A Concise Total Synthesis of (±)-Mesembrine

Article abstract of DOI:10.1055/s-0036-1591547

A concise total synthesis of (±)-mesembrine has been successfully accomplished in seven steps and 24% overall yield from commercially available 3-ethoxy-2-cyclohexen-1-one. Central to the assembly of the skeleton of mesembrine are a Johnson-Claisen rearra

Full text of DOI:10.1055/s-0036-1591547

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
H. Kim et al.
Letter
Synlett
A Concise Total Synthesis of (±)-Mesembrine
Hyoungsu Kima
Hosam Choib
Kiyoun Lee*b
MeO
OH
O
amidation/aza-
conjugate
addition
MeO
MeO
Johnson−Claisen
MeO
rearrangement
MeO
OEt
H
N
a College of Pharmacy and Research Institute of Pharmaceuti-
Me
O
MeO
cal Science and Technology(RIPST), Ajou University, Suwon
16499, R. of Korea
b Department of Chemistry, The Catholic University of Korea,
Bucheon 14662, R. of Korea
mesembrine
kiyoun@catholic.ac.kr
Received: 02.01.2018
Accepted after revision: 28.01.2018
Published online: 16.02.2018
N
Me
OH
H
MeO
MeO
HO
DOI: 10.1055/s-0036-1591547; Art ID: st-2018-u0001-l
H
O
N
Abstract A concise total synthesis of (±)-mesembrine has been suc-
cessfully accomplished in seven steps and 24% overall yield from com-
mercially available 3-ethoxy-2-cyclohexen-1-one. Central to the assem-
H
OH
Morphine
Sceletium A-4
Mesembrine (1)
Maritidine
OMe
bly of the skeleton of mesembrine are
a
Johnson–Claisen
N
rearrangement for the formation of the benzylic quaternary stereocen-
ter and direct allylic oxidation to generate the substrate for the amida-
tion/transannular aza-conjugate addition reaction.
H
Me
MeO
MeO
N
O
O
H
H
O
N
Me
Key words mesembrine, natural products, total synthesis, allylic
transfer, benzylic quaternary stereogenic center, 3a-(aryl)octahydro-
indole.
OH
Pretazettine
OMe
O
Me
MeO
MeO
Mesembrine (1, Figure 1) was originally isolated from
the South African plant Sceletium Tortuosum.1 While Bo-
dendorf and Krieger reported the initial structural elucida-
tion of mesembrine in 1957,2 three years later, the com-
plete structure, including absolute configuration, was es-
tablished by Popelak and co-workers through degradation
and synthetic methods.3 Since its isolation and structural
elucidation, mesembrine has attracted strong interest from
many chemists and biologists due to its intriguing structur-
al features and therapeutic potential. Mesembrine has been
known to bind to the 5-hydroxytryptamine (5-HT) trans-
porter to potently inhibit 5-HT uptake (IC50 27 nM).4 This
has led to mesembrine being viewed as a promising lead in
many different medicinal applications, including antianxi-
ety and antiaddiction treatment.5 Structurally, mesembrine
is an alkaloid that possesses a 3a-(aryl)octahydroindole
core structure with a synthetically challenging quaternary
benzylic carbon. To address this challenge, great emphasis
has been placed on synthetic strategies that provide reliable
and efficient access to the benzylic quaternary stereocenter
motifs.6 Among those strategies, the Claisen [3,3]-sigma-
tropic rearrangement7,8 has been recognized as one of the
most useful approaches to produce quaternary all-carbon-
substituted stereocenters and has been extensively investi-
gated by Chida and co-workers.9
N
O
H
N
Me
OH
Galanthamine
Figure 1 Natural products containing benzylic quarternary stereocenter
Mesembrine’s interesting biological profile and unique
structural features have made its synthesis the subject of
extensive studies over the last half century. Since the first
racemic total synthesis by Shamma and Rodriguez
in 196510 and the first optically active form of unnatural
(+)-mesembrine by Yamada and co-workers in 1971,11
more than 40 total and formal syntheses of mesembrine
have been reported.12 Herein, we report a remarkably con-
cise total synthesis of (±)-mesembrine in only seven steps
from the commercially available 3-ethoxy-2-cyclohexen-1-
one (6).
