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Synlett 2003(1): 0051-0054
DOI: 10.1055/s-2003-36227
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Short Enantioselective Synthesis of Naturally Occurring Muscarine Alkaloids from 1,4-Hexadiene

Jens Hartung*, Patricia Kunz, Stefanie Laug, Philipp Schmidt
Institut für Organische Chemie, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
Fax: +49(931)8884606; e-Mail: hartung@chemie.uni-wuerzburg.de;
Further Information

Publication History

Received 24 September 2002
Publication Date:
18 December 2002 (online)

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Abstract

Short enantioselective syntheses of naturally occurring muscarine alkaloids 1a-d starting from (Z)-1,4-hexadiene (2) and its E-configured isomer 4 have been devised. Key transformations in both sequences were (i) asymmetric dihydroxylation of 1,4-hexadienes 2 and 4 and (ii) application of a novel diastereoselective bromoetherification of (2S,3R)-5-hexene-2,3-diol (3) (40% ee) and (2S,3S)-5-hexene-2,3-diol (5) (90% ee) which was initiated by a vanadium(V)-catalyzed oxidation of bromide using tert-butyl hydroperoxide as primary oxidant.

Key words

bromide - cyclization - muscarine alkaloids - oxidation - tetrahydrofuran - vanadium

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  • 28 Preparation of tetrahydrofurans 6a and 6b (from 3) and 6c and 6d (from 5) was performed according to the following general procedure: A solution of (2S,3S)-hexene-2,3-diol(5) (116 mg, 1.00 mmol), [VOL(EtO)(EtOH)] (L = N-(2-hydroxyphenyl)salicylideneimine dianion) (36.9 mg, 0.10 mmol),25-27 pyridinium hydrobromide (176 mg, 1.10 mmol) and tert-butyl hydroperoxide (200 µL, 5.5 M in nonane, 1.10 mmol) in CHCl3 (10 mL) was stirred at 20 °C until diol 5 has been completely consumed (˜ 6 h). Afterwards, the reaction mixture was concentrated under reduced pressure (40 °C/250 mbar) and the crude product was purified by filtration through a short pad Al2O3(Et2O) to afford an oil which was subjected to a Kugelrohr-distillation (130 °C/20 mbar). Yield: 113 mg (0.058 mmol, 59%), 6c:6d = 27:73, colorless liquid. MS (70 eV, EI), m/z (%): 242/240(6) [M+], 160(15) [M+ - HBr], 147(100) [M+ - CH2Br], 131(41) [C10H11 +], 129(23) [M+ - CH2Br - H2O], 117(16) [C9H9 +], 91(66) [C7H7 +], 77(10) [C6H5 +], 41(12) [C3H5 +]. C11H13BrO (241.1) calc. C 54.80 H 5.85 found C 54.51 H 5.31. Separation of diastereomers 6c and 6d was achieved by column chromatography [SiO2, petroleum ether/Et2O, 1:2 (v/v)]. (2S,3S,5S)-5-Bromomethyl-3-hydroxy-2-methyltetra-hydrofuran (6c): Rf = 0.50 (petroleum ether/Et2O, 1:2 (v/v); [α]D 25 = -7.3 (c = 0.8, CHCl3); 1H NMR (250 MHz): δ = 1.30 (d, 3 H, 3 J = 6.4 Hz, 6-H), 1.83 (s, 1 H, OH), 1.88 (ddd, 1 H, 3 J = 1.3, 4.9 Hz, 2 J = 14.3 Hz, 4-H), 2.41 (ddd, 1 H, 3 J = 6.0, 8.9 Hz, 2 J = 14.3 Hz, 4-H), 3.50 (dd, 1 H, 3 J = 4.6 Hz, 2 J = 10.4 Hz, -H), 3.61 (dd, 1 H, 3 J = 5.3 Hz, 2 J = 10.4 Hz, -H), 3.86 (qd, 1 H, 3 J d = 3.1 Hz, 3 J q = 6.4 Hz, 2-H), 4.10-4.23 (m, 2 H, 3-H, 5-H); 13C NMR (CDCl3, 63 MHz): δ = 13.9, 36.7, 39.8, 73.3, 76.4, 79.8. (2S,3S,5R)-5-Bromomethyl-3-hydroxy-2-methyltetrahydrofuran (6d): Rf = 0.45 (petroleum ether/ Et2O, 1:2 (v/v)); [α]D 25 = -21.8 (c = 1.0, CHCl3); 1H NMR (250 MHz): δ = 1.26 (d, 3 H, 3 J = 6.4 Hz, 6-H), 1.69 (s, 1 H, OH), 1.88 (ddd, 1 H, 3 J = 4.7, 9.2 Hz, 2 J = 13.8 Hz, 4-H), 2.20 (ddd, 1 H, 3 J = 1.2, 6.7 Hz, 2 J = 13.8 Hz, 4-H), 3.456 (d, 1 H, 3 J = 5.7 Hz, -H), 3.458 (d, 1 H, 3 J = 5.0 Hz, -H), 4.12 (qd, 1 H, 3 J d = 2.8 Hz, 3 J q = 6.4 Hz, 2-H), 4.24 (mc, 1 H, 3-H) 4.41-4.53 (m, 1 H, 5-H); 13C NMR (CDCl3, 63 MHz): δ = 14.1, 36.5, 40.5, 74.2, 76.1, 79.0.Ee values for trisubstituted tetrahydrofurans 6a-d were determined for their derived (R)-configured Mosher esters. Samples which contained the enantiomers of 6a-d in excess were available from a previous study: Hartung J. Kneuer R. Eur J. Org. Chem.  2000,  1677 
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17

(Z)-1,4-Hexadiene(2) (Fluka) (E)-1,4-hexadiene(4) (Chemsampco) are commercially available and were used as recieved.

20

R f values of hexenediols (SiO2, Et2O): 0.61 for (2S,3R)-5-hexene-2,3-diol(3), [19] 0.59 for (2S,3S)-5-hexene-2,3-diol(5), [19] 0.69 for (Z)-4-hexene-1,2-diol and for (E)-4-hexene-1,2-diol. Ee values of diols 3 and 5 were determined by GC on a β-Dex-325 column (Supelco).

25

Hartung, J.; Greb, M.; pehar, K.; Köhler, F.; Kluge, M.; Csuk, R. in preparation.

31

Analytical data (1H NMR and 13C NMR in D2O) obtained for alkaloids 1a-d matched with the values reported in the literature; [10-13] 1a: 40% ee; [α]D 25 = +6.0° (c = 1.0, EtOH); 1b: 40% ee; [α]D 25 = -13.1° (c = 1.9, EtOH); 1c: 90% ee; [α]D 25 = +19.8° (c = 0.9, EtOH); 1d: 90% ee; [α]D 25 = +14.6° (c = 2.2, EtOH). [32]