Synthesis of vinca alkaloids and related compounds. Part 101: A new convergent synthetic pathway to build up the aspidospermane skeleton. Simple synthesis of 3-oxovincadifformine and 3-oxominovincine. Attempts to produce 15β-hydroxyvincadifformine

Article abstract of DOI:10.1016/S0040-4020(02)01179-1

A molecule with an indole skeleton, containing a latent acrylic ester function - acting as a diene - was produced from N_b-trityl-2-(hydroxy-methyl)-tryptamine and reacted with esters containing an aldehyde or aldehyde-equivalent structural unit, yielding 3-oxo-16,17-dihydro-Δ²⁰-secodin-17-ol type intermediates from which dehydration, followed by [4+2]cycloaddition, furnished 3-oxovincadifformine and 3-oxominovincine. We also wished to apply the method to produce 15β-hydroxyvincadifformine, however, the appearance of a dimeric product with indole skeleton was observed instead of the expected cycloaddition.

Full text of DOI:10.1016/S0040-4020(02)01179-1

Tetrahedron 58 (2002) 8921–8927
Synthesis of vinca alkaloids and related compounds. Part 101: A
new convergent synthetic pathway to build up the aspidospermane
skeleton. Simple synthesis of 3-oxovincadifformine and
3-oxominovincine. Attempts to produce
15b-hydroxyvincadifformineq
a,b
Janos Eles, Gyorgy Kalaus, Istvan Greiner, Maria Kajtar-Peredy, Pal Szabo, Lajos Szabo
a
b
c
c
a
,
´
*
´
´
´
and Csaba Szantay
´
´
´
´
¨
a,c
,
*
´
a
´
´
Department for Organic Chemistry, Budapest University of Technology and Economics, Gellert ter 4, H-1111 Budapest, Hungary
˝ ´
´
Chemical Research Center, Institute of Chemistry, 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 9 July 2002; revised 28 August 2002; accepted 19 September 2002
Abstract—A molecule with an indole skeleton, containing a latent acrylic ester function—acting as a diene—was produced from Nb-trityl-2-
(hydroxy-methyl)-tryptamine and reacted with esters containing an aldehyde or aldehyde-equivalent structural unit, yielding 3-oxo-16,17-
dihydro-D20-secodin-17-ol type intermediates from which dehydration, followed by [4þ2]cycloaddition, furnished 3-oxovincadifformine
and 3-oxominovincine. We also wished to apply the method to produce 15b-hydroxyvincadifformine, however, the appearance of a dimeric
product with indole skeleton was observed instead of the expected cycloaddition. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
successfully produced (Fig. 1). We note here that the
subsequent formation of ring D caused problems in
particular cases.9 This work aims at developing a simple
synthetic strategy in the biomimetic way to build up the
aspidospermane skeleton through stable 3-oxo-16,17-
dihydro-D20-secodin-17-ol derivatives. In our publication,
Earlier, Kuhne et al. developed a simple entry2 into
alkaloids and related compounds with the aspidospermane
skeleton. Their synthetic strategy was based on the reaction
of appropriately formed aldehyde and indolazepine ester. In
this reaction, reactive and occasionally easily dimerizing3
secodine-type intermediates are generated, from which the
aspidospermane skeleton can be easily formed. In our
former publications4–8 we also reported on an effective
convergent synthetic pathway in which a reaction of
appropriately arranged aldehyde or aldehyde-equivalent
and Nb-benzyl-tryptamine derivative results in molecules
with the D-seco-aspidospermane skeleton. Ring D was
obtained by intramolecular acylation or alkylation. By
means of this method, numerous alkaloids and alkaloid-like
molecules with the aspidospermane and c-aspidospermane
skeleton, such as 3-oxovincadifformine (4), vincadifformine
(6), 3-oxominovincine (5) and minovincine (7), were
q For Part 100, see Ref. 1.
Keywords: indoles; tryptamines; 3-oxovincadifformine; 3-oxominovincine;
aspidospermane; alkaloids.
*
Corresponding authors. Address: Department for Organic Chemistry,
´
´
Budapest University of Technology and Economics, Gellert ter 4, H-1111
Budapest, Hungary. Fax: þ361-4633297; e-mail: szantay@mail.bme.hu
Figure 1.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01179-1

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J. Eles et al. / Tetrahedron 58 (2002) 8921–8927
8922
we describe the formation of the key intermediate 1 as well
as the synthesis of the alkaloid molecule 5 and alkaloid-like
molecule 4 obtained from 1. We also describe our attempts
to produce 15b-hydroxyvincadifformine (16).
