Synthesis of vinca alkaloids and related compounds. Part 102: Simple synthesis and ring transformation of (±)-minovincine. First synthesis of (±)-vincaminine

Article abstract of DOI:10.1016/S0040-4020(03)00902-5

A molecule with an indole skeleton, containing a latent acrylic ester function - acting as a diene - readily reacted with benzoic acid (4-bromomethylene-5-oxo)hexyl ester that had been built up from pentane-2,4-dione. Dehydration of the enamine and subseq

Full text of DOI:10.1016/S0040-4020(03)00902-5

Tetrahedron 59 (2003) 5661–5666
Synthesis of vinca alkaloids and related compounds. Part 102:
Simple synthesis and ring transformation of (6)-minovincine.
First synthesis of (6)-vincaminineq
a
Gyorgy Kalaus, Laszlo Leder, Istvan Greiner, Maria Kajtar-Peredy, Karoly Vekey,
a,b
b
c
c
,
*
´
´ ´
´
´
´
´
´
¨
a
Lajos Szabo and Csaba Szantay
a,c
,
*
´
´
aDepartment for Organic Chemistry, Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences, Budapest University of
´
´
Technology and Economics, Gellert ter 4, H-1521 Budapest, Hungary
˝ ´
´
Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri ut 59-67, H-1025 Budapest, Hungary
b
¨
Chemical Works of Gedeon Richter Ltd, Gyomroi ut 19-21, H-1103 Budapest, Hungary
c
Received 4 April 2003; revised 9 May 2003; accepted 5 June 2003
´
Dedicated to Professor G. Bernath on the occasion of his 70th birthday
Abstract—A molecule with an indole skeleton, containing a latent acrylic ester function—acting as a diene—readily reacted with benzoic
acid (4-bromomethylene-5-oxo)hexyl ester that had been built up from pentane-2,4-dione. Dehydration of the enamine and subsequent [4þ2]
cycloaddition supplied epimers having the D-secoaspidospermane skeleton. These compounds directly or after epimerization gave (^)-
minovincine. Oxidative ring transformation of (^)-minovincine under different conditions led to (^)-16-acetyl-16-deethylapovincamine and
(^)-vincaminine.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
thought that benzoic acid (4-bromomethylene-5-oxo)hexyl
ester (10) met all synthetic requirements.
In 1997 we reported the first synthesis of (^)-3-oxomino-
vincine (1) from which we obtained (^)minovincine (2).2
Building on our experience in synthesizing alkaloids with
the aspidospermane skeleton as well as related com-
pounds,2–4 we saw a chance of producing 2 directly and
performing subsequent ring transformation. The successful
oxidative aspidospermane!eburnane skeleton transform-
ation may allow production of both 3 and 4 (Fig. 1).
Molecule 10 was prepared from pentane-2,4-dione (6).
Firstly 6 was alkylated with benzoic acid (3-iodo-propyl)
ester,5 then the diketoester (7) was allowed to react with
aqueous formaldehyde in the presence of potassium
2. Results and discussion
As a result of a retrosynthetic analysis of our convergent
synthetic strategies,2,3 an activated vinyl halide derivative
(aldehyde enol equivalent) was chosen as the reaction agent
of the tryptamine derivative (5),3 used earlier several times
successfully, by which Nb-alkylation could be realized. We
q Part 101, see Ref. 1.
Keywords: indoles; tryptamines; minovincine; vincaminine; alkaloids;
natural products; cycloaddition; total synthesis.
*
Corresponding authors. Address: Department for Organic Chemistry,
´ ´
Budapest University of Technology and Economics, Gellert ter 4, H-1111
Budapest, Hungary. Fax: þ36-1-463-3297;
e-mail: szantay@mail.bme.hu
Figure 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00902-5

5662
G. Kalaus et al. / Tetrahedron 59 (2003) 5661–5666
Scheme 3. Reagents and conditions: (a) H2, Pd/C, CH3COOH, rt, 95%;
(b) 15, KI, DMF, K, 2 h, 34%; (c) 16, KI, DMF, K, 4 h, 34%.
Scheme 1. Reagents and conditions: (a) 6, I(CH2)3OBz, K2CO3, KI,
acetone, K, 84%; (b) 7, CH2O, K2CO3, H2O, rt, 43%; (c) 8, Br2, CH2Cl2, rt,
92%; (d) 9, (nBu)4NF, HMPA, rt, 63%.
carbonate at rt6 giving the unsaturated derivative 8.
Addition of bromine to 8 led to 9 and subsequent
elimination of hydrogen bromide7 from 9 resulted in the
expected compound 10 (Scheme 1).
Scheme 4. Reagents and conditions: (a) 2, NCS, TFA, rt, 4 h then K, 3 h,
Ar, 50%; (b) 2, (HOOC–(CH2)2–COO)2, MeOH, H2O, cc. HCl, rt, dark,
39%.
a 1:1 mixture of the epimers (13 and 14) was isolated in 50%
yield (Scheme 2).
