Synthesis of 18-hydroxyvincamines and epoxy-1,14-secovincamines; A new proof for the aspidospermane-eburnane rearrangement

Article abstract of DOI:10.3987/COM-07-11114

Chemical transformations started from tabersonine were studied. A one-pot oxidative ring-transformation with permaleic acid in methanol yielded 17,18-dehydrovincamine. Hydroboration-oxidation of the latter compound led to alkaloid 17,18-dehydrovincamone. Hydroboration-oxidation of tabersonine resulted 14β-hydroxyvincadifformine and 15β-hydroxyvincadifformine. Allowing 14β- and 15β- hydroxyvincadifformines to react with permaleic acid/methanol provided 1,14-secovincamines, serving as new evidence for the mechanism of the aspidospermane-eburnane transformation. On the other hand 18β-hydroxyvincamine was obtained from 14β-hydroxyvincadifformine by reaction with 3-chloroperbenzoic acid and successive treatment with triphenylphosphine/aqueous acetic acid.

Full text of DOI:10.3987/COM-07-11114

HETEROCYCLES, Vol. 71, No. 11, 2007
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HETEROCYCLES, Vol. 71, No. 11, 2007, pp. 2347 - 2362. © The Japan Institute of Heterocyclic Chemistry
Received, 21st May, 2007, Accepted, 18th July, 2007, Published online, 27th July, 2007. COM-07-11114
SYNTHESIS OF 18-HYDROXYVINCAMINES AND EPOXY-1,14-SECO-
VINCAMINES; A NEW PROOF FOR THE ASPIDOSPERMANE-
EBURNANE REARRANGEMENT
András Nemes,1* Csaba Szántay Jr.,2 László Czibula,1 and István Greiner
Chemical Works of Gedeon Richter Ltd. 1Technological Research Laboratory No.I.
2 Spectroscopic Research Division, H 1475 Budapest 10. POB 27., Hungary
Corresponding author.Tel. (+36-1) 431-4747; e-mail: a.nemes@richter.hu
Abstract—Chemical transformations started from tabersonine were studied. A
one-pot oxidative ring-transformation with permaleic acid in methanol yielded
17,18-dehydrovincamine. Hydroboration-oxidation of the latter compound led to
alkaloid 17,18-dehydrovincamone. Hydroboration-oxidation of tabersonine
resulted 14β-hydroxyvincadifformine and 15β-hydroxyvincadifformine. Allowing
14β- and 15β- hydroxyvincadifformines to react with permaleic acid/methanol
provided 1,14-secovincamines, serving as new evidence for the mechanism of the
aspidospermane-eburnane transformation. On the other hand 18β-
hydroxyvincamine was obtained from 14β-hydroxyvincadifformine by reaction
with
3-chloroperbenzoic
acid
and
successive
treatment
with
triphenylphosphine/aqueous acetic acid.
INTRODUCTION
(+)-Vincamine (1), (-)-eburnamonine (2), (members of the eburnamine-vincamine alkaloid group1 and
semisynthetic derivatives such as (-)-ethyl apovincaminate [vinpocetine (3)] and 11-bromovincamine
[brovincane (4)] have been marketed as nootropic drugs for the treatment of cerebral insufficiencies
(Fig.1). New clinical and non-clinical observations have confirmed the beneficial cerebrovascular effect
of compounds (1-4), adding a neuroprotective profile to it.2,3 The endeavors of the last decade in synthetic
research have resulted in new racemic and enantioselective entries to this class of alkaloids.4 Extending of
our efforts on the synthesis of (+)-vincamine and derivatives,5 we became interested in synthesizing 18-
hydroxyvincamines (5a-d).
RESULTS AND DISCUSSION
Synthesis. In the retrosynthetic analysis depicted in Scheme 1 the trans-fused pentacyclic compounds
(5b,d) are prepared from the cis isomer (5a). The functionalization of the 18-hydroxy group takes place

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HETEROCYCLES, Vol. 71, No. 11, 2007
9
6
10
11
5
H
H
H
N
N
N
19
18
N
N
X
N
14
4
3
16
12 HO
O
EtO2C
17
15
MeO2C
2
3
1 X = H
4 X = Br
Figure 1
through the hydroboration-oxidation reaction of the 17,18-dehydrovincamine (6), an alkaloid of
Crioceras longiflorus6a and Amsonia elliptica,6b which is obtainable from tabersonine (7) by ring
transformation6c,7 (route A). Alternatively, the rearrengement could be preceded by the hydroboration-
oxidation of 7 to 14-hydroxyvincadifformine (8) (route B) (Scheme 1).
H
H
H
Route A
N
N
N
N
N
N
R1
R2
HO
HO
OH
OH
MeO2C
MeO2C
5b R1 = OH, R2 = CO2Me
5d R1= CO2Me, R2 = OH
5a
N
6
Route B
3
5
4
N
OH
14
15
H
H
9
6
7
2
8
10
11
1
17
N
H
13
N
H
16
12
CO2Me
CO2Me
7
8
Scheme 1
To accomplish the process according to route A, first the ring transformation of 7 to 6 was studied. The
original multistep reaction sequence of Le Men and coworkers6c follows the line of their biomimetic
transformation of vincadifformine (9) to vincamine (1) and its 14-epimer.8,9 This includes the oxidation of
9 to 16-hydroxyindolenine N-oxide (10) with an aromatic peroxycarbonic acid, followed by treatment
with triphenylphosphine and acetic acid (Scheme 2). The intermediacy of N-oxides (10) and (11), as well
as that of 16-hydroxyindolenines (12) and (13), in the synthesis of 1 and 6 was proved through step by
step isolation.9,10 However, intermediates (14) and (15) have, up until now, not been isolated, and their
existence was only proposed on the basis of the fact that there is a retention of configuration on C-20 and
C-21 (C-16 and C-3 for the eburna skeleton), and an epimerization on C-16 (C-14).9

HETEROCYCLES, Vol. 71, No. 11, 2007
2349
The subsequent syntheses avoid the formation of the Nb-oxide by protonation with mineral acids.10-12
A
wide range of oxidizing agents was employed, such as aromatic perbenzoic acid,11 ozon,12 as well as dye-
sensitized photo-oxidation.10 Recent transformations apply aliphatic percarbonic, such as persuccinic13 or
-
O
+
N
N
14
15
N
H
H
H
N
N
N
H
OH
OH
CO2Me
CO2Me
CO2Me
12 14,15: H2
13 14,15: ∆
10 14,15: H2
11 14,15: ∆
9 14,15: H2
7 14,15: ∆
H
N
H
H
N
N
N
14
N
N
HO
H
MeO2C
HO
18
MeO2C
MeO2C
17
O
1+ 14-epimer 17,18: H2
6+ 14-epimer 17,18: ∆
15
14
Scheme 2
permaleic14 acids. The latter compound was selected as non hazardous, in situ preparable peracid,15 which
was characterized as being much more reactive than the usual peracids. Since maleic acid is a strong acid
(pK = 2), it was anticipated that no separate salt formation with mineral acid will be necessary. Indeed,
when tabersonine (7) was allowed to react in methanol with permaleic acid reagent, prepared from maleic
anhydride and 35% hydrogenperoxide in DMF at 30º C, a mixture of 6 and its 14-epimer (55:45) was
obtained in 75%. Epimerization of this mixture to 6 was established by a catalytic amount of sodium
methoxide. Similar transformation of vincadifformine (9) to a 96:4 mixture of vincamine (1) and its 14-
epimer, followed by epimerization was carried out in 60% (Scheme 3).
Recently, the hydroboration-oxidation of 17,18-dehydroapovincamine to 17- and 18-hydroxy-
apovincamines was reported by Zsadon et al.16 The same reaction with 17,18-dehydrovincamine 6, in
contrast to expectations, led to (–)-17,18-dehydroeburnamonine (16) (Scheme 3).
17,18-Vincamone 16 was prepared earlier from 17,18-dehydrovincanol by Baassou.17 A recent account
reported 16 as a minor alkaloid of Voacanga africana.18 To define the formation of 16, the product of the
first step of the reaction sequence, intermediate (17) was isolated after the hydroboration process.
Compound (17) was assigned as 17,18-dehydro-14,15-dihydro-14-hydroxymethyl-ebunamenine-14-ol.

