An efficient approach to new dihydroxyquinolizidines

Article abstract of DOI:10.1016/j.tetasy.2010.05.036

Using d-glyceraldehyde acetonide as a starting material, a four-step synthesis of enantiomerically pure 3,4-dihydroxyquinolizidines is described. The key steps of the synthesis consist of a Mitsunobu ring-closing reaction and the subsequent reduction of a pyridinium ring.

Full text of DOI:10.1016/j.tetasy.2010.05.036

Tetrahedron: Asymmetry 21 (2010) 2032–2036
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An efficient approach to new dihydroxyquinolizidines
*
Tony Tite, Feïmida Jacquelin, Laurent Bischoff , Corinne Fruit, Francis Marsais
ECOFH-UMR 6014 COBRA, IRCOF-INSA Rouen Université de Rouen, Place Emile Blondel, 76130 Mont-Saint-Aignan, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Using D-glyceraldehyde acetonide as a starting material, a four-step synthesis of enantiomerically pure
Received 13 May 2010
Accepted 24 May 2010
Available online 19 June 2010
3,4-dihydroxyquinolizidines is described. The key steps of the synthesis consist of a Mitsunobu ring-clos-
ing reaction and the subsequent reduction of a pyridinium ring.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
mechanisms of action and their metabolism, further providing
new classes of potent inhibitors. Since the first synthesis by Ganem
Since the discovery of swainsonine in 1973, considerable efforts
have been made in isolating or synthesizing parent compounds.1
This molecule, as well as other naturally occurring iminosugars
(azasugars), in particular polyhydroxylated indolizidine alkaloids
such as lentiginosine and castanospermine (Fig. 1) was found to
be potent glycosidase inhibitors.2 This activity makes them poten-
tial candidates for antidiabetic, antibacterial, immunosuppressive,
or antiviral compounds.3 Over the last 20 years, many structural
modifications have been published, as well as the design of new
stereocontrolled synthetic routes to such substances or their
unnatural isomers,4 which might be of interest for SAR studies.
Thus, numerous stereochemically different and ring-expanded
analogues of polyhydroxylated bicyclic iminosugars have been
synthesized and evaluated.5 Many of these compounds isolated
from plants and microorganisms belong to the family of indolizi-
dines. They have also been obtained through various synthetic
pathways and the number of unnatural analogues is becoming
increasingly important.
et al. in 1987,6 the synthesis of polyhydroxylated quinolizidines is
scarcely reported, and has attracted much lesser interest. Indeed,
although these compounds represent the formal homologation of
the indolizidine scaffold, there has not been any discovered in Nat-
ure. Most of the approaches to date are based on those for quino-
lizidines/indolizidines and polyhydroxylated indolizidines. Many
synthetic methods published to date often involve ring-closure
metathesis using first and second generation Grubb’s catalysts.7
Some other elegant strategies using one or double-reductive ami-
nation,8 hetero-Diels–Alder reaction,9 intramolecular SN2 reactions
with a mesylate leaving group,10 intramolecular 1,3-cycloaddition
via nitrones and sulfones,11 and double-Michael additions12 have
also been reported. The syntheses of hydroxylated quinolizidines
with up to five hydroxyl groups have been achieved. Some deriva-
tives including homocastanospermine and homonojirimycin were
found to be potent inhibitors of
a- and b-glucosidases, even if
the introduction of several hydroxyl groups sometimes triggers
lower selectivities. However, one limitation of many of these meth-
odologies is the lower availability of carbohydrate precursors for
such compounds. This consequently leads to the use of time-con-
suming protective and deprotective sequences. To the best of our
knowledge, only two syntheses of dihydroxyquinolizidines have
been reported before.13 Marquart et al. have reported the synthesis
of I and II (Fig. 2) in nine steps [0.80% and 0.92% overall yield,
respectively, from a bromobutyl phtalimide]. Later, the derivative
II, as well as III was synthesized by West and Vanecko using a ster-
eoselective silyl-directed Stevens [1,2]-shift of ammonium ylides
[six steps, 17% overall yield from Boc-pyrrolidine].
OH
OH
OH
OH
OH
H
N
H
N
H
N
HO
HO
OH
OH
(+)-lentiginosine
castanospermine
swainsonine
Figure 1. Naturally occurring polyhydroxyindolizidines.
However, ring-expanded analogues, such as quinolizidines still
remain little explored, although they are interesting targets. As
they differ from indolizidines, which are closely related to natural
sugars, quinolizidines may lead to a better understanding of the
2. Results and discussion
Dihydroxyquinolizidines with the stereochemical patterns gi-
ven in Scheme 1 have not been described in the literature and thus
represent interesting targets. We have recently demonstrated how
the Mitsunobu reaction can be successfully employed to readily
* Corresponding author. Fax: +33 2 35522962.