2. Results and discussion
For the synthesis of 1 we chose Nb-trityl-2-(hydroxy-
methyl)-tryptamine10 (8) as the starting material. The
carbon chain of molecule 8 was elongated by the reaction
sequence developed by Kutney et al.11 (8!9!10!11, 80%
overall yield).
Scheme 2. Reagents and conditions: (a) H2, Pd/C, MeOH, rt; (b) 13,
benzene, D, 79% (a and b steps); (c) 14, benzene, D, 76% (a and c steps);
(d) 15, Et3N, MeOH, rt, 82% (a and d steps); (e) Ac2O, toluene, D, 48%,
Ref. 14; (f) TsOH, xylene, D, 42%.
Hydroxymethylation of ester 11 was realized by the
method of Battersby12 resulting in formation of 12 (73%)
(Scheme 1).
substrate. Processing the reaction mixture offered a surprise
as the dioxolanyl protection group dissociated and 3,19-
dioxo-16,17-dihydro-D20-secodin-17-ol (3, 76%) was
obtained as the product.
The trityl protection group was removed by catalytic
hydrogenolysis (Pd/C/H2) in methanol. The resulting key
intermediate (1) of the reaction tends to decompose,
therefore, we allowed it to react with aldehyde and
aldehyde-equivalent partners without isolation.
The reaction was repeated also with an alternative to the
aldehyde14 mentioned above. We allowed 4-acetyl-5-
bromo-4-pentenoic acid methyl ester8 (15) to react with
the tryptamine derivative 1 in methanol in the presence of
triethylamine, then the reaction mixture was processed from
which the secodine derivative 3 was isolated in a good yield
(82%). Spontaneous cyclization in boiling xylene in the
presence of TsOH after dehydration led to the alkaloid
3-oxominovincine (5, 42%) (Scheme 2).
First, we boiled the tryptamine derivative 1 and 4-formyl-
hexanoic acid methyl ester13 (13) in benzene (Fig. 2).
Having processed the reaction mixture, we obtained the
expected 3-oxo-16,17-dihydro-D20-secodin-17-ol (2, 79%)
in crystalline form. We had already produced 214 in another
way from which after dehydration-in the biomimetic way-3-
oxovincadifformine (4) can be yielded.
In light of the successfully applied strategy, the synthesis of
15b-hydroxyvincadifformine (16) (Fig. 3) seemed to be a
reasonable idea.
For the synthesis of 3-oxominovincine8 (5), 4-(2-methyl-
[1,3]dioxolan-2-yl)-5-oxo-pentanoic acid methyl ester9 (14)
was chosen as the reaction partner of 1. The reaction was
effected here again by refluxing in benzene using the crude
evaporation residue from the conversion 12!1 as the
The activated vinylchloride derivative 19 was chosen as the
reaction partner of 1. The synthesis of 19 was realized by
starting from 3-chloro-2-ethyl-acrolein15 (17). Reformatsky
reaction of aldehyde 17 and bromo-acetic-acid ethyl ester in
the presence of zinc powder led to hydroxy ester 18 in an
excellent yield (78%). Oxidation of alcohol 18 by Jones’
reagent resulted in the expected molecule (19, 84%)
(Scheme 3).
Scheme 1. Reagents and conditions: (a) PhCOCl, Et3N, THF, rt, 95%;
(b) KCN, DMSO, 608C, 98%; (c) HCl (g), MeOH, rt, 86%; (d) NaH,
HCOOCH3, rt; (e) NaBH4, MeOH, 08C, 73% (d and e steps).
Figure 3.
Scheme 3. Reagents and conditions: (a) BrCH2COOC2H5, Zn, benzene, D,
78%; (b) CrO3, H2SO4, acetone, rt, 84%.
Figure 2.

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J. Eles et al. / Tetrahedron 58 (2002) 8921–8927
8923
rings C and E. However, the reaction did not supply the
expected result either. Having processed the reaction
mixture which contained two components according to
chromatography, we found that the expected compound 25
did not appear among the products. Structure elucidation
studies revealed that the major product was molecule 2616
(27%) with the D-seco-aspidospermane skeleton as a
consequence of carbon–carbon bond cleavage, while the
by-product Nb-benzyl-indolazepinester (27)2d (23%)
(Scheme 5) was also found.
3. Conclusion
A new biomimetic synthetic strategy has been developed to
build up molecules with the aspidospermane skeleton. A
simple synthesis of 3-oxovincadifformine and 3-oxomino-
vincine has been realized. However, generation of 15b-
hydroxyvincadifformine failed because of unexpected side
reactions.
Scheme 4. Reagents and conditions: (a) H2, Pd/C, MeOH, rt; (b) 19, Et3N,
MeOH, rt 58% (a and b steps); (c) TsOH, toluene, D, 42%.
