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Synlett 2003(2): 0274-0276
DOI: 10.1055/s-2003-36777
LETTER
© Georg Thieme Verlag Stuttgart · New York

Diastereocontrolled Synthesis of (-)-Codonopsinine

Mansour Haddad, Marc Larchevêque*
Laboratoire de Synthèse Organique associé au CNRS, ENSCP, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Fax: +33(1)43257975; e-Mail: larchm@ext.jussieu.fr;
Further Information

Publication History

Received 11 December 2002
Publication Date:
22 January 2003 (online)

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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

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Haddad, M.; Larchevêque, M., unpublished results.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