Parallel solid-phase synthesis of novel 3,7-diazabicyclo[3.3.1]nonane derivatives starting from natural alkaloid cytisine

Article abstract of DOI:10.1007/s11172-008-0269-3

A parallel solid-phase synthesis of combinatorial library of 436 amides of 4-(3,7-diorganyl-3,7-diazabicyclo[3.3.1]nonan-2-yl)butanoic acid has been accomplished starting from natural alcaloid (-)-cytisine. A five-step liquid-phase synthesis resulted in the conversion of cytisine to 7-benzyl-3-[(9H-fluoren-9-yl)methyl]-substituted acids, which were further diversified with the use of solid-phase technology on the acid-susceptible amine resins. The combinatorial library obtained is intended for a discovery of new physiologically active compounds.

Full text of DOI:10.1007/s11172-008-0269-3

Russian Chemical Bulletin, International Edition, Vol. 57, No. 9, pp. 1999—2004, September, 2008
1999
Parallel solidꢀphase synthesis of novel 3,7ꢀdiazabicyclo[3.3.1]nonane
derivatives starting from natural alkaloid cytisine
Yu. B. Sandulenko,a A. V. Ivashchenko,b D. V. Kravchenko,a S. E. Tkachenko,b and V. Yu. Vvedenskyb
aChemical Diversity Research Institute,
2a ul. Rabochaya, 141401 Khimki, Moscow Region, Russian Federation.
Fax: +7 (495) 626 9780. Eꢀmail: ys@iihr.ru
bChemDiv, Inc., 6605 Nancy Ridge Dr., San Diego, CA 92121, USA.
Fax: +1 (858) 794 4931
A parallel solidꢀphase synthesis of combinatorial library of 436 amides of 4ꢀ(3,7ꢀdiorganylꢀ
3,7ꢀdiazabicyclo[3.3.1]nonanꢀ2ꢀyl)butanoic acid has been accomplished starting from natural
alcaloid (–)ꢀcytisine. A fiveꢀstep liquidꢀphase synthesis resulted in the conversion of cytisine to
7ꢀbenzylꢀ3ꢀ[(9Hꢀfluorenꢀ9ꢀyl)methyl]ꢀsubstituted acids, which were further diversified with
the use of solidꢀphase technology on the acidꢀsusceptible amine resins. The combinatorial
library obtained is intended for a discovery of new physiologically active compounds.
Key words: alcaloids, cytisine, physiologically active compounds, nicotine acetylcholine
receptors, solidꢀphase synthesis.
Synthetic and natural compounds with 3,7ꢀdiazaꢀ
bicyclo[3.3.1]nonane (bispidine) fragment possess highly
diverse physiological activity.* Thus, this series includes
ionꢀchannel modulators displaying antiunrhythmical
properties (for example, drugs Bisaramil and Tedisamil,
which are under clinical testing at present),1 analgesic anꢀ
tagonists of tachichinine receptors NK1,2 antiepilepsy
ligands of γꢀaminobutiric acid GABA(B) receptors,3 etc.
One of the well known compounds of this type, alcaloid
(–)ꢀcytisine (1), found in appreciable amounts in the
broom kind plants (for example, Cytisus laburnum L) and
the leguminous family thermopsis (Thermopsis lanceolaꢀ
ta).4 Alcaloid 1 and a number of its derivatives are selective
ligands of nicotine acetylcholine receptors (nAChR),5—7
which now are considered as one of the most promising
biotargets in the development of new drugs for treatment
of neurodegenerative diseases and psychotic states.8 Takꢀ
ing into account a high potential and wide range of physioꢀ
logical activity of substituted 3,7ꢀdiazabicyclo[3.3.1]ꢀ
nonanes, a design of new compounds of this type seems
quite reasonable, as well as a development of methods for
their synthesis and creation of corresponding combinatoꢀ
rial libraries for the direct search of compoundsꢀleaders.
Earlier,9 we have reported on the synthesis of a small
test liquidꢀphase combinatorial library on the basis of
3,7ꢀdiazabicyclo[3.3.1]nonane ring. In the framework of
our research in the field of highly productive solidꢀphase
synthesis, we used similar technology for the synthesis of
more largely scaled combinatorial library on the basis of
bispidine core. The major goal of the present work is to
synthesize a combinatorial library on the basis of amiꢀ
noacids suitable for the solidꢀphase synthesis through the
hydrogenation of the pyridone fragment of cytisine, subseꢀ
quent opening of the lactam ring formed, and introduction
of suitable protecting group at the nitrogen atoms.
