Total Synthesis of (+)-Hyacinthacine A₆ and (+)-Hyacinthacine A₇

Abstract

(+)-Hyacinthacines A₆ and A₇ have been synthesized from a common, late-stage intermediate, prepared in high yield through stereoselective [2+2] cycloaddition of dichloroketene to a chiral enol ether. The flexibility of aminonitrile chemistry is central to the approach.

Key words

asymmetric synthesis - cycloaddition - glycosidase inhibitors - aminonitriles - iminosugars

• References and Notes

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• 25 Our synthetic hyacynthacine A₇ is dextrorotatory {[α]_D +48}, as was Donohoe’s^9b (but not Izquierdo’s¹⁰) with the same indicated absolute stereochemistry. Based on the reported⁸ levorotation {[α]_D –52} of natural hyacynthacine A₇ and the dextrorotation of natural and synthetic hyacynthacine A₆, the two alkaloids, most surprisingly, would appear to belong to different enantiomeric series. Previous workers^9b have reached the same conclusion from the rotational data.
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• 27 Experimental Procedures for Methyl Introductions (2S,3aR,4S,6R,8aR,8bS)-4-{[Dimethyl(phenyl)silyl]-methyl}-6-methyl-2-phenylhexahydro-3aH-[1,3]dioxolo[4,5-a]pyrrolizine (10) To a degassed solution of aminonitriles 8 (14.7 mg, 0.035 mmol) in THF (1.0 mL) at –60 °C was added a degassed solution of LDA (1.0 M, 0.073 mL). After 15 min, MeI (0.011 mL, 0.177 mmol) was added, and the resulting solution was stirred at –60 °C for 30 min before the addition of sat. aq NH₄Cl. After being allowed to warm to r.t., the reaction mixture was processed with EtOAc to give 17 mg of crude aminonitriles 9, which were used without further purification. To a solution of this material in anhydrous THF (0.21 mL) at 0 °C was added dropwise a solution of LiBHEt₃ (1.0 M in THF, 0.17 mL, 0.17 mmol). The reaction mixture was stirred for 30 min at this temperature and then quenched with H₂O and processed with EtOAc. The resulting crude product was purified by silica gel chromatography (2–5% MeOH saturated with NH₃ in EtOAc) to afford 13.0 mg (78%) of 10: [α]_D ²¹ –4 (c 1.2, CHCl₃). IR (film): 3065, 3022, 2950, 2915, 1660 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.34 (s, 3 H), 0.36 (s, 3 H), 0.95 (d, J = 6.3 Hz, 3 H), 0.97 (A of ABX, J = 14.6, 8.6 Hz, 1 H), 1.07 (B of ABX, J = 14.6, 6.4 Hz, 1 H), 1.48 (dddd, J = 11.5, 8.5, 7.6, 7.6 Hz, 1 H), 1.60 (dddd, J = 12.0, 7.6, 7.6, 7.6 Hz, 1 H), 1.86 (dddd, J = 11.5, 7.6, 6.3, 5.3 Hz, 1 H), 1.96 (dddd, J = 12.0, 8.5, 5.3, 5.3 Hz, 1 H), 3.05 (ddddd, J = 7.6, 6.3, 6.3, 6.3, 6.3 Hz, 1 H), 3.47 (ddd, J = 8.5, 6.4, 1.9 Hz, 1 H)_, 3.50 (ddd, J = 7.6, 5.3, 5.3 Hz, 1 H), 4.44 (dd, J = 6.2, 1.9 Hz, 1 H), 4.54 (dd, J = 6.2, 5.3 Hz, 1 H), 5.75 (s, 1 H), 7.29–7.44 (m, 6 H), 7.47–7.59 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = –2.4 (CH₃), 18.1 (CH₃), 20.1 (CH₂), 23.2 (CH₂), 34.7 (CH₂), 54.5 (CH), 57.9 (CH), 66.3 (CH), 81.9 (CH), 91.2 (CH), 105.5 (CH), 126.7 (CH), 127.7 (CH), 128.2 (CH), 128.7 (CH), 129.0 (CH), 133.6 (CH), 136.8 (C), 139.5 (C). ESI-MS: m/z = 394 [MH⁺]. ESI-HRMS: m/z calcd for C₂₄H₃₂NO₂Si: 394.2197; found: 394.2194 [MH⁺]. (2S,3aR,4R,6S,8aR,8bS)-4-(Benzyloxymethyl)-6-methyl-2-phenylhexahydro-4H-[1,3]dioxolo[4,5-a]pyrrolizine (14) To a solution of pyrrolizidine 13 (15.0 mg, 0.030 mmol) in anhydrous DMF (0.30 mL) was added solid TBAF·H₂O (84 mg, 0.30 mmol), and the reaction mixture was heated at 80 °C for 16 h. An additional portion of solid TBAF·H₂O (42 mg, 0.15 mmol) was then added, and the resulting mixture was stirred at 80 °C for 8 h. After the addition of sat. aq NH₄Cl, the reaction mixture was processed with EtOAc. The resulting crude material was purified by silica gel chromatography (0–5% MeOH saturated with NH₃ in CH₂Cl₂) to afford 9.1 mg (83%) of 14: [α]_D ²⁵ +32 (c 0.9, CHCl₃). IR (film): 3027, 2921, 2850, 1456 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.06 (d, J = 5.9 Hz, 3 H), 1.51 (dddd, J = 11.9, 9.5, 9.5, 9.5 Hz, 1 H), 1.94 (dddd, J = 12.8, 9.5, 9.5, 2.4 Hz, 1 H), 2.06 (dddd, J = 11.9, 9.5, 5.9, 2.4 Hz, 1 H), 2.22 (dddd, J = 12.8, 9.5, 9.5, 4.9 Hz, 1 H), 3.32 (ddddd, J = 9.5, 5.9, 5.9, 5.9, 5.9 Hz, 1 H), 3.38–3.47 (m, 2 H), 3.50–3.57 (m, 1 H), 3.83 (ddd, J = 9.5, 4.9, 4.9 Hz, 1 H), 4.52 (A of AB, J = 12.0 Hz, 1 H), 4.59 (B of AB, J = 12.0 Hz, 1 H), 4.64 (dd, J = 6.1, 4.9 Hz, 1 H), 4.85 (d, J = 6.1 Hz, 1 H), 5.77 (s, 1 H), 7.27–7.30 (m, 1 H), 7.31–7.36 (m, 4 H), 7.37–7.42 (m, 3 H), 7.44–7.50 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.2 (CH₃), 22.9 (CH₂), 34.9 (CH₂), 60.6 (CH), 66.0 (CH), 67.5 (CH), 72.9 (CH₂), 73.3 (CH₂), 85.0 (CH), 87.6 (CH), 105.7 (CH), 126.8 (CH), 127.5 (CH), 128.3 (CH), 128.4 (CH), 129.4 (CH), 136.3 (C), 138.3 (C). ESI-MS: m/z = 366 [MH⁺]. ESI-HRMS: m/z calcd for C₂₃H₂₈NO₃: 366.2064; found: 366.2069 [MH⁺].