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HETEROCYCLES, Vol. 71, No. 11, 2007
14
15
N
a,b
H
H
H
c
H
d
N
N
N
N
14
N
14
N
14
HO
HO
HOCH2
18
18
18
O
N
H
17
MeO2C
17
17
CO2Me
6
1
17,18: ∆
17,18: H2
16 17,18: ∆
17,18: H2
17 17,18: ∆
18 17,18: H2
7 14,15: ∆
9 14,15: H2
2
Scheme 3. Reagents and conditions: (a) permaleic acid (maleic anhydride, DMF, H2O2, 30 °C), MeOH,
5 °C; (b) KOtBu, MeOH, ∆ (75% for 6, 60% for 1); (c) NaBH4, BF3·OEt2, THF, O °C (46% for 17, 51%
for 18); (d) NaOH, H2O2, 60 °C (16: 57% from 6, 2: 52% from 1).
Similarly, vincamine (1) was transformed to vincamone (2) by the same reaction sequence. Here the
isolated intermediate was the known 14,15-dihydro-14-hydroxymethyl-ebunamenine-14-ol (18), obtained
earlier from 1 by means of reduction with lithium aluminium hydride.19a,b
Turning to route B we followed the line of Le Men,20 who described a synthesis of 5a from tabersonine
(7) via 14β-hydroxyvincadifformine (8). In our hands the hydroboration-oxidation reaction led to 8 as the
major component and (−)-15β-hydroxyvincadifformine (19) proved to be the minor product (Scheme 4).
Compound +-(19) was isolated by Atta-ur-Rahman as a minor alkaloid of Rhazya stricta.21 Racemic 19
was synthesized earlier by Kuehne.22 A recent report by Kalaus et al. described an alternative approach to
racemic 19.23
OH
N
N
N
H
H
H
OH
a,b
N
H
N
H
N
H
+
CO2Me
CO2Me
CO2Me
7
8
19
Scheme 4. Reagents and conditions: (a) NaBH4, BF3·OEt2, THF, O °C; (b) NaOH, H2O2, 60 °C (8: 41.9%,
19: 6.6%).
Modified ring transformation reaction conditions (Scheme 3) were tested on vincadifformine (8). A new
1,14-secoeburnamenine derivative, 20 was isolated from this one-pot transformation. A similar reaction
product, 21 was obtained from 15β-hydroxyvincadifformine 19. The formation of secovincamines (20)
and (21) from hydroxyvincadifformines can be explained through intermediates (22) and (23), since in
methanol/dimethylformamide solution the hydroxy-ketoesters stabilize by formation of an ether ring
(Scheme 5). To the best of our knowledge this is the first direct proof for the existence of 15 (or 14) types
of intermediates as being the last step in the aspidospermane-eburnane ring transformation.
Applying the original reaction sequence of Le Men20 8 was transformed to 18β-hydroxyvincamine (5a)

HETEROCYCLES, Vol. 71, No. 11, 2007
2351
and and its 14-epimer (5c) in 50 and 9 % respectively. The intermediate (24) was also isolated (Scheme 6).
A C-3 epimerization on 5a was achieved by an oxidation-reduction process, described by Szántay
R1
R2
N
H
H
H
N
N
on 8
N
H
N
H
O
HO
MeO2C
N
H
R1
MeO2C
20
O
R2
CO2Me
on 19
22
23
8
19
R1 = OH, R2 = H
R1 = H, R2 = OH
H
N
N
H
O
HO
MeO2C
21
Scheme 5. Reagents and conditions: permaleic acid (maleic anhydride, DMF, H2O2, 30 °C), MeOH, 5 °C
(50% for 20, 42% for 21).
et al.24 Oxidation with sodium dichromate, followed by sodium borohydride reduction led to trans 18β-
hydroxyvincamine epimers (5b) and (5d) in 10 and 5% resp.,13% of cis isomer (5a) was also isolated
(Scheme 6).
-
O
+
OH
OH
a
N
N
H
H
H
N
N
b,c
d,e
MeO2C
HO
N
H
N
OH
OH
CO2Me
CO2Me
24
5c
8
H
H
H
N
+
N
N
N
N
N
HO
MeO2C
HO
HO
OH
OH
OH
MeO2C
MeO2C
5b
5d
5a
Scheme 6. Reagents and conditions: (a) 3-chloroperbenzoic acid, toluene, rt (50%); (b)AcOH, rt; (c)
triphenylphosphine, AcOH, rt (5a: 50%, 5c: 9% from 8) ; (d) Na2Cr2O7, AcOH, rt; (e) NaBH4, MeOH, rt
(5d: 10%, 5b: 5%).
Structure elucidation. All compounds were structurally verified by HRSM and NMR data, as given in the
1
experimental section. H and 13C NMR assignments were confirmed by 2D (COSY, HSQC, HMBC,

2352
HETEROCYCLES, Vol. 71, No. 11, 2007
NOESY) measurements. Some structurally significant NMR parameters were also revealed in the
experimental section. Since secoeburnamenines (20) and (21) represent new molecular entities, their
NMR structure assignment is additionally commented upon as follows. For both 20 and 21, the
stereostructures that emerge from the NMR data are shown in Figures 2 and 3 (the ethyl groups rotate
freely abot the C(16)-C(20) bond, and are shown in their most preferred conformation). Some of the most
significant H-H NOE interactions are depicted by arrows. The constitutional position and stereochemistry
of the O-ring formation involving C(18) (in 20) and C(17) (in 21) follows readily from the observed JH,H
scalar coupling pattern of the C(17)H2-C(18)H-C(19)H2 (in 20) and C(17)H-C(18)H2-C(19)H2 (in 21)
spin systems (see the experimental section), as well as from the observed NOEs in these systems as
denoted in Figures 2 and 3. In 20, all vicinal H-H couplings in C(17)H2-C(18)H-C(19)H2 are around or
less than 2 Hz. Analogously, both vicinal couplings of H-17 in 21 are similarly small. These data are fully
consistent with the stereostructures as shown in Figure 2. For both compounds the configuration of C(14)
follows from the observed C(14)-OH ↔ Hβ-6, Hβ-5, Hβ-19 NOEs. In both cases the OH chemical shift is
larger than 9 ppm which, in addition to the aforementioned NOEs, suggests a C(14)-OH … N(4)
hydrogen bridge formation.
COOMe
14
x
15
y
6
1
9
18
10
5
4
19
3
17
16
11
y
12
x
20
21
20
Figure 2
CONCLUSION
A short, one-pot method was elaborated for the transformation of tabersonine (7) to 17,18-
dehydrovincamine (6), avoiding the formation both the Nb-oxide and a mineral acid salt. The
hydroboration-oxidation of 6 led to 17,18-dehydrovincamone (16), an alkaloid of Voacanga africana.
Hydroboration-oxidation of tabersonine resulted in 14β-hydroxyvincadifformine (8) and 15β-
hydroxyvincadifformine (19). Secovincamines (20) and (21) were obtained from the oxidative
transformation of 8 and 19 with permaleic acid in methanol/dimethylformamide. 18β-Hydroxyvincamine

