Subscribe to RSS
DOI: 10.1055/s-2003-36777
Diastereocontrolled Synthesis of (-)-Codonopsinine
Publication History
Publication Date:
22 January 2003 (online)
![](https://www.thieme-connect.de/media/synlett/200302/lookinside/thumbnails/10.1055-s-2003-36777-1.jpg)
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
-
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 - 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 - 17
Fuji K.Ichikawa K.Node M.Fujita E. J. Org. Chem. 1979, 44: 1661
References
Haddad, M.; Larchevêque, M., unpublished results.
16Experimental 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.
18Selected 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).