Synthesis and antineoplastic activity of cyclolignan aldehydes

Article abstract of DOI:10.1016/S0223-5234(00)00176-8

Several aldehydes related to methyl 9-deoxy-9-oxo-α- apopicropodophyllate, a selective antitumour agent against the HT-29 colon carcinoma, have been prepared and evaluated for their cytotoxic activities on four neoplastic cell lines (P-388, A-549, HT-29 and MEL-28). All of them lacked the lactone ring but maintained their cytotoxicity at, or under, the μM level. (C) 2000 Editions scientifiques et medicales Elsevier SAS.

Full text of DOI:10.1016/S0223-5234(00)00176-8

Eur. J. Med. Chem. 35 (2000) 691−698
© 2000 Éditions scientifiques et médicales Elsevier SAS. All rights reserved
S0223523400001768/FLA
Original article
Synthesis and antineoplastic activity of cyclolignan aldehydes
Marina Gordalizaa*, Ma Angeles Castroa, José Ma Miguel del Corrala, Ma Luisa López-Vázqueza,
Pablo A. Garcíaa, Ma Dolores García-Grávalosb, Arturo San Felicianoa
a Departamento de Química Farmacéutica, Facultad de Farmacia, Universidad de Salamanca, E-37007-Salamanca, Spain
b Biomar S.A., Calera 3, Tres Cantos, E-28760-Madrid, Spain
Received 17 November 1999; revised 8 February 2000; accepted 10 February 2000
Abstract – Several aldehydes related to methyl 9-deoxy-9-oxo-α-apopicropodophyllate, a selective antitumour agent against the HT-29 colon
carcinoma, have been prepared and evaluated for their cytotoxic activities on four neoplastic cell lines (P-388, A-549, HT-29 and MEL-28).
All of them lacked the lactone ring but maintained their cytotoxicity at, or under, the µM level. © 2000 Éditions scientifiques et médicales
Elsevier SAS
cyclolignan aldehydes / non-lactonic derivatives / podophyllotoxin / selective cytotoxicity
1. Introduction
Two semi-synthetic derivatives of the cyclolignan
Podophyllotoxin (1), etoposide and teniposide, are widely
used anticancer drugs which show good clinical effects
against several types of neoplasms, including testicular
and small-cell lung cancers, lymphoma, leukaemia, Ka-
posi’s sarcoma, etc. [1]. However, several limitations,
such as myelosuppression, development of drug resis-
tance and cytotoxicity towards normal cells still exist. In
order to overcome the limitations of these compounds
and to develop new compounds with better antitumour
activity, numerous structural modifications have been
performed on the cyclolignan skeleton [2–4]. In this
sense, our group has been engaged in the design and
synthesis of novel analogues of podophyllotoxin [5–10]
and has also described new activities for these kind of
compounds [11, 12].
Recently, we have reported the synthesis of several
heterocycle-fused cyclolignans lacking the lactone moi-
ety [5–7]. Most of these compounds showed similar
effects in all the neoplastic systems tested, except the
aldehyde: methyl 9-deoxy-9-oxo-α-apopicropodophyllate
(2) [6] (figure 1). This compound was tested at the
National Cancer Institute (USA) against 60 different
Figure 1. Structure of podophyllotoxin 1 and the selective
aldehyde 2.
types of cancers and it showed a highly selective cyto-
toxicity towards colon carcinoma lines, with an IC50 in
the range of trans-lactonic cyclolignans, which have
always been the most potent compounds [8–10].
With the aim of showing the influence of the aldehyde
group on the antineoplastic selectivity and of establishing
structure–activity relationships for these kinds of com-
pounds, we have prepared and tested other aldehydes
derived from podophyllotoxin with different configura-
* Correspondence and reprints: mliza@gugu.usal.es

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M. Gordaliza et al. / Eur. J. Med. Chem. 35 (2000) 691–698
Figure 2. Reduction of the lactonic derivatives.
tions at the C-7, C-8 and C-8′ positions. Intermediates
have also been tested on cultures of different tumour cell
lines.
HCl. Reduction of 4 gave the triol 9 as a mixture of
epimers at C-7. They were also transformed into the
dehydration product 10 by refluxing them in acidified
CHCl3.
