Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000083.xml
Synlett 2014; 25(2): 209-212
DOI: 10.1055/s-0033-1340107
DOI: 10.1055/s-0033-1340107
letter
Total Synthesis of (+)-Hyacinthacine A6 and (+)-Hyacinthacine A7
Further Information
Publication History
Received: 22 August 2013
Accepted after revision: 06 October 2013
Publication Date:
21 November 2013 (online)
![](https://www.thieme-connect.de/media/synlett/201402/lookinside/thumbnails/10.1055-s-0033-1340107-1.jpg)
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 - iminosugarsSupporting Information
- for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
- Supporting Information
-
References and Notes
- 1 Iminosugars . Compain P, Martin OR. John Wiley and Sons; West Sussex: 2007
- 2a Gloster TM, Davies GJ. Org. Biomol. Chem. 2010; 8: 305
-
2b See also: Lillelund VH, Jensen HH, Liang X, Bols M. Chem. Rev. 2002; 102: 515
- 3a Lopez O, Merino-Montiel P, Martos S, Gonzalez-Benjumea A. Carbohydr. Chem. 2012; 38: 215
- 3b Witte MD, van der Marel GA, Aerts JM, Overkleeft HS. Org. Biomol. Chem. 2011; 9: 5908
- 3c Wardrop DJ, Waidyarachchi SL. Nat. Prod. Rep. 2010; 27: 1431
- 4a Asano N, Nash RJ, Molyneux RJ, Fleet GW. J. Tetrahedron: Asymmetry 2000; 11: 1645
- 4b Butters TD, Dwek RA, Platt FM. Chem. Rev. 2000; 100: 4683
- 4c Robina I, Moreno-Vargas AJ, Carmona AT, Vogel P. Curr. Drug Metab. 2004; 5: 329
- 4d Borges de Melo E, da Silveira Gomes A, Carvalho I. Tetrahedron 2006; 62: 10277
- 4e Gerber-Lemaire S, Juillerat-Jeanneret L. Mini Rev. Med. Chem. 2006; 6: 1043
- 5a Ritthiwigrom T, Au CW. G, Pyne SG. Curr. Org. Synth. 2012; 9: 583
- 5b Yoda H. Curr. Org. Chem. 2002; 6: 223
- 5c Liddell JR. Nat. Prod. Rep. 2002; 19: 773
- 5d Nash RJ, Watson AA, Asano N In Alkaloids: Chemical and Biological Perspectives . Vol. 11. Pelletier SW. Elsevier Science; Oxford: 1996: 345
- 6 Kato A, Kato N, Adachi I, Hollinshead J, Fleet GW, Kuriyama C, Ikeda K, Asano N, Nash RJ. J. Nat. Prod. 2007; 70: 993
- 7a Chabaud L, Landais Y, Renaud P. Org. Lett. 2005; 7: 2587
- 7b Desvergenes S, Py S, Vallée Y. J. Org. Chem. 2005; 70: 1459
- 7c Donohoe TJ, Sintim HO, Hollinshead J. J. Org. Chem. 2005; 70: 7297
- 7d Dewi-Wülfing P, Blechert S. Eur. J. Org. Chem. 2006; 1852
- 7e Donohoe TJ, Thomas RE. Chem. Rec. 2007; 7: 180
- 7f Chandrasekhar S, Parida BB, Rambabu C. J. Org. Chem. 2008; 73: 7826
- 7g Delso I, Tejero T, Goti A, Merino P. Tetrahedron 2010; 66: 1220
- 7h Liu W.-J, Ye J.-L, Huang P.-Q. Org. Biomol. Chem. 2010; 8: 2085
- 7i Liu X.-K, Qiu S, Xiang Y.-G, Ruan Y.-P, Zheng X, Huang P.-Q. J. Org. Chem. 2011; 76: 4952
- 7j D’Adamio G, Goti A, Parmeggiani C, Moreno-Clavijo E, Robina I, Cardona F. Eur. J. Org. Chem. 2011; 7155
- 7k Royzen M, Taylor MT, DeAngelis A, Fox JM. Chem. Sci. 2011; 2: 2162
- 7l Brock AE, Davis SG, Lee JA, Roberts PM, Thomson JE. Org. Biomol. Chem. 2013; 11: 3187 ; see also refs. 9b, 15a, 23
- 8 Hyacinthacines A6 and A7 have been isolated in low yield (0.7 mg/kg and 0.6 mg/kg, respectively) from bulbs of Scilla sibirica by Asano and co-workers: Yamashita T, Yasuda K, Kizu H, Kameda Y, Watson AA, Nash RJ, Fleet GW, Asano N. J. Nat. Prod. 2002; 65: 1875
- 9a Zhang T.-X, Zhou L, Cao X.-P. Chem. Res. Chin. Univ. 2008; 24: 469
