Synthesis of New Substituted Quinolizidines as Potential Inhibitors of Ergosterol Biosynthesis.

Article abstract of DOI:10.1016/0040-4020(95)00062-D

Carbocationic species (High Energy Intermediates) have been postulated as intermediates in the course of enzymatic synthesis of ergosterol.Protonated aza-analogues of the sterol are thus potential inhibitors.The synthesis of substituted quinolizidines (3) is reported. 4-Methoxy-2,3-dimethylpyridine (4) was metalated and reacted with substituted 3-chloropropanal to build the 1-methyl-2-quinolizidinone.The lateral chain was prepared via a Wittig-Horner reaction.

Full text of DOI:10.1016/0040-4020(95)00062-D

Tetrahedron Vol. 5 No. pp.
Copyright 1995
Science Ltd
Printed in Great Britain. All rights reserved
Synthesis of New Substituted Quinolizidines as Potential
Inhibitors of Ergosterol Biosynthesis.
Philippe
Pierre
and Guy
Chimie Organique Fine et
de
1429,
National
Sciences
Rouen,
France.
76131 Mont-Saint-Aignan
species (High Energy Intermediates) have been
the course of enzymatic synthesis of ergosterol.
potential inhibitors. The synthesis of substituted
as intermediates in
of the sterol are thus
(3) is reported.
dimethylpyridine (4) was
and reacted with substituted
to build the
methyl-2quinolizidinone. The lateral chain was prepared via a Wittig-Homer reaction.
Fungitoxicity of fenpropidin and other commercial compounds such as
tridemorph and fenpropimorph appears to be due to their capacity to inhibit ergosterol
biosynthesis.1 Recently the inhibition of enzymatic cyclization of squalene
oxydosqualene have received increasing attention.2
Ergosterol
It was assumed twenty years ago that several enzymes implicated in sterol
biosynthesis catalyzed reactions involving postulated carbocationic high energy
intermediates
For example, a key step in ergosterol biosynthesis, the
transformation of fecosterol to episterol with
intermediate as described in scheme 1.1
is rationalized by an
3247

A. GODARD et
3 2 4 8
Scheme 1
Thus, molecules possessing structural or electronic analogy with such
intermediates
could be inhibitors of the corresponding reactions.4
reported the preparation of
to inhibit the action of the
such as
1 (scheme 2) which have been shown
isomerase blocking the synthesis of the
Under biological conditions, 1 presumably exists as the ammonium ion 2 in which the
nitrogen mimics the in
As part of a project aimed to the development of ergosterol biosynthesis
inhibitors, we were interested in whether structural relatives of 1 could also inhibit
isomerase activity. Our approach led us to the substituted quinolizidine 3, which has an
endocyclic nitrogen which could be protonated, an hydroxy propyl chain at C-2 which
could mimic ring A of the sterols and finally a benzyl group at C-7 chosen for its
lipophilicity.
Herein, we report the preparation and separation of several isomers of
quinoliidine 3.

3249
New substituted quinolizidines
RESULTS AND DISCUSSION
Our selected starting compound,
(4) was
(5). Pyridine N-oxide 6 was
Nitration of 6, according to
prepared in four steps starting from
prepared by oxidation of 5 as described by
method6 for dimethylpyridine N-oxides, afforded the nitro N-oxide (7). Reduction of 7
and nucleophilic substitution with methanol led to 4 in 36% overall yield (Scheme 3).
.
.
i
1 1
l
l
1 1 1
iv
77%
4
(i)
reflux;
reflux
(iii)
-20°C
(iv)
Scheme 3
The intermediate picolyllithium obtained by reaction of 4 with n-butyllithium
(scheme according to Beumel’s procedure,’ was allowed to react with
chloropropane to give 9, which then underwent in refluxing ethanol to
afford the pyridinium salt 10. Compound 1 0 was reduced by sodium borohydride in
methanol to give the enol ether 11 which was then hydrolyzed to l-methyl-Z
quinoliidinone (12) by reaction with aqueous hydrochloric acid. An excellent overall
yield (60%
indicated the presence of two stereoisomers of 12 in a ratio of
mixture was then equilibrated with ethanolic potassium hydroxide to a 19 1 ratio as
by vpc and NMR analysis. Isomers and 1 2 b could not be separated
by column chromatography.
4) was obtained.*
and
NMR analysis of the raw product
The product

