Regio- and diastereoselective functionalization of (-)-cytisine

Article abstract of DOI:10.1016/j.tet.2006.09.057

(-)-N-Benzyl cytisine has been stereoselectively substituted in moderate to high yields on its carbon 6 (Csp³ α to the pyridone nitrogen). The reaction involved the in situ trapping of the carbanion formed by reaction of lithium diisopropyl ami

Full text of DOI:10.1016/j.tet.2006.09.057

Tetrahedron 62 (2006) 11679–11686
Regio- and diastereoselective functionalization of (L)-cytisine
*
Nicolas Houllier, Sonia Gouault, Marie-Claire Lasne and Jacques Rouden
´
Laboratoire de Chimie Moleculaire et Thioorganique UMR CNRS 6507, ENSICAEN, Universite de Caen Basse-Normandie,
´
´
6 Boulevard du Marechal Juin, 14050 Caen Cedex, France
Received 2 August 2006; revised 13 September 2006; accepted 14 September 2006
Abstract—(ꢀ)-N-Benzyl cytisine has been stereoselectively substituted in moderate to high yields on its carbon 6 (Csp3 a to the pyridone
nitrogen). The reaction involved the in situ trapping of the carbanion formed by reaction of lithium diisopropyl amide (LDA) and its reaction
with electrophiles (alkyl, allyl, benzyl halides, non-enolizable aldehydes, and Weinreb amide). In the absence of an electrophile or with its
addition after the formation of the carbanion, a dimeric structure was isolated (yield: 42%) resulting from the 1,4-addition of the carbanion on
the pyridone ring of another cytisine molecule. Deprotection of the benzyl group (Olofson’s reagent) allowed the formation of 6-substituted
derivatives of the natural product, cytisine, a potent agonist of nicotinic receptors of subtype a4b2.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
A few years ago, we reported a stereoselective functionaliza-
tion of the C-6 position of cytisine.21 This was the result of
an N/C acyl migration. When N-acyl cytisines were
treated with LDA in the presence of an excess of LiCl,
6a-acylcytisines were obtained in 51–79% yield. The effi-
ciency of the N–C acyl transfer was shown to be dependent
on the nature of the N-acyl group. Complete epimerization
6a/6b of the newly created stereocenter was observed
under basic conditions (Scheme 1). We report here the direct
synthesis of new 6b-substituted cytisines. The strategy is
based on the intermolecular reaction of the carbanion
formed on the position adjacent to the pyridone ring with
different electrophiles.
Cytisine was recognized as a nicotinic agonist as far back as
1912.1 With an affinity for neuronal nicotinic acetyl choline
receptors (AChRs) greater than that of nicotine,2 and a high
specificity for the a4b2 subtype, it is marketed as Tabex, for
use as a smoking cessation aid. Its structure has only been
exploited very recently as a template for the synthesis of
new compounds with pharmaceutical interest,3–7 as medical
imaging agents8–10 or as chiral sources for asymmetric syn-
thesis.11–13
Analogs have been limited to those easily obtained from the
natural material. Substitution of the secondary amine was
easily achieved by alkylation or acylation and has led to
compounds of various biological activities.7,14,15 Particu-
larly, N-methyl cytisine had reduced potency and affinities
for the nAChRs16 and its biodistribution in vivo was not
consistent with that expected for a4b2 nicotinic receptors.8
Introduction of a substituent on the pyridone ring of cytisine
usually started with an electrophilic substitution (nitration,
halogenation). A mixture of C-9 and C-11 regioisomers
was obtained, the affinity toward nAChRs of these C-11-
substituted derivatives being usually lower than cytisine.17
Halogen substitution at C-9 and particularly bromo-substitu-
tion led to increased affinity and functional potency.18,19
Cross coupling reactions from these analogs allowed the
introduction of alkyl or (hetero)aryl groups.9,3a Recently,
functionalization of the C-10 position of cytisine substituted
was described.4 It was not achieved directly from cytisine
but by using a recently described total synthesis,20 introduc-
ing the substituent early in the synthesis.
11
1
O
i) LDA, LiCl
N
R2
N
N
N
O
ii) R2X
9
R1
H
R1
6
O
O
51-79%
R1 = Et
R2 = Bn
R1 = Et, i-Pr, t-Bu, OMe
6α-isomer
R2 = H, Me, Bn
NaOH, reflux
85%
R2
N
N
H
O
R1
O
6β-isomer
Scheme 1. Intramolecular functionalization of cytisine via an N/C trans-
fer of an acyl group.
2. Results and discussion
In order to study the alkylation of the 6-position of cytisine
while avoiding the N/C transfer observed previously with
acyl groups, we protected the secondary amine with a benzyl
* Corresponding author. Tel.: +33 2 3145 2893; fax: +33 2 3145 2877;
e-mail: rouden@ensicaen.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.057

11680
N. Houllier et al. / Tetrahedron 62 (2006) 11679–11686
Me
Me
11'
group. In our first attempts, N-benzyl cytisine 1 was treated
by LDA (5 equiv) in THF at ꢀ78 ꢁC. To the mixture was
added methyl iodide (2.6 equiv). No expected 6-methyl
cytisine 3a was obtained but a complex mixture was formed
from which we could detect, by mass spectrometry, a dimeric
product. To simplify NMR spectra of such a compound,
N-methyl cytisine 2 was submitted to the same reaction
conditions but quenched with NH4Cl to give the adduct 5
(Scheme 2).
N
N
N
N
H5
10'
H5
H6
H
10'
H6
H9'
O
O
H
11'
H
N
O
N
O
N
N
Me
Me
C-6 to C-9'
C-6 to C-10'
Figure 1. Possible connections for dimer 5.
i) LDA,
On the 1H NMR spectrum, only one pyridone subunit
remained (protons H9–H11 with characteristic chemical
shifts at 5.95, 6.40, and 7.23 ppm). On signals in the range
THF, -78°C
RN
N
ii) MeI
O
Me
3a R = Bn
4a R = Me
0
3–5 ppm: first, a doublet at 4.61 ppm (JH6–H10 ¼5.6 Hz)
RN
N
11
O
attributed to H6 (a common chemical shift for this type of
proton) connected to sp3 carbon (HMQC), and a doublet
10
9
O
1 R = Bn
2 R = Me
N
R= Me
N
0
0
0
(JH11 –H10 ¼5.1 Hz) at 4.33 ppm attributed to H11 connected
5
6
to sp2 carbon (HMQC), both coupling with the same proton,
H
i) LDA, THF, -78°C
ii) NH4Cl
11'
H
10'
0
H10 , at 3.6–3.7 ppm showing as a multiplet (COSY). Also in
the same H NMR range at 3.66 and 3.58 ppm, one might
9'
1
N
O
0
recognize two characteristic signals for the H6 of the second
0
cytisine subunit showing as a doublet (mixed with H10 mul-
6'
N
5
tiplet) and a doublet of doublet. The absolute configuration
of C-6 was clearly assigned based on our previous work.21
Indeed, the observed coupling constant for H6 is due to
Scheme 2. Reaction of LDA with N-substituted-cytisines.
