Enantioselective Desymmetrization of Tropinone Derivatives by Hydroboration

 

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Abstract

N-Protected tropenone derivatives 3, prepared from the respective pyrroles 5 and tetrabromoacetone (6), were used as starting materials for desymmetrization by hydroboration of the C-C double bond. Hydroboration of 3a with (-)-(Ipc)₂BH followed by oxidation, however, gave the desired 6-hydroxylated product 4a only in low yield due to byproduct formation. After acetalization of the carbonyl group in 3, the corresponding acetals 8 were desymmetrized with (Ipc)₂BH and oxidative workup to chiral alcohols 11 in good yields with excellent enantiomeric excesses in most cases.

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N -Benzyloxycarbonyl-spiro{8-azabicyclo[3.2.1]oct-6-ene-3,2′-[1,3]dioxolane} (8b). A solution of 3b (5.63 g, 21.9 mmol), ethylene glycol (15 mL) and PPTS (0.8 g, 2.3 mmol) in benzene (200 mL) was heated under Dean-Stark conditions at reflux for 8 h. The reaction mixture was then diluted with EtOAc (250 mL) and washed with H₂O and a solution of NaCl (100 mL each). The organic layer was dried (Na₂SO₄) and concentrated. Flash chromatography on SiO₂ with EtOAc/hexanes, 3:1 (R_f = 0.14) gave 3.49 g (84% referred to conversion) of 8b and 2.11 g of unreacted 3b. ¹H NMR (300 MHz, CDCl₃): δ = 1.83 (dd, J = 13.7 Hz, J = 5.3 Hz, 2 H, 2-H_eq,4-H_eq), 2.10 (dd, J = 13.7 Hz, J = 3.4 Hz, 1 H, 2-H_ax), 2.21 (dd, J = 13.7 Hz, J = 3.4 Hz, 1 H, 4-H_ax), 3.75-3.92 (m, 4 H, OCH₂), 4.65 (br, 1 H, 5-H), 4.70 (br, 1 H, 1-H), 5.12 (d, J = 12.1 Hz, 1 H, CH₂Ar), 5.19 (d, J = 12.1 Hz, 1 H, CH₂Ar), 6.09-6.22 (br m, 2 H, 6-H, 7-H), 7.27-7.38 (m, 5 H, Ar) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 38.6, 39.5 (C-2, C-4), 56.4 (C-1, C-5), 63.2, 64.3 (OCH₂), 66.7 (CH₂Ar), 106.9 (C-3), 127.8, 127.9, 128.4 (Ar), 132.5, 132.9 (C-6, C-7), 136.6 (Ar), 152.2 (CO) ppm. FT-IR (ATR): 2958 (m), 2926 (m), 2881 (m), 2360 (m), 2341 (m), 1695 (vs), 1411 (s), 1345 (s), 1300 (vs), 1088 (vs)cm^-1. MS (EI): m/z (%) = 301 (15) [M⁺], 257 (10) [M⁺ - C₂H₆O₂], 170 (10), 91 (100) [C₇H₇ ⁺]. Anal. Calcd for C₁₇H₁₉NO₄ (301.3): C, 67.76; H, 6.36; N, 4.65. Found: C, 67.56; H, 6.44; N, 4.60.

(-)- N -Benzyloxycarbonyl-6- exo -hydroxy-{spiro-8-azabicyclo[3.2.1]octane-3,2′-[1,3]dioxolane} (11b). A solution of 8b (5.08 mg, 16.88 mmol) in absolute THF (8 mL) was added at -28 °C to crystalline (Ipc)₂BH (7.4 g, 25.96 mmol), and the reaction mixture stirred at -28 °C for 18 h. After hydrolysis of excess borane with MeOH (2.3 mL), a 3 N NaOH solution (10 mL) and 30% H₂O₂ (10.7 mL) were added and the reaction mixture heated to 55 °C with vigorous stirring. EtOAc (100 mL) was added and the solution washed with a NaCl solution (50 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (Na₂SO₄) and concentrated. Purification by flash chromatography on SiO₂ (EtOAc) (R_f = 0.55) gave 5.21 g (96%) of 11b as a colorless solid. Mp 112 °C (i-Pr₂O/CH₂Cl₂), [α]_D ²⁰ = -8.2 (c 1.0, CHCl₃), >99% ee. ¹H NMR (500 MHz, CDCl₃): δ = 1.65-1.78 (br m, 2 H, 2-H_eq,4-H_eq), 1.79-2.08 (br m, 4 H, OH, 2-H_ax,4-H_ax,7-H_exo), 2.65 (dd, J = 13.4 Hz, J = 7.0 Hz, 1 H, 7-H_endo), 3.75-3.85 (m, 2 H, OCH₂), 3.90-3.95 (m, 2 H, OCH₂), 4.15 (br, 1 H, 1-H), 4.44 (br, 1 H, 5-H), 4.54 (br t, J = 5.7 Hz, 1 H, 6-H), 5.13 (s, 2 H, CH₂Ar), 7.28-7.37 (m, 5 H, Ar) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 38.1 (br, C-2), 39.7 (br, C-4), 40.3 (br, C-7), 53.3 (CH₂Ar), 62.3 (C-1), 63.4, 64.5 (OCH₂), 67.0 (C-5), 73.8 (br, C-6), 106.8 (C-3), 127.9, 128.0, 128.5, 136.6 (Ar), 154.2 (CO) ppm. FT-IR (ATR): 3375 (s), 3288 (s), 2950 (s), 2874 (s), 2360 (vs), 2341 (vs), 1699 (vs), 1654 (vs), 1442 (s), 1408 (s), 1108 (vs), 1063 (s)cm^-1. MS (EI): m/z (%) = 319 (8) [M⁺], 228 (30) [M⁺ - benzyl], 184 (20), [M⁺ - Z], 140 (15), 98 (20), 91 (100) [C₇H₇ ⁺]. Anal. Calcd for C₁₇H₂₁NO₅ (319.4): C, 63.94; H, 6.63; N, 4.39. Found: C, 63.94; H, 6.67; N, 4.30.

GC was performed on a Bondex unβ column (20 m × 0.25 mm) with 0.4 bar H₂ as carrier gas. Compound 11a: temperature program: 3 min at 60 °C, then 1 °C min^-1 gradient to 200 °C, t_R(R-11a) = 106.35 min, t_R(S-11a) = 107.26 min, >99% ee. Compound 11b: temperature program: 3 min at 150 °C, then 2.5 °C min^-1 gradient to 200 °C, t_R(R-11b) = 49.32 min, t_R(S-11b) = 49.93 min, >99% ee.

GC was performed on a HP-5 TA column (30 m × 0.32 mm) with a temperature program: 16 °C min^-1 gradient from 80 °C to 300 °C. Compound 12b: t_R(R-12b) = 19.54 min, t_R(S-12b) = 19.62 min, >99% ee. Compound 13b: t_R(R-13b) = 19.85 min, t_R(S-13b) = 19.99 min, 81% ee.

CCDC 215377(11a), CCDC 215376(8c) and CCDC 217879(11c) contain the supplementary crystallographic data of these structures. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html [or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].