A. GODARD et al.
3250
i i
I
l
4
9
. . .
111
i v
.
+
.
I
75% (from 10)
1 1
ratio (4 : 1)
equil.
ratio
(i) a)
(iv)
THF,
r.t.
b)
-30°C (ii)
Scheme 4
(iii)
If
trans-fused conformation has been demonstrated by
Compounds 12 shows Bohlman IR absorptions in the 2850-2700
region, indicating the presence of the predominantly conformer.
may exist in solution as an equilibrium, the predominance of the
NMR and
1 2 a
As a consequence of the hydrolysis of the intermediate enol-ether 11, the major
isomer was assumed to have an equatorial methyl group. spectra present a
doublet for the methyl group at 1.02 ppm for the preponderant isomer and at 1.20 ppm
for the other one. The NMR spectra show a signal at 9.5 ppm for the methyl group
of the major isomer and at 12.0 ppm for the other one.
In view of our requirement for introducing methyl and
at C-7 of compound 3 it was desirable to prepare a
groups
propane as bis electrophile. The suitably substituted I-iodo-3-
chloro propane was synthetized as follows (scheme 5).

3251
New substituted quinolizidines
Diethyl methyhnalonate was alkylated with
resulting diester 13 reduced with lithium
bromide and the
hydride to give the diol 14. One
hydroxyl group of 14 was replaced by a chlorine atom with a good yield as described
by The second hydroxyl group was then replaced by an atom the
method described by The chloroiodopropane 16 was obtained in 56% overall
yield from diethyl methyhnalonate.
9 1 %
HOCK,
8 6 %
1 3
1 4
iv
.
9 0 %
1 5 %
HOC”,
(i) a)
b)
b) DMF, 100°C (iv)
(ii)
a)
Scheme
5
Unlike the parent example, this dihalogeno compound 16 proved totally
unreactive with the lithiated derivative of 4 (see scheme 6). Obviously steric hindrance
prevents nucleophilic substitution
alternative route for carbon-carbon bond formation would be to add the
lithiated derivative of 4 to an appropriate aldehyde such additions are known to be
less dependant on steric hindrance, The required aldehyde 17 was synthesized by
oxidation of the chloropropanol15 with
(scheme 5).
The addition of picolyllithium obtained by metalation of 4 to aldehyde 17
afforded the expected alcohol in good yield (84%) (scheme 6). Dehydration of the
secondary alcohol 18 in the presence of triphenylphosphine and carbon
gave the alkene 19. Hydrogenation of the double bond
excellent yield (95%).
compound 20 in an
The pyridinium salt 21 was obtained by intramolecular quatemarization in
refluxing ethanol. Reduction of 21 with sodium borohydride the enol-ether 22

A.
et al.
3252
which was then hydrolyzed into ketones 23. The
(4).
yield was 51% starting
vi
.
76% (from
3
23
(i) a)
THF,
(iv)
b) 1 7 , THP, -60°C (ii)
(iii)
Scheme 6
As shown by
NMR analysis of crude
four diastereoisomers were
formed in a
ratio Flash chromatography on silicagel delivered two pure
diastereoisomers,
and
each one in a racemic mixture.
Because 23 presents four stereogenic centers, sixteen stereoisomers could be
obtained. Nevertheless several features of the intermediates make the synthesis more
selective. On one hand, it could be expected, as for compound 12, that major
stereoisomers bear the methyl group at C-l in an equatorial position in a bicyclic