Several conditions were tried to optimize the reaction
(Table 1). Under the best ones, product 5 was isolated with
a 42% yield along with unreacted starting material. Attempts
to reduce the temperature (entry 2), to use lithium chelating
agent such as TMEDA (entry 3) or to use alkyllithium as
bases (entries 4 and 5) did not improve the yield of the
reaction.
0
H10 and not H5. Therefore, since no coupling is occurring
between H6 and H5, the configuration of C-6 is S (H6 in a po-
sition). We were not able to define the absolute configuration
of C-100. However, based on the known stereochemical
outcome of the pyridone hydrogenation of cytisine,11a we
assumed that the addition has occurred on the less hindered
exo face at the C-100 position. Next we needed to assert the
position of the connection between both cytisine units, i.e.,
between C-6 and C-100, mainly because of the rearrange-
ment described in Katritzky’s paper.22 Beside coupling
Such a type of dimerization was previously observed
when 1-alkyl-4,6-diphenyl-2-pyridones were treated with
LDA.22 The mechanism postulated was a carbonyl directed
lithiation on carbon adjacent to nitrogen (equivalent to C-6
of cytisine) then a Michael addition on a second molecule
of alkyl pyridone (addition equivalent to C-10 of cytisine),
and finally a migration of the first subunit to the carbon
adjacent of the carbonyl of the second pyridone. This should
lead, in our case to a connection of the cytisine molecules,
C-6 to C-90. However, we did not observe the subsequent
rearrangement described in this paper. Based on this publica-
tion and a series of NMR experiments (1H, 13C, JMOD,
COSY, HMQC, and HMBC) the structure of 5, among the
two possible (Fig. 1), was assigned unambiguously.
0
with H6 and H11 , the COSY experiment revealed for H10
0
two correlations with signals at 2.53 ppm (dd, J¼7, 16 Hz,
1H) and at 2.66 ppm (part of a multiplet). These two protons
were connected to the same carbon (HMQC), which was
a CH2 type of carbon (JMOD). This carbon was therefore as-
signed to C-90. All attributions (protons and carbons) were
confirmed by an HMBC experiment. In the other hypothesis
connecting C-6 with C-90 (involving a migration following
the Michael addition) the coupling patterns would be nota-
bly different.
We used N-benzyl cytisine 1 for the following part of the
study in order to remove easily the nitrogen protecting
group. Because of the high reactivity of the carbanion gener-
ated at C-6, we attempted to trap it by an electrophile imme-
diately after its formation using the inverse addition
procedure.23 Under these conditions, the treatment of a
mixture of 1 and methyl iodide in THF by LDA (2 equiv)
afforded 6b-methyl cytisine 3a in 75% yield (not optimized).
A quick search of the most appropriate base to carry out this
selective deprotonation using chlorotrimethylsilane as the
electrophile was undertaken (Scheme 3). Some relevant
results are presented in Table 2. Three bases of increas-
ing pKa were tested. Lithium hexamethyldisilylamide
(LHMDS) gave no reaction, while lithium tetramethylpiperi-
dinamide (LTMP) afforded a mixture of products arising
Table 1. Optimization of the dimerization of 2a
Entry
Base
T (ꢁC)
Ratio 2/5 (yield, %)c
1
2
3
4
5
LDA
LDA
LDA
BuLi
MeLi
ꢀ78
ꢀ120
ꢀ78b
ꢀ78
17/83 (42)
23/77
13/87d
40/60
32/68
ꢀ78
a
Reaction conditions: 2 (1 mmol), base (5 equiv), THF, 4 h at ꢀ78 ꢁC then
NH4Cl, ꢀ78 ꢁC/room temperature, 3 h.
b
c
Addition of TMEDA (5 equiv), quench with MeI.
Ratio of starting material 2/dimer 5 from 1H NMR of the crude product.
Isolated yield of 5 are in parentheses.
d
Complex mixture.

N. Houllier et al. / Tetrahedron 62 (2006) 11679–11686
11681
from mono or disilylation (3b, 6, 7). LDA appeared as the
most selective base as previously shown.24
using IBX27 (Scheme 4). Only one ketone 8 was formed
and the coupling constant JH5–H6¼0 Hz showed unambigu-
ously that H6 proton was in the alpha position. A low
asymmetric induction was occurring at C-13 since alcohols
3h and 3i were isolated as mixture of diastereoisomers, in
61/39 and 54/46 ratios, respectively. The absolute configura-
tion of C13 for each diastereoisomer was assigned by com-
paring the observed vicinal coupling constants between
protons H6 and H13 and those calculated from molecular
modeling simulations (AM1, SpartanÒ). After minimization
of the structures of both isomers of 3h, a dihedral angle of
50ꢁ was measured for the (R) isomer and 96ꢁ for the (S) iso-
mer corresponding to coupling constants JH6–H13 of 5 Hz
10
BnN
9
N
i) Me3SiCl,
THF, -78 °C
6
O
Me3Si
1
ii) base, THF
-78 °C, 2h
3b
SiMe3
BnN
BnN
N
N
SiMe3
O
O
Me3Si
Me3Si
1
and 0 Hz (Fig. 2). In the H NMR spectrum of compounds
6
7
3h, we found JH6–H13¼7.4 Hz for the major diastereo-
isomer (61%), therefore assigned as the (R)-C13 and
JH6–H13¼2.0 Hz for the (S)-C13 minor product. The same
calculations were carried out with diastereoisomers of 3i.
Dihedral angles of the calculated structures were 40ꢁ and
92ꢁ for (R) and (S) diastereoisomers, respectively, corres-
ponding to JH6–H13 of 6.9 Hz and 0.0 Hz. The (R)-C13 major
isomer (54%) had a coupling constant JH6–H13 of 7.8 Hz and
the (S) minor isomer of 0 Hz.
Scheme 3. Selectivity of the deprotonation of N-benzyl cytisine 1.
