Synthesis and biological activity of the structural analogues of (-)-cabenegrin A-I

Article abstract of DOI:10.1002/1521-4184(200102)334:2<53::AID-ARDP53>3.0.CO;2-C

A series of phenylbutene and butanol derivatives (6a-j, 12, 13, 15, 17, 24b,c, 26, 27a,b) were prepared from the readily available resorcinol derivatives 2a-f and 7-hydroxy-chroman (18). The products were tested for inhibitory activity on the LPS-induced

Full text of DOI:10.1002/1521-4184(200102)334:2<53::AID-ARDP53>3.0.CO;2-C

Structural Analogues of (–)-Cabenegrin A-I
53
Synthesis and Biological Activity of the Structural Analogues of
(–)-Cabenegrin A-I
a)
a)
a)
b)
c)
d)
d)
Katalin Gulácsi , György Litkei , Sándor Antus* , Csaba Szántay , László L. Darkó , Judith Szelényi , György Haskó ,
d)
and Szilveszter E. Vizi
a) Department of Organic Chemistry, University of Debrecen, P.O.Box 20, H-4010 Debrecen, Hungary
b) Institute of Organic Chemistry, Technical University, P.O.Box 91, H-1111 Budapest, Hungary
c) Farmacon Inc., 90 Grove Street, Suite 109 Ridgefield, Connecticut 06877-4118, USA
d) Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, P.O.Box 67, H-1450 Budapest, Hungary
Key Words: Cabenegrin; structure-activity relationship; tumor necrosis factor
ing a hydroxyisoprenyl side chain with E-geometry, seems to
be the most essential for the biological activity.
Summary
A series of phenylbutene and butanol derivatives (6a–j, 12, 13, 15,
17, 24b,c, 26, 27a,b) were prepared from the readily available
resorcinol derivatives 2a–f and 7-hydroxy-chroman (18). The
products were tested for inhibitory activity on the LPS-induced
TNF-α production in the plasma in comparison with that of ca-
benegrin A-I (1a).
Results and Discussion
Chemistry
A simple synthesis of (E)-but-2-ene derivatives (6a,b)
could be achieved from the respective resorcinol derivatives
Introduction
Pterocarpans are naturally occurring plant products carry-
[1]
ing a cis-fused benzofuranyl-benzopyran ring system , and
many of them exhibit various biological effects, most particu-
[2]
[3]
larly antifungal , antibacterial, and anti-HIV activity . In
1982 one of us demonstrated that two representatives of these
natural products, cabenegrin A-I [(–)-1a] and A-II [(–)-1b]
(Figure 1) are the active components of a Brazilian folk
[4,5]
medicine used against snake venoms
. Although the most
active component, (–)-cabenegrin A-I (1a), is synthetically
[6]
[7]
available both in racemic and optically pure forms, these
multistep procedures are not suitable for industrial produc-
tion.
Figure 1
In order to establish the pharmacophore of this molecule, it
appeared reasonable to synthesize a series of phenylbutene
and butanol derivatives (6a–j, 12, 13, 15, 17, 24b,c, 26,
27a,b) for a structure-activity relationship study, with the fact
in mind that the A-ring of (–)-cabenegrin A-I [(–)-1a] carry-
Scheme 1
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0365-6233/01/0202/0053 $17.50 +.50/0

54
Antus and co-workers
(2a,b). Our approach (Scheme 1) was based on the method
[8–10]
described by Bohlmann et al.
, who recognized that
various C-3,3-dimethylallylphenols could be stereoselec-
tively transformed by oxidation with selenium dioxide in
acetic anhydride into the corresponding (E)-1-acetoxy-2-
methylprop-2-en-1-yl derivatives in good yield.
Accordingly, resorcinol dimethyl ether (2a) was regioselec-
tively lithiated with n-butyllithium in cyclohexane, followed
by trapping of the formed lithium intermediate (3a) by addi-
tion of 3,3-dimethylallyl bromide to result 4a in a moderate
yield (51%). In a good agreement with Bohlmann’s observa-
[8–10]
tions
, oxidation of 4a took place regioselectively in the
presence of a stoichiometric amount of selenium dioxide to
furnish the acetoxy derivative 5a, whose saponification with
sodium methoxide in methanol at room temperature afforded
6a in 37% yield. As shown in Scheme 1, the same sequence
(2b → 3b → 4b) was used for the preparation of 4b. It is to
be noted that oxidation of 4b with selenium dioxide under the
conditions used for 4a resulted in a ca. 1:2 mixture of 5b and
1
5c based on the H-NMR spectra. Although our attempts for
the separation of this mixture were unsuccessful, reduction
with lithium aluminium hydride yielded our target molecule
(6b) in a good yield (70%). In the case of the dimethylallyl-
phenol derivative 4e, prepared from 2c in four steps (2c → 3c
[11]
→ 4c → 4d → 4e) according to the literature
, oxidation
with selenium dioxide provided also an astonishing result.
Thus, introduction of the acetoxy group into the dimethylallyl
side chain took place with an opposite regioselectivity (Z)
than found in the case of 4a or 4b. The Z-geometry of the
double bond of 5d and 6c (prepared by simple saponification
of 5d with sodium methoxide) could be unequivocally de-
tected by NOE experiments.
The intermediate 4a was found to be an appropriate starting
material also for the synthesis of 6d. Thus, oxidation of 4a
with 2 molar equivalents of selenium dioxide for a fourfold
prolonged period than used in the case of the transformation
of 4a or 4b, resulted in the diacetate 5e, which was isolated
by means of column chromatography on silica gel with 14%
yield. Saponification of this latter with sodium methoxide in
methanol at room temperature gave 6d in a moderate yield
(41%).
Scheme 2
was commercially available, and 2e and 2f were prepared
from the readily available resorcinol monomethyl ether and
orcinol by simple alkylation according to the literature
In the case of 2g, we started from the readily available
3,5-dimethoxybenzaldehyde (2h), whose Grignard reaction
with ethylmagnesium bromide in ether at room temperature
resulted in the benzyl alcohol 2i in good yield (88%). Finally,
catalytic hydrogenation of 2i in the presence of palladium on
charcoal in acetic acid at room temperature afforded 2g in
68% yield.
[13,14]
.
Starting from 2a, the synthesis of the (E)-but-2-ene deriva-
tive 6a could also be achieved by the Wittig methodology
which had been previously used for the synthesis of the
[6,7]
racemic and optically active cabenegrin A-I (1a)
. In the
first step, the lithium salt 3a of 2a was alkylated with the
commercially available bromoacetaldehyde diethyl acetal,
and the resulting acetal was hydrolyzed under mild acidic
conditions to the aldehyde 7a as shown in Scheme 2. Accord-
[6,7]
ing to earlier procedures
, the Wittig reaction of the
aldehyde 7a with α-ethoxycarbonyltriphenylphosphonium
[12]
bromide
in the presence of sodium ethoxide in ethanol at
room temperature furnished the respective α,β-unsaturated
ester 8a. Finally, reduction of 8a with lithium aluminium
hydride in ether at room temperature resulted in the allyl
alcohol derivative 6a in a moderate yield (37%). In order to
influence the lipophilicity of 6a, and therefore to modify its
pharmacological profile, its substituted derivatives (6e–j)
were also synthesized by the Wittig methodology starting
from the phenol derivatives 2d–g as depicted in Scheme 2.
Among these starting materials resorcinol diethyl ether (2d)
Scheme 3
Arch. Pharm. Pharm. Med. Chem. 334, 53–61 (2001)

Structural Analogues of (–)-Cabenegrin A-I
55
It seemed also to be interesting to find out the influence of
the position of the double bond and the stereochemistry in the
side chain of 6a on the biological activity. Therefore, we
prepared the structural analogues 12 and 13 from the ester 8a
as depicted in Scheme 3. Interconversion of the (E)-but-2-ene
8a by photoisomerization in benzene at room temperature
resulted in a mixture of the butene derivatives 9, 10, and 11,
whose separation could be achieved by column chromatog-
raphy on silica gel. Reduction of the esters 9 and 10 gave the
corresponding primary alcohols 12 and 13, respectively. The
allyl alcohol 12 was also formed in a moderate yield (23%)
when 6a was irradiated in benzene at room temperature.
