Access to novel substituted diazaadamantanes via semi-natural tetrahydrocytisine

Article abstract of DOI:10.1016/j.tetlet.2004.07.056

Novel 1,3-diazaadamantane structures 3 and 6 were prepared from tetrahydro(-)-cytisine 1 using intermolecular conversions within the bispidine moiety. 2-Oxo derivative 6 was synthesized using a microwave-assisted procedure, which reduces the reaction time and increases the purity of the crude reaction mixture. Alternative possibilities of intermolecular cyclizations were also explored. Though less successful, they provided interesting insights into the chemistry of bispidine systems.

Full text of DOI:10.1016/j.tetlet.2004.07.056

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6733–6736
Access to novel substituted diazaadamantanes via semi-natural
tetrahydrocytisine
Alexandre V. Ivachtchenko,* Alexandre Khvat, Sergey E. Tkachenko,
Yuri B. Sandulenko and Vladimir Y. Vvedensky
Chemical Diversity Labs Inc., 11558 Sorrento Valley Rd., Suite 5, San Diego, CA 92121, USA
Received 27 May 2004; revised 10 July 2004; accepted 13 July 2004
Available online 30 July 2004
Abstract—Novel 1,3-diazaadamantane structures 3 and 6 were prepared from tetrahydro(ꢀ)-cytisine 1 using intermolecular conver-
sions within the bispidine moiety. 2-Oxo derivative 6 was synthesized using a microwave-assisted procedure, which reduces the reac-
tion time and increases the purity of the crude reaction mixture. Alternative possibilities of intermolecular cyclizations were also
explored. Though less successful, they provided interesting insights into the chemistry of bispidine systems.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
H
RO
H
Synthetic and natural compounds containing 3,7-diaza-
bicyclo[3.3.1]nonane (also known as bispidine) moiety
have been described as cardiovascular drugs,1 antipsy-
chotic,2 and analgesic3 agents. Due to interesting physio-
logical activities, chemistry of bispidines attracted
serious attention of researchers in the past years. Several
synthetic approaches4 and studies about crystal struc-
tures, stereochemistry, and conformational analysis5 of
bispidines have been reported. Recently, we developed
an efficient synthetic approach to novel 3,4,7-trisubsti-
tuted bispidine core building blocks and bispidine com-
binatorial libraries,6 which are of great interest in the
discovery of potent and selective nAChRligands.
N
N
N
N
N
HN
O
O
acosmine (R = H)
acosmine acetate (R = Ac)
panacosmine
Figure 1. Structures of natural biologically active 1,3-diazaadaman-
tane derivatives.
ands of j-opiate and r-receptors,9 and oncolytics.10 It
can be concluded that 1,3-diazaadamantane systems
are of pharmacological interest and are interesting syn-
thetic targets.11
In this work, we explore the possible use of the obtained
bispidines for construction of novel molecular scaffolds,
such as 1,3-diazaadamantane, which have been the sub-
ject of considerable interest. Three biologically active
alkaloids acosmine, acosmine acetate, and panacosmine
with diazaadamantane skeleton have been recently iso-
lated from the seeds of Acosmium panamense7 (Fig. 1).
Several synthetic 1,3-diazaadamantane derivatives were
described as potent blockers of sodium channels,8 lig-
Here we communicate our success in developing conven-
ient approaches toward the synthesis of novel 1,3-diaza-
adamantanes starting from the recently described
bispidine-containing structures. Recently, we have dem-
onstrated that the amide bond of the N-alkylated tetra-
hydrocytisine derivatives can be efficiently cleaved using
acidic hydrolysis, and the resulting products can be eas-
ily isolated as methyl or isopropyl esters.6 In this work,
methyl and isopropyl esters 2a,b were efficiently synthe-
sized from tetrahydro(ꢀ)-cytisine 1 using a similar meth-
od (Scheme 1). After pH adjustment by sodium
bicarbonate and acetic acid, the reaction mixture
Keywords: 1,3-Diazaadamantane; Tetrahydro(ꢀ)-cytisine; Microwave-
assisted; Intermolecular cyclizations; (1S,5S)-1,3-Diaza-tricyclo-
[3.3.1.1*3,7*]decanes.
*
Corresponding author. Tel.: +1-858-7944860; fax: +1-858-7944931;
e-mail: av@chemdiv.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.056