Table 2. Choice of base for the deprotonation of 1
25
pKa
Entry
Basea
Yield (%)b
Ratio (%)c
3b
6
7
d
1
2
3
LHMDS
LDA
LTMP
29.5
35.7
37.3
0
100
32
0
0
64
0
0
4
78
56
E
a
Reaction conditions: 1 (1 mmol), Me3SiCl (2.6 equiv), THF, ꢀ78 ꢁC then
3a Me
base (2.6 equiv), 2 h, ꢀ78 ꢁC.
Me3Si
3b
i) EX
ii) LDA
1
b
c
d
Et
3c
BnN
Isolated yields.
N
Bn
Determined from 1H NMR of the crude product.
Starting material was recovered quantitatively.
3d
3e
3f
Allyl
O
E
i) RCHO
ii) LDA
Me3Sn
3g EtC(O)
The reaction with LDA was regio- and diastereoselective at
C-6. Only product 3b resulting from the silylation of 1 in the
position 6b was observed, the absolute configuration of the
R= Ph
IBX, EtOAc
reflux, 16 h
BnN
BnN
N
O
6
1
N
R
6
product being determined by H NMR as described in our
previous report.21 Alkyl, allyl, benzyl, and trimethylstannyl
halides were successfully used as electrophiles (Table 3,
entries 1–6). Weinreb amide26 and non-enolizable aldehydes
can be employed in the inverse addition conditions affording
ketone 3g or alcohols 3h and 3i, respectively (entries 7–9).
O
13
O
13
HO
R
3h Ph
3i tBu
8
Scheme 4. Regio- and diastereoselective alkylation of N-Bn-cytisine 1.
Next, we tried to introduce a second alkyl group on the
6-position of compound 3a. The reaction was carried out
under the same conditions as for the first alkylation. No
product 9 was obtained and the starting material was
recovered quantitatively. The second deprotonation did not
seem to occur (Scheme 5).
Alkylation of N-benzyl cytisine carbanion with aldehydes
generated a second stereogenic center, carbon 13 in 3h or
3i. Only two diastereoisomers were produced showing
a very high asymmetric induction at one carbon and a poor
selectivity for the other (Table 3, entries 8 and 9). The stereo-
chemistry at C-6 of compounds 3h was deduced from that of
the ketone 8 obtained by a mild oxidation of alcohols 3h
Finally, in order to test the new compounds towards
nAChRs, debenzylation of the tertiary amine was carried
out (Scheme 6). Hydrogenolytic removal of N-benzyl groups
is traditional but is clearly inapplicable to residues such as
allyl groups. Therefore we turned our attention towards
Olofson’s reagent, a-chloroethyl chloroformate (ACE-Cl).28
Table 3. Diastereoselective alkylation of N-Bn-cytisine 1a
Entry
EX
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
MeI
3a
3b
3c
3d
3e
3f
3g
3h
3i
98
78
70
62
69
44
42
76c
78d
Me3SiCl
EtBr
BnBr
Allyl-Br
Me3SnCl
EtC(O)N(Me)OMe
PhCHO
t-BuCHO
N
H
N
H
BnN
BnN
HO
O H
H
H
O
O
a
96°
Reaction conditions: 1 (1 mmol) and electrophile (2.6 equiv), THF,
ꢀ78 ꢁC then LDA (3 equiv), ꢀ78 ꢁC, 2 h then room temperature for 16 h.
Isolated yields.
As a 61/39 ratio of diastereoisomers.
As a 54/46 ratio of diastereoisomers.
50°
3h major, (R)-C13
b
c
d
3h minor, (S)-C13
Figure 2. Molecular modeling simulations for C-13 epimer 3h.

11682
N. Houllier et al. / Tetrahedron 62 (2006) 11679–11686
a wide variety of new ligands for receptors of the central
nervous system or of new chiral sources for asymmetric
synthesis.
i) MeI, THF, -78 °C
BnN
BnN
N
N
ii) LDA, -78 °C, 2 h
then to r. t. 16 h
Me
O
O
Me
Me
3a
9
4. Experimental
Scheme 5.
4.1. General methods and starting materials
The reactions were carried out under nitrogen or argon in
flasks dried in an oven at 110 ꢁC. THF and CH2Cl2 were
dried with a PURESOLVÔ apparatus (Innovative Technol-
ogy Inc.). Diisopropylamine was distilled from calcium
hydride. Methyl iodide, ethyl bromide, benzyl bromide, allyl
bromide, trimethylsilyl chloride, benzaldehyde, and pival-
aldehyde were distilled before use. A commercial solution
of trimethyltin chloride (1 M in THF, Aldrich) was used.
Thin layer chromatography (TLC) was performed using
aluminum sheets precoated with silica gel 60 F254 (Merck).
Flash chromatography was carried out on silica gel SI 60
(0.040–0.063 mm, Merck). Melting points were obtained
O
Cl
i)
Cl
O
N
solvent, T °C, time
ii) MeOH, reflux, 2 h
N
HN
N
O
Me
O
Me
10
3a
Scheme 6. Debenzylation of 3a.
Debenzylation was tried on N-benzyl-6b-methyl-cytisine
3a. Several attempts were needed to determine the optimal
conditions (Table 4). In dichloromethane, reaction was not
reproducible and starting material was mainly recovered
(entries 1–4). Debenzylation took place in refluxing di-
chloroethane for 24 h with an excess of ACE-Cl to afford
6b-methyl-cytisine 10 in 72% isolated yield (Table 4,
entry 8).
€
using a Kofler bench apparatus (uncorrected). Optical rota-
tions were measured using a Perkin–Elmer 241 polarimeter.
Infrared spectra (IR) were recorded with a FT-IR Perkin–
Elmer 684 spectrometer. Mass and high resolution mass
spectra (HRMS) were obtained on a Waters-Micromass
Q-Tof micro instrument. NMR spectra were recorded on
a Brucker Avance DPX-250 (1H at 250.1 MHz; 13C at
62.9 MHz; TMS as internal standard). Elementary analyses
were performed on a Thermoquest apparatus by the micro-
analytical service of the Laboratory of Molecular and
Thioorganic Chemistry of ENSICaen, Caen. Cytisine
[(ꢀ)-(1R,5S)-1,2,3,4,5,6-hexahydro-1,5-methanopyrido[1,2-a]-
[1,5]diazocin-8-one] was extracted from commercially
available seeds of Cytisus laburnum anagyro€ıdes (Vilmorin
Company, France). The procedure was reported in the sup-
porting information (free of charge via the Internet at
http://pubs.acs.org) of a previous publication.9
Table 4. Debenzylation of N-benzyl-6b-methyl-cytisine 3a
Entry ACE-Cla (equiv) Solvent
Temp Time (h) Yieldb (%)
c
1
2
3
4
5
6
7
8
1.3
1.5
1.5
4
1.5
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
rt
1.5
0.5
(25)d
c
16
16
2
c
ClCH2CH2Cl Reflux
ClCH2CH2Cl Reflux
ClCH2CH2Cl Reflux 16
ClCH2CH2Cl Reflux 24
(30)d
49
53
72
6
4
4
a
b
c
d
a-Chloroethyl chloroformate (number of equivalent).