The simple aldol condensation of the aldehyde 7a in the
presence of sodium ethoxide in ethanol at room temperature
gave the α,β-unsaturated aldehyde 14 in 56% yield, whose
reduction with lithium aluminium hydride under standard
conditions afforded the specifically substituted but-2-ene de-
rivative 15. In the course of our detailed study on the struc-
ture-biological activity relationship, the chroman derivatives
24b,c, carrying a hydroxyisoprenyl side chain at C-8, were
also synthesized from 7-hydroxychroman (18) according to
our procedure employed for the total synthesis of (–)-cabene-
[7]
grin A-I (1a). In the first step, 7-hydroxychroman (18) was
transformed by alkylation with allyl bromide in the presence
of sodium hydride in DMF into the allyl ether 19 in good yield
(72%), whose thermal Claisen rearrangement in xylene at
200 °C gave the chroman derivative 20 in 50% yield. In the
next step, 20 was alkylated with chloromethyl methyl ether
(20 → 21a) and the product was reacted with osmium tetrox-
ide, followed by oxidation with sodium metaperiodate in
dioxane at room temperature to give aldehyde 22a in an
overall yield of 85%. The last two steps of the synthesis (22a
→ 23a → 24a) were performed as in the case of 6a and 6e–f,
and thus 24a could be isolated in 63% yield, whose deprotec-
tion under mild acidic conditions furnished the target mole-
cule 24c. Its methyl ether 24b was also synthesized according
to the same sequence (20 → 21b → 22b → 23b → 24b)
starting from the chroman derivative 20 in an overall yield of
31%.
Scheme 4
Taking into consideration that cabenegrin A-II (1b) pos-
sesses a reduced antidote activity against the venom of
Bothrops atrox as compared to cabenegrin A-I (1a), and also
that they are different in the side chains located in ring-A, it
Scheme 5
Scheme 6
Arch. Pharm. Pharm. Med. Chem. 334, 53–61 (2001)

56
Antus and co-workers
seemed to be reasonable to prepare some analogues of ca- unsaturated side chain on A ring of 1a and its E-geometry, as
benegrin A-II (1b), as well. The synthesis ofthese compounds well as the position of the double bond is essential for the
(26, 27a,b) is depicted in Scheme 6. In the first step, 8a was inhibitory activity. Since elongation of the side chain of 6a
reduced by catalytic hydrogenation over 10% palladium on with one or two carbon atoms (6i, 6j) resulted in a significant
charcoal to give the saturated esters 25 in good yield, whose loss of the inhibitory action of the molecule, therefore it is
reduction with lithium aluminium hydride in ether at room presumable that the four carbon atom length of the side chain
temperature resultedinthecorrespondingprimaryalcohol26. of 1a may also play an important role in its activity. In this
The synthesis of 27a and 27b could be achieved by simple context it is to be noted that substitution of the methyl group
reduction of 24b and 24c over 10% palladium on charcoal in at C-2 of 6a with a 2,6-dimethoxyphenyl group (6a→15) gave
methanol, respectively.
rise to a remarkably smaller influence on the inhibition.
Moreover, it is noteworthy that further analogues of 6a (i.e.
6b, 6c, 6f–h) possessing higher lipophilicity were found to be
still less active in the inhibition of the endotoxin-induced
TNF-α production, than 6a itself.
The mechanism how cabenegrin A-I (1a) could suppress
TNF-α synthesis is not known yet. A number of structurally
unrelated compounds were reported to inhibit the endotoxin
evoked TNF-α response affecting various steps of the signal
Pharmacology
It is well known that several infections, particularly with
Gram-negative bacteria, leads to septic shock
it has also become clear that the tumor necrosis factor (TNF-
[15]
. Recently
α) characterized originally by its antitumor activity and cyto-
[16]
toxic response
occupies a key role in the phytophysiology
associated with diverse inflammatory states and other severe
illnesses including septic and endotoxic shocks, such as
cachexia, as well as non-insulin-dependent diabetes
transduction pathway. Inhibitors of the arachidonate metabo-
[19]
lism like 4-aryl-5-pyridinylimidazoles
acid
and acetylsalicylic
[17]
[20]
.
are affecting possibly the activation of the transcrip-
Since TNF-α neutralization in the treatment of septic shock
tion factor NF-kB. There are literary data on the inhibitory
[18]
is now well accepted
, therefore measuring of the immune
effect on TNF-α production of phosphodiesterase inhibi-
[21]
response via modulating the endotoxin-induced TNF-α pro-
duction seems to be an appropriate model also for the char-
acterization of the pharmacological profile of the phenyl-
butene derivatives 6a–c, 6e–j, 12, 13 and 24b in comparison
with that of rac.-cabenegrin (1a). The values of the TNF-α
levels are given in Table 1.
tors
and that of p38 MAP kinase inhibitors as well, dem-
onstrating the effectiveness of drugs with unrelated chemical
[22]
structures
.
On the basis of these results it is presumed that the pharma-
cological activity of cabenegrin (1a) may be closely related
to its chroman moiety carrying a hydroxyisoprenyl side chain
with E-geometry. Further work on the evaluation of this
influence is currently in progress.
Table 1. The inhibitory effects of 1a, 6a-c, 6e-j, 13, 15, and 24b on the
LPS-induced TNF-α production in the plasma.
——————————————————————————————
Compound
Dose
TNF-α level %
mmol/kg× 10–4 of control
——————————————————————————————
Acknowledgement
mg/kg
The authors thank the Ministry of Culture and Education (Grant No.
460/1977) and the National Science Foundation (OTKA, Grant No. T-
029090 and 023687) for valuable financial support.
1a
5
10
20
40
40
40
40
40
40
40
40
40
40
40
40
40
1.4
2.7
5.4
53 ± 10
42 ± 8
18 ± 3
6a
6b
6c
6e
6f
6g
6h
6i
18.0
15.8
19.2
16.0
16.9
16.9
15.1
16.9
16.0
18.0
18.0
11.6
16.1
10 ± 7 **
59 ± 8 *
24 ± 6 *
58 ± 10 *
51 ± 22
57 ± 20
56 ± 10 *
76 ± 15
79 ± 18
68 ± 14
62 ± 20
37 ± 11 *
6 ± 2 **
Experimental
Melting points were determined with a Kofler hot stage microscope and
are uncorrected. The reactions and the purity of compounds were controlled
by TLC using precoated Silica gel 60 F254 plates (Merck). Detection of the
components was by UV light and/or treatment with molybdatophosphoric
acid hydrate/EtOH. Preparative separations were performed by column or
flash chromatography using Merck Silica gel 60 (0.063–0.200 nm). The
200-MHz 1H-NMR spectra were recorded on a Brucker WP-200 SY spec-
trometer with TMS as internal standard (δ = 0) in CDCl3. Coupling constants
(J) are given in Hz. Elemental analyses were determined by Carlo-Erba
analysator Tpy 1106 and given within ±0.4% unless otherwise stated.
6j
12
13
15
24b
——————————————————————————————
± Standard error of means. Significance: *p>0.05; **p>0.01.
General Procedure for the Preparation of 4a–c
A solution of 29.7 mmol of resorcinol derivative in 100 ml absolute
cyclohexane was cooled to 0 °C under N2 atmosphere and 41 mmol of
n-butyllithium (solution of 15% in hexane) were added under the above
conditions. The reaction mixture was boiled for 30 minutes. After cooling to
room temperature, 43.3 mmol of 3,3-dimethylallylbromide were added drop-
wise and the mixture boiled for 2 hours. After cooling the reaction mixture
was poured in a saturated solution of NaHCO3, extracted with ethyl acetate,
washed with water and dried over MgSO4. After evaporation of the solvent
the residue was purified by column chromatography on silica gel.
According to our assumption, cabenegrin A-I (1a) inhibited
significantly and dose-dependently the increase of the plasma
TNF-α level, and its activity is strongly connected with its A
and B rings, since the 24b chroman derivative has been found
to possess the same order of inhibitory activity as found for
the rac.-1a itself. The inhibitory values of 6a, 6e, 12, and 13
have also clearly indicated that both of the presence of the
Arch. Pharm. Pharm. Med. Chem. 334, 53–61 (2001)

Structural Analogues of (–)-Cabenegrin A-I
57
4-(2,6-Dimethoxyphenyl)-2-methylbut-2-ene (4a)
(Z)-1-Acetoxy-4-(2-acetoxy-6-methoxyphenyl)-2-methylbut-2-ene (5d)
Eluent: hexane-ethyl acetate 4:1; colourless oil; yield 30%.– 1H-NMR
(CDCl3): δ (ppm) = 1.75 (s, 3H, Me), 2.10 (s, 3H, OAc), 3.3 (d, J = 7.5, 2H,
CH2Ar), 3.85 (s, 3H, OMe), 4.45 (s, 2H, CH2OAc), 5.50 (t, J = 7.5, 1H,
=CH-), 6.65–7.30 (m, 3H, ArH).– Anal. C16H20O5.
