A practical total synthesis of (±)-cermizine D and a formal synthesis of (±)-cermizine C

Article abstract of DOI:10.3184/174751918X15271572210923

A practical total synthesis of (±)-cermizine D and a formal synthesis of (±)-cermizine C were achieved. The four-step total synthesis comprised mainly a Michael addition, a Weinreb amide-activated substitution and a sequence of ketalation/PtO₂-catalysed dearomatisation/reductive amination reactions that resulted in ring closure in 13.7% overall yield. The formal synthesis was accomplished in 29.7% overall yield.

Full text of DOI:10.3184/174751918X15271572210923

274 RESEARCH PAPER
VOL. 42 MAY, 274–279
JOURNAL OF CHEMICAL RESEARCH 2018
A practical total synthesis of (±)-cermizine D and a formal synthesis of
±)-cermizine C
(
a, b, c
a, b, c
a, b, c
b, c
b
a
Xin Shi
Qin-Shi Zhao *
a
, Ying Bao
, Zhen-Tao Deng
, Yu Zhu , Li-Dong Shao , Hong-Bin Zhang and
b
Key Laboratory of Medicinal Chemistry for Natural Resources (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan
University, Kunming 650091, P.R. China
b
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201,
P.R. China
c
University of Chinese Academy of Sciences, Beijing 100049, P.R. China
Apracticaltotalsynthesisof(±)-cermizineDandaformalsynthesisof(±)-cermizineCwereachieved.Thefour-steptotalsynthesiscomprised
mainly a Michael addition, a Weinreb amide-activated substitution and a sequence of ketalation/PtO -catalysed dearomatisation/reductive
2
amination reactions that resulted in ring closure in 13.7% overall yield. The formal synthesis was accomplished in 29.7% overall yield.
Keywords: cermizine C, cermizine D, total synthesis, Michael addition, reductive amination
1
27
Lycopodium alkaloids contain a variety of structurally complex
of complanadine B on the basis of oxygenation of picolines. In
natural products. Owing to both their synthetically challenging
polycyclic skeletons and extensive biological activities, a
cornucopia of total syntheses of Lycopodium alkaloids has been
addition, 2-picoline and its analogues could be used as versatile
building blocks in the synthesis of Lycopodium alkaloids due not
only to easy deprotonation at the methyl group by n-BuLi but also
the relative stability of the metalised methyl pyridine. In 2009,
the Sarpong group reported a total synthesis of (+)-lyconadin A
2
published. Belonging to the Lycopodium alkaloids, cernuane-
type alkaloids exhibit various biologically important activities
3,4
(
Fig. 2). Cermizine C and cermizine D are members of the
28
from a union of a vinylogous ester and bromomethoxypicoline.
cernuane-type alkaloids, which are structurally characterised by
a 5,7-disubstituted quinolizidine ring. Along with cermizine A
and cermizine B, cermizines C and D were isolated from the club
Later, an efficient total synthesis of (-)-huperzine A was
published by Lin and co-workers, which introduced pyridine by
29
using bromomethoxypicoline and an alkylation reaction. In our
previous work we proved that introducing a pyridine group via
conjugate addition of the metalated 2-picoline was more direct
3
moss Lycopodiumcernuumin2004byKobayashiandcoworkers,
and cermizine D was found to exhibit significant cytotoxicity
−1 3
against murine lymphoma L1210 cells (IC50 = 7.5 μg mL ).
Many laboratories, therefore, have focused their attention on
10
and more effective.
To make use of 2-picoline in other lycopodium alkaloids,
herein we describe a total synthesis of (±)-cermizine D through
the orderly combination of commercial methyl crotonate and
metalated 2-picoline. In addition, we report the formal synthesis
of (±)-cermizine C.
5
–12
cermizine-related alkaloids (Fig. 1). Although cermizine C
7,8,13–22
has been the topic of numerous synthetic papers,
there have been only three total syntheses of cermizine D.
to date
2
0,23–25
In 2008, Takayama and co-workers reported the first
asymmetric total synthesis of (+)cermizine D, which consisted
of an 18-step route featuring an oxazolidinone intermediate as
Results and discussion
2
0,23
a key cyclisation precursor.
In 2012, a second synthesis of
In the retrosynthetic analysis (Scheme 1), we reasoned that the
dearomatisation/cyclisation of 1 would provide (±)-cermizine
D. Bicyclic intermediate 1 can be accessed from a substitution
reaction of 2-picoline with 2. Compound 2 can be obtained from
(+)-cermizine D was published by Carter and collaborators,
which included two different approaches, a nine-step cuprate
addition strategy and a PhSCH I alkylation pathway in 16 steps
2
2
4
overall. Recently, Comins and co-workers reported a six-
step total synthesis of (-)-cermizine D through an asymmetric
nucleophilic addition of a pyridinium salt. In the present
study, (±)-cermizines C and D were prepared effectively using
3
0
the Michael addition of 2-picoline with methyl crotonate.
The known compound 2 was reported by the Herradón group
2
5
3
0
and resulted from commercial methyl crotonate. Initially, we
attempted to perform the direct substitution of the methyl ester
group of 2 with lithiated methyl pyridine to deliver the desired
bicyclic intermediate 1 (Table 1). The direct substitution of 2
with lithiated methyl pyridine at room temperature failed (Table
1, entry 1). The reaction did not occur even when the reaction
was heated to 50 °C (Table 1, entry 2). However, the desired
bicyclic intermediate 1 could be obtained in 12% yield when the
reaction temperature was lowered to −78 °C and stirred for 20 h.
2-picoline in five and four steps, respectively (Fig. 1).
Pyridine and piperidine rings are not only universal structures
in intricate and physiologically active natural products but can
also be used as a platform to access other classes of Lycopodium
alkaloids. In 2010, the synthesis of (+)-complanadine A was
published by Siegel’s team, which comprised Co(I)-mediated
2
6
[
2+2+2] cycloadditions of a pyridylalkyne product. In 2013,
Sarpong and co-workers reported the strategy of total synthesis
7,13,16–18,20
18,20,25
8,14,15,17
Fig. 1 Syntheses of cermizines C and D.