Isolated yields.
Starting material was recovered quantitatively.
4.1.1. Synthesis of (L)-(1R,5S)-N-benzyl cytisine 1.29,11d
To a solution of cytisine (1.0 g, 5.26 mmol) in 20 mL of
CH2Cl2 was added Na2CO3 (1.1 g, 10.5 mmol, 2 equiv) in
10 mL of H2O followed by benzyl bromide (6.31 mmol,
1.2 equiv) at room temperature. After stirring 4 h at reflux
temperature, the reaction mixture was extracted three times
with CH2Cl2. The combined organic layers were dried over
Na2SO4 and concentrated under vacuum. Purification of the
crude product by flash chromatography (CH2Cl2/MeOH,
95:5) afforded 1 as a white solid (1.13 g, 77%): mp 142–
144 ꢁC; [a]2D2 ꢀ219 (c 1, CHCl3); 1H NMR (CDCl3)
d 1.8–1.9 (m, 2H), 2.3–2.5 (m, 3H), 2.8–3.0 (m, 3H), 3.37
and 3.46 (AB, JAB¼13.6 Hz, 2H, CH2Bn), 3.91 (dd,
J¼15.4, 6.5 Hz, 1H, H-6b), 4.10 (d, J¼15.4 Hz, 1H,
H-6a), 5.90 (dd, J¼6.9, 1.3 Hz, 1H, H-11), 6.48 (dd,
J¼9.0, 1.3 Hz, 1H, H-9), 6.9–7.0 (m, 2H), 7.1–7.3 (m,
4H); 13C NMR (CDCl3) d 26.3, 28.5, 35.9, 50.3, 60.3,
60.4, 62.3, 105.0, 116.8, 127.2, 128.5, 138.4, 138.9, 151.8,
164.0; IR (NaCl, cmꢀ1) 2926, 2794, 1652, 1546, 1140,
800, 736, 698; HRMS (EI) calcd for C18H20N2O2
280.1576, found 280.1578.
Conversion determined by 1H NMR.
3. Conclusion
This work demonstrated the possibility of intermolecular
functionalization of cytisine on carbon 6 via an original
lithiation reaction. The key step was the regiospecific car-
bonyl directed deprotonation of cytisine by LDA followed
by in situ trapping of the anion by various electrophiles
(inverse addition procedure). With alkyl halides the alkyl-
ation was totally stereoselective at C-6 (position 6b) and
opposite to the acyl migration previously observed (position
6a), but poorly diastereoselective on the second stereogenic
center created when using aldehydes. To avoid the described
carbonyl migration following the deprotonation when
cytisine was N-substituted by an acyl residue, a benzyl group
was used to protect cytisine, which allowed for its easy
and selective removal by a-chloroethyl chloroformate. A
dimer of cytisine was isolated while using the normal addi-
tion conditions for the deprotonation–alkylation sequence
or in the absence of electrophile. Finally, the reaction
developed here offers the potential for the synthesis of
4.1.2. Dimerization of N-methyl-cytisine 2. To a solution
of N-methyl-cytisine 2 (250 mg, 1.22 mmol, 1 equiv) in

N. Houllier et al. / Tetrahedron 62 (2006) 11679–11686
11683
10 mL of THF was added dropwise an LDA solution [pre-
pared in situ from diisopropylamine (0.52 mL, 3.68 mmol,
3 equiv) and n-butyllithium (1.6 M solution in hexanes,
2.30 mL, 3.68 mmol, 3 equiv) in 5 mL of THF at ꢀ20 ꢁC]
at ꢀ78 ꢁC under nitrogen. After stirring 4 h at ꢀ78 ꢁC, the
reaction was quenched with a saturated aqueous ammonium
chloride solution. Ammonia was then added until basic pH.
The aqueous phase was extracted three times with CH2Cl2
and the combined organic layers were dried over magnesium
sulfate, filtered, and concentrated under vacuum. The crude
product was purified by flash chromatography (CH2Cl2/
MeOH, 92:8) to afford dimer 5 as a yellow oil (0.105 g,
4.2.2. (D)-(1R,5S,6S)-N-Benzyl-6-trimethylsilyl-cytisine
3b. The electrophile added was chlorotrimethylsilane. The
crude product was purified by flash chromatography
(CH2Cl2/MeOH, 99:1) to afford 3b as a yellow oil
(0.245 g, 78%); [a]2D2 +16 (c 0.6, CHCl3); 1H NMR
(CDCl3) d 0.06 (s, 9H, Si(CH3)3), 1.7–1.8 (m, 2H), 1.82
(dd, J¼1.7, 10.5 Hz, 1H), 2.39 (br s, 1H), 2.50 (dd, J¼2.6,
11.0 Hz, 1H), 2.91 (s, 1H), 2.94 (dt, J¼1.8, 8.8 Hz, 1H),
2.98 (d, J¼11.0 Hz, 1H), 3.26 and 3.49 (AB, JAB¼13.7 Hz,
2H, CH2Bn), 4.26 (s, 1H, H-6a), 5.87 (dd, J¼1.3, 6.9 Hz,
1H, H-11), 6.47 (dd, J¼1.4, 9.0 Hz, 1H, H-9), 6.8–6.9 (m,
2H), 7.1–7.2 (m, 4H); 13C NMR (CDCl3) d ꢀ0.9, 25.8,
30.7, 35.4, 53.2, 60.2, 61.7, 62.4, 104.4, 115.5, 126.6,
126.7, 127.9, 128.0, 137.4, 138.1, 150.9, 163.3; IR (NaCl,
cmꢀ1) 3421, 2938, 2793, 1647, 1546, 1247, 840, 732, 698;
HRMS (EI) calcd for C21H29N2OSi 353.2049, found
353.2032.
