Diastereocontrolled Synthesis of (-)-Codonopsinine

Abstract

An efficient process is described for the total synthesis of the alkaloid (-)-codonopsinine. The synthetic strategy is based on the diastereoselective hydrocyanation of a 2,3-dialkoxyaldehyde derived from l-threonine followed by a reductive alkylation of the nitrile function with a Grignard compound and sodium borohydride. The resulting aminotriol was then cyclized into the target molecule after selective mesylation.

Key words

alkaloid - aminoalcohol - cyanohydrine - pyrrolidine

References

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• 13b

  Haddad, M.; Larchevêque, M. Synth. Commun. 2003, in press.

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10

Haddad, M.; Larchevêque, M., unpublished results.

16

Experimental procedure for 11: Nitrile 4 (0.70 g, 2.68 mmol) was placed in anhydrous Et₂O (40 mL) and cooled to -13 °C. A 0.5 M solution of 4-methoxyphenylmagnesium bromide in THF (8 mL, 4.0 mmol) was added dropwise via a syringe through a septum and the reaction was allowed to warm to room temperature. Stirring was continued for 4 h before being cooled to -13 °C. Anhydrous methanol (5 mL) and a 1:1 (v/v)solution of methylamine in anhydrous methanol (5 mL) were added successively and the mixture was stirred for 45 min at room temperature. Sodium borohydride (254 mg, 6.7 mmol) was then added. The resultant mixture was stirred overnight and water (50 mL) was added. The mixture was extracted with Et₂O (3 × 50 mL), and the combined organic layers were washed with brine. After the usual work-up, the residue was subjected to column chromatography (CH₂Cl₂ then CH₂Cl₂/MeOH, 95:5) to give 774 mg (80%) of a mixture of the amine 11 and its epimer.

18

Selected data: 14: [α]_D ²⁰ -13.1 (c = 1.43, CH₂Cl₂); ¹H NMR (200 MHz, CDCl₃): d (ppm) 1.28-1.38 (m, 9 H), 1.60 (m, 1 H), 2.22 (s, 3 H), 3.06 (s, 3 H), 3.61 (d, 1 H, J = 5.2 Hz), 3.78 (s, 3 H), 3.88 (dd, 1 H, J = 3.4 Hz, 7.8 Hz), 4.19 (dd, 1 H, J = 5.2 Hz, 7.8 Hz), 4.58 (dq, 1 H, J = 3.4 Hz, 6.4 Hz), 6.88 and 7.22 (AB system, 2 H, J = 8.6 Hz). ¹³C (50 MHz, CDCl₃): d (ppm) 18.1, 26.6, 27.1, 27.8, 34.0, 38.5, 55.1, 78.0, 79.3, 80.0, 80.7, 109.3, 113.8, 129.0, 130.6, 159.0. MS (CI, NH₃) m/z (%) = 374 (MH⁺, 100%).
1: mp: 170-171 °C: lit. 172.5-173.5 °C. [4b] [α]_D ²⁰ -10.5 (c = 1.1, MeOH): lit. +12.5 (c 2.55, MeOH) for the enantiomer. [4b] ¹H NMR (400 MHz, DMSO): d (ppm) 1.18 (d, 3 H, J = 6.4 Hz), 2.00 (s, 3 H), 3.13 (dq, 1 H, J = 4.1 Hz, 6.7 Hz), 3.58 (d, 1 H, J = 6.3 Hz), 3.69 (t, 1 H, J = 4.1 Hz), 3.78 (s, 3 H), 3.96 (dd, 1 H, J = 4.0 Hz, 6.4 Hz), 6.91 and 7.28 (AB system, 4 H, J = 8.8 Hz). ¹³C (50 MHz, DMSO): d (ppm) 13.5, 35.0, 55.6, 65.6, 74.3, 84.7, 86.0, 114.7, 130.8, 133.0, 160.7. MS (EI) m/z (%) = 237 (11), 222 (5), 176 (100), 162 (26), 121 (23).