3253
New substituted quinolizidines
structure having a
On the other hand, a new stereogenic center at C-7 is
now present. Finally, four major stereoisomers were isolated as two racemates 23a and
the structures of which were established by NMR, COSY and
NOESY spectra analysis.
23a
tram
Scheme
7
The main difference between the two stereoisomeric pairs is the relative position
of benzyl and methyl groups at C-7. Structures having (C-7)-benzyl bond and
bond in a cis position have been called cis and the others trans.
of the two
rings is
by the presence of Bohhnann
spectra of the
in IR spectra of 23a and 23b at 2760 and 2800
two quinolizidiiones 23s and 23b present a doublet at 0.98 ppm and 1.02 ppm
respectively which can be attributed to the l-Me group in an equatorial position as seen
before for compound 12. In the
manner
NMR spectra show signals at 9.8
NMR spectra of the two
ppm for the equatorial l-Me group. Moreover,
quinoliidones 23 show different features attributed to the methyl group and to the
methylene of the benzyl group at C-7. On one hand, the signals of the methylenic
hydrogen of the benzyl group are quite different. For compound
at 2.40 ppm and for compound there is an AB pattern (J
2.93 ppm. Finally, the NOESY spectra of compound
DMX 500 spectrometer in CDC13 revealed conclusive correlations for
and and (scheme
there is a singlet
=
13.0 Hz) at 2.54 and
recorded on a Bruker
Scheme 8

3254
A.
et al.
On the other hand,
has shown that for
, the axial
methyl group close to the electron
of nitrogen is deshielded (6 1.08 ppm)
compared to the equatorial methyl group (6 = 0.82 ppm). In the same way, the singlet
at 1.02 ppm was ascribed to the trans isomer 23b in which the methyl group is in an
axial position, the singlet at 0.71 ppm was ascribed to the equatorial methyl group of
cis isomer 23a.
Wittig-Homer
reaction of
quinolizidinones
23a
with
cyanomethylphosphonate according to Corey’s procedure18 led to compounds 24a.
Sequential reductions of the double bond with
diisobutylahuninium the substituted
compounds 3a was performed by reaction of methyllithium in
and of the
group with
26a. Synthesis of
presence of
trichloride to prevent
The C-7 epimeric mixture 23b was converted to
3b in a similar way. The stereochemistry of the new stereogenic centers at C-2 and at
the C bearing the secondary alcohol were not controled and mixtures of stereoisomers
were obviously obtained (scheme 9).
Z = CN
Z
CHO
b :
(i)
DME, argon
12h.
Pd-C
DIBAH,
-70°C
(iv)
THF,
Scheme
9

3255
New substituted quinolizidines
In conclusion, compounds 3a and 3b have been
starting
dimethylpyridine (5) in 1.15% and 4.65% overall yields, respectively. These compounds
were tested for their activity on the
sterol isomerase by using the cell-free
system
Saccharomyces cerevisiae as described by Isomer 3b proved
isomerase as strong as fenpropidin used as standard
to be an inhibitor of
whereas isomer 3a was slightly less active
= 0.96
The synthesis of
potential inhibitors of ergosterol biosynthesis by variation of substituents at C-7 of 3
can easily be achieved by use of other biselectrophiles in the metalation step (scheme
6).
EXPERIMENTAL PART
NMR spectra were recorded in
on a VARIAN 360L (60 MHz)
spectrometer, on a BRUCKER AC 200F (200 MHz) or on a BRUCKER AM 360
(360 MHz) spectrometer. Chemical shifts are in parts per million with respect to TMS
in
Melting points were determined on a Kofler apparatus. Infrared spectra were
recorded on a BECKMAN IR 4250 spectrometer. Flash chromatography was carried
out on MERCK Silica gel 60, 0.063-0.200 mm (70-730 mesh ASTM).
were performed on a CARLO ERBA 1106 apparatus. Mass spectral data were
obtained on a
JMS-AX 500 mass spectrometer.
(8). A solution of 7 (46 g, 0.273 mol) in
(180 ml) was cooled to
(40 ml) was then added and the temperature maintained at
after addition. The solution was heated to
cold water (30 ml) was added and the solution neutralized with diluted aqueous
The organic layer was washed with water, dried and evaporated to
dryness to afford compound 8 (38.3 92%) which was used in the next step without
A solution of freshly distilled
(30 ml) in
for 15 min
and stirred for 15 min. After cooling to
purification.
(60 MHz,
2.4 (s,
2.7 (s,
7.4 (d, = 5.5 Hz,
8.5 (d, = 5.5 Hz,
(4).
(70 0.5 1 mol) was added to a
stirred solution of 8 (38.85 0.255 mol) in anhydrous methanol (510 ml). The mixture
was refluxed for 20 h and solvent was evaporated. Water (50 ml) and ether (150 ml)
were then added, the aqueous layer removed and organic layer washed with water (50
ml), dried
yielded
(15
and evaporated to dryness. Distillation under reduced pressure
(26.9 77%) as a colorless oil; bp
NMR (60 MHz,
2.1 (s,
2.45 (s,
3.8 (s,
6.6