2. Chemistry
In order to obtain the lignan derivatives with an
aldehyde group at C-9 and C-9′, Swern oxidation of the
corresponding alcohols was performed [14] and the
aldehydes 11, 12 and 13 were obtained from the neoan-
hydropodophyllols 6, 8 and 10 (figure 3).
With this aim in mind we used, as starting materials,
the trans-lactone podophyllotoxin (1) and cis-lactones
picropodophyllin (3) and isopicropodophyllone (4). These
were transformed into the corresponding triols 5, 7 and 9
by reduction with LiAlH4 which is known to maintain the
stereochemistry at the centres cited above [13] (figure 2).
In the case of the reduction of 1, the triol 5 was
accompanied by the dehydration product neoanhydro-
podophyllol 6. The formation of 6 can be explained by
the presence of acid in the work up, because the triol 5
can be transformed quantitatively into the alcohol 6 by
keeping it under CHCl3-HCl reflux [13]. Reduction of 3
led only to the triol 7 which was transformed into
neoanhydropicropodophyllol 8 when it was refluxed in
chloroform solution acidified with a few drops of 2 N
The main reaction product of the Swern oxidation of
triol 5 was the dialdehyde 14, in which, not only did the
oxidation of the hydroxyl groups at C-9 and C-9′ take
place, but also the elimination of the benzylic hydroxyl
group took place. Elimination to generate α,ꢀ-unsaturated
carbonyl compounds is a common side reaction when
carbonyl compounds with suitable leaving groups are
generated in the presence of bases [15]. During oxidation,
the epimerization of the C-8′ position, which is α to a
carbonyl, also occurred in those cases where the stereo-
chemistry of the parent alcohol was α.

M. Gordaliza et al. / Eur. J. Med. Chem. 35 (2000) 691–698
693
The dialdehyde 14 was also obtained from the alde-
hyde 2 (figure 5) by protection of the carbonyl group as
its dithiolane to give compound 17, followed by reduc-
tion of the methyl ester with LAH to give the alcohol 18.
Deprotection of 18 with HgO-BF3.Et2O produced the
hydroxyaldehyde 19 that led to the corresponding unsat-
urated dialdehyde 14 by Swern oxidation. Attempts to
obtain the corresponding lactol from the hydroxyalde-
hyde 19 by treatment with PPTS were unsuccessful,
leading instead to the methyl ether 20.
Acetates and triacetates of the corresponding alcohols
and triols were also prepared in order to assign unequivo-
1
cally all the signals in the H- and 13C-NMR spectra.
3. Biological results and discussion
The prepared compounds were evaluated in vitro to
establish their cytotoxicity against cell cultures of P-388
murine leukaemia, A-549 human lung carcinoma, HT-29
human colon carcinoma and MEL-28 human malignant
melanoma [16]. The results obtained are shown in table I.
The tested derivatives showed cytotoxicity levels two
or three orders lower than those of podophyllotoxin (1).
However, some general observations can be made. It is
worth noticing that several compounds (4, 7, 8, 8a and
11) are twice as potent against P-388 than the other tested
lines.
Opening and reduction of the lactone ring led, in
general, to much less cytotoxic compounds and the
acetylation of the hydroxyl groups did not modify po-
tency (6, 8, 10 and 19 vs. 6a, 8a, 10a and 19a) except in
the case of triol 7, in which acetylation improves the
potency significantly. Transformation of the triols into the
dialdehyde 14 improved potency slightly or left it un-
Figure 3. Swern oxidation of neoanhydropodophyllols.
Together with 14, another two secondary compounds
were also isolated from 5: compound 15, with the central
ring of the cyclolignan skeleton aromatized, and com-
pound 16 which had undergone deformylation. The
formation of the latter can be explained through the
intermediate dimethyl alkoxysulfonium salt, which reacts
with the base to give the ylide 5′. Then, by an intramo-
lecular cyclic mechanism, the doubly benzylic hydrogen
atom at C-7′ is abstracted instead of the proton α to the
oxygen, the one normally removed in the Swern oxida-
tion, to eliminate formaldehyde and dimethylsulfide (fig-
ure 4).