1
42%); [a]2D2 +259 (c 1, CHCl3); H NMR (CDCl3) d 1.41
(d, J¼11.0 Hz, 1H), 1.47 (d, J¼13.0 Hz, 1H), 1.65 (d,
J¼13.0 Hz, 1H), 2.02 (s, 3H), 2.0–2.1 (m, 2H), 2.11 (s,
3H), 2.1–2.2 (m, 3H), 2.24 (br s, 1H), 2.3–2.4 (m, 2H),
2.53 (dd, J¼7.0, 16.0 Hz, 1H, H-90), 2.59–2.70 (m, 3H),
2.73 (d, J¼10.0 Hz, 1H), 2.8–2.9 (m, 2H), 3.58 (dd,
J¼7.0, 13.2 Hz, 1H, H-60b), 3.6–3.7 (m, 2H, H-60a and
H-100), 4.33 (d, J¼5.1 Hz, 1H, H-110), 4.61 (d, J¼5.6 Hz,
1H, H-6a), 5.95 (dd, J¼1.4, 6.8 Hz, 1H, H-11), 6.40 (dd,
J¼1.4, 9.0 Hz, 1H, H-9), 7.23 (dd, J¼6.8, 9.0 Hz, 1H,
H-10). 13C NMR (CDCl3) d 23.8, 26.4, 27.6, 29.5, 31.2,
34.5, 35.4, 36.5, 46.1, 46.5, 47.5, 61.6, 62.1, 63.0, 63.6,
101.5, 104.6, 117.8, 138.6, 142.4, 151.6, 163.4, 169.5; IR
(NaCl, cmꢀ1) 3419, 2937, 2780, 1645, 1544, 907, 723;
HRMS (ESI) calcd for C24H33N4O2 409.2604, found
409.2593.
4.2.3. (L)-(1R,5S,6S)-N-Benzyl-6-ethyl-cytisine 3c. The
electrophile added was ethyl bromide. The crude product
was purified by flash chromatography (CH2Cl2/MeOH,
99:1) to afford 3c as a white solid (0.192 g, 70%): mp
161 ꢁC; [a]2D2 ꢀ13 (c 0.5, CHCl3); 1H NMR (CDCl3)
d 1.02 (t, J¼7.4 Hz, 3H), 1.3–1.4 (m, 1H), 1.6–1.7 (m,
1H), 1.7–2.0 (m, 1H), 2.1–2.3 (m, 3H), 2.49 (dd, J¼11.0,
2.6 Hz, 1H), 2.65 (d, J¼10.4 Hz, 1H), 2.90 (s, 1H), 2.96
(d, J¼11.0 Hz, 1H), 3.27 and 3.46 (AB, JAB¼13.7 Hz, 2H,
CH2Bn), 4.42 (d, J¼8.3 Hz, 1H, H-6a), 5.82 (d, J¼6.8 Hz,
1H, H-11), 6.48 (d, J¼9.0 Hz, 1H, H-9), 6.8–6.9 (m, 2H),
7.1–7.3 (m, 4H); 13C NMR (CDCl3) d 12.0, 23.9, 27.5,
30.7, 36.4, 60.6, 61.0, 61.1, 62.2, 104.9, 117.8, 127.1,
128.4, 138.4, 138.6, 151.2, 163.5; IR (KBr, cmꢀ1) 3421,
2935, 2801, 1649, 1569, 1544, 735, 699; HRMS (EI) calcd
for C20H24N2O 309.1967, found 309.1962.
4.2. General procedure for alkylation at C-6 position
To a solution of N-benzyl-cytisine 1 (250 mg, 0.89 mmol,
1 equiv) in 7 mL of THF was added the electrophile
(2.32 mmol, 2.6 equiv) at ꢀ78 ꢁC under nitrogen. An LDA
solution [prepared in situ from diisopropylamine (0.37 mL,
2.67 mmol, 3 equiv) and n-butyllithium (1.6 M solution in
hexanes, 1.67 mL, 2.67 mmol, 3 equiv) in 5 mL of THF at
ꢀ20 ꢁC] was then added dropwise. After stirring 2 h at
ꢀ78 ꢁC, the reaction was stirred overnight at room temper-
ature. The mixture was quenched with a saturated aqueous
ammonium chloride solution and then ammonia was added
until basic pH. The aqueous phase was extracted three times
with CH2Cl2 and the combined organic layers were dried
over magnesium sulfate, filtered, and concentrated under
vacuum.
4.2.4. (L)-(1R,5S,6S)-N-Benzyl-6-benzyl-cytisine 3d. The
electrophile added was benzyl bromide. The crude product
was purified by flash chromatography (CH2Cl2/MeOH,
98:2) to afford 3d as a yellow oil (0.204 g, 62%); [a]D22
ꢀ101 (c 1.0, CHCl3); 1H NMR (CDCl3) d 1.6–1.7 (m,
2H), 2.0–2.5 (m, 4H), 2.54 (d, J¼10.9 Hz, 1H), 2.66 (d,
J¼10.9 Hz, 1H), 2.66 (br s, 1H), 3.22 and 3.42 (AB,
JAB¼13.7 Hz, 2H, NCH2Bn), 3.45 (d, J¼12.9 Hz, 1H),
4.79 (d, J¼10.3 Hz, 1H, H-6a), 5.89 (d, J¼6.8 Hz, 1H,
H-11), 6.57 (d, J¼9.0 Hz, 1H, H-9), 6.8–6.9 (m, 2H), 7.1–
7.4 (m, 9H); 13C NMR (CDCl3) d 23.6, 29.9, 36.4, 39.9,
53.7, 60.5, 60.9, 61.1, 62.1, 105.2, 117.9, 126.8, 127.1,
128.4, 128.4, 128.8, 129.9, 138.5, 138.8, 138.9, 139.4,
151.3, 163.4; IR (NaCl, cmꢀ1) 3416, 2939, 2794, 1648,
1567, 1546, 910, 800, 733, 699; HRMS (ESI) calcd for
C25H27N2O 371.2123, found 371.2105.