For this, the starting (–)ꢀcytisine 1 was converted to
decahydroꢀ8Hꢀ1,5ꢀmethanopyrido[1,2ꢀa][1,5]diazocinꢀ
8ꢀone (tetrahydrocytisine) 2 by the catalytic hydrogenaꢀ
tion in water in the presence of platinum(IV) oxide10—12
(Scheme 1). After alkylation of compound 2 with benzyl
bromide and 3ꢀfluorobenzyl bromide, the corresponding
3ꢀsubstituted lactams 3a,b were obtained. According to
the HPLC/MS data, both the acidic and the basic hydrolꢀ
yses of these compounds lead to the lactam ring opening
and formation of the corresponding aminoacid salts 3´a,b,
however, all attempts to isolate them in the free state reꢀ
sulted in spontaneous dehydration back to the starting lacꢀ
tams. To prevent the reverse cyclization, we carried out
methanolysis of compounds 3a,b catalyzed by HCl, that
allowed us to obtain and isolate 7ꢀsubstituted methyl
4ꢀ(3,7ꢀdiazabicyclo[3.3.1]nonꢀ2ꢀyl)butanoates 4a,b in
form of hydrochlorides. These compounds are rather staꢀ
ble on standing, but on conversion to the free bases also
gradually cyclize to the corresponding lactams 3a,b.
Treatment of compounds 4a,b with [(9Hꢀfluorenꢀ9ꢀ
yl)methyl]chlorocarbonate (FmocꢀCl) in aqueous dioxane
in the presence of NaHCO3 led to the Fmocꢀprotected
products 5a,b. After hydrolysis of the ester group in
* http://integrity.prous.com
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1964—1970, September, 2008.
1066ꢀ5285/08/5709ꢀ1999 © 2008 Springer Science+Business Media, Inc.

2000
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 9, September, 2008
Sandulenko et al.
Scheme 1
R1 = H (a), F (b)
Reagents and conditions: i. H+ or OH–; ii. HCl, water—dioxane, Δ.
the mixture of dioxane and hydrochloric acid, the Fmocꢀ
protected aminoacids 6a,b were isolated in form of hydroꢀ
chlorides. The compounds obtained were used as preꢀcomꢀ
binatorial building blocks containing the first point of diꢀ
versity R1, which are convenient for the loading on polyꢀ
meric support in order to carry out subsequent modificaꢀ
tions on a solidꢀphase.
and with sulfonyl chlorides (on the example of ethaneꢀ
sulfonyl chloride).
3ꢀAcyl derivatives 9 were obtained with the best results.
The nature of amine resins 7 and carboxylic acid R3COOH
(aliphatic, aromatic, and heteroaromatic acids were used)
did not have considerable effect on the purity and yield of
the combinatorial samples 9.
The combinatorial part of the library was performed by
the "teaꢀbags" technology13 using the substituted acidꢀlaꢀ
bile amine resins 7 on the basis of polystyrene (PS)14
(Scheme 2).
During the reaction of resins 8 with isocyanates
R3NCO, ureas 10 formed additionally reacted with excess
of isocyanate giving Nꢀcarbamoylureas 11. Aromatic isoꢀ
cyanates underwent this reaction especially readily. An
attempt to decrease excess of isocyanate to 1—2 equiv. led
to a decrease of product 11 content in the sample, leaving a
considerable amount of amine 8 unreacted under these
conditions. The formation of such admixtures made puriꢀ
fication of the target ureas 10 considerably more difficult,
therefore, we refused their largeꢀscale production.
A possibility to obtain 3ꢀsulfonamides has been also
demonstrated. After treatment of resins 8a with ethaneꢀ
sulfonyl chloride and subsequent cleavage, product 12 was
isolated.
The reaction of amine resins 7a—h with Fmocꢀamiꢀ
noacids 6a,b was carried out in the presence of DIPC.15
The thus obtained amide resins 8, already having substituꢀ
ents at two points of diversity, were treated with piperidine
in DMF to remove the protecting Fmoc group, then, after
washing and drying, they were sealed into the labeled bags
made of polypropylene net (the soꢀcalled teaꢀbags).
