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.

alkaloid - aminoalcohol - cyanohydrine - pyrrolidine

References

1a Matkhalikova SF. Malikov VM. Yunosov SY. Khim. Pri. Soedin  1969,  5:  30 

1b Matkhalikova SF. Malikov VM. Yunosov SY. Khim. Prir. Soedin  1969,  5:  607 

2 Matkhalikova SF. Malikov VM. Yugadaev MR. Yunosov SY. Farmakol. Alkaloidov Serdech. Glikoyidov.  1971,  210 ; Chem. Abstr. 1972, 77, 135091r

3 Matkhalikova SF. Malikov VM. Yugadaev MR. Yunosov SY. Khim. Prir. Soedin  1971,  7:  210 

4a Iida H. Yamazaki N. Kibayashi C. Tetrahedron Lett.  1986,  27:  5393 

4b Iida H. Yamazaki N. Kibayashi C. J. Org. Chem.  1987,  52:  1956 

5 Wang CLJ. Calabrese JC. J. Org. Chem.  1991,  56:  4341 

6a Yoda H. Nakajima T. Takabe K. Tetrahedron Lett.  1996,  37:  5531 

6b Severino EA. Correia CRD. Org. Lett.  2000,  2:  3039 

7a Krepski LR. Jensen KM. Heilmann M. Rasmussen JK. Synthesis  1986,  301 

7b Brussee J. Dofferhoff F. Kruse CG. Van der Gen A. Tetrahedron  1990,  46:  1653 

7c Jackson WR. Jacobs HA. Jayatilafe GS. Matthews BR. Watson KG. Aust. J. Chem.  1990,  43:  2045 

7d Effenberger F. Gutterer B. Ziegler T. Liebigs Ann. Chem.  1991,  269 

7e Urabe H. Aoyama Y. Sato F. J. Org. Chem.  1992,  57:  5056 

8a Reetz MT. Kesseler K. Jung A. Angew. Chem., Int. Ed. Engl.  1985,  24:  989 

8b Gu J. Okamoto M. Terada M. Mikami K. Nakai T. Chem. Lett.  1992,  1169 

9 Hutin P. Larchevêque M. Tetrahedron Lett.  2000,  417:  2369 

10

Haddad, M.; Larchevêque, M., unpublished results.

Both enantiomers are commercially available from Acros Organics. Alternatively, they can be prepared according to:

11a Petit Y. Sanner C. Larchevêque M. Synthesis  1988,  538 

11b Cf also: Petit Y. Larchevêque M. Org. Synth.  1998,  75:  37 

12a Chini M. Crotti P. Flippin LA. Gardelli C. Giovani E. Macchia F. Pineschi M. J. Org. Chem.  1993,  58:  1221 

13a Riego J. Costa A. Saa JM. Chem. Lett.  1986,  1565 

13b

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

14 Ward DE. Hrapchak MJ. Sales M. Org. Lett.  2000,  2:  57 

15 Brussee J. van der Gen A. Recl. Trav. Chim. Pays-Bas  1991,  110:  25 

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.

17 Fuji K. Ichikawa K. Node M. Fujita E. J. Org. Chem.  1979,  44:  1661 

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).