4.2.1. (L)-(1R,5S,6S)-N-Benzyl-6-methyl-cytisine 3a. The
electrophile added was methyl iodide. The crude product
was purified by flash chromatography (CH2Cl2/MeOH,
98:2) to afford 3a as a white solid (0.257 g, 98%): mp
152 ꢁC; [a]2D2 ꢀ51 (c 0.9, CHCl3); 1H NMR (CDCl3)
d 1.40 (d, J¼6.4 Hz, 3H), 1.6–1.8 (m, 2H), 2.02 (s, 1H),
2.22 (d, J¼1.3 Hz, 1H), 2.26 (d, J¼1.3 Hz, 1H), 2.43 (dd,
J¼2.5, 11.0 Hz, 1H), 2.67 (dd, J¼1.6, 10.4 Hz, 1H), 2.91
(br s, 1H), 3.03 (d, J¼11.0 Hz, 1H), 3.27 and 3.45 (AB,
JAB¼13.6 Hz, 2H, CH2Bn), 4.78 (q, J¼6.4 Hz, 1H, H-6a),
5.86 (dd, J¼1.2, 6.7 Hz, 1H, H-11), 6.48 (dd, J¼1.2,
9.0 Hz, 1H, H-9), 6.9–7.1 (m, 5H), 7.2–7.3 (m, 1H); 13C
NMR (CDCl3) d 20.8, 23.5, 34.9, 36.1, 54.7, 59.9, 60.8,
61.8, 104.8, 117.5, 126.8, 128.1, 138.1, 150.9, 163.2; IR
(KBr, cmꢀ1) 3423, 2918, 2809, 1648, 1569, 1542, 801,
735, 698; HRMS (ESI) calcd for C19H23N2O 295.1810,
found 295.1809.
4.2.5. (L)-(1R,5S,6S)-N-Benzyl-6-allyl-cytisine 3e. The
electrophile added was allyl bromide. The crude product
was purified by flash chromatography (CH2Cl2/MeOH,
98:2) to afford 3e as a yellow oil (0.197 g, 69%); [a]D22
1
ꢀ26 (c 0.5, CHCl3); H NMR (CDCl3) d 2.1–2.2 (m, 5H),
2.4–2.5 (m, 1H), 2.6–2.7 (m, 1H), 2.7–3.0 (m, 3H), 3.27
and 3.46 (AB, JAB¼13.6 Hz, 2H, CH2Bn), 4.56 (t,
J¼7.7 Hz, 1H, H-6a), 5.0–5.1 (m, 2H), 5.8–5.9 (m, 2H),
6.50 (d, J¼9.0 Hz, 1H, H-9), 6.8–6.9 (m, 2H), 7.1–7.2 (m,
4H); 13C NMR (CDCl3) d 23.6, 30.7, 36.4, 38.7, 53.8,
58.6, 60.4, 61.0, 62.1, 105.1, 117.8, 117.9, 127.1, 128.4,

11684
N. Houllier et al. / Tetrahedron 62 (2006) 11679–11686
128.5, 135.9, 138.6, 138.6, 151.2, 163.4; IR (NaCl, cmꢀ1
3397, 2938, 2794, 1648, 1546, 912, 800, 732, 698; HRMS
(EI) calcd for C21H24N2O 321.1967, found 321.1952.
)
4.2.9. (L)-(1R,5S,6R)-N-Benzyl-6-[(hydroxy,tert-butyl)-
methyl]-cytisine 3i. The electrophile added was pival-
aldehyde. The crude product was purified by flash
chromatography (CH2Cl2/MeOH, 99:1) to afford 3i as a
54/46 mixture of diastereoisomers (0.254 g, 78%). Analy-
tical samples of each diastereoisomer were obtained from
a second tedious chromatography of the mixture using the
same eluting system.
4.2.6. (D)-(1R,5S,6S)-N-Benzyl-6-trimethylstannyl-cyti-
sine 3f. The electrophile added was trimethyltin chloride.
The crude product was purified by flash chromatography
(CH2Cl2/MeOH, 99:1) to afford 3f as a colorless oil
(0.174 g, 44%); [a]2D2 +114 (c 1.2, CHCl3); 1H NMR
(CDCl3) d 0.03 (s, J2
¼51.3 Hz, 9H, Sn(CH3)3), 1.7–
Major diastereoisomer at C-13, (R): [a]2D2 ꢀ24 (c 1.0,
CHCl3); 1H NMR (CDCl3) d 1.17 (s, 9H), 1.6–1.7 (m,
2H), 2.1–2.2 (m, 2H), 2.26 (br s, 1H), 2.45 (dd, J¼2.6,
11.1 Hz, 1H), 2.66 (d, J¼10.3 Hz, 1H), 2.95 (s, 1H), 3.01
(d, J¼11.1 Hz, 1H), 3.2–3.3 (m, 2H), 3.25 and 3.52 (AB,
JAB¼13.7 Hz, 2H, CH2Bn), 4.76 (d, J¼7.8 Hz, 1H, H-6a),
5.94 (d, J¼6.9 Hz, 1H, H-11), 6.51 (d, J¼8.9 Hz, 1H,
H-9), 6.8–6.9 (m, 2H), 7.1–7.2 (m, 3H), 7.2–7.3 (m, 1H);
13C NMR (CDCl3) d 23.0, 27.5, 33.2, 35.8, 37.1, 59.2,
60.4, 60.8, 61.8, 81.6, 106.5, 117.0, 126.9, 128.1, 128.2,
138.1, 139.3, 152.0, 166.4; IR (NaCl, cmꢀ1) 2949, 2794,
1644, 1542, 1134, 912, 800, 731, 698; HRMS (ESI) calcd
for C23H31N2O2 367.2386, found 367.2368.
Sn–H
1.8 (m, 2H), 2.26 (dd, J¼1.7, 10.5 Hz, 1H), 2.4–2.5 (m,
2H), 2.80 (dt, J¼1.7, 10.5 Hz, 1H), 2.9–3.0 (m, 2H), 3.33
and 3.46 (AB, JAB¼13.6 Hz, 2H, CH2Bn), 4.14 (s, J2
¼
Sn–H
51.3 Hz, 1H, H-6a), 5.95 (dd, J¼1.3, 6.9 Hz, 1H, H-11),
6.48 (dd, J¼1.4, 8.9 Hz, 1H, H-9), 6.9–7.0 (m, 2H), 7.1–
7.3 (m, 4H); 13C NMR (CDCl3) d ꢀ8.1, 26.3, 32.6, 36.1,
54.0, 56.1, 61.0, 62.5, 63.0, 106.1, 115.3, 127.3, 128.7,
128.7, 137.7, 138.8, 151.1, 162.9; IR (NaCl, cmꢀ1) 2925,
2795, 1638, 1543, 1142, 769, 731, 698; HRMS (EI) calcd
for C21H29N2OSn 445.1302, found 445.1317.
4.2.7. (L)-(1R,5S,6R)-N-Benzyl-6-propionyl-cytisine 3g.21
The electrophile added was N-methoxy-N-methylpropiona-
mide. The crude product was purified by flash chromato-
graphy (CH2Cl2/MeOH, 95:5) to afford 3g as a viscous
colorless oil (0.125 g, 42%).
