Synthetic study of matrine-type alkaloids: Stereoselective construction of the AB rings of the quinolizidine skeleton

Article abstract of DOI:10.1055/s-0033-1340179

A new method has been developed for the stereoselective construction of the AB rings of the quinolizidine skeleton of ?matrine-type alkaloids with a cis-cis stereochemistry. The key features of this method involve: (i)? construction of the quinolizidine by reduction of an acylpyridinium cation; and (ii)? late-stage introduction of methoxypyridine by sequential Stille coupling and diastereo?selective hydrogenation reactions. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340179

LETTER
▌653
lSetyternthetic Study of Matrine-Type Alkaloids: Stereoselective Construction of
the AB Rings of the Quinolizidine Skeleton
Towards Matrine-Type Alkaloids
Chihiro Tsukano, Atsuko Oimura, Iderbat Enkhtaivan, Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan
Fax +81(75)7534569; E-mail: takemoto@pharm.kyoto-u.ac.jp
Received: 12.12.2013; Accepted after revision: 06.01.2014
O
O
O
A
O
Abstract: A new method has been developed for the stereoselective
construction of the AB rings of the quinolizidine skeleton of
matrine-type alkaloids with a cis-cis stereochemistry. The key fea-
tures of this method involve: (i) construction of the quinolizidine by
reduction of an acylpyridinium cation; and (ii) late-stage introduc-
tion of methoxypyridine by sequential Stille coupling and diastereo-
selective hydrogenation reactions.
H
H
H
D
B
N
H
N
H
N
C
N
H
H
H
H
H
H
H
N+
O–
N
N
N
(–)-leontine
[(–)-allomatrine]
matrine-type alkaloids (+)-matrine matrine N-oxide
Key words: quinolizidines, stereoselective synthesis, alkaloids,
matrine, pyridines
O
O
O
O
H
H
N
N
H
N
H
N
H
H
H
H
H
H
H
H
H
H
Matrine is representative of the alkaloids derived from
Sophora flavescens Ait., and has been used for many years
as a traditional Chinese medicine (KuShen).1 The struc-
ture of matrine is characterized by a tetracyclic core con-
sisting of two quinolizidine moieties and four contiguous
stereogenic centers (Figure 1).2 To date, over 30 matrine-
type alkaloids have been reported, and these compounds
typically only differ from each other in terms of their
oxidation level and relative stereochemistry.3 Alkaloids
belonging to this structural class also exhibit a variety
of biological properties, including antitumor,4a,e anti-
viral,4b,c and anti-inflammatory4d activities. Because of
their interesting and diverse biological activities, these
compounds have attracted considerable attention from
medicinal chemists.
N
N
N
N
isosophoramine
sophocarpine
sophoramine
lehmannine
cis-cis
trans-trans
Figure 1 Matrine and related quinolizidine alkaloids
cause the resulting products could be readily derivatized.
With this in mind, we became interested in investigating
the application of our method to the stereoselective syn-
thesis of the AB rings of matrine-type alkaloids with cis-
cis stereochemistry.
Retrosynthetically, alcohol 1 was set as a suitable synthet-
ic target, because it was envisaged that this compound
would provide comprehensive access to matrine and sev-
eral related alkaloids through cyclization of the C ring and
adjustment of the oxidation levels (Scheme 1). The cis-cis
stereochemistry of 1 could be successfully installed by hy-
drogenation of 2 or 5. Compound 2 could be accessed
through the introduction of a C1 unit to the quinolizidine
core of compound 3, which could be constructed by re-
duction of the acylpyridinium cation derived from carbox-
ylic acid 4 (route a). Alternatively, the addition of a
pyridyl moiety to compound 6, which could be derived
from 7, could also be used to provide access alcohol 1
(route b). Herein, we report the development of a stereo-
selective synthesis of the key cis-cis intermediate 1 based
on our reductive cyclization strategy by examining both
possibilities.