*
Correspondent. E-mail: 1060137@hnust.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2018 275
Fig. 2 Representative cernuane-type alkaloids and cermizines A–D.
Scheme 1 Retrosynthetic analysis of (±)-cermizine C and (±)-cermizine D.
Table 1 Optimisation of the substitution
Then, the PtO -catalysed hydrogenation was performed steadily,
2
followed by work-up with HCl to form an iminium intermediate
O
O
n
6, which was subsequently trapped by the hydrogen anion using
NaBH4, to give (±)-cermizine D (9) in 20% yield.
With the Weinreb amide 3 in hand, we obtained the
known intermediate 11 resulting from the substitution by the
methyllithium reagent in 90% yield. Then, the same sequence
was executed, as in the synthesis of (±)-cermizine D, to give
-
BuLi, 2-Picoline
N
R
N
N
10,33
o
THF, t C
R = OCH or
1
3
NMe(OMe)
a
Entry
R
t (°C)
r.t.
50 °C
−78 °C
−78 °C
Result and yield (%)
NR
NR
12%
95%
1
2
3
4
OCH3
OCH3
OCH3
(
±)-cermizine C (15) in 46% yield.
1
13
Comparing the H and C NMR data for the (±)-cermizine
C and (±)-cermizine D TFA salts with the literature, the NMR
NMe(OCH3)
2
0
data revealed a good match. The relative stereochemistry of
±)-cermizine C was deduced from cross-peaks observed in
a
Isolated yield.
(
the phase-sensitive ROESY spectrum correlations of H-9/H-7.
The relative stereochemistry of (±)-cermizine D was deduced
from cross-peaks observed in the phase-sensitive ROESY
spectrum correlations of H-5/H-7 and H-15, H-7/H-5 and
H-15 and H-15/H-5 and H-7 (for further details, see Electronic
supplementary information).
In conclusion, a practical total synthesis of (±)-cermizine D
and a formal synthesis of (±)-cermizine C were successfully
accomplished in 13.7% and 29.7% overall yields, respectively,
through two effective sequences from commercial methyl
crotonate. These syntheses will benefit the synthesis of other
cernuane-type alkaloids and ring-fused Lycopodium alkaloids.
Inspired by the condensation reactions of lithiated alkylanes with
31,32
different activated carboxyl groups,
amide method for activation of the carboxyl group. Consequently,
was converted into the corresponding Weinreb amide and then
smoothly condensed with lithiated methyl pyridine to deliver the
we chose the Weinreb
2
31,32
desired product 1 in 95% yield (Table 1, entry 4). Afterwards,
the dipyridinium 1 was prepared through a sequence of Weinreb
amidation/condensation in 90% yield.
Next, the ketalation/PtO -catalysed dearomatisation/reductive
2
amination sequence was performed. To avoid destroying the
carbonyl group during the Pt-catalysed hydrogenation, the
carbonyl group of 1 was protected using ethylene glycol/PTSA.

276 JOURNAL OF CHEMICAL RESEARCH 2018
O
O
O
a
b
OCH3
N
OCH3
N
NMe(OMe)
ꢉetꢃꢊl crotonꢋte
ꢀ
ꢅ
O
O
O
c
ꢆ
N
N
N
N
1
4
H
O
O
N
Cl
N
e
ꢇ
ꢈ
H
NH
H
N
H H
H
5
6
H
H
H
H
N
N
N
N
H
H
H
H
H
H
H
H
N
N
N
N
H
H
H
H
ꢄ
ꢃ
32ꢁ
ꢁ
2ꢂꢁ
ꢄTFꢅ
1ꢂ 23ꢁ
1ꢂꢄTFꢅ
ꢃ
ꢃ
ꢃ
ꢀꢁ
ꢃꢄTFꢅ
ꢁ
Scheme 2 Total synthesis of (±)-cermizine D. Reagents and conditions: (a) n-BuLi (3 equiv.), 2-picoline (3 equiv.), CuCN (1.5 equiv.), THF, r.t. to −70 °C,
6
3
h, 77%; (b) (MeO)NMe·HCl (1.55 equiv.), i-PrMgCl (3 equiv.), THF, −25 °C, 15 min, 95%; (c) n-BuLi (1.54 equiv.), 2-picoline (1.54 equiv.), THF, −78 °C,
h, 95%; (d) pTSA (0.2 equiv.), ethylene glycol (4.2 equiv.), toluene, reflux, 4 d; (e) PtO (0.1 equiv.), H (1 atm), HOAc, r.t., 24 h; (f) work-up with 2 N HCl,
2
2
CH OH, r.t., 2 d; (g) NaBH (7.8 equiv.), CH OH, 0 °C to r.t., 24 h, 20%; (h) TFA (one drop), CH OH, r.t., quantitative.
3
4
3
3
O
O
O
O
ꢀ
NMe(OMe)
ꢁ
N
c
N
N
ꢀ
11
1ꢁ
H
O
O
H
N
H
N
e
ꢂ
N
N
H
1ꢀ
1ꢄ
1
ꢃ ꢆꢇꢈ
1ꢂ ꢆꢉꢈ
1ꢂꢃTFꢄ
ꢅ
ꢅ
1ꢃꢃTFꢄ
Scheme 3. Formal synthesis of (±)-cermizine C. Reagents and conditions: (a) CH Li (2 equiv.), THF, −78 °C, 5 h, 90%; (b) pTSA (0.2 equiv.), ethylene
3
glycol (4.2 equiv.), toluene, reflux, 24 h, 98%; (c) PtO (0.1 equiv.), H (1 atm), HOAc, r.t., 24 h; (d) work-up with 2 N HCl, CH OH, r.t., 2 d; (e) NaBH
2
2
3
4
(
5.3 equiv.), CH OH, 0 °C to r.t., 24 h, 46% for 15, 45% for 16; (f) TFA (one drop), CH OH, r.t., quantitative.