4. Experimental
4.1. General
Compounds 1 and 19 readily reacted in methanol in the
presence of triethyl amine. Having processed the reaction
mixture, we found that the carbonyl function in position 15
was present exclusively in the enol form (20, 58%).
Compound 20 was then boiled in toluene in the presence
of TsOH and surprisingly we found that after dehydration an
anomalous dimerization (22, 42%) had occurred instead of
the expected cyclization (21) (Scheme 4).
Melting points (uncorrected): Hotstage microscope Boetius.
1
IR spectra: Specord JR-75 Spectrophotometer. H and 13C
NMR spectra: Varian Unity INOVA-400. Chemical shifts
(in ppm) are relative to Me4Si. Mutual 1H–1H couplings are
given only once, at their first occurrence. Mass spectra: VG
ZAB-SEQ double focussing high resolution mass spec-
trometer. Preparative thin-layer chromatography: Silica gel
plates F254 (Merck).
Afterwards, we tried to produce alkaloid 16 with the
synthetic strategy published by us earlier.8 In this case the
formation of rings C,E precedes the build-up of ring D. We
allowed the activated vinyl halide 19 to react in methanol
with 234 in the presence of triethyl amine. Processing the
reaction mixture led to enamine 24 in a good yield (70%).
The toluene solution of 24 was then boiled in order to form
4.1.1. Nb-Trityl-2-[(benzoyloxy)methyl]tryptamine (9).
To an ice-cooled solution of 8 (20.0 g, 47.8 mmol) and
Et3N (9.0 g, 88.8 mmol) in anhydrous THF (380 mL) was
added benzoyl chloride (10.4 g, 74.1 mmol) dropwise. The
reaction mixture was allowed to stir for 4 h at rt then the
solvent was evaporated. To the residue 10% NaOH solution
(80 mL) was added and extracted with CH2Cl2 (3£80 mL).
The combined organic layers were dried (MgSO4) and
evaporated in vacuo. The brown oil was crystallized from
methanol, and filtration yielded 23.7 g (95%) of 9 as white
crystals. Rf¼0.46 (acetone/hexane¼1/2); mp 151–1538C;
IR (KBr) nmax 3390, 1710, 1450, 1265, 1100; dH (CDCl3):
1.73 (1H, brs; NH), 2.49þ3.03 (2£2H, 2£t, J¼6.6 Hz;
3-CH2CH2NH), 5.48 (2H, s; 2-CH2O), 7.03 (1H, m; 5-H),
7.11 (3H, m;0 3£40-H), 7.16 (1H, m; 6-H), 7.17 (3£2H, m;
3£30-Hþ3£5 -H), 7.29 (1H,00m; 7-H), 7.38 (3£2H, m; 3£20-
Hþ3£60-H), 7.39 (2H, m; 3 -Hþ500-H), 7.47 (1H, m; 4-H),
7.53 (1H, m; 400-H), 7.94 (2H, m; 200-Hþ600-H), 8.57 (1H,
brs; indole-NH); dC (CDCl3): 25.45 (3-CH2), 44.65 (CH2–
NH), 58.10 (2-CH2O), 70.96 (CPh3), 111.00 (C7), 114.32
(C3), 119.37þ119.51 (C4þC5), 122.086 (C60), 126.14
(3£C40), 127.59 (C3a), 127.73 (3£C2 þ3£C6 ), 128.41
(C300þC500),00 128.59 (3£C30þ3£C50), 129.70 (C2þC100),
129.78 (C2 þC600), 133.26 (C400), 135.79 (C7a), 146.17
(3£C10), 167.76 (COO); MS m/z (rel inten) 536 (5.0, Mþ),
243 (74.0), 165 (50.0), 143 (38.0), 122 (78.0), 105 (100.0),
91 (10.0), 77 (90.0). Anal. calcd for C37H32N2O2: C, 82.81;
H, 6.01; N, 5.22; found: C, 82.90; H, 5.91; N, 5.68.
Scheme 5. Reagents and conditions: (a) 19, Et3N, MeOH, rt, 70%;
(b) toluene, D, 27% for 26, 23% for 27.

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J. Eles et al. / Tetrahedron 58 (2002) 8921–8927
8924
4.1.2. Nb-Trityl-2-(cyanomethyl)tryptamine (10). To a
solution of 9 (20.0 g, 38.3 mmol) in anhydrous DMSO
(400 mL) was added KCN (7.6 g, 116.9 mmol) and the
reaction mixture was stirred for 3 h at 60–628C. After the
mixture cooled, it was poured into 5% NaHCO3 solution
(1.5 L) and extracted with CH2Cl2 (3£80 mL). The
combined organic layers were washed with 10% aqueous
NaCl (3£80 mL), dried (MgSO4), and evaporated in vacuo.