Figure 4. Swern oxidation of triol 5.

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M. Gordaliza et al. / Eur. J. Med. Chem. 35 (2000) 691–698
Table I. Antineoplastic activity of cyclolignan derivatives
(IC50 µM).
Compound
P-388
A-549
HT-29
MEL-28
1
2
3
4
5
6
6a
7
7a
8
0.012
0.2
6.0
6.0
1.2
12.5
11.3
23.9
4.6
6.3
5.7
0.2
0.2
0.6
0.3
2.5
0.3
0.6
0.2
1.0
0.3
0.2
0.012
0.1
6.0
12.1
1.2
12.5
11.3
47.9
4.6
12.5
11.3
0.2
0.2
0.6
0.6
2.5
0.3
0.6
0.2
1.0
0.3
0.2
0.029
0.01
6.0
12.1
1.2
12.5
11.3
23.9
7.4
12.5
11.3
0.2
0.2
0.6
0.6
2.5
0.3
0.6
0.2
1.0
1.2
12.1
8a
9
0.2
0.2
0.6
0.6
2.5
0.3
0.6
0.2
1.0
0.3
0.2
10
10a
11
12
13
14
17
18
19
19a
0.3
0.2
the aldehyde and trimethoxyphenyl groups both display
pseudo-equatorial dispositions. Hence, in either of these
compounds the ideal relative disposition of these groups,
presumably achieved by 1 is not obtainable, at least
without significant distortion of ring C from its ground
state conformation. Whilst 12 should dispose the C-9 and
C-7′ substituents in near-ideal orientations, it also places
the methyleneoxy bridge in areas of space which have
hitherto not been thoroughly explored and which may not
be available for ligands at the site of interaction of these
compounds. Indeed, previous observations [7] on the
cis-saturated aldehyde derived from 2 may also be
interpreted as suggesting a lack of space in the active site
for the ꢀ face of the C ring.
From these results it may be concluded that, in general,
aldehydes at C-9 are more potent than alcohols at this
position. This is consistent with previous suggestions [5]
that an electrophilic group at this position is critical for
the possible interaction with the biomolecules. The modi-
fications made in the structural vicinity of the aldehyde
function of 2 did not significantly modify cytotoxic
potency against the tested cell lines, but the selectivity of
the compound against HT-29 cells was lost. These find-
ings indicate that the selectivity of these compounds is
affected not only by the presence of the aldehyde function
at C-9, but also by other aspects such as the absence of
the ∆7 double bond in all the substances tested in this
Figure 5. Synthesis of other derivatives from 2.
changed (14 vs. 5, 7 and 9) but selectivity of compound
2 against HT-29 was lost.
The formation of the alcohols with the methyleneoxy
bridge (6, 8 and 10) decreased the potency, which was
partially recovered when these hydroxyl groups were
transformed into the respective aldehydes (11, 12 and 13),
although the selectivity against HT-29 was lost again.
Even when the electrophilic aldehyde group at C-9 was
present, compounds 11, 13 and especially 12 showed
disappointingly poor activity. While the stereochemistry
of the substituents in 11 is formally the same as in 1, the
constraint imposed by the addition of the epoxy bridge on
the ring conformation is such that the trimethoxyphenyl
group is expected to adopt a pseudo-equatorial orienta-
tion and the aldehyde a pseudo-axial orientation, the
reverse of their conformational distribution in 1. In 13 the
stereochemistry of the C ring is formally different from
that in 1, with the consequence that in the half-chair form,

M. Gordaliza et al. / Eur. J. Med. Chem. 35 (2000) 691–698
695
work. The degree of oxidation at C-9′ could also be
important for this selectivity, although further studies will
be necessary to elucidate the mechanism of action at the
molecular level.
Acetylation of alcohol 10: to a solution of 10 (30 mg)
in pyridine (1 mL), acetic anhydride (0.5 mL) was added.
The reaction mixture was kept at room temperature for
12 h. Then ice was added and the mixture was extracted
with EtOAc. The organic layer was washed successively
with 2 N HCl, aq. sat. NaHCO3 and brine, dried over
Na2SO4 and the organic solvent was evaporated to yield
31 mg (93%) of acetate 10a. [α]22 (λ): –52.8° (589),
–57.1° (578), –66.7° (546), –123.3° (436) (c = 0.21%).