E-mail address: laurent.bischoff@insa-rouen.fr (L. Bischoff).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.036

T. Tite et al. / Tetrahedron: Asymmetry 21 (2010) 2032–2036
2033
R
OH
OH
H
N
H
N
OH
OH
OH HO
OH
OH
OH
N
Dhavale, OBC 2008
R = H, OH
Blechert, OL 2000
Dhavale, Tet 2004
HO
OH OH
H
OH OH
H
H
H
OH
N
N
II
N
III
N
OH
I
Marquart, JOC 1994
Lesma, Tet 2004
West, OL 2002
Figure 2. Synthetic polyhydroxyquinolizidines published in the literature.
OH
OH
OH
i
O
O
O
O
N
N
N
N
1a
1b
ii
v
OBn
OH
OH
O
O
N+
H
-
BF4
2
5
iii
ii
OH
OH
OBn
N+
OH
OH
N+
H
-
-
BF4
BF4
3
6
iv
iii
H
OH
OH
OBn
N
N+
OH
-
BF4
7
4
iv
H
H
OBn
OH
OBn
OH
N
N
8a
8b
vi
H
OH
OH
N
9a
Scheme 1. Reagents and conditions: (i) n-BuLi, THF, ꢀ78 °C then
D
-glyceraldehyde acetonide, ꢀ78 °C, overnight; (ii) HBF4 (OCH2CH3)2 (1.1 equiv), CH3OH, 20 h, rt; (iii) PPh3
(1.1 equiv), DIAD (1.1 equiv), CH3CN, 24 h, rt; (iv) (a) H2, PtO2, 1 atm, 22 h; (b) Et3N; (v) NaH, BnBr, THF; (vi) H2, PdCl2, 1 atm, 3 h.
access 5/6 bicyclic azasugar lentiginosine derivatives using quater-
narization of a pyridinium polyol as the key step.14 As part of our
ongoing efforts toward the synthesis of new azasugars using this
synthesis of 6/6 bicyclic azasugar dihydroxyquinolizidine alka-
loids. As this ring-closing step considerably differs when a (6+6)
system is involved, we wished to examine the reactivity and ste-
reochemical outcome of both pyridine alkylation and further
methodology, we disclose
a practical and diastereoselective

2034
T. Tite et al. / Tetrahedron: Asymmetry 21 (2010) 2032–2036
pyridinium reduction to illustrate this synthetic strategy with the
obtention of new dihydroxyquinolizidines, namely homolentigi-
nosine.
prior to hydrolysis of the acetonide. The cyclization under Mitsun-
obu conditions was not improved for compound 6 versus 2, how-
ever the purification of the resulting pyridinium 7 by flash
chromatography was greatly facilitated. Bearing the benzyl group
as a more hindered substituent at C-2 position, hydrogenation
led to a 2:1 ratio of compounds 8a and 8b, respectively. Unfortu-
nately, whatever the reaction conditions, the de could not be im-
proved upon for this compound, probably due to the higher
flexibility and different spatial orientation of substituents in a
(6+6) ring system versus its (6+5) indolizinium analogue. In addi-
tion, we observed that even under atmospheric pressure, PtO2-
mediated debenzylation also led to the reduction of the aromatic
ring of the benzyl group.
The usefulness of glyceraldehyde as a chiral-pool reagent has al-
ready been illustrated in many syntheses,15 therefore this material
was chosen as the chiral building block required for the construc-
tion of the dihydroxyl-substituted six-membered ring. Thus, the
adjunction of a picoline subunit leads to the whole backbone of
the target molecule. As depicted in Scheme 1, lithiation of picoline
readily took place with n-BuLi and was followed by quenching
with glyceraldehyde acetonide. Better yields were obtained when
the reaction mixture was stirred at ꢀ78 °C overnight, as slow
warming to room temperature resulted in some degradation. Both
diastereomers 1a and 1b were obtained in a 3/1 ratio,16 and were
easily separated via chromatography through silica gel. The assign-
ment of the absolute configuration of the new stereocenter was
first postulated on the basis of previous results,14 and confirmed
with the NMR NOESY spectrum of compound 9a. In the following
steps, only the cis-diastereomer 1a was used as a free alcohol, since
we expected that in the case of the minor diastereomer 1b, hardly
any facial selectivity would be observed for the reduction step. Fur-
ther hydrolysis of the acetonide was achieved upon treatment with
1 M equiv of aqueous tetrafluoroboric acid (Et2O complex). Both
HCl and HBF4 resulted in quantitative deprotection, however the
choice of the counterion was crucial for the following step. The ring
closing was based on a Mitsunobu reaction, in which the acidic,
nucleophilic component of the reaction consisted of the pyridini-
um itself, and relies on the highly selective activation of the pri-
mary alcohol. During this process, a non-nucleophilic counterion
was required to avoid the transformation of the alcohol into the
corresponding halide. Whereas in the case of a (6+5) ring system,
the ring closing was considerably facilitated, in the present case
much degradation occurred in our previously reported conditions
(excess PPh3/DIAD, rt, overnight). We believe that the alkaline con-
ditions of the Mitsunobu reaction led to a retro-aldol-mediated
loss of the hydroxylated part of the molecule, since the formation
of a picolinium was observed. Thus, the ring-closure step required
some optimization and better results were obtained when the tet-
rafluoroborate salt 2 was treated in the presence of triphenylphos-
phine (1.1 equiv) by slow addition of di-isopropyl azadicarboxylate
(DIAD, 1.1 equiv) in an ice-cold bath.