To introduce combinatorial substituents at position
3ꢀbispidine fragment, the acylation with carboxylic acids
in the presence of DIPC was performed, as well as the
reactions with isocyanates (the lists of the reagents used
are given in the corresponding sections of Experimental)
In some combinatorial samples, impurities of comꢀ
pounds of the type 13 (resulting from acylation or carbamꢀ

3,7ꢀDiazabicyclo[3.3.1]nonane derivatives
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 9, September, 2008
2001
Scheme 2
R2 = (3ꢀpyridyl)methyl (a), cyclopentyl (b), 1ꢀpropyl (c), cyclopropyl (d), 2ꢀphenylethyl (e), 2ꢀmethoxyethyl (f), ethyl (g), 3ꢀmethoxypropyl (h)
Reagents and conditions: i. 1) Diisopropylcarbodiimide (DIPC), DMF; 2) piperidine in DMF. ii. 1) R3COOH/DIPC in DMF;
2) 25% TFA in CH2Cl2. iii. 1) EtSO2Cl in DMF; 2) 25% TFA in CH2Cl2.
oylation of resins 7) or unreacted amines 14 were also
detected (Scheme 3). Note that the side product of the
type 15 known from the literature16 as forming by the
alternative cleavage with the linker fragment was not obꢀ
served in the reaction mixtures.
A total of 436 compounds of the structures 9 and 10
were synthesized by this technology using two Fmocꢀproꢀ
tected aminoacids 6a,b, eight amine resins 7a—h, 101 acꢀ
ids, five isocyanates, and ethanesulfonyl chloride. After
purification on silica gel, the yields of the target products 9
and 10, calculated from equivalency of the resins, varied in
the range from 5 to 80% with average content of the major
substance being 90—95% (HPLC/MS data).
1H NMR spectra of some compounds 9, their HPLC/
MS mass spectra, and yields after purification are given in
Table 1.
The solidꢀphase technology used in this work allowed
us to considerably reduce amount of labor on the carrying
out and quenching of the reaction due to the conveꢀ
nience of manipulations with teaꢀbags in comparison with

2002
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 9, September, 2008
Sandulenko et al.
Scheme 3
the UV light with the wavelength of 254 nm or in a chamber with
iodine vapors. Flash chromatography was performed using EM
63 μm silica gel and THF solution (5—10%) in dichloromethane
as the eluent. 1H and 13C NMR spectra were recorded on a Varian
Geminiꢀ300 spectrometer (300 MHz) in CDCl3 or DMSOꢀd6
with Me4Si as the internal standard. HPLC/MS spectra were
obtained on a chromatoꢀmass spectrometer equipped with a Shiꢀ
madzu 10Avp liquid chromatograph, a UV detector (λ = 215 and
254 nm), a Sedex 75 detector for the light scattering, and a PE
SCIEX API 150EX mass spectrometer (ionization method, ESI),
with a C18 Synergi 2u HydroꢀRP Mercury column (20×2 mm),
with a linear gradient of the ratio acetonitrile : water from 5 : 95
to 95 : 5 (vol.) at a flow rate of 0.5 mL min–1 and analytical cycle
of 4 min.
(1S,5S)ꢀDecahydroꢀ8Hꢀ1,5ꢀmethanopyrido[1,2ꢀa][1,5]diꢀ
azocinꢀ8ꢀone (tetrahydrocytisine) (2). A solution of cytisine (20 g,
0.104 mol) in deionized water (100 mL) was hydrogenated under
stirring for 24 h at 50 °C and under pressure of 5 atm in the
presence of platinum dioxide (0.5 g). The colorless solution obꢀ
tained was filtered from the platinum precipitate, water was reꢀ
moved on a rotary evaporator at 80 °C until the weight was conꢀ
stant. The yield was 20 g (98%), white powder, m.p. 99—102 °C.
1H NMR (CDCl3), δ: 4.64 (dt, 1 H, J = 13.8 Hz, J = 1.9 Hz);
3.45—3.56 (m, 1 H); 3.31 (d, 1 H, J = 14.2 Hz); 3.06 (d, 1 H,
J = 13.5 Hz); 2.70—3.00 (m, 3 H); 2.15—2.52 (m, 3 H); 1.54—2.05
(m, 7 H); 1.49 (br.s, 1 H). 13C NMR (CDCl3), δ: 169.9, 59.9,
51.9, 46.9, 46.8, 33.5, 33.1, 33.0, 28.5, 28.2, 20.2. HPLC/MS
(ESI), m/z: 285 [M + H]+.