The brown oil was crystallized from methanol, and the
filtration yielded 16.0 g (98%) of 10 as light brown crystals.
Rf¼0.39 (acetone/hexane¼1/2); mp 127–1308C; IR (KBr)
nmax 3390, 2245, 1490, 1450, 750, 705; dH (CDCl3): 1.75
(1H, brs; NH), 2.47þ2.90 (2£2H, 2£t, J¼6.6 Hz; 3-CH2-
CH2NH), 3.87 (2H, s; 2-CH2CN), 7.09 (1H, m; 5-H), 7.17
(3H, m; 3£40-H), 7.23 (7H, m; 6-Hþ3£30-Hþ3£50-H), 7.32
(1H, m; 7-H), 7.38 (6H, m; 3£20-Hþ3£60-H), 7.44 (1H, m;
4-H), 8.12 (1H, brs; indole-NH); dC (CDCl3): 15.69
(CH2CN), 25.32 (3-CH2), 43.88 (CH2NH), 71.04 (CPh3),
110.91 (C7), 112.53 (C3), 116.50 (CN), 119.03þ119.97
(C4þC5), 122.23 (C2),0 122.77 (C6), 126.30 (3£C40),
poured onto water (300 mL) and extracted with CH2Cl2
(3£100 mL). The combined organic layers were dried
(MgSO4) and evaporated in vacuo. The residue was purified
by column chromatography (eluting with acetone/
hexane¼1/2, Rf¼0.52) to afford 3.9 g (73%) of product 11
as amorf solid. IR (KBr) nmax 3424, 1728, 1596, 1448, 1168;
dH (CDCl3): 1.67 (1H, br; OHþNH), 2.47 (2H, t, J¼6.8 Hz;
CH2NH), 2.96 (2H, m; 3-CH2), 3.60 (3H, s; OMe),
3.96þ4.07 (2£1H, 2£dd, Jgem¼11.2 Hz, Jvic¼5.4, 4.7 Hz,
respectively; 2-CHCH2OH), 4.14 (1H, dd; 2-CHCH2), 7.03
(1H, m; 5-H), 7.14 (4H, m; 6-Hþ3£40-H), 7.20 (6H, m;
3£30-Hþ3£50-H), 7.29 (1H, m; 7-H), 7.36 (6H, m; 3£20-
Hþ3£60-H), 7.42 (1H, m; 4-H), 8.80 (1H, brs; indole-NH);
dC (CDCl3): 25.35 (3-CH2), 44.23 (CH2NH), 44.53 (2-CH),
52.48 (OMe), 64.27 (CH2OH), 71.08 (CPh3), 110.93 (C7),
111.84 (C3), 118.99þ119.36 (C4þC5), 122.13 (C6), 126.21
(3£C400), 127.75 (3£C20þ3£C60), 127.88 (C3a), 128.67
(3£C30þ3£C50), 129.49 (C2), 135.64 (C7a), 146.07
(3£C1 ), 173.12 (COOMe); HRMS (FAB) calcd for
C33H33N2O3 505.2491, found for [MHþ] 505.2491.
127.81
(3£C20þ3£C6 ),
128.11
(C3a)0,
128.58
(3£C30þ3£C50), 135.73 (C7a), 145.98 (3£C1 ); MS m/z
(rel inten) 441 (6.0, Mþ), 243 (100.0), 194 (5.0), 170 (12.0),
165 (38.0), 142 (4.0), 115 (4.0), 91 (4.0), 77 (6.0). Anal.
calcd for C31H27N3: C, 84.32; H, 6.16; N, 9.52; found: C,
84.48; H, 6.23; N, 9.60.