UV λmax (ε): 214 (21 500), 290 (3 800). IR: 1 740, 1 589,
4. Experimental protocols
4.1. Chemistry
Melting points were determined by heating in an
external silicone bath and were uncorrected. Optical
rotations were recorded on a Perkin-Elmer 241 polarim-
eter in chloroform solution and UV spectra on a Hitachi
100-60 spectrophotometer in ethanol solution. IR spectra
were obtained on a Beckmann (Acculab VIII) spectro-
photometer in chloroform solution. EIMS were run in a
VG-TS-250 spectrometer working at 70 eV. NMR spectra
1
1 505, 1 485, 1 231, 1 126, 1 038 cm–1. H-NMR (table
II). 13C-NMR (table III).
4.1.4. Swern oxidations
4.1.4.1. Neoanhydropodophyllal 11
To a pre-cooled (–55 °C) and stirred solution of oxalyl
chloride (1.2 mL, 2 M) in dry CH2Cl2 (3 mL) was added
dropwise DMSO (0.34 mL) in dry CH2Cl2 (3 mL). After
5 min at –55 °C, a solution of 320 mg (0.8 mmol) of the
alcohol 6 in 5 mL of dry CH2Cl2 was slowly added. The
reaction mixture was kept at the same temperature for
30 min, then triethylamine (1.1 mL) was added. The
mixture was warmed to 0 °C over 1 h, quenched with
water and extracted with CH2Cl2. The reaction product
gave, after flash chromatography (CH2Cl2/EtOAc, 8:2 as
eluent), 252 mg (79%) of the aldehyde 11. M.p. 73–75 °C
(Hex/CH2Cl2). Anal. calcd. for C22H22O7: C, 66.33; H,
5.53; found: C, 66.04; H, 5.52. MS m/z: 398 (M+), 380,
339, 324, 198, 173, 115. [α]22 (λ): 0°. UV λmax (ε): 208
(21 300), 238 (8 700), 335 (6 500). IR: 1 730, 1 600,
1
were recorded at 200 MHz for H- and 50.3 for 13C- in
deuterochloroform using TMS as internal reference, on a
Bruker WP 200 SY. Chemical shift (δ) values are
expressed in ppm followed by multiplicity and coupling
constants (J) in Hz. Flash chromatography was per-
formed on silica gel (Merck No 9385). Elemental analy-
ses were carried out on a Perkin-Elmer 2400 CHN
Elemental Analyzer.
4.1.1. Isolation and preparation of compounds 1–8
Podophyllotoxin 1 was isolated from Podophyllum
emodi resin and transformed into the derivatives 2–8 by
described procedures [7, 13, 17].
1
1 510, 1 495, 1 470, 1 240, 1 140, 1 050, 950 cm–1. H-
NMR (table II). 13C-NMR (table III).
4.1.2. Isopicropodophyllol 9
Isopicropodophyllone 4 (180 mg, 0.44 mmol) in dry
ether (15 mL) was slowly added to a suspension of
LiAlH4 (220 mg, 5.79 mmol) in dry ether. The reaction
mixture was stirred at room temperature under argon for
3 h. Then wet EtOAc was added, filtered, dried and
evaporated to afford 168 mg (92%) of 9, after flash
chromatography (CH2Cl2/MeOH, 95:5). IR: 3 600, 1 590,
In the same way as described for 11 and after column
chromatography of the reaction product, the following
aldehydes were obtained using the corresponding starting
materials.
4.1.4.2. Neoanhydroepipicropodophyllal 12
From alcohol 8 (79%). M.p. 92–94 °C (MeOH/
CH2Cl2). Anal. calcd. for C22H22O7: C, 66.33; H, 5.53;
found: C, 66.12; H, 5.51. [α]22 (λ): +73.2° (589), +77.8°
(578), +91.0° (546), +172.3°(436) (c = 0.08%). UV λmax
(ε): 208 (22 100), 271 (9 100), 313 (7 200). IR: 1 730,
1 600, 1 510, 1 490, 1 470, 1 220, 1 140, 1 050, 950 cm–1.