In the current report, mesembrine (1) was envisioned to
arise via a late-stage amidation/lactamization by utilizing
an aza-conjugate addition to its corresponding ester 4 and
the subsequent reduction of the resulting lactam 2 (Scheme
1). The central feature of this approach is the direct forma-
tion of enone 4 via an allylic oxidation that would permit
rapid assembly of the mesembrine skeleton through the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
H. Kim et al.
Letter
Synlett
tandem amidation/transannular aza-conjugate addition
reaction sequence. We envisioned that ester 3 could be se-
cured from allylic transfer of alcohol 5 through either Refor-
matsky reaction13 of α-halo esters or the Claisen [3,3]-sigma-
tropic rearrangement. Further analysis indicated that 5
should be derived from the known condensation of the
lithioveratrole 7 with 3-ethoxy-2-cyclohexen-1-one (6).14
Li
O
MeO
MeO
DIBAL-H
toluene
−78 °C, 20 min
OEt
7
MeO
MeO
−78 °C, 1 h
then HCl
70%
87%
6
10
O
O
OH
OR
O
BzCl, Et3N
CH2Cl2
MeO
MeO
MeO
H
MeO
MeO
MeO
H
0 to 25 °C
75%
N
N
Me
Me
MeO
MeO
5
8, R = COPh
mesembrine (1)
2
O
amidation/aza-conjugate
addition
MeO
MeO
various Cu cat.
BrZn CO2Et
O
MeO
MeO
MeO
MeO
OEt
8
X
3
O
OEt
OEt
3
Scheme 2 Attempts on Reformatsky-type SN2′ displacement
O
O
4
allylic
transfer
the key benzylic quaternary stereocenter by way of an
organozinc addition proved unsuccessful despite extensive
experimentation.
Li
OH
MeO
MeO
OEt
Ultimately, the Johnson–Claisen rearrangement exten-
sively investigated by Chida and co-workers was employed
because of its great utility in efficient and concise forma-
tion of scaffolds bearing chiral arylated quaternary stereo-
centers.9,15,16 Toward this end, allyl alcohol 5 was treated
with triethyl orthoacetate (140 °C, 20 h) in the presence of a
catalytic amount of 2-nitrophenol (3 mol%), which cleanly
proceeded to provide the desired 3 in 73% yield (Table 1, en-
try 2).17
We were also pleased to find that the reaction is easily
performed on a multigram scale without special precau-
tions. Other variant reaction conditions of the Claisen rear-
rangement of 5 by treatment with powdered molecular
sieves (4 Å, Table 1, entry 4, 0%), microwave conditions (Ta-
ble 1, entry 3, 32%), or a catalytic amount of alternative
phenols (Table 1, entries 5–8, 40–55%) proved to be less ef-
fective. Subsequent direct conversion of 3 into the α,β-un-
saturated ketone 4 via an allylic oxidation (CrO3, 3,5-di-
methylpyrazole, CH2Cl2, –10 °C to 25 °C, 20 h, 71%) set the
stage for studies on its cyclization.18 It should be noted that
the direct formation of the enone 4 potentially allows for
shortening of synthetic sequences and ultimately permits a
concise assemblage of the parent mesembrine skeleton.
Although previously reported studies presented an ap-
proach for the formation of the bicyclic keto lactam 2 with a
similar substrate,19 here, we summarized our efforts to im-
prove upon the existing approaches, in order to provide a
more scalable synthesis. It is additionally notable that there
are no spectroscopic data of 2 available in the literature
which led us to establish its structure spectroscopically and
7
MeO
MeO
O
commercially
available 6
5
Scheme 1 Retrosynthetic analysis of mesembrine
As outlined in Scheme 2, our synthetic efforts for
mesembrine (1) commenced with the preparation of allyl
alcohol 5 which served further as a precursor to the benzyl-
ic quaternary stereocenter bearing intermediate 3. Toward
this end, 3-methoxy-2-cyclohexen-1-one (6) was con-
densed with a lithiated 4-bromo-1,2-dimethoxybenzene
(7) followed by workup with aqueous acid yielding the
known enone 10.14 Reduction of the enone carbonyl of 10
upon treatment with DIBAL-H (–78 °C, 20 min) furnished
allyl alcohol 5 in 87% yield.
With allyl alcohol 5 in hand we focused on the forma-
tion of the benzylic quaternary stereogenic center uniquely
embedded in the core structure of the natural product. In
our search for a highly efficient approach involving the qua-
ternary stereogenic center, we initially considered the
Reformatsky-type SN2′ displacement of diethylphosphate,
acetate, benzoate, or pivaloate substrates for the incorpora-
tion of the quaternary carbon (Scheme 2). However, we do
note that simple acylation of the allyl alcohol 5 was found
to be problematic (diethylphosphate, acetate, and pivaloate
of 5) and led to nonproductive elimination of the starting
material presumably because of the presence of two elec-
tron-donating dimethoxy phenyl groups in 5. Although the
desired benzoate 8 was obtained (75%), all efforts to install
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
H. Kim et al.
Letter
Synlett
Table 1 Johnson–Claisen Rearrangement for Formation of 3
O
MeO
MeO
MeO
MeO
CrO3, 3,5-DMP
CH2Cl2
MeO
OH
−10 to 25 °C
OEt
O
OEt
MeO
71%
Claisen
4
3
OEt
MeO
O
O
O
MeO
3
5
MeO
ethylene glycol
TsOH (cat.)