Although there are many congeners in this structural
class, only four racemic total syntheses and three semi-
syntheses have been reported to date, including those of
matrine,6–8,9a leontine,6a sophoramine,9b and isosophora-
mine.9c,10 These syntheses revealed that stereoselective
construction of the tetracyclic core of these compounds
represents a significant synthetic challenge. Brown et al.11
recently reported the synthesis of (+)-allomatrine, where-
by the tetracyclic core was elegantly constructed in a dia-
stereoselective manner by using an imino-aldol reaction
and N-acyliminium cyclization. However, methods for
the stereoselective synthesis of tetracyclic cores with a
cis-cis configuration, such as those found in sophoramine
and matrine, remain scarce. We recently reported a proce-
dure for the synthesis of quinolizidines by the reduction of
acylpyridinium cations under mild conditions.5 It was en-
visaged that this method could be used as a powerful tool
for the concise synthesis of quinolizidine alkaloids, be-
To begin, we examined route a, which required the chal-
lenging selective reduction of one of two pyridines. The
synthesis of the cyclization precursor 4 started with the
Stille coupling of 2-iodopicolinate methyl ester 812 and
pyridylstannane 913 by using catalytic amounts of
SYNLETT 2014, 25, 0653–0656
Advanced online publication: 10.02.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340179; Art ID: ST-2013-U1135-L
© Georg Thieme Verlag Stuttgart · New York

654
C. Tsukano et al.
LETTER
MeO
BnO
MeO
MeO
HO
I
matrine
D
B
N
H
N
N
a
b
N
H
MeO2C
sophocarpine
sophoramine
lehmannine
b
H
H
MeO
N
SnBu3
MeO2C
N
matrine N-oxide
A
8
9
N
N
10
a
1
5
O
O
MeO
MeO
O
MeO
O
MeO
MeO
O
N
N
N
N
N
N
O
c–e
f
N
MeO2C
H
N
BnO
H
H
H
H
MeO
MeO
P
HO2C
N
N
N
O
3
4
O
11
2
3
6
O
O
O
cyclization via
reduction of
acylpyridinium
cations
MeO
O
Ar
N
H
g
H
H
MeO
O
N
O
BnO
H
O
N
N
O
N
H
NOE
12
O
N
CO2H
7
Scheme 2 Synthesis and cyclization of bipyridine 4. Reagents and
conditions: (a) Pd(PPh3)4, CuI, DMF, 110 °C, 74%; (b) n-BuLi,
MeP(O)(OMe)2, THF, –78 °C; (c) t-BuOK, EtO2CCHO, DME,
–20 °C, 57% (two steps); (d) H2, Pd/C, EtOAc; (e) LiOH, THF–H2O,
88% (two steps); (f) Ghosez reagent, 4 Å MS then Hantzsch ester,
DCE, 36%; (g) H2, Pd/C, EtOH, 70%.
HO2C
4
Scheme 1 Retrosynthetic analysis of matrine-type alkaloids
Pd(PPh3)4 and CuI (Scheme 2). CuI was essential for the
production of bipyridine 10.14 Compound 10 was convert-
ed into carboxylic acid 4 by the Horner–Wadsworth–
Emmons reaction of 11 with ethyl glyoxylate, followed by
sequential hydrogenation and hydrolysis reactions, which
gave the cyclization precursor 4 in 50% yield from the
coupling product 10.15 The quinolizidine skeleton was
constructed by reduction of the acylpyridinium cation in-
termediate, which was produced by the activation of one
of the two pyridine rings of 4. Treatment of 4 with Gho-
sez’s reagent followed by the Hantzsch ester gave the de-
sired product 3 in 36% yield. This low yield was attributed
to unfavorable nucleophilic attack of the nitrogen of the
second pyridine on the acid chloride generated in situ. Hy-
drogenation of the cyclized product 3 proceeded stereose-
lectively to give the desired compound 12 as a single
isomer. The newly generated stereochemistry was con-
firmed by NOE experiments. Although ketone 12 was ac-
cessed in a stereoselective manner, quinolizidine ring
formation was low-yielding, and we decided to focus our
efforts on the second route for accessing the cis-cis inter-
mediate 1.
boxylic acid 7 in 65% yield over two steps.5,17 Compound
7 was then successfully converted into 6 by treatment with
Ghosez’s reagent followed by the Hantzsch ester.18 Com-
pound 6 was found to be unstable, and was immediately
hydrogenated over Pd/C to give ketone 16, the stereo-
chemistry of which was confirmed by NOE experiments
and the coupling constants in its 1H NMR spectrum (Fig-
ure 2). The second route performed more effectively than
the first in terms of both the number of steps required and
the yield of the key cyclization step.