3
3
Experimental
were used as references (CDCl : δ = 77.0 ppm, MeOD: δ = 49.0 ppm;
3 C C
CDCl : δ = 7.26 ppm, MeOD: δ = 4.870 ppm). High-resolution mass
All NMR spectra were recorded on a Bruker Avance III spectrometer
at 400, 600 and 800 MHz ( H) and at 100, 150 and 200 MHz ( C) in
3
H
H
1
13
spectra (HRMS) were recorded on an Agilent 6540 Q-Tof (ESIMS)
instrument. All reactions were carried out under an argon atmosphere
and in dry conditions and were monitored by analytical thin-layer
CDCl and MeOD. Chemical shifts (δ) are given in parts per million
3
(ppm), coupling constants (J) in hertz (Hz), and the solvent signals

JOURNAL OF CHEMICAL RESEARCH 2018 277
chromatography (TLC), which was visualised by ultraviolet light
254 nm). All solvents were obtained from commercial sources and
purified by flash column chromatography, eluting with PE/EA (1:2)
to yield 1: Yellow oil; yield 200 mg (95%); H NMR (400 MHz,
1
(
were purified according to standard procedures.
CDCl ): δ (ppm) 8.51 (d, J = 4.9 Hz, 1H), 8.49 (d, J = 4.6 Hz, 1H), 7.62
3
(
td, J = 7.7, 1.7 Hz, 1H), 7.55 (td, J = 7.6, 1.7 Hz, 1H), 7.19–7.06 (m,
H), 3.86 (s, 2H), 2.73 (dd, J = 13.1, 6.6 Hz, 1H), 2.66–2.61 (m, 1H),
Methyl 3-methyl-4-(pyridin-2-yl)butanoate (2)
4
2
3
1
1
A solution of n-BuLi in hexanes (3.0 equiv., 2.4 M, 3.75 mL) was added
to a stirred solution of 2-picoline (3.0 equiv., 9 mmol, 838.2 mg) in
THF (45 mL) at 0 °C, and the resultant dark red solution was stirred
for 30 min. The reaction was cooled to −78 °C and CuCN (1.5 equiv.,
.61–2.48 (m, 2H), 2.42 (dd, J = 15.7, 7.0 Hz, 1H), 0.90 (d, J = 6.4 Hz,
13
H); C NMR (100 MHz, CDCl ): δ (ppm) 207.0, 160.6, 154.9, 149.6,
3
49.3, 136.7, 136.3, 124.3, 123.7, 122.0, 121.3, 52.8, 49.3, 45.2, 30.2,
−1
9.9; IR (film) (νmax/cm ): 2958, 1715, 1592, 1474, 1435, 1150, 755;
4.5 mmol, 403 mg) was added. The reaction was stirred for 30 min
+
HRMS m/z: 277.1313 [M+Na] ; Calcd for C H N O: 277.1311.
16
18
2
at r.t., after which time it was cooled to −78 °C. A solution of methyl
crotonate (1.0 equiv., 3 mmol, 300.4 mg) in THF (1 mL) was then
added over 3 min, and the reaction was stirred for 6 h at −70 °C.
Aqueous NH /NH Cl (7.5 mL) was added, the cold bath was removed,
(±)-Cermizine D (9) and (±)-epi-cermizine D (7, 8, 10)
To a stirred solution of ketone 1 (1.0 equiv., 1.925 mmol, 489 mg,) in
toluene (10 mL) were added pTSA (0.2 equiv., 0.4 mmol, 77 mg) and
ethylene glycol (4.16 equiv., 8 mmol, 0.45 mL) at room temperature.
The reaction mixture was stirred at reflux for 4 d with a Dean-Stark
trap. After being cooled to room temperature, the reaction mixture
3
4
and, after warming to room temperature, the mixture was transferred
to a separation funnel containing H O (10 mL) and the layers were
2
separated. The aqueous layer was extracted with ethyl acetate (EA)
(3 × 10 mL), and the combined organic phases were then washed with
was quenched with saturated aqueous NaHCO (7.5 mL) and then
3
aqueous NH /NH Cl (pH ∼9, 2 × 7.5 mL) and brine (10 mL), dried
partitioned between CH Cl and, sequentially, water and brine. The
3
4
2
2
over Na SO , and then concentrated to dryness under reduced pressure.
combined organic extract was dried (Na SO ) and then concentrated
2
4
2 4
The crude material was purified by flash chromatography, eluting
under reduced pressure to yield a residue, which was used in the next
step without further purification.
with petroleum ether/ethyl acetate (PE/EA) (4:1) to yield 2: Yellow
1
oil; yield 446 mg (77%); H NMR (400 MHz, CDCl ): δ (ppm) 8.51
A suspension of the above crude product (375 mg) and PtO (10%,
3
2
(
1
7
d, J = 4.3 Hz, 1H), 7.57 (td, J = 7.7, 1.7 Hz, 1H), 7.13 (d, J = 7.8 Hz,
H), 7.09 (dd, J = 7.1, 5.4 Hz, 1H), 3.62 (s, 3H), 2.79 (dd, J = 13.3,
.0 Hz, 1H), 2.68 (dd, J = 13.3, 7.5 Hz, 1H), 2.48 (td, J = 13.8, 6.9 Hz,
m/m, 40 mg) in HOAc (3 mL) was stirred for 24 h at 25 °C under H2
(1 atm). The reaction mixture was filtered and concentrated under
reduced pressure to yield a residue, which was used in the next step
without further purification.
To a stirred solution of the above residue (460 mg) in MeOH (5 mL)
was added HCl (2 N, 2.5 mL) at room temperature. After being stirred
at room temperature for 2 d, the reaction mixture was concentrated,
including high-vacuum pumping, to give the crude product, which was
used in the next step without further purification.