3256
A. GODAR D et al.
1585, 1480, 1420, 1290, 1130,
1095, 1010, 810 cm-l. Anal. calcd for
: C, 70.04;
8.08; N, 10.21. Found :
C, 69.80;
7.99; N, 10.23.
chloride (10).
Butyllithium
solution in hexane, 1.5 ml, 2.2 mmol) was added
to a
cooled at -25°C under
(340
solution of 4 (274 mg, 2 mmol) in anhydrous THF (15
argon. The solution was stirred at
3.4 mmol) was then added
for 1 h.
and the mixture stirred at
(5 ml) at
for 1 h. After
hydrolysis with saturated aqueous
(50 ml) was added.
The usual workup (the aqueous layer was removed and the organic layer was washed
with water, dried and evaporated to dryness) a crude
product which was diluted with absolute ethanol (20 ml) and brought to reflux for 20 h.
Washings with hexane (4x5 ml) of the residue obtained after evaporation of the ethanol
a white solid (342 mg, 80%) which was used in the next step without further
mp
NMR (60 MHz,
7.55 (d, =
2.15 (m,
9.3 (d, J =
2.3 (s,
3.2
4.2 (s,
4.8
(film) 3446, 1630, 1498, 1308, 1107 cm-l.
(12a and
To a solution of 10 (1.5
7
in absolute methanol
ml) was added sodium borohydride (2.66 70 mmol)
in several portions for 36 h at r.t.. Aqueous
was evaporated. Extraction with
(10 ml) was added and methanol
and evaporation in
a crude
enol-ether 11 which was dissolved in 10% aqueous
ml) and stirred overnight at
After addition of
(50 ml). After usual workup, crude 12 was purified by distillation under
reduced pressure to give a slightly yellow oil (937 mg, 80%); bp (15 mm Hg).
1.18 (d, = 7. I Hz,
2.1-2.4 2.55-2.75 (m,
until neutral
the aqueous layer was extracted with
NMR (200 MHz,
1.20-1.25 (m,
2.8-3.05 (m,
55.4, 55.8, 67.9, 209.6; 12b 12.0, 23.3, 24.9, 28.1, 37.8, 49.1, 55.6, 64.1, 212.5.
(film) v 2934, 2856, 2801, 2760, 1716, 1363, 1351, 1290 Anal. calcd for
: C, 71.81; H, 10.25; N, 8.38. Found : C, 71.54; 10.40; N, 8.51.
1 .O (d, = 6.7 Hz,
1.45-1.8 (m,
NMR
1.8-2.05
12a 9.5, 23.2, 25.1, 31.2, 41.1, 49.4,
Diethyl
(13). Sodium (1.8
78.2
50
mmol) was added to absolute ethanol (60 ml). Then diethyl methylmalonate (8.6
mmol) was added
cooled at 0°C and
and the mixture was stirred at r.t. for 2 h. The mixture was
bromide (13.8 ml, 75 mmol) was added. After