HETEROCYCLES, Vol. 71, No. 11, 2007
2353
(5a), achieved by ring-transformation of 14β-hydroxyvincadifformine (8) by standard method epimerized
at C-3 to yield trans 18β-hydroxyvincamine epimers (5b) and (5d).
COOMe
14
x
6
5
y
15
19
9
10
11
4
17
3
y
1
16
18
x
12
20
21
21
Figure 3
EXPERIMENTAL
Melting points were determined with a Büchi 510 apparatus and are uncorrected. The [α]D observed using
a Perkin Elmer 243B polarimeter. IR spectra were recorded on a Nicolet-205-FT-IR spectrometer using
1
KBr pellets. H NMR spectra were recorded on a Varian INOVA 500 spectrometer. 2D NMR
experiments (COSY, HSQC, HMBC, NOESY) experiments were recoded by using the standard
spectrometer software package; 0.75 s mixing time was used in the NOESY experiments. Mass
spectrometric (low and high-resolution /LRMS and HRMS/) measurements were performed on a
Finnigan MAT 95XP mass spectrometer, using the electron ionization (EI) method at 70 eV, with direct
sample introduction at a source temperature of 220°C. Perfluorotributyl amine was used as a reference
compound for HRMS measurements. FIB (fast ion bombardment) measurements (Cs+ ion, glycerol
matrix, 20 kV) were carried out on a Finnigan MAT 95SQ mass spectrometer.
17,18-Dehydrovincamine (6)
To a solution of maleic anhydride (25g, 255 mmol) in dimethylformamide (48 mL) hydrogen peroxide
solution (35 wt % in water, 12.5 mL, 140 mmol) was added at 5°C. The solution was stirred for 1 h at
30°C. The solution, peracidic content of which was 108 mmol according to potentiometric titration, was
then diluted with MeOH (400 mL) and cooled to 2°C. Tabersonine 7 (36 g, 107 mmol) was added and
the mixture stirred for 2 h at 5°C. The excess of peroxide was decomposed by adding a solution of
Na2S2O5 (1.6 g) in water (2mL). After stirring for 2 h at 40°C the mixture was diluted with water (480
mL) and the pH was adjusted to 8.5 with 5% NH4OH solution, cooled, and stirred for 1 h at 5°C. The

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HETEROCYCLES, Vol. 71, No. 11, 2007
separated crystals were filtered, washed with MeOH (2×80 mL) to obtain 32 g of crude product. The
ratio of dehydrovincamine and its 14-epimer was 55:45, according to HPLC. The epimeric mixture (32 g)
was refluxed with a solution of potassium ter.butylate (1 g) in anhydrous MeOH (160 mL) under
nitrogen, for 4 h. After cooling the separated crystals was filtered, washed with MeOH (2×30 mL ) to
6a
yield 26.6 g, 75.5% of 6. mp 224-225 °C, (218 °C, 222-223 °C 6b); [α]D + 129°(CHCl3, c 1), (+
116°(CHCl3) 6a).
Vincamine (1)
To a solution of maleic anhydride (3.95 g, 30 mmol) in dimethylformamide (6 mL) hydrogen peroxide
solution (35 wt % in water, 1.5 mL, 17 mmol) was added at 5°C. The solution was stirred for 1 h at 30°C,
then diluted with MeOH (50 mL) and cooled to 2°C. Vincadifformine (9) (4 g, 13.3 mmol) was added
and the mixture stirred for 2 h at 5°C. The excess of peroxide was decomposed by adding a solution of
Na2S2O5 (0.2 g) in water (0.3 mL). After stirring for 2 h at 40°C the mixture was diluted with water (60
mL) and the pH was adjusted to 8.5 with 5% NH4OH solution, cooled, and stirred for 1 h at 5°C. The
separated crystals were filtered, washed with MeOH (2×10 mL) to obtain 3.1 g of crude product
(vincamine : 14-epivincamine = 95.5:4.5, according to HPLC), which was refluxed with a solution of
potassium tert.butylate (0.1 g) in anhydrous MeOH (12 mL) under nitrogen, for 2 h. After cooling the
separated crystals was filtered, washed with MeOH (2×3 mL ) to yield 2.86 g, 60.0% of 1. mp 233-234
°C (chlorobenzene), (234-235 °C.23); [α]D + 42°(c 1, pyridine), (+ 44°, pyridine23).
Preparation of diols 17 and 18
To a solution of vincamine (1) or (6) (2,8 mmol) in THF (30 mL) NaBH4 (0.7 g, 18 mmol) was added.in
small portions at 0 °C, then BF3.OEt2 (1.34 g, 1.2 mL, 9.5 mmol) was dropped within 0.5 h at the same
temperature, under N2. After stirring for 2 h water (0.5 mL), then NaOH (12% aqueous solution, 1.5 mL)
was added. The precipitate was filtered, the filtrate was evaporated to dryness. To the residue water (10
mL) and CH2Cl2 (20 mL) was added. The organic solvent was evaporated, the main component was
separated by column chromatography (eluent: CH2Cl2/MeOH 10:1) to give diols (17) or (18).
17,18-Dehydro-14,15-dihydro-14-hydroxymethylebunamenin-14-ol (17): 0.45 g, 46%. mp 153-154
°C (from toluene); [α]D + 137.8° (CHCl3, c0.9); IR (cm-1): 3452, 3021, 2918, 2840, 1660, 1612, 1450,
1
1340, 1295, 1240, 1178, 1054, 1028, 953, 844, 748, 681, 525; H NMR (CDCl3, δTMS=0.00 ppm;
multiplicities set in italics indicate small, typically less than 2 Hz couplings): 1.01 (3H, t, H3-21), 1.61
(1H, dq, Hx-20), 1.90 (1H, dq, Hy-20), 2.21 (IH, d, Hx-15), 2.30 (1H, brs, OH), 2.39 (1H, d, Hy-15), 2.54
(1H, ddd, Hx-6), 2.62 (1H, brs, OH), 2.87 (1H, dt, Hx-19), 3.04 (1H, dm, Hy-19), 3.06 (1H, m, Hx-6), 3.28
(1H, m, Hx-5), 3.38 (1H, dd, Hy-5), 3.95 (1H, d, -CHxHy-OH), 3.96 (1H, s, H-3), 3.95 (1H, d, -CHxHy-