Eluent: hexane; colourless oil; yield 70%.– 1H-NMR (CDCl3): δ (ppm) =
1.65 and 1.75 (s, 6H, 2×Me), 3.4 (d, J = 7.5, 2H, CH2Ar), 3.85 (s, 6H,
2×OMe), 5.2 (t, J = 7.5, 1H, =CH), 6.55 (d, J = 10.0, 2H, 3-,5-H, aromat.),
7.15 (t, J = 10.0, 1H, H-4, aromat.).– Anal. C13H18O2.
1-Acetoxy-2-acetoxymethyl-4-(2,6-dimethoxyphenyl)but-2-ene (5e)
4-(2,4,6-Trimethoxyphenyl)-2-methylbut-2-ene (4b)
1
Eluent: hexane-acetone 9:1; colourless oil; yield94%.–1H-NMR (CDCl3):
δ (ppm) = 1.6 and 1.75 (s, 6H, 2×Me), 3.25 (d, J = 7.5, 2H, CH2Ar), 3.75 (s,
9H, 3×OMe), 5.15 (t, J = 7.5, 1H, =CH), 6.1 (s, 2H, 3-,5-H, aromat.).– Anal.
C14H20O3.
Eluent: hexane-ethyl acetate 5:2; oil; yield 14%.– H-NMR (CDCl3): δ
(ppm) = 2.05 and 2.1 (s, 6H, 2×OAc), 3.5 (d, J = 7.5, 2H, CH2Ar), 3.80 and
3.85 (s, 6H, 2×OMe), 4.55 and 4.9 (s, 4H, 2×OCH2), 5.9 (t, J = 7.5, 1H, =CH),
6.5 and 6.6 (d, J = 7.5, 2H, 3-,5-H, aromat.), 7.15 (t, J = 7.5, 1H, 4-H,
aromat.).– Anal. C17H22O5.
4-[2-(2-Tetrahydropyranyloxy)-6-methoxyphenyl]-2-methylbut-2-ene (4c)
General Procedure for the Preparation of 6a–d
1. Preparation of 6a,c,d from 5a,d,e
Eluent: hexane-ethyl acetate 20:1; yellow oil; yield 52%.– 1H-NMR
(CDCl3): δ (ppm) = 1.2, 1.55 and 1.8 (m, 6H, 3×CH2), 1.6 and 1.8 (s, 6H,
2×Me), 3.3 (d, J = 7.5, 2H, CH2Ar), 3.55 and 3.85 (m, 2H, CH2), 3.75 (s, 3H,
OMe), 5.15 (t, J = 7.5, 1H, =CH), 5.35 (t, 1H, -OCHO-), 6.5 and 6.7 (d, J =
7.5, 2H, 3-,5-H, aromat.), 7.0 (t, J = 7.5, 1H, 4-H, aromat.).– Anal. C17H24O3.
The mixture of 1.78 mmol of acetate, 10 ml abs. methanol and 4 ml of 1N
NaOCH3 was stirred under N2 atmosphere for 20 hours at room temperature.
The solvent was evaporated, the residue diluted with water, neutralized with
acetic acid, extracted with ethyl acetate, washed with water and dried over
MgSO4. After evaporation of the solvent, the residue was purified by column
chromatography on silica gel.
2-(3-Methylbut-2-ene-1-yl)-3-methoxyphenol (4d)
4c (4.85 g, 0.0175 mol), 250 ml of methanol and oxalic acid (3.7 g, 0.041
mol) dissolved in 20 ml water were stirred at room temperature, for 1 hour.
The methanol was evaporated, the residue was diluted with water, extracted
with dichloromethane, washed with water, dried over MgSO4. After evapo-
ration of the solvent the oily residue was sufficiently pure for further use.
Yield 98%.– 1H-NMR (CDCl3): δ (ppm) = 1.85 (s, 3H, Me), 3.4 (d, J = 7.5,
2H,CH2Ar), 3.8 (s, 3H, OMe), 5.0 (t, J = 7.5, 1H, =CH), 5.65 (s, 1H, Ar-OH),
6.4 (d, J = 7.5, 2H, 4-,6-H, aromat.), 7.0 (t, J = 7.5, 1H, 5-H, aromat.).– Anal.
C12H16O2.
(E)-4-(2,6-Dimethoxyphenyl)-2-methylbut-2-en-1-ol (6a)
Eluent: hexane-acetone 5:2; colourless oil; yield35%.– 1H-NMR (CDCl3):
δ (ppm) = 1.85 (s, 3H, Me), 2.0 (brs, 1H, OH), 3.4 (d, J = 7.5, 2H, CH2Ar),
3.8 (s, 6H, 2×OMe), 3.95 (s, 2H, CH2-O), 5.45 (t, J = 7.5, 1H, =CH), 6.55
(d, J = 7.5, 2H, 3-,5-H, aromat.), 7.15 (t, J = 7.5, 1H, 4-H, aromat.).– Anal.
C13H18O3.
(Z)-4-(2-Hydroxy-6-methoxyphenyl)-2-methylbut-2-en-1-ol (6c)
1-(2-Acetoxy-6-methoxyphenyl)-3-methylbut-2-ene (4e)
Eluent: toluene-ethyl acetate 4:1; colourless oil; yield 40%.– 1H-NMR
(CDCl3): δ (ppm) = 1.88 (s, 3H, Me), 3.41 (d, J = 7.5, 2H, CH2Ar), 3.82 (s,
3H, OMe), 4.05 (s, 2H, -CH2OH), 5.12 (s, 1H, OH), 5.55 (t, J = 7.5, 1H,
=CH-), 6.48 (t, J = 8.0, 2H, 3-,5-H), 7.05 (t, J = 8.0, 1H, 4-H).– Anal.
C12H16O3.
4d (3.53 g, 0.018 mol), 20 ml of acetic anhydride and 0.5 ml abs. pyridine
were kept on water bath for 1 hour. Then the mixture was poured in cold
water, stirred 0.5 h, extracted with ethyl acetate, washed with NaHCO3
solution, water, dried over MgSO4 and evaporated. The obtained brown oil
was sufficiently pure. Yield 87%.– 1H-NMR (CDCl3): δ (ppm) = 1.65 and
1.75 (s, 6H, 2×Me), 2.3 (s, 3H, OAc), 3.3 (d, J = 7.5, 2H,CH2Ar), 3.85 (s,
3H, OMe), 5.15 (t, J = 7.5, 1H, =CH), 6.7–7.2 (m, 3H, 3-,4-,5-H, aromat.).–
Anal. C14H18O3.
2-Hydroxymethyl-4-(2,6-dimethoxyphenyl)but-2-en-1-ol (6d)
Eluent: hexane-acetone 2:1; mp 71–73 °C; yield 41%.– 1H-NMR (CDCl3):
δ (ppm) = 2.15 and 2.6 (brs, 2H, OH), 3.45 (d, J = 8.0, 2H, CH2Ar), 3.85 (s,
6H, 2×OMe), 4.2 and 4.4 (s, 4H, 2×CH2O), 5.65 (t, J = 8.0, 1H, =CH), 6.6
(d, J = 8.0, 2H, 3-,5-H, aromat.), 7.15 (t, J = 8.0, 1H, 4-H, aromat.).– Anal.
C13H18O4.
General Procedure for the Preparation of 5a–e
A mixture of 0.028 mmol prenylated compound, 70 ml of acetic anhydride
and 0.68 mol SeO2 was boiled for 30 minutes (4 days in case of 4a → 5e).
The reaction mixture was poured in cold water, extracted with ethyl acetate,
washed with water, NaHCO3 solution, water, dried over MgSO4. After
evaporation of the solvent the residue was purified by column chromatogra-
phy on silica gel.
2. Preparation of 6b from 5b,c
LiAlH4 (2.8 g, 0.073 mol) was suspended in 90 ml abs. ethyl ether, under
N2 atmosphere, at room temperature. 4.77gof5b,c mixture dissolved in ether
were added dropwise during 1 hour. The reaction mixture was stirred for 10
min at room temperature, then ethyl acetate was added dropwise to decom-
pose the excess of LiAlH4. Then saturated solution of NH4Cl was added,
extracted with ethyl acetate, washed with water and dried over MgSO4. After
evaporation of the solvent the residue was purified by column chromatogra-
phy on silica gel.