Subsequently, the secondary amine (5) was allowed to react
with vinyl halide (10) in methanol at rt in the presence of
N,N-diisopropyl-ethyl-amine. The expected8 enamine (11)
was obtained in 30% yield. The enamine 11 was refluxed in
xylene in the presence of p-toluenesulphonic acid to give-
via the non-isolable intermediate (12) as a [4þ2] cyclo-
addition-the tetracyclic compounds 13 and 14 having the
D-secoaspidospermane skeleton. The starting enamine (11)
disappeared from the reaction mixture on refluxing for 18 h,
The epimers 13 and 14 were separated by chromatography,
and the benzyl-group was removed at rt by catalytic
hydrogenolysis giving secondary amines 15 and 16.
Intramolecular N-alkylation (when boiling in the presence
of potassium iodide in dimethylformamide) we obtained
(^)-minovincine (2) directly or by epimerization9
(Scheme 3).
Minovincine (2) was then converted, by ring transformation
into the eburnane skeleton derivatives. When the reaction
was carried out with N-chlorosuccinimide in refluxing
trifluoroacetic acid,10 (^)-16-acetil-16-deethylapovinc-
amine (3) was obtained as the product. Using 4-(3-
carboxy-propionylperoxy)-4-oxobutyric acid11 in aqueous
methanolic hydrocholic acid,12 (^)-vincaminine13 (4) was
obtained as the product (Scheme 4).
3. Conclusion
By regioselective alkylation of the tryptamine derivative 5
with vinyl bromide 10, the enamine 11 was obtained.
Subsequent dehydration followed by intramolecular [4þ2]
cycloaddition resulted in compounds with the D-seco-
aspidospermane skeleton (13, 14). Hydrogenolysis of
tertiary amines led to secondary amines (15, 16), from
which (^)-minovincine (2) could be obtained by intra-
molecular alkylation. The aspidospermane!eburnane ring
transformation was realized in two ways. In the first case we
obtained compound 3, and the second case resulted in the
first synthesis of (^)-vincaminine (4).
Scheme 2. Reagents and conditions: (a) (iPr)2NEt, MeOH, rt, 30%; (b) 11,
TsOH, xylene, K, 22% for 13, 23% for 14.

G. Kalaus et al. / Tetrahedron 59 (2003) 5661–5666
5663
4. Experimental
filtered, and concentrated in vacuo. The main component
was separated by column chromatography (eluent: hexane/
ether 1:1) to yield a colourless oil (Rf¼0.59), which was
crystallized from methanol to afford 8 (2.3 g, 43%) as white
crystals. Mp 38–408C; IR (KBr) n: 1725 (ester CO), 1665
(CO), 1630 (CvC) cm21; dH (CDCl3): 1.92 (m, 2H,
CH2CH2O), 2.35 (s, 3H, COCH3), 2.44 (t, J¼7.0 Hz, 2H,
vC–CH2), 4.32 (t, J¼6.3 Hz, 2H, OCH2), 5.84þ6.06 (2£d,
Jgem¼1.6 Hz, 2£1H, CvCH2), 7.44 (m, 2H, PhC(3)-
HþPhC(5)-H), 7.56 (m, 1H, PhC(4)-H), 8.05 (m, 2H,
PhC(2)-HþPhC(6)-H) ppm; dC (CDCl3): 25.90 (COCH3),
27.30þ27.38 (vC–CH2CH2), 64.31 (OCH2), 125.80
(CvCH2), 128.35 (PhC-3þPhC-5), 129.55 (PhC-2þPhC-
6), 130.31 (PhC-1), 132.90 (PhC-4), 147.96 (CvCH2),
166.58 (OCOPh), 199.50 (COCH3) ppm; MS m/z (rel inten):
110 (48.0), 105 (100.0), 95 (25.0), 77 (51.0), 67 (28.0), 50
(8.0), 42 (23.0). Anal. calcd for C14H16O3: C, 72.39; H,
6.94; found C, 72.40; H, 7.01.
4.1. General
Melting points were determined with a hot-stage micro-
¨
scope Boetius and are given uncorrected. IR spectra were
recorded with a Specord JR-75 spectrophotometer. NMR
spectra were recorded with a Varian Unity INOVA-400
1
instrument at 400 MHz for H and 100 MHz for 13C. All
NMR spectra were registered at rt. The assignments denoted
by x, þ and p may be interchanged. Jlr, long range
coupling constant. Chemical shifts are relative to Me4Si
1
(d¼0 ppm). Mutual H–1H couplings are given only once,
at their first occurrences. MS spectra were determined on a
VG ZAB2-SEQ tandem mass spectrometer using electron
impact (70 eV) for ionization and direct probe for sample
introduction at source temperature of 1808C. Mass range m/z
25–620 was considered in low resolution spectra. Exact
mass measurements on molecular ions were carried out at
resolution of 10000. Preparative TLC analyses were
performed on silica gel F254 plates, and column chroma-
tography was carried out on Merck Kieselgel 60 (0.063–
0.200 mm). The organic layers were dried with MgSO4.