As far as the stereochemistries are concerned, the absolute (S)-
configuration at C-2 corresponds to that of D-glyceraldehyde. It can
be expected, according to the literature, that the major diastereo-
mer obtained via the addition of lithiated picoline to the aldehyde
had the (2S,3R) configuration. This is also in agreement with the
good diastereoselectivity observed for the reduction of the pyridi-
nium cis-diol 3. The addition of hydrogen onto the pyridinium ring
should occur at the less-hindered face, providing the (2S,3R,9aR)
diastereomer from compound 3. These structural features were
confirmed by means of NOE experiments as depicted in Figure 3
for compound 4, which allowed us to observe strong correlation
peaks between H-9a/H-2 and H-9a/H-4ax in agreement with a cis
relationship between these protons. Moreover, the clear NOE
cross-peaks between H-2ax/H-3eq; H-2ax/H-4ax; H-2ax/H-1eq; H-
9a/H-4ax support the syn relationship of these two protons and also
confirm the structure depicted in 4. In structure 8a a clear NOE
cross-peak between H-9a/H-2ax was observed in accordance with
a cis relationship between these protons. The strong NOE cross-
peaks between H-2ax/H-4ax, H-3ax/H-4eq, support the (2R,3R,9aS)
configuration for 8a.
Finally, the benzyl group of 8a was easily cleaved in the pres-
ence of palladium chloride to yield almost quantitatively the target
derivative 9a.
3. Conclusion
In conclusion, we have prepared two novel dihydroxyquinolizi-
dines which could be viewed as homolentiginosine analogues. The
synthetic approach was proven to be short, efficient, and stereose-
lective. Its application in the synthesis of mono-hydroxyquinolizi-
dine through the reduction of a 2-benzyl-3-xanthate derivative
using a Barton McCombie reaction is currently in progress.
Under these conditions, much less degradation compounds
were observed, and the dihydroxyquinolizinium 3 was obtained
as a 1:1 mixture together with 2 as indicated by 1H NMR spectros-
copy. We observed that 3 was difficult to be purified by chroma-
tography on silica gel, subsequent catalytic hydrogenation of the
crude material in the presence of PtO2 proceeded with a 90% de
as indicated by NMR spectroscopy and GC/MS, affording the ring-
expanded analogue 4 of lentiginosine.
On the other hand, in order to both enhance the diastereoselec-
tivity at the reduction step of the pyridinium bearing the trans-diol
system and facilitate further separation of the stereoisomers, we
carried out the benzylation of the free alcohol in compound 1b
4. Experimental
4.1. General experimental procedures
Unless otherwise stated, reactions were performed under a
nitrogen atmosphere using freshly distilled solvents. All reactions
H
H
H
H
5
7
H
H
4
2
H
H
3
H
H
H
N
6
3
4
H
H
HO
6
HO
H
5
8
H
H
H
O
9a
N
1
9
OH
1
H
H
9a
2
H
H
H
8
H
H
H
7
H
H
9
H
H
Figure 3. NOE experiments.