(E)-1-Acetoxy-4(2,6-dimethoxyphenyl)-2-methylbut-2-ene (5a)
Eluent: hexane; yellow colourless oil; yield 38%.– 1H-NMR (CDCl3): δ
(ppm) = 1.8 (s, 3H, Me), 2.0 (s, 3H, OAc), 3.3 (d, J = 7.5, 2H, CH2Ar), 3.85
(s, 6H, 2×OMe), 4.4 (s, 2H, CH2O), 5.15 (t, J = 7.5, 1H, =CH), 6.7 and 6.8
(d, J = 7.5, 2H, 3-H, 5-H, aromat.), 7.2 (t, J = 7.5, 1H, H-4, aromat.).– Anal.
C15H20O4.
(E)-4-(2,4,6-Trimethoxyphenyl)-2-methylbut-2-en-1-ol (6b)
Eluent: toluene-acetone 4:1; mp 51-53 °C; yield 47%.– 1H-NMR (CDCl3):
δ (ppm) = 1.85 (s, 3H, Me), 3.45 (d, J = 7.5, 2H, CH2Ar), 3.8 (s, 9H, 3×OMe),
3.95 (s, 2H, CH2OH), 5.45 (t, J = 7.5, 1H, =CH), 6.2(s, 2H, 3-,5-H, aromat.).–
Anal. C14H20O4.
(E)-1-Acetoxy-4-(2,4,6-trimethoxyphenyl)-2-methylbut-2-ene (5b) and (E)-
4-(2,4,6-Trimethoxyphenyl)-2-methylbut-2-ene-1-al (5c)
Eluent: hexane-ethyl acetate 5:2; colourless oil. 5b: 1H-NMR (CDCl3): δ
(ppm) = 1.8 (s, 3H, Me), 1.9 (s, 3H, OAc), 3.35 (d, J = 7.5, 2H, CH2Ar), 3.85
(s, 9H, 3×OMe), 4.4 (s, 2H, CH2O), 5.5 (t, J = 7.5, 1H, =CH), 6.15 (s, 2H,
3-,5-H, aromat.). 5c: 1H-NMR (CDCl3): δ (ppm) = 1.8 (s, 3H, Me), 3.6 (d, J
= 7.5, 2H, CH2Ar), 3.85 (s, 9H, 3×OMe), 6.1 (s, 2H, 3-,5-H, aromat.), 5.15
(t, J = 7.0, 1H, =CH), 9.35 (s, 1H, CHO).
1-(3,5-Dimethoxyphenyl)-propane-1-ol (2i)
To the ethylmagnesiumbromide [prepared freshly from magnesium
(0.6 g), ethylbromide (2 ml) and anhydrous ether (20 ml)] was dropped the
solution of 3,5-dimethoxybenzaldehyde (2h, 4.15 g, 21 mmol) in anhydrous
Arch. Pharm. Pharm. Med. Chem. 334, 53–61 (2001)

58
Antus and co-workers
ether (40 ml) with stirring at room temperature during 30 min. The reaction
mixture was boiled for 2 hours. To the cooled mixture NH4Cl solution was
added and then extracted with ether. The organic phase was washed, dried
and evaporated yielding the crude product which was purified by flash
column chromatography with hexane-ethyl acetate (5:1). 4.35 g (88%) of 2i
was obtained (Rf = 0.4).– 1H-NMR (CDCl3): δ (ppm) = 0.95 (t, J = 7.5, 3H,
Me), 1.7 (m, 2H, CH2), 2.2 (s, 1H, OH), 3.8 (s, 6H, 2×OMe), 4.5 (t, J = 7.5,
1H, CH), 6.35 (dd, J = 1.0 and 1.5, 1H, 4-H, aromat.), 6.5 (d, J = 2.0, 2H,
2-,6-H, aromat.).
General Procedure for the Preparation of 8a–g
The mixture of 0.05 mol of aldehyde, 0.075 mol of phosphonium salt,[23]
100 ml of anhydrous ethanol and 0.1 mol of 1N NaOC2H5 was stirred at room
temperature under N2 atmosphere for 2 hours. The solvent was partially
evaporated, water was added and the solution extracted with ethyl acetate,
washed with water, dried over MgSO4. After evaporation of the solvent the
residue was purified by column chromatography on silica gel, hexane-ethyl
acetate 10:1 as eluent.
(E)-Ethyl 4-(2,6-dimethoxyphenyl)-2-methylcrotonate (8a)
3,5-Dimethoxy-n-propylbenzene (2g)
Yellow oil; yield 75%.– 1H-NMR (CDCl3): δ (ppm) = 1.25 (t, J = 7.5, 3H,
Me), 3.0 (s, 2H, Me), 3.5 (d, J = 7.5, 2H, CH2Ar), 3.8 (s, 6H, 2×OMe), 4.15
(q, J = 7.5, 2H, CH2), 6.5 (d, J = 7.5, 2H, 3-,5-H, aromat.), 6.8 (t, J = 7.5, 1H,
=CH), 7.15 (t, J = 7.5, 1H, 4-H, aromat.).– Anal. C15H20O4.
4.2 g (21.4 mmol) of 2i was reduced with H2 in glacial acetic acid (70 ml)
in the presence of 10% Pd/C (3.5 g). After 30 hours (using 550 ml of H2) the
catalyst was filtered off, the solvent was evaporated and the residue was flash
chromatographed on silica gel with hexane-ethyl acetate (5:2) as the eluent
yielding 2.6 g (68%) of 2g.– 1H-NMR (CDCl3): δ (ppm) = 1.0 (t, J = 7.5,
3H, Me), 1.7 (m, 2H, CH2), 2.55 (t, J = 8.0, CH2Ar), 3.8 (s, 6H, 2×OMe),
6.3–6.4 (m, 3H, 2-,4-,6-H, aromat.).
(E)-Ethyl 4-(2,6-diethoxyphenyl)-2-methylcrotonate (8b)
Thick oil; yield 66%.– 1H-NMR (CDCl3): δ (ppm) = 1.2 (t, J = 7.5, 3H,
Me), 1.4 (t, J = 7.5, 6H, 2×Me), 2.0 (s, 3H, Me), 3.5 (d, J = 7.5, 2H, CH2Ar),
4.0 (q, J = 7.5, 4H, 2×CH2), 4.1 (q, J = 7.5, 4H, CH2), 6.5 (d, J = 7.5, 2H,
3-,5-H, aromat.), 6.8 (t, J = 7.5, 1H, =CH), 7.15 (m, 1H, 4-H, aromat.).– Anal.
C17H24O4.
General Procedure for the Preparation of 7a–e
To the solution of 0.05 mol resorcinol derivative in 200 ml anhydrous
cyclohexane butyllithium (0.1 mol, 42 ml 15% solution in hexane) was added
dropwise at 0 °C, N2 atmosphere and stirring. The reaction mixture was
boiled for 1.5 hours. After cooling, 0.0625 mol of bromoacetaldehyde diethyl
acetal was added dropwise and the mixture boiled for another 1.5 hours. After
cooling, the mixture was diluted with NaHCO3 solution, extracted with
dichloromethane, washed with water, dried over MgSO4. After evaporation
of the solvent, the residue was dissolved in ethanol and stirred with 10% HCl
at room temperature. The solvent was distilled off, water was added and the
mixture extracted with CH2Cl2, washed, dried over MgSO4 and concentrated
in vacuo. The residue was purified by column chromatography on silica gel.
(E)-Ethyl 4-(2-ethoxy-6-methoxyphenyl)-2-methylcrotonate (8c)
Colourless oil; yield 56%.– 1H-NMR (CDCl3): δ (ppm) = 1.3 (t, J = 7.5,
3H, Me), 1.45 (t, J = 7.5, 3H, Me), 2.0 (s, 3H, Me), 3.55 (d, J = 7.5, 2H,
CH2Ar), 3.8 (s, 3H, OMe), 4.0 and 4.15 (q, J = 7.5, 4H, 2×CH2), 6.5 (d, J =
7.0, 2H, 3-,5-H, aromat.), 6.75 (t, J = 7.5, 1H, =CH), 7.1 (m, 1H, 4-H,
aromat.).– Anal. C16H22O4.
