On the stereochemistry of vincetene

Article abstract of DOI:10.1007/s007060170092

The absolute configuration of the centre of asymmetry in the side chain of the alkaloid vincetene (1) was determined by ozonolysis and subsequent unequivocal transformations affording the (S)-enantiomer of 1,2-propanediyl dibenzoate (4).

Full text of DOI:10.1007/s007060170092

Monatshefte fuÈr Chemie 132, 765±768 (2001)
Short Communication
On the Stereochemistry of Vincetenea
David Jirovsky1;2, Andreas Sellmer1, Pierre Guiswe1, Karel Lemr2,
and Wolfgang Wiegrebe1;Ã
1
Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany
2
Department of Analytical Chemistry, Palacky University, CZ-77146 Olomouc, Czech Republic
Summary. The absolute con®guration of the centre of asymmetry in the side chain of the alkaloid
vincetene (1) was determined by ozonolysis and subsequent unequivocal transformations affording
the (S)-enantiomer of 1,2-propanediyl dibenzoate (4).
Keywords. Alkaloids; Vincetene; Absolute con®guration; Ozonolysis; 1,2-Propanediyl dibenzoate;
Chiral resolution.
Introduction
Vincetene (1) is a minor and rather unstable alkaloid of Cynanchum vincetoxicum
(Asclepiadaceae) [1]. Whereas alkaloids of the phenanthroindolizidine type occur in
various plants [2], Cynanchum vincetoxicum seems to be the only source of
naphthoindolizidine type alkaloids as vincetene up to now [3]. Degradation of 1
with OsO4 afforded aldehyde 2, whereas the complementary C3 increment could not
be isolated [1]. Here we report on the stereochemistry of the asymmetric centre in
the side chain of 1 which was split off by ozonolysis.
Scheme 1. Conditions: a) O3, 78ꢀC, CH2Cl2, b) NaBH4, MeOH, 20ꢀC, c) PhCOCl, pyridine
a
Dedicated to Prof. Dr. Dr. Dr. h.c. mult. E. Mutschler, Frankfurt/Main, Germany, on the occasion
of his 70th birthday
Ã
Corresponding author

766
D. Jirovsky et al.
Fig. 1. Vincentene and its derivatives
Results and Discussion
In order to ®nd suitable reaction conditions, the double bond of racemic (E)-4-(3,4-
dimethoxyphenyl)-3-butene-2-yl benzoate (3) was cleaved by ozone. This ester was
prepared by benzoylation of the pertinent alcohol (Scheme 1). Ozonolysis of 3,
followed by borohydride reduction and benzoylation, yielded (‡/ )-1,2-propane-
diyl dibenzoate (4) which was resolved on a column of native ꢀ-cyclodextrin. The
enantiomers were compared with optically pure reference compounds, obtained
by twofold benzoylation of commercially available (S)- and (R)-1,2-propanediol.
The retention times for the (S)- and (R)-enantiomer are 26.9 min and 29.0 min,
respectively.
The allylic alcohol increment of 1 was converted into its benzoic acid ester (5).
Ozonolysis as described above followed by reductive work-up led to crude
2-benzoyloxypropanol which was directly benzoylated to an enantiomer of 1,2-
propanediyl dibenzoate (4). Neither aldehyde 2 nor any other de®ned compound
resulting from the heterocyclic part of 1 could be identi®ed.
The structure of the enantiomer under consideration was assured by HPLC/
APCI MS. The pertinent enantiomer as well as the reference compound showed an
‡
ion at m=z ˆ 285 corresponding to (M‡H) which loses benzoic acid, thus afford-
ing a fragment at m=z ˆ 163 (protonated O-benzoylacetone-enol). The authenticy
of this ion was con®rmed by MS-MS analysis.
The retention time of the enantiomer of 4 obtained from 1 corresponds to that
of (S)-1,2-propanediyl dibenzoate, indicating (S)-con®guration at this centre of
asymmetry in 1.
Experimental
General
1
IR: Nicolet 510M FT-IR; H NMR: Bruker WM 250 (250 MHz), TMS as internal standard; MS:
Varian MAT 311 A, EI, 70 eV.
Preparation
Extraction of dried leaves of Cynanchum vincetoxicum and separation of the alkaloids (cf. Ref. [1])
led to approximately 0.1% of a partially crystalline mixture of alkaloids. Vincetene (1) was obtained