6734
A. V. Ivachtchenko et al. / Tetrahedron Letters 45 (2004) 6733–6736
H
H
N
N
N
b
a
O
N
NH
N
O
OR
O
2a: R = Me
2b: R = i-Pr
O
1
3 (87%)
c
O
N
N
N
N
O
O
6 (32% from 1)
X
N
O
d
S
N
NH
O
N
O
4: X = O
5: X = S
7
O
Scheme 1. Reagents and conditions: (a) HCl/ROH, reflux, 12–24h; (b) paraform, THF, rt, 12h; (c) CDI (for 4) or TCDI (for 5), MeOH, rt, 30min;
(d) MW irradiation, 20min.
containing esters 2a or 2b could be used in the next step
without further purification.
H
OC(CH3)3
O
N
OC(CH3)3
O
Treatment of 2b with paraform in THF at room temper-
ature smoothly provided compound 312 in a high yield
(87%). Treatment of 2a with 1,10-carbonyldiimidazole
(CDI) in a water–methanol solution yielded the reactive
intermediate 4, which could be carried on directly into
the next step without separation. Irradiation of the reac-
tion mixture in the microwave reactor at 130ꢁC led to
ester 6.13 The reaction performed under microwaves
was completed after 15–20min. There is a clear advan-
tage in using this mode as compared to the more com-
mon thermal conditions. Based on LC–MS data, the
yield under microwaves was higher, than under thermal
conditions. This reflects a cleaner reaction with fewer
side-products, as observed on analysis of the crude reac-
tion mixtures, and thus easier purification. Interestingly,
our attempts to obtain the corresponding 2-thioxo
derivative 7 using the same experimental protocols
failed. Based on LC–MS analysis of the reaction mix-
ture, interaction of 2 with 1,10-thiocarbonyldiimidazole
(TCDI) instead of CDI led to 7-(imidazole-1-carbo-
thioyl) derivative 5. However, even after prolonged
microwave or standard thermal activation of 5, TLC
or LC–MS analysis could not detect any traces of 7 in
the reaction mixture.
N
b
N
N
OH
OR
O
10 (97%)
8: R = Me
O
a
9: R = H (88%)
c
O
OC(CH3)3
O
OC(CH3)3
O
N
N
N
O
N
12 (58%)
11
Scheme 2. Reagents and conditions: (a) 3N NaOH, H2O/1,4-dioxane,
reflux, 24h; (b) H2/Pd, MeOH, atm press., 12h; (c) CDI, CH2Cl2,
reflux, 24h.
NMRspectra. However, after the pure crystals of this
compound were obtained, X-ray crystallographic analy-
sis conclusively established its true constitution and
revealed the intact bispidine structure annulated with a
2-piperidone moiety (Fig. 2). Apparently, under the
described reaction conditions, unusual N3 !N7 migra-
tion of Boc protecting group prevents formation of the
original eight-membered ring of compound 11 and
results in restoration of an initial tetrahydro(ꢀ)-cytisine
scaffold of compound 12.
In this work, we also attempted to obtain 8-oxo-3,9-di-
aza-tricyclo[7.3.1.0*4,11*]tridecane-3-carboxylic acid tert-
butyl ester 11 belonging to a new, earlier unknown, type
of tricyclic bispidine derivatives (Scheme 2). Ester 8,
described in our recent paper,6 was hydrolyzed with
aqueous sodium hydroxide to give acid 9.14 Mild palla-
dium-catalyzed hydrogenation of 9 in methanol (H2/Pd,
rt, 12h) resulted in selective 3-N-debenzylation, which
afforded 10 in a high yield.15
1
All new compounds were characterized by H NMR ,
13C NMR, LC–MS, and HRMS.
In summary, we have developed an original synthetic
approach to new (1S,S)-1,3-diaza-tricyclo[3.3.1.1*3,7*]-
decanes representing interesting tetrahedral bispidine
adducts. Access to various related derivatives is now
possible. Compounds 3 and 6 represent useful interme-
diates for discovery of novel physiologically active
Treatment of acid 10 with 1,10-carbonyldiimidazole in
dichloromethane at room temperature yielded a prod-
uct, which could be erroneously characterized as 11
1
based on interpretation of LC–MS, H NMR, and 13C