MeNH2, EtOH
MeO
H
Entry
Conditionsa
Time
Yield (%)b
benzene
120 °C, 5 h
82%
60 °C, 3 h
94%
N
Me
1
2
3
4
5
6
7
8
2-nitrophenol
30 h
64
73
32
0
O
2
c
2-nitrophenol, MeC(OEt)3
20 h
O
O
2-nitrophenol, microwaved
4 Å MS (500 w/w%), microwaved
4-nitrophenol
70 min
60 min
32 h
O
MeO
MeO
MeO
a. LiAlH4, THF
reflux, 5 h
MeO
H
H
46
55
40
51
b. 1 M HCl, THF
reflux, 4 h
97%
N
N
Me
Me
4-cyanophenol
32 h
mesembrine (1)
11
O
4-bromo-2-nitrophenol
2,3-dichlorophenol
32 h
Scheme 3 Total synthesis of mesembrine
32 h
a MeC(OEt)3(20 equiv), acid (3 mol%), o-xylene (0.05 M), 140 °C in a sealed
tube.
crucial amidation/transannular aza-conjugate addition re-
action. Continued examination of the asymmetric synthesis
of 1 based on the optically active form of allyl alcohol 6 that
take advantage of the asymmetric reduction of the enone
10 and further studies to examine more concise and effi-
cient synthetic approaches to these types of natural alka-
loids are in progress and will be disclosed in due course.
b Yield of the isolated 3 after purification by column chromatography on
silica gel.
c MeC(OEt)3was used as a solvent (0.05 M).
d Microwave (160 °C, 800 W).
complete the synthesis of mesembrine (1) confirming the
anticipated configuration assignment for the natural prod-
uct (see Supporting Information).
After optimization of the conditions, we were delighted
to find that the treatment of 4 with MeNH2 in EtOH (60 °C,
3 h) proceeded smoothly not only to undergo the desired
amidation but also to promote the intramolecular aza-con-
jugate addition reaction to furnish bicyclic keto lactam 2 in
excellent yield (94%) in a single step. Compound 2 was
transformed into 11 via acetal formation in 82% yield. In
turn, reductive removal of the lactam carbonyl of 11 upon
treatment with LiAlH4 (5 equiv, THF, reflux, 5 h) and its sub-
sequent in situ hydrolysis proceeded smoothly (1 M HCl, re-
flux, 4 h) to furnish the Sceletium alkaloid, (±)-mesembrine
(1) in 97% yield, which proved to be identical in all respects
with reported properties of the natural product (Scheme 3).20
Alternatively, direct removal of the carbonyl by treatment
of 2 with LiAlH4 (10 equiv, THF, reflux, 4 h), subsequent oxi-
dation of the corresponding secondary alcohol to the ketone
also provided 1 (32% overall), albeit in lower overall conver-
sions.
In summary, a concise total synthesis of mesembrine (1)
has been completed in seven steps and 24% overall yield
from commercially available 3-ethoxy-2-cyclohexen-1-one
(6). This marks one of the shortest syntheses of mesem-
brine reported to date. Central to the assembly of the skele-
ton of mesembrine are a Johnson–Claisen rearrangement
for the formation of the benzylic quaternary stereocenter
and direct allylic oxidation to generate the substrate for the
Funding Information
This work was supported by the Basic Science Research Program from
the
National
Research
Foundation
of
Korea
(NRF-
2016R1C1B1008816) funded by the Ministry of Education and the
2017 Research Fund of the Catholic University of Korea.
N
oaitn
a
l
Reseacrh
F
o
u
n
d
oaitn
of
K
o
er
a
N(RF-2
0
1
6
R
1
C
1
B
1
0
0
8
8
1
6)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591547.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(1) Jeffs, P. W. In The Alkaloids;
1
V9o.
l
Rodrigo, R. G. A., Ed.; Chap.; Aca-
demic Press: New York, 1981.
(2) Bodendorf, K.; Krieger, W. Arch. Pharm. 1957, 290, 441.