Stereochemistry of Vincetene
767
1
by repeated chromatography of the fractions after separation of the main alkaloids [1]. H NMR
3
(CDCl3): ꢁ ˆ 6:55 (d, 1H, Jcis ˆ 11:4 Hz), 5.80 (dd, 1H, Jcis ˆ 11:3 Hz, J ˆ 9:2 Hz) ppm.
O-Benzoylvincetene (5)
For methodology, cf. Ref. [4]. A solution of crude vincetene (1; 120 mg, 0.35 mmol), 5 mg of 4-N,N-
dimethylaminopyridine, and benzoyl chloride (0.1cm3, 0.86 mmol) in pyridine (2 cm3) was stirred at
room temperature for 12 h. Saturated NaHCO3 solution (10 cm3) was added, and the mixture was
stirred for 30 min. After extraction with CH2Cl2 (3 Â 10 cm3), the organic layer was washed with 2 N
HCl (3 Â 10 cm3) and H2O (3 Â 10 cm3) and dried (Na2SO4).
Yield: 70 mg of crude material (completely degraded upon attempted puri®cation); IR (®lm):
1
‡Á
‡Á
1717 cm (allylic ester); MS: m=z (%)ˆ 457 (1, M ), 335 (7, M-(PhCOOH) , McLafferty), 266
(12, retro-Diels-Alder from m=z ˆ 335).
Ozonolysis of 5
For methodology, cf. Ref. [5]. A stream of O3 was bubbled through a solution of crude 5 (30 mg,
0.07 mmol) in CH2Cl2 at 78ꢀC until saturation of the solution with O3 was indicated by a light blue
colour. After stirring for 2 h, excess O3 was removed by a stream of N2; then, NaBH4 (7.44 cm3,
0.19 mmol) and MeOH (2 cm3) were added. This mixture was allowed to reach room temperature, the
solvent was removed in vacuo, and the crude product was benzoylated with benzoyl chloride
(0.02 cm3, 0.17 mmol) as described above. According to HPLC analysis (see below), (S)-1,2-
propanediyl dibenzoate (4) was obtained.
Ozonolysis of (E)-4-(3,4-dimethoxyphenyl)-3-butene-2-yl benzoate (3) was performed anal-
ogously. For (E)-4-(3,4-dimethoxyphenyl)-3-butene-2-one, see Ref. [6]; for (‡/ )-(E)-4-(3,4-
dimethoxyphenyl)-3-butene-2-ol, see Ref. [7].
(‡/ )-(E)-4-(3,4-Dimethoxyphenyl)-3-butene-2-yl benzoate (3)
A solution of (‡/ )-(E)-4-(3,4-dimethoxyphenyl)-3-butene-2-ol (0.35 g, 1.67 mmol), a catalytic
amount of 4-N,N-dimethylaminopyridine (1.0 mg), and benzoyl chloride (0.97 cm3, 8.36 mmol) in
pyridine (2.5 cm3) was stirred at room temperature for 12 h. Saturated NaHCO3 solution (20 cm3) was
added, and the mixture was stirred for 30 min. Then it was extracted with CH2Cl2 (3 Â 10 cm3), the
organic layer was washed with 2 N HCl (3 Â 10 cm3) and H2O (3 Â 10 cm3), dried (Na2SO4), and
puri®ed by column chromatography (SiO2, CH2Cl2). After evaporation, the ester was obtained as a
colourless oil (0.36 g, 69%).
1
1
IR (®lm): 1717 cm (C=O); H NMR (CDCl3): ꢁ ˆ 8.10±6.68 (m, 8H, aromat.), 6.64 (dd, 1H,
3
4
3
3
=CHPh, Jtrans ˆ 15:9 Hz, J ˆ 1:1 Hz), 6.17 (dd, 1H, PhCH=CH, Jtrans ˆ 15:9 Hz, J ˆ 6:8 Hz),
5.78 (ddd, 1H, CH=CH±CH±CH3, 3J ˆ 6:8 Hz, 4J ˆ 1:1 Hz, 3J ˆ 6:5 Hz), 3.90 (s, 3H, OCH3), 3.88
3
(s, 3H, OCH3), 1.55 (d, 3H, CH3, J ˆ 6:5 Hz) ppm; C19H20O4 (312.4); calcd.: C 73.06, H 6.45;
found: C 72.91, H 6.59.
Separation of the enantiomers of (‡/ )-1,2-propanediyl dibenzoate (4)
The separation was performed using a native ꢀ-cyclodextrin 250 Â 4 mm i.d. ChiraDex 5.75 m
LiChroCart column (Merck, Darmstadt, FRG) thermostatted at 20ꢀC. The samples (0.1mg/cm3 in
MeOH) were injected by a 50 mm3 syringe (Hamilton, Reno, NV, USA) and a manual 7125 injector
equipped with a 20 mm3 loop (Rheodyne, Cotati, CA, USA). The mobile phase was prepared by
mixing gradient grade acetonitrile with redistilled water (20:80 (v/v)). The ¯ow rate of the mobile
phase was 0.8 cm3/min. The chromatograms were recorded at 235 nm. HPLC pump: Kontron