T. Tite et al. / Tetrahedron: Asymmetry 21 (2010) 2032–2036
2035
were monitored by thin-layer chromatography using aluminium-
backed Silica Gel 60 F254 plates (0.25 mm). Flash chromatography
added di-isopropyl azodicarboxylate (DIAD) (121.1
l
L, 0.605
mmol) dropwise at 0 °C. After stirring for 24 h at room tempera-
ture, CH3CN was evaporated and the residue was dissolved in
H2O, washed with Et2O, and freeze-dried to afford an inseparable
mixture of 2 and 3 (ratio 1:1, 160 mg). 1H NMR (300 MHz, CH3OD):
d 3.50–3.65 (m, 2H), 4.25–4.35 (m, 1H), 4.40–4.45 (m, 1H), 4.65–
4.85 (m, 2H), 7.72–7.82 (m, 2H), 8.25 (t, 1H, J = 7.72 Hz), 8.50 (d,
1H, J = 6.21 Hz). 13C NMR (75 MHz, CH3OD): d 33.09, 58.72, 70.31,
74.02, 125.52, 129.18, 144.75, 146.71, 154.10.
was performed using silica gel (particle size 30–63 lm). Chroma-
tography solvents were distilled prior to use. 1H and 13C NMR spec-
tra were recorded at 300 MHz for 1H and 75 MHz for 13C. Chemical
shifts are reported relative to TMS, calibrated with CDCl3, CH3OD,
or D2O. Coupling constants J are in Hz and are reported as d (dou-
blet), t (triplet), q (quartet). Melting points were determined on a
Hot Kofler bench and are uncorrected.
4.2. Experimental procedures and data
4.2.4. (2S,3R,9aR)-Octahydro-1H-quinolizine-2,3-diol 4
A solution of 2 and 3 (ratio 1:1, 153.8 mg, 0.587 mmol) in eth-
anol (16 mL) was stirred at room temperature in the presence of
PtO2ꢃH2O (20 mg, 10 mol %) under an atmospheric pressure of
hydrogen. After 22 h under stirring, the solution was filtrated
through a Celite pad, which was washed with MeOH, and the fil-
trate was evaporated in vacuo. The resulting yellow oil (160 mg)
was redissolved with a mixture of CH2Cl2/MeOH/Et3N (5/5/2,
12 mL) and the solution was stirred for 20 min at room tempera-
ture. Then, the solution was evaporated to dryness to give an or-
ange oil. After purification by chromatography on silica gel using
[CH2Cl2/MeOH/NH3 5/1/0.12] as eluent, 4 was obtained as a white
4.2.1. (2S,3R)-3,4-O-Isopropylidene-1-(20-pyridyl)-2,3,4-
trihydroxy-butane 1a and (2R,3R)-3,4-O-isopropylidene-1-
(20-pyridyl)-2,3,4 trihydroxy-butane 1b
To a solution of freshly distilled 2-picoline (0.60 mL, 6.41 mmol)
in dry THF (30 mL) at ꢀ78 °C was added under nitrogen n-BuLi
(4.40 mL, 7.05 mmol, 1.6 M solution in hexane). The reaction
mixture was stirred at ꢀ78 °C for 15 min and the temperature
was allowed to rise gradually to ꢀ45 °C over 1 h 30 min. Then,
the resulting red solution was cooled to ꢀ78 °C and a solution of
the aldehyde (1 g, 7.69 mmol) in dry THF (5 mL) was added drop-
wise during 15 min. The reaction mixture was stirred at ꢀ78 °C
for 15 h and then the reaction was quenched with a saturated solu-
tion of ammonium chloride (40 mL). After extraction with CH2Cl2
(4 ꢁ 30 mL) and then EtOAc (2 ꢁ 30 mL) the combined organic lay-
ers were dried (Na2SO4), filtrated, and evaporated under reduced
pressure to give an orange oil. Flash chromatography on silica gel
using [pet ether/EtOAc 2/1] as the eluent afforded first 1a
(470 mg, 36%) and then 1b (160 mg, 12%) as a pale yellow oil. Data
solid (43 mg, 0.251 mmol, 42%). ½a D20
¼ ꢀ21 (c 0.52, CH3OH). Mp:
ꢂ
31 °C. 1H NMR (300 MHz, CH3OD): d 1.26–1.41 (m, 2H, H-9, H-8),
1.52–1.74 (m, 4H, H-7, H-1), 1.76–1.88 (m, 1H, H-9a), 1.90–2.04
(m, 1H, H-6), 2.19 (dd, 1H, H-4ax, J = 1.70 Hz, J = 12.62 Hz), 2.72–
2.82 (m, 1H, H-6), 2.89 (dd, 1H, H-4eq, J = 3.20 Hz, J = 12.62 Hz),
3.51–3.61 (m, 1H, H-2), 3.76–3.82 (m, 1H, H-3). 13C NMR
(75 MHz, CH3OD): d 24.98 (C-8), 26.27 (C-7), 33.55 (C-9), 36.56
(C-1), 56.73 (C-6), 61.39 (C-4), 61.95 (C-9a), 69.47 (C-3), 70.81
(C-2). HRMS: calcd 172.1338, found 172.1347 (MH+).