(E)-Ethyl 4-(2,6-dimethoxy-4-methylphenyl)-2-methylcrotonate (8d)
Colourless oil; yield 62%.– 1H-NMR (CDCl3): δ (ppm) = 1.25 (t, J = 7.5,
3H, Me), 2.0 (s, 3H, Me), 2.32 (s, 3H, Me), 3.5 (d, J = 7.5, 2H, CH2Ar), 3.8
(s, 6H, 2×OMe), 4.15 (q, J = 7.5, 2H, CH2), 6.35 (s, 2H, 3-,5-H, aromat.),
6.75 (t, J = 7.5, 1H, =CH).– Anal. C16H22O4.
2,6-Dimethoxyphenylacetaldehyde (7a)
Eluent: hexane-ethyl acetate 5:1; mp 37–38 °C; yield 33%.– 1H-NMR
(CDCl3): δ (ppm) = 3.7 (d, J = 1.5, 2H, CH2Ar), 3.85 (s, 6H, 2×OMe), 6.6
(d, J = 6.5, 2H, 3-,5-H, aromat.), 7.25 (t, J = 8.0, 1H, 4-H, aromat.), 9.5 (t, J
= 1.5, 1H, CHO).– Anal. C10H12O3.
(E)-Ethyl 4-(2,6-dimethoxy-4-propylphenyl)-2-methylcrotonate (8e)
Eluent: dichloromethane-benzene 3:1; colourless oil; yield 40%.– 1H-
NMR (CDCl3): δ (ppm) = 0.9 (t, J = 7.5, 3H, Me), 1.3 (s, 3H, Me), 1.7 (m,
2H, CH2), 2.0 (s, 3H, Me), 2.6 (t, J = 6.0, 2H, CH2), 3.5 (d, J = 6.0, 2H,
CH2Ar), 3.8 (s, 6H, 2×OMe), 4.2 (q, J = 7.5, 2H, CH2), 6.4 (s, 2H, 3-,5-H,
aromat.), 6.8 (t, J = 6.0, 1H, =CH).– Anal. C18H26O4.
2,6-Diethoxyphenylacetaldehyde (7b)
Eluent: hexane-ethyl acetate 10:1; colourless oil; yield 50%.– 1H-NMR
(CDCl3): δ (ppm) = 1.4 (t, J = 7.5, 6H, 2×Me), 3.7 (d, J = 1.0, 2H, CH2Ar),
4.0 (q, J = 7.5, 4H, 2×CH2), 6.5 (d, J = 5.0, 2H, 3-,5-H, aromat.), 7.2 (t, J =
7.5, 1H, 4-H, aromat.), 9.6 (t, J = 1.0, 1H, CHO).– Anal. C12H16O3.
(E)-Ethyl 2-ethyl-4-(2,6-dimethoxyphenyl)crotonate (8f)
Thick oil; yield 18%.– 1H-NMR (CDCl3): δ (ppm) = 1.1 and 1.25 (t, J =
7.5, 6H, 2×OMe), 2.5 (q, J = 7.5, 2H, CH2), 3.55 (d, J = 7.5, 2H, CH2Ar),
3.8 (s, 6H, 2×OMe), 4.15 (q, J = 7.5, 2H, CH2O), 6.55 (d, J = 7.5, 2H, 3-,5-H,
aromat.), 6.7 (t, J = 7.5, 1H, =CH), 7.2 (t, J = 7.5, 1H, 4-H, aromat.).– Anal.
C16H22O4.
2-Ethoxy-6-methoxyphenylacetaldehyde (7c)
Eluent: hexane-ethyl acetate 10:1; colourless oil; yield 38%.– 1H-NMR
(CDCl3): δ (ppm) = 1.4 (t, J = 7.5, 3H, Me), 3.65 (d, J = 1.5, 2H, CH2Ar),
3.85 (s, 3H, OMe), 4.05 (q, J = 7.5, 2H, CH2), 6.6 (d, J = 7.5, 2H, 3-,5-H,
aromat.), 7.25 (t, J = 8.0, 1H, 4-H, aromat.), 9.65 (t, J = 1.5, 1H, CHO).–
Anal. C11H14O3.
(E)-Ethyl 4-(2,6-dimethoxyphenyl)-2-propylcrotonate (8g)
Thick oil; yield 15%.– 1H-NMR (CDCl3): δ (ppm) = 0.95 and 1.25 (t, J =
7.5, 6H, 2×OMe), 1.5 (m, 2H, CH2), 2.5 (t, J = 7.5, 2H, CH2), 3.55 (d, J =
7.5, 2H, CH2Ar), 3.8 (s, 6H, 2×OMe), 4.2 (q, J = 7.5, 2H, CH2O), 6.0 (d, J
= 3.5, 2H, 3-,5-H, aromat.), 6.8 (t, J = 7.5, 1H, =CH), 7.2 (t, J = 7.5, 1H, 4-H,
aromat.).– Anal. C17H24O4.
2,6-Dimethoxy-4-methylphenylacetaldehyde (7d)
Eluent: hexane-ethyl acetate 10:1; colourless oil; yield 34%.– 1H-NMR
(CDCl3): δ (ppm) = 2.35 (s, 3H, Me), 3.65 (d, J = 1.0, 2H, CH2Ar), 3.8 (s,
6H, 2×OMe), 6.4 (s, 2H, 3-,5-H, aromat.), 9.5 (t, J = 1.0, 1H, CHO).– Anal.
C11H14O3.
General Procedure for the Preparation of 6a,e–j
LiAlH4 (1.0 g, 26 mmol) was suspended in 100 ml anhydrous ether and
cooled at 0 °C, under N2 atmosphere and stirring. A solution of esther (3.7
mmol) in abs. ether was added dropwise. After stirring for 2 hours at room
temperature, ethyl acetate was added dropwise to decompose the excess of
LiAlH4. The mixture was diluted with a saturated solution of NH4Cl,
extracted with ethyl acetate, washed, dried, evaporated and purified by
column chromatography on silica gel.
2,6-Dimethoxy-4-n-propylphenylacetaldehyde (7e)
Eluent: hexane-acetone 9:1; colourless oil; yield20%.–1H-NMR (CDCl3):
δ (ppm) = 1.0 (t, J = 7.5, 3H, Me), 1.7 (m, 2H, CH2), 2.55 (m, 2H, CH2), 3.65
(d, J = 1.0, 2H, CH2Ar), 3.8 (s, 6H, 2×OMe), 6.45 (s, 2H, 3-,5-H, aromat.),
9.6 (t, J = 1.0, 1H, CHO).– Anal. C13H18O3.
Arch. Pharm. Pharm. Med. Chem. 334, 53–61 (2001)

Structural Analogues of (–)-Cabenegrin A-I
59
(E)-4-(2,6-Diethoxyphenyl)-2-methylbut-2-en-1-ol (6e)
4.15 (q, J = 7.5, 2H, CH2), 6.5 (d, J = 7.5, 2H, 3-,5-H, aromat.), 6.55 (d, 2H,
3-,5-H, aromat.), 6.7 (d, 1H, J = 1.5, H-α), 6.75 (d, 1H, J = 1.5, H-β), 7.15
(t, J = 7.5, 1H, 4-H, aromat.).
Eluent: hexane-ethyl acetate 5:2; mp 74–76 °C; yield 71%.– 1H-NMR
(CDCl3): δ (ppm) = 1.35 (t, J = 7.5, 6H, 2×Me), 1.5 (brs, 1H, OH), 1.85 (s,
3H, Me), 3.45 (d, J = 7.5, 2H, CH2Ar), 4.0 (q, J = 7.5, 4H, 2×CH2), 4.05 (s,
2H, CH2OH), 5.5 (t, J = 7.5, 1H, =CH), 6.5 (d, J = 7.5, 2H, 3-,5-H, aromat.),
7.05 (t, J = 7.5, 1H, 4-H, aromat.).– Anal. C15H22O3.
(Z)-4-(2,6-Dimethoxyphenyl)-2-methylbut-2-en-1-ol (12)
Prepared from 9 as described for 6b. Eluent: hexane-acetone 5:1; colour-
less oil; yield 23%.– 1H-NMR (CDCl3): δ (ppm) = 1.85 (s, 3H, Me), 1.95 (s,
1H, OH), 3.45 (d, J = 7.5, 2H, CH2Ar), 3.85 (s, 6H, 2×OMe), 4.25 (s, 2H,
CH2OH), 5.4 (t, J = 7.5, 1H, =CH), 6.55 (d, J = 7.5, 2H, 3-,5-H, aromat.),
7.15 (t, J = 7.5, 1H, 4-H, aromat.).
(E)-4-(2-Ethoxy-6-methoxyphenyl)-2-methylbut-2-en-1-ol (6f)
Eluent: hexane-ethyl acetate 5:2; thick oil; yield 60%.– 1H-NMR (CDCl3):
δ (ppm) = 1.4 (t, J = 7.5, 3H, Me), 1.5 (brs, 1H, OH), 1.85 (s, 3H, Me), 3.4
(d, J = 7.5, 2H, CH2Ar), 3.8 (s, 3H, OMe), 4.0 (m, 4H, 2×CH2), 5.5 (t, J =
7.5, 1H, =CH), 6.5 (d, J = 7.5, 2H, 3-,5-H, aromat.), 7.05 (t, J = 7.5, 1H,
4-H).– Anal. C14H20O3.
(E)-4-(2,6-Dimethoxyphenyl)-2-methylbut-3-en-1-ol (13)
Prepared from 10 as described for 6b. Eluent: hexane-acetone 5:2; colour-
less oil; yield 65%.– 1H-NMR (CDCl3): δ (ppm) = 0.9 (d, J = 7.5, 3H, Me),
2.0 (brs, 1H, OH), 3.3 (d, J = 8.0, 2H, OCH2), 3.4 (m, 1H, CH), 3.75 (s, 6H,
2×OMe), 5.5 (t, J = 10.0, 1H, H-β), 6.2 (d, J = 10.0, 1H, H-α), 6.5 (d, J =
7.5, 2H, 3-,5-H, aromat.), 7.15 (t, J = 7.5, 1H, 4-H, aromat.).
(E)-4-(2,6-Dimethoxy-4-methylphenyl)-2-methylbut-2-en-1-ol (6g)
Eluent: hexane-ethyl acetate 5:2; thick oil; yield 30%.– 1H-NMR (CDCl3):
δ (ppm) = 1.5 (s, 1H, OH), 1.8 (s, 1H, Me), 2.35 (s, 3H, Me), 3.4 (d, J = 7.5,
2H, CH2Ar), 3.8 (s, 6H, 2×OMe), 4.0 (s, 2H, CH2OH), 5.45 (t, J = 7.5, 1H,
=CH), 6.4 (s, 2H, 3-,5-H, aromat.).– Anal. C14H20O3.
2,4-[Bis(2,6-Dimethoxyphenyl)]but-2-ene-1-al (14)
7a (1.04 g, 5.7 mmol), anhydrous ethanol (50 ml) and 1N NaOC2H5 (15
ml) were stirred at room temperature for 2 hours. The solvent was distilled
off, the residue extracted with ethyl acetate, washed with water, dried over
MgSO4. After evaporation of the solvent the residue was purified by column
chromatography on silica gel, using hexane-ethyl acetate (5:1) as eluent, to
give 14 as colourless prisms. Mp 133–134 °C; yield 56% (0.55 g).– 1H-NMR
(CDCl3): δ (ppm) = 3.5 (d, J = 7.5, 2H, CH2Ar), 3.7 and 3.8 (s, 12H, 4×OMe),
6.55 and 6.7 (d, J = 7.5, 4H, 2×3-,5-H, aromat.), 6.95 (t, J = 7.5, 1H, =CH),
7.15 and 7.35 (t, J = 7.5, 2H, 2×4-H, aromat.), 9.6 (s, 1H, CHO). MS (m/e):
342 (75), 313 (100), 151 (95), 91 (80).– Anal. C20H22O5.
(E)-4-(2,6-Dimethoxy-4-propylphenyl)-2-methylbut-2-en-1-ol (6h)
Eluent: hexane-acetone 4:1; colourless oil; yield50%.–1H-NMR (CDCl3):
δ (ppm) = 0.9 (t, J = 7.5, 3H, Me), 1.3 (brs, 1H, OH), 1.6 (m, 2H, CH2), 1.8
(s, 3H, Me), 2.55 (t, J = 7.5, 2H, CH2), 3.4 (d, J = 7.5, 2H, CH2Ar), 3.75 (s,
6H, 2×OMe), 3.95 (s, 2H, CH2OH), 5.5 (t, J = 7.5, 1H, =CH), 6.4 (s, 2H,
3-,5-H, aromat.).– Anal. C16H24O3.
(E)-2-Ethyl-4-(2,6-dimethoxyphenyl)but-2-en-1-ol (6i)
Eluent: hexane-acetone 5:2; thick oil; yield 46%.– 1H-NMR (CDCl3): δ
(ppm) = 1.05 (t, J = 7.5, 3H, Me), 1.6 (brs, 1H, OH), 2.3 (q, J = 7.5, 2H, CH2),
3.4 (d, J = 7.5, 2H, CH2Ar), 3.75 (s, 6H, 2×OMe), 3.95 (s, 2H, CH2OH), 5.45
(t, J = 7.5, 1H, =CH), 6.55 (d, J = 7.5, 2H, 3-,5-H, aromat.), 4.15 (t, J = 7.5,
1H, 4-H, aromat.).– Anal. C14H20O3.
2,4-[Bis(2,6-Dimethoxyphenyl)]but-2-en-1-ol (15)
Prepared from 14 as described for 6b. Mp 138–140 °C; yield 80% (0.2 g).–
1H-NMR (CDCl3): δ (ppm) = 2.0 (brs, 1H, OH), 3.15 (d, J = 7.5, 2H, CH2Ar),
3.65 and 3.75 (s, 12H, 4×OMe), 4.25 (s, 2H, CH2O), 6.05 (t, J = 7.5, 1H,
=CH), 6.45 and 6.65 (d, J = 7.5, 4H, 2×3-,5-H, aromat.), 7.05 and 7.2 (t, J =
7.5, 2H, 4-H, aromat.). MS (m/e): 344 (5), 327 (20), 313 (25), 151 (65), 91
(70).– Anal. C20H24O5.
(E)-4-(2,6-Dimethoxyphenyl)-2-propylbut-2-en-1-ol (6j)
Eluent: hexane-acetone 5:2; thick oil; yield 75%.– 1H-NMR (CDCl3): δ
(ppm) = 0.95 (t, J = 7.5, 3H, Me), 1.4 (brs, 1H, OH), 2.2 (m, 2H, CH2), 2.2
(t, J = 7.5, 2H, CH2), 3.45 (d, J = 7.5, 2H, CH2Ar), 3.8 (s, 6H, 2×OMe), 3.95
(s, 2H, CH2OH), 5.5 (t, J = 7.5, 1H, =CH), 6.6 (d, J = 7.5, 2H, 3-,5-H,
aromat.), 7.15 (t, 1H, 4-H, aromat.).– Anal. C15H22O3.
2,4-[Bis(2,6-Dimethoxyphenyl)]butanal (16)
The solution of 14 (0.3 g, 0.87 mmol) in glacial acetic acid (25 ml) was
added to the suspension of 10% Pd/C catalyst (0.5 g) in glacial acetic acid
(10 ml), previously saturated with hydrogen. The hydrogenation was contin-
ued for 20 hours using 50 ml of H2. The catalyst was filtered off and the
filtrate was evaporated in vacuo. The residue was purified by column
chromatography on silica gel, using hexane-ethyl acetate (5:1) as eluent to
give 16. Yield 67% (0.23 g).– 1H-NMR (CDCl3): δ (ppm) = 1.8 and 2.5 (m,
4H, 2×CH2), 3.7 and 3.75 (s, 12H, 4×OMe), 4.05 (dd, J = 6.0 and 4.0, 1H,
CH), 6.45 and 6.55 (d, J = 7.5, 4H, 2×3-,5-H, aromat.), 7.1 and 7.2 (t, J =
7.5, 2H, 2×4-H, aromat.).– Anal. C20H24O5.
General Method for the Photoisomerization of 8a and 6a
1.3 g of Compound dissolved in 280 ml anhydrous benzene were placed
into a quartz pot and irradiated with a mercury lamp (450 W) for 3 hours.
The solvent was evaporated in vacuo and the residue was chromatographed
several times on silica gel column using hexane-methyl ethyl ketone 20:1
and toluene-methyl ethyl ketone 40:1 as eluent.
(Z)-Ethyl 4-(2,6-dimethoxyphenyl)-2-methylcrotonate (9)
2,4-[Bis(2,6-Dimethoxyphenyl)]butanol (17)
Colourless oil; yield 13%.– 1H-NMR (CDCl3): δ (ppm) = 1.35 (t, J = 7.5,
3H, Me), 1.9 (s, 3H, Me), 3.85 (s, 6H, 2×OMe), 3.9 (d, J = 7.0, 2H, CH2Ar),
4.3 (q, J = 7.5, 2H, CH2), 5.9 (t, J = 7.0, 1H, =CH), 6.6 (d, J = 7.5, 2H, 3-,5-H,
aromat.), 7.15 (t, J = 7.5, 1H, 4-H, aromat.).