A. V. Ivachtchenko et al. / Tetrahedron Letters 45 (2004) 6733–6736
6735
9. Brandt, W.; Drosihn, S.; Haurand, M.; Holzgrabe, U.;
Nachtsheim, C. Arch. Pharm. (Weinheim, Ger.) 1996, 329,
311–324.
10. Arutyunyan, G.; Chachoyan, A.; Agadzhanyan, Ts.;
Garibdzhanyan, B. Pharm. Chem. J. (Engl. Transl.)
1996, 30, 739–741.
11. For an example of synthetic and crystallographic studies
of 1,3-diazaadamantanes, see: Aghajanian, T. Y.; Arutyu-
nian, G. L.; Shahkhatuni, R. K. Chem. Heterocycl. Comp.
2003, 39, 767–770.
12. A solution of diamine 2b (0.10g, 0.39mmol) and paraform
(30mg, 1mmol) in THF (5mL) was stirred at 20ꢁC for
12h. The reaction mixture was filtered through a silica gel
pad (THF). The filtrate was concentrated in vacuo to
afford 3 (0.091g, 87%) as an oil. 1H NMR(CDCl ) d 4.93
3
(d, J = 6.2Hz, 1H), 4.58–4.72 (m, 1H), 4.54 (d,
J = 12.0Hz, 1H), 4.35 (d, J = 12.0Hz, 1H), 3.05–4.80 (m,
6H), 1.40–2.30 (m, 10H), 1.16 (d, J = 6.2Hz, 6H); 13C
NMR(CDCl 3) d 172.5, 67.6, 66.8, 62.0, 57.4, 55.9,
50.2, 34.4, 33.7, 29.2, 27.3, 24.3, 21.7, 21.4; LC–MS
m/z 267 (M++1). HRMS: MH+ 266.3921 (expected
266.3925).
Figure 2. ORTEP plot for X-ray crystal structure of 12.
compounds. Biological testing of the obtained com-
pounds and their further exploration as initial synthons
for synthesis of novel polycyclic structures are currently
under way.
13. A suspension of tetrahydrocytisine 1 (0.145g, 0.75mmol)
in a 4N solution of HCl in MeOH (2.5mL) was heated at
reflux for 24h. The reaction mixture was cooled to 20ꢁC,
and sodium bicarbonate was added until pH8. The
mixture was filtered to give a water–methanol solution
of 2a (LC–MS m/z 227 (M++1)), which was used in the
next step without purification. The obtained solution of 2a
was acidified with concentrated AcOH (until pH6), then
1,10-carbonyldiimidazole (0.19g, 1mmol) was added and
the reaction mixture was stirred at 20ꢁC. Conversion of 2a
into the imidazolide 4 was controlled by LC–MS. The
reaction was complete after 30min. The reaction mixture
was irradiated in the microwave reactor at 130ꢁC for
20min, and then concentrated in vacuo. Flash column
chromatography (silica gel, EtOH–THF, 20–100%) of the
obtained residue provided 6 (0.061g, 32% yield from 1) as
a white solid. Mp 103–105ꢁC; 1H NMR(CDCl 3) d 4.74 (d,
J = 13.6Hz, 1H), 4.57 (d, J = 13.9Hz, 1H), 4.17 (dd,
J = 1.8, 13.5Hz, 1H), 3.57 (s, 3H), 3.43 (dt, J = 3.0,
11.4Hz, 1H), 3.05 (dt, J = 2.2, 13.3Hz, 1H), 2.72–2.88 (m,
2H), 2.25–2.45 (m, 2H), 2.00–2.23 (m, 1H), 1.70–1.95 (m,
5H), 1.40–1.70 (m, 2H); 13C NMR(CDCl 3) d 169.8
(C@O), 156.0 (C@O), 59.4 (CH), 52.5 (CH), 49.0 (CH2),
45.7 (CH2), 44.2 (CH2), 33.3 (CH2), 33.1 (CH), 32.7
(CH2), 27.8 (CH2), 27.7 (CH3), 20.0 (CH2); LC–MS
m/z 253 (M++1). HRMS: MH+ 252.3298 (expected
252.329).
Acknowledgements
The authors would like thank Dr. Scott R. Wilson from
University of Illinois for solving the X-ray structure.
References and notes
1. (a) Wick, E.; Bell, U.; Dengler, H. J. Med. Welt 1971, 22,
