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

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.

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

References

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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.

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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).

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25

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

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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): R_f = 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): R_f = 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 (m_c, 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 

29 Dale JA. Dull DL. Mosher HS. J. Org. Chem.  1969,  34:  2543 

30 Kirby AJ. In The Anomeric Effect and Related Stereoelectronic Effects at Oxygen   Springer-Verlag; Berlin: 1983. 

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]

32 An optical rotation of [α]_D ²⁵ ≥ 0° has been reported for enantiopure (+)-epiallo-muscarine(1d): De Amici M. De Micheli C. Moteni G. Pitrè D. Carrea G. Riva S. Spezia S. Zetta L. J. Org. Chem.  1991,  56:  67 ; this value was confirmed by us in an independent study using enantiopure 1d. The origin for the significant positive [α]_D ²⁵ for the enantioenriched sample which was prepared in the present study using the AD bromocycloetherification sequence is unclear