(3) (a) Popelak, A.; Haack, E.; Lettenbauer, G.; Spingler, H. Natur-
wissenschaften 1960, 47, 156. (b) Popelak, A.; Lettenbauer, G.;
Haack, E.; Spingler, H. Naturwissenschaften 1960, 47, 231.
(4) Harvey, A. L.; Young, L. C.; Viljoen, A. M.; Gericke, N. P. J. Ethno-
pharmacol. 2011, 137, 1124.
(5) (a) Pelletier, S. W. Alkaloids: Chemical and Biological Perspec-
tives;
1
5
V
o.
l
Elsevier Science: Oxford, 2001, 34. (b) Smith, M. T.;
Crouch, N. R.; Gericke, N.; Hirst, M. J. Ethnopharmacol. 1996, 50,
119. (c) Jeffs, P. W.; Archie, W. C.; Hawks, R. L.; Farrier, D. S. J. Am.
Chem. Soc. 1971, 93, 3752.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
H. Kim et al.
Letter
Synlett
(6) For representative reviews on the synthesis of quaternary all-
carbon-sterecenter, see: (a) Martin, S. F. Tetrahedron 1980, 36,
419. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5363. (c) Christoffers, J.; Baro, A. Adv. Synth. Catal.
2005, 347, 1473. (d) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(7) Claisen, L. Ber. Dtsch. Chem. Ges. 1912, 45, 3157.
(8) For recent reviews on the Claisen rearrangement, see:
(a) Martín Castro, A. M. Chem. Rev. 2004, 104, 2939.
(b) Majumdar, K. C.; Nandi, R. K. Tetrahedron 2013, 69, 6921.
(c) Rehbein, J.; Hiersemann, M. Synthesis 2013, 45, 1121.
(9) (a) Chida, N.; Sugihara, K.; Amano, S.; Ogawa, S. J. Chem. Soc.,
Perkin Trans. 1 1997, 0, 275. (b) Bohno, M.; Sugie, K.; Imase, H.;
Yusof, Y. B.; Oishib, T.; Chida, N. Tetrahedron 2007, 63, 6977.
(c) Tanimoto, H.; Kato, T.; Chida, N. Tetrahedron Lett. 2007, 48,
6267. (d) Tanimoto, H.; Saito, R.; Chida, N. Tetrahedron Lett.
2008, 49, 358. (e) Ichiki, M.; Tanimoto, H.; Miwa, S.; Saito, R.;
Sato, T.; Chida, N. Chem. Eur. J. 2013, 19, 264.
nitrophenol (3.65 mg, 0.026 mmol, 3 mol%). After stirring for
20 h at 140 °C, the resulting mixture was cooled to room tem-
perature and quenched with the addition of sat. aq NaHCO3 and
diluted with H2O and EtOAc. The layers were separated, and the
aqueous layer was extracted with EtOAc. The combined organic
layers were washed with sat. aq NaCl, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography (SiO2, 10% EtOAc/hexanes) to provide 3
(193 mg, 73%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ =
6.89–6.83 (m, 2 H), 6.80–6.76 (m, 1 H), 6.13–6.05 (m, 1 H), 5.92
(dt, J = 10.2, 3.5 Hz, 1 H), 3.96 (dq, J = 7.1, 0.7 Hz, 1 H), 3.86 (s, 3
H), 3.84 (s, 3 H), 2.76 (d, J = 14.1 Hz, 1 H), 2.65 (d, J = 14.2 Hz, 1
H), 2.06–1.95 (m, 2 H), 1.95–1.78 (m, 2 H), 1.60–1.47 (m, 1 H),
1.44–1.26 (m, 1 H), 1.08 (t, J = 7.1 Hz, 3 H). 13C NMR (125 MHz,
CDCl3): δ = 171.2, 148.2, 147.0, 139.4, 132.2, 128.3, 119.1, 110.4,
110.3, 59.8, 55.8, 55.7, 46.9, 41.5, 37.1, 25.0, 18.6, 14.0. IR (film):
νmax = 2934, 2834, 1730, 1517, 1255, 1149, 1029, 467 cm–1
.
(10) (a) Shamma, M.; Rodriguez, H. R. Tetrahedron Lett. 1965, 6,
4847. (b) Shamma, M.; Rodriguez, H. R. Tetrahedron 1968, 24,
6583.
HRMS (ESI): m/z calcd for C18H24O4: 304.1675; found: 304.1677
[M+].
(18) Corey, E. J.; Fleet, G. W. J. Tetrahedron Lett. 1973, 14, 4499.