4.1.3. Benzoic acid (4-bromo-4-bromomethyl-5-oxo)-
hexyl ester (9). To a solution of 8 (2.5 g, 10.8 mmol) in
CH2Cl2 (50 mL) was added a solution of bromine (1.8 g,
0.6 mL, 11.7 mmol) in CH2Cl2 (5 mL) dropwise at rt. After
the solution was stirred for 1 h the excess bromine was
removed by washing with saturated Na2S2O3 solution until
the solution was discolored. The organic layer was
separated and washed with water (20 mL), dried and
concentrated in vacuo. The residue was crystallized from
methanol to yield 9 (3.9 g, 92%) as white crystals. Mp 50–
528C; IR (KBr) n: 1730 (ester CO), 1720 (CO) cm21; dH
(CDCl3): 1.90þ2.04 (2£m, 2£1H, CH2CH2O), 2.34 (m, 2H,
CH2CH2CH2O), 2.47 (s, 3H, COCH3), 3.85þ4.09 (2£d,
Jgem¼10.7 Hz, 2£1H, C–CH2–Br), 4.41 (m, 2H, OCH2),
7.45 (m, 2H, PhC(3)-HþPhC(5)-H), 7.57 (m, 1H, PhC(4)-
H), 8.05 (m, 2H, PhC(2)-HþPhC(6)-H) ppm; dC (CDCl3):
24.36 (COCH3), 24.39 (CH2CH2O), 32.27 (CH2CH2CH2O),
34.09 (C–CH2–Br), 64.07 (OCH2), 67.43 (Br–C–CH2Br),
128.41 (PhC-3þPhC-5), 129.59 (PhC-2þPhC-6), 130.06
(PhC-1), 133.04 (PhC-4), 166.48 (OCOPh), 199.44
(COCH3) ppm; MS m/z (rel inten): 313 (11.0), 311 (11.0),
271 (3.0), 189 (10.0), 110 (35.0), 105 (100.0), 95 (20.0),
77 (52.0), 67 (23.0), 42 (42.0). Anal. calcd for C14H16Br2O3:
C, 42.89;H, 4.11; Br, 40.76;found C, 42.92;H, 4.28; Br40.75.
4.1.1. Benzoic acid (4-acetyl-5-oxo)hexyl ester (7). To a
solution of benzoic acid (3-iodopropyl) ester5 (10.3 g,
35.5 mmol) in anhydrous acetone (120 mL) was added
pentane-2,4dione (4.8 g, 48.0 mmol) and anhydrous K2CO3
(7.1 g, 51.6 mmol). The heterogeneous reaction mixture
was refluxed for 48 h then was filtered and evaporated in
vacuo. The main component was separated by column
chromatography (eluent: hexane/acetone 5:1) to yield 7
(7.8 g, 84%) as a yellow oil (Rf¼0.34). IR (neat) n: 1720
(ester CO), 1715–1680 (CO) cm21; oxo-form dH (CDCl3):
1.73 (m, 2H, CH2CH2O), 2.01 (m, 2H, CHCH2), 2.20 (s, 6H,
2£COCH3), 3.70 (t, J¼7.2 Hz, 1H, CHCH2), 4.33 (t,
J¼6.3 Hz, 2H, OCH2), 7.4–7.6 (m, 3H, PhC(3)-
HþPhC(5)-HþPhC(4)-H), 8.05 (m, 2H, PhC(2)-
HþPhC(6)-H); enol-form: 1.89 (m, 2H, CH2CH2O), 2.17
(s, 6H, 2£CH3), 2.41 (m, 2H, vC–CH2), 4.36 (t, J¼6.3 Hz,
2H, OCH2), 7.4–7.6 (m, 3H, PhC(3)-HþPhC(5)-
HþPhC(4)-H), 8.05 (m, 2H, PhC(2)-HþPhC(6)-H), 16.73
(enol-OH) ppm, (oxo-enol tautomeric ratio ,4:3); oxo-
form: dC (CDCl3): 24.71 (CH2CH2O), 26.70 (CHCH2),
29.10 (2£COCH3), 64.15 (OCH2), 68.29 (CHCH2), 128.43
(PhC-3þPhC-5), 129.48 (PhC-2þPhC-6), 130.17 (PhC-1),
133.07 (PhC-4), 166.52 (OCOPh), 203.84 (2£COCH3);
enol-form: 22.85 (2£CH3), 24.22 (CH2CH2O), 29.68 (vC–
CH2), 64.18 (OCH2), 109.36 (vC–CH2), 128.48 (PhC-
3þPhC-5), 129.57 (PhC-2þPhC-6), 130.15 (PhC-1), 133.04
4.1.4. Benzoic acid (4-bromomethylene-5-oxo)hexyl ester
(10). To a homogeneous solution of tetrabutylammonium
fluoride monohydrate (2.6 g, 9.3 mmol) in HMPA (5 mL)
was added a solution of 9 (3.0 g, 7.65 mmol) in HMPA
(10 mL) over a 15 min period at 08C. After being stirred for
12 h at rt, the brown mixture was cooled (08C) and quenched
with an aqueous solution of sulphuric acid (15 mL, 1 M) and
then extracted with hexane (5£20 mL). The combined
organic extracts were washed with water until neutrality of
the aqueous layer. The organic layer was dried and
concentrated in vacuo. The main component was separated
by column chromatography (eluent: hexane/ether 1:1) to
yield 10 (1.5 g, 63%) as a yellow oil (Rf¼0.68). IR (neat) n:
1710 (ester CO), 1665 (CO), 1590 (CvC) cm21; dH
(CDCl3): 1.90 (m, 2H, CH2CH2O), 2.33 (s, 3H, COCH3),
2.66 (m, 2H, vC–CH2), 4.32 (t, J¼6.3 Hz, 2H, OCH2),
7.44 (m, 2H, PhC(3)-HþPhC(5)-H), 7.55 (s, 1H, CvCH–
Br), 7.56 (m, 1H, PhC(4)-H), 8.06 (m, 2H, PhC(2)-
(PhC-4),
166.54
(OCOPh),
191.09
(COCH3þ
vC(OH)CH3) ppm; MS m/z (rel inten): 262 (5.0), 219
(3.0), 140 (15.0), 125 (24.0), 105 (100.0), 98 (35.0), 83
(18.0), 77 (39.0), 43 (86.0); HRMS calcd for [C15H18O4–
H]þ 263.1283; found 263.1268.