4.1.5. 4-Chloromethylene-3-hydroxy-hexanoic acid ethyl
ester (18). A 100 mL, 3-necked flask fitted with a
condenser, mechanical stirrer, and 20 mL dropping funnel
was purged with nitrogen. Freshly activated zinc powder
(1.2 g, 18 mmol), and anhydrous benzene (10 mL) were
placed in the flask. Ethyl bromoacetate (2.5 g, 15 mmol),
2-chloromethylene-butyraldehyde (2.2 g, 18 mmol), and
anhydrous benzene (10 mL) were placed in the dropping
funnel. Nitrogen was introduced into the apparatus via a
septum on the condenser with a septum on the dropping
funnel as outlet. Without applied stirring, the bromide–
aldehyde solution (,2 mL) was added to the zinc suspen-
sion and the mixture was cautiously brought to reflux. After
ca. 10 min of gentle reflux the heating mantle was removed
and the rest of the bromide–aldehyde solution was then
added at such a rate as to maintain a gentle reflux. After the
addition was complete the dark yellow reaction mixture was
vigorously stirred and again brought to reflux with the
heating mantle. Over the course of 1 h reflux, the reaction
mixture became a cloudy pale green colour and most of the
zinc reacted. The reaction mixture was cooled and 10%
H2SO4 (15 mL), ethyl acetate (15 mL) were added. The
mixture was shaken well, and the two-phase system was
filtered to remove unchanged zinc. The aqueous layer was
then further extracted with ethyl acetate (3£15 mL). The
combined organic layers were washed with saturated brine
(2£20 mL), dried (MgSO4) and evaporated in vacuo. The
residue was purified by column chromatography (eluting
with acetone/hexane¼1/2, Rf¼0.53) to afford 3.0 g (78%)
of product 18 as yellow oil. IR (neat) nmax 2990, 1730, 1725,
1510, 1350, 1180; dH (CDCl3): 1.09 (3H, t, J¼7.6 Hz;
4-CH2CH3), 1.28 (3H, t, J¼7.0 Hz; COOCH2CH3),
2.16þ2.32 (2£1H, 2£dq, Jgem¼13.5 Hz, Jvic¼7.6 Hz;
4-CH2CH3), 2.54þ2.60 (2£1H, 2£dd, Jgem¼16.1 Hz,
J2,3¼8.7, 3.8 Hz, respectively; 2-CH2), 3.18 (1H, brd,
J¼3.8 Hz; 3-OH), 4.19 (2H, q, J¼7.0 Hz; COOCH2CH3),
4.57 (1H, brdddd, J3,5¼1.3 Hz; 3-H), 6.20 (1H, d; 5-H).
NOE: 6.20 (5-H)!4.57 (3-H), 3.18 (3-OH), 2.54þ2.60
(2-H2); dC (CDCl3): 12.22 (4-CH2CH3), 14.14 (COOCH2-
CH3), 21.21 (4-CH2CH3), 40.24 (C2), 61.01 (COOCH2-
CH3), 70.12 (C3), 115.99 (C5), 144.18 (C4), 172.23
(COOEt); MS m/z (rel inten) 188 (10.0, M2H2Oþ), 171
4.1.3. Nb-Trityl-2-[(methoxycarbonyl)methyl]trypta-
mine (11). A solution of 10 (20.0 g, 38.3 mmol) in saturated
methanolic HCl (300 mL) was allowed to stir at rt for 3 h.
The reaction mixture was poured onto ice-cooled 25%
aqueous NH3 solution (300 mL). The mixture was extracted
with CH2Cl2 (3£100 mL). The combined organic layers
were dried (MgSO4) and evaporated in vacuo. The brown
oil was crystallized from methanol, and the filtration yielded
19.2 g (86%) of 11 as light brown crystals. Rf¼0.42
(acetone/hexane¼1/2); mp 128–1308C; IR (KBr) nmax
3390, 1730, 1490, 1450, 750, 705; dH (CDCl3): 1.70 (1H,
brs; NH), 2.42þ2.90 (2£2H, 2£t, J¼6.5 Hz; 3-CH2CH2-
NH), 3.66 (3H, s; OMe), 3.80 (2H, s; 2-CH2), 7.03 (1H, m;
5-H), 7.13 (4H, m; 6-Hþ3£40-H), 7.19 (6H, 0 m; 3£300-
Hþ3£50-H), 7.28 (1H, m; 7-H), 7.37 (6H, m; 3£2 -Hþ3£6 -
H), 7.40 (1H, m; 4-H), 8.50 (1H, brs; indole-NH); dC
(CDCl3): 25.41 (3-CH2), 31.70 (2-CH2), 44.17 (CH2NH),
52.33 (OMe), 71.00 (CPh3), 110.66 (C7), 111.55 (C3),
118.79þ119.30 (C4þC5), 0 121.82 0 (C6), 126.16 (3£C40),
127.02 (C2), 127.73 (3£C2 þ3£C6 ), 128.25 (C3a), 128.66
(3£C30þ3£C50), 135.69 (C7a), 146.23 (3£C10), 171.11
(COOMe); MS m/z (rel inten) 474 (3.0, Mþ), 397 (0.1), 243
(100.0), 202 (40.0), 175 (44.0), 165 (30.0), 142 (13.0),
115 (7.0), 91 (6.0), 77 (6.0). Anal. calcd for C32H30N2O2:
C, 80.98; H, 6.37; N, 5.90; found: C, 80.95; H, 6.45; N,
6.05.