303–304; (b) Bosch, R. F.; Milek, I. V.; Popovic, K.;
Mermi, J.; Mewis, C.; Khlkamp, V.; Seipel, L. J. Cardio-
vasc. Pharmacol. 1999, 33, 762–771; (c) Hahn, K.-J.;
Kirchengast, M. EP 0701442, 1996; Chem. Abstr.
121(15)170560S; (d) Schon, U.; Heitmann, W.; Matzel,
U. EP 0550383, 1995; Chem. Abstr. 119(19)203392C; (e)
Pugsley, M. K.; Goldin, A. L. Eur. J. Pharmacol. 1998,
342, 93–104.
2. Krahling, H.; Fuchs, A.; Ruhland, M.; Scho¨n, U.; Mol,
F.; Tulp, M. Pharmacopsychiatry 1988, 21, 399–
401.
14. A solution of ester 84 (0.454g, 1.09mmol) and 3N NaOH
(1mL) in dioxane (5mL) was stirred at 20ꢁC for 24h. The
reaction mixture was concentrated in vacuo, acidified with
10% H2SO4 (until pH3) and then extracted with EtOAc
(2 · 3mL). The combined organic layer was washed with
water (2 · 2mL), dried over magnesium sulfate, and
filtered. The filtrate was concentrated in vacuo to afford
9 (0.388g, 88%). 1H NMR(CDCl 3) d 10.05 (br s, 1H),
7.22–7.32 (m, 5H), 4.08–4.20 (m, 2H), 3.44, 3.38 (AB,
J = 12.9Hz, 2H), 3.12 (dd, J = 3.2, 13.2Hz, 1H), 2.83 (d,
J = 11.3Hz, 1H), 2.57 (d, J = 10.2Hz, 1H), 1.90–2.30 (m,
7H), 1.68–1.85 (m, 1H), 1.42–1.67 (m, 3H), 1.45 (s, 9H),
1.20–1.32 (m, 1H); 13C NMR(CDCl 3) d 178.7, 156.2,
138.6, 129.3, 128.1, 127.0, 79.3, 67.1, 63.1, 58.7, 54.5,
42.9, 33.8, 29.6, 29.3, 28.5, 27.9, 27.6, 22.1; LC–MS
m/z 403 (M++1). HRMS: MH+ 402.5446 (expected
402.5449).
3. Siener, T.; Cambareri, A.; Kuhl, U.; Englberger, W.;
Haurand, M.; Kogel, B.; Holzgrabe, U. J. Med. Chem.
2000, 43, 3746–3751.
4. (a) Mannich, C.; Veit, F. Chem. Ber. 1935, 68B, 506–512;
(b) Miyahara, Y.; Goto, K.; Inazu, T. Synthesis 2001, 3,
364–366; (c) Bohlmann, F.; Ottawa, N.; Keller, R.
Annalen 1954, 587, 162–176; (d) Scho¨n, U.; Antel, J.;
Bruckner, R.; Messinger, J. J. Med. Chem. 1998, 41,
¨
318–331.
5. (a) Zefirov, N. S.; Palyulin, V. A. Top. Stereochem. 1991,
20, 171–230; (b) Jeyaraman, R.; Avila, S. Chem. Rev. 1981,
81, 149–174.
6. Ivachtchenko, A. V.; Tkachenko, S. E.; Sandulenko, Y.
B.; Vvedensky, V. Y.; Khvat, A. A. J. Comb. Chem., in
press.
7. Nuzillard, J.-M.; Connolly, J.; Delaude, C.; Richard, B.;
Zeches-Hanrot, M.; Le Men-Olivier, L. Tetrahedron 1999,
55, 11511–11518.
8. Yamawaki, I.; Bukovac, S.; Sunami, A. Chem. Pharm.
Bull. 1994, 42, 2365–2369.
15. A solution of 9 (0.378g, 0.94mmol) in methanol (10mL)
containing 10% palladium on carbon (5mg) was stirred in
an atmosphere of hydrogen at room temperature for 12h.

6736
A. V. Ivachtchenko et al. / Tetrahedron Letters 45 (2004) 6733–6736
The reaction mixture was filtered, and the solvent was
2.30–2.55 (m, 2H), 1.80–2.20 (m, 5H), 1.60–1.80 (m, 3H),
1.47 (s, 9H); 13C NMR(CDCl 3) d 175.5, 156.4, 81.6, 57.8,
48.6, 48.5, 43.9, 33.4, 30.4, 30.3, 28.4, 28.4, 25.7, 20.6; LC–
MS 313 (M++1). HRMS: MH+ 312.4125 (expected
312.4122).
removed in vacuo to give 10 (0.284g, 97%). 1H NMR
(CDCl3) d 10.05 (br s, 1H), 7.25 (br s, 1H), 4.25 (d,
J = 13.2Hz, 1H), 4.08 (d, J = 12.9Hz, 1H), 3.18–3.66 (m,
3H), 3.04 (d, J = 2.2Hz, 1H), 2.88 (d, J = 13.2Hz, 1H),