4.1.2. Benzoic acid (4-methylene-5-oxo)hexyl ester (8).
To a mixture of 7 (6.0 g, 22.9 mmol) and 30% aqueous
formaldehyde (4.6 mL) was added a solution of K2CO3
(6.3 g, 45.6 mmol) in water (4.3 mL) at rt. The hetero-
geneous reaction mixture was stirred for 12 h then diluted
with water (60 mL), and the solution was extracted with
ether (3£35 mL). The combined organic layers were dried,
HþPhC(6)-H) ppm;
NOE:
2.33
(COCH3)!7.55

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G. Kalaus et al. / Tetrahedron 59 (2003) 5661–5666
(CvCHBr) ppm;dC (CDCl3):25.63þ26.81(CH2CH2CH2O),
26.13 (COCH3), 64.38 (OCH2), 125.33 (CvCHBr), 128.36
(PhC-3þPhC-5), 129.59 (PhC-2þPhC-6), 130.41 (PhC-1),
132.87 (PhC-4), 146.58 (CvCHBr), 166.55 (OCOPh),
194.80 (COCH3) ppm; HRMS calcd for [C14H15BrO3–
H]þ 311.0283; found 311.0267.
J10,11¼7.3 , J10,12¼1.0 Hz, 1H, 10-H), 7.16 (ddd,
J9,11¼1.2 Hz, 1H, 11-H), 7.19 (br d, 1H, 9-H), 7.20–7.60
(m, 8H, 200-Hþ300-Hþ400-H0þ500-Hþ600-Hþ30-Hþ40-Hþ50-
H), 7.92 (m, 2H, 20-Hþ6 -H), 8.74 (br s, 1H, N(1)-
H) ppm; dC (CDCl3): 25.31 (C-14), 26.00 (COCH3), 28.99
(C-17), 29.65 (C-15), 42.53 (C-6), 51.07 (OCH3), 53.05
(C-5), 58.69x (C-7), 59.64x (C-20), 61.66 (NCH2Ph), 64.83
(C-3), 68.35 (C-21), 89.84 (C-160)0, 109.51 (C-12), 121.19
(C-10), 122.04 (C-9), 127.18 (C-40 ), 127.74 (C-110)0, 128.35
(C-300þC-500), 128.37 (C-30þC-50), 128.52 (C-2 þC-600),
129.52 (C-20þC-60), 130.06 (C-1 ), 132.89 (C-40), 137.38
(C-8), 139.36 (C-100), 142.52 (C-13), 166.52 (OCOPh),
167.11 (C-2), 167.90 (16-COOCH3), 211.74 (COCH3) ppm;
HRMS calcd for [C35H36N2O5–H]þ 565.2702; found
565.2734. The less polar compound (rac-14, Rf¼0.42)
was obtained as white crystals after crystallization from
methanol (0.22 g, 23%). Mp 169–1718C; IR (KBr) n: 3392
(indole-NH), 1720 (ester CO), 1688 (CO), 1648 (conj. ester
CO), 1612 (CvC) cm21; dH (CDCl3): 0.98þ1.82 (2£ddd,
Jgem¼13.5 Hz, J14,15¼12.5þ4.5, 4.0þ12.0 Hz, respectively,
2£1H, 15-H2), 1.33þ1.51 (2£m, 2£1H, 14-H2), 1.69þ2.20
(2£dd, Jgem¼12.1 Hz, J5,6¼5.5þ1.0, 12.0þ6.7 Hz, respect-
ively, 2£1H, 6-H2), 2.45 (s, 3H, COCH3), 2.66þ2.98 (2£ddd,
Jgem¼9.8 Hz, 2£1H, 5-H2), 2.93þ2.96 (2£d, Jgem¼15.0 Hz,
2£1H, 17-H2), 3.28 (br s, 1H, 21-H), 3.64þ4.09 (2£d,
Jgem¼13.4 Hz, 2£1H, NCH2Ph), 3.77 (s, 3H, COOCH3),
4.04þ4.13 (2£ddd, Jgem¼10.6 Hz, J3,14¼5.7þ6.8, 6.0þ
6.2 Hz, respectively, 2£1H, 3-H2), 6.76–6.88 (m, 3H,
9-Hþ10-Hþ12-H), 7.10–7.470 (m, 8H, 11-Hþ200-Hþ300-