3257
New substituted quinolizidines
refluxing for 3 h and then cooling, water (20 ml) and
(200 ml) were added.
Usual workup gave the raw product which was purified by distillation under reduced
pressure (13.8 g, 86%); bp 145°C (1.5 mm Hg).
NMR (60 MHz,
4.2 (q,
1.28
7.07 (d,
8.81.
(t,
1.33 (s,
7.31 (d,
1.38 (s,
3.2 (s,
=
=
Anal. Calcd for
: C, 71.22;
Found : C, 71.01; H, 8.97.
(14). To a suspension of
(2.34 g, 61.7 mmol) in dry ether (50 ml) was added a solution of 13
(13.15 g, 4 1.1 mmol) in dry ether (90 ml). The mixture was stirred for 4 h at and
(2.4 ml) and water (7.6 ml) were added. The
and the organic layers concentrated in
water (2.4 ml), 15 % aqueous
precipitate was filtered off, washed with
to give 14 (9.4 g, 97%).
(200 MHz,
7.13 (d, =
0.80 (s,
1.35 (s,
2.68 (s,
3.02 (s,
3.57 (s,
Hz, 7.32 (d, = 10
Hz,
(15). To a solution of
14 (1.624 6.88 mrnol) in anhydrous THF (30 ml) cooled to
added
triamide (1.25 ml, 6.88 mmol) was introduced
mixture was stirred for 1.5 h at then 3 h at
in
was heated to
the residue in ether was filtered on silicagel (eluent ether). After removal of the
under argon was
(1.92 ml, 19.9 mmol). Then freshly distilled hexamethylphosphorous
within 0.5 h. The reaction
The solvent was then evaporated
the crude salt was dissolved into freshly distilled DMF (9 ml) and the mixture
for 16 h. DMF was then removed by distillation. A solution of
solvent, the crude oil (1.57 g, 90
was used without
2.3 (s,
purification.
3.45 (m,
NMR
7.1
1.3 (s,
(d, J = 10 Hz,
7.3 (d, J =
(16). To a stirred
solution of 15 (5 14 mg, 2.02 mmol) in dry toluene (50 ml) were added in the following
order (2.098 g, 8 mmol), imidazole (545 mg, 8 mmol) and (1.52 g, 6 mmol).
The mixture was refluxed for
stirring for 5 a small quantity of was added to
cooled and treated with aqueous
(50 ml).
the organic layer,
until
the mixture stirred for 10 min and excess reduced with
The organic layer was washed with water (20 ml), dried
and concentrated
under reduced pressure. Crude 16 was purified by chromatography on silicagel (eluent
n-hexane) to give a pale yellow oil (550 mg, 75%).
(s, 1.3 (s, 2.7 (s, 3.25 (s, 3.4 (s,
(60 MHz,
1.05
7.3
7.1 (d, J = IO Hz,

3258
A.
et al.
(d,
=
Hz,
Anal.
for
: C, 49.4; H, 6.08. Found : C, 49.5; H,
6.14.
(17). A solution of 15
(508 mg, 2
in dry
was added to a suspension of pyridinium
chlorochromate (647 mg, 3 mmol) in dry
(4 ml) at
The mixture was
stirred for 2 h and dry
solid was washed with dry
and concentrated in
(3 ml) introduced. The reaction mixture was filtered, the
and the combined organic filtrates filtered on Florisil
Purified product (colorless oil) was obtained by flash
chromatography (eluent ether/n-hexane,
1.20 (s, 1.35 (s, 2.88 (d, = 13.8 Hz,
3.55
7.35 (d, = 8.4 Hz, 21-Q 9.67 (s,
g, 78%). NMR (200 MHz,
3.02 (d, = 13.8 Hz,
MS
252
methylpyridine (18). To a solution of 4 (180 mg, 1.31 mmol) in anhydrous THF
ml) cooled at under argon, was added n-butyllithium (2.5 M solution in
hexane, 640 1.6 mmol). The mixture was stirred at for 1 h and cooled to
before introduction of a solution of 17 ( 383 mg, 1.6 rnmol) in anhydrous THF
(4 ml). After 3 h at the reaction mixture was hydrolyzed at -10°C with saturated
aqueous
(5 ml). Aqueous layer was extracted with
(50 ml) and the
The crude product was purified
to afford a white
combined organic layers were concentrated in
by flash chromatography on silicagel (eluent
solid (0.43 g, 84%) as a mixture of two diastereomers
NMR (200 MHz,
1.02 (s,
1.32 (s,
2.18 (s,
2.70-3.15 (m,
J=
6.70 (d, = 6.2 Hz,
IR (film) v 3300, 2960, 2900, 2860, 1590, 1480, 1290, 1270, 1100
for C, 70.84; H, 8.27; N, 3.59. Found : C, 70.48; H, 8.34;
3.37 (d, = 11.4 Hz,
J=
3.78 (d, J=
3.85 (s,
4.15 (m,
7.3 (m,
8.25 (d, J =
6.2 Hz,
N, 3.45.
methylpyridine (19). To a refluxed solution of 18 (113 mg, 0.29 mmol) and
mg, 0.35 mmol) in dry (2 ml) was added mmol). After 20 min,
the solvent was evaporated and water (3 ml) added. The aqueous layer was extracted
with (20 ml), the organic layer was dried and concentrated in
The crude product was purified by flash chromatography on silicagel (eluent
to a colorless oil (92 mg, 85 NMR (200 MHz,
(91