1H-NMR (table II). 13C-NMR (table III).
1
1 505, 1 484, 1 234, 1 126, 1 039, 875 cm–1. H-NMR
(table II). 13C-NMR (table III).
4.1.3. Neoanhydroisopicropodophyllol 10
A few drops of 2 N HCl were added to a solution of the
triol 9 (95 mg, 0.23 mmol) in CHCl3 and heated under
reflux for 1 h. After washing with water, drying over
Na2SO4 and evaporation of the solvent, 90 mg (98%) of
10 was obtained. [α]22 (λ): –75.2° (589), –79.1° (578),
–91.8° (546), –163.4° (436) (c = 0.16%). UV λmax (ε):
214 (18 800), 292 (2 900). IR: 3 400, 1 589, 1 505, 1 484,
1 461, 1 231, 1 127, 1 039, 935, 874 cm–1. 1H-NMR
(table II). 13C-NMR (table III).
4.1.4.3. Neoanhydroisopicropodophyllal 13
From alcohol 10 (75%). [α]22 (λ): –71.3° (589), –75.8°
(578), –87.6° (546), –164.3° (436) (c = 0.09%). UV λmax
(ε): 219 (19 700), 290 (6 100). IR: 1 723, 1 589, 1 505,
1 485, 1 231, 1 126, 1 039, 935, 875 cm–1. 1H-NMR
(table II). 13C-NMR (table III).

Table II. 1H-NMR data of compounds 9–20.
H
9
10
10a
11
12
13
14
15
16
17
18
19
19a
20
2
5
7
8
6.82 s
6.45 s
4.75 d (2.9)
2.35 m
6.67 s
6.58 s
4.69 s
2.60 m
6.70 s
6.57 s
4.68 s
2.59 m
6.74 s
6.54 s
5.00 d (5.2)
3.28 m
6.72 s
6.48 s
5.08 s
3.05 m
9.66 s
6.75 s
6.60 s
5.14 s
3.11 m
9.81 s
5.93 d
(1.5)
5.96 d
(1.5)
6.42 s
4.52 d
(3.3)
6.87 s
6.74 s
7.47 s
7.32 s
6.98 s
8.25 s
7.32 s
6.26 s
8.16 s
6.71 s
6.57 s
6.68 s
6.66 s
6.59 s
6.63 s
7.28 s
6.70 s
6.87 s
7.31 s
6.71 s
6.88 s
7.29 s
6.68 s
6.72 s
9
3.40–3.70 m 3.70 m
4.13 m 9.66 d (1.1)
9.71 s
6.02 d
(1.8)
6.03 d
(1.8)
6.18 s
4.71 d
(2.0)
3.99 d
(2.0)
9.99 s
6.13 s
10.12 s
6.10 s
5.34 s
5.90 s
5.23 s
5.92 s
9.54 s
6.01 s
9.56 s
6.03 s
9.57 s
6.03 s
O–CH2–O
5.85 s
5.86 s
6.57 s
5.92 d
(1.1)
5.89 d
(1.1)
5.91 s
5.95 s
6.40 s
5.92 d (1.8) 5.87 d
(1.1)
5.96 d (1.8) 5.93 d
(1.1)
2′,6′
7′
6.41 s
6.36 s
6.16 s
4.18 s
6.58 s
10.6 s
6.65 s
6.26 s
4.36 d (1.6)
6.24 s
4.21 s
6.18 s
4.31 s
6.15 s
4.12 s
6.19 s
4.30 s
4.12 d (6.2) 4.48 d
4.50 d 4.57 d (4.5)
(3.6)
(3.3)
2.50 m
8′
9′
2.11 m
2.59 m 3.04 c (4.5) 3.05 m
3.90 m 3.60–3.90 m 3.75 m
4.00 m
3.81 s
3.83 s
2.11 s
3.04 m
7.76 d
(1.8)
3.03 m
2.80 m
3.25 m
3.40 m
3.32 m
3.32 m
3.40–3.70 m 3.90 m
3.60 m
9.51 s
3.43 dd
(10.3; 8.4)
3.85 m
3.74 s
3.77 s
3.80 m 3.60–3.90 m
3.80 m
3.72 s
3.76 s
4.00 m
CH3O-3′,5′
CH3O-4′
COCH3
3.76 s
3.81 s
3.80 s
3.84 s
3.80 s
3.84 s
3.73 s
3.79 s
3.81 s
3.85 s
3.72 s
3.76 s
3.86 s
3.97 s
3.88 s
3.95 s
3.74 s
3.77 s
3.73 s
3.76 s
2.00 s
3.74 s
3.78 s
COOCH3
CH2–CH2
CH3
3.63 s
2.97–3.17 m 3.03–3.24 m
3.49 s

M. Gordaliza et al. / Eur. J. Med. Chem. 35 (2000) 691–698
Table III. 13C-NMR data of compounds 9–20.