BnO
RO
O
O
Br
b or c, d
e
O
O
+
N
N
CO2H
15
7
13 R = H
a
14 R = Bn
BnO
BnO
O
O
H
N
f
8
The second route started from 2-bromo-3-hydroxymeth-
ylpyridine (13),16 which was converted into the corre-
sponding benzyl ether 14 by using standard techniques
(Scheme 3). Subsequent treatment of 14 with n-butyllith-
ium followed by addition of succinic anhydride (15) gave
carboxylic acid 7, albeit in low yield (45%). To improve
the yield and reproducibility of this step, compound 14
was first converted into the 2-TMS-pyridine species,
which was treated with succinic anhydride 15 to give car-
N
6
16
O
O
Scheme 3 Synthesis of quinolizidine 16. Reagents and conditions:
(a) BnBr, NaH, DMF, 68%; (b) n-BuLi then succinic anhydride 15,
Et2O, –78 °C to r.t., 45%; (c) n-BuLi, TMSCl, Et2O, –78 °C to r.t.;
(d) 15, DCE, 100 °C, 65% (two steps); (e) (i) Ghosez reagent, 4 Å
MS; (ii) Hantzsch ester, DCE, 0°C to r.t., 61%; (f) H2, Pd/C, EtOH,
53%.
Synlett 2014, 25, 653–656
© Georg Thieme Verlag Stuttgart · New York

LETTER
Towards Matrine-Type Alkaloids
655
Figure 2 1H NMR coupling constant and NOESY experiments with
compound 16 (left) and a stable conformation calculated by Spartan
at the B3LYP/6-31+G(d) level of theory (DFT) (right)
Figure 3 Regioselectivity of hydrogenation of compound 5 (left), a
stable conformation calculated by Spartan at the B3LYP/6-31+G(d)
level of theory (DFT) (middle), NOESY experiments of compound 19
(right).
We then investigated the stereoselective introduction of
the pyridyl moiety into compound 16. Preliminary studies
revealed that the structurally related ketone 12 was readily
enolized rather than attacked by nucleophiles such as
TMSCH2Li and Ph3P=CH2.19 Treatment of 16 with NaH-
MDS and Comins’ reagent gave enol triflate 17 together
with a significant amount of its regioisomer 18 in a com-
bined yield of 61% (17/18 = 1.3:1; Scheme 4). A variety
of different bases (i.e., LDA, LiTMP, TrLi, KHMDS,
NaHMDS, LiHMDS, Et3N) and triflating reagents (i.e.,
Tf2O, Tf2NPh, and Comins’ reagent20) were evaluated for
this transformation, but none of these combinations led to
an improvement in the low regioselectivity. Pleasingly, it
was possible to separate these two compounds by silica
gel column chromatography, and this allowed for suffi-
cient quantities of the enol triflate 17 to be obtained for the
subsequent Stille coupling. Following an extensive inves-
tigation of the conditions required for the coupling of 17
with 9 using several copper salts such as CuTC,21
CuBr·SMe2, and CuDPP,22 it was found that the reaction
proceeded smoothly in the presence of catalytic Pd(PPh3)4
with copper(I) diphenylphosphinate (CuDPP) and LiCl in
THF at 50 °C to give the coupling product 5 in good yield.
Hydrogenation of 5 gave compound 19 as a single isomer,
because the α-face was shielded by the hydroxymethyl
group (Figure 3, left). The newly generated stereochemis-
try was confirmed by NOE experiments (Figure 3, right).
Finally, reduction with LiAlH4 gave the common interme-
diate 1 with the required cis-cis stereochemistry.23
In summary, we have developed a concise synthesis of
quinolizidine 1 in a stereoselective manner. The key fea-
tures of this method include: (i) construction of the quino-
lizidine ring by reduction of an acylpyridinium cation; and
(ii) late-stage introduction of a pyridyl group by sequen-
tial Stille coupling and hydrogenation reactions. This syn-
thetic strategy represents a reasonable technique for the
stereoselective construction of quinolizidine rings with
cis-cis stereochemistry. The synthesis of matrine-type
alkaloids such as sophoramine, sophocarpine, and matrine
from quinolizidine 1 through construction of the C ring
and subsequent adjustment of the oxidation levels is un-
derway in our laboratory.