3259
New substituted quinolizidines
1.25 (s,
1.31 (s,
2.15 (s,
2.83 (d, = 13.4 Hz,
2.93 (d,
=
Hz,
8.35 (d, = 5.6 Hz,
v
1650, 1570, 1515, 1470, 1440, 1270,
: C, 74.27; 8.13; N, 3.77. Found :
1100, 975, 740
for
C, 74.10;
8.11; N, 3.80.
pyridine (20). To a solution of 19 (2.468 g, 6.64 mmol) in absolute ethanol (110 ml)
was added 10% Pd on charcoal (245 mg) and acetic acid (760 ml, 15.3 mmol). The
mixture was stirred under
mixture was filtered on Celite and eluted with ethanol. The solvent was evaporated in
To the residue was added aqueous (5 ml) and the aqueous layer was
extracted with (20 ml). The organic layer was dried
The crude slightly yellow oil (2.35 g, 95
atmosphere. After the end of absorption,
reaction
and
was used in the
1.04 (s,
concentrated in
next step without
purification.
2.20 (s,
NMR (200 MHz,
1.31 (s,
1.77 (m,
2.84 (m,
7.3 (d, = 8.3 Hz,
2.62 (d, = 13.4 Hz,
2.77 (d, = 13.4
7.16 (d,
IR (film) 2960,
373
Hz,
3.41 (s,
3.85 (s,
6.64 (d,
8.29 (d, = 5.7 Hz,
= 8.3 Hz,
2860, 1580, 1510, 1475, 1460, 1435, 1285, 1095,740 cm-l. MS
quinolizinium chloride (21). A solution of 20 (3.6 g, 9.6 mmol) in absolute ethanol
(12 ml) was refluxed for 68 h. The ethanol was evaporated, a crude oil was obtained in
a quantitative yield (3.6 g) and used in the next step without further purification,
1.21 (s,
4.35 (s,
2.15 (s,
6.98 (d, = 8.3 Hz,
2.61
7.23 (d,
(m,
3.00 (m,
4.05 (s,
(22).
Compound 21 (3.6 g, 9.6 mmol) was dissolved in absolute methanol (100 ml) and
sodium borohydride (3.63 g, 96 mmol) was added by portions within 12 h. The mixture
was stirred for 12 h and the solvent removed.
added. The organic layer was dried
(10 ml) and
(50 ml) were
The crude
NMR (200
3.55 (s,
and concentrated in
product (3.27 g) was used without
purification in the next step.
1.3 (s, 1.65-3.05
MHz, CDCI,) 0.8 (s,
1.05 (s,
7.1 (d, J = 8.3 Hz,
7.3 (d, J = 8.3 Hz,