- 9b Donohoe TJ, Thomas RE, Cheeseman MD, Rigby CL, Bhalay G, Linney ID. Org. Lett. 2008; 10: 3615
- 9c Izquierdo I, Plaza MT, Tamayo JA, Franco F, Sanchez-Cantalejo F. Tetrahedron 2010; 66: 3788
- 10 Hyancinthacine A7: Izquierdo I, Plaza MT, Tamayo JA, Yanez V, Lo Re D, Sanchez-Cantalejo F. Tetrahedron 2008; 64: 4613 ; and ref. 9b
- 11 Greene AE, Charbonnier F. Tetrahedron Lett. 1985; 26: 5525
- 12a Kanazawa A, Gillet S, Delair P, Greene AE. J. Org. Chem. 1998; 63: 4660
- 12b Delair P, Brot E, Kanazawa A, Greene AE. J. Org. Chem. 1999; 64: 1383
- 12c Ceccon J, Poisson J.-F, Greene AE. Synlett 2005; 1413
- 13a Pourashraf M, Delair P, Rasmussen M, Greene AE. J. Org. Chem. 2000; 65: 6966
- 13b Rasmussen M, Delair P, Greene AE. J. Org. Chem. 2001; 66: 5438
- 13c Ceccon J, Poisson J.-F, Greene AE. Org. Lett. 2006; 8: 4739
- 13d Ceccon J, Danoun G, Greene AE, Poisson J.-F. Org. Biomol. Chem. 2009; 7: 2029
- 14a Roche C, Delair P, Greene AE. Org. Lett. 2003; 5: 1741
- 14b Roche C, Kadlecíková K, Veyron A, Delair P, Philouze C, Greene AE, Flot D, Burghammer M. J. Org. Chem. 2005; 70: 8352 ; and ref. 15
- 15a Reddy PV, Veyron A, Koos P, Bayle A, Greene AE, Delair P. Org. Biomol. Chem. 2008; 6: 1170
- 15b Reddy PV, Koos P, Veyron A, Greene AE, Delair P. Synlett 2009; 1141
- 15c Reddy PV, Smith J, Kamath A, Jamet H, Veyron A, Koos P, Philouze C, Greene AE, Delair P. J. Org. Chem. 2013; 78: 4840
- 16a Opatz T. Synthesis 2009; 1941
- 16b Enders D, Shilvock JP. Chem. Soc. Rev. 2000; 29: 359
- 16c Husson H.-P, Royer J. Chem. Soc. Rev. 1999; 28: 383
- 16d Shafran YM, Bakulev VA, Mokrushin VS. Russ. Chem. Rev. 1989; 58: 148 ; see also ref. 15b,c
- 17 (R)- and (S)-Stericol are available from Sigma-Aldrich. (S)-Stericol was chosen on the basis of previous work that indicated it would lead to natural hyacinthacine A6.
- 18 Kim S, Ahn KH. J. Org. Chem. 1984; 49: 1717
- 19 Chuang T.-H, Yang C.-C, Chang C.-J, Fang J.-M. Synlett 1990; 733
- 20 For a review, see: Jones GR, Landais Y. Tetrahedron 1996; 52: 7599
- 21 Smitrovich JH, Woerpel KA. J. Org. Chem. 1996; 61: 6044
- 22a Bruylants P. Bull. Soc. Chim. Belges 1924; 33: 467
- 22b Beaufort-Droal V, Pereira E, Théry V, Aitken DJ. Tetrahedron 2006; 62: 11948
- 22c Sun P, Sun C, Weinreb SM. J. Org. Chem. 2002; 67: 4337
- 22d Agami C, Couty F, Evano G, Darro F, Kiss R. Eur. J. Org. Chem. 2003; 2062
- 22e Reimann E, Ettmayr C. Monatsh. Chem. 2004; 135: 1289 ; and ref. 23
- 23 Hu X.-G, Jia Y.-M, Xiang J, Yu C.-Y. Synlett 2010; 982
- 24 Heitzman CL, Lambert WT, Mertz E, Shotwell JB, Tinsley JM, Va P, Roush WR. Org. Lett. 2005; 7: 2405
- 25 Our synthetic hyacynthacine A7 is dextrorotatory {[α]D +48}, as was Donohoe’s9b (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 workers9b have reached the same conclusion from the rotational data.
- 26 Asano N, Ikeda K, Kasahara M, Arai Y, Kizu H. J. Nat. Prod. 2004; 67: 846
- 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+].
For a review on polyhydroxylated pyrrolizidines, see:
For reviews on pyrrolizidines, see:
For recent examples, see:
Hyancinthacine A6:
Pyrrolidines:
Indolizidines:
Pyrrolizidines:
Hyacinthacines:
For reviews, see:
For mechanistic studies, see:
For recent applications in synthesis, see: