Synthesis of a new class of bisheterocycles via the Heck reaction of eudesmane type methylene lactones with 8-bromoxanthines

Article abstract of DOI:10.1016/j.tet.2017.03.016

The eudesmane-type methylene lactones (isoalantolactone, alantolactone, 4,15-epoxyisoalantolactone, 2′,2′-dichloro-4H-spiro[cyclopropane-1′,4-eudesma-11(13)-en-8β,12-olide], and alantolactone) react with 8-bromoxanthines (8-bromocaffeine, 8-bromotheobromine, 8-bromo-3-butyltheobromine, 8-bromotheophylline, 8-bromo-9-butyltheophylline) under Heck reaction conditions to produce the target (E)-13-(2,6-dioxo-2,3-dihydro-1H-purin-8-yl)eudesma-4(15),11(13)-dien-8β,12-olides and the subsequent endocyclic isomers - 11-(2,6-dioxo-2,3-dihydro-1H-purin-8-yl)-13-normethyleudecma-4(15)-7(11)-dien-8α,12-olides. It was revealed that the yield and product ratio depends on the reaction conditions and the structure of methylene lactone. The effectiveness of Pd(OAc)₂–caffeine catalytic system has been demonstrated in this reaction. The electric eel acetylcholinesterase inhibitory activity of the eudecmanolide-xanthine hybrids was evaluated. Among the new type bisheterocycles compound 27 with butyl and 2-oxodecahydronaphtho[2,3-b]furan-3(2H)-ylidene)methyl substituents at C-7 and C-8 of the xanthine core showed moderate activity with IC₅₀ value of 40?μM.

Full text of DOI:10.1016/j.tet.2017.03.016

Accepted Manuscript
Synthesis of a new class of bisheterocycles via the Heck reaction of eudesmane type
methylene lactones with 8-bromoxanthines
Sergey S. Patrushev, Tatyana V. Rybalova, Igor D. Ivanov, Valentin A. Vavilin, Elvira
E. Shults
PII:
S0040-4020(17)30240-5
10.1016/j.tet.2017.03.016
TET 28522
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 November 2016
Revised Date: 23 February 2017
Accepted Date: 6 March 2017
Please cite this article as: Patrushev SS, Rybalova TV, Ivanov ID, Vavilin VA, Shults EE, Synthesis of
a new class of bisheterocycles via the Heck reaction of eudesmane type methylene lactones with 8-
bromoxanthines, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.016.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of a new class of bisheterocycles via the Heck reaction
of eudesmane type methylene lactones with 8-bromoxanthines
Synthetic transformations of natural
compounds
S. S. Patrushev, T. V. Rybalova, I. D. Ivanov, V. A. Vavilin, E. E. Shults*

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of a new class of bisheterocycles via the Heck reaction of eudesmane
type methylene lactones with 8-bromoxanthines
Sergey S. Patrusheva,b, Tatyana V. Rybalovaa,b, Igor D. Ivanovc , Valentin A. Vavilinb,c
and Elvira E. Shultsa,b
a Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentyev Avenue 9, 630090 Novosibirsk, Russia
b Novosibirsk State University, Pirogova St. 1, Novosibirsk 630090, Russia
c Insitute of Molecular Biology and Biophysics, Timakova St. 2/12, Novosibirsk 630117, Russia
ARTICLE INFO
ABSTRACT
The eudesmane-type methylene lactones (isoalantolactone, alantolactone, 4,15-
epoxyisoalantolactone, 2',2'-dichloro-4H-spiro[cyclopropane-1',4-eudesma-11(13)-en-8β,12-
Article history:
Received
olide], and alantolactone) react with 8-bromoxanthines (8-bromocaffeine, 8-bromotheobromine,
8-bromo-3-butyltheobromine, 8-bromotheophylline, 8-bromo-9-butyltheophylline) under the
Heck reaction conditions to produce the target (E)-13-(2,6-dioxo-2,3-dihydro-1H-purin-8-
yl)eudesma-4(15),11(13)-dien-8β,12-olides and the subsequent endocyclic isomers - 11-(2,6-
dioxo-2,3-dihydro-1H-purin-8-yl)-13-normethyleudecma-4(15)-7(11)-dien-8α,12-olides. It was
revealed that the yield and product ratio depends on the reaction conditions and the structure of
methylene lactone. The effectiveness of Pd(OAc)2–caffeine catalytic system has been
demonstrated in this reaction. The electric eel acetylcholinesterase inhibitory activity of the
eudecmanolide-xanthine hybrids was evaluated. Among the new type bisheterocycles compound
27 with butyl and 2-oxodecahydronaphtho[2,3-b]furan-3(2H)-ylidene)methyl substituents at C-7
and C-8 of the xanthine core showed moderate activity with IC50 value of 40 ꢀM.
Received in revised form
Accepted
Available online
Keywords:
Sesquiterpene lactones
Isoalantolactone
Xanthine
Heck reaction
Acetylcholinesterase inhibitors
2016 Elsevier Ltd. All rights reserved
.
———
Corresponding author. Tel.: +7-383-330-5688; fax: +7-383-330-9752; e-mail: schultz@nioch.nsc.ru

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
of isoalantolactone 1 with 8-bromoxanthines. For completing the
knowledge on the influence of the methylene lactones structure
on the results of the Heck reaction, 4,15-epoxyisoalantolactone 2,
2',2'-dichloro-4H-spiro[cyclopropane-1',4-eudesma-11(13)-en-
8β,12-olide] 3 and alantolactone 4 were taken into account. The
electric eel acetylcholinesterase inhibitory activity in vitro (AChE
IC50) of the eudecmanolide - xanthine hybrids has been was
evaluated.
Xanthines – that belong to an important group of heterocyclic
compounds – have gained significance in the synthesis of drugs
and pharmaceutical products. Indeed, a great variety of di-, tri- or
tetrasubstituted xanthines described in the literature have been
found to be potent inhibitors of protein kinases,
phosphodiesterases,
acetylcholinesterase,
leucotriene
A4
hydrolase, sulfotransferases, and microtubuline assembly,
inducers of interferon and dedifferentiation and antagonists of
adenosine receptors and corticotropin-releasing hormone
receptors.1 Xanthines plays a vital role in neurotransmission and
neuromodulation.2 Some xanthine derivatives were identified as
attractive new classes of drug candidates against Mycobacterium
tuberculosis.3 This group of heterocyclic compounds include the
accessible plant alkaloids caffeine, theophylline and
theobromine. The activities of xanthines are linked to the
diversity of substituents that can be introduced, espeshially on the
C-3, C-6, C-8, and N-9 positions.4-17 Substitution on the C-8
position of xanthine ring was found to enhance adenosine
receptor affinity.10-14 The role of synthetic xanthine-based
agonists and antagonists of adenosine receptors in medicinal
chemistry have systematically been investigated.
2. Results and discussion
2.1. Chemistry
The key step of our synthetic strategy to eudecmanolide-
xanthine hybrids relied on the Heck reaction of accessible
methylene
lactones
–
isoalantolactone
1,
4,15-
epoxyisoalantolactone 2, 2',2'-dichloro-4H-spiro[cyclopropane-
1',4-eudesma-11(13)-en-8β,12-olide] 3, and alantolactone 4 with
8-bromocaffeine 5, 8-bromotheobromine 6, 1-(n-butyl)-8-
bromotheobromine 7, 8-bromotheophylline 8, and 7-(n-butyl)-8-
bromotheophylline 9 (Fig. 1).
Literature review on the structure-activity relationships
reveals that the incorporation of aryl, styryl or hetaryl substituent
on C-8 position of xanthine ring increases antagonist activity
towards adenosine receptors.12 An additional vinyl or
(cyclopentyloxy)phenyl substituent on the 8-th position results
in enhanced potency and human A2A adenosine receptor
selectivity.13 The adenosine A2A receptor antagonist (A2A
antagonist) properties of (E)-8-styrylcaffeinyl analogues have
been of special interest because A2A antagonists are currently
being investigated as possible therapeutic agents for the
symptomatic treatment of motor deficits in Parkinson’s
diseases15. (E,E)-8-(4-phenylbutadien-1-yl)caffeine analogues are
characterized as dual-acting compounds, possibly with enhanced
A2A antagonism properties and MAO-B inhibition.16 An electron
deficient functionalized styryl substituent at C-8 are found in
several potent competitive inhibitors of MAO-B.17 Since MAO-B
inhibitors are also considered to be antiparkinsonian agents, the
possibility of designing drugs for neurodegenerative diseases that
act both as A2A antagonists and inhibitors of MAO-B are of
interest. Generally, the preparation and study of xanthine
derivatives substituted on the 8-th position with fragments of various
substituents has thus been an important challenge in organic
synthesis.
We have focused our attention on the development of
effective methods for the construction of a xanthine structural
framework with a 3-(methylene)butenolide substituent on the 8-
th position. The butenolide (γ-butyrolactone) motif was found in
a large number of natural products, especially sesquiterpene
lactones. The presence of this motif is considered to be a major
factor in the diverse biological activity observed for
sesquiterpene lactones. Our ongoing efforts focused on the
introduction of the eudesmane type methylene lactone –
isoalantolactone 1 in the xanthine molecular framework. It
should be mentioned that the biological properties of
Fig. 1. The structures of methylene lactones 1-4 and 8-bromoxanthines 5-9.
We have previously shown that the reaction of
isoalantolactone 1 with iodobenzenes, catalyzed by a Pd(OAc)2-
(o-Tol)3P system (4:16 mol %) in the presence of Et3N as a base
proceeds upon heating in DMF (120oC, 16 h) and led to a mixture
of the respective (E)-13-aryleudesma-4(15),11(13)-dien-8β,12-
olides (50-85% yields) and 13-nor-11-arylmethyleudesma-
4(15),7(11)-dien-8α,12-olides (3-25% yields).21a Performing of
the reaction of methylene lactone 1 with 8-bromocaffeine 5 under
the indicated conditions after 20h of heating led to a mixture of
xanthine substituted (E)-13-eudesma-4(15),11(13)-dien-8β,12-
olide 10 (yield 52%) and endocyclic isomer 13-
normethyleudecma-4(15)-7(11)-dien-8α,12-olide 11 (yield 32%)
after the purification by column chromatography (Table 1, entry
a, Scheme 1). The equimolar product ratio at a 75% conversion
degree was obtained by performing the Pd-catalyzed reaction in
the absence of phosphine ligand (Table 1, entry b; the ratio was
1
determined from H NMR spectral data of the reaction mixture).
isoalantolactone
1 are well studied: it is used as an
antiinflammatory and antiulcerogenic agents,18 has a high
cytotoxic activity19 and was characterized as an inhibitor of Myb-
dependent gene expression.20 Recently, we have shown the
possibility for structural modification of isoalantolactone21 and its
derivatives22 using the cross-coupling reaction for the preparation
of eudesmanolides with aryl-, pyridine or pyrimidinyl-
substituents. We present herein the regioselective synthesis of a
series of eudesmane-xanthine hybrids by cross-coupling reaction
It was shown by specific experiments that bearing of 13-
subsituted eudesmanolide 10 under the reaction conditions
(Pd(OAc)2, (o-Tol)3P, Et3N, DMF, 120oC, 40 h) did not result in
the isomerization into compound 11. The results started that 11
must be formed directly by the Heck reaction. An efficient way
to improve the yield and ratio of the cross-coupling products in
particular in the Heck reaction, was the addition of
tetraalkylammonium salts to the reaction mixture as proposed by

3
Jeffery.23 The reaction of isoalantolactone
bromocaffeine 5 in the presence of tetrabutylammonium bromide
1
with 8-
ACCEPTED MANUSCRIPT
(TBAB) (Table 1, entries c,d,) was characterized by increasing
the selectivity for endocyclic compound 11 (ratio 10-11, 1:3 or
1:6). The conversion and selectivity of the formation of
compound 11 was further increased by heating of the reaction
mixture up to 140oC (Table 1, entry e). Increasing of the
selectivity of the formation of compound 11 was also observed
by using of following additives: benzyltrimethylammonium
bromide (BTMAB), tetraethylammonium chloride (TEBA)
(Table 1, entries f,g). So, we demonstrated that n-Bu4NBr plays a
crucial role as phase transfer catalyst in this process resulting 11
as major product. The structure of compound 11 was confirmed
by single crystal X-ray analysis (Fig. 2). By column
chromatography some side reaction products have been isolated:
natural compound asterolide 1224 (yield 5%), caffeine 13 (9-18%)
and its dimerisation product 14 (11-23%).
Scheme 2. Formation of proposed catalytic active species A, B.
Table 1
The conditions and product yields in reactions of isoalantolactone 1
with 8-bromocaffeine 5*
Recent studies have considered xanthine derivatives, caffeine
and theophylline, as effective ligands for Pd-catalyzed cross-
coupling reactions, including the Heck reaction.25 The
effectiveness of Pd(OAc)2-caffeine system was demonstrated by
as in the reaction of isoalantolactone 1 with bromopyridines.21c
Originally, we believed that the generation of caffeine 13 under
in the reaction conditions may be involved with Pd-mediated
coupling by formation in situ of some active catalytic species A,
B which could be employed as ligands (Scheme 2).
Our results (Table 1, entries c,d) show that the reaction in
phosphine ligand-free conditions provided the conversion of the
reaction and also the formation of compound 10. To testify our
guess, in “phosphine ligand-free” Pd-catalyzed coupling reaction
we used neat water as the solvent (Table 1, entry h), because
local hydrophobicity has been found to be important in Heck
coupling reactions, especially catalyzed by Pd-complex with N-
heterocyclic carbene ligands.26 The results revealed that only
compound 10 was obtained by carrying out the reaction in water
medium (conversion 90%, isolated yield 55%) (Table 1, entry h).
Addi- Sol-
tive vent
Ratio, Yield,
(o-Tol)3P
(mol%)
Conver-
T, °С t, h
sion, %
Entry
10: 11
%
52 (10),
32 (11)
a
(16)
-
-
-
DMF
120
120
20
20
85
75
3:2
37 (10),
36 (11)
b
c
d
DMF
1:1
1:3
1:6
20 (10),
61 (11)
-
TBAB DMF
TBAB DMF
120
120
20
40
82
70
10 (10),
60 (11)
(16)
e
f
(16)
(16)
(16)
-
TBAB DMF
TEBA DMF
BTMAB DMF
TBAB Water
140
140
140
120
40
40
40
20
>98
100
88
1:50 92 (11)
1:25
1:14
-
-
g
h
90
95:1 55 (10)
* General conditions: 3.0 mmol of lactone 1, 1.2 equiv (a-d, h), or 1.5 equiv
(e-g) of 8-bromoxanthine 5, 4 mol % of Pd(OAc)2 (27 mg, 0.12 mmol,), 1.5
equiv. Et3N, 1 equiv. of additive; in entries (f,g) the reaction mixture was not
subject to colomn chromatography.
We also investigated the possibility for synthesis of
compounds 10 or 11 by a Pd/Cu-catalyzed dehydrogenative Heck
coupling of the lactone 1 with caffeine 13. The reaction was
performed in DMF at 120°С (20 h) in the presence of Pd(OAc)2
(10 mol%), CuCl (20 mol%), and pyridine (2 equiv).27 The
conversion of this reaction was only 10%, formation of exocyclic
isomer 10 was observed (NMR 1H data).
So, we have found conditions for the synthesis of compounds
10 or 11 in 55 or 92% isolated yields. In light of the results
obtained from the optimization of reaction parameters, we
decided to explore the reaction of isoalantolactone 1 using
different halogenated xanthenes 6-9 in the conditions (a) and (e).
O
N
H
H
H
H
O
O
N
N
O
N
O
+
+
+
(a) - (h)
O
O
1+ 5
O
H
H
N
H
N
12
N
13
N
N
N
O
N
O
N
O
N
N
O
N
N
N
+
O
O
N
N
N
O
11
10
O
14
Scheme 1. Synthesis of isoalantolactone-caffeine hybrids: (a)
o
Pd(OAc)2, (o-Tol)3P, Et3N, DMF, 120 C, 20 h; (b) Pd(OAc)2,
Et3N, DMF, 120 oC, 20 h; (c) Pd(OAc)2, Et3N, TBAB, DMF, 120
oC, 20 h; (d) Pd(OAc)2, (o-Tol)3P, TBAB, Et3N, DMF, 120oC, 40
8-Bromotheobromine
6
shown comparable activity and
o
selectivity in the Heck reaction with compound 1 (Scheme 3).
Compounds 15 and 16 were isolated in the yield 44, 32%
(conditions a) or 8 and 87% (conditions e). Reaction of
isoalantolactone 2 with 1-(n-butyl)-8-bromotheobromine 7 led to
the mixture of isomeric compounds 17 and 18 in the yield 44 and
32% or 4 and 92% accordingly. As expected the cross-coupling
reaction of theobromine 6 and N-1 protected xanthine 7 with
lactone 1 in the presence of TBAB, proceeds with higher
selectivity for the formation of endocyclic compounds 16 and 18.
In addition, asterolide 12 (yield 4 %), 1-n-butyltheobromine 20
(6 %), and 8,8'-bis-(1-R-3,7-dimethyl)xanthines 22 (13 %) were
isolated.
h; (e) Pd(OAc)2, (o-Tol)3P, TBAB, Et3N, DMF, 140 C, 40 h; (f)
Pd(OAc)2, (o-Tol)3P, TEBA, Et3N, DMF, 140 oC, 40 h; (g)
o
Pd(OAc)2, (o-Tol)3P, BTMAB, Et3N, DMF, 140 C, 40 h; (h)
Pd(OAc)2, Et3N, TBAB, water, 120 oC, 20 h.

4
Tetrahedron
isolated after column chromatography. The reaction of lactone 2
ACCEPTED MANUSCRIPT
with compound 5 at higher temperature (entry 2) accompanied by
formation of unidentified compounds; the isolated yield of the
majour compound 31 was decreased. In the reaction of lactone 2
with 8-bromotheobromine 6 compounds 32 and 33 were obtained
along with the oxirane ring opening compound 34 (entry 3). The
selectivity of the exo-cyclic compouns formation (in conditions
a) was also observed.
The reaction of 2',2'-dichloro-4H-spiro[cyclopropane-1',4-
eudesma-11(13)-en-8β,12-olide]
3 with 8-bromocaffeine 5
afforded a mixture of isomeric lactones 35, 36 (Scheme 6, Table
2, entries 4,5). Selectivity for the endocyclic compound 36 was
Scheme 3. Synthesis of isoalantolactone-theobromine hybrids: (a)
o
Pd(OAc)2, (o-Tol)3P, Et3N, DMF, 120 C, 20 h; (e) Pd(OAc)2, (o-
observed in the reaction of methylene lactone
3 with
Tol)3P, TBAB, Et3N, DMF, 140 oC, 40 h.
bromocaffeine 5 in the presence of TBAB. Compound 35 (yield
40%) was also obtained by the cyclopropanation reaction of
compound 11 under the conditions described22a (Scheme 6).
The reaction of isoalantolactone 1 with 8-bromotheophylline
8 (Scheme 4, conditions a) afforded a mixture of isomeric
lactones 23, 24 and compound 25; the latter being the product of
Michael addition of lactone 1 to theophylline 26; the ratio
between 23, 24 and 25 was equal to 3 : 1 : 3 (Scheme 4).
Compounds 23, 24 and 25 were isolated in the yield 20, 6 and
17%. In a control experiment, by heating of compounds 1 and 26
in the presence of triethylamine we obtained the Michael adduct
25 in the yield 88%. The Heck reaction of 1 with bromide 8
proceeds more selectively in the presence of TBAB (e); in this
case, the ratio 23:24 was 1 : 2, compounds 23 and 24 were
isolated in the yield 22 and 48%. In the Heck reaction of
compound 1 with 7-(n-butyl)-protected 8-bromotheophylline 9
compounds 27 and 28 were isolated as the main products: 39 and
34 % (conditions a) or 14 and 75% (conditions e). Compound 29
was also formed (yield 4%).
Scheme 5. Synthesis of epoxyisoalantolactone-xanthine hybrids:
(a) Pd(OAc)2, (o-Tol)3P, Et3N, DMF, 120 oC, 20 h; (e) Pd(OAc)2, (o-Tol)3P,
TBAB, Et3N, DMF, 140 oC, 40 h
.
Methylene lactone 4 showed lower activity in the Heck
reaction with 8-bromocaffeine 5 (Scheme 6, Table 2, entries 6,7).
The only isolated product of this reaction was the endocyclic
isomer 13-normethyleudecma-4(15)-7(11)-dien-8α,12-olide 37.
The corresponding exo-cyclic compound was not observed.
Scheme 4. Synthesis of isoalantolactone-theophylline hybrids: (a)
Pd(OAc)2, (o-Tol)3P, Et3N, DMF, 120 oC, 20 h; (e) Pd(OAc)2, (o-Tol)3P,
TBAB, Et3N, DMF, 140 oC, 40 h.
The results of reaction of the compound 1 reacting with 8-
bromoxanthines revealed that this Heck reaction proceeds
selectively on the 11,13-double bond. The stereochemistry of a
xanthine moiety in compounds 10, 15, 17, 23, 27 is assigned as
E-form based on the spectral data. The formation of a significant
quantity of endocyclic compounds 11, 16, 18, 24, 28 (non-
classical variant of the Heck reaction; syn-β-elimination of H-7
proton occurs) is observed. These results should depend on the
steric hindrance create by a xanthine fragment of the transition
states (around the cyclic palladium intermediate) in this reaction.
Moreover, this reaction caused C-8 epimerization resulting from
a relief of the steric factors. The chair-chair–like conformation
of the decalin unit realized in this case would determine the
epimerization process.
Scheme 6. Reaction of methylene lactones 3,4 with 8-bromocaffeine
5: (a) Pd(OAc)2, (o-Tol)3P, Et3N, DMF, 120 oC, 20 h; (e) Pd(OAc)2, (o-
o
Tol)3P, TBAB, Et3N, DMF, 140 C, 40 h; (c) 50% NaOH, CHCl3, TEBA, 0-
10 oC, 2.5 h.
Thus, our results showed that the yield of the reaction
products significantly depended on the structure of the methylene
lactone. The structure of methylene lactones 1-4 is distinguished
by the cis-annulation of the lactone ring to the
octahydronaphthalene fragment. Compound 4 has no the suitable
αH-atom at position C(5), and has a C(4,5) bouble bond. That,
probably, is the reason to the lowering the activity in the Heck
reaction and for the formation of the product with the endocyclic
double bond (syn-β-elimination of H-7 proton).
Encouraged by the successful results we examined reactions
of lactones 2, 3 with 8-bromoxanthines 5, 6. The results are
summarized in Table 2 (Scheme 5,6). The reactions of
epoxyisoalantolactone 2 with 8-bromocaffeine 5 produced
similar results (Table 2, entries 1, 2); compounds 30, 31 were

5
The bond lengths are the same as the statistical values.28
Table 2
ACCEPTED MANUSCRIPT
The conversion and products yields in reactions of methylene
The trans-fused six-membered rings of the decaline fragment
adopt the chair conformation. The lactone ring is plane within
±0.012(2) Å with O(2) and C(13) atom deviations from cycle
plane equal to 0.018(2) and 0.086(2) Å. Only three lactones of
eudesmane type having the same conformation and configuration
of the asymmetric centers in the tricyclic fragment.21a,29,30 The
position of bicyclic xanthine fragment is defined by the torsion
angles С(12)–С(11)–С(13)–C(8') equal to -89.3(2)° and С(11)–
С(13)– С(8')– N(9') equal to -79.1(2)°. There exists the
intramolecular hydrogen bond C(16)-H(16A)...O2 between
lactone carboxyl group and xanthine methyl substituent (Table
3). The bicyclic xanthine fragment is plane within ±0.035(2)Å
with the substituent atom deviation as follows: O(3) – 0.035(2),
O(4) – -0.083(1), C(13) – -0.112(2), C(16) – 0.070(2), C(17) – -
0.073(2) and C(18) – 0.050(2) Å. There are three intramolecular
hydrogen bonds in the xanthine fragment which define the
orientation of the substituent methyl groups. The crystal structure
of compound 11 is passerses various C-H…O hydrogen bonds
and C-H… π-interactions (Table 3).
lactones 2-4 with 8-bromoxanthines 5-6*
Entry Lactone Xantine Condi-
tions
Conversion
(products ratio)
Isolated compounds
(yield, %)
1
2
3
2
2
2
5
5
6
a
e
a
96 (30:31, 2:1)
99 (30:31, 1:7)
30 (53); 31 (27)
30 (3); 31 (46)
100(32:33:34,
32(38); 33(28);
34(30);
2:1:2)
4
5
6
7
3
3
4
4
5
5
5
5
a
e
a
e
86 (35:36, 2:1)
96 (35:36, 1:8)
30 (37)
35 (52); 36 (31)
35 (8); 36 (76)
37 (26)
96 (37)
37 (46)
* Conditions: 3.0 mmol of lactone 1, 1.2 equiv of 8-bromoxanthines, 4 mol %
of Pd(OAc)2 16 mol % (o-Tol)3P, 1.5 equiv. Et3N; (a) Pd(OAc)2, (o-Tol)3P,
o
Et3N, DMF, 120 C, 20 h; (e) Pd(OAc)2, (o-Tol)3P, TBAB, Et3N, DMF, 140
oC, 40 h.
The structure of synthesized compounds was established by
1H, 13C, IR and UV spectroscopy, mass-spectrometry, and
elemental analysis data. The (E)-configuration of the
C(11)=C(13) double bond in compounds 10, 15, 17, 23, 27, 30,
32, and 35 was confirmed from the presence in the 13C NMR
spectrum (monoresonance mode) of the cis-spin-spin coupling
constant between the olefin proton and the carbonyl carbon atom
of the lactone ring (3Jcis = 6.5-6.7 Hz). The signal for the proton
Table 3
Parameters of the intra- and intermolecular hydrogen bonds and
C-H…π-interactions in the crystals of compound 11
H-bond/
H…A/
D…A/
D-H…A/
C-H… π-interaction
H…Cg* (Å)
Dpln* (Å)
C-H…Cg* (°)
C16-H16A...O2(intra)
C16-H16B...O4(intra)
C17-H17B...O4(intra)
C18-H18C...N9'(intra)
C16-H16C...O3(inter)
C17-H17A...O1(inter)
C2-H2A… πlactone
C15-N15B… πimidazole
C17-N17B… πimidazole
* Parameters of C-H… π-interactions: distances H to ring center - H…Cg,
H to ring plane Dpln and angle C-H…Cg.
2.46
2.48
2.26
2.52
2.57
2.51
2.88
2.73
2.93
3.357(3)
3.130(3)
2.710(3)
2.913(2)
3.488(2)
3.360(3)
2.78
156
125
108
105
160
148
147
134
154
1
H(13) in the H NMR spectra of (E)-isomers 10, 15, 17, 23, 27,
1
30, 32, and 35 manifests itself at 7.05-7.27 ppm. The H NMR
spectra of compounds 6—8, 13, 15, 17—20, and 27 are
characterized by a downfield shift of the signal for the proton
H(7) (δ 3.28-4.07 ppm) as compared to the signal for the
corresponding proton in the spectrum of isoalantolactone 1 (δ
1
2.89 ppm). An indicative feature of the H NMR spectra of
compounds 11, 16, 18, 24, 28, 31, 33, 36 and 37 is the presence
of signals for the protons of the methylene group at the C(13)
atom (for example, for compound 11, at δ = 3.63 and 3.68 (both
d, 2 H, H(13), J = 15.7 Hz)) and a significant increase in the
difference of chemical shifts for the protons H(9) (ꢁδ 1.2 ppm).
The upfield signal for the proton H(9) (d 1.10 for 11) has an
axial-axial constant with the proton H(8) (J = 11.4 Hz). The (8S)-
configuration of compounds 11, 16, 18, 24, 28, 31, 33, 36, and 37
was confirmed by the data of the NOESY experiments: the cross-
peaks between the signals for the protons of the methyl group
C14H3 and the proton H(8) were observed.
2.72
2.70
2.2. Biochemistry
Next, taking into account the data about the selective inhibition
of human acetylcholinesterase enzyme by xanthine derivatives
caffeine, pentoxifylline, and propentofylline31 we evaluated the
inhibition of electric eel acetylcholinesterase by the synthesized
xanthine - eudecmanolide hybrids 10,11, 15-18, 23-28 and 30-34.
Among the synthesized compounds 17, 25 and 27 were the most
potent AChE inhibitors (AChE IC50 = 40-120 ꢀM) (Fig.3).
The structure of compound 11 was determined by single crystal
X-ray analysis (Fig. 2).
Fig. 2. ORTEP view of compound 11 according to XRD data
(thermal ellipsoids at 30% probability).
Fig. 3. Inhibition of electric eel acetylcholinesterase by the xanthine
- eudecmanolide hybrids 17, 25, 27.

6
Tetrahedron
ACCEPTED MANUSCRIPT
The parent molecule caffeine 13 provided inhibition in the
(DMF, PhH, PhCH3, CH3CN, CHCl3, EtOAc), as well as Et3N
were purified according to standard methods and distilled under
argon flow immediately before use in the reactions. Pd(PPh3)4, o-
Tol3P, Cs2CO3, ТВАВ, ТEACl, TEBA, BTMAB and 8-
concentration AChE IC50 30±2.4 ꢀM. The AChE inhibition of the
xanthine - eudecmanolide hybrid 27 was compared with that of
caffeine 13.The electric eel AChE inhibitory potency was of the
order: 17 < 25 < 27 (AChE IC50 = 120±5.5 ꢀM, 80±1.5 ꢀM and
40±2.5 ꢀM respectively). The addition of an N-7 butyl substituent
in compound 27 or N-1 butyl substituent in compound 17,
instead of a smaller methyl group in compound 10, provided
better AChE inhibition relative to 10; the Michael adduct 25 was
not as potent as the subsequent exocyclic compound 27. The
exocyclic compounds 17 and 27 were the most potent AChE
inhibitors than the subsequent endocyclic isomers 18, 28.
bromoxanthines 6,
8 were purchased from Alfa Aesar.
Isoalantolactone 1 and alantolactone 4 used in this work was
isolated by extraction from Inula helenium L. with subsequent
separation of morpholine adducts.32 4,15-Epoxyisoalantolactone
233, 2',2'-dichloro-4H-spiro[cyclopropane-1',4-eudesma-11(13)-
en-8β,12-olide] 322a and 8-bromocaffeine 534 were obtained
according to the known procedures.
4.2. Synthetic procedures and characterization data
3. Conclusion
4.2.1.
8-Вromo-7-butyl-1,3-dimethyl-1H-purine-2,6(3H,7H)-
dione (7). A solution of n-BuBr (411 mg, 3.3 mmol) was added
dropwise with stirring to a hot mixture ( 60°C) of 8-bromo-3,7-
dimethyl-1H-purine-2,6(3H,7H)-dione (777 mg, 3 mmol) and
NaH (72 mg, 3 mmol) in DMF (40 mL). The reaction mixture
was heated at 60°C for 12 h (TLC). After cooling, 80 mL of
water was added. The formed precipitate was filtrated off,
washed with water (2×10 mL) and recrystallizated from EtOH.
Yield 765 mg (81%), colorless solid, mp 134-136°C. δH (400
MHz, CDCl3) 3.90 (dd, J 8.8, 7.4 Hz, 2H, NCH2), 3.88 (s, 3H,
NMe), 3.46 (s, 3H, NMe), 1.54 (ddd, J 8.2, 7.6, 7.5 Hz, 2H,
CH2), 1.33 (ddd, J=8.2, 7.7, 7.4 Hz, 2H, CH2), 0.87 (t, J 7.4 Hz,
3H, CH3); δC (100.8 MHz, CDCl3) (101 MHz, CDCl3) 156.5 (C-
In summary, we have shown that the cross-coupling reaction
of eudecmane type methylene lactones with 8-bromoxanthines is
an effective method for the preparation of a new group of
biologically interesting eudecmanolide - xanthine hybrids.
Variation of the catalytic system composition allowed to modify
the selectivity of the reaction increasing the yield of exo-cyclic
compounds or theirs endocyclic isomers. The nature of
methylene lactone had a substantial effect on the yield and
composition of the reaction products.
The availability of eudecmanolide - xanthine hybrids encouraged
further design of therapeutically relevant analogues based of
these types of this compounds.
4'), 153.2 (C-2'), 150.2 (C-6'), 130.2 (C-8'), 111.6 (C-5'), 43.4
(NCH2), 36.1 (NMe), 32.2 (CH2), 31.9 (NMe), 22.3 (CH2), 15.9
(Me). Anal. calcd for C11H15BrN4O2 (%): C 41.92; H 4.80; N
17.78; Br 25.35; found (%): C 41.94; H 4.77; N 17.85; Br 25.41.
4. Experimental
4.1. General
1H and 13C NMR spectra were acquired on Bruker AV-400
(1H: 400.13 MHz, 13C: 100.78 MHz) or Bruker AV-600 (1H:
600.30 MHz, 13C: 150.95 MHz) (Bruker BioSpin GmbH,
Rheinstetten, Germany) instruments, using tetramethylsilane
(TMS) as an internal standard. The 13C NMR signal multiplicity
was determined by standard methods of recording spectra in
single resonance mode. NMR signals were assigned by using
various types of 1H–1H and 1H–13C correlation spectroscopy
(COSY, HMBC, COXH, NOESY with 1 s mixing time and 2 s
delay between pulses). In the description of the 1H and 13C-NMR
spectra for compounds 10, 11, 12, 15-18, 23-25, 27, 28, and 30-
37 the isoalantolactone skeleton atoms numeration system given
in structure 1 was used. IR spectra were recorded by means of the
KBr pellet technique on a Bruker Vector-22 spectrometer. UV
spectra were obtained on an HP 8453 UV-Vis spectrometer
(Hewlette-Packard, Waldbronn, Germany) in EtOH solutions
(10-4 mol/l). The specific rotation values [α]D were determined on
a PolAAr 3005 polarimeter, and expressed in (deg·ml)/(g·dm),
while concentration was expressed in g per 100 ml of solution.
Mass spectra were recorded on a DFS Thermo Scientific high
resolution mass spectrometer (evaporator temperature 50-260°С,
electron impact ionization at 70 eV). The melting points were
determined on a Stuart SMF-38 melting point apparatus (Bibby
Scientific, Staffordshire, UK) and are uncorrected. Elemental
analysis was carried out on a Carlo-Erba 1106-Elemental analysis
instrument (Carlo-Erba, Milan, Italy). X-ray structural study of
compound 11 was performed on a Bruker KAPPA APEX II
diffractometer with a two-dimensional CCD detector (MoKα
radiation with graphite monochromator, ω-φ-scanning). The
reaction progress and the purity of the obtained compounds were
monitored by TLC on Silufol UV-254 plates (Kavalier, Czech
Republic, CHCl3-EtOH, 10:1 or C6H6-EtOAc, 3:1; detection
under UV light or by treatment with iodine vapor). Column
chromatography was performed by using silica gel 60 (0.063-
0.200 mm, Merck KGaA, Darmstadt, Germany).The solvents
4.2.2.
8-Bromo-7-butyl-1,3-dimethyl-1H-purine-2,6(3H,7H)-
dione (9). n-BuBr (548 mg, 4 mmol) was added to a stirred
mixture of 8-bromo-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione
(518 mg, 2 mmol), K2CO3 (553 mg, 4 mmol) in DMF (20 m) for
20 min at room temperature. After 6 h stirring (TLC), cold water
(40 mL) was added. The formed precipitate was filtrated off,
washed with water (2×10 mL) and dried. Crystallization from
EtOH afforded 504 mg (80%) of compound 9 as colorless
needles; mp 126-128°C. δH (600 MHz, CDCl3) 4.25 (dd, J 8.8,
7.4 Hz, 2H, NCH2), 3.48 (s, 3H, NMe), 3.32 (s, 3H, NMe), 1.72
(ddd, J 8.2, 7.6, 7.5 Hz, 2H, CH2), 1.32 (ddd, J 8.2, 7.7, 7.4 Hz,
2H, CH2), 0.89 (t, J 7.4 Hz, 3H, CH3); δC (151 MHz, CDCl3)
153.8 (C-4
'), 151.0 (C-2'), 148.0 (C-6'), 127.1 (C-8'), 108.6 (C-
5
'), 47.2 (NCH2), 32.1 (CH2), 29.6 (NMe), 27.8 (NMe), 19.4
(CH2), 13.4 (Me). Anal. Calcd for C11H15BrN4O2 (%): C 41.92; H
4.80; N 17.78; Br 25.35; found (%): C 41.99; H 4.79; N 17.87;
Br 25.40.
4.2.3. Heck reaction of methylenelactones 1-4 with
8-bromoxanthines 5-9
A glass ampoule was charged under argon with methylene
lactone (1.0 mmol), 8-bromoxanthine (1.2 mmol), Pd(OAc)2 (9
mg, 0.04 mmol, 4 mol %), NEt3 (152 mg, 1.5 mmol), DMF (5
mL), 3-Å molecular sieves (3 mg), and appropriate ligand (16
mol %), as well as TBAB (1.0 mmol) when needed. The
ampoule was sealed and heated under the conditions given in
Tables 1 and 2. When the reaction was complete, the ampoule
was cooled, opened, the mixture was filtrated, the filtrate was
poured into a saturated NaCl solution (20 mL) and extracted
with EtOAc (4×10mL). The combined organics extracts were
dried over MgSO4, filtered and concentrated under reduced
pressure. The oily residue was dissolved in CHCl3 and separated
by silica gel coloumn chromatography (eluent CHCl3-EtOH,

7
gradient 100:1→100:4). The starting lactone was eluted first (in
the case of incomplated conversion), followed by exo-, endo-
compounds, and xanthenes.
1H, H-8), 4.40 (d, J 0.9 Hz, 1H, H-15), 4.10 (s, 3H, NMe), 4.04
ACCEPTED MANUSCRIPT
(ddd, J 11.7, 6.0, 5.7 Hz, 1H, H-7), 3.52 (s, 3H, NMe), 2.33 (d, J
14.7 Hz, 1H, H-3), 2.25 (ddd, J 13.8, 7.0, 2.5 Hz, 1H, H-6), 2.24
(dd, J 15.7, 0.9 Hz, 1H, H-9), 2.06 (ddd, J 13.1, 12.8, 5.2 Hz, 1H,
H-3), 1.97 (dd, J 12.5, 1.2 Hz, 1H, H-5), 1.63 (dd, J 15.7, 4.6 Hz,
1H, H-9), 1.54-1.63 (m, 3H, H-1, H-2, H-2), 1.31 (ddd, J 13.2,
12.9, 4.0 Hz, 1H, H-1), 1.23 (dd, J 13.1, 12.6 Hz, 1H, H-6), 0.86
4.2.3.1. 1,3,7-Trimethyl-8-((E)-((3aR,4aS,8aR,9aR)-8a-methyl-
5-methylene-2-oxodecahydronaphtho[2,3-b]furan-3(2H)-
ylidene)methyl)-1H-purine-2,6(3H,7H)-dione (10). Yield: 220
mg (52%, a, 20 h) or 233 mg (55%, h, 20 h). White powder; mp
(s, 3H, Me); δC (151 MHz, CDCl3) 171.0 (C-12), 154.8 (C-4
150.9 (C-2 ), 150.2 (C-4), 148.9 (C-6 ), 146.8 (C-8 ), 141.4 (C-
11), 115.3 (C-13), 108.6 (C-5 ), 106.6 (C-15), 77.7 (C-8), 46.1
'),
'
'
'
293-295°C (EtOH); [α]
22 +267 (c 0.25, CHCl3). IR (KBr): 2928,
D
'
1753, 1711, 1659, 1599, 1553, 1439, 1341, 1227, 1215, 1180,
756, 748 cm–1; UV, λmax (lgε): 229 (4.05), 248 (4.07), 279 (3.92),
350 (4.33) nm; δH (600 MHz, CDCl3) 7.20 (d, J 1.4 Hz, 1H, H-
13) 4.72 (d, J 1.4 Hz, 1H, H-15), 4.57 (ddd, J 5.3, 4.9, 1.5 Hz,
1H, H-8), 4.36 (d, J 1.4 Hz, 1H, H-15), 4.07 (s, 3H, NMe), 4.02
(ddd, J 11.6, 6.4, 5.3 Hz, 1H, H-7), 3.53 (s, 3H, NMe), 3.39 (s,
3H, NMe), 2.32 (d, J 13.5 Hz, 1H, H-3), 2.25 (ddd, J 13.9, 7.1,
2.8 Hz, 1H, H-6), 2.24 (dd, J 15.4, 1.6 Hz, 1H, H-9), 2.03 (ddd, J
13.4, 12.9, 5.5 Hz, 1H, H-3), 1.92 (dd, J 12.4, 1.1 Hz, 1H, H-5),
1.52-1.63 (m, 3H, H-1, H-2, H-2), 1.56 (dd, J 15.4, 4.2 Hz, 1H,
H-9), 1.27 (ddd, J 13.2, 12.8, 3.1 Hz, 1H, H-1), 1.23 (dd, J 13.3,
12.1 Hz, 1H, H-6), 0.83 (3H, s, Me); δC (151 MHz, CDCl3),
(C-5), 42.0 (C-9), 41.1 (C-1), 40.2 (C-7), 36.8 (C-3), 34.2 (C-10),
31. 9 (NMe), 28.9 (NMe), 23.7 (C-6), 22.5 (C-2), 17.5 (Me); m/z
(%): 410 (100), 123 (94), 83 (42), 365 (27), 85 (27), found
410.1943. C22H26O4N4 requires 410.1949.
4.2.3.4. 3,7-Dimethyl-8-(((4aS,8aR,9aS)-8a-methyl-5-methylene-
2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydronaphtho[2,3-b]furan-3-
yl)methyl)-1H-purine-2,6(3H,7H)-dione (16). Yield: 32% (a, 20
h) or 87% (b, 20 h). White solid; mp 236-238°C (EtOH);
[α]D30+172 (c 0.51, CHCl3); IR (KBr): 3570, 3518, 3155, 2982,
2934, 2830, 1744, 1690, 1595, 1551, 1497, 1441, 1429, 1406,
1385, 1341, 1298, 1223, 1124, 1065, 1036, 1013, 897, 870, 856,
760, 680 cm–1; UV, λmax (lgε): 212 (4.40), 277 (4.18) nm; δH (600
MHz, CDCl3) 9.53 (s, 1H, NH), 4.89 (dd, J 11.4, 6.4 Hz, 1H, H-
8), 4.81 (d, J 1.0 Hz, 1H, H-15), 4.53 (d, J 1.0 Hz, 1H, H-15),
3.93 (s, 3H, NMe), 3.67 (d, J 15.8 Hz, 1H, H-13), 3.63 (d, J 15.8
Hz, 1H, H-13), 3.36 (s, 3H, NMe), 2.95 (dd, J 13.6, 3.5 Hz, 1H,
H-6), 2.54–2.56 (m, 1H, H-3), 2.31 (dd, J 13.6, 13.2 Hz, 1H, H-
6), 2.29 (dd, J 12.2, 6.5 Hz, 1H, H-9), 1.84-1.89 (m, 2H, H-3, H-
5), 1.52-1.60 (m, 3H, H-1, H-2, H-2), 1.24 (ddd, J 13.7, 13.5, 4.9
Hz, 1H, H-1), 1.11 (dd, J 11.9, 11.8 Hz, 1H, H-9), 0.84 (s, 3H,
Me); δC (151 MHz, CDCl3) 173.5 (C-12), 167.6 (C-7), 154.7 (C-
171.1 (C-12), 155.2 (C-4
), 146.2 (C-8 ), 140.9 (C-11), 115.6 (C-13), 108.4 (C-5
(C-15), 77.7 (C-8), 46.1 (C-5), 42.0 (C-9), 41.2 (C-1), 40.2 (C-7),
36.8 (C-3), 34.3 (C-10), 31.8 (N7 -Me), 29.6 (N1 -Me), 27.9
(N3 -Me), 23.7 (C-6), 22.6 (C-2), 17.5 (Me); m/z (%): 424 (100),
'), 151.4 (C-2
'), 149.0 (C-4), 148.4 (C-
6
'
'
'), 106.6
'
'
'
379 (40), 425 (26), 67 (21), 208 (16), found 424.2106.
C23H28N4O4 requires 424.2105. Anal. Calcd for C23H28N4O4 + 0.3
CHCl3: C 59.88; H 6.07; N 12.15; found (%): C 60.36; H 5.97; N
12.12.
4.2.3.2.
1,3,7-Trimethyl-8-(((4aS,8aR,9aS)-8a-methyl-5-
4
'), 151.1 (C-2
'), 150.6 (C-4), 149.4 (C-6
'), 147.8 (C-8'), 118.3
methylene-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydronaphtho[2,3-
b]furan-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione (11). Yield:
136 mg (32%, a, 20 h) or 390 mg (92%, e, 40 h). Colorless
crystals; mp 201-203°C (EtOH); [α]D28+165 (c 0.37, CHCl3); IR
(KBr): 2936, 2866, 2854, 1749, 1703, 1661, 1607, 1545, 1493,
1439, 1408, 1385, 1342, 1290, 1221, 1126, 1099, 1069, 1057,
1043, 1016, 980, 891, 760, 750 cm–1; UV, λmax (lgε): 208 (4.45),
211 (4.46), 277 (4.06) nm; δH (600 MHz, CDCl3) 4.87 (dd, J
11.4, 6.4 Hz, 1H, H-8), 4.81 (d, J 1.2 Hz, 1H, H-15), 4.53 (d, J
1.2 Hz, 1H, H-15), 3.96 (s, 3H, NMe), 3.68 (d, J 15.6 Hz, 1H, H-
13), 3.64 (d, J 15.6 Hz, 1H, H-13), 3.41 (s, 3H, NMe), 3.31 (s,
3H, NMe), 2.98 (dd, J 13.6, 3.5 Hz, 1H, H-6), 2.31–2.34 (1H, m,
H-3), 2.30 (dd, J 13.6, 13.2 Hz, 1H, H-6), 2.28 (dd, J 12.2, 6.4
Hz, 1H, H-9), 1.83-1.89 (m, 2H, H-3, H-5), 1.52-1.60 (3H, m, H-
1, H-2, H-2), 1.24 (ddd, J 13.8, 13.3, 4.3 Hz, 1H, H-1), 1.10 (dd,
J 11.9, 11.8 Hz, 1H, H-9), 0.85 (s, 3H, Me); δC (151 MHz,
(C-11), 108.0 (C-5
'
), 107.0 (C-15), 78.6 (C-8), 49.8 (C-5), 47.5
(C-9), 40.5 (C-1), 36.7 (C-10), 36.0 (C-3), 32.0 (NMe), 28.5
(NMe), 26.0 (C-6), 22.0 (C-2), 20.7 (C-13), 16.3 (Me); m/z (%):
410 (100), 411 (27), 365 (26), 83 (24), 85 (16), found 410.1948.
C22H26N4O4 requires 410.1949.
4.2.3.5.
1-Butyl-3,7-dimethyl-8-((E)-((3aR,4aS,8aR,9aR)-8a-
methyl-5-methylene-2-oxodecahydronaphtho[2,3-b]furan-3(2H)-
ylidene)methyl)-1H-purine-2,6(3H, 7H)-dione (17). Yield: 44%
(a, 20 h) or 4% (e, 40 h). Yellowish oil; [α]D29+411 (c 0.33,
CHCl3); IR (KBr): 2953, 2930, 1755, 1663, 1601, 1551, 1439,
1339, 1225, 1213, 1177, 895, 762, 683 cm–1; UV, λmax (lgε): 223
(4.01), 249 (4.06), 280 (3.90), 351 (4.35) nm; δH (600 MHz,
CDCl3) 7.20 (d, J 1.2 Hz, 1H, H-13), 4.71 (d, J 1.2 Hz, 1H, H-
15), 4.57 (ddd, J 5.3, 4.8, 1.2 Hz, 1H, H-8), 4.36 (d, J 1.2 Hz, 1H,
H-15), 4.07 (s, 3H, NMe), 4.02 (ddd, J 11.4, 6.8, 5.7 Hz, 1H, H-
7), 3.98 (dd, J 9.1, 7.6 Hz, 2H, CH2), 3.51 (s, 3H, NMe), 2.32 (d,
J 13.5 Hz, 1H, H-3), 2.25 (ddd, J 13.7,7.0, 2.6 Hz, 1H, H-6), 2.24
(dd, J 16.0, 1.6 Hz, 1H, H-9), 2.02 (ddd, J 13.9, 13.2, 5.6 Hz, 1H,
H-3), 1.92 (dd, J 12.0, 2.0 Hz, 1H, H-5), 1.54-1.62 (m, 5H, H-1,
H-2, H-2, CH2), 1.56 (dd, J 16.0, 3.2 Hz, 1H, H-9), 1.36 (ddd, J
8.0, 7.6, 7.5 Hz, 2H, CH2), 1.27 (ddd, J 13.0, 12.8, 2.9 Hz, 1H,
H-1), 1.22 (dd, J 13.2, 12.6 Hz, 1H, H-6), 0.92 (t, J 7.3 Hz, 3H,
CH3), 0.83 (s, 3H, Me); δC (151 MHz, CDCl3) 171.2 (C-12),
CDCl3) 173.2 (C-12), 167.2 (C-7), 155.0 (C-4
149.9 (C-4), 147.8 (C-6 ), 147.6 (C-8 ), 118.5 (C-11), 107.3 (C-
), 106.9 (C-15), 77.4 (C-8), 49.8 (C-5), 47.6 (C-9), 40.5 (C-1),
'), 151.4 (C-2'),
'
'
5
'
36.7 (C-10), 36.0 (C-3), 31.9 (NMe), 29.3 (NMe), 27.6 (NMe),
26.0 (C-6), 22.0 (C-2), 20.8 (C-13),16.3 (Me); m/z (%): 424
(38), 121 (100), 41 (75), 39 (71), 91 (54), found 424.2101.
C23H28N4O4 requires 424.2105. Anal. Calcd for C23H28N4O4 (%):
C 65.09; H 6.60; N 13.21; found (%): C 64.50; H 6.30; N 13.19.
155.1 (C-4
140.8 (C-11), 115.6 (C-13), 108.5 (C-5
'
), 151.1 (C-2
'
), 149.0 (C-4), 148.4 (C-6
'), 146.2 (C-8'),
4.2.3.3. 3,7-Dimethyl-8-((E)-((3aR,4aS,8aR,9aR)-8a-methyl-5-
methylene-2-oxodecahydronaphtho[2,3-b]furan-3(2H)-
'), 106.6 (C-15), 77.7 (C-
8), 46.1 (C-5), 42.0 (C-9), 41.2 (NCH2), 41.2 (C-1), 40.2 (C-7),
36.8 (C-3), 34.3 (C-10), 31.8 (NMe), 30.0 (CH2), 29.6 (NMe),
22.6 (C-2), 23.7 (C-6), 20.1 (CH2), 17.5 (Me), 13.7 (Me); m/z
(%): 466 (38), 83 (100), 85 (62), 47 (29), 18 (19), found
466.2572. C26H34N4O4 requires 466.2575.
ylidene)methyl)-1H-purine-2,6(3H,7H)-dione (15). Yield: 44%
(a, 20 h) or 8% (e, 40 h). White powder; mp 270-272°C (dec,
EtOH); [α]D30+441 (c 0.34, CHCl3); IR (KBr): 2930, 1753, 1709,
1666, 1591, 1547, 1441, 1341, 1219, 985, 890, 750 cm–1; UV,
λmax (lgε): 225 (4.06), 249 (4.05), 275 (3.91), 349 (4.35) nm; δH
(600 MHz, CDCl3) 9.59 (s, 1H, NH), 7.22 (d, J 1.3 Hz, 1H, H-
13), 4.75 (d, J 0.9 Hz, 1H, H-15), 4.63 (ddd, J 5.5, 4.6, 1.6 Hz,
4.2.3.6.
1-Butyl-3,7-dimethyl-8-(((4aS,8aR,9aS)-8a-methyl-5-
methylene-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydronaphtho[2,3-

8
Tetrahedron
b]furan-3-yl)methyl)-1H-purine-2,6(3H, 7H)-dione (18). Yield:
(Me); m/z (%): 410 (2), 218 (100), 107 (83), 91 (62), 79 (43),
ACCEPTED MANUSCRIPT
32% (a, 20 h) or 92% (e, 40 h). White solid; mp 121-123°C
(EtOH); [α]D29 +96 (c 0.25, CHCl3); IR (KBr): 2955, 2932, 2870,
1751, 1703, 1661, 1610, 1543, 1439, 1408, 1339, 1219, 1059,
1045, 1016, 762 cm–1; UV, λmax (lgε): 204 (4.52), 278 (4.02) nm;
δH (600 MHz, CDCl3) 4.90 (dd, J 11.4, 6.5 Hz, 1H, H-8), 4.85 (d,
J 1.0 Hz, 1H, H-15), 4.56 (d, J 1.0 Hz, 1H, H-15), 3.99 (s, 3H,
NMe), 3.95 (dd, J 7.7, 7.6 Hz, 2H, NCH2), 3.71 (d, J 15.8 Hz,
1H, H-13), 3.66 (d, J 15.8 Hz, 1H, H-13), 3.44 (s, 3H, NMe),
3.00 (dd, J 13.6, 3.5 Hz, 1H, H-6), 2.35–2.37 (m, 1H, H-3), 2.32
(dd, J 12.2, 6.6 Hz, 1H, H-9), 2.32 (dd, J 13.5, 13.4 Hz, 1H, H-
6), 1.88-1.91 (m, 2H, H-3, H-5), 1.56-1.64 (m, 5H, H-1, H-2, H-
2, CH2), 1.35 (ddd, J 8.2, 7.6, 7.3 Hz, 2H, CH2), 1.27 (ddd, J
13.6, 13.2, 4.4 Hz, 1H, H-1), 1.14 (dd, J 12.1, 11.9 Hz, 1H, H-9),
0.91 (t, J 7.3 Hz, 3H, CH3), 0.88 (s, 3H, Me); δC (151 MHz,
found 410.1953. C22H26N4O4 requires 410.1949;
4.2.3.9. 1,3-Dimethyl-7-(((3R,3aR,4aS,8aR,9aR)-8a-methyl-5-
methylene-2-oxododecahydronaphtho[2,3-b]furan-3-yl)methyl)-
1H-purine-2,6(3H,7H)-dione (25). Yield 17% (a). This compound
was also obtained (88%) by stirring of a mixture of lactone 1 (2.0
mmol), theophilline 26 (2.2 mmol) and NEt3 (2.2 mmol) in EtOH (10
mL) (60°C, 12 h). White solid; mp 174-175°C (decomp., EtOH).
[α]D30+26 (c 0.58, CHCl3); IR (KBr): 3578, 2932, 1757, 1705,
1661, 1547, 1476, 1458, 1443, 1410, 1368, 1223, 1190, 1178,
1155, 980, 953, 745 cm–1; UV, λmax (lgε): 225 (3.78), 252 (3.81),
274 (3.85) nm; δH (600 MHz, CDCl3) 7.78 (s, 1H, H-8’), 4.77 (d,
J 1.3 Hz, 1H, H-15), 4.62 (dd, J 14.1, 5.1 Hz, 1H, H-13), 4.49
(ddd, J 4.6, 4.1, 1.9 Hz, 1H, H-8), 4.44 (dd, J 14.1, 8.3 Hz, 1H,
H-13), 4.43 (d, J 1.3 Hz, 1H, H-15), 3.55 (s, 3H, NMe), 3.39
(ddd, J 8.3, 6.1, 5.1 Hz, 1H, H-11), 3.36 (s, 3H, NMe), 2.63
(d.t.d, J 12.3, 6.2, 6.1, 4.6, 1H, H-7), 2.32 (d, J 14.1, 1H, H-3),
2.14 (dd, J 15.5, 1.9 Hz, 1H, H-9), 1.96 (ddd, J 14.1, 12.8, 5.8
Hz, 1H, H-3), 1.77 (d, J 12.3 Hz, 1H, H-5), 1.66 (ddd, J 13.1,
5.5, 1.5 Hz, 1H, H-6), 1.50-1.57 (m, 3H, H-1, H-2, H-2), 1.43
(dd, J 15.5, 4.1 Hz, 1H, H-9), 1.26 (dd, J 12.4, 12.6 Hz, 1H, H-
6), 1.19-1.23 (m, 1H, H-1), 0.79 (s, 3H, Me); δC NMR (151 MHz,
CDCl3) 173.4 (C-12), 167.3 (C-7), 155.0 (C-4
149.9 (C-4), 147.9 (C-6 ), 147.7 (C-8 ), 118.6 (C-11), 107.5 (C-
), 107.0 (C-15), 78.5 (C-8), 49.9 (C-5), 47.6 (C-9), 41.0
'), 151.3 (C-2'),
'
'
5
'
(NCH2), 40.6 (C-1), 36.8 (C-10), 36.1 (C-3), 32.0 (NMe), 30.0
(CH2), 29.3 (NMe), 26.1 (C-6), 22.1 (C-2), 20.9 (C-13), 20.1
(CH2), 16.4 (Me), 13.7 (Me); m/z (%): 466 (100), 305 (40), 467
(29), 421 (24), 449 (11), found 466.2569. C26H34N4O4 requires
466.2575.
CDCl3) 176.3 (C-12), 155.2 (C-4
'), 151.4 (C-2
'), 149.1 (C-6
'),
4.2.3.7. 1,3-Dimethyl-8-((E)-((3aR,4aS,8aR,9aR)-8a-methyl-5-
methylene-2-oxodecahydronaphtho[2,3-b]furan-3(2H)-
148.8 (C-4), 142.5 (C-8 ), 106.4 (C-15), 106.3 (C-5'
'
), 77.8 (C-8),
47.3 (C-11), 46.2 (C-5), 43.1 (C-13), 41.9 (C-1), 41.1 (C-9), 39.0
(C-7), 36.5 (C-3), 34.5 (C-10), 29.7 (NMe), 27.9 (NMe), 22.4 (C-
2), 21.1 (C-6), 17.6 (Me). Anal. Calcd for C22H28N4O4 (%): C
64.06; H 6.84; N 13.58; found (%): C 64.01; H 6.81; N 13.62.
ylidene)methyl)-1H-purine-2,6(3H,7H)-dione (23). Yield 20%
(a, 20 h) or 22% (e, 40 h). White powder; mp 258-260°C (dec,
EtOH); [α]D30+407 (c 0.51, CHCl3); IR (KBr): 3171, 2924, 1753,
1724, 1715, 1670, 1655, 1630, 1597, 1568, 1491, 1261, 1215,
1182, 1171, 1010, 901, 767, 748 cm–1; UV, λmax (lgε): 228
(4.02), 247 (4.06), 274 (3.85), 349 (4.35) nm; δH (600 MHz,
CDCl3+CD3OD) 7.11 (d, J 1.2 Hz, 1H, H-13), 4.73 (d, J 1.1 Hz,
1H, H-15), 4.62 (ddd, J 5.6, 4.9, 1.4 Hz, 1H, H-8), 4.38 (d, J 1.1
Hz, 1H, H-15), 4.06 (ddd, J 11.8, 6.4, 5.6 Hz, 1H, H-7), 3.58 (s,
3H, NMe), 3.40 (s, 3H, NMe), 2.33 (d, J 13.3 Hz, 1H, H-3), 2.28
(ddd, J 13.6, 7.8, 2.4 Hz, 1H, H-6), 2.24 (dd, J 15.6, 1.1, 1H, H-
9), 2.05 (ddd, J 13.5, 12.9, 4.7 Hz, 1H, H-3), 1.96 (dd, J 12.5, 1.3
Hz, 1H, H-5), 1.56-1.62 (m, 3H, H-1, H-2, H-2, H-9), 1.30 (ddd,
J 13.3, 12.5, 2.5 Hz, 1H, H-1), 1.24 (dd, J 13.2, 12.3 Hz, 1H, H-
6), 0.83 (s, 3H, Me); δC (151 MHz, CDCl3+CD3OD) 172.3 (C-
4.2.3.10.
7-Butyl-1,3-dimethyl-8-((E)-((3aR,4aS,8aR,9aR)-8a-
methyl-5-methylene-2-oxodecahydronaphtho[2,3-b]furan-3(2H)-
ylidene)methyl)-1H-purine-2,6(3H,7H)-dione (27). Yield: 39%
(а, 20 h) or 14% (e, 40 h). White powder; mp 235-237°C
30
(EtOH); [α]D +428 (c 0.43, CHCl3). IR (KBr): 2928, 1749,
1705, 1665, 1601, 1547, 1412, 1213, 1175, 975, 940, 780, 740
cm–1; UV, λmax (lgε): 228 (4.06), 248 (4.08), 279 (3.91), 350
(4.33) nm; δ H (600 MHz, CDCl3) 7.17 (d, J 1.5 Hz, 1H, H-13),
4.71 (d, J 1.3 Hz, 1H, H-15), 4.57 (ddd, J 5.3, 4.9, 1.5 Hz, 1H, H-
8), 4.45 (dd, J 9.2, 7.5 Hz, 1H, CH2), 4.40 (dd, J 9.2, 7.5 Hz, 1H,
CH2), 4.36 (d, J 1.3 Hz, 1H, H-15), 4.02 (ddd, J 11.6, 6.3, 5.3 Hz,
1H, H-7), 3.52 (s, 3H, NMe), 3.38 (s, 3H, NMe), 2.32 (d, J 13.4
Hz, 1H, H-3), 2.26 (ddd, J 13.8, 6.9, 2.6 Hz, 1H, H-6), 2.24 (dd,
J 15.4, 1.5 Hz, 1H, H-9), 2.03 (ddd, J 13.6, 13.1, 5.7 Hz, 1H, H-
3), 1.92 (dd, J 12.3, 0.9 Hz, 1H, H-5), 1.76 (ddd, J 8.0, 7.8, 7.5
Hz, 2H, CH2), 1.50-1.62 (m, 3H, H-1, H-2, H-2), 1.56 (dd, J
15.4, 4.0 Hz, 1H, H-9), 1.36 (ddd, J 8.0, 7.8, 7.5 Hz, 2H, CH2),
1.27 (ddd, J 12.9, 12.0, 3.1 Hz, 1H, H-1), 1.23 (dd, J 12.9, 12.5
Hz, 1H, H-6), 0.93 (dd, J 8.0, 7.3 Hz, 3H, CH3), 0.83 (s, 3H,
Me); δC (151 MHz, CDCl3) 171.2 (C-12), 154.8 (C-4’), 151.4 (C-
12), 155.3 (C-4
'), 152.1 (C-2
'), 149.6 (C-6
'), 149.3 (C-4), 146.7
(C-8 ), 140.0 (C-11), 119.6 (C-13), 106.8 (C-5
'
'), 106.8 (C-15),
78.5 (C-8), 46.3 (C-5), 42.3 (C-9), 41.4 (C-1), 40.3 (C-7), 37.0
(C-3), 34.5 (C-10), 30.3 (NMe), 28.3 (NMe), 24.1 (C-6), 22.8 (C-
2), 17.7 (Me); m/z (%): 410 (100), 365 (38), 411 (26), 366 (10),
194 (8), found 410.1947. C22H26N4O4 requires 410.1949.
4.2.3.8. 1,3-Dimethyl-8-(((4aS,8aR,9aS)-8a-methyl-5-methylene-
2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydronaphtho[2,3-b]furan-3-
yl)methyl)-1H-purine-2,6(3H,7H)-dione (24). Yield 6% (a, 20 h)
or 88% (e, 40 h). White powder; mp 140-142°C (EtOH).
[α]D29+18 (c 0.39, CHCl3). IR (KBr): 2941, 2920, 2909, 1749,
1267, 1146, 964, 939, 784, 734 cm–1; UV, λmax (lgε): 211 (4.10),
278 (4.15) nm; δH (600 MHz, CDCl3) 12.0 (s, 1H, NH), 4.92 (dd,
J 11.5, 6.4 Hz, 1H, H-8), 4.84 (d, J 1.0 Hz, 1H, H-15), 4.54 (d, J
1.0 Hz, 1H, H-15), 3.84 (d, J 15.9 Hz, 1H, H-13), 3.80 (d, J 15.9
Hz, 1H, H-13), 3.54 (s, 3H, NMe), 3.42 (s, 3H, NMe), 2.90 (dd, J
13.8, 3.5 Hz, 1H, H-6), 2.34–2.36 (m, 1H, H-3), 2.34 (dd, J 13.6,
13.2 Hz, 1H, H-6), 2.32 (dd, J 12.2, 6.5 Hz, 1H, H-9), 1.88-1.94
(m, 2H, H-3, H-5), 1.54-1.65 (m, 3H, H-1, H-2, H-2), 1.27 (ddd,
J 13.6, 13.3, 4.0 Hz, 1H, H-1), 1.17 (dd, J 12.0, 11.9 Hz, 1H, H-
9), 0.87 (s, 3H, Me); δC (151 MHz, CDCl3) 174.0 (C-12), 167.0
2’), 149.0 (C-4), 148.5 (C-6
'), 145.7 (C-8'), 140.8 (C-11), 115.8
(C-13), 107.9 (C-5 ), 106.6 (C-15), 77.7 (C-8), 46.1 (C-5), 45.3
'
(NCH2), 42.0 (C-9), 41.2 (C-1), 40.3 (C-7), 36.8 (C-3), 34.3 (C-
10), 33.5 (CH2), 29.6 (NMe), 27.9 (NMe), 23.7 (C-6), 22.6 (C-2),
19.6 (CH2), 17.5 (Me), 13.5 (Me); m/z (%): 466 (100), 467 (30),
235 (18), 421 (17), 41 (12), found 466.2573. C26H34N4O4 requires
466.2575.
4.2.3.11. 7-Butyl-1,3-dimethyl-8-(((4aS,8aR,9aS)-8a-methyl-5-
methylene-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydronaphtho[2,3-
b]furan-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione (28). Yield:
34% (а, 20 h) or 75% (е, 40 h). White needles; mp 98-100°C
(EtOH); [α]D29 +32 (c 0.49, CHCl3); IR (KBr): 2936, 1755, 1707,
1665, 1543, 1456, 1418, 1344, 1221, 1045, 910, 788, 750 cm–1.
UV, λmax (lgε): 230 (3.66), 250 (3.77), 277 (4.06) nm; δH (600
MHz, CDCl3): 4.90 (dd, J 11.5, 6.5 Hz, 1H, H-8), 4.85 (d, J 1.2
Hz, 1H, H-15), 4.55 (d, J 1.2 Hz, 1H, H-15), 4.34 (dd, J 7.7, 7.6
(C-7), 155.1 (C-4
'), 151.5 (C-2
'), 150.2 (C-4), 148.6 (C-8
'), 147.9
(C-6 ), 118.9 (C-11), 107.1 (C-15), 107.0 (C-5
'
'), 78.8 (C-8), 49.9
(C-5), 47.4 (C-9), 40.6 (C-1), 36.8 (C-10), 36.1 (C-3), 30.0
(NMe), 28.2 (NMe), 26.1 (C-6), 23.1 (C-13), 22.1 (C-2), 16.4

9
Hz, 2H, NCH2), 3.72 (d, J 15.9 Hz, 1H, H-13), 3.67 (d, J 15.9
Hz, 1H, H-13), 3.45 (s, 3H, NMe), 3.37 (s, 3H, NMe), 3.02 (dd, J
13.5, 3.5 Hz, 1H, H-6), 2.35–2.37 (m, 1H, H-3), 2.33 (dd, J 12.3,
6.5 Hz, 1H, H-9), 2.32 (dd, J 13.6, 13.2 Hz, 1H, H-6), 1.83-1.89
(m, 2H, H-3, H-5), 1.76 (ddd, J 8.2, 7.5, 4.7 Hz, 2H, CH2), 1.54-
1.62 (m, 3H, H-1, H-2, H-2), 1.39 (ddd, J 8.1, 7.8, 7.5 Hz, 2H,
CH2), 1.27 (ddd, J 13.5, 13.2, 4.4 Hz, 1H, H-1), 1.15 (dd, J 12.1,
11.8 Hz, 1H, H-9), 0.95 (dd, J 8.0, 7.3 Hz, 3H, CH3), 0.88 (s, 3H,
Me); δC (151 MHz, CDCl3) 173.3 (C-12), 167.3 (C-7), 154.7 (C-
oxirane]-3(4aH,6H,7H,8H,8aH,9H,9aH)-ylidene)methyl)-1H-
ACCEPTED MANUSCRIPT
purine-2,6(3H,7H)-dione (32). Yield: 38% (a, 20 h); Colorless
crystals; mp 219-221°C (dec, EtOAc); [α]D29+322 (c 0.48,
CHCl3); IR (KBr): 2930, 1753, 1690, 1591, 1547, 1439, 1341,
1223, 1215, 1178, 1148, 980, 764 cm–1; UV, λmax (lgε): 223
(4.01), 249 (3.99), 276 (3.85), 350 (4.29) nm; δH (600 MHz,
CDCl3) 9.08 (s, 1H, NH), 7.15 (d, J 1.3 Hz, 1H, H-13), 4.56 (ddd,
J 5.2, 4.9, 1.3 Hz, 1H, H-8), 4.02 (s, 3H, NMe), 3.91 (ddd, J 11.2,
6.3, 5.3 Hz, 1H, H-7), 3.50 (s, 3H, NMe), 2.61 (dd, J 4.4, 1.8 Hz,
1H, H-15), 2.48 (d, J 4.4 Hz, 1H, H-15), 2.24 (dd, J 15.9, 1.3 Hz,
1H, H-9), 2.19 (ddd, J 13.7, 6.9, 2.4 Hz, 1H, H-6), 1.91 (ddd, J
13.1, 12.0, 6.3 Hz, 1H, H-3), 1.74 (dd, J 12.8, 2.3 Hz, 1H, H-5),
1.66-1.71 (m, 2H, H-2, H-2), 1.60 (d, J 12.9 Hz, 1H, H-1), 1.56
(dd, J 16.1, 4.7 Hz, 1H, H-9), 1.33 (d, J 12.5 Hz, 1H, H-3), 1.17
(ddd, J 13.6, 13.1, 6.1 Hz, 1H, H-1), 0.98 (s, 3H, Me), 0.78 (dd, J
13.2, 12.0 Hz, 1H, H-6); δC (151 MHz, CDCl3) 170.9 (C-12),
4’), 151.6 (C-2’), 149.5 (C-4), 148.0 (C-6’), 147.9 (C-8
'), 118.7
(C-11), 107.0 (C-5 ), 106.9 (C-15), 78.4 (C-8), 49.9 (C-5), 47.7
'
(C-9), 45.4 (NCH2), 40.7 (C-1), 36.8 (C-10), 36.1 (C-3) 33.5
(CH2), 29.4 (NMe), 27.8 (NMe), 26.2 (C-6), 22.1 (C-2), 21.0 (C-
13), 19.7 (CH2), 16.5 (Me), 13.6 (Me); m/z (%): 466 (100), 467
(29), 235 (20), 305 (12), 421 (10), found 466.2579, C26H34N4O4
requires 466.2575.
154.6 (C-4
11), 115.7 (C-13), 108.6 (C-5
15), 44.2 (C-5), 41.7 (C-9), 41.3 (C-1), 40.2 (C-7), 35.3 (C-3),
34.3 (C-10), 31.9 (NMe), 28.9 (NMe), 20.2 (C-2), 19.6 (C-6),
18.5 (Me); m/z (%): 426 (81), 149 (100), 57 (64), 41 (59), 43
(57), found 426.1895. C22H26N4O5 requires 426.1898.
'
), 150.7 (C-2
'
), 150.3 (C-6
'), 146.6 (C-8'), 140.8 (C-
4.2.3.12.
1,3,7-Trimethyl-8-((E)-((2'R,3aR,4aR,8aR,9aR)-8a-
'), 77.5 (C-8), 58.6 (C-4), 50.5 (C-
methyl-2-oxodihydro-2H-spiro[naphtho[2,3-b]furan-5,2'-
oxirane]-3(4aH,6H,7H,8H,8aH,9H,9aH)-ylidene)methyl)-1H-
purine-2,6(3H,7H)-dione (30). Yield: 53% (a, 20 h) or 3% (e, 40
h). White powder; mp 188-191°C (EtOH); [α]D30+232 (c 0.50,
CHCl3). IR (KBr): 2932, 1755, 1709, 1661, 1597, 1551, 1439,
1341, 1223, 1213, 1192, 1178, 762, 748 cm–1; UV, λmax (lgε): 226
(4.03), 248 (4.03), 279 (3.90), 349 (4.29) nm; δH (600 MHz,
CDCl3) 7.16 (d, J 1.4 Hz, 1H, H-13), 4.54 (ddd, J 5.3, 4.6, 1.1
Hz, 1H, H-8), 4.04 (s, 3H, NMe), 3.91 (ddd, J 11.3, 6.3, 4.6 Hz,
1H, H-7), 3.54 (s, 3H, NMe), 3.36 (s, 3H, NMe), 2.57 (dd, J 4.4,
1.7 Hz, 1H, H-15), 2.47 (d, J 4.4 Hz, 1H, H-15), 2.23 (dd, J 15.7,
1.1 Hz, 1H, H-9), 2.18 (ddd, J 13.6, 6.9, 2.6 Hz, 1H, H-6), 1.90
(ddd, J 13.1, 12.7, 6.8 Hz, 1H, H-3), 1.73 (dd, J 12.8, 2.3 Hz, 1H,
H-5), 1.65-1.70 (m, 2H, H-2, H-2), 1.55 (dd, J 15.8, 4.6 Hz, 1H,
H-9), 1.31 (d, J 12.7 Hz, 1H, H-3), 1.20 (ddd, J 13.1, 12.5, 5.6
Hz, 1H, H-1), 0.97 (s, 3H, Me), 0.76 (dd, J 13.1, 12.1 Hz, 1H, H-
4.2.3.15. 3,7-dimethyl-8-(((2'R,4aR,8aR,9aS)-8a-methyl-2-oxo-
4,4a,6,7,8,8a,9,9a-octahydro-2H-spiro[naphtho[2,3-b]furan-
5,2'-oxirane]-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione
(33).
Yield: 28% (a, 20 h); White solid; mp 162-164°C (dec, EtOH);
29
[α]D +72 (c 0.29, CHCl3); IR (KBr): 2936, 1749, 1697, 1599,
1545, 1441, 1408, 1219, 1065, 750 cm–1; UV, λmax (lgε): 207
(4.39), 277 (3.96) nm; δH (600 MHz, CDCl3) 9.15 (s, 1H, NH),
4.87 (dd, J 11.4, 6.5 Hz, 1H, H-8), 3.94 (s, 3H, NMe), 3.66 (d, J
15.9 Hz, 1H, H-13), 3.61 (d, J 15.9 Hz, 1H, H-13), 3.43 (s, 3H,
NMe), 2.91 (dd, J 13.2, 3.1 Hz, 1H, H-6), 2.75 (dd, J 4.0, 1.2 Hz,
1H, H-15), 2.59 (d, J 4.1 Hz, 1H, H-15), 2.29 (dd, J 12.3, 6.5 Hz,
1H, H-9), 1.80 (dd, J 13.2, 13.1 Hz, 1H, H-6), 1.68-1.76 (m, 4H,
H-2, H-2, H-3, H-5), 1.58 (d, J 13.6 Hz, 1H, H-1), 1.34 (d, J 11.6
Hz, 1H, H-3), 1.20 (ddd, J 13.4, 12.8, 5.4 Hz, 1H, H-1), 1.13 (dd,
J 12.0, 11.9 Hz, 1H, H-9), 1.02 (s, 3H, Me); δC (151 MHz,
6); δC (151 MHz, CDCl3) 171.0 (C-12), 155.1 (C-4
), 148.4 (C-6 ), 146.0 (C-8 ), 140.2 (C-11), 115.9 (C-13), 108.4
(C-5 ), 77.4 (C-8), 58.4 (C-4), 50.4 (C-15), 44.1 (C-5), 41.6 (C-
'), 151.3 (C-
2
'
'
'
'
9), 41.2 (C-1), 40.1 (C-7), 35.2 (C-3), 34.3 (C-10), 31.8 (NMe),
29.7 (NMe), 27.9 (NMe), 20.2 (C-2), 19.5 (C-6), 18.5 (Me); m/z
(%): 440 (100), 91 (31), 83 (29), 107 (25), 395 (25), found:
440.2061. C23H28N4O5 requires 440.2054.
CDCl3) 173.17 (C-12), 166.02 (C-7), 154.6 (C-4
'
), 151.0 (C-2
'),
150.4 (C-8 ), 149.6 (C-6 ), 118.8 (C-11), 107.7 (C-5'
'
'
), 78.3 (C-8),
58.7 (C-4), 50.2 (C-15), 48.0 (C-9), 47.6 (C-5), 39.8 (C-1), 36.9
(C-10), 35.0 (C-3), 32.0 (NMe), 28.8 (NMe), 22.1 (C-6), 20.7 (C-
13), 20.2 (C-2), 17.2 (Me); m/z (%): 426 (3), 83 (100), 85 (66),
18 (64), 43 (16), found 426.1897. C22H26N4O5 requires 426.1898.
4.2.3.13.
1,3,7-Trimethyl-8-(((2'R,4aR,8aR,9aS)-8a-methyl-2-
oxo-4,4a,6,7,8,8a,9,9a-octahydro-2H-spiro[naphtho[2,3-
b]furan-5,2'-oxirane]-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione
(31). Yield: 27% (a, 20 h) or 46% (e, 40 h); Colorless crystals;
mp 240-242°C (EtOH); [α]D29+71 (c 0.7, CHCl3); IR (KBr):
1747, 1705, 1686, 1651, 1549, 1440, 1422, 1340, 1218, 1188,
980, 766, 750 cm–1;UV, λmax (lgε): 228 (4.53), 277 (4.09 nm); δH
(600 MHz, CDCl3): 4.87 (dd, J 11.5, 6.4 Hz, 1H, H-8), 3.99 (s,
3H, NMe), 3.68 (d, J 15.8, 1H, H-13), 3.62 (d, J 15.8, 1H, H-13),
3.50 (s, 3H, NMe), 3.36 (s, 3H, NMe), 2.94 (dd, J 13.2, 3.2 Hz,
1H, H-6), 2.75 (dd, J 4.2, 1.5 Hz, 1H, H-15), 2.60 (d, J 4.2 Hz,
1H, H-15), 2.32 (dd, J 12.4, 6.4 Hz, 1H, H-9), 1.80 (dd, J 13.2,
13.0 Hz, 1H, H-6), 1.71-1.78 (m, 4H, H-2, H-2, H-3, H-5), 1.60
(d, J 13.4 Hz, 1H, H-1), 1.36 (d, J 11.2 Hz, 1H, H-3), 1.22 (ddd,
J 13.7, 12.6, 5.2 Hz, 1H, H-1), 1.13 (dd, J 12.0, 11.9 Hz, 1H, H-
9), 1.04 (s, 3H, Me); δC (151 MHz, CDCl3) 173.2 (C-12), 165.9
4.2.3.16. 8-((E)-((3aR,8aR,9aR)-5-(hydroxymethyl)-8a-methyl-2-
oxo-3a,4,6,7,8,8a,9,9a-octahydronaphtho[2,3-b]furan-3(2H)-
ylidene)methyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (34).
Yield: 30% (а, 20 h); Yellowish powder; mp 260-263°C (EtOH);
[α]D27+180 (c 0.10, CHCl3); IR (KBr): 1753, 1695, 1653, 1549,
1204, 1177, 967, 780, 745 cm–1; UV, λmax (lgε): 249 (4.05), 272
(3.92), 352 (4.32) nm; δH (600 MHz, CDCl3) 7.24 (d, J 1.5 Hz,
1H, H-13), 4.60 (ddd, J 5.9, 4.8, 3.1 Hz, 1H, H-8), 4.20 (d, J 11.4
Hz, 1H, H-15), 4.06 (d, J 11.4 Hz, 1H, H-15), 4.06 (s, 3H, NMe),
3.95 (ddd, J 11.8, 6.5, 5.4 Hz, 1H, H-7), 3.55 (s, 3H, NMe), 3.29
(ddd, J 14.4, 7.9 Hz, 1H, H-6), 2.18 (dd, J 15.6, 2.8 Hz, 1H, H-
9), 2.13-2.17 (m, 2H, H-3, H-3), 1.87 (dd, J 14.1, 12.1 Hz, 1H,
H-6), 1.77 (dd, J 15.6, 4.8 Hz, 1H, H-9), 1.57-1.62 (m, 3H, H-1,
H-2, H-2), 1.37-1.42 (m, 1H, H-1), 1.16 (s, 3H, Me); δC (151
(C-7), 155.2 (C-4
'), 151.6 (C-2
'), 149.8 (C-8'), 147.8 (C-6'), 119.1
MHz, CDCl3): 171.7 (C-12), 155.2 (C-4
), 146.9 (C-8 ), 140.4 (C-11), 135.4 (C-5), 132.0 (C-4), 116.4
(C-13), 109.1 (C-5 ), 78.2 (C-8), 62.01(C-15), 42.1 (C-7), 41.9
(C-9), 39.5 (C-1), 33.6 (C-10), 32.0 (NMe), 28.9 (NMe), 28.7 (C-
3), 26.8 (Me), 24.3 (C-6), 18.5 (C-2); m/z (%): 426 (77), 408
(100), 67 (90), 180 (83), 349 (67), found 426.1892. C22H26N4O5
requires 426.1898.
'), 151.4 (C-2'), 150.4 (C-
(C-11), 107.5 (C-5
'
), 78.3 (C-8), 58.7 (C-4), 50.2 (C-15), 48.1
6
'
'
(C-9), 47.7 (C-5), 40.0 (C-1), 37.0 (C-10), 35.0 (C-3), 32.0
(NMe), 29.6 (NMe), 27.8 (NMe), 22.2 (C-6), 20.9 (C-13), 20.4
(C-2), 17.3 (Me); m/z (%): 440 (100), 441 (27), 67 (18), 395 (16),
208 (10), found 440.2048. C23H28N4O5 requires 440.2054.
'
4.2.3.14.
3,7-Dimethyl-8-((E)-((2'R,3aR,4aR,8aR,9aR)-8a-
methyl-2-oxodihydro-2H-spiro[naphtho[2,3-b]furan-5,2'-