3260
A. GODAR D
a l.
(23). The crude
compound 22 (3.27 g) was dissolved in 10% aqueous HCI
stirred overnight and then
ml). The mixture was
was added to bring the solution to
9. The
aqueous layer was extracted with
(200 ml). The organic layer was dried
The crude product was purified by flash chromatography on
and concentrated in
silicagel (eluent
23a white solid (1.16 g, 37 %
to afford two compounds
20) mp
and 23b. Isomer
(360 MHz,
1.50 (m, 1.65
0.71 (s,
0.98
1.04
1.26 (s,
2.34
2.47 (dd, = 2.3 and 11.4 Hz,
2.54 (d, = 13.0 Hz,
26.1, 28.2, 31.4,
=
7.25 (d,
34.0, 34.6, 35.0, 41.2, 41.6, 49.7, 55.8, 64.7, 68.3, 124.5, 130.2, 136.2, 148.4, 210.6.
2960, 2920, 2860, 2800, 2760, 1720, 1510, 1465, 1365 cm-l. MS @I)
327
80.52; H, 10.32; N, 4.06. Isomer 23b white solid (1.16 g, 37 %
NMR (360 MHz, 0.95 (d, = 6.6 Hz, 1.02 (s,
1.26 (s, 1.4 (m, 1.63 1.75 (m,
2.25 (m, 2.40 (s, 2.50 (d, Hz, 2.65 (m,
7.0 (d, J = 7.6 Hz, 7.2 (d, J = 7.6 Hz, v 2960, 2940, 2860, 2800,
2760, 1720, 1520, 1460, 1360 cm-l. MS 327 Anal. calcd for
calcd for
: C, 80.68; 10.16; N, 4.28. Found : C,
20) mp
1.15
(m,
1.95 (d, = II Hz,
2.95 (m,
=
: C, 80.68; H, 10.16; N, 4.28. Found : C, 80.55; H, 10.56; N, 3.98.
(24a).
To a suspension of
(60% in mineral oil, 444 mg, 11.1 mmol) in distilled
(20
ml) under argon was added a solution of diethyl cyanomethylphosphonate (1.966 g,
11.1 mmol) in distilled (5 ml). The mixture was stirred for 5 min and a solution of
23a (1.209 g, 3.7 mmol) in distilled (10 ml) was added. The mixture was stirred
for 27 h at and poured into water (100 ml). The aqueous layer was extracted with
(200 ml), the organic layer was dried and concentrated under
The residue was purified by flash chromatography on silicagel (eluent
3: 1) to give 24a (1.10 g, 85%) mp: 106°C.
(200 MHz,
1.4-1.75
5.05 (s,
0.75 (s,
1.8
7.05 (d, J =
1.05 (d, J =
2.1 (m,
1.25 (m,
2.5 (m,
1.35 (s,
2.3 (m,
2.95 (m,
7.6 Hz,
7.25 (d, J = 7.6 Hz,
v 2960, 2900, 2860, 2800, 2760,
for : C, 82.23;
2365, 2220, 1635, 1460, 1365, 1110
H, 9.78; N, 7.99. Found : C, 82.12; H, 10.12; N, 7.74.

3261
New substituted quinolizidines
(24b).
Isomer 24b was prepared as described above and purified by flash chromatography on
silicagel (eluent ether) to a slightly yellow solid (1.165 g, 90%): mp:
144°C.
1.6-2.0
(200 MHz,
1.0
1.2 (m,
2.45
1.3 (s,
2.9
1.4 (m,
5.05
2.45 (s,
(s,
7.05 (d, = 7.6 Hz,
7.25 (d, = 7.6 Hz,
v 2960, 2900,
: C,
2860, 2800, 2760, 2215, 1630, 1460, 1365, 1015 cm-l. Anal. calcd for
82.23; H, 9.78; N, 7.99. Found : C, 82.32; 10.10; N, 7.79,
(25a). To
a solution of 24a (1.17 g, 34
The reaction mixture was stirred under
the mixture was filtered on and
in and aqueous
extracted with (2x20
in The mixture of diastereomers
in
(30 ml) was added 10% Pd-C (117 mg).
atmosphere. When absorption was finished,
with ethanol. The filtrate was concentrated
(15 ml) added to the residue. The aqueous solution was
the organic phase was dried
and concentrated
was isolated by flash chromatography on
as a pale yellow oil (826 mg, 69%).
silicagel (eluent
(200 MHz,
1.4-1.75
0.75 (s,
0.95 (d,
2.3-2.65 (m,
for
=
1.1 (m,
2.75-3.0
1.3 (s,
7.1 (d,
1.75-2.2 (m,
=
7.6 Hz,
7.3 (d, = 7.6 Hz, 2H). Anal.
: C, 81.76; H, 10.29;
N, 7.94. Found : C, 81.54; H, 10.22; N, 8.01.
(25b).
The mixture of diastereomers 25b was prepared as described above and purified by
flash chromatography on silicagel (eluent ether/n-hexane as a yellow solid (766
mg, 64%) mp 103°C. NMR (200 MHz,
1.2 (m, 1.3 (s, 1.4 1.6 (m,
7.05 (d,
8 0.9
=
1.65-2.2 (m,
7.25 (d,
1.0
2-2.5
21-I).
Anal.
N, 7.64.
for
: C, 81.76; H, 10.29; N, 7.94. Found : C, 82.02; H, 10.32;
(26a). To
a solution of
(759 mg, 2.15 mmol) in distilled n-hexane (30 ml) cooled at
under argon was added
hydride
and the temperature was kept at
solution in
2.8 ml, 2.8
for 4.5 h. The reaction
solution (14 ml) and
mixture was hydrolyzed at
with a saturated aqueous
stirred for 15 min. Then a solution of sulfuric acid (333
and the aqueous layer was extracted with Aqueous
in water (7 ml) was added
was added to bring