for 1a: ½a 2D0
ꢂ
¼ þ24 (c 1, CH2Cl2). 1H NMR (300 MHz, CDCl3): d 1.35
(s, 3H), 1.42 (s, 3H), 2.85–2.89 (m, 1H, CH2), 3.15 (dd, 1H,
J = 2.07 Hz, J = 14.26 Hz), 3.90–4.17 (m, 4H), 5.64 (br s, 1H, OH),
7.14–7.23 (m, 2H), 7.64 (dt, 1H, J = 1.89 Hz, J = 7.72 Hz), 8.42–
8.50 (m, 1H). 13C NMR (75 MHz, CDCl3): d 25.44, 26.85, 39.35,
67.26, 72.54, 78.12, 109.35, 121.74, 124.07, 137.02, 148.47,
159.91. HRMS: calcd 224.1287, found 224.1288 (MH+) Data for
4.2.5. (2R,3R)-2-Benzyloxy-3,4-O-isopropylidene-1-(20-pyridyl)-
2,3,4-trihydroxybutane 5
To a solution of 4 (160 mg, 0.71 mmol) in dry THF (15 mL)
under nitrogen, was added cautiously NaH 95% (49.23 mg,
1.95 mmol) at 0 °C. After 1.5 h under stirring at room temperature,
benzyl bromide (0.123 mL, 1.03 mmol) was added dropwise at
0 °C. Then, the resulting mixture was stirred at room temperature
overnight, neutralized with a saturated solution of NaHCO3, and
extracted with CH2Cl2 (4 ꢁ 30 mL) and EtOAc (2 ꢁ 30 mL). The col-
lected organic phases were dried over Na2SO4, and evaporated un-
der reduced pressure. Purification by chromatography on silica gel
of the residue using [pet ether/EtOAc 1/1] as eluent afforded pure
1b: ½a 2D0
ꢂ
¼ ꢀ12 (c 1, CH2Cl2). 1H NMR (300 MHz, CDCl3): d 1.36
(s, 3H), 1.45 (s, 3H), 2.83–3.00 (m, 2H, CH2), 3.86 (dd, 1H, CH2,
J = 6.59 Hz, J = 8.29 Hz), 4.00–4.20 (m, 3H), 4.57 (br s, 1H, OH),
7.11–7.21 (m, 2H), 7.61 (dt, 1H, J = 1.89 Hz, J = 7.72 Hz), 8.43–
8.52 (m, 1H). 13C NMR (75 MHz, CDCl3): d 25.37, 26.59, 39.92,
65.79, 71.63, 78.42, 109.53, 121.77, 124.04, 136.86, 148.88,
159.27. HRMS: calcd 224.1287, found 224.1281 (MH+).
5 as a yellow oil (118 mg, 53%). ½a D20
ꢂ
¼ þ35 (c 1, CH2Cl2), 1H NMR
4.2.2. 2-(2S,3R)-2,3,4-Trihydroxybutyl)pyridinium
tetrafluoroborate 2
Compound 1a (166 mg, 0.74 mmol) was taken up in methanol
(4 mL) and a solution of tetrafluoroboric acid diethyl etherate
(400 MHz, CDCl3): d 1.37 (s, 3H), 1.44 (s, 3H), 2.88–3.02 (m, 2H,
CH2), 3.79–3.86 (m, 1H), 3.95–4.07 (m, 2H), 4.18–4.28 (m, 1H),
4.40 (d, 1H, J = 11.68 Hz), 4.58 (d, 1H, J = 11.68 Hz), 7.05, 7.27 (m,
7H), 7.57 (dt, J = 7.72 Hz, J = 1.70 Hz), 8.48–8.56 (m, 1H). 13C
NMR (75 MHz, CDCl3): d 25.59, 26.62, 40.08, 65.99, 73.16, 78.18,
79.70, 109.48, 121.50, 124.63, 127.48, 127.86, 128.24, 136.23,
138.54, 149.33, 158.75. HRMS: calcd 314.1756, found 314.1759
(MH+).