1
H), 2.37 (dd, J = 15.0, 5.6 Hz, 1H), 2.19 (dd, J = 15.0, 8.2 Hz, 1H),
13
0
.96 (d, J = 6.6 Hz, 3H); C NMR (100 MHz, CDCl ): δ (ppm) 173.4,
3
160.5, 149.4, 136.3, 123.7, 121.3, 51.5, 45.3, 41.0, 31.4, 19.8; IR (film)
−1
(νmax/cm ): 2957, 1737, 1590, 1436, 1206, 1159, 1010, 760; HRMS m/z:
+
216.0997 [M+Na] ; Calcd for C H NO : 216.0995.
11
15
2
Methyl 3-methyl-4-(pyridin-2-yl)butanoate (3)
To a stirred solution of the above crude product in MeOH (15 mL) was
An oven-dried flask containing a stirrer bar and fitted with a septum
was purged with argon. The flask was then charged with N,O-
dimethylhydroxylamine hydrochloride (1.55 equiv., 1.55 mmol,
added NaBH (7.8 equiv., 15 mmol, 567.5 mg) carefully in small portions
4
over 10 min at 0 °C. After being stirred at room temperature for 24 h,
the reaction mixture was concentrated under reduced pressure and then
1
51 mg), compound 2 (1.0 equiv., 1 mmol, 193 mg) and dry THF
5 mL). The mixture was cooled to −25 °C and stirred for 5 min before
addition of i-PrMgCl (3.0 equiv., 3 mmol, 1.5 mL) dropwise over
min. The resulting mixture was stirred for a further 10 min before
quenching with saturated aqueous NaHCO solution (5 mL) and H O
extracted with EA (5 × 5 mL) and CHCl /MeOH(5/1, v/v, 5 × 6 mL).
3
(
The combined organic extract was dried (Na SO ) and concentrated.
2
4
The residue was purified by flash column chromatography, eluting with
PE/Detn (diethylamine) (20:1) to yield 7 (39 mg) as a pale yellow oil in
5
3
2
8
% yield, then with PE/Detn (10:1) to yield 8 (152 mg) as a pale yellow
(5 mL). The mixture was allowed to warm to room temperature and
oil in 32% yield, then with PE/Detn (6:1) to yield 9 (98 mg) as a pale
yellow oil in 20% yield, then with PE/Detn (4:1) to yield 10 (113 mg) as a
was stirred vigorously for 10 min. EA (10 mL) was added and the
phases were separated. The aqueous layer was re-extracted with EA
pale yellow oil in 23% yield.
(
3 × 5 mL). The combined organic phases were dried (Na SO ), filtered
2 4
1
(
±)-Cermizine D (9): H NMR (600 MHz, MeOD): δ (ppm) 3.36
and concentrated under reduced pressure to yield a residue. The crude
(d, J = 14.2 Hz, 1H), 3.32–3.28 (m, 1H), 3.13 (t, J = 10.1 Hz, 1H),
material was purified by flash chromatography, eluting with PE/EA
3.05–2.97 (m, 2H), 2.65–2.55 (m, 3H), 1.98 (ddd, J = 25.9, 13.0,
1
(
2:3) to yield 3: Yellow oil; yield 211 mg (95%); H NMR (400 MHz,
4.1 Hz, 1H), 1.89–1.81 (m, 3H), 1.81–1.73 (m, 2H), 1.68–1.58 (m, 3H),
CDCl ): δ (ppm) 8.50 (d, J = 4.3 Hz, 1H), 7.58 (td, J = 7.7, 1.7 Hz, 1H),
3
1.57–1.48 (m, 2H), 1.45–1.40 (m, 2H), 1.36 (td, 1H), 1.22–1.12 (m, 3H),
7
(
2
.18 (d, J = 7.8 Hz, 1H), 7.09 (dd, J = 6.9, 5.3 Hz, 1H), 3.61 (s, 3H), 3.14
s, 3H), 2.83 (dd, J = 13.2, 6.8 Hz, 1H), 2.69 (dd, J = 13.2, 7.4 Hz, 1H),
.52 (dd, J = 13.6, 6.8 Hz, 1H), 2.36–2.25 (m, 1H), 2.19 (s, 1H), 0.97
1
1
.11–1.06 (m, 1H), 0.90 (d, J = 6.5 Hz, 3H), 0.79 (dd, J = 23.9, 11.5 Hz,
H); C NMR (150 MHz, MeOD): δ (ppm) 59.1, 54.9, 50.0, 48.6, 47.6,
13
4
1.3 (2C), 40.4, 34.6, 26.7, 26.5 (2C), 25.8, 25.3, 22.8, 19.6; IR (KBr)
13
(
d, J = 6.6 Hz, 3H); C NMR (100 MHz, CDCl ): δ (ppm) 160.9, 149.2,
3
−1
−1
(νmax/cm ): 3425, 2926, 2854, 1633, 1444, 1122, 726; HRMS m/z:
2
1
3
2
36.3, 123.7, 121.2, 61.3, 45.5, 38.5, 31.1, 20.1; IR (film) (νmax/cm ):
+
51.2484 [M+H] ; Calcd for C H N : 251.2482.
440, 2961, 1660, 1591, 1435, 1385, 1003, 760, 499; HRMS m/z:
16 30
2
1
+
(±)-C5, C7, C13-epi-cermizine D (7): H NMR (800 MHz, MeOD): δ
ppm) 3.32 (d, J = 11.2 Hz, 1H), 3.31–3.30 (m, 1H), 3.11–3.07 (m, 1H),
23.1445 [M+H] ; Calcd for C H N O : 223.1441.
