Materials and methods
Chiral aziridines are available from Aldrich. All commercially available compounds were used as received unless stated otherwise. All reactions were carried out under an atmosphere of nitrogen in oven-dried glassware with magnetic stirrer. Reactions were monitored by thin layer chromatography (TLC) with 0.25 mm E. Merck pre-coated silica gel plates (60 F254). Visualization was accomplished with either UV light, or by immersion in solutions of ninhydrin, p-anisaldehyde, or phosphomolybdic acid (PMA) followed by heating on a hot plate for about 10 sec. Purification of reaction products was carried out by flash chromatography using Kieselgel 60 Art 9385 (100–200 mesh). 1H-NMR and 13C-NMR spectra were obtained using Bruker AVANCE 400 MHz spectrometer. Chemical shifts are reported relative to acetonitrile (δ = 1.94), chloroform (δ = 7.26) for 1H NMR and acetonitrile (δ = 118.26), chloroform (δ = 77.0) for 13C NMR. Data are reported as (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplet). Coupling constants are given in Hz. Optical rotations were obtained JASCO P-2000.Optical rotation data was reported as follows: [α]20 (concentration c = g/100 mL, solvent).
4-[( R )-1-( R )-1-Phenylethyl)aziridin-2-yl]butyl-4-methylbenzenesulfonate (15): To a stirred solution of aziridinyl alcohol 14 [20] (600 mg, 2.74 mmol) and Et3N (1.15 mL, 8.22 mmol) in 100 mL two neck round bottom flask in anhydrous CH2Cl2 (15 mL) at 0°C was added p-toluenesulfonyl chloride (781 mg, 4.11 mmol) freshly recrystallized from hexanes followed by catalytic DMAP (33 mg, 0.27 mmol) under N2 atmosphere. The resulting mixture was stirred for another 2 hrs at rt and the completion of reaction was confirmed by TLC (EtOAc: hexanes, 7:3). After complete conversion of starting alcohol, the reaction mixture was quenched with water and extracted with CH2Cl2 (3 x 30 mL), dried over anhydrous Na2SO4 and concentrated under vacuums to get crude tosylate, which was purified by flash column chromatography to get pure tosylate 15 (961 mg, 94% yield) as a viscous liquid. 1H NMR (400 MHz, CD3CN) δ = 7.73 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.35–7.13 (m, 5H), 3.76 (t, J = 6.4 Hz, 2H), 2.45 (s, 3H), 2.37 (q, J = 6.5 Hz, 1H), 1.50 (d, J = 3.2 Hz, 1H), 1.39–1.17 (m, 8H), 1.11–0.91 (m, 3H). 13C NMR (101 MHz, CD3CN) δ = 146.4, 146.2, 133.9, 130.9, 129.0, 128.6, 127.9, 127.8, 71.8, 70.5, 38.9, 34.0, 32.6, 28.7, 23.7, 23.0, 21.6 ppm.
(6R)-1-(R)-1-phenylethyl)-1-azoniabicyclo[4.1.0]heptane tosylate (16)
The freshly prepared 4-[(R)-1-(R)-1-Phenylethyl)aziridin-2-yl]butyl-4-methylbenzenesulfonate (15) (900 mg, 2.41 mmol) was stored in anhydrous CH3CN (20 mL) at room temperature for 24h to accomplish the complete conversion to bicyclic aziridinium ion 16 as confirmed by NMR spectrum. 1H NMR (400 MHz, CD3CN) δ = 7.65–7.49 (m, 7H), 7.15 (d, J = 7.8 Hz, 2H), 4.12 (q, J = 7.0 Hz, 1H), 3.82–3.74 (m, 1H), 3.48 (dt, J = 13.3, 5.3 Hz, 1H), 3.24 (dd, J = 9.0, 4.2 Hz, 1H), 3.19–3.11 (m, 1H), 3.04 (dd, J = 7.9, 4.2 Hz, 1H), 2.33 (s, 3H), 2.15–2.02 (m, 2H), 1.72 (d, J = 7.0 Hz, 3H), 1.53–1.43 (m, 1H), 1.38–1.28 (m, 2H), 0.94–0.82 (m, 1H). 13C NMR (101 MHz, CD3CN) δ = 146.7, 139.4, 134.5, 131.2, 130.2, 129.4, 129.2, 126.6, 71.9, 49.7, 49.5, 43.0, 21.2, 20.7, 15.5, 14.0 ppm.