697
C
9
10
10a
11
12
13
14
15
17
18
19
19a
20
1
2
3
4
5
6
7
8
128.7
106.5
145.0
146.5
109.1
133.3
77.2
129.7
107.5
146.0
147.5
110.1
134.3
78.2
129.5
107.5
146.1
147.6
110.0
133.8
78.2
129.9
107.6
146.5
148.4
110.2
132.6
76.4
132.3
107.8
146.8
148.2
110.9
129.3
76.8
129.7
107.5
146.4
148.0
110.6
132.6
76.9
134.4 132.3* 130.6
133.7
107.1
146.7
147.5
110.3
129.7
126.5
127.2
58.0
101.0
139.3
105.9
153.0
137.3
47.5
136.0
108.7
147.3
150.5
110.9
134.3
146.2
125.2
192.6
101.7
139.3
105.4
153.3
135.4
45.1
134.5
108.8
147.8
150.5
110.8
133.7
146.0
125.2
191.5
101.8
139.1
105.3
153.3
138.0
45.6
133.1
108.7
147.0
151.0
110.9
131.2
146.7
124.6
192.6
101.7
139.2
105.5
153.3
136.0
45.2
109.0
147.6
151.0
110.4
103.8
145.7
150.3
105.7
107.4
146.9
147.6
109.4
130.9 132.3* 129.2
147.0 128.4 127.4
124.7 130.8* 127.0
50.0
61.3
51.0
62.3
52.7
65.8
43.9
43.9
52.1
9
198.9
101.2
138.2
107.3
153.5
–
48.0
57.7
69.0
56.5
200.3
101.2
139.6
106.7
153.5
137.6
52.9
53.4
70.8
56.4
60.7
200.5
101.3
138.0
106.1
153.3
137.0
47.4
59.4
66.3
56.2
60.8
191.0
101.9
192.7
102.2
58.1
101.2
O-CH2-O
1′
2′,6′
3′,5′
4′
7′
8′
9′
CH3O-3′,5′
CH3O-4′
COCH3
COCH3
COOCH3
CH2–CH2
100.0
137.9
105.5
152.1
135.6
51.0
43.2
65.0
55.2
59.8
101.0
138.9
106.5
153.1
136.6
53.0
44.2
66.0
56.2
60.8
101.0
138.5
106.5
153.1
136.8
47.7
44.4
63.8
56.2
60.9
137.9 130.1* 138.3
105.3
153.5
138.6
52.1
42.5
197.0
56.4
107.8
153.4
138.1
132.2*
130.8*
193.7
56.3
105.6
153.1
136.8
49.3
47.6
172.9
56.4
46.1
64.2
56.4
60.6
42.5
63.5
56.3
60.7
38.2
64.6
56.3
60.7
170.8
20.7
42.5
63.8
56.4
60.7
60.9
60.7
61.1
60.8
171.0
20.9
52.3
38.4
39.3
38.7
39.4
CH3O-9′
56.4
* Exchangeable assignments.
4.1.4.4. α -Apopicropophyllal 14
(CH2Cl2). [α]22 (λ): –96.1° (589), –102.6° (578), –122.2°
(546), –302.2° (436) (c = 0.23%). UV λmax (ε): 238
(15 300), 311 (8 400). IR: 1 735, 1 600, 1 510, 1 490,
According to the same procedure described above and
after column chromatography of the reaction product of
Swern oxidaton of triol 5, the following compounds were
eluted with a mixture of CH2Cl2/EtOAc, 96:4: aldehyde
1
1 470, 1 230, 1 145, 1 050, 1 010 cm–1. H-NMR (table
II). 13C-NMR (table III).