12
18
2
2
(
4
-Methyl-1,5-di(pyridin-2-yl)pentan-2-one (1)
2.76–2.73 (m, 1H), 2.71 (dd, J = 12.4, 3.0 Hz, 1H), 2.12 (s, 1H), 1.99–1.93
(m, 1H), 1.83–1.74 (m, 5H), 1.73–1.69 (m, 2H), 1.68–1.65 (m, 1H), 1.61
(dd, J = 9.8, 2.2 Hz, 1H), 1.55 (dd, J = 13.0, 4.6 Hz, 2H), 1.53–1.48 (m,
2H), 1.46–1.40 (m, 2H), 1.33 (td, J = 12.9, 3.2 Hz, 3H), 1.29 (s, 1H),
1.18–1.11 (m, 1H), 1.03 (dd, J = 25.0, 11.8 Hz, 1H), 0.92 (d, J = 6.5 Hz,
A solution of n-BuLi in hexanes (1.85 equiv., 2.4 M, 0.64 mL)
was added to a stirred solution of 2-picoline (1.85 equiv., 143 mg,
1
.532 mmol) in THF (15 mL) at 0 °C, and the resultant dark red
solution was stirred for 30 min. After the reaction was cooled to
78 °C, a solution of compound 3 (1.0 equiv., 0.8284 mmol, 184 mg)
13
−
3H); C NMR (201 MHz, MeOD): δ (ppm) 64.7, 62.0, 56.4, 52.9, 47.2,
in THF (1 mL) was added over 3 min. The reaction was allowed to
proceed for 3 h at −78 °C before quenching with water. EA (5 mL)
was added and the phases were separated. The aqueous layer was
then re-extracted with EO (3 × 5 mL). The combined organic phases
were dried (Na SO ), passed through a hydrophobic frit, and then
42.9, 42.0, 40.3, 34.5, 32.2, 31.4, 27.0, 25.9, 25.3, 24.9, 22.3; IR (KBr)
−1
(νmax/cm ): 3428, 3301, 2929, 2791, 1660, 1447, 1205, 1176, 1135, 837,
+
723, 508; HRMS m/z: 251.2482 [M+H] ; Calcd for C H N : 251.2482.
16
30
2
1
(±)-C7, C13-epi-cermizine D (8): H NMR (600 MHz, MeOD): δ
(ppm) 3.34 (d, J = 11.4 Hz, 1H), 3.30 (s, 1H), 2.98 (d, J = 13.0 Hz, 1H),
2.58–2.50 (m, 2H), 2.04 (dd, J = 10.5, 8.5 Hz, 1H), 1.93 (t, J = 9.4 Hz,
2
4
concentrated under reduced pressure to yield a residue that was

278 JOURNAL OF CHEMICAL RESEARCH 2018
1
H), 1.85 (m, 1H), 1.81–1.72 (m, 4H), 1.70 (d, J = 8.9 Hz, 2H), 1.64 (d,
J = 13.3 Hz, 1H), 1.59 (d, J = 8.9 Hz, 2H), 1.53 (d, J = 11.2 Hz, 3H),
.43–1.38 (m, 2H), 1.34–1.29 (m, 2H), 1.20–1.10 (m, 2H), 0.98–0.93
8.51 (d, J = 4.6 Hz, 1H), 7.58 (td, J = 7.6, 1.4 Hz, 1H), 7.18–7.05 (m, 2H),
2.70 (ddd, J = 30.8, 13.2, 6.9 Hz, 2H), 2.56–2.43 (m, 2H), 2.28 (dd, J = 16.0,
8.1 Hz, 1H), 2.08 (s, 3H), 0.92 (d, J = 6.5 Hz, 3H); C NMR (100 MHz,
13
1
13
(
6
m, 1H), 0.91 (d, J = 6.3 Hz, 3H); C NMR (150 MHz, MeOD): δ (ppm)
CDCl ): δ (ppm) 208.7, 160.6, 149.3, 136.4, 123.8, 121.3, 50.4, 45.4, 30.5,
3
−1
4.6, 61.6, 55.9, 47.6, 42.0, 34.5, 34.3, 31.4, 27.0, 26.7, 25.7, 25.4, 22.4; IR
30.4, 20.0; IR (KBr) (νmax/cm ): 3429, 2926, 1711, 1630, 1592, 1435, 1368,
761; HRMS m/z: 178.1225 [M+H] ; Calcd for C H NO: 178.1226.
−1
+
(
KBr) (νmax/cm ): 3438, 2927, 2854, 1660, 1623, 1452, 1398, 834, 704;
11
15
+
HRMS m/z: 251.2486 [M+H] ; Calcd for C H N : 251.2482.
1
6
30
2
2-(2-Methyl-3-(2-methyl-1,3-dioxolan-2-yl)propyl)pyridine (12)
1
(
±)-C13-epi-cermizine D (10): H NMR (600 MHz, MeOD): δ (ppm)
To a stirred solution of ketone 11 (1.0 equiv., 1.15 mmol, 203 mg) in
toluene (10 mL) were added pTSA (0.2 equiv., 0.23 mmol, 45 mg) and
ethylene glycol (3.74 equiv., 4.3 mmol, 240 μL) at room temperature.
The reaction mixture was stirred at reflux for 24 h with a Dean-Stark
trap. After being cooled to room temperature, the reaction mixture
was quenched with saturated aqueous NaHCO3 (7.5 mL) and then
partitioned between CH Cl and, sequentially, water and brine. The
3.34 (d, J = 15.0 Hz, 1H), 3.30 (dt, J = 3.1, 1.5 Hz, 1H), 3.07 (dd, J = 10.8,
8.7 Hz, 1H), 3.03–2.97 (m, 2H), 2.65–2.54 (m, 3H), 1.96 (qd, J = 12.9,
4.1 Hz, 1H), 1.87 (d, J = 12.6 Hz, 1H), 1.82–1.70 (m, 5H), 1.62–1.56 (m,
2H), 1.54 (dt, J = 12.9, 3.9 Hz, 1H), 1.51–1.46 (m, 1H), 1.45–1.34 (m,
3H), 1.21 (ddd, J = 13.7, 8.9, 5.2 Hz, 2H), 1.18–1.13 (m, 1H), 1.05 (dd,
J = 21.9, 10.8 Hz, 1H), 0.89 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 12.5 Hz,
13
1
H); C NMR (150 MHz, MeOD): δ (ppm) 59.1, 55.6, 50.1, 49.0, 47.7,
2
2
combined organic extract was dried (Na SO ) and concentrated under
41.9, 41.2, 40.6, 33.0, 26.9, 26.7, 26.6, 25.5, 25.2, 22.7, 19.5; IR (KBr)
2
4
−1
reduced pressure to yield a residue that was purified by flash column
(
νmax/cm ): 3433, 2925, 2851, 1663, 1621, 1453, 1401, 834, 703; HRMS
+
chromatography, eluting with PE/EA (2:1) to yield 12: Colourless oil;
m/z: 251.2485 [M+H] ; Calcd for C H N : 251.2482.