Minor diastereoisomer at C-13, (S) isolated as an enriched
mixture with its epimer. H NMR (CDCl3) d 1.10 (s, 9H),
1
1.4–1.5 (m, 1H), 2.1–2.2 (m, 1H), 2.2–2.4 (m, 2H), 2.6–
2.7 (m, 2H), 2.7–2.8 (m, 1H), 2.8–2.9 (m, 2H), 3.26 and
3.50 (AB, JAB¼13.4 Hz, 2H, CH2Bn), 3.4–3.5 (m, 1H),
4.08 (s, 1H), 4.88 (s, 1H, H-6a), 5.88 (d, J¼7.5 Hz, 1H,
H-11), 6.46 (d, J¼8.9 Hz, 1H, H-9), 6.8–6.9 (m, 2H), 7.1–
7.2 (m, 4H); 13C NMR (CDCl3) d 25.3, 27.5, 29.5, 36.0,
36.1, 60.2, 60.7, 61.0, 61.8, 78.8, 104.9, 117.1, 126.7,
128.0, 128.1, 138.2, 138.3, 152.9, 163.5; HRMS (ESI) calcd
for C23H31N2O2 367.2386, found 367.2400.
4.2.8. (L)-(1R,5S,6R)-N-Benzyl-6-[(hydroxy,phenyl)-
methyl]-cytisine 3h. The electrophile added was benz-
aldehyde. The crude product was purified by flash
chromatography (CH2Cl2/MeOH, 99:1) to afford 3h as a
61/39 mixture of diastereoisomers (0.261 g, 76%). Analyti-
cal samples of each diastereoisomer were obtained from
a second tedious chromatography of the mixture using the
same eluting system.
4.2.10. (D)-(1R,5S,6S)-N-Benzyl-6,9-bistrimethylsilyl-
cytisine 6. Same procedure as for compound 3b with
LTMP as base. The crude product was purified by flash chro-
matography (CH2Cl2/MeOH, 98:2) to afford 6 as a yellow
Major diastereoisomer at C-13, (R): [a]2D2 ꢀ99 (c 1.0,
CHCl3); 1H NMR (CDCl3) d 1.27 (d, J¼13.1 Hz, 1H),
1.49 (d, J¼13.1 Hz, 1H), 2.0–2.1 (m, 2H), 2.19 (dd, J¼
2.5, 11.1 Hz, 1H), 2.4–2.5 (m, 1H), 2.6–2.7 (m, 2H), 3.09
and 3.29 (AB, JAB¼13.7 Hz, 2H, CH2Bn), 4.89 (d, J¼
7.3 Hz, 1H, H-6a), 5.04 (d, J¼7.4 Hz, 1H), 5.31 (br s,
1H), 5.86 (d, J¼6.9 Hz, 1H, H-11), 6.53 (d, J¼8.9 Hz, 1H,
H-9), 6.7–6.8 (m, 2H), 7.0–7.1 (m, 3H), 7.1–7.2 (m, 6H);
13C NMR (CDCl3) d 23.4, 28.9, 36.1, 60.3, 60.9, 61.6,
63.6, 75.9, 106.6, 117.1, 127.2, 127.8, 128.1, 128.4, 128.5,
138.1, 139.6, 142.4, 151.7, 166.0; IR (NaCl, cmꢀ1) 3279,
2939, 2794, 1642, 1542, 1136, 908, 726, 698; HRMS
(ESI) calcd for C25H27N2O2 387.2073, found 387.2081.
1
oil (186 mg, 36%); [a]2D2 +46 (c 0.8, CHCl3); H NMR
(CDCl3) d 0.03 (s, 9H), 0.29 (s, 9H), 1.7–1.8 (m, 2H), 2.23
(dd, J¼1.6, 10.4 Hz, 1H), 2.34 (br s, 1H), 2.50 (dd, J¼2.4,
10.9 Hz, 1H), 2.72 (dt, J¼1.7, 10.4 Hz, 1H), 2.87 (br s,
1H), 2.99 (d, J¼10.9 Hz, 1H), 2.80 and 3.46 (AB,
JAB¼13.9 Hz, 2H, CH2Bn), 4.33 (s, 1H, H-6a), 5.85 (d,
J¼6.7 Hz, 1H, H-11), 6.8–6.9 (m, 2H), 7.0–7.1 (m, 3H),
7.30 (d, J¼6.7 Hz, 1H); 13C NMR (CDCl3) d ꢀ1.5, ꢀ0.7,
26.0, 31.2, 35.9, 53.1, 60.7, 61.7, 62.5, 105.1, 125.3,
126.8, 128.1, 128.2, 138.7, 143.5, 151.9, 165.6; IR (NaCl,
cmꢀ1) 2942, 2802, 2760, 1624, 1544, 1242; MS (EI) m/z
(%) 424 (M+, 25), 409 (42), 290 (47), 202 (38), 91 (100),
73 (77), 57 (46).
Minor diastereoisomer at C-13, (S): [a]2D2 ꢀ139 (c 1.0,
CHCl3); 1H NMR (CDCl3) d 1.48 (d, J¼12.3 Hz, 1H),
2.1–2.2 (m, 3H), 2.5–2.7 (m, 2H), 2.8–2.9 (m, 1H), 2.94
(br s, 1H), 3.20 and 3.40 (AB, JAB¼13.7 Hz, 2H, CH2Bn),
3.6–3.7 (m, 1H), 4.85 (d, J¼2.0 Hz, 1H, H-6a), 5.74 (br s,
1H), 5.96 (d, J¼6.9 Hz, 1H, H-11), 6.45 (d, J¼9.0 Hz, 1H,
H-9), 6.8–6.9 (m, 2H), 7.1–7.2 (m, 3H), 7.2–7.3 (m, 4H),
7.52 (d, J¼7.1 Hz, 2H); 13C NMR (CDCl3) d 24.9, 28.1,
36.5, 60.8, 61.5, 63.9, 73.3, 105.5, 117.2, 126.9, 127.0,
127.1, 128.2, 128.3, 128.7, 138.4, 139.0, 142.5, 152.7,
164.1; IR (NaCl, cmꢀ1) 3282, 2931, 2794, 2758, 1643,
1542, 1134, 908, 803, 734, 699; HRMS (ESI) calcd for
C25H27N2O2 387.2073, found 387.2068.