16 (11%) (MS m/z: 366 (M+), 351, 323, H-NMR, table
1
II), dialdehyde 15 (25%, MS m/z: 394 (M+), 363, 379,
1H-NMR, table II. 13C-NMR, table III) and dialdehyde
14 (41%). (λ): –87.5° (589), –93.1° (578), –117.3° (546)
(c = 0.10%). UV λmax (ε): 208 (16 200), 275 (8 300), 350
(7 900). IR: 1 600, 1 510, 1 490, 1 470, 1 240, 1 135,
1 045, 945, 870 cm–1. 1H-NMR (table II). 13C-NMR
(table III).
4.1.5.2. Ethylene thioacetal
of 9-deoxy-9-oxo-α-apopicropodophyllol 18
A solution of compound 17 (40 mg, 0.08 mmol) in dry
ether (3 mL) was slowly added to a suspension of LAH
(50 mg, 1.32 mmol) in dry ether. Following the procedure
described above and after flash chromatography (CH2Cl2/
EtOAc, 9:1), 37 mg (98%) of 18 were obtained. [α]22 (λ):
–16.2° (589), –17.7° (578), –23.1° (546), –71.5° (436)
(c = 0.13%). UV λmax (ε): 214 (23 200), 313 (8 200). IR:
3 500, 1 600, 1 510, 1 490, 1 470, 1 230, 1 130, 1 040,
4.1.5. Transformations on aldehyde 2
1
940 cm–1. H-NMR (table II). 13C-NMR (table III).
4.1.5.1. Ethylene thioacetal
of methyl 9-deoxy-9-oxo-α-apopicropodophyllate 17
To a solution of 100 mg (0.23 mmol) of 2 in 3 mL of
dry CH2Cl2, was added 0.15 mL of 1,2-ethanedithiol and
0.3 mL of ClSiMe2. The reaction mixture was stirred at
room temperature under argon for 20 h. Then CH2Cl2
was added, washed with NaOH 4% and brine, dried and
evaporated to afford 112 mg (97%) of 17. M.p. 82–84 °C
4.1.5.3. 9-Deoxy-9-oxo-α-apopicropodophyllol 19
To a solution of 40 mg of HgO and 0.25 mL of
BF3.Et2O in 5 mL of THF/H2O, 85:15 was added 40 mg
(0.08 mmol) of 17. The reaction mixture was stirred at
room temperature under argon for 3 h. After addition of
water, the precipitate was filtered. The filtrate was ex-

698
M. Gordaliza et al. / Eur. J. Med. Chem. 35 (2000) 691–698
tracted with EtOAc. After removing the solvent and flash
chromatography (CH2Cl2/EtOAc, 8:2) 30 mg (94%) of
19 was obtained. [α]22 (λ): –85.1° (589), –90.2° (578),
–113.0° (546), –431.6° (436) (c = 0.22%). UV λmax (ε):
215 (16 500), 245 (14 300), 356 (8 200). IR: 3 450,
1 670, 1 600, 1 510, 1 490, 1 240, 1 135, 1 045, 940 cm–1.
1H-NMR (table II). 13C-NMR (table III).
Acknowledgements
Financial support for this work came from EC (COST
BIO4-CT98-0451), Spanish DGICYT (PB 96-1275),
CICYT (SAF 98-0096) and Junta de Castilla y León
(Consejería de Educación y Cultura, SA-26/97).
Acetylation of 19, following the above procedure,
yielded acetate 19a (95%). [α]22 (λ): –87.2° (589), –92.7°
(578), –116.0° (546) (c = 0.19%). UV λmax (ε): 214
(15 200), 256 (13 100), 326 (7 400). IR: 1 730, 1 680,
1 600, 1 510, 1 495, 1 470, 1 250, 1 140, 1 050 cm–1.
1H-NMR (table II). 13C-NMR (table III).
Following the same procedure described before for the
Swern oxidations, 130 mg of 19 afforded 40 mg (31%) of
14.
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