Acknowledgment
This work was supported by a Grant-in-Aid for Young Scientists
(B) (C.T.) from the Japan Society for the Promotion of Science.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
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BnO
BnO
BnO
OTf
O
O
OTf
O
H
N
H
N
a
b
8
+
MeO
N
N
16
17
MeO
HO
18
O
MeO
BnO
Bu3Sn
MeO
9
N
H
N
HO
H
N
H
H
c
d
H
N
N
N
5
19
O
1
O
Scheme 4 Synthesis of common intermediate 1. Reagents and conditions: (a) NaHMDS, Comins reagent, THF, –78 to 0 °C, 61%,
(17/18 = 1.3:1); (b) 9, Pd(PPh3)4, CuDPP, LiCl, THF, 50 °C, 67%; (c) Pd/C, H2 (5 atm), EtOH, 70 °C, 65%; (d) LiAlH4, THF, 50 °C, 80%.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 653–656

656
C. Tsukano et al.
LETTER
Alkaloids; Vol. 31; Brossi, A., Ed.; Academic Press: New
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in CH2Cl2 (50 mL) at 0 °C was added Ghosez reagent (1.00
mL, 7.41 mmol). The mixture was stirred at 0 °C for 30 min,
then Hantzsch ester (5.58 g, 22.0 mmol) was added. After
stirring at room temperature for 2 h, the mixture was filtered
and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (Et2O–
toluene, 2–3%) to afford dihydropyridine 6 (1.28 g, 4.52
mmol, 61%) as a solid. IR (ATR): 2979, 2721, 1689, 1235,
1089, 893 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.35–7.25
(m, 5 H), 7.08 (dt, J = 8.0, 1.7 Hz, 1 H), 5.13 (dt, J = 8.3,
3.5 Hz, 1 H), 4.60–4.57 (m, 2 H), 4.49 (s, 2 H), 3.19–3.17
(m, 2 H), 2.74 (ddd, J = 8.3, 6.0, 1.5 Hz, 2 H), 2.67 (ddd,
J = 8.3, 6.0, 1.5 Hz, 2 H). 13C NMR (126 MHz, CDCl3): δ =
192.3, 165.3, 138.1, 132.8, 128.9, 128.5, 127.8, 127.7,
122.7, 108.1, 73.0, 69.7, 35.9, 29.7, 25.9; MS (FAB): m/z =
284 [M + H]+. HRMS (FAB): m/z [M + H]+ calcd for
C17H18NO3: 284.1287; found: 284.1296.
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(23) Synthesis of Quinolizidine 1: To a solution of alcohol 19
(11.3 mg, 0.0390 mmol) in THF (1 mL) was added dropwise
a solution of LiAlH4 (2.2 mg, 0.058 mmol, 1.5 equiv) in
anhydrous THF (0.6 mL) at 0 °C under argon, and the
resulting mixture was stirred at 50 °C for 30 min. After
careful hydrolysis with 3 M aq NaOH (1 mL), EtOAc
(1 mL) was added and the organic layer was separated. The
aqueous layer was extracted with EtOAc (2 mL) and the
combined organic layers were dried over Na2SO4, filtered,
and concentrated. The crude residue was purified by column
chromatography (CHCl3–MeOH, 20:1) to give alcohol 1
(10.8 mg, 0.035 mmol, 80%) as an oil. IR (ATR): 3356,
2928, 2857, 2754, 2683, 1578, 1466 cm–1. 1H NMR (500
MHz, CDCl3): δ = 7.47 (dd, J = 8.0, 7.4 Hz, 1 H), 7.00 (d, J
= 7.4 Hz, 1 H), 6.57 (d, J = 8.0 Hz, 1 H), 3.91 (s, 3 H), 3.65–
3.54 (m, 2 H), 3.46 (dd, J = 11.2, 3.0 Hz, 1 H), 3.20 (dd,
J = 8.5, 6.3, 4.0 Hz, 1 H), 2.98 (br d, J = 11.7 Hz, 1 H),
2.87–2.83 (m, 2 H), 2.30–2.14 (m, 3 H), 2.10–2.02 (m, 2 H),
1.86–1.81 (m, 2 H), 1.59–1.43 (m, 3 H). 13C NMR (126
MHz, CDCl3): δ = 163.1, 160.8, 138.3, 116.2, 107.7, 67.2,
64.9, 57.7, 53.3, 45.2, 37.9, 31.9, 30.7, 29.6, 21.7, 21.6. MS
(FAB): m/z = 277.2 [M + H]+. HRMS (FAB): m/z [M + H]+
calcd for C16H25N2O2: 277.1911; found: 277.1913.
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(18) Synthesis of 1,4-Dihydropyridine 6: To a solution of
carboxylic acid 7 (2.20 g, 7.34 mmol) and MS (4 Å; ca. 5 g)
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