4.1.4. Hydroxymethylation of 11. To a solution of 11
(5.0 g, 10.5 mmol) in anhydrous methyl formate (90 mL)
was added oil free NaH (1.5 g, 62.5 mmol) and the reaction
mixture was allowed to stir for 0.5 h. The mixture was
cooled to below 2158C. At this temperature anhydrous
methanol (175 mL) and glacial acetic acid (5.9 mL) were
added. With the temperature below 2158C sodium
borohydride (6.1 g, 160.8 mmol) was added. The reaction
mixture was allowed to warm to 08C and was stirred for 1 h,

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J. Eles et al. / Tetrahedron 58 (2002) 8921–8927
8925
(18.0), 119 (45.0), 89 (23.0), 83 (100.0); HRMS (EI) calcd
for C9H12ClO2 188.0604, found for [M2H2Oþ] 188.0602.
171.74 (COOMe), 194.37 (COCH3); MS m/z (rel inten)
385.3 (100.0), 367.3 (58.0), 316.3 (12.0). Anal. calcd for
C21H24N2O5: C, 65.61; H, 6.29; N, 7.29; found: C, 65.44; H,
6.40; N, 7.12.
4.1.6. 4-Chloromethylene-3-oxo-hexanoic acid ethyl
ester (19). Jones’ reagent was prepared by the addition of
concentrated H2SO4 (5 mL) to CrO3 (5.6 g) followed by the
careful dilution with water (to give 42 mL of total solution).
Then the Jones’ reagent (18 mL, 18 mmol) was added
dropwise to a stirred solution of 18 (3.0 g, 14 mmol) in
acetone (70 mL) at 08C. After complete addition of the
oxidizing agent, the mixture was allowed to warm up to rt
and stirred for 12 h. Methanol (10 mL) was added to quench
excess Jones’ reagent. The reaction mixture was extracted
with diethyl ether (3£70 mL). The organic extracts were
washed with water (3£70 mL) and then 5% NaHCO3
(50 mL). The combined organic layers were dried (MgSO4)
and evaporated in vacuo. The residue was purified by
column chromatography (eluting with ether/hexane¼1/3,
Rf¼0.71) to afford 2.5 g (84%) of product 19 as yellow oil.
IR (neat) nmax 2952, 1740, 1684, 1624, 1396, 1236; dH
(CDCl3): 1.01 (3H, t, J¼7.5 Hz; 4-CH2CH3), 1.27 (3H, t,
J¼7.0 Hz; COOCH2CH3), 2.50 (2H, q, J¼7.5 Hz;
4-CH2CH3), 3.66 (2H, s; 2-H2) 4.20 (2H, q, J¼7.0 Hz;
COOCH2CH3), 7.24 (1H, s; 5-H); dC (CDCl3): 12.02
(4-CH2CH3), 14.08 (COOCH2CH3), 20.01 (4-CH2), 45.71
(C2), 61.62 (COOCH2CH3), 134.48 (C5), 145.37 (C4),
167.04 (C1), 190.06 (C3); MS m/z (rel inten) 204 (2.0, Mþ)
169 (17.0), 141 (43.0), 117 (48.0), 88 (29.0), 69 (48.0), 53
(100.0); HRMS (EI) calcd for C9H12ClO3 204.0553, found
for [Mþ] 204.0551.
4.3. General method II for synthesis of secodin type
intermediates (3, 20). Reaction of 1 with esters
containing aldehyde-equivalent structural unit
A mixture of 12 (5.00 g 18.2 mmol) and 3 g of 10%
palladium/charcoal in methanol (50 mL) was hydrogenated
for 12 h at rt and then filtered. To the filtrate, Et3N (3.8 mL.
27.3 mmol) and 15 or 19 (27.0 mmol) was added. After
being stirred for 24 h at rt, the mixture was concentrated in
vacuo. The residue was purified by column
chromatography.
4.3.1. 3,19-Dioxo-16,17-dihydro-D20-secodin-17-ol (3).
Yield: 3.3 g (82%). The compound was identical to that
prepared by method I.
