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Synlett 2014; 25(2): 209-212
DOI: 10.1055/s-0033-1340107
letter
© Georg Thieme Verlag Stuttgart · New York

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

Julien Smith
SERCO, Département de Chimie Moléculaire, Univ. Grenoble Alpes, ICMG FR-2607, CNRS, UMR-5250, 38041 Grenoble, France   Fax: +33(4)76514494   Email: philippe.delair@ujf-grenoble.fr
,
Anushree Kamath
SERCO, Département de Chimie Moléculaire, Univ. Grenoble Alpes, ICMG FR-2607, CNRS, UMR-5250, 38041 Grenoble, France   Fax: +33(4)76514494   Email: philippe.delair@ujf-grenoble.fr
,
Andrew E. Greene
SERCO, Département de Chimie Moléculaire, Univ. Grenoble Alpes, ICMG FR-2607, CNRS, UMR-5250, 38041 Grenoble, France   Fax: +33(4)76514494   Email: philippe.delair@ujf-grenoble.fr
,
Philippe Delair*
SERCO, Département de Chimie Moléculaire, Univ. Grenoble Alpes, ICMG FR-2607, CNRS, UMR-5250, 38041 Grenoble, France   Fax: +33(4)76514494   Email: philippe.delair@ujf-grenoble.fr
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Further Information

Publication History

Received: 22 August 2013

Accepted after revision: 06 October 2013

Publication Date:
21 November 2013 (online)

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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

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • References and Notes

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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+].