(98%, 112 lL, 0.81 mmol) was added. After 20 h stirring at room
temperature, solvents were evaporated in vacuo and the residue
was dissolved in H2O, freeze-dried to afford the pyridinium deriv-
ative 2 (192 mg, 95%) as its tetrafluoroborate salt. 1H NMR
(300 MHz, CH3OD): d 3.12 (dd, 1H, J = 8.83 Hz, J = 14.13 Hz), 3.41
(dd, 1H, J = 3.0 Hz, J = 14.13 Hz), 3.46–3.55 (m, 1H), 3.69 (dd, 1H,
J = 5.66 Hz, J = 11.30 Hz), 3.75 (dd, 1H, J = 4.15 Hz, J = 11.30 Hz),
3.86–3.98 (m, 1H), 7.90 (t, 1H, J = 6.97 Hz), 7.99 (d, 1H,
J = 7.91 Hz), 8.45–8.54 (m, 1H), 8.68 (d, 1H, J = 5.46 Hz). 13C NMR
(75 MHz, CH3OD): d 38.14, 64.12, 71.78, 75.61, 126.02, 129.50,
141.82, 147.50, 156.47. HRMS: calcd 184.0974, found 184.0961
(pyridinium M+).
4.2.6. 2-(2R,3S)-3-(Benzyloxy)-2,3,4-trihydroxybutyl)pyridinium
tetrafluoroborate 6
Applying the procedure described for compound 2, acetonide 5
(116 mg, 0.37 mmol) afforded pure triol 6 as a pale yellow oil
(97%). 1H NMR (300 MHz, CH3OD):
d 3.19 (dd, 1H, CH2,
J = 9.60 Hz, J = 13.94 Hz), 3.28–3.39 (m, 1H, CH2), 3.65–3.86 (m,
3H), 3.94–4.05 (m, 1H), 4.25 (d, 1H, J = 11.68 Hz), 4.58 (d, 1H,
J = 11.68 Hz), 6.99–7.24 (m, 5H), 7.78–7.91 (m, 2H), 8.39 (dt,
J = 7.91 Hz, J = 1.51 Hz), 8.48–8.55 (m, 1H). 13C NMR (75 MHz,
CH3OD): d 36.59, 63.60, 74.28, 74.42, 79.55, 126.21, 128.87,
129.41, 129.45, 129.48, 138.78, 141.78, 147.49, 156.04.
4.2.3. (2S,3R)-2,3-Dihydroxy-2,3-dihydro-1H-quinolizidinium
tetrafluoroborate 3
To a solution of 2 (164 mg, 0.605 mmol) and triphenylphos-
phine (173 mg, 0.665 mmol) in anhydrous CH3CN (6 mL) was

2036
T. Tite et al. / Tetrahedron: Asymmetry 21 (2010) 2032–2036
4.2.7. (2S,3S)-2-O-Benzyl-3-hydroxy-3,4-dihydro-1H-quino-
lizidinium tetrafluoroborate 7
Applying the procedure described for compound 3, triol 6
(101.1 mg, 0.28 mmol) purification by chromatography on silica
gel using [CH2Cl2/CH3OH 15/1] as eluent afforded 30 mg of 7 as a
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Carvalho, I. Tetrahedron 2006, 62, 10277; Martin, O. R.; Compain, P. Curr. Top. Med.
Chem. 2003, 3, 541; Goss, P. E.; Reid, C. L.; Bailey, D.; Dennis, J. W. Clin. Cancer Res.
1997, 3, 1077; Jacob, G. S. Curr. Opin. Struct. Biol. 1995, 5, 605; Wrodnigg, T. M.;
Sprenger, F. K. Mini-Rev. Med. Chem 2004, 4, 437; Sun, J. Y.; Zhu, M. Z.; Wang, S.
W.; Miao, S.; Xie, Y. H.; Wang, J. B. Phytomedicine 2007, 14, 353.
pale yellow oil (31%).
½
a 2D0
ꢂ
¼ ꢀ16 (c 2.3, CH3OH). 1H NMR
(300 MHz, CH3OD): d 3.47 (dd, 1H, CH2, J = 3.20 Hz, J = 18.46 Hz),
3.67 (dd, 1H, CH2, J = 4.71 Hz, J = 18.46 Hz), 4.00–4.06 (m, 1H),
4.40–4.48 (m, 1H), 4.61 (dd, 1H, CH2, J = 3.01 Hz, J = 14.51 Hz),
4.71 (s, 2H, CH2), 4.88 (dd, 1H, CH2, J = 2.93 Hz, J = 14.51 Hz),
7.25–7.28 (m, 5H), 7.84–7.98 (m, 2H), 8.42 (dt, J = 7.91 Hz,
J = 1.32 Hz), 8.74 (d, 1H, J = 6.40 Hz). 13C NMR (75 MHz, CH3OD):
d
32.27, 59.42, 65.81, 72.31, 73.59, 126.63, 128.99, 129.50,
130.38, 139.08, 146.00, 146.47, 155.52. HRMS: calcd 256.1338,
found 256.1336 (pyridinium cation M+).