Hþ400-Hþ500-Hþ600-Hþ30-Hþ5 -H), 7.54 (m, 1H, 40-H),
7.95 (m, 2H, 20-Hþ60-H), 8.91 (br s, 1H, N(1)-H) ppm; dC
(CDCl3): 23.47 (C-14), 23.98 (C-17), 30.42 (C-15), 31.21
(COCH3), 40.78 (C-6), 51.10 (OCH3), 51.85 (C-5), 56.87x
(C-20), 57.84x (C-7), 61.06 (NCH2Ph), 64.74 (C-3), 76.83
(C-21), 89.11 (C-16), 109.41 (C-12), 120.96 (C-100)0, 122.73
(C-9), 127.09 (C-400), 128.13 (C-11), 128.25 (C-3 þC-500),
1028.31 (C-30þC-50), 129.13 (C-200þC-600), 129.54 (C-20þC-
6 ), 130.39 (C-10), 132.75 (C-40), 136.84 (C-8), 138.41 (C-100),
142.79 (C-13), 164.79 (C-2), 166.33 (OCOPh), 168.26 (16-
COOCH3), 213.64 (COCH3) ppm; MS: m/z (rel inten): 564
(0.8) [Mþ], 521 (0.4), 350 (16), 227 (9.0), 105 (45.0), 91
(100.0), 77 (15.0). Anal. calcd for C35H36N2O5: C, 74.45; H,
6.43; N, 4.96; found C, 74.32; H, 6.65; N, 5.02.
4.1.5. Enamine (11). To a mixture of 53 (1.0 g, 2.84 mmol)
and N,N-diisopropylethylamine (1.0 g, 7.75 mmol) in
anhydrous methanol (200 mL) was added a solution of 10
(1.0 g, 3.21 mmol) in anhydrous methanol (20 mL) drop-
wise at rt. After being stirred for 48 h at rt the reaction
mixture was concentrated in vacuo. The residue was
purified by column chromatography (eluent: hexane/
acetone 3:1) to yield 11 (0.49 g, 30%) as a yellow
amorphous solid (Rf¼0.31). IR (neat) n: 3450–3260
(indole-NHþOH), 1735 (ester CO), 1720 (CO), 1630
(conj. ester CO), 1580 (CvC) cm21; dH (CDCl3): 1.78
(m, 2H, CH2CH2O), 2.01 (s, 3H, COCH3), 2.51 (m, 2H,
vC–CH2), 2.92–3.07 (m, 2H, 3-CH2), 3.50 (t, J¼7.0 Hz,
2H, 3-CH2CH2N), 3.67 (s, 3H, OCH3), 3.95–4.17 (m, 3H,
2-CHCH2OH), 4.24 (t, J¼6.3 Hz, 2H, OCH2), 4.42 (s, 2H,
NCH2Ph), 7.08 (m, 1H, 5-H), 7.09 (m, 2H, 200-Hþ600-H),
7.17 (m, 1H,06-H), 7.24 (s, 1H, CvCH), 7.25–7.42 (m, 7H,
4-Hþ7-Hþ3 -Hþ50-Hþ300-Hþ400-Hþ500-H), 7.50 (m, 1H,
40-H), 7.89 (m, 2H, 20-Hþ60-H), 8.92 (br s, 1H, indole-
NH) ppm; dC (CDCl3): 21.04 (3-CH2), 23.91x (CH2CH2O),
24.85 (COCH3), 29.93x (CH2CH2CH2O), 44.77 (2-CH),
52.55 (OCH3), 54.11 (3-CH2CH2N), 56.00 (NCH2Ph), 63.80p
(2-CHCH2OH), 65.02p (CH2OCOPh), 109.72þ (NCHvC),
110.22þ (C-3), 111.35 (C-7), 118.05 (C-4), 119.68 (C-5),
122.36 (C-6), 126.83 (C-200þC-600), 127.26 (C-3a), 127.73
(C-4000), 1208.24 (C-30þC-50), 128.88 (C-300þC-500), 129.40
(C-2 þC-6 ), 129.87 (C-2), 130.22 (C-10), 132.73 (C-40),
135.73 (C-7a), 137.18 (C-100), 150.47 (NCHvC), 166.66
(OCOPh), 172.50 (COOCH3), 196.82 (COCH3) ppm; HRMS
calcd for [C35H38N2O6–H]þ 583.2808; found 583.2847.