Prepared from 16 as described for 6b. Mp 96–97 °C; yield 65% (0.15 g).–
1H-NMR (CDCl3): δ (ppm) = 1.8 and 2.5 (m, 4H, 2×CH2), 2.0 (s, 1H, OH),
3.65 (d, J = 7.0, 2H, CH2), 3.7 and 3.8 (s, 12H, 2×OMe), 3.95 (m, 1H, CH),
6.5 and 6.6 (d, J = 7.5, 4H, 2×3-,5-H, aromat.), 7.1 and 7.2 (t, J = 7.5, 2H,
2×4-H, aromat.).– Anal. C20H26O5.
(E)-2-Ethoxycarbonyl-4-(2,6-dimethoxyphenyl)-2-methylbut-3-ene (10)
Colourless oil; yield 11%.– 1H-NMR (CDCl3): δ (ppm) = 1.2 (t, J = 6.0,
3H, Me), 1.3 (d, J = 6.0, 3H, Me), 3.1 (m, 1H, CH), 3.75 (s, 6H, 2×OMe),
4.15 (q, J = 7.5, 2H, CH2), 5.9 (t, 1H, J = 10.0, H-α), 6.3 (d, 1H, J = 10.0,
H-β), 6.6 (d, J = 7.5, 2H, 3-,5-H, aromat.), 7.3 (t, J = 7.5, 1H, 4-H, aromat.).
7-Allyloxychroman (19)
To a stirred solution of 18 (10 g, 66.6 mmol) in anhydrous dimethylfor-
mamide (130 ml), NaH (3.4 g) was added under N2 atmosphere and at 0 °C.
After 15 min allylbromide (10.5 ml) in anh. DMF (15 ml) was added
dropwise, during 30 min. The reaction mixture was stirred at 0 °C 2 hours,
then was diluted with water, extracted with ethyl ether, washed with 10%
solution of NaOH, with water, dried over MgSO4, evaporated and purified
by column chromatography using toluene as eluent to afford 19 as colourless
(Z)-2-Ethoxycarbonyl-4-(2,6-dimethoxyphenyl)-2-methylbut-3-ene (11)
Colourless oil ; yield 3.5%.– 1H-NMR (CDCl3): δ (ppm) = 1.25 (t, J = 7.5,
3H, Me), 1.4 (d, 3H, Me), 3.25 (q, J = 7.5, 1H, CH), 3.85 (s, 6H, 2×OMe),
Arch. Pharm. Pharm. Med. Chem. 334, 53–61 (2001)

60
Antus and co-workers
oil, 12.2 g (72%).– 1H-NMR (CDCl3): δ (ppm) = 2.0 (m, 2H, 3-CH2), 2.7 (t,
J = 7.5, 2H, 4-CH2), 4.1 (t, J = 7.0, 2H, 2-CH2O), 4.5 (d, J = 6.0, 2H, CH2-O),
5.35 (m, 2H, CH2=), 6.0 (m, 1H, =CH), 6.4 (m, 2H, 6,8-H, aromat.), 6.9 (d,
J = 7.5, 1H, 5-H, aromat.).– Anal. C12H14O2.
6.6 (d, J = 7.5, 1H, 6-H, aromat.), 6.75 (t, J = 7.5, 1H, CH=), 6.9 (d, 1H, 5-H,
aromat.).– Anal. C18H24O5.
(E)-Ethyl 4-(7-methoxychroman-8-yl)-2-methylcrotonate (23b)
Prepared as described for 8a–g. Eluent: hexane-acetone 10:1; oil; yield
60%.– 1H-NMR (CDCl3): δ (ppm) = 1.3 (t, J = 7.5, 3H, Me), 1.95 (m, 2H,
3-CH2), 2.0 (s, 3H, Me), 2.75 (t, J = 6.0, 2H, 4-CH2), 3.5 (d, J = 7.5, 2H,
CH2Ar), 3.8 (s, 2H, OMe), 4.2 (m, 4H, 2-CH2, OCH2), 6.45 (d, J = 7.5, 1H,
6-H, aromat.), 6.75 (t, J = 7.5, 1H, CH=), 6.9 (d, J = 7.5, 1H, 5-H, aromat.).–
Anal. C17H22O4.
8-Allyl-7-hydroxychroman (20)
7-Allyloxychroman 19 (6 g, 0.031 mol) in xylene (110 ml) was heated in
a closed tube at 200 °C for 20 hours. The solvent was evaporated in vacuo
and the residue purified by flash chromatography on silica gel, toluene as
eluent, togive20ascolourless oil, 3.12g(50%).–1H-NMR (CDCl3): δ (ppm)
= 1.95 (m, 2H, 3-CH2), 2.7 (t, J = 7.5, 2H, 4-CH2), 3.4 (d, J = 6.5, 2H,
CH2-Ar), 4.15 (t, J = 6.0, 2H, 2-CH2), 5.1 (m, 2H, CH2=), 6.0 (m, 1H, =CH),
6.45 and 6.8 (d, J = 7.5, 2H, 5-,6-H, aromat.).– Anal. C12H14O2.
(E)-4-(7-Methoxymethoxychroman-8-yl)-2-methylbut-2-en-1-ol (24a)
Prepared as described for 6b. Eluent: toluene-ethyl acetate 4:1; oil; yield
63%.– 1H-NMR (CDCl3): δ (ppm) = 1.85 (s, 3H, Me), 2.0 (m, 2H, 3-CH2),
2.75 (t, J = 6.0, 2H, 4-CH2), 3.4 (d, J = 7.5, 2H, CH2Ar), 3.5 (s, 3H, OMe),
3.95 (s, 2H, CH2-O), 4.2 (t, J = 6.0, 2H, 2-CH2), 5.2 (s, 2H, OCH2O), 5.5 (t,
J = 7.5, 1H, =CH), 6.6 (d, J = 7.5, 1H, 6-H, aromat.), 6.85 (d, J = 7.5, 1H,
5-H, aromat.).– Anal. C16H22O4.
8-Allyl-7-Methoxymethoxychroman (21a)
To a solution of 20 (1.66 g, 8.7 mmol) in abs. DMF (20 ml), NaH (0.8 g)
was added under N2 atmosphere and at 0 °C and stirred for 15 min. Then
chloromethyl methyl ether (2 ml) in abs. DMF (5 ml) was added dropwise
and the mixture stirred overnight at room temperature. Then the mixture was
diluted with water, extracted with ethyl ether, washed with a solution of 10%
NaOH, water, dried over MgSO4 and evaporated to obtain an oil, (1.95 g,
95%), wich was sufficiently pure for further use.– 1H-NMR (CDCl3): δ
(ppm) = 1.95 (m, 2H, 3-CH2), 2.75 (t, J = 7.0, 2H, 4-CH2), 3.4 (d, J = 7.0,
2H, CH2Ar), 3.5 (s, 3H, OMe), 4.2(d, J = 6.0, 2H, 2-CH2), 5.0 (m, 2H, CH2=),
5.15 (s, 2H, OCH2O), 6.0 (m, 1H, =CH), 6.6 and 6.85 (d, J = 7.5, 2H, 5-,6-H,
aromat.).– Anal. C14H18O3.
(E)-4-(7-Methoxychroman-8-yl)-2-methylbut-2-en-1-ol (24b)
Prepared as described for 6b. Eluent: toluene-ethyl acetate 4:1; mp 56.5–
57.5 °C; yield 65%.– 1H-NMR (CDCl3): δ (ppm) = 1.5 (t, 1H, OH, deuter-
able), 1.85 (s, 3H, Me, 2.0 (m, 2H, 3-CH2), 2.75 (t, J = 6.0, 2H, 4-CH2), 3.35
(d, J = 7.5, 2H, CH2Ar), 3.75 (s, 3H, OMe), 3.95 (s, 2H, CH2-O), 4.2 (t, J =
6.0, 2H, 2-CH2), 5.5 (t, J = 7.5, 1H, CH=), 6.45 (d, J = 7.5, 1H, 6-H, aromat.),
6.9 (d, J = 7.5, 1H, 5-H, aromat.).– Anal. C15H20O3.