4.2.8. (2R,3R,9aS)-2-(Benzyloxy)-octahydro-1H-quinolizin-3-ol
8a
5. Murphy, P. V.; Cronin, L. Org. Lett. 2005, 7, 2691; Furukubo, S.; Moriyama, N.;
Onomura, O.; Matsamura, Y. Tetrahedron Lett. 2004, 45, 8177; Abrams, J. N.;
Satheesh Babu, R.; Guo, H.; Le, D.; Le, J.; Osbourn, J. M.; O’Doherty, G. A. J. Org.
Chem. 2008, 73, 1935; Pyne, S. G. Curr. Org. Synth. 2005, 2, 39; Romero, A.;
Wong, C.-H. J. Org. Chem. 2000, 65, 8264; Winkler, D. A.; Holan, G. J. Med. Chem.
1989, 32, 2084; Alam, M. A.; Kumar, A.; Vankar, Y. D. Eur. J. Org. Chem. 2008,
4972.
Applying the same procedure described for compound 4, the
reduction of the pyridinium salt 7 (18.9 mg, 0.055 mmol) with
1.4 mg of PtO2 followed by neutralisation of the crude material
afforded a pale yellow oil. Purification by chromatography on
silica gel using successively as the eluents [CH2Cl2/MeOH 15/
1], then [CH2Cl2/MeOH 12/1] and finally [CH2Cl2/MeOH 9/1],
afforded first compound 8a as a pale yellow oil (6 mg, 40%),
then a mixture of 8a and 8b (3 mg, 20%). 1H NMR (300 MHz,
CH3OD): d 1.10–1.37 (m, 5H, H-1, H-7, H-8, H-9), 1.42–1.80
(m, 2H, H-8, H-7), 1.81–1.94 (m, 1H, H-9a), 1.95–2.40 (m, 3H,
H-6, H-4, H-1), 2.81–2.96 (m, 2H, H-6, H-4), 3.20–3.27 (m, 1H,
H-2), 3.60–3.71 (m, 1H, H-3), 4.67 (br s, 2H, CH2), 7.21–7.42
(m, 5H). 13C NMR (75 MHz, CH3OD): d 24.81, 26.06, 33.19,
56.58, 61.77, 61.82, 72.01, 72.01, 72.65, 81.99, 128.53, 128.90,
129.27, 140.24.
6. Hamana, H.; Ikota, N.; Ganem, B. J. Org. Chem. 1987, 52, 5492.
7. Kumari, N.; Vankar, Y. D. Org. Biomol. Chem. 2009, 7, 2104–2109;
Chandrasekhar, B.; Venkateswara Rao, B.; Veera Mohana Rao, K.; Jagadeesh,
B. Tetrahedron: Asymmetry 2009, 20, 1217; Lesma, G.; Colombo, A.; Landoni, N.;
Sacchetti, A.; Silvani, A. Tetrahedron: Asymmetry 2007, 18, 1948; Katoh, M.;
Mizutani, H.; Honda, T. Tetrahedron Lett. 2005, 46, 5161; Ma, S. M.; Ni, B. K.;
Liang, Z. Q. J. Org. Chem. 2004, 69, 6305; Skaanderup, P. R.; Madsen, R. J. Org.
Chem. 2003, 68, 2115; Lesma, G.; Crippa, S.; Danieli, B.; Passarella, D.; Sacchetti,
A.; Silvani, A.; Virdis, A. Tetrahedron 2004, 60, 6437; Randl, S.; Blechert, S. J. Org.
Chem. 2003, 68, 8879; Wijdeven, M. A.; Botman, P. N. M.; Wijtmans, R.;
Schoemaker, H. E.; Rutjes, F. P. J. T.; Blaauw, R. H. Org. Lett. 2005, 7, 4005;
Kinderman, S. S.; de Gelder, R.; van Maarseveen, J. H.; Schoemaker, H. E.;
Hiemstra, H.; Rutjes, F. P. J. T. J. Am. Chem. Soc. 2004, 126, 4100; Voigtmann, U.;
Blechert, S. Org. Lett. 2000, 2, 3971; Overkleeft, H. S.; Bruggeman, P.; Pandit, U.
K. Tetrahedron Lett. 1998, 39, 3869; Voigtmann, U.; Dhavale, D. D.; Jachak, S. M.;
Karche, N. P.; Trombini, C. Synlett 2004, 9, 1549; Verhelst, S. H. L.; Martinez, B.
P.; Timmer, M. S. M.; Lodder, G.; van der Marel, G. A.; Overkleeft, H. S.; van
Boom, J. H. J. Org. Chem. 2003, 68, 9598.