4.3.2. 3-Oxo-16,17-dihydro-D14,20-secodin-15,17-diol
(20). Yield: 2.2 g (58%). Rf¼0.32 (CH2Cl2/methanol¼
15/1); mp 106–1098C; IR (KBr) nmax 3408, 1728, 1660,
1548, 1440, 1232; dH (CDCl3): 0.72 (3H, t, J¼7.4 Hz; 30-
CH2CH3), 2.12 (2H, m; 30-CH2), 3.07þ3.17 (2£1H, 2£dt,
Jgem¼14.5, Jvic¼6.8 Hz; 3-CH2), 3.58 (3H, s; OMe),
3.66þ3.99 (2£1H, 2£m; 2-CHCH2OH), 3.98þ4.14
(2£1H, 2£m; N10 –CH2), 4.02 (1H, m; 2-CH), 5.2 (2H, br;
CH2OHþ40-OH), 6.07 (1H, s; 50-H), 6.25 (1H, s; 20-H), 7.09
(1H, m; 5-H), 7.14 (1H, m; 6-H), 7.29 (1H, d, J6,7¼7.9 Hz;
7-H), 7.50 (1H, d, J4,5¼7.7 Hz; 4-H), 9.10 (1H, brs; indole-
NH); dC (CDCl3): 13.10 (30-CH2CH3), 19.76 (30-CH2),
23.75 (3-CH2), 45.53 (2-CH), 49.70 (N10 –CH2), 52.54
(OMe), 63.74 (CH2OH), 99.19 (C50), 109.04 (C3), 111.39
(C7), 117.85 (C30), 117.97 (C4), 119.61 (C5), 122.16 (C6),
127.34 (C3a), 130.30 (C2), 135.59 (C20), 135.86 (C7a),
164.26 (C60), 169.93 (C40), 173.45 (COOMe); MS m/z (rel
inten) 385.3 (70.0), 367.3 (100.0), 316.3 (15.0). Anal. calcd
for C21H24N2O5: C, 65.61; H, 6.29; N, 7.29; found: C,
65.51; H, 6.32; N, 7.24.
4.2. General method I for synthesis of secodin type
intermediates (2, 3). Reaction of 1 with esters containing
aldehyde structural unit
A mixture of 12 (5.0 g 18.2 mmol) and 3 g of 10%
palladium/charcoal in methanol (50 mL) was hydrogenated
for 12 h at rt and then filtered. The filtrate was evaporated in
vacuo. To the solution of the residue in benzene (50 mL) 13
or 14 (27.0 mmol) was added. The reaction mixture was
refluxed for 1 h. The solvent was evaporated. The residue
was purified by column chromatography.
4.3.3. (6)-3-Oxominovincine (5). A solution of 3 (1.0 g,
2.5 mmol) and p-toluenesulfonic acid monohydrate (10 mg,
0.06 mmol) in xylene (100 mL) was refluxed under argon
for 24 h. The reaction mixture was extracted with brine
(2£40 mL), and the combined brines were extracted with
CH2Cl2 (2£40 mL). The combined organic layers were
dried (MgSO4) and evaporated in vacuo. The residue was
purified by column chromatography (eluting with
acetone/hexane¼1/2, Rf¼0.28) to afford 0.4 g (42%) of
product 3 as white crystals. The authenticity of product was
4.2.1. 3-Oxo-16,17-dihydro-D20-secodin-17-ol (2). Yield:
3.0 g (79%). The authenticity of product was confirmed by
comparison of Rf,14 mp,14 IR,14 1H NMR,14 13C NMR14 and
mass spectrum14 with those of genuine sample.
4.2.2. 3,19-Dioxo-16,17-dihydro-D20-secodin-17-ol (3).
Yield: 3.1 g (76%). Rf¼0.46 (CH2Cl2/methanol¼15/1);
mp 169–1708C; IR (KBr) nmax 3392, 3232, 1728, 1668,
1616, 1440, 1384, 1300, 1180, 1088; dH (DMSO-d6): 1.90
(3H, s; COCH3), 2.28þ2.39 (2£2H, 2£m; 40-H2þ50-H2),
2.97 (2H, t, J¼7.0 Hz; 3-CH2), 3.63 (3H, s; OMe), 3.67–
3.84 (3H, m; CH2Nþ20-CH), 4.13 (2H, m; CH2OH), 5.13
(1H, t, J¼4.7 Hz; OH), 6.69 (1H, m; 5-H), 7.03 (1H, m;
6-H), 7.12 (1H, s; 20-H), 7.31 (1H, brd, J¼8.0 Hz; 7-H), 7.49
(1H, brd, J¼7.9 Hz; 4-H), 10.80 (1H, brs; indole-NH); dC
(DMSO-d6): 18.11 (C40), 23.15 (3-CH2), 24.34 (COCH3),
30.21 (C50), 46.07 (2-CH), 47.58 (CH2N), 52.04 (OMe),
61.90 (CH2OH), 108.87 (C3), 111.28 (C7), 116.72 (C30),
118.01 (C4), 118.62 (C5), 121.15 (C6), 127.78 (C3a),
130.61 (C2), 135.86 (C7a), 142.71 (C20), 169.43 (C60),
confirmed by comparison of Rf,8 mp,8 IR,8 1H NMR,8 13
C
NMR8 and mass spectrum8 with those of a genuine sample.