Synthesis of 3ꢀalkyldecahydroꢀ8Hꢀ1,5ꢀmethanopyrido[1,2ꢀa]ꢀ
[1,5]diazocinꢀ8ꢀones (3ꢀalkyltetrahydrocytisines) 3 (general proꢀ
cedure). A mixture of tetrahydrocytisine 2 (1 equiv.), alkylation
agent (1.05 equiv.), dry K2CO3 (2.85 equiv.), and anhydrous
acetone (2 mL per every mmole of tetrahydrocytisine 2) was
shaken at ~20 °C for 48 h. After filtration and concentration until
the weight was constant, compound 3 was obtained, in which,
according to the HPLC/MS data, the content of the major subꢀ
stance was >95%.
i. TFA in CH2Cl2.
X = CO, SO2, NHCO
Synthesis of methyl esters 4 (general procedure). Compound
3 was mixed with methanol (2.5 mL mmol–1) and concentrated
hydrochloric acid (0.5 mL mmol–1). The mixture obtained was
refluxed for 24 h. The reaction mixture was treated with excess of
dry NaHCO3, filtered, and concentrated on rotary evaporator.
To completely remove the salts, the concentrate obtained was
diluted with THF, filtered, and again concentrated until the
weight was constant. The content of the major substance in comꢀ
pounds 4 obtained exceeded 95% (HPLC/MS data).
the liquid reaction mixtures, to increase the total yield, as
well as to decrease the cost of purification of compounds
obtained since the greater part of impurities can be reꢀ
moved during the washing of the polymer.
In conclusion, we developed a method for the transforꢀ
mation of natural cytisine to Fmocꢀprotected bispidine
aminoacids 6 convenient for the solidꢀphase combinatoriꢀ
al synthesis. Application of the solidꢀphase technology with
the use of teaꢀbags allowed us to quickly synthesize and
isolate a combinatorial library of compounds 9 and 10
with three points of diversity for performing biological tests.
Synthesis of Fmocꢀmethyl esters 5 (general procedure). Sodiꢀ
um hydrogen carbonate (3 equiv.) was added to a solution of the
corresponding compound 4 (1 equiv.) in a mixture of dioxane
(1 mL mmol–1) and water (1 mL mmol–1) followed by addition
of a solution of FmocꢀCl (1 equiv.) in dioxane (1 mL mmol–1
)
for 30 min at cooling in an iceꢀwater bath and stirring. The
reaction mixture was stirred for 18 h at ~20 °C (TLC monitoring,
20% ethyl acetate in toluene). After the inorganic salts were
filtered off, the solution was concentrated in vacuo. The residue
was used in the next step without additional purification.
Synthesis of Fmocꢀcarboxylic acids 6 (general procedure).
Hydrochloric acid (6 M, 8 mL mmol–1) was added to a soluꢀ
tion of the corresponding compound 5 (1 equiv.) in dioxane
(8 mL mmol–1) with stirring. The mixture was refluxed for 24 h
followed by cooling to ~20 °C. A precipitate formed was filtered
Experimental
In this work, commercially available materials and reactants
were used. Teaꢀbags (30×40 mm) were made of polypropylene
tissue by the SI Corporation production (catalog No. 1004421)
and sealed using an AmeriVacS AVPꢀ20 pneumatic blow maꢀ
chine. Analytical TLC was carried out on EM Separations Techꢀ
nology F254 silica gel plates. Substances were visualized under

3,7ꢀDiazabicyclo[3.3.1]nonane derivatives
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 9, September, 2008