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D. Jirovsky et al.: Stereochemistry of Vincetene
Instruments 420 (Kontron/Bio-Tek, Neufahrn, FRG), UV detector 430 (Kontron), thermostat: Optilab
column oven (Berlin, FRG). Data were recorded on a MacLab data aquisition system (Wiss Tech,
Spechbach, FRG) and analyzed with Peak Software on an Apple Macintosh computer.
HPLC-MS analysis of 1,2-propanediyl dibenzoate (4)
These analyses were carried out using a Gold liquid chromatograph (pump 125S and diode array
detector 168, scan 190±360 nm, Beckman, Fullerton, CA, USA) connected with a mass spectrometer
LCQ equipped with atmospheric pressure chemical ionization (APCI; Finnigan MAT, San Jose, CA,
USA). A LiChroCart column (250 Â 4 mm i.d.) and a guard column (4 Â 4 mm i.d.) packed with
LiChrospher 60 RP Select B, 5 mm (Merck, Darmstadt, FRG) were employed for sample separation.
The mobile phase MeOH:H2O ˆ 90:10 (v/v) and a ¯ow rate of 1.0 cm3/min were applied. The ¯ow
was split between the diode array detector and the mass spectrometer in a ratio of 85:15. Injections of
samples (5 mm3) were performed by a microliter syringe (25 mm3) via an injection valve Rheodyne
7725i. The response of the mass spectrometer was tuned to the standard solution. The following
parameters of APCI were utilized: source current: 5.0 mA, APCI vaporizer temperature: 450ꢀC, sheat
gas ¯ow: 40 arbitrary units, capillary temperature: 150ꢀC, capillary voltage: 4.0 V.
Acknowledgements
D. Jirovsky thanks the Freistaat Bayern (FRG) for a scholarship; D. Jirovsky and K. Lemr gratefully
acknowledge the support by a grant of the Ministry of Education, Czech Republic, No. MSM
153100013. W. Wiegrebe thanks the Fonds der Chemischen Industrie, Frankfurt/Main (FRG) for
®nancial support of this project.
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Received February 22, 2001. Accepted March 1, 2001
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