4.1.6. (6)-20-Acetyl-4-benzyl-3-benzoyloxy-20-deethyl-
2,16-didehydro-16-methoxycarbonyl-3,4-secoaspido-
spermidine (20a, 21a) (13) and (6)-20-acetyl-4-benzyl-
3-benzoyloxy-20-deethyl-2,16-didehydro-16-(methoxy-
carbonyl)-3,4-secoaspidospermidine (20b, 21a) (14). A
solution of 11 (1.0 g, 1.72 mmol) and p-toluenesulphonic
acid monohydrate (0.01 g, 0.05 mmol) in xylene (50 mL)
was refluxed under argon for 24 h. The reaction mixture was
extracted with brine (2£50 mL) and the combined brine
washes were extracted with CH2Cl2 (2£50 mL). The
combined organic layers were dried and evaporated in
vacuo. The two main components were separated by column
chromatography (eluent: hexane/ether 1:1). The more polar
compound (rac-13, Rf¼0.23) was obtained as a yellow
amorphous solid (0.21 g, 22%). IR (neat) n: 3398 (indole-
NH), 1722 (ester CO), 1680 (CO), 1640 (conj. ester CO),
1620 (CvC) cm21; dH (CDCl3): 1.61þ1.82 (2£m, 2£1H,
14-H2), 1.74þ2.04 (2£ddd, Jgem¼12.2 Hz, J5,6¼5.5þ1.3,
11.9þ6.6 Hz, respectively, 2£1H, 6-H2), 1.99 (s, 3H,
COCH3), 1.93þ2.35 (2£m, 2£1H, 15-H2), 2.67þ2.95
(2£d, Jgem¼15.5 Hz, 2£1H, 17-H2), 2.67þ3.02 (2£ddd,
Jgem¼9.8 Hz, 2£1H, 5-H2), 3.78þ4.23 (2£d, Jgem¼13.4 Hz,
2£1H, NCH2Ph), 3.79 (s, 3H, OCH3), 4.04 (d, Jlr¼2.0 Hz,
1H, 21-H), 4.21 (t, J¼6.5 Hz, 2H, 3-H2), 6.81 (d,
J11,12¼7.8 Hz, 1H, 12-H), 6.94 (ddd, J9,10¼7.5 Hz,
4.1.7. (6)-20-Acetyl-3-benzoyloxy-20-deethyl-2,16-dide-
hydro-16-methoxycarbonyl-3,4-secoaspidospermidine
(20a, 21a) (15). A mixture of rac-13 (0.5 g, 0.89 mmol)
and 10% palladium/charcoal (0.25 g) in glacial acetic acid
(10 mL) was hydrogenated for 1 h at rt and then filtered. The
filtrate was poured into ice-water (50 mL) and neutralized
with saturated Na2CO3 solution. The solution was extracted
with CH2Cl2 (3£50 mL) and the combined organic layers
were dried and evaporated in vacuo. The main component
was separated by preparative TLC (eluting with CH2Cl2/
methanol 20:1) to yield rac-15 (0.40 g, 95%) as a yellow oil
(Rf¼0.42). IR (neat) n: 3424 (indole-NH), 2928, 2880, 1716
(ester CO), 1680 (CO), 1652 (conj. ester CO), 1608
(CvC) cm21; dH (CDCl3): 1.43þ1.78 (2£m, 2£1H, 14-
H2), 1.80þ1.88 (2£m, 2£1H, 6-H2), 1.80þ2.08 (2£m,
2£1H, 15-H2), 1.97 (s, 3H, COCH3), 2.44þ2.86 (2£d,
Jgem¼15.4 Hz, 2£1H, 17-H2), 3.14þ3.23 (2£ddd, Jgem¼9.5
Hz, J5,6¼6.2þ1.2, 11.8þ5.0 Hz, respectively, 2£1H, 5-H2),
3.70 (br s, 1H, N(4)-H), 3.77 (s, 3H, OCH3), 4.29 (t,

G. Kalaus et al. / Tetrahedron 59 (2003) 5661–5666
5665
J3,14¼6.3 Hz, 2H, 3-H2), 4.30 (d, Jlr¼2.0 Hz, 1H, 21-H),
6.81 (d, 1H, 12-H), 6.95 (dd, 1H, 10-H), 7.18 (dd, 1H, 11-
H), 7.28 (d, 1H, 9-H), 7.45 (m, 02H, 30-Hþ50-H), 7.58 (m,
1H, 40-H), 8.02 (m, 2H, 20-Hþ6 -H), 8.78 (br s, 1H, N(1)-
H) ppm; dC (CDCl3): 24.58 (C-14), 25.34 (COCH3), 28.09
(C-17), 29.72 (C-15), 44.46 (C-6), 45.14 (C-5), 51.05
(OCH3), 57.12x (C-20), 58.41x (C-7), 60.82 (C-21), 64.78
(C-3), 89.33 (C-16), 109.50 (C-12), 121.18 (C-10), 121.34
(C-9), 127.64 (C-11), 128.45 (C-300þC-50), 129.54
(C-20þC-60), 130.22 (C-10), 133.04 (C-4 ), 137.88 (C-8),
142.56 (C-13), 166.58 (OCOPh), 167.85 (16-COOCH3),
167.94 (C-2), 211.65 (COCH3) ppm; HRMS calcd for
C28H30N2O5 474.2155; found 474.2161.