16
30
2
1
yield 216 mg (98%); H NMR (400 MHz, CDCl ): δ (ppm) 8.52 (d,
3
(±)-Cermizine D TFA salt (9-TFA) and (±)-epi-cermizine D TFA salt (8-
J = 4.3 Hz, 1H), 7.57 (td, J = 7.6, 1.7 Hz, 1H), 7.17–7.02 (m, 2H), 3.91
TFA, 10-TFA)
(ddd, J = 18.9, 10.0, 6.7 Hz, 4H), 2.88 (dd, J = 13.3, 6.4 Hz, 1H), 2.58
To a solution of compound 8, 9 or 10 (3 mg) in MeOH (0.5 mL) was
added TFA (1 drop, excess). The mixture was concentrated under
reduced pressure to yield 12 mg of corresponding TFA salt as a yellow
oil. The compound was detected directly by NMR spectrometry without
(dd, J = 13.3, 8.1 Hz, 1H), 2.20 (qd, J = 13.0, 7.6 Hz, 1H), 1.73 (dd,
J = 14.3, 4.7 Hz, 1H), 1.55 (dd, J = 14.3, 7.9 Hz, 1H), 1.30 (s, 3H), 0.96
13
(d, J = 6.6 Hz, 3H); C NMR (100 MHz, CDCl ): δ (ppm) 161.2, 149.2,
3
136.1, 123.7, 120.9, 110.3, 64.4, 64.2, 46.6, 44.9, 30.2, 24.0, 20.8; IR
−1
further purification.
(KBr) (νmax/cm ): 3429, 2929, 1631, 1592, 1435, 1381, 1062, 761; HRMS
1
+
(±)-Cermizine D TFA salt (9-TFA): H NMR (600 MHz, MeOD): δ
m/z: 244.1306 [M+Na] ; Calcd for C H NO : 244.1308.
13
19
2
(
(
2
(
ppm) 3.95 (t, J = 11.1 Hz, 1H), 3.74–3.66 (m, 2H), 3.41 (s, 1H), 3.36–3.33
m, 1H), 3.14 (td, J = 13.7, 2.9 Hz, 1H), 3.04 (dd, J = 17.6, 7.9 Hz, 1H),
.32 (m, 1H), 2.21 (dd, J = 13.8, 11.6 Hz, 1H), 2.18–2.12 (m, 1H), 2.01
d, J = 13.8 Hz, 1H), 1.97–1.85 (m, 4H), 1.82–1.52 (m, 11H), 1.17 (dd,
(±)-Cermizine C (15) and (±)-epi-cermizine C (16)
A suspension of the above product 12 (1.0 equiv., 0.977 mmol, 216 mg)
and PtO (10%, m/m, 22 mg) in HOAc (5 mL) was stirred for 24 h
2
1
3
at 25 °C under H2 (1 atm). The reaction mixture was filtered and
concentrated under reduced pressure to yield a residue, which was used
in the next step without further purification.
To a stirred solution of the above residue (300 mg) in MeOH (5 mL)
was added HCl (2 N, 2.5 mL) at room temperature. After being stirred
at room temperature for 2 d, the reaction mixture was concentrated,
including high-vacuum pumping, to give the crude product.
J = 26.1, 12.2 Hz, 1H), 0.98 (d, J = 6.5 Hz, 3H); C NMR (150 MHz,
MeOD): δ (ppm) 62.4, 54.2, 51.4, 50.0, 45.9, 38.9, 38.0, 36.3, 31.0, 24.9,
−1
2
4.6, 23.7, 23.2, 23.1, 21.6, 18.6; IR (KBr) (νmax/cm ): 3438, 2955, 1677,
+
1459, 1203, 1131, 833, 800, 721, 601; HRMS m/z: 251.2482 [M+H] ;
Calcd for C H N : 251.2482.
16
30
2
1
(
±)-C7, C13-epi-cermizine D TFA salt (8-TFA): H NMR (800 MHz,
MeOD): δ (ppm) 3.85 (d, J = 12.3 Hz, 1H), 3.39 (d, J = 12.8 Hz, 1H),
.31–3.29 (m, 1H), 3.29–3.28 (m, 1H), 3.27–3.23 (m, 1H), 3.09 (t,
J = 11.6 Hz, 1H), 3.02 (td, J = 12.9, 3.0 Hz, 1H), 2.78 (td, J = 13.2, 2.9 Hz,
To a stirred solution of the above crude product in MeOH (15 mL) was
3
added NaBH
(5.3 equiv., 195 mg, 5.2 mmol) carefully in small portions
4
1
2
H), 2.41 (ddd, J = 15.0, 6.9, 3.5 Hz, 1H), 2.10 (dd, J = 14.4, 2.7 Hz, 1H),
.02–1.96 (m, 2H), 1.93 (dd, J = 10.7, 2.1 Hz, 1H), 1.88–1.84 (m, 3H),
over 5 min at 0 °C. After being stirred at room temperature for 24 h, the
reaction mixture was concentrated under reduced pressure, and then
1.83–1.80 (m, 1H), 1.76–1.73 (m, 1H), 1.70–1.65 (m, 2H), 1.63–1.55 (m,
extracted with EA (5 × 5 mL) and CHCl /MeOH (5/1, v/v, 5 × 6 mL).
3
4
=
H), 1.50 (ddd, J = 15.2, 12.6, 3.4 Hz, 1H), 1.31–1.23 (m, 2H), 0.98 (d, J
6.5 Hz, 3H); C NMR (200 MHz, MeOD): δ (ppm) 66.6, 62.5, 55.3,
The combined organic extract was dried (Na SO ) and concentrated. The
2
4
13
residue was purified by flash column chromatography, eluting with PE/
Detn (60:1) to yield 16 (73 mg) as a pale yellow oil in 45% yield, and then
with PE/Detn (40:1) to yield 15 (75 mg, 46% yield) as a pale yellow oil in
46% yield.