8-Allyl-7-Methoxychroman (21b)
4-(7-Hydroxychroman-8-yl)-2-methylbut-2-en-1-ol (24c)
To the mixture of 20 (1.9 g, 0.01 mol), water (25 ml) and KOH (2.5 g,
0.044 mol) after stirring for 15 min at room temperature, dimethyl sulphate
(3.5 ml, 0.037 mol) was added dropwise. The mixture was stirred 10 hours
at room temperature, extracted with dichloromethane, washedwith a solution
of 10% KOH, water, dried over Na2SO4, evaporated to give on oil, (1.8 g,
90%), which was sufficiently pure for further use.– 1H-NMR (CDCl3): δ
(ppm) = 1.95 (m, 2H, 3-CH2), 2.7 (t, J = 7.0, 2H, 4-CH2), 3.4 (d, J = 7.5, 2H,
CH2=), 3.8 (s, 3H, OMe), 4.2 (t, J = 6.0, 2H, 2-CH2), 5.0 (m, 2H, CH2=),
5.95 (m, 1H, =CH), 6.5 and 6.9 (d, 2H, 5-,6-H, aromat.).– Anal. C13H16O2.
24a (0.7 g, 2.5 mmol) in methanol (20 ml) was stirred with 1:1 HCl (1 ml)
at room temperature for 16 hours. The reaction mixture was diluted with
water, extracted with ethyl acetate, washed with water, dried over MgSO4
and evaporated. The residue was purified by column chromatography on
silica gel, toluene-ethyl acetate (4:1) as eluent, to give 24c (0.35 g, 60%), mp
1
84–86 °C.– H-NMR (CDCl3): δ (ppm) = 1.85 (s, 3H, Me), 2.0 (m, 2H,
3-CH2), 2.75 (t, J = 6.0, 2H, 4-CH2), 3.4 (d, J = 7.5, 2H, CH2Ar), 3.95 (s,
2H, CH2O), 4.2 (t, J = 6.0, 2H, 2-CH2), 5.3 (brs, 1H, OH), 5.5 (t, J = 7.5, 1H,
=CH), 6.3 (d, J = 7.5, 1H, 6-H, aromat.), 6.75 (d, J = 7.5, 1H, 5-H, aromat.).–
Anal. C14H18O3.
General Procedure for the Preparation of 22a,b
To27.4mmol ofallyl-derivatives 21a,b in 356 ml dioxane, 5.6 mmol OsO4
in 30 ml dioxane was added and the mixture was stirred in dark for 30 min
at room temperature. Then NaIO4 (0.065 mol) in 1070 ml water was added
dropwise during 75 min. The mixture was diluted with water (200 ml),
extracted with ethyl acetate, washed with a solution of 20% sodium thiosul-
phate, water and dried over MgSO4. Evaporation of the solution gave an oil,
which was purified by column chromatography using hexane-ethyl acetate
9:1 as eluent.
Procedures for Preparation of 25, 26, 27a,b,c
Reduction of 8a to 25 as well as 24b,c to 27a,b was carried out as described
at aldehyde 14, using methanol instead of glacial acetic acid. Reduction of
25 to 26 was carried out with LiAlH4 as described for 6b.
Ethyl 4-(2,6-dimethoxyphenyl)-2-methylbutyrate (25)
Eluent: hexane-acetone 5:2; colourless oil; yield85%.– 1H-NMR (CDCl3):
δ (ppm) = 1.2 (t, J = 7.5, 3H, Me), 1.3 (d, J = 6.0, 3H, Me), 1.6, 1.9 and 2.4
(m, 3H, CH, CH2), 2.7 (t, J = 7.5, 2H, CH2Ar), 3.75 (s, 6H, 2×OMe), 4.1 (q,
J = 7.5, 2H, CH2), 6.5 (d, J = 7.5, 2H, 3-,5-H, aromat.), 7.15 (t, J = 7.5, 1H,
4-H, aromat.).– Anal. C15H22O4.
(7-Methoxymethoxychroman-8-yl)acetaldehyde (22a)
Colourless oil; yield 85%.– 1H-NMR (CDCl3): δ (ppm) = 2.0 (m, 2H,
3-CH2), 2.75 (t, J = 7.0, 2H, 4-CH2), 3.4 (s, 3H, OMe), 3.7 (d, J = 5.0, 2H,
CH2Ar), 4.2 (t, J = 6.0, 2H, 2-CH2), 5.15 (s, 2H, OCH2O), 6.7 (d, J = 7.5,
1H, 6-H, aromat.), 6.95 (d, J = 7.5, 1H, 5-H, aromat.), 9.65 (t, J = 1.0, 1H,
CHO).– Anal. C13H16O4.
4-(2,6-Dimethoxyphenyl)-2-methylbutanol (26)
Eluent: hexane-acetone 5:2; colourless oil; yield83%.– 1H-NMR (CDCl3):
δ (ppm) = 1.0 (d, J = 7.5, 3H, Me), 1.45, 1.65 and 2.75 (m, 5H, 1-CH2, 2-CH,
3-CH2), 1.9 (s, 1H, OH), 3.5 (m, 2H, CH2Ar), 3.85 (s, 6H, 2×OMe), 6.5 (d,
J = 7.5, 2H, 3-,5-H, aromat.), 7.1 (t, J = 7.5, 1H, 4-H, aromat.).– Anal.
C13H20O3.
(7-Methoxychroman-8-yl)acetaldehyde (22b)
Colourless oil; yield 90%.– 1H-NMR (CDCl3): δ (ppm) = 2.0 (m, 2H,
3-CH2), 2.75 (t, J = 7.0, 2H, 4-CH2), 3.65 (d, J = 1.0, 2H, CH2Ar), 3.8 (s,
3H, OMe), 4.2 (t, J = 6.0, 2H, 2-CH2), 6.5 (d, J = 7.5, 1H, 6-H, aromat.), 7.0
(d, J = 7.5, 1H, 5-H, aromat.), 9.65 (t, J = 1.0, 1H, CHO).– Anal. C12H14O3.
4-(7-Methoxychroman-8-yl)-2-methylbutanol (27a)
(E)-Ethyl 4-(7-methoxymethoxychroman-8-yl)-2-methylcrotonate (23a)
Eluent: hexane-acetone 5:2; colourless oil.– 1H-NMR (CDCl3): δ (ppm) =
0.98 (d, J = 5.0, 3H, Me), 1.39–2.10 (bm, 3H, CH2-CH-), 2.75 (m, 4H, 4-CH2
and ArCH2), 3.61 (t, J = 4.0, CH2OH), 3.85 (s, 3H, OMe), 4.18 (t, J = 5.0,
2H, 2-CH2), 4.85 (s, 1H, OH), 6.45 (d, J = 6.0, 1H, 6-H, aromat.), 6.87 (d, J
= 6.0, 1H, 5-H, aromat.).– Anal. C15H22O3.
Prepared as described for 8a–g. Eluent: hexane-acetone 10:1; oil; yield
70%.– 1H-NMR (CDCl3): δ (ppm) = 1.3 (t, J = 7.5, 3H, Me), 1.95 (m, 2H,
3-CH2), 2.0 (s, 3H, Me), 2.75 (t, J = 6.0, 2H, 4-CH2), 3.45 (s, 3H, OMe), 3.5
(d, J = 7.5, 2H, CH2Ar), 4.15 (m, 4H, 2-CH2, OCH2), 5.2 (s, 2H, OCH2O),
Arch. Pharm. Pharm. Med. Chem. 334, 53–61 (2001)

Structural Analogues of (–)-Cabenegrin A-I
61
8-(3-Hydroxymethylbutyl)chroman-7-ol (27b)
[4] M. Nakagawa, K. Nakanishi, L.L. Darko, J.A. Vick, Tetrahedron Lett.
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Eluent: toluene-acetone 3:1; colourless oil; yield 22%.– 1H-NMR
(CDCl3): δ (ppm) = 0.98 (d, J = 5.0, 3H, Me), 1.39–2.10 (bm, 3H, CH2-CH-),
2.75 (m, 4H, 4-CH2 and ArCH2), 3.61 (t, J = 4.0, CH2OH), 4.18 (t, J = 5.0,
2H, 2-CH2), 4.85 (s, 1H, OH), 6.45 (d, J = 6.0, 1H, 6-H, aromat.), 6.87 (d, J
= 6.0, 1H, 5-H, aromat.).– Anal. C14H20O3.
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Received: October 18, 2000 [FP525]
Arch. Pharm. Pharm. Med. Chem. 334, 53–61 (2001)