HETEROCYCLES, Vol. 71, No. 11, 2007
2355
OH), 4.33 (1H, d, -CHxHy-OH), 5.58 (1H, dm, H-18), 5.70 (1H, dm, H-17), 7.10-7.15 (2H, m, H-10,11),
7.46 (1H, dm, H-9), 7.62 (1H, dm, H-12); 13C NMR (CDCl3, δTMS=0.0 ppm): 8.4 (C-21), 16.6 (C-6), 34.7
(C-20), 36.2 (C-16), 42.8 (C-15), 43.8 (C-19), 49.3 (C-5), 57.8 (C-3), 66.6 (C-3), 66.6 (-CH2OH); 85.2
(C-14), 106.2 (C-7), 112.5 (C-12), 118.3 (C-9), 120.1 (C-10), 121.3 (C-11), 127.8 (C-18), 127.8 (C-17),
129.5 (C-8), 132.6 (C-2), 134.2 (C-13); MS (EI) m/z (%): 324(100), 306(29.4), 295(66.7), 293(50.9),
277(57.0), 265(20.6), 249(35.1), 235(11.4), 221(14.5), 170(43.9), 144(21.9); HRMS: calcd 324.1832 (for
C20H24N2O2), found 324.1835 (delta: 0.8 ppm). Anal. Calcd: C, 74.04; H, 7.45; N, 8.63. Found: 73.80; H,
7.38; N, 8.59.
14,15-Dihydro-14-hydroxymethylebunamenin-14-ol (18): 0.50 g, 51%. mp 180-182 °C (from
toluene) (180 °C, benzene19a,b); [α]D + 10.6° (CHCl3, c 1,pyridine); IR(cm-1): 3535, 3193, 2952, 2850,
1
1615, 1588, 1458, 1368, 1304, 1264, 1185, 1054, 1016, 911, 844, 741, 684, 525; H NMR (CDCl3,
δTMS=0.00 ppm; multiplicities set in italics indicate small, typically less than 2 Hz couplings): 0.93 (3H, t,
H3-21), 1.24-1.35 (2H, m, Hax-17, Heq-18), 1.43 (1H, dq, Hx-20), 1.52 (1H, dm, Hax-17), 1.74 (1H, m, Hax-
18), 2.08 (1H, d, Hx-15), 2.21 (1H, d, Hy-15), 2.22 (1H, dq, Hy-20), 2.37 (1H, td, Hax-19), 2.40 (1H, brs,
OH), 2.52 (1H, ddd, Heq-6), 2.54 (1H, dm, Heq-19), 2.91 (1H, brs, OH), 3.96 (1H, m, Hax-6), 3.21 (1H, m,
Hx-5), 3.28 (1H, dd, Hy-5), 3.76 (1H, s, H-3), 3.91 (1H, d, -CHxHy-OH), 4.16 (1H, d, -CxHy-OH), 5.58
(1H, dm, H-18), 7.11-7.18 (2H, m, H-10,11), 7.50 (1H, dm, H-9), 7.63 (1H, dm, H-12); 13C NMR (CDCl3,
δTMS=0.0 ppm): 7.5 (C-21), 16.7 (C-6), 20.6 (C-18), 25.9 (C-17), 28.7 (C-20), 34.3 (C-16), 44.0 (C-15),
44.2 (C-19), 50.6 (C-5), 59.3 (C-3), 67.4 (C-3); 66.6 (-CH2OH), 84.7 (C-14), 105.6 (C-7), 112.4 (C-12),
118.3 (C-9), 119.9 (C-10), 121.1 (C-11), 129.2 (C-8), 132.2 (C-2), 133.7 (C-13); MS (EI) m/z (%):
326(78.4), 325(38.5), 308(61.0), 295(25.7), 279(100), 267(50.5), 252(15.6), 238(61.5), 171(23.4);
HRMS: calcd 326.1989 (for C20H26N2O2), found 326.1995 (delta: 1.9 ppm).
Preparation of vincamones (2) and (16)
To a solution of vincamine (1) or (6) (17 mmol) in THF (60 mL) NaBH4 (2.1 g, 55 mmol) was added.in
small portions at 0 °C, then BF3.OEt2 (8.04 g, 7.2 mL, 9.5 mmol) was dropped within 0.5 h at the same
temperature, under N2. After stirring for 2 h water (3 mL), then 3N NaOH (9 mL) was added. Hydrogen
peroxide solution (35 wt % in water, 13.2 mL, 149 mmol) was added at 5 °C. The mixture was stirred at
60 °C for 45 min, cooled and extracted with CHCl3 (3×60 mL). The combined organic extracts were
washed with water (60 mL), dried and concentrated in vacuo. The main component was separated by
column chromatography (eluent: toluene/MeOH 5:1)
17-18-Dehydro-14-15-dihydroeburnamenine-14-on (16): 2.87 g, 57%. Rf = 0.83; mp 129 °C (from
17
MeOH); [α]D + 27.5°, (c 1, CHCl3) (mp 127 °C, acetone; [α]D + 20°, CHCl3 ) ; IR (cm-1): 3030, 2969,
1
2892, 2847, 1694, 1627, 1454, 1383, 1334, 1272, 1183, 1136, 1102, 970, 874, 752, 716, 610; H NMR