8. Pandey, G.; Grahacharya, D.; Shashidhara, K. S.; Khan, M. I.; Puranik, V. G. Org.
Biomol. Chem. 2009, 7, 3303; Gradnig, G.; Berger, A.; Grassberger, V.; Stutz, A. E.
Tetrahedron Lett. 1991, 32, 4889; for a double-intramolecular N-alkylation
using a azide group see: Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61,
5537; Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 5546.
9. Barluenga, J.; Mateos, C.; Aznar, F.; Valdés, C. Org. Lett. 2002, 4, 1971; Herczegh,
P.; Kovács, I.; Szilágyi, L.; Sztaricskai, F.; Berecibar, A.; Riche, C.; Chiaroni, A.;
Olesker, A.; Lukacs, G. Tetrahedron 1995, 51, 2969.
10. Liu, P. S.; Rogers, R. S.; Kang, M. S.; Sunkara, P. S. Tetrahedron Lett. 1991, 32, 5853.
11. From nitrone see: Dhavale, D. D.; Jachak, S. M.; Karche, N. P.; Trombini, C.
Tetrahedron 2004, 60, 3009; Gebarowski, P.; Sas, W. Chem. Commun. 2001, 915;
Alcaide, B.; Pardo, C.; Saez, E. Synlett 2002, 85–88; Broggini, G.; La Rosa, C.;
Pilati, T.; Terraneo, A.; Zecchi, G. Tetrahedron 2001, 57, 8323; from sulfone see:
Carretero, J. C.; Arrayas, R. G.; de Gracia, I. S. Tetrahedron Lett. 1997, 38, 8537.
12. Zou, W.; Sandbhor, M.; Bhasin, M. J. Org. Chem. 2007, 72, 1226.
13. For syntheses and pharmacological activities see: Ajish Kumar, K. S.; Chaudhari,
V. D.; Dhavale, D. D. Org. Biomol. Chem. 2008, 6, 703; Pandey, G.; Grahacharya, D.;
Shashidhara, K. S.; Khan, M. I.; Puranik, V. G. Org. Biomol. Chem. 2009, 7, 3303;
Kumari, N.; Vankar, Y. D. Org. Biomol. Chem. 2009, 7, 2104; Schaller, C.; Vogel, P.
Helv. Chim. Acta 2000, 83, 193; Marquart, A. L.; Podlogar, B. L.; Huber, E. W.;
Demeter, D. A.; Peet, N. P.; Weintraub, H. J. R.; Angelastro, M. R. J. Org. Chem. 1994,
59, 2092; Vanecko, J. A.; West, F. G. Org. Lett. 2002, 4, 2813.
4.2.9. (2R,3R,9aS)-Octahydro-1H-quinolizin-2,3-diol 9a
A solution of 8a (6.5 mg, 0.024 mmol) in methanol (2 mL) was
stirred at room temperature in the presence of PdCl2 (1.5 mg) un-
der an atmospheric pressure of hydrogen. After 3 h under stirring,
the solution was filtrated through a Celite pad, which was washed
with MeOH, and the filtrate evaporated in vacuo, affording a clear
oil (4 mg, 97%). ½a D20
ꢂ
¼ ꢀ6:5 (c 0.38, CH3OH). 1H NMR (300 MHz,
CH3OD): d 1.10–2.11 (m, 11H), 2.79–2.91 (m, 2H, H-6, H-4),
3.33–3.39 (m, 1H, H-2), 3.42–3.52 (m, 1H, H-3). 13C NMR
(75 MHz, CH3OD): d 24.92, 26.17, 33.27, 40.74, 56.65, 61.87,
61.89, 73.07, 74.41. HRMS: calcd 172.1338, found 172.1332
(MH+).
Acknowledgments
We are grateful to the Region Haute-Normandie (pôle Chimie
Biologie Santé/CRUNCh network) for generous financial support
and a post-doctoral financial support for Tony Tite. The INSA Rouen
is also gratefully acknowledged for financial support to F. Jacquelin.
Pr. A. Vasella (ETH, Zürich) is also gratefully acknowledged for very
interesting discussions concerning indolizidines and quinoli-
zidines.
14. Azzouz, R.; Fruit, C.; Bischoff, L.; Marsais, F. J. Org. Chem. 2008, 73, 1154; Petit,
S.; Azzouz, R.; Fruit, C.; Bischoff, L.; Marsais, F. Tetrahedron Lett. 2008, 49, 3663.
15. Sugisaki, C.-H.; Ruland, Y.; Baltas, M. Eur. J. Org. Chem. 2003, 672–676.
16. Determined by 1H NMR and HPLC of the crude material.