aqueous NaOH solution (2£50 mL, 2 M). The organic layer
was dried and evaporated in vacuo. The residue was purified
by preparative TLC (eluting with hexane/acetone 1:1) to
yield a yellow oil (Rf¼0.42), which was crystallized from
ether to afford rac-3 (49 mg, 50%) as pale-yellow crystals.
Mp 154–1568C; IR (KBr) n: 2920, 1736 (CO), 1712 (conj.
ester CO), 1632, 1608 (CvC) cm21
; dH (CDCl3):
1.05þ2.19 (2£ddd, Jgem¼13.5 Hz, J14,15¼12.8þ4.5,
3.3þ2.8 Hz, respectively, 2£1H, 15-H2), 1.39–1.54 (m,
2H, 14-H2), 2.48 (s, 3H, COCH3), 2.53þ3.03 (2£m, 2£1H,
6-H2), 2.60–2.66 (m, 2H, 3-H2), 3.29–3.40 (m, 2H, 5-H2),
3.95 (s, 3H, OCH3), 4.90 (br s, 1H, 21-H), 6.01 (s, 1H,
17-H), 7.15 (m, 1H, 10-H), 7.18 (m, 1H, 11-H), 7.24 (m, 1H,
12-H), 7.48 (m, 1H, 9-H) ppm; dC (CDCl3): 16.35 (C-6),
22.16 (C-14), 26.80 (COCH3), 28.47 (C-15), 44.70 (C-3),
51.46 (C-5), 51.88 (C-20), 52.75 (OCH3), 53.53 (C-21),
109.78 (C-7), 112.58 (C-12), 118.41 (C-9), 120.74 (C-10),
121.21 (C-17), 122.35 (C-11), 129.24þ129.32þ129.75þ
134.07 (C-2þC-8þC-13þC-16), 163.29 (16-COOCH3),
208.79 (COCH3) ppm; HRMS calcd for C21H22N2O3
350.1630; found 350.1647.
4.1.8. (6)-20-Acetyl-3-benzoyloxy-20-deethyl-2,16-dide-
hydro-16-methoxycarbonyl-3,4-secoaspidospermidine
(20b, 21a) (16). The procedure was same as in the case of
compound 15 to yield rac-16 (0.40 g, 95%) as a yellow oil
(Rf¼0.48). IR (neat) n: 3368 (indole-NH), 2928, 2880, 1716
(ester CO), 1670 (CO), 1645 (conj. ester CO), 1608
(CvC) cm21; dH (CDCl3): 1.20þ1.47 (2£ddd, Jgem¼13.5
Hz, J14,15¼12.0þ3.8, 12.0þ2.8 Hz, respectively, 2£1H, 15-
H2), 1.30þ1.57 (2£m, 2£1H, 14-H2), 1.78þ1.96 (2£m,
2£1H, 6-H2), 1.80 (br s, 1H, N(4)-H), 2.28 (s, 3H, COCH3),
2.59þ2.93 (2£d, Jgem¼15.8 Hz, 2£1H, 17-H2), 3.03–3.13
(m, 2H, 5-H2), 3.75 (d, Jlr¼1.8 Hz, 1H, 21-H), 3.77 (s, 3H,
OCH3), 4.05þ4.09 (2£ddd, Jgem¼10.9 Hz, J3,14¼6.5þ5.5,
6.3þ5.5 Hz, respectively, 2£1H, 3-H2), 6.80 (d,
J11,12¼7.8 Hz, 1H, 12-H), 6.90 (ddd, J9,10¼7.5 Hz,
J10,11¼7.6 Hz, J10,12¼1.0 Hz, 1H, 10-H), 7.17 (ddd,
J9,11¼1.3 Hz, 1H, 11-H), 7.18 (br d, 1H, 9-H), 7.42 (m,
2H, 30-Hþ50-H), 7.55 (m, 1H, 40-H), 7.91 (m, 2H, 20-Hþ60-
H), 8.96 (br s, 1H, N(1)-H) ppm; dH (CDCl3): 22.20 (C-14),
23.60 (C-17), 28.80 (COCH3), 29.93 (C-15), 44.37 (C-6),
45.22 (C-5), 51.11 (OCH3), 56.82x (C-20), 58.00x (C-7),
64.45 (C-3), 68.95 (C-21), 89.61 (C-16), 109.49 (C-12),
120.96 (C-10), 121.82 (C-9), 0 128.16 (C-11), 128.32
(C-300þC-50), 129.50 (C-20þC-6 ), 130.21 (C-10), 132.88
(C-4 ), 137.31 (C-8), 143.03 (C-13), 165.58 (C-2), 166.28
(OCOPh), 168.53 (16-COOCH3), 212.66 (COCH3) ppm;
HRMS calcd for C28H30N2O5 474.2155; found 474.2142.
