOAc 9:1).

General method for the aminohydroxylation process
To a solution of allylic carbamate 8 or 11 (2.00 g, 10.24 mmol) in iPrOH (180 mL), freshly prepared 0.33% aqueous solution of NaOH (80 mL) was added. The solution was allowed to stir for 5 min, then t-BuOCl (1.026 mL, 10.30 mmol) was added. After stirring for 5 min, N,Ndiisopropylethylamine (59 mg, 79.5 μL, 0.46 mmol) and potassium osmate(VI) dihydrate (135 mg, 0.366 mmol) were added to the solution in one portion. After the addition of 0.33% aqueous NaOH solution (20 mL), the mixture was stirred for 24 h (TLC monitoring), then quenched with Na2SO3 (500 mg) and allowed to stir for 30 min. The mixture was extracted with EtOAc (3 × 50 mL) and the organic layer was washed with brine (1 × 50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to yield the crude product, which was purified by column chromatography on silica gel (n-hexane/EtOAc 1:2).

General method for the alkaline hydrolysis of oxazolidinones
To a solution of oxazolidinone 9 or 12 (1.70 g, 8.05 mmol) in dry EtOH (21 mL), 14% aqueous solution of NaOH (10 mL) was added and the mixture was heated under reflux for 6 h. The solution was evaporated to approx. 10 mL volume, then extracted with DCM (3 × 30 mL). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to yield crude product 13, which was purified as a hydrochloride salt by recrystallization from an EtOH/Et2O mixture.

General method for the LAH reduction of oxazolidinones 9 and 12
To the stirred suspension of LiAlH4 (0.25 g, 6.59 mmol) in dry THF (5 mL) the solution of 9 or 12 (0.35 g, 1.656 mmol) in dry THF (5 mL) was added dropwise under ice cooling. The reaction mixture was treated under reflux conditions for 2 h, then a mixture of H2O (0.50 mL) and THF (5 mL) was added dropwise with cooling. After 30 min of stirring, the inorganic material was filtered off and washed with THF (3 × 30 mL). The filtrate was dried (Na2SO4), filtered and evaporated. The obtained crude product was purified by column chromatography on silica gel (toluene/EtOH 1:1).

Preparation of the 15A-E tautomeric mixture
Aminodiol 13 (20.0 mg, 0.11 mmol) and benzaldehyde (10.2 µL, 10.6 mg, 0.11 mmol) were dissolved in dry ethanol (2 mL) and stirred for 2 h at room temperature. Then, the solvent was evaporated under reduced pressure to afford the mixture of 15A-E that was examined in CDCl3. To a solution of aminodiol 14 (liberated base, 0.60 g, 3.24 mmol) in dry ethanol (20 mL) benzaldehyde (0.343 g, 0.328 mL, 3.24 mmol) was added in one portion, and the solution was stirred at room temperature for 1 h and then evaporated to dryness. The residue was dissolved in dry THF (3 mL) and then added dropwise to the stirred suspension of dry THF (10 mL) and LiAlH4 (0.491 g, 12.95 mmol). The reaction mixture was treated under reflux conditions for 3 h, then a mixture of H2O (1.00 mL) and THF (8 mL) was added dropwise with cooling. After stirring for 30 min, the inorganic material was filtered off and washed with THF (3 × 30 mL). The filtrate was dried (Na2SO4), filtered and evaporated. The obtained crude product was purified by column chromatography on silica gel (CHCl3/MeOH 9:1).  ((3aS,4R,6R,7aS)

]heptan-3-ol (18)
To the stirred suspension of LiAlH4 (0.166 g, 4.38 mmol) in dry THF (5 mL) the solution of 17 or 19 (1.46 mmol) in dry THF (5 mL) was added dropwise at room temperature. After a 12 h treatment under reflux conditions a mixture of H2O (0.30 mL) and THF (4 mL) was added dropwise with cooling to the reaction mixture. After 30 min of stirring, the inorganic material was filtered off and washed with THF (3 × 20 mL). The filtrate was dried (Na2SO4), filtered, and evaporated. The obtained crude product was purified by column chromatography on silica gel (DCM/MeOH 19:1).

X-Ray structure determinations
The crystals of 9 and 17 were immersed in cryo-oil, mounted in a loop, and measured at a temperature of 120 K. The X-ray diffraction data were collected on a Rigaku Oxford Diffraction Supernova diffractometer using Cu Kα radiation. The CrysAlisPro [4] software package was used for cell refinements and data reductions. A multi-scan (9) or an analytical absorption correction (17) was applied to the intensities before structure solutions by using CrysAlisPro [4] software. The structures were solved by intrinsic phasing (SHELXT [5]) method. Structural refinements were carried out using SHELXL [6] software with SHELXLE [7] graphical user interface. The NH and OH hydrogen atoms were located from the difference Fourier map and refined isotropically. All other hydrogen atoms were positioned geometrically and constrained to ride on their parent atoms, with C-H = 0.95-1.00 Å and Uiso = 1.2-1.5 Ueq(parent atom). The crystallographic details are summarized in Table S1.

X-Ray structure determinations
The crystals of 9 and 17 were immersed in cryo-oil, mounted in a loop, and measured at a temperature of 120 K. The X-ray diffraction data were collected on a Rigaku Oxford Diffraction Supernova diffractometer using Cu Kα radiation. The CrysAlisPro software package was used for cell refinements and data reductions. A multi-scan (9) or an analytical absorption correction (17) was applied to the intensities before structure solutions by using CrysAlisPro software. The structures were solved by intrinsic phasing (SHELXT) method. Structural refinements were carried out using SHELXL software with SHELXLE graphical user interface. The NH and OH hydrogen atoms were located from the difference Fourier map and refined isotropically. All other hydrogen atoms were positioned geometrically and constrained to ride on their parent atoms, with C-H = 0.95-1.00 Å and Uiso = 1.2-1.5 Ueq(parent atom). The crystallographic details are summarized in Table S1. The deposition number CCDC 2063842 (9) and CCDC 2063843 (17) contain supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: (internat.) + 44-1223-336-033; E-mail: deposit@ccdc.cam.ac.uk) S9