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HETEROCYCLES, Vol. 71, No. 11, 2007
(CDCl3, δTMS=0.00 ppm; multiplicities set in italics indicate small, typically less than 2 Hz couplings):
1.00 (3H, t, H3-21), 1.68 (1H, dq, Hx-20), 1.89 (1H, dq, Hy-20), 2.47 (1H, ddd, Heq-6), 2.72 (1H, d, Hx-15)
2.78 (1H, d, Hy-15), 2.91 (1H, dm, Hx-19), 3.04 (1H, m, Hax-6), 3.13 (1H, dm, Hy-19), 3.30 (1H, ddd, Hx-
5), 3.43 (1H, dd, Hy-5), 4.04 (1H, s, H-3), 4.98 (1H, d, H-17), 5.54 (1H, dt, H-18), 7.24-7.32 (2H, m, H-
10,11), 7.41 (1H, dm, H-9), 8.33 (1H, dm, H-12); 13C NMR (CDCl3, δTMS=0.0 ppm): 8.5 (C-21), 16.3 (C-
6), 34.1 (C-20), 40.9 (C-16), 43.3 (C-15), 43.9 (C-19), 49.4 (C-5), 56.4 (C-3), 112.3 (C-7), 116.1 (C-12),
118.0 (C-9), 123.7 (C-10), 124.2 (C-11), 127.0 (C-17,18), 130.1 (C-8), 132.9 (C-2), 134.2 (C-13), 167.0
(C-14); MS (EI) m/z (%): 292(100), 291(45.6), 263(46.5), 261(22.8), 250(7.9), 235(40.4), 224(16.7),
206(12.3); HRMS: calcd 292.1570 (for C19H20N2O), found 292.1564 (delta: -2.1 ppm).
14-15-Dihydroeburnamenine-14-on (2): 2.5 g, 52%; Rf = 0.75; mp 173 °C (from MeOH); [α]D −90°,
19b
(c 1, CHCl3) (mp 173 °C, acetone; [α]D −90°,CHCl3
)
Hydroboration-oxidation of tabersonine (7)
To a solution of 7 (6 g, 17.8 mmol) in THF (60 mL) NaBH4 (2.1 g, 55 mmol) was added.in small portions
at 0 °C, then BF3.OEt2 (8.04 g, 7.2 mL, 9.5 mmol) was dropped within 0.5 h at the same temperature,
under N2. After stirring for 2 h water (3 mL), then 3N NaOH (9 mL) was added. Hydrogen peroxide
solution (35 wt % in water, 13.2 mL, 149 mmol) was added at 5 °C. The mixture was stirred at 60 °C for
45 min, cooled and extracted with CHCl3 (3×60 mL). The combined organic extracts were washed with
water (60 mL), dried and concentrated in vacuo. Chromatography of the residue on a 150 g silica gel
column, eluting with 4% MeOH in CHCl3, gave 1.45 g unchanged 7 (Rf =0.85), 8, (Rf =0.55), and
19 (Rf =0.45)
14β-Hydroxyvincadifformine (8): Amorphous. (2.65 g, 41.9%). [α]D −521.5°, (c 1, CHCl3) ([α]D −431°,
21
c 1, CHCl3 ); IR (cm-1): 3375, 2937, 2784, 1675, 1609, 1465, 1436, 1381, 1279, 1253, 1166, 1114, 1046,
1
1018, 921, 806, 746; H NMR (CDCl3, δTMS=0.00 ppm; multiplicities set in italics indicate small,
typically less than 2 Hz couplings): 0.55 (4H, m, H3-18, Hx-19), 1.05 (1H, m, Hy-19), 1.42 (1H, dd, Hx-
15), 1.76 (1H, m, Hx-6), 2.03 (1H, d, Hy-15); 2.08 (1H, m, Hy-6), 2.52 (1H, brs, Hα-14), 2.57 (1H, d, Hx-
17), 2.69 (1H, d, Hy-17); 2.72 (1H, m, Hx-5); 2.75 (1H, d, Hx-3), 2.95 (1H, m, Hy-5), 3.18 (1H, d, Hy-3),
3.76 (3H, s, OCH3), 3.97 (1H, s, H-21), 7.05-7.15 (3H, m, H-10,11,12), 7.45 (1H, dm, H-12). [J
couplings that verify the β (axial) stereoposition of the 14-OH group: J15x,14α = 4.0 Hz, J15y,14α = 2.2 Hz,
13
J3x,14α ~ 1 Hz, J3y,14α ~ 1 Hz]; C NMR (CDCl3, δTMS=0.0 ppm): 7.11 (C-18), 27.8 (C-17), 29.7 (C-19),
38.6 (C-20), 40.1 (C-15), 44.9 (C-6), 51.0 (OMe), 51.3 (C-5), 55.3 (C-7), 57.6 (C-3), 66.7 (C-21), 73.8
(C-14), 93.1 (C-16), 109.4 (C-12), 120.5 (C-10), 121.1 (C-9), 127.7 (C-11), 137.6 (C-8), 143.2 (C-13),
166.9 (C-2), 168.9 (COOMe); MS (EI) m/z (%): 354(25.4), 323(2.2), 253(3.5), 222(2.6), 140(100);
HRMS: calcd 354.1938 (for C21H26N2O3), found 354.1932 (delta: -1.7 ppm).

HETEROCYCLES, Vol. 71, No. 11, 2007
2357
15β-Hydroxyvincadifformine (19): Amorphous. (0.42 g, 6.6%). [α]D −531.5°, (c 1, CHCl3); IR(cm-1):
1
3364, 3050, 2937, 2774, 1676, 1632, 1607, 1464, 1366, 1235, 1152, 1036, 746; H NMR (DMSO-d6,
δTMS=0.00 ppm): 0.59 (3H, t, H3-18); 0.82 (1H, m, Hx-19); 1.00 (1H, dd, Hy-19); 1.52 (1H, m, Hx-6); 1.64
(1H, m, Heq-14); 1.74 (1H, m, Hax-14); 1.90 (1H, m, Hy-6); 2.39 (1H, m, Hx-5); 2.44-2.58 (3H, m, Hx-3,
H2-17); 2.55 (1H, s, H-21); 2.83 (1H, dd, Hy-3); 3.01 (1H, m, Hy-5); 3.56 (1H, ddd, Hα-15); 3.68 (3H, s,
OCH3); 4.53 (1H, d, OH), 6.80 (1H, td, H-10); 7.01 (1H, dd, H-12); 6.08 (1H, td, H-11); 7.21 (1H, dd, H-
12). [JH,H couplings that verify the β (equatorial) stereoposition of the 15-OH group: J15α (ax) 14α(eq)
,
= 5.5
13
Hz, J15α(ax) 14β(ax)
,
= 11.0 Hz]. C NMR (CDCl3, δTMS=0.0 ppm): 8.5 (C-21); 22.9 (C-17); 26.2 (C-19);
31.3 (C-14); 42.4 (C-20); 46.6 (C-6); 47.3 (C-5); 50.5 (OMe); 50.7 (C-3); 55.4 (C-7); 69.3 (C-21); 72.7
(C-15); 91.2 (C-16); 111.0 (C-12); 119.9 (C-10); 120.4 (C-9); 127.2 (C-11); 137.1 (C-8); 143.6 (C-13);
167.1 (C-2); 167.7 (COOMe); MS (EI) m/z (%): 354(31.6), 323(2.2), 253(3.5), 222(4.4), 140(100);
HRMS: calcd 354.1938 (for C21H26N2O3), found 354.1933 (delta: -1.4 ppm).
Preparation of secoeburnamenines (20) and (21)
To a solution of maleic anhydride (0.32 g, 2.5 mmol) in dimethylformamide (6.4 mL) hydrogen peroxide
solution (35 wt % in water, 0.16 mL, 1.8 mmol) was added at 5°C. The solution was stirred for 1 h at
30°C, then diluted with MeOH (4 mL) and cooled to 2°C. Hydroxyvincadifformine 8 or 19 (0.4 g, 1.1
mmol) in MeOH (3 mL) was added and the mixture stirred for 2 h at 5°C. The excess of peroxide was
decomposed by adding a solution of Na2S2O5 (0.1 g) in water (0.4 mL). After stirring for 2 h at 40°C the
mixture was diluted with water (6.4 mL) and the pH was adjusted to 8.5 with 5% NH4OH solution, cooled,
and stirred for 1 h at 5°C. The separated crystals were filtered, washed with 50% water/MeOH (2×1.5
mL) to obtain the crude product.
14,18-Epoxy-14-hydroxy-14,15-dihydro-1,14-secoeburnamenine-14-carboxylic acid methyl ester
(20): Colorless powder (0.2 g, 50%). mp 195 °C (from MeOH); [α]D −74.9º, (c 1, CHCl3); IR(cm-1):
1
3386, 2948, 2846, 1760, 1618, 1493, 1464, 1318, 1266, 1161, 1075, 1022, 840, 760, 663, 547; H NMR
(CDCl3, δTMS=0.00 ppm; multiplicities set in italics indicate small, typically less than 2 Hz couplings):
1.26 (3H, t, H3-21), 1.61 (1H, m, Hx-20), 1.70 (1H, dm, Hβ-17), 1.82 (1H, dm, Hα-17), 1.86 (1H, dm, Hx-
15), 2.03 (1H, m, Hy-20), 2.07 (1H, d, Hy-15), 2.64 (1H, d, Hα-19), 2.75 (1H, m, Hα-6), 2.85 (1H, m, Hα-
5), 3.10 (1H, m, Hβ-6), 3.17 (1H, m, Hβ-5), 3.28 (1H, dm, Hβ-19), 3.66 (1H, s, H-3), 3.77 (3H, s, OMe),
4.40 (1H, m, H-18), 7.10 (1H, t, H-10), 7.17 (1H, t, H-11), 7.32 (1H, d, H-12), 7.45 (1H, d, H-9), 7.93
(1H, brs, NH), 10.05 (1H, brs, OH). [Structurally significant JH,H couplings: J
17α,17β = 13.1 Hz, J19α,19β =
12.5 Hz, J17α (ax) 18α(eq) ~ J17β (eq) 18α(eq) ~ J19α (ax) 18α(eq) ~ J19β (eq) 18α(eq)
,
,
,
,
< 2 Hz]; 13C NMR (CDCl3, δTMS=0.0
ppm): 7.7 (C-21), 21.0 (C-6), 34.1 (C-20), 35.8 (C-16), 36.3 (C-17), 39.8 (C-15), 52.7 (C-5), 52.7 (OMe),
58.2 (C-19), 64.4 (C-3), 68. 3 (C-18), 93.3 (C-14), 110.8 (C-12), 111.8 (C-7), 118.2 (C-9), 119.7 (C-10),