2003
Table 1. 1H NMR spectra, HPLC/MS mass spectra, and yields of some compounds 9 after flashꢀchromatography
Comꢀ
pound
R1
H
R2
R3
Yield
(%)*
1H NMR (CDCl3),
MS (ESI),
δ (J/Hz)
m/z [M + H]+
9a
12
7.28—7.40 (m, 5 H); 7.22 (t, 1 H, J = 8.1); 6.73 (d, 1 H,
J = 8.3); 6.67 (s, 1 H); 6.63 (d, 1 H, J = 7.3); 6.36 (br.s,
1 H); 3.90—4.02, 3.70—3.84 (both m, 1 H each); 3.35—3.65
(m, 3 H); 3.05—3.24 (m, 2 H); 2.96 (s, 6 H); 1.52—2.68
(m, 12 H); 1.46 (q, 2 H, J = 7.3); 1.21—1.40 (m, 2 H);
0.86 (t, 3 H, J = 7.3)
491
9b
F
9
7.23—7.32 (m, 3 H); 7.20 (d, 2 H, J = 7.7); 7.00—7.10
(m, 2 H); 6.96 (t, 1 H, J = 8.2); 6.24 (br.s, 1 H); 4.73—5.00,
3.71—3.93 (both m, 1 H each); 3.35—3.59 (m, 3 H);
3.15—3.32 (m, 2 H); 2.90—3.04, 2.47—2.58 (both m,
1 H each); 2.38 (s, 3 H); 1.90—2.25 (m, 7 H); 1.50—1.86
(m, 4 H); 1.33—1.44 (m, 1 H); 1.06 (t, 3 H, J = 7.1)
466
478
9c
9d
9e
9f
F
H
H
H
25
41
37
49
7.41 (d, 1 H, J = 6.0); 7.10—7.34 (m, 7 H); 6.72 (br.s, 1 H);
4.54—4.79 (m, 1 H); 4.19 (d, 1 H, J = 12.6); 4.11 (d, 1 H,
J = 12.6); 3.05—3.99, 2.40—2.85 (both m, 4 H each); 2.38
(s, 3 H); 2.19—2.33 (m, 3 H); 1.43—2.12 (m, 6 H);
0.64—0.76, 0.43—0.52 (both m, 2 H each)
7.39—7.53 (m, 5 H); 7.30—7.39 (m, 4 H); 6.47 (br.s, 1 H);
4.56—4.77, 4.24—4.37 (both m, 1 H each); 4.17 (d, 1 H,
J = 12.2); 3.76—3.92 (m, 2 H); 3.64 (d, 1 H, J = 12.2);
3.38—3.50 (m, 5 H); 3.32 (s, 3 H); 2.59—2.78, 2.40—2.54
(both m, 2 H each); 2.15—2.38 (m, 3 H); 1.38—2.12 (m, 5 H)
498,
500
7.37—7.53 (m, 5 H); 6.74—6.97 (m, 3 H); 6.44 (br.s, 1 H);
5.99 (s, 2 H); 4.52—4.69 (m, 1 H); 4.08—4.33 (m, 2 H);
3.82—3.98 (m, 1 H); 3.51—3.82 (m, 2 H); 3.37—3.48 (m, 4 H);
3.33 (s, 3 H); 3.19—3.36 (m, 1 H); 2.63—2.82 (m, 2 H);
2.08—2.51, 1.35—2.08 (both m, 5 H each)
508
7.51 (d, 2 H, J = 8.0); 7.37—7.48 (m, 5 H); 7.23—7.33
(m, 2 H); 6.56 (br.s, 1 H); 4.54—4.73, 4.30—4.44 (both m,
1 H each); 4.20 (d, 1 H, J = 10.8); 3.73—4.00 (m, 2 H);
3.65 (d, 1 H, J = 10.8); 3.35—3.49 (m, 5 H); 3.31 (s, 3 H);
542,
544
2.66—2.83, 2.42—2.53 (both m, 2 H each); 2.13—2.39 (m, 3 H);
1.38—2.12 (m, 5 H)
9g
9h
9i
H
H
H
H
77
52
76
7
7.29—7.51 (m, 6 H); 6.88—7.03 (m, 2 H); 6.82 (br.s, 1 H);
4.66—4.84 (m, 1 H); 4.39, 4.20 (both d, 1 H each, J = 12.2);
3.36—3.96 (m, 8 H); 3.31 (s, 3 H); 2.79—2.90 (m, 2 H);
2.14—2.62, 1.38—2.06 (both m, 5 H each)
500
7.14—7.51 (m, 9 H); 6.67 (br.s, 1 H); 4.57—4.98 (m, 1 H);
4.34, 4.20 (both d, 1 H each, J = 10.6); 3.53—3.78 (m, 3 H);
3.37—3.50 (m, 5 H); 3.32 (s, 3 H); 2.65—2.84 (m, 2 H);
2.19—2.58, 1.35—2.09 (both m, 5 H each)
498,
500
7.33—7.52 (m, 6 H); 7.11—7.31 (m, 2 H); 6.76 (br.s, 1 H);
4.55—4.95 (m, 1 H); 4.42, 4.22 (both d, 1 H each, J = 11.9);
3.52—4.01 (m, 3 H); 3.37—3.50 (m, 5 H); 3.31 (s, 3 H);
2.68—2.89 (m, 2 H); 2.19—2.61 (m, 4 H); 1.34—2.14 (m, 6 H)
532,
534,
536
9j
7.41—7.54 (m, 5 H); 7.31 (d, 1 H, J = 6.9); 7.17—7.26 (m, 2 H);
7.09 (d, 1 H, J = 6.9); 6.73 (br.s, 1 H); 4.75—4.90 (m, 1 H);
4.45, 4.29 (both d, 1 H each, J = 12.6); 3.62—3.89 (m, 3 H);
3.42—3.57 (m, 5 H); 3.34 (s, 3 H); 2.70—2.88 (m, 2 H);
2.52—2.64 (m, 1 H); 2.32—2.49 (m, 3 H); 2.27 (s, 3 H);
1.38—2.10 (m, 6 H)
478
* Calculated from the theoretical loading of resins.