4.3.4. Dimer (22). A solution of 20 (1.00 g, 2.5 mmol) and
p-toluenesulfonic acid monohydrate (10 mg, 0.06 mmol) in
toluene (100 mL) was refluxed under argon for 24 h. The
reaction mixture was extracted with brine (2£40 mL), and
the combined brines were extracted with CH2Cl2
(2£40 mL). The combined organic layers were dried
(MgSO4) and evaporated in vacuo. The residue was purified
by column chromatography (eluting with CH2Cl2/

´
J. Eles et al. / Tetrahedron 58 (2002) 8921–8927
8926
methanol¼15/1, Rf¼0.53) to afford 0.4 g (42%) of product
22 as an amorphous solid. IR (KBr) nmax 3416, 2960, 1724,
1660, 1552, 1440, 1224; dH (CDCl3þDMSO-d6): 0.81 (3H,
t, J¼7.4 Hz; 300-CH2CH3), 0.87 (3H, t, J¼7.4 Hz, 3000-
CH2CH3), 2.14 (2H, brq; 300-CH2), 2.18 (2H, brq; 3000-CH2),
2.89þ3.37 (2£1H, 2£ddd, Jgem¼15.4 Hz, Jvic¼7.8þ6.8 Hz;
vCH–CH2CH), 2.97 (2H, t, J¼6.6 Hz; 3-CH2), 3.11þ3.19
(2£1H, 2£dt, Jgem¼14.5 Hz, Jvic¼7.5 Hz, 30-CH2), 3.62
(3H, s; CH–COOMe), 3.69 (3H, s; vC–COOM0e0 ),
3.98þ4.11 (2£1H, 2£m; N1000 –CH2), 4.00 (2H, m; N1 –
CH2), 4.18 (1H, t, J¼7.5 Hz; 20-CH), 5.93 (1H, s; 500-H),
5.95 (1H, s; 5000-H), 6.13 (1H0,00t, J¼7.2 Hz; 2-CvCH), 6.43
(1H, s; 200-H), 6.65 (1H, s; 2 -H), 6.99 0(1H, m; 5-H), 7.00
(1H, m; 50-H), 7.07 (2H, m; 6-Hþ6 -H), 7.27 (1H, d,
J¼8.0 Hz; 7-H), 7.34 (1H, d, J¼8.0 Hz; 70-H), 7.55 (2H, d,
J¼7.6 Hz; 4-Hþ40-H), 10.49 (2H, brs; 2£indole-NH); dC
(CDCl3þDMSO-d6): 13.30 (300-CH2CH3), 13.38 (3000-
CH2CH3), 19.75 (300-CH2), 19.86 (3000-CH2), 24.02 (30-
CH2), 24.22 (3-CH2), 32.38 (vCH–CH2CH), 42.11 (20-
CH), 48.76 (N100 –CH2), 49.31 (N1000 –CH2), 51.81 (vC–
COOCH3), 52.10 (CH–COOCH3), 98.61 (C5000), 98.70
(C50000), 108.63 (C30), 109.14 (C3), 111.19 (C7), 111.30
(C7 ), 115.22 (C300), 0 115.67 (C3000), 118.05þ118.39
(C4þC40), 118.89 (C5 ), 118.98 (C5), 121.37 (C60),
121.92 (C60), 126.72 (C8), 127.56 (C3a0), 127.70 (C3a),
132.09 (C2 ), 132.430 (C2), 135.21 (C200), 135.30 (C2000),
135.71þ136.07 (C7a þC7a), 140.12 (2-CvCH), 163.45
(C600), 163.56 (C6000), 166.94 (vC–COOMe), 167.30 (C400),
167.60 (C4000), 172.44 (CH–COOMe); HRMS (FAB) calcd
for C42H45N4O8 733.3237 found for [MH]þ 733.3305.
toluene (100 mL) was refluxed under argon for 24 h. The
reaction mixture was extracted with brine (2£40 mL), and
the combined brines were extracted with CH2Cl2
(2£40 mL). The combined organic layers were dried
(MgSO4) and evaporated in vacuo. The residue was purified
by
column
chromatography
(eluting
with
acetone/hexane¼2/3). The less polar compound (26,
Rf¼0.89) was obtained as white crystals (0.2 g, 27%) after
crystallization from methanol. The authenticity of product
was confirmed by comparison of Rf,16b mp,16b IR,16b 1
H
NMR,16b 13C NMR16b and mass spectrum16b with those of
genuine sample.
The less polar compound (27, Rf¼0.75) was obtained as
white crystals (0.15 g, 23%) after crystallization from
methanol. The authenticity of product was confirmed by
comparison of Rf,4 mp,4 IR,4 1H NMR,4 13C NMR4 and
mass spectrum4 with those of genuine sample.
Acknowledgements
´
´ ´
The authors are grateful to Istvan Vago for helping with the
preparative work and the National Scientific Research
Foundation (OTKA T31920) for financial support of this
work.
References
´
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40-CH2CH3), 1.26 (3H, t, J¼7.1 Hz; COOCH2CH3), 2.37
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