52.3, 46.0, 40.3, 40.0, 36.9, 32.3, 30.3, 29.7, 24.9, 23.2, 23.1, 23.0, 21.3;
−1
IR (KBr) (νmax/cm ): 3440, 2957, 1678, 1457, 1203, 1135, 836, 801, 722;
HRMS m/z: 251.2482 [M+H] ; Calcd for C H N : 251.2482.
+
16
30
2
1
1
(
±)-C13-epi-cermizine D TFA salt (10-TFA): H NMR (600 MHz,
MeOD): δ (ppm) 3.79 (t, J = 11.2 Hz, 1H), 3.64 (d, J = 13.5 Hz, 2H), 3.38
d, J = 12.7 Hz, 1H), 3.29–3.23 (m, 2H), 3.14–3.07 (m, 1H), 3.00 (td,
J = 12.8, 2.7 Hz, 1H), 2.23–2.04 (m, 4H), 1.96–1.83 (m, 4H), 1.78–1.53
(±)-Cermizine C (15): H NMR (600 MHz, MeOD): δ (ppm) 3.19
(m, 1H), 3.05 (d, J = 12.4 Hz, 1H), 2.68 (td, J = 13.7, 2.5 Hz, 1H), 1.98
(ddd, J = 26.2, 13.0, 4.1 Hz, 1H), 1.88 (m, 1H), 1.76 (m, 1H), 1.70–1.50
(m, 4H), 1.40 (td, J = 12.9, 5.3 Hz, 1H), 1.22 (d, J = 17.8 Hz, 2H), 1.08
(d, J = 6.3 Hz, 3H), 0.93 (dd, J = 24.5, 11.9 Hz, 2H), 0.89 (d, J = 6.5 Hz,
(
(m, 9H), 1.41 (td, J = 14.6, 2.9 Hz, 1H), 1.16 (dd, J = 25.5, 12.7 Hz, 1H),
13
13
0
5
.94 (d, J = 6.5 Hz, 3H); C NMR (150 MHz, MeOD): δ (ppm) 62.3,
3H); C NMR (150 MHz, MeOD): δ (ppm) 59.1, 50.2, 47.6, 44.4, 40.6,
−1
4.6, 51.6, 50.0, 46.0, 38.3, 38.0, 35.4, 28.7, 24.9, 24.5, 23.7, 23.3, 22.7,
26.9, 26.4, 24.9, 22.6, 19.8, 19.0; IR (KBr) (νmax/cm ): 3440, 2924, 2853,
−1
+
2
1.6, 18.5; IR (KBr) (νmax/cm ): 3438, 2957, 2873, 1677, 1431, 1203,
1681, 1458,1383, 1208, 1140, 839; HRMS m/z: 168.1750 [M+H] ; Calcd
+
1131, 834, 799, 721, 600, 517; HRMS m/z: 251.2482 [M+H] ; Calcd for
for C H N: 168.1747.
11
21
1
C H N : 251.2482.
(±)-epi-Cermizine C (16): H NMR (600 MHz, MeOD): δ (ppm)
.12–2.04 (m, 1H), 1.90 (t, J = 10.3 Hz, 1H), 1.81–1.74 (m, 1H), 1.73–1.66
16
30
2
2
4
-Methyl-5-(pyridin-2-yl)pentan-2-one (11)
(m, 2H), 1.63 (dd, J = 13.2, 3.2 Hz, 1H), 1.60–1.50 (m, 4H), 1.36–1.27
A solution of CH Li in hexanes (1.6 M, 1.7 mL) was added to a stirred
3
(m, 3H), 1.10 (d, J = 6.3 Hz, 3H), 1.03 (dd, J = 22.8, 9.8 Hz, 1H), 0.97
solution of compound 3 (300 mg, 1.31 mmol) in THF (11 mL) at −78 °C.
The reaction was allowed to proceed for 5 h at −78 °C before quenching
with water. EA (5 mL) was added and the phases were separated. The
aqueous layer was then re-extracted with EA (3 × 5 mL). The combined
organic phases were dried (Na SO ), passed through a hydrophobic frit and
13
(
dd, J = 22.2, 10.0 Hz, 1H), 0.89 (d, J = 6.4 Hz, 3H); C NMR (150 MHz,
MeOD): δ (ppm) 64.1, 60.3, 52.7, 44.5, 43.2, 34.3, 31.7, 26.8, 25.4, 22.3,
−1
2
0.3; IR (KBr) (νmax/cm ): 3442, 2957, 2854, 1731,1682, 1463, 1133, 834;
+
HRMS m/z: 168.1748 [M+H] ; Calcd for C H N: 168.1747.
1
1
21
2
4
(±)-Cermizine C TFA salt and (±)-epi-cermizine C TFA salt
concentrated under reduced pressure to yield a residue that was purified
by flash column chromatography, eluting with PE/EA (2:1) to yield 11:
To a solution of compound 15 or 16 (3 mg) in MeOH (0.5 mL) was added
TFA (1 drop, excess). The mixture was concentrated under reduced
1
Colourless oil; yield 216 mg (90%); H NMR (400 MHz, CDCl ): δ (ppm)
3

JOURNAL OF CHEMICAL RESEARCH 2018 279
pressure to yield 12 mg of corresponding TFA salt as a yellow oil. The
compound was detected directly by NMR spectrometry without further
4
D.B. Zhang, J.J. Chen, L. Zhang, Q.Y. Song and K. Gao, Phytochem. Lett., 2014,
10, 76.
5
6
7
L. Cui, Y. Peng and L.M. Zhang, J. Am. Chem. Soc., 2009, 131, 8394.
T.K. Beng and R.E. Gawley, J. Am. Chem. Soc., 2010, 132, 12216.
