Catalytic Asymmetric Total Syntheses of (-)-Galanthamine and (-)-Lycoramine

Article abstract of DOI:10.1021/acs.joc.9b01971

The catalytic asymmetric total syntheses of the biologically important and therapeutically valuable Amaryllidaceae alkaloids (-)-galanthamine and (-)-lycoramine have been divergently achieved from commercially available 3-butyn-1-ol. A newly developed spirocyclic pyrrolidine (SPD)-catalyzed enantioselective Robinson annulation rapidly constructs the key cis-hydrodibenzofuran core, which bears an all-carbon quaternary stereocenter of the target molecules with an excellent stereoselective control. Additionally, the current asymmetric synthetic strategy provides an alternative approach toward the syntheses of (-)-galanthamine and its analogues.

Full text of DOI:10.1021/acs.joc.9b01971

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Note
Catalytic Asymmetric Total Syntheses
of (#)-Galanthamine and (#)-Lycoramine
Qing Zhang, Fu-Min Zhang, Chang-Sheng Zhang, Si-Zhan Liu, Jin-
Miao Tian, Shao-Hua Wang, Xiao-Ming Zhang, and Yong-Qiang Tu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01971 • Publication Date (Web): 09 Sep 2019
Downloaded from pubs.acs.org on September 11, 2019
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Catalytic Asymmetric Total Syntheses of (‒)-Galanthamine and (‒)-Lycoramine
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Qing Zhang,† Fu-Min Zhang,*,† Chang-Sheng Zhang,† Si-Zhan Liu,† Jin-Miao Tian,‡ Shao-Hua Wang,† Xiao-Ming Zhang†
and Yong-Qiang Tu*,†,‡
†State Key Laboratory of Applied Organic Chemistry & College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou 730000, P. R. China
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‡School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
Correspondence and requests for materials should be addressed to Y.-Q.T. (email: tuyq@lzu.edu.cn; tuyq@sjtu.edu.cn) or
to F.-M.Z. (email: zhangfm@lzu.edu.cn).
ABSTRACT
OBn
BnO
N
O
N
D
O
Br
H
OTBDPS
steps
4 steps
C
+
A
A
C
B
O
OH
B
O
OH
gram scale
Catalytic asymmetric
Robinson annulation
O
OMe
OH
MeO
MeO
OMe
O
1a