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HETEROCYCLES, Vol. 71, No. 11, 2007
122.3 (C-11), 126.6 (C-8), 130.7 (C-2), 136.0 (C-13), 171.2 (COOMe); MS (EI) m/z (%): 370(100),
369(77.6), 355(14.9), 338(7.9), 309(48.7), 283(57.0), 268(27.6), 265(16.7), 251(7.0), 224(6.6), 213(29.8),
197(11.4), 184(37.7), 170(78.9), 156(18.4), 144(13.2); HRMS: calcd 370.1887 (for C21H26N2O4), found
370.1885 (delta: -0.5 ppm). Anal. Calcd: C, 68.08; H, 7.07; N, 7.56. Found: 67.54; H, 7.06; N, 7.51.
14,17-Epoxy-14-hydroxy-14,15-dihydro-1,14-secoeburnamenine-14-carboxylic acid methyl ester
(21): Colorless powder (0.17 g, 42%). mp 206 °C (from iPrOH); [α]D −160°, (c 1, CHCl3); IR (cm-1):
1
3326, 2938, 2858, 1744, 1518, 1465, 1432, 1318, 1254, 1187, 1105, 1063, 1025, 827, 748, 674, 546; H
NMR (CDCl3, δTMS=0.00 ppm; multiplicities set in italics indicate small, typically less than 2 Hz
couplings): 1.16 (3H, t, H3-21); 1.83 (1H, m, Hx-20); 1.89 (1H, d, Hx-15); 1.90 (1H, m, Hα-18); 1.99 (1H,
m, Hy-20); 2.29 (1H, ddd, Hβ-18); 2.40 (1H, d, Hy-15); 2.61 (1H, td, Hα-5); 2.68 (1H, t, Hα-19); 2.75 (1H,
dm, Hα-6); 3.01 (1H, m, Hβ-6); 3.12 (1H, m, Hβ-5); 3.39 (1H, ddd, Hβ-19); 3.74 (3H, s, OMe), 3.89 (1H, s,
H-3), 4.38 (1H, t, H(α)-17); 7.11 (1H, t, H-10); 7.17 (1H, t, H-11); 7.32 (1H, d, H-12); 7.47 (1H, d, H-9);
7.71 (1H, brs, NH), 9.50 (1H, brs, OH). [Structurally significant JH,H couplings: J19α 19β
,
= 10.0 Hz,
J19β,18α = 8.5 Hz, J19β,18β = 8.5 Hz, J
,
19α 18α = 10.0 Hz, J
,
19α 18β < 1 Hz, J18β,18α = 15.0 Hz, J17α,18β ~ J17α 18α ~
,
13
3 Hz]. C NMR (CDCl3, δTMS=0.0 ppm): 9.1 (C-21); 20.8 (C-6); 24.2 (C-18), 31.6 (C-20), 45.0 (C-15),
48.0 (C-19), 50.0 (C-16), 51.8 (C-5), 52.6 (OMe), 58.5 (C-3), 83.2 (C-19), 103.3 (C-14), 110.8 (C-12),
112.4 (C-7), 118.3 (C-9), 119.9 (C-10), 122.4 (C-11), 126.6 (C-8), 131.2 (C-2), 136.5 (C-13), 170.4
(COOMe); MS (EI) m/z (%): 370(86.8), 369(100), 355(10.5), 338(15.8), 311(36.0), 309(12.3), 283(7.0),
265(11.4), 251(6.1), 224(10.5), 197(74.6), 185(43.0), 170(45.6), 156(19.3), 143(7.9); HRMS: calcd
370.1887 (for C21H26N2O4), found 370.1880 (delta: -1.8 ppm). Anal. Calcd: C, 68.08; H, 7.07; N, 7.56.
Found: 67.77; H, 6.96; N, 7.49
18β-Hydroxyvincamine (5a) and 18β-hydroxy-14-epivincamine (5c)
To a solution of 8 (4g, 11.2 mmol) in toluene (800 mL) 3-chloroperbenzoic acid (77%, 6.0 g, 26 mmol)
was added. After 2 h stirring the solution was evaporated in vacuo and the residue was dissolved in 90%
AcOH (250 ml), the solution was stirred for 0.5 h, then triphenylphosphine (4.88 g, 18.6 mmol) was
added. The reaction mixture was stirred for 15 h, then water (240 mL) was added. The mixture was
washed with toluene (5×150 mL), then the pH was adjusted to 7 with NaHCO3 and
extracted with CH2Cl2 (2×160 mL). The combined organic layers were dried, filtered, and
concentrated in vacuo. The vincamine epimers were separated by column chromatography (eluent:
CH2Cl2/MeOH 10:1)
18β-Hydroxyvincamine (5a): 2.07 g, 49.6% (Rf=0.58). mp 202-203 °C (from MeOH); [α]D + 39.6º
(c 1, pyridine) (mp 250 °C, MeOH-acetone20; [α]D + 18º, pyridine20); IR (cm-1): 3464, 2951, 2852, 1729,
1
1617, 1458, 1435, 1327, 1260, 1213, 1168, 1108, 1082, 1041, 923, 736, 607, 530; H NMR (CDCl3,