G. Cheng, X. Wang, D. Su, H. Liu, F. Liu and Y. Hu, J. Org. Chem., 2010, 75,
purification.
1
(±)-Cermizine C·TFA (15·TFA): H NMR (600 MHz, MeOD): δ
(
1
3
(
3
2
1
ppm) 3.81 (d, J = 5.1 Hz, 1H), 3.63 (d, J = 13.6 Hz, 1H), 3.60–3.55 (m,
H), 3.06 (td, J = 13.6, 3.0 Hz, 1H), 2.18–2.10 (m, 1H), 1.99–1.88 (m,
H), 1.80–1.75 (m, 2H), 1.71–1.65 (m, 1H), 1.64–1.58 (m, 2H), 1.57–1.49
m, 1H), 1.29 (d, J = 6.4 Hz, 3H), 1.21–1.12 (m, 1H), 0.94 (d, J = 6.3 Hz,
1
911.
S.S.P. Chou, Y.C. Chung, P.A. Chen, S.L. Chiang and C.J. Wu, J. Org. Chem.,
011, 76, 692.
8
9
2
13
B. Bradshaw, C. Luque-Corredera and J. Bonjoch, Chem. Commun., 2014, 50,
7099.
X. Shi, Z.T. Deng, Y. Zhu, Y. Bao, L.D. Shao and Q.S. Zhao, J. Org. Chem.,
H); C NMR (151 MHz, MeOD): δ (ppm) 61.4, 51.1, 49.9, 41.9, 38.5,
−1
5.4, 24.6, 23.8, 21.6, 18.4, 17.7; IR (KBr) (νmax/cm ): 3426, 2977, 1640,
10
+
454, 1384, 1086, 1047, 879, 716; HRMS m/z: 168.1744 [M+H] ; Calcd
2017, 82, 11110.
for C H N: 168.1747.
11
21
1
1
J.F. Grabowski and B.B. Snider, J. Org. Chem., 2007, 72, 1039.
1
(
±)-epi-Cermizine C·TFA (16·TFA): H NMR (600 MHz, MeOD): δ
ppm) 3.73 (d, J = 12.5 Hz, 1H), 3.14–3.07 (m, 1H), 3.00 (t, J = 11.4 Hz,
H), 2.68 (t, J = 12.0 Hz, 1H), 1.90 (dd, J = 29.9, 14.1 Hz, 3H), 1.83
d, J = 14.8 Hz, 1H), 1.77 (ddd, J = 9.1, 8.5, 3.0 Hz, 2H), 1.66 (dd,
J = 27.3, 13.6 Hz, 1H), 1.53–1.46 (m, 2H), 1.31 (d, J = 6.4 Hz, 3H),
12 M. Saha and R. Carter, Synlett, 2017, 28, 2212.
(
1
(
1
3
T.K. Beng and R.E. Gawley, J. Am. Chem. Soc., 2010, 132, 12216.
L. Cui, Y. Peng and L. Zhang, J. Am. Chem. Soc., 2009, 131, 8394.
S.S.P. Chou and C.H. Kao, J. Chin. Chem. Soc., 2013, 60, 1260.
6 I. Bosque, J.C. Gonzalez-Gomez, F. Foubelo and M. Yus, J. Org. Chem., 2012,
1
4
1
5
1
1
3
1.23 (t, J = 11.8 Hz, 2H), 0.92 (d, J = 6.5 Hz, 3H); C NMR (150 MHz,
77, 780.
MeOD): δ (ppm) 65.6, 62.5, 52.0, 41.8, 40.4, 32.2, 30.0, 24.9, 23.2, 21.4,
1
7
B.B. Snider and J.F. Grabowski, J. Org. Chem., 2007, 72, 1039.
N. Veerasamy, E.C. Carlson, N.D. Collett, M. Saha and R.G. Carter, J. Org.
Chem., 2013, 78, 4779.
−1
17.9; IR (KBr) (νmax/cm ): 3447, 2926, 1639, 1456, 1384, 1203, 1045,
18
+
878, 722; HRMS m/z: 168.1744 [M+H] ; Calcd for C H N: 168.1747.
11 21
19
S.E. Benimana, N.E. Cromwell, H.N. Meer and C.C. Marvin, Tetrahedron
Lett., 2016, 57, 5062.
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (U1502223, U0932602 and
20 Y. Nishikawa, M. Kitajima, N. Kogure and H. Takayama, Tetrahedron, 2009,
65, 1608.
21
N. Veerasamy and R.G. Carter, Tetrahedron, 2016, 72, 4989.
81603000), the National Basic Research Program of China
22
M. Amat, R. Griera, R. Fabregat and J. Bosch, Tetrahedron: Asymmetry, 2008,
(973 Program No. 2011CB915503), the Science and Technology
19, 1233.
Program of Yunnan Province (2017FB135) and the Youth
Innovation Promotion Association CAS (L.-D. Shao).
23
24
25
Y. Nishikawa, M. Kitajima and H. Takayam, Org. Lett., 2008, 10, 1987.
N. Veerasamy, E.C. Carlson and R.G. Carter, Org. Lett., 2012, 14, 1596.
M.F. Enamorado, C.M. Connelly, A. Deiters and D.L. Comins, Tetrahedron
Lett., 2015, 56, 3683.
Electronic Supplementary Information
The ESI is available through:
http://ingentaconnect.com/content/stl/jcr/2018/00000042/00000005/art00012
2
6
7
C.X. Yuan, C.T. Chang, A. Axelrod and D. Siegel, J. Am. Chem. Soc., 2010,
132, 5924.
2
J.N. Newton, D.F. Fischer and R. Sarpong, Angew. Chem. Int. Ed., 2013, 52,
Received 22 March 2019; accepted 9 May 2018
Paper 1805334
https://doi.org/10.3184/174751918X15271572210923
Published online: 4 June 2018
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28 S.P. West, A. Bisai, A.D. Lim, R.R. Narayan and R. Sarpong, J. Am. Chem. Soc.,
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2
2
9
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