10
Tetrahedron
4.2.3.17. 8-((E)-((1S,3a'R,4a'R,8a'R,9a'R)-2,2-dichloro-8a'-
(NMe), 27.8 (NMe), 25.9 (Me), 22.1 (C-15), 21.5 (C-13), 16.4
ACCEPTED MANUSCRIPT
methyl-2'-oxo-2'H-spiro[cyclopropane-1,5'-naphtho[2,3-
(C-2); m/z (%): 424 (100), 365 (55), 67 (31), 425 (29), 409 (16),
b]furan]-3'(3a'H,4'H,4a'H,6'H,7'H,8'H,8a'H,
9'H,9a'H)-
found 424.2109. C23H28N4O4 requires 424.2105.
ylidene)methyl)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione
(35). Yield: 52% (а, 20 h) or 9% (e, 40 h); Yellowish powder;
mp 240-242°C (EtOH); [α]D30+287 (c 0.31, CHCl3); IR (KBr):
2928, 1757, 1705, 1666, 1597, 1547, 1441, 1423, 1341, 1242,
1219, 1202, 1177, 1140, 1043, 982, 760, 748 cm–1; UV, λmax
(lgε): 226 (4.09), 247 (4.07), 280 (3.92), 352 (4.30) nm; δH (600
MHz, CDCl3) 7.17 (d, J 1.3 Hz, 1H, H-13), 4.53 (ddd, J 5.5, 4.8,
1.3 Hz, 1H, H-8), 4.05 (s, 3H, NMe), 4.01 (ddd, J 11.7, 6.6, 5.5
Hz, 1H, H-7), 3.54 (s, 3H, NMe), 3.37 (s, 3H, NMe), 2.88 (ddd, J
13.5, 6.6, 2.1 Hz, 1H, H-6), 2.21 (dd, J 15.8, 1.2 Hz, 1H, H-9),
1.92 (dd, J 12.3, 2.2 Hz, 1H, H-5), 1.91 (ddd, J 13.9, 13.6, 6.3
Hz, 1H, H-3), 1.67 (d, J 13.8 Hz, 1H, H-3), 1.59 (dd, J 15.8, 4.7
Hz, 1H, H-9), 1.54-1.59 (m, 3H, H-1, H-2, H-2), 1.42 (d, J 7.8
Hz, 1H, H-15), 1.22 (d, J 7.8 Hz, 1H, H-15), 1.21 (ddd, J 13.4,
12.2, 5.2 Hz, 1H, H-1), 0.99 (s, 3H, Me), 0.86 (dd, J 13.5, 12.2
4.2.3.20. 8,8’-Bis-(1,3,7-trimethylxanthine) (14). Yield (11-23%)
was filtrated off after ampoule opening. Greenish crystals; mp >
360°C (DMF). IR (KBr): 1699, 1670, 1603, 1539, 1450, 1423,
1339, 746 cm–1; m/z (%): 368 (100), 67 (32), 385 (19), 387 (19),
82 (9), found 386.1447. C16H18N8O4 required 386.1446. Anal.
Calcd for C16H18N8O4: C 49.74; H 4.70; N 29.00; found (%): C
49.14; H 4.57; N 29.44.
4.2.3.21. 8,8’-Bis-(1-butyl-3,7-dimethyl-1H-purine-2,6(3H,7H)-
dione) (22). Yield 13 %. White solid; mp 338°C (dec, DMF); IR
(KBr): 2957, 1697, 1672, 1605, 1537, 1450, 1429, 1337, 1327,
748 cm–1; UV (EtOH+CHCl3), λmax (lgε): 347 (3.97) nm; δH (400
MHz, CDCl3) 4.37 (s, 3H, NMe), 3.97 (dd, J 9.3, 7.6 Hz, 2H,
NCH2), 3.55 (s, 3H, NMe), 1.59 (ddd, J 8.5, 7.8, 7.5 Hz, 2H,
CH2), 1.35 (ddd, J 7.9, 7.8, 7.5 Hz, 2H, CH2), 0.90 (t, J 7.4 Hz,
Hz, 1H, H-6); δC (151 MHz, CDCl3) 171.0 (C-12), 155.1 (C-4
151.3 (C-2 ), 148.4 (C-6 ), 145.9 (C-8 ), 140.0 (C-11), 115.8 (C-
13), 108.4 (C-5 ), 76.9 (C-8), 66.4 (CCl2), 42.4 (C-9), 42.3 (C-5),
41.6 (C-1), 41.0 (C-7), 36.0 (C-3), 34.2 (C-10), 31.8 (NMe), 31.7
(C-4), 29.8 (NMe), 27.9 (NMe), 27.5 (C-15), 22.9 (C-6), 19.1
(Me), 18.8 (C-2); m/z (%): 506 (7), 410 (100), 411 (27), 365 (16),
351 (13), found 506.1489. C24H28Cl2N4O4 requires 506.1482.
'),
3H, CH3); δC (100.8 MHz, CDCl3) 154.9 (C-4,4
'), 150.9 (C-2,2'),
'
'
'
147.0 (C-6,6 ), 139.3 (C-8,8 ), 108.6 (C-5,5 ), 41.1 (NCH2), 34.5
'
'
'
'
(NMe), 29.6 (CH2), 29.3 (NMe), 19.8 (CH2), 13.3 (Me); m/z (%):
470 (100), 358 (80), 453 (37), 414 (30), 67 (29), found 470.2389.
C22H30N8O4 requires 470.2385. Anal. Calcd for C22H30N8O4 (%):
C 56.16; H 6.43; N 23.81; found (%): C 45.40; H 6.02; N 23.55.
4.3. X-ray crystal structure analysis for compound (11).
4.2.3.18. 8-(((1S,4a'R,8a'R,9a'S)-2,2-dichloro-8a'-methyl-2'-oxo-
4',4a',6',7',8',8a',9',9a'-octahydro-2'H-spiro[cyclopropane-1,5'-
naphtho[2,3-b]furan]-3'-yl)methyl)-1,3,7-trimethyl-1H-purine-
2,6(3H,7H)-dione (36). Yield: 31% (a, 20 h) or 76% (e, 40 h).
White solid; mp 244-246°C (EtOH); [α]D30+91 (c 2.41, CHCl3);
IR (KBr): 1751, 1697, 1651, 1547, 1426, 1433, 1221, 1042,
1029, 945, 737 cm–1;UV, λmax (lgε): 209 (4.50), 277 (4.05) nm;
δH (400 MHz, CDCl3) 4.86 (dd, J 11.7, 6.3 Hz, 1H, H-8), 3.94 (s,
3H, NMe), 3.86 (dd, J 13.9, 4.0 Hz, 1H, H-6), 3.68 (d, J 15.8 Hz,
1H, H-13), 3.63 (d, J 15.8 Hz, 1H, H-13), 3.50 (s, 3H, NMe),
3.35 (s, 3H, NMe), 2.25 (dd, J 12.5, 6.5 Hz, 1H, H-9), 2.04 (dd, J
12.8, 4.0 Hz, 1H, H-5), 1.86 (dd, J 13.5, 13.3 Hz, 1H, H-6), 1.72-
1.77 (m, 2H, H-3, H-3), 1.54-1.64 (m, 3H, H-1, H-2, H-2), 1.55
(d, J 7.8 Hz, 1H, H-15), 1.35 (d, J 7.8 Hz, 1H, H-15), 1.23 (ddd,
J 13.8, 13.4, 4.8 Hz, 1H, H-1), 1.11 (dd, J 12.1, 12.0 Hz, 1H, H-
9), 1.03 (s, 3H, Me); δC (151 MHz, CDCl3) 173.3 (C-12), 166.4
Crystallographic data for compound 11: C23H28N4O4 M =
424.49, monoclinic, P21, a 8.7736(4), b 11.5782(5), c 11.3315(6)
Å, β 107.367(2)°, V 1098.61(9) Å3, Z 2, Dcalcd 1.283 g·cm–3,
ꢀ(Mo-Kα) 0.089 mm–1, F(000) 452, (θ 2.43
– 27.44°,
completeness 99.99%), T 296(2) K, colorless, (0.73 × 0.30 ×
0.15) mm3, transmission 0.8035 – 0.8621, 20349 measured
reflections in index range -11<=h<=11, -15<=k<=15,
-
14<=l<=14, 5028 independent (Rint 0.0352), 284 parameters, R1
0.0360 (for 4485 observed I> 2σ(I)), wR2 = 0. 1041 (all data),
GOOF 1.047, largest diff. peak and hole 0.201 and -0. 158 e.A-3.
The structures was solved by direct methods using the SHELXS-
97 program35 and refined by anisotropic (isotropic for all H
atoms) full-matrix least-squares method against F2 of all
reflections also by SHELX-97. The positions of the hydrogen
were calculated geometrically and refined in riding model.
CCDC 1417705 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the
(C-7), 155.1 (C-4
'), 151.5 (C-2
'), 147.8 (C-6'), 147.6 (C-8'), 119.4
(C-11), 107.5 (C-5
'), 77.7 (C-8), 65.7 (CCl2), 48.6 (C-9), 46.6 (C-
Cambridge
Crystallographic
Data
Center
via
5), 40.4 (C-1), 37.5 (C-10), 36.6 (C-3), 33.6 (C-4), 32.0 (NMe),
29.6 (NMe), 27.7 (NMe), 27.5 (C-15), 25.1 (C-6), 21.0 (C-13),
19.3 (C-2), 17.5 (Me); m/z (%): 506 (89), 410 (100), 423 (99),
508 (62), 207 (59), found 506.1479. C24H28Cl2N4O4 requires
506.1482;
www.ccdc.cam.ac.uk/data_request/cif.
4.4. Biochemical method
The enzymatic activity was measured using an adaptation of
the method described.36 We performed the Ellman assay in 96-
well microtiter plates in a final reaction volume of 200 mL. 1 E-2
units of acetylcholinesterase was added to solutions of DTNB
500 mkM in 0.05 M Tris–HCl buffer (pH 7.4) and mixed with 2
mkL tested compounds dissolved in DMSO. Plates was stored 30
min, cooled at 4 ºC, then 10 mkL of 1 mM acetylthiocholine
iodide was added. Substrate hydrolysis is monitored by repeated
spectrophotometric (PerkinElmer 2103 Multilabel Reader)
readings at 3 min.
4.2.3.19.
8-(((5S,8aR,9aS)-5,8a-dimethyl-2-oxo-
2,5,6,7,8,8a,9,9a-octahydronaphtho[2,3-b]furan-3-yl)methyl)-
1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione (37). Yield 26% (а,
20 h) or 46% (e, 40 h). Yellowish oil; [α]D29-102 (c 0.54,
CHCl3). IR (KBr): 2934, 1749, 1705, 1601, 1545, 1441, 1030,
940, 760, 748 cm–1; UV, λmax (lgε): 226 (4.30), 282 (4.28) nm; δH
(600 MHz, CDCl3) 6.25 (s, 1H, H-6), 5.04 (dd, J 13.3, 4.8 Hz,
1H, H-8), 3.96 (s, 3H, NMe), 3.76 (d, 1H, J 16.0, H-13), 3.72 (d,
1H, J 16.0, H-13), 3.53 (s, 3H, NMe), 3.37 (s, 3H, NMe), 2.63
(ddd, J 13.8, 7.4, 6.6 Hz, 1H, H-4), 2.10 (dd, J 11.6, 4.8 Hz, 1H,
H-9), 1.85 (ddd, J 13.5, 13.4, 3.5 Hz, 1H, H-2), 1.58-1.64 (m,
3H, H-1, H-3, H-3), 1.45-1.51 (m, 2H, H-2, H-9), 1.34 (s, 3H,
Me), 1.32 (ddd, 1H, J 13.6, 13.4, 3.5 Hz, H-1), 1.20 (d, J 7.6 Hz,
3H, Me); δC (151 MHz, CDCl3) 173.9 (C-12), 164. 5 (C-7), 160.4
Acknowledgements
This work was supported in part by the Russian Science
Foundation (Grant Nom 14-13-00822) and the Russian
Foundation for Basic Research (projects 15-03-06546 and 16-33-
00830). Authors would like to acknowledge the Multi-Access
(C-4
(C-6), 113.7 (C-11), 107.6 (C-5
(C-1), 38.3 (C-4), 38.2 (C-10), 32.4 (C-3), 32.1 (NMe), 29.6
'
), 155.2 (C-5), 151.6 (C-2
'), 150.2 (C-8
'), 147.7 (C-6'), 113.9
'), 76.4 (C-8), 46.5 (C-9), 41.7

11
Chem. Nat. Compd. 2012, 48, 238-244; (b) Shul’ts E. E.,
Chemical Service Center SB RAS for spectral and analytical
measurements.
ACCEPTED MANUSCRIPT
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