HETEROCYCLES, Vol. 71, No. 11, 2007
2359
δTMS=0.00 ppm; multiplicities set in italics indicate small, typically less than 2 Hz couplings): 0.51 (3H, t,
H3-21); 1.41 (1H, dq, Hx-20); 1.61 (1H, t, Hax-17), 1.80 (1H, dd, Heq-17), 2.05 (1H, dq, Hy-20), 2.14 (1H,
d, Hx-15), 2.22 (1H, d, Hy-15), 2.26 (1H, t, Hax-19), 2.62 (1H, ddd, Heq-6), 2.87 (1H, dd, Heq-19), 2.91
(1H, m, Hax-6), 3.25-3.38 (2H, m, H2-5), 3.80 (3H, s, OMe), 3.93 (1H, m, H-18), 3.98 (1H, s, H-3), 7.05-
7.15 (3H, m, H-10,11,12), 7.45 (1H, dm, H-12). [JH,H couplings that verify the β (equatorial)
stereoposition of the 18-OH group: J18α(ax) 17ax
,
= 12.7 Hz, J18α(ax),17eq = 3.2 Hz, J18α(ax),19ax = 10.6 Hz,
J18α(ax) 19eq
,
= 3.5 Hz]; 13C NMR (CDCl3, δTMS=0.0 ppm): 7.58 (C-21), 16.5 (C-6), 29.6 (C-20), 34.4 (C-17),
36.2 (C-16), 43.6 (C-15), 43.9 (C-19), 50.0 (C-5), 51.3 (C-19), 54.2 (OMe), 58.1 (C-3), 63.64 (C-18),
81.8 (C-14), 105.7 (C-7), 110.5 (C-12), 118.6 (C-9), 120.5 (C-10), 122.1 (C-11), 128.5 (C-8), 129.3 (C-2),
134.4 (C-13), 173.8 (COOMe). The C-14 configuration is verified by the fact that a) ⎜δH-15x-δH-15y⎜=0.08
ppm25; b) δC-15=43.6 ppm25; MS (EI) m/z (%): 370(100), 369(36.8), 355(5.3), 341(4.4), 323(13.2),
311(22.4), 293(19.7), 284(18.4), 283(22.8), 268(59.6), 253(12.3), 224(19.3); HRMS: calcd 370.1887 (for
C21H26N2O4), found 370.1881 (delta: -1.6 ppm).
18β-Hydroxy-14-epivincamine (5c). 0.37 g, 9% (Rf=0.41). mp 214-215 °C (from MeOH); [α]D −58.4º
(c 1, pyridine); IR(cm-1): 3509, 2952, 2928, 1718, 1618, 1458, 1417, 1316, 1272, 1244, 1162, 1081, 1057,
750, 632, 534; 1H NMR (CDCl3, δTMS=0.00 ppm; multiplicities set in italics indicate small, typically less
than 2 Hz couplings): 0.92 (3H, t, H3-21), 1.24 (1H, t, Hax-17), 1.40 (1H, dq, Hx-20), 1.57 (1H, dd, Heq-
17), 2.02 (1H, dq, Hy-20), 2.10 (1H, d, Hx-15), 2.31 (1H, d, Hy-15), 2.31 (1H, t, Hax-19), 2.54 (1H, ddd,
Heq-6), 2.79 (1H, dd, Heq-19), 2.96 (1H, m, Hax-6), 3.20-3.32 (2H, m, H2-5), 3.72 (3H, s, OMe), 3.82 (1H,
s, H-3), 3.89 (1H, m, H-18), 7.05-7.18 (2H, m, H-10,11), 7.28 (1H, dm, H-12), 7.47 (1H, dm, H-12). [JH,H
couplings that verify the β (equatorial) stereoposition of the 18-OH group: J18α(ax) 17ax
,
= 11.9 Hz,
13
J18α(ax) 17eq = 3.5 Hz, J18α(ax),19ax = 10.2 Hz, J18α(ax),19eq = 4.5 Hz]. C NMR (CDCl3, δTMS=0.0 ppm): 7.64
,
(C-21); 16.6 (C-6); 30.2 (C-20); 34.2 (C-17); 37.5 (C-16); 46.7 (C-15); 50.5 (C-5); 52.4 (C-19); 53.6
(OMe); 57.9 (C-3); 64.5 (C-18); 82.2 (C-14); 106.3 (C-7); 111.7 (C-12); 118.3 (C-9); 120.4 (C-10); 121.8
(C-11); 128.6 (C-8); 130.8 (C-2); 135.3 (C-13); 172.8 (COOMe). The C-14 configuration is verified by
the fact that a) ⎜δH-15x-δH-15y⎜=0.21 ppm25; b) δC-15=46.7 ppm25; MS (EI) m/z (%): 370(100), 369(61.4),
352(2.6), 341(7.0), 323(18.4), 311(15.8), 309(19.3), 293(9.6), 284(8.8), 281(8.8), 268(91.7), 253(13.2),
224(15.8); HRMS: calcd 370.1887 (for C21H26N2O4), found 370.1878 (delta: -2.5 ppm).
14,16-Dihydroxy-1,2-dehydrovincadifformine N-oxide (24)
To a solution of 8 (1.4g, 3.9 mmol) in toluene (280 mL) 3-chloroperbenzoic acid (77%, 2.1 g, 9 mmol)
was added. After 2 h stirring the solution was evaporated in vacuo and the residue was dissolved in 90%
AcOH (85 ml), the solution was stirred for 0.5 h and diluted with water (80 mL) The mixture was
washed with toluene (5×40 mL), then the pH was adjusted to 7 with NaHCO3 and