A. G ODAR D et al.
3262
aqueous solution to
9 and extracted with AcOEt. The organic layers were dried
and concentrated in
flash chromatography on silicagel (eluent
The mixture of diastereomers 26a was isolated by
to yield a pale yellow oil
0.95 1.2
7.1 (d, = 7.6 Hz,
(534 mg, 70%).
1.3 (s,
NMR (200 MHz,
2.3-2.8 (m,
0.75 (s,
2.9 (m,
1.4-2.2
9.8
(film) v 2960, 2900, 2800, 2755, 1715,
: C, 81.07; H, 10.49; N, 3.94.
7.3 (d, = 7.6 Hz,
1465, 1365, 1125 cm-l.
Anal. calcd for
Found : C, 81.29; I-I, 10.40; N, 3.81.
(26b).
Compounds 26b were prepared as described above starting from
by flash chromatography on silicagel (eluent ether/n-hexane l/l) to
and were isolated
a yellow oil
1.2 (m,
(618 mg,
NMR (200
0.95
2.2 (m,
7.25 (d, = 7.6 Hz,
1365, 1125 Anal. calcd for
81.07; H, 10.49; N, 3.94. Found : C, 80.77; H, 10.48; N, 3.81.
1.0 (s,
2.4 (m,
9.8 (m,
2.7 (m,
2.75
1.3 (s,
1.4
1.5-2.0
(m,
7.05 (d, = 7.6 Hz,
1725, 1465,
IR (film) v
: C,
(3a). A suspension of
(468 mg, 1.89 mmol) in anhydrous
for 2 h then cooled at
(10 ml) was
stirred under argon at
Methyllithium (1.6 M solution
in ether, 1.27 ml, 2.04 mmol) was added dropwise. The mixture was stirred for 1 h and
a solution of 26a (520 mg, 1.46
in anhydrous
(8 ml) was added. The
was added at -10°C.
mixture was stirred at -65°C for 4.5 h, saturated aqueous
The mixture was filtered on Celite and eluted with AcOEt. The aqueous phase was
extracted with AcOEt, the organic layer was dried and concentrated in
Compounds 3a were isolated by flash chromatography on silicagel as a mixture
of diastereomers (eluent to give a pale yellow oil (168 mg, 3 1%).
(200 MHz,
1.4-2.2 (m, 2.3-2.8 (m,
0.75 (s,
2.9 (m,
0.95 (m,
1.2 (m,
7.1 (d, = 7.6 Hz,
Anal. calcd for
3.61.
1.3 (s,
3.9 (m,
7.3 (d, = 7.6 Hz, 21-I). MS (CI)
372
: C,
C,
(3b). Compounds 3b were synthesized as described above. The only change was the
stirring at overnight instead of 4.5 h. Compounds 3b were isolated by flash
chromatography on basic alumina (eluent ether/n-hexane to afford a yellow oil
(379 mg, 70%). (200 MHz, 0.9 (m, 1.05 (s, 1.2 (m,

3263
New substituted quinolizidines
1.3 (s,
1.4 (m,
1.5-2.0
2.2
2.4
2.7 (m,
3.9
Anal. calcd for
N, 3.66.
: C, 80.80; H, 11.12; N, 3.77. Found : C, 80.94;
11.41;
Acknowledgements: Dr. P. Masner of Dr. R. Maag Mt., Dielsdorf, for carrying
out the enzyme assays and Ciba-Geigy Ltd., Basel, for financial support.
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(Received in Belgium 18 July 1994; accepted 13 January