2004
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 9, September, 2008
Sandulenko et al.
off, washed with water, and dried in air and in vacuo. The total
yield calculated from compound 4 was 70—75%.
were purified on silica gel with THF (5—10%) in dichloꢀ
romethane as the eluent.
Amine resins 7a—h were synthesized according to the proceꢀ
dure described earlier.14
Ureas 10 were synthesized similarly to amides 9 carrying out
the reaction with a solution of the corresponding isocyanate
(10.0 mmol) in DMF (160 mL). Cyclohexylisocyanate, benzylꢀ
isocyanate, 3ꢀmethoxypropylꢀ1ꢀisocyanate, 3ꢀethoxypropylꢀ1ꢀ
isocyanate, and isobutylisocyanate were used in the reaction.
Synthesis of amide resins 8 (general procedure). Triethylamine
(0.162 mol) was added to a suspension of compound 6 (0.162 mol)
in dichloromethane (350 mL). The mixture was shaken until
dissolution, after which the corresponding resins 7 (0.108 mol)
and DIPC (0.162 mol) were added. The reaction mixture was
shaken for 48 h at ~20 °C. The resins were filtered off and washed
two times each with DMF, dichloromethane, methanol, dichloꢀ
romethane, and methanol, and dried in vacuo. To remove the
Fmoc groups, the resins obtained (10 g, ~8.5 mmol) were shaken
for 1 h with a solution of piperidine in DMF (20% (v/v), 500 mL).
The polymer was filtered off, washed two times each with DMF,
methanol, dichloromethane, and methanol; dried in air and
in vacuo.
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Synthesis of amides 9 (general procedure). Resins 8 (200 mg,
0.210 mmol) were placed into teaꢀbags and a combinatorial seꢀ
ries was formed from them consisting of 16 teaꢀbags (in each of
them, the resins have a unique combination of substituents R1
and R2, R1 = H, F; R2 = (3ꢀpyridyl)methyl, cyclopentyl,
1ꢀpropyl, cyclopropyl, 2ꢀphenylethyl, 2ꢀmethoxyethyl, ethyl,
3ꢀmethoxypropyl), then they were placed into a solution of the
corresponding acid R3COOH (10.0 mmol, 3 equiv.) and DIPC
(10.0 mmol) in DMF (160 mL) prior kept for 1 h at ~20 °C. The
teaꢀbags were shaken in the reaction solution for 48 h at ~20 °C,
then the liquid was decanted, the teaꢀbags were washed on
a shaker sequentially two times each with DMF, dichloroꢀ
methane, methanol, dichloromethane, hexane and dried in vacuo.
A single washing cycle time was 3—5 min with the solvent volꢀ
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the teaꢀbags into testꢀtubes to provide an efficient stirring during
cleavage of the product from the polymer and treated with a 10%
solution of TFA in dichloromethane (3 mL) at ~20 °C for 2 h.*
The resins were filtered off and washed with some methanol.
After the solvent was removed, compounds 9 were obtained as
viscous oil (see Table 1). If needed, the compounds obtained
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* Though the transfer of resins from a teaꢀbag into a testꢀtube
often increases product yields, this additional step, as a rule,
is not used in our laboratory and treatment of resins is performed
with a large volume of TFA solution directly in a teaꢀbag. Howꢀ
ever, taking into account exceptionally high cost of starting
cytisine, we decided that application of this version of cleavage
is economically justified in this case.
Received February 28, 2008;
in revised form April 2, 2008