4.3. Oxidation of epimeric alcohols 3h
4.3.1. (L)-(1R,5S,6R)-N-Benzyl-6-benzoyl-cytisine 8. To
a solution of a mixture of diastereoisomers 3h (70 mg,
0.181 mmol, 1 equiv) in 5 mL of ethyl acetate was added
IBX (301 mg, 1.08 mmol, 6 equiv). The mixture was heated
at 80 ꢁC for 16 h. The reaction was filtered and the filtrate
was concentrated under vacuum. The crude product was pu-
rified by flash chromatography (CH2Cl2/MeOH, 99.5:0.5) to
afford 8 as a colorless oil (0.054 g, 76%); [a]2D2 ꢀ123 (c 0.6,

N. Houllier et al. / Tetrahedron 62 (2006) 11679–11686
11685
CHCl3); 1H NMR (CDCl3) d 1.62 (dt, J¼3.0, 13.0 Hz, 1H),
2.13 (d, J¼13.0 Hz, 1H), 2.3–2.4 (m, 2H), 2.46 (dd, J¼3.0,
11.0 Hz, 1H), 2.88 (d, J¼11.0 Hz, 1H), 3.02 (s, 1H), 3.14 (d,
J¼10.0 Hz, 1H), 3.45 and 3.55 (AB, JAB¼14.0 Hz, 2H,
CH2Bn), 5.90 (s, 1H, H-6a), 6.03 (d, J¼8.0 Hz, 1H,
H-11), 6.49 (d, J¼9.0 Hz, 1H, H-9), 7.0–7.1 (m, 2H), 7.2–
7.3 (m, 3H), 7.3–7.4 (m, 1H), 7.4–7.5 (m, 2H), 7.5–7.6 (m,
1H), 8.06 (d, J¼8.0 Hz, 2H); 13C NMR (CDCl3) d 23.0,
30.7, 35.2, 59.7, 59.9, 62.0, 62.6, 104.9, 116.8, 127.2,
128.3, 128.4, 128.6, 128.9, 133.3, 135.0, 137.9, 139.5,
151.7, 162.9; IR (NaCl, cmꢀ1) 2939, 2800, 1691, 1650,
1544, 1219, 1142, 908, 798, 723, 693; HRMS (ESI) calcd
for C25H25N2O2 385.1916, found 385.1923.
Farmaco 1999, 54, 438–451; (c) Imming, P.; Klaperski, P.;
€
Stubbs, M. T.; Seitz, G.; Gundisch, D. Eur. J. Med. Chem.
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4. Chellappan, S. K.; Xiao, Y.; Tueckmantel, W.; Kellar, K. J.;
Kozikowski, A. P. J. Med. Chem. 2006, 49, 2673–2676.
5. Khisamutdinova, R. Y.; Yarmukhamedov, N. N.;
Gabdrakhmanova, S. F.; Karachurina, L. T.; Sapozhnikova,
T. A.; Baibulatova, N. Z.; Baschenko, N. Zh.; Zarudii, F. S.
Pharm. Chem. J. (Translation of Khimiko-Farmatsevticheskii
Zhurnal) 2004, 38, 311–313; Chem. Abstr. 2004, 142,
411207.
6. Bakbardina, O. V.; Rakhimzhanova, N. Z.; Gazalieva, M. A.;
Fazyov, S. D.; Baimagambetov, E. Z. Russ. J. Appl. Chem.
2006, 79, 504–505.
7. (a) Nicolotti, O.; Canu Boido, C.; Sparatore, F.; Carotti, A.
Farmaco 2002, 57, 469–478; (b) Canu Boido, C.; Tasso, B.;
Boido, V.; Sparatore, F. Farmaco 2003, 58, 265–277.
4.4. Debenzylation of 3a
4.4.1. (D)-(1R,5S,6S)-6-Methyl-cytisine 10. To a solution of
N-benzyl-6-methyl-cytisine 3a (50 mg, 0.17 mmol, 1 equiv)
in 1 mL of anhydrous dichloroethane was slowly added
a-chloroethyl chloroformate (75 mL, 0.68 mmol, 4 equiv)
under nitrogen. The reaction was heated to 80 ꢁC during
24 h. After evaporation of the solvent, the residue was dis-
solved in 2 mL of methanol and the solution was refluxed
for 2 h. Methanol was evaporated and ammonia was added
until basic pH. After extraction four times with CH2Cl2
and evaporation of the solvent, the crude product was puri-
fied by flash chromatography (CH2Cl2/MeOH, 9:1+1%
NH3 28%) affording 10 as a colorless oil (25 mg, 72%);
[a]2D2 +107 (c 0.96, CHCl3); 1H (CDCl3) d 1.38 (d,
J¼6.3 Hz, 3H), 1.60 (br s, 1H), 1.91 (d, J¼6.1 Hz, 2H),
2.24 (d, J¼12.7 Hz, 1H), 2.8–2.9 (m, 2H), 3.1–3.2 (m,
2H), 4.79 (q, J¼6.1 Hz, 1H, H-6a), 5.99 (dd, J¼1.0,
6.8 Hz, 1H, H-11), 6.4 (dd, J¼1.0, 9.0 Hz, 1H, H-9), 7.26
(dd, J¼6.8, 9.0 Hz, 1H, H-10); 13C NMR (CDCl3) d 20.7,
22.9, 33.6, 35.1, 51.1, 54.3, 58.5, 106.0, 118.2, 138.9,
149.0, 163; IR (NaCl, cmꢀ1) 2944, 2800, 1650, 1548; MS
(EI) m/z (%) 204 (M+, 29), 46 (15), 109 (16), 44 (100).
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2000, 2, 1121–1124.
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L. A.; Letchworth, S. R.; Bohme, G. A.; Benavides, J.;
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Lasne, M.-C.; Bottlaender, A.; Dolle, F. Bioorg. Med. Chem.
2003, 11, 5333–5343.
11. (a) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P.
J. Am. Chem. Soc. 2002, 124, 11870–11871; (b) Hermet,
J.-P. R.; Porter, D. W.; Dearden, M. J.; Harrison, J. R.;
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Acknowledgements
We gratefully acknowledge the CNRS (Centre National de la
ꢀ
Recherche Scientifique), the Region Basse-Normandie for
a fellowship to N.H., PunchOrga Network (Pole Universi-
ꢁ
taire Normand de Chimie Organique), the Ministere de
l’Education Nationale de l’Enseignement Superieur et de
la Recherche, and the European Union (FEDER funding)
for financial support.
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ꢀ
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