4.1.11. (6)-Vincaminine (4). To a mixture of rac-2 (0.10 g,
0.28 mmol), water (2.5 mL) and methanol (7.5 mL) was
added conc. HCl (56.5 mL, 0.68 mmol, 2.4 equiv.) and 4-(3-
carboxy-propionylperoxy)-4-oxobutyric acid11 (80.0 mg,
0.34 mmol, 1.2 equiv.). The solution was stirred for 24 h
at rt, protecting from light, then the pH of the mixture was
adjusted to 8 with 25% NH4OH solution. After that, the
solution was extracted with ether (2£20 mL) and with
CH2Cl2 (2£20 mL). The combined organic layers were
dried and evaporated in vacuo. The main component was
separated by preparative TLC (eluting with hexane/acetone/
triethylamine 2:1:0.1) to yield a yellow oil (Rf¼0.35), which
was crystallized from acetone to afford rac-4 (40 mg, 39%)
as pale-yellow crystals. Mp 203–2058C; (205–2068C,
acetone13a); IR (KBr) n: 3440 (OH), 2952, 2880, 1744
(ester CO), 1708 (CO) cm21; dH (CDCl3): 1.45þ1.55 (2£m,
2£1H, 14-H2), 1.84þ2.14 (2£dm, Jgem¼14.2 Hz, 2£1H, 15-
H2), 2.16þ2.39 (2£d, Jgem¼13.8 Hz, 2£1H, 17-H2), 2.40 (s,
3H, COCH3), 2.52þ2.63 (2£m, 2£1H, 3-H2), 2.60þ3.01
(2£dm, Jgem¼16.0 Hz, 2£1H, 6-H2), 3.35þ3.39 (2£ddd,
Jgem¼14.0 Hz, J5,6¼6.8þ1.0, 11.4þ5.3 Hz, respectively,
2£1H, 5-H2), 3.82 (s, 3H, OCH3), 4.73 (br, 1H, 16-OH),
4.84 (br s, 1H, 21-H), 7.08 (m, 1H, 12-H), 7.02–7.17 (m,
2H, 10-Hþ11-H), 7.49 (m, 1H, 9-H) ppm; NOE: 4.84 (21-
Ha)!2.40 (COCH3), 2.39 (17-Ha), 3.39 (5-Ha); 4.72 (16-
OH)!7.08 (12-H), 2.16 (17-Hb) ppm; dC (CDCl3): 17.01
(C-6), 23.05 (C-14), 25.55 (C-15), 25.75 (COCH3), 42.97
(C-17), 44.32 (C-3), 49.88 (C-20), 50.84 (C-5), 54.52
(OCH3), 54.69 (C-21), 81.86 (C-16), 106.77 (C-7), 110.35
(C-12), 118.59 (C-9), 120.54 (C-10), 121.98 (C-11), 129.15
(C-8), 130.62 (C-2), 134.24 (C-13), 173.68 (16-COOCH3),
210.34 (COCH3) ppm. Anal. calcd for C21H24N2O4: C,
68.46; H, 6.57; N, 7.60; found C, 68.39; H, 6.61; N, 7.31;
HRMS calcd for C21H24N2O4 368.1736; found 368.1729.
4.1.9. (6)-Minovincine (2). Method A: A mixture of rac-15
(0.20 g, 0.42 mmol) and KI (0.07 g, 0.42 mmol) in
anhydrous DMF (10 mL) was refluxed for 2 h, then was
evaporated in vacuo. The main component was purified by
preparative TLC (eluting with hexane/acetone 3:1) to yield
a yellow oil (Rf¼0.41), which was crystallized from
methanol to afford rac-2 (0.05 g, 34%) as white crystals.
Method B: A mixture of rac-16 (0.20 g, 0.42 mmol) and KI
(0.07 g, 0.42 mmol) in anhydrous DMF (10 mL) was
refluxed for 4 h, then was worked up as in the case of
compound 15 to yield rac-2 (0.05 g, 34%) as white crystals.
In both cases the melting points and the spectroscopic data
are agreement with those reported previously.2
4.1.10. (6)-16-Acetyl-16-deethyl-apovincamine (3). A
mixture of rac-2 (0.10 g, 0.28 mmol) and N-chlorosuccini-
mide (37 mg, 0.28 mmol) in dry trifluoroacetic acid (10 mL)
was stirred under argon at rt for 4 h, then refluxed for 3 h.
After that, the solution was evaporated in vacuo, the residue
was diluted with ethylacetate (100 mL) and extracted with
Acknowledgements
The authors are grateful to the National Scientific Research
Foundation(OTKAT31920)forfinancialsupportofthiswork.

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9. Kalaus, I. Gy.; Juhasz, J.; Eles, I.; Greiner, M.; Kajtar-Peredy,
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