(19) (a) Hackett, S.; Livinghouse, T. J. Org. Chem. 1986, 51, 1629.
(b) Yamada, O.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 7747.
(20) Procedure for the Synthesis of Mesembrine (1)
(11) Yamada, S.; Otani, G. Tetrahedron Lett. 1971, 12, 1133.
(12) For recent syntheses of mesembrine, see: (a) Zhao, Y.; Zhou, Y.;
Liang, L.; Yang, X.; Du, F.; Li, L.; Zhang, H. Org. Lett. 2009, 11, 555.
(b) Gu, Q.; You, S.-L. Chem. Sci. 2011, 2, 1519. (c) Honda, T.; Arai,
H.; Yamamoto, N.; Takahashi, K. Heterocycles 2012, 84, 327.
(d) Zhang, Q.-Q.; Xie, J.-H.; Yang, X. H.; Xie, J.-B.; Zhou, Q.-L. Org.
Lett. 2012, 14, 6158. (e) Geoghegan, K.; Evans, P. J. Org. Chem.
2013, 78, 3410. (f) Geoghegan, K.; Evans, P. Tetrahedron Lett.
2014, 55, 1431. (g) Ozaki, T.; Kobayashi, Y. Org. Chem. Front.
2015, 2, 328. (h) Nunokawa, S.; Minamisawa, M.; Nakano, K.;
Ichikawa, Y.; Kotsuki, H. Synlett 2015, 26, 2301. (i) Gan, P.;
Smith, M. W.; Braffman, N. R.; Snyder, S. A. Angew. Chem. Int. Ed.
2016, 55, 3625. (j) Spittler, M.; Lutsenko, K.; Czekelius, C. J. Org.
Chem. 2016, 81, 6100. (k) Bhosale, V. A.; Ukale, D. U.;
Waghmode, S. B. New J. Chem. 2016, 40, 9432. (l) Wang, L.-N.;
Cui, Q.; Yu, Z.-X. J. Org. Chem. 2016, 81, 10165.
(13) Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210.
(14) Keck, G. E.; Webb, R. R. J. Org. Chem. 1982, 47, 1302.
(15) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.;
Li, T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92,
741.
(16) For a review of the Johnson–Claisen rearrangements, see:
Fernandes, R. A.; Chowdhury, A. K.; Kattanguru, P. Eur. J. Org.
Chem. 2014, 2833.
A cooled (0 °C) solution of ketal 11 (252 mg, 0.726 mmol) in
THF (9 mL, 0.08 M) was treated with LiAlH4 (3.6 mL, 1.0 M in
THF, 3.63 mmol, 5 equiv). After refluxing for 5 h, the resulting
mixture was quenched with the addition of MeOH and cooled
to room temperature. The resulting mixture was added 1 M HCl
(9 mL, 0.08 M) and stirred at reflux. After stirring for 4 h, the
resulting mixture was basified with the addition of 1 M NaOH
and diluted with EtOAc. The layers were separated, and the
aqueous layer was extracted with EtOAc. The combined organic
layers were washed with sat. aq NaCl, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified by
flash chromatography (SiO2, 2% Et3N gradient elution: 5%
MeOH/CH2Cl2 to 10% MeOH/CH2Cl2) to provide (±)-mesembrine
(1, 204 mg, 97%) as a white foam. 1H NMR (500 MHz, CDCl3): δ =
6.93 (dd, J = 8.4, 2.1 Hz, 1 H), 6.89 (d, J = 1.9 Hz, 1 H), 6.84 (d, J =
8.4 Hz, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.16–3.10 (m, 1 H), 2.94
(t, J = 3.4 Hz, 1 H), 2.60 (t, J = 3.1 Hz, 2 H), 2.48–2.38 (m, 1 H),
2.37–2.28 (m, 1 H), 2.31 (s, 3 H), 2.26–2.03 (m, 5 H).13C NMR
(125 MHz, CDCl3): δ = 211.5, 149.0, 147.4, 140.2, 117.9, 110.9,
109.9, 70.4, 56.0, 55.9, 54.8, 47.5, 40.5, 40.1, 38.8, 36.2, 35.2. IR
(film): νmax = 3468, 2941, 2835, 2782, 1716, 1519, 1254, 1148,
1027 cm–1. HRMS (ESI): m/z calcd for C17H23NO3: 289.1678;
found: 289.1677 [M+].
(17) Procedure for the Preparation of Compound 3
A sealed tube charged with alcohol 5 (205 mg, 0.876 mmol) in
triethyl orthoacetate (17.5 mL, 0.05 M) was treated with 2-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D