[( R )-1-( R )-1-Phenylethyl)piperidin-2-yl)]methyl acetate (17): To a stirred solution of (6R)-1-(R)-1-phenylethyl)-1-azoniabicyclo[4.1.0]heptane tosylate (16) (900 mg, 2.41 mmol) in 25 mL anhydrous acetonitrile at 0°C was added anhydrous sodium acetate (592 mg, 7.23 mmol) and reaction mixture was allowed to stir for 12 hrs at room temperature. After completion of reaction as confirmed from TLC, the reaction mixture was quenched with water and extracted with CH2Cl2 (3 x 30 mL). The combined organic layer were dried over Na2SO4 and concentrated under vacuum to get crude product, which was purified by column chromatography using 10% EtOAc: hexanes to get 483 mg of compound 17 and 120 mg of compound 17a in 96% combined yield. Analytical data of compound 17: [α]20D = + 74.5 (c = 0.43, CHCl3). 1H NMR (400 MHz, CD3CN) δ = 7.37–7.14 (m, 5H), 4.27 (dd, J = 11.3, 4.8 Hz, 1H), 4.18–4.08 (m, 1H), 4.02 (q, J = 6.8 Hz, 1H), 2.78–2.66 (m, 2H), 2.37 (ddd, J = 12.1, 6.2, 3.4 Hz, 1H), 1.94 (s, 3H), 1.65–1.40 (m, 5H), 1.38–1.18 (m, 4H). 13C NMR (101 MHz, CD3CN) δ = 171.5, 145.1, 128.9, 128.5, 127.5, 63.7, 59.3, 55.6, 45.3, 28.7, 26.2, 22.1, 21.1, 20.9 ppm. HRMS-MALDI (m/z): calcd. for C16H24NO2 [M + H]+ 262.1801; found 262.1803.
Analytical data of compound 17a: (S)-1-[(R)-1-Phenylethyl)]azepan-3-yl acetate (17a): [α]20D = − 57.9 (c = 1.0, CHCl3). 1H NMR (400 MHz, CD3CN) δ = 7.43–7.17 (m, 5H), 4.83–4.72 (m, 1H), 3.83 (q, J = 6.8 Hz, 1H), 2.89 (dd, J = 14.0, 4.7 Hz, 1H), 2.68–2.54 (m, 3H), 1.93–1.90 (m, 1H), 1.86 (s, 3H), 1.71–1.43 (m, 5H), 1.32 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CD3CN) δ = 170.9, 145.4, 128.9, 128.4, 127.5, 74.9, 64.1, 56.0, 54.2, 33.4, 30.5, 22.2, 21.4, 17.5 ppm. HRMS-MALDI (m/z): calcd. for C16H24NO2 [M + H]+ 262.1801; found 262.1809.
(2 S,3R)-tert-Butyl-3-hydroxy-2-(hydroxymethyl)piperidine-1-carboxylate (18): To the stirred solution of [(R)-1-(R)-1-Phenylethyl)piperidin-2-yl)]methyl acetate 17 (400 mg, 1.53 mmol) in methanol (15 mL) was added CH3ONa (82 mg, 1.16 mmol) and the reaction mixture was stirred for 1 hr at room temperature. After complete conversion of starting acetate as confirmed by TLC (25% EtOAc/Hexane), methanol was removed under vacumm and the crude product was dissolved in water and extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to get crude alcohol, which was used as such for next reaction. The crude alcohol obtained was dissolved in methanol (15 mL) and degas for 30 minutes. (Boc)2O (833 mg, 3.82 mmol), triethylamine (0.53 mL, 3.82 mmol) and Pd(OH)2/C (40 mg, 50% wet) was added and reaction was stirred under H2 balloon for 12 hrs. After complete conversion, reaction mixture was filtered using celite and washed with methanol. The combined organic layer were concentrated under vaccum and crude product was purified by column chromatography to get pure compound 18 (312 mg, 95% yield) as a white solid. Rf: 0.7 (50% EtOAc/Hexane), m.p. 82–84°C. [α]20D = + 37.8 (c = 0.85, CHCl3). [lit. [11] reported for enantiomer, [α]25D − 40.5 (c 1.0, CHCl3]. 1H NMR (400 MHz, CDCl3) δ = 4.34–4.22 (m, 1H), 3.93 (d, J = 12.9 Hz, 1H), 3.80 (td, J = 10.8, 4.9 Hz, 1H), 3.65–3.53 (m, 1H), 2.85 (t, J = 11.6 Hz, 1H), 2.30 (br s, 1H), 1.75–1.36 (m, 15H). 13C NMR (101 MHz, CDCl3) δ = 156.3, 79.8, 61.4, 52.4, 40.0, 28.5, 25.3, 25.2, 19.5 ppm. HRMS-MALDI (m/z): calcd. for C12H21NO3Na [M + Na]+ 238.1413; found 238.1416.