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HETEROCYCLES, Vol. 71, No. 11, 2007
extracted with CH2Cl2 (2×30 mL). The combined organic layers were dried, filtered, and
concentrated in vacuo to obtain 0.77 g (50%) of 24. mp 194-195 °C (from MeOH); [α]D −104.5º, (c 1,
CHCl3); IR (cm-1): 3271, 2967, 1745, 1579, 1458, 1363, 1214, 1117, 1072, 1040, 874, 772, 752, 656,
572; NMR. 1H NMR (DMSO-d6, δTMS=0.00 ppm): 0.62 (3H, t, H3-18), 0.69 (1H, m, Hx-19), 0.90 (1H, m,
Hy-19), 1.48 (1H, dd, Hx-15), 1.65 (1H, d, Hy-15), 2.35 (1H, d, Hx-17),2.62 (1H, m, Hx-6), 2.84 (1H, m,
Hy-6), 3.19 (1H, d, Hy-17), 3.39 (1H, m, Hx-5), 3.50 (1H, s, H-21), 3.58 (1H, d, Hx-3), 3.75 (3H, s,
OCH3), 3.84 (1H, d, Hy-3), 4.17 (1H, brs, Hα-14); 4.59 (1H, m, Hy-5), 5.88 (1H, s, 14-OH), 6.90 (1H, s,
16-OH), 7.23 (1H, t, H-10), 7.30 (1H, t, H-11); 7.48 (1H, d, H-12), 8.12 (1H, d, H-9). [J couplings that
verify the β (axial) stereoposition of the 14-OH group: J15x,14α = 3.3 Hz, J15y,14α ~ 1.0 Hz, J3x,14α ~ 2.6 Hz,
J3y,14α ~ 1 Hz]; 13C NMR (CDCl3, δTMS=0.0 ppm): 7.0 (C-18), 33.0 (C-19), 35.0 (C-6), 35.9 (C-15), 37.1
(C-20), 42.0 (C-17), 52.2 (OMe), 59.4 (C-7), 64.0 (C-14), 68.3 (C-5), 68.8 (C-3), 73.6 (C-16), 89.9 (C-
21), 120.3 (C-12), 124.5 (C-9), 126.8 (C-10), 127.9 (C-11), 146.3 (C-8), 152.6 (C-13), 173.8 (COOMe),
182.9 (C-2); MS. FIB: [M+H]+ = 387, daughter ion spectrum of m/z=387 (%): 387(100), 370(48.5),
352(46.3), 341(11.8), 323(13.6), 310(44.1), 283(19.9), 268(12.5), 244(11.0), 214(5.9), 196(15.1),
170(10.3), 157(6.6), 140(10.3); HRMS (EI): calcd 386.1836 (for C21H26N2O5), found 386.1829 (delta: -
1.8 ppm).
Trans 18β-hydroxyvincamine (5b) and trans 18β-hydroxy-14-epivincamine (5d)
To a solution of 5a (1 g, 2.7 mmol) in AcOH (3 mL) sodium dichromate dihydrate (0.85 g, 2,8 mmol) in
AcOH (3 mL) was added and the mixture was stirred for 20 h. After addition of water (20 mL) and
CH2Cl2 (20 mL) the pH was adjusted to 9 with NH4OH solution. The organic layer was washed with
water (10 mL) and evaporated in vacuo. The residue was dissolved in MeOH (10 mL) and NaBH4 (0.1 g)
was added. After 1 h stirring the mixture was evaporated and the vincamine epimers were separated by
column chromatography (eluent: CH2Cl2/MeOH 10:1)
Trans 18β-hydroxy-3-epi-14-epivincamine (5d): 0.1 g, 10% (Rf=0.82). mp 199-200 °C (from
MeOH); IR (cm-1): 3518, 3233, 2944, 2926, 1742, 1644, 1449, 1386, 1309, 1265, 1201, 1147, 1064,
1
1031, 751, 654, 594; H NMR (CDCl3, δTMS=0.00 ppm; multiplicities set in italics indicate small,
typically less than 2 Hz couplings): 0.88 (3H, t, H3-21), 0.98 (1H, t, Hax-17); 1.30 (1H, dq, Hx-20), 1.61
(1H, dd, Hy-20), 1.71. (1H, br s, OH), 2.07 (1H, d, Hx-15), 2.13 (1H, 1, Hax-19); 2.28 (1H, dd, Heq-17);
2.32 (1H, d, Hy-15); 2.62 (1H, td, Hax-5); 2.72 (1H, ddd, Heq-6), 2.94 (1H, m, Hax-6), 2.99 (1H, s, H-3),
3.14 (1H, dd, Heq-5), 3.31 (1H, dd, Heq-19), 3.83 (3H, s, OMe), 4.14 (1H, m, H-18), 4.65 (1H, br s, OH),
7.10 (3H, m, H-10, 11,12), 7.44 (1H, dm, H-9). [JH,H couplings that verify the β (equatorial)
stereoposition of the 18-OH group: J18α(ax) 17ax
,
= 11.2 Hz, J18α(ax),17eq = 4.3 Hz, J18α(ax),19ax = 10.3 Hz,
J18α(ax) 19eq
,
= 4.4 Hz]; 13C NMR (CDCl3, δTMS=0.0 ppm): 7.07 (C-21), 20.7 (C-20), 21.3 (C-6), 36.9 (C-16),

HETEROCYCLES, Vol. 71, No. 11, 2007
2361
41.5 (C-17), 43.6 (C-15), 52.7 (C-5), 54.3 (OMe), 63.2 (C-19), 64.4 (C-18), 66.2 (C-3), 82.4 (C-14),
106.5 (C-7), 110.8 (C-12), 118.5 (C-9), 120.2 (C-10), 121.5 (C-11), 128.7 (C-8), 132.0 (C-2), 134.8 (C-
13), 174.0 (COOMe). The C-14 configuration is verified by the fact that δC-15=43.6 ppm25; MS (EI) m/z
(%): 370(100), 369(66.7), 355(36.0), 341(8.8), 324(10.5), 311(36.8), 309(23.7), 293(3.5), 281(12.3),
268(53.5), 253(24.6), 224(4.8); HRMS: calcd 370.1887 (for C21H26N2O4), found 370.1877 (delta: -2.7
ppm). Anal. Calcd: C, 68.08; H, 7.07; N, 7.56. Found: 67.86; H, 6.96; N, 7.49.
Trans 18β-hydroxy-3-epivincamine (5b): 0.05 g, 5% (Rf=0.73). IR (cm-1): 3392, 2948, 1749, 1655,
1
1576, 1445, 1386, 1310, 1257, 1200, 1144, 1062, 1031, 742, 651; H NMR (CDCl3, δTMS=0.00 ppm;
multiplicities set in italics indicate small, typically less than 2 Hz couplings): 0.68 (3H, t, H3-21), 0.95
(1H, t, Hax-17), 1.19 (1H, dq, Hx-20), 1.57 (1H, dd, Hy-20), 1.93 (1H, d, Hx-15), 2.08 (1H, dq, Hax-19),
2.18 (1H, dd, Heq-17), 2.54 (1H, td, Hax-5), 2.68 (1H, d, Hy-15), 2.69 (1H, ddd, Heq-6), 2.92 (1H, m, Hax-
6), 3.04 (1H, s, H-3), 3.08 (1H, dd, Heq-5), 3.25 (1H, dd, Heq-19), 3.74 (3H, s, OMe), 4.04 (1H, m, H-18),
7.08 (3H, m, H-10,11,12), 7.44 (1H, dm, H-9). [JH,H couplings that verify the β (equatorial) stereoposition
of the 18-OH group: J18α(ax) 17ax = 10.9 Hz, J18α(ax),17eq = 4.5 Hz, J18α(ax),19ax = 10.1 Hz, J18α(ax),19eq = 4.9
,
13
Hz]; C NMR (CDCl3, δTMS=0.0 ppm): 7.07 (C-21), 20.0 (C-20), 21.3 (C-6), 38.3 (C-16), 41.7 (C-17),
46.0 (C-17), 52.5 (C-5), 53.6 (OMe), 63.0 (C-19), 64.3 (C-18), 65.5 (C-3), 81.8 (C-14), 106.7 (C-7),
110.6 (C-12), 118.5 (C-9), 120.2 (C-10), 121.5 (C-11); 128.4 (C-8), 132.6 (C-2), 135.5 (C-13), 173.2
(COOMe). The C-14 configuration is verified by the fact that δC-15=46.0 ppm25; MS (EI) m/z (%):
370(100), 369(94.7), 355(8.8), 352(10.1), 341(9.2), 324(24.6), 311(26.3), 309(28.9), 293(3.9), 281(14.9),
268(67.5), 253(23.7); HRMS: calcd 370.1887 (for C21H26N2O4), found 370.1879 (delta: -2.1 ppm).
18β-Hydroxyvincamine (5a) 0.13 g, 13% (Rf=0.58) was also recovered.
ACKNOWLEDGEMENTS
The authors thank Dr. Tamás Gáti, dr. Viktor Háda, János Kóti and Erika Sziki for their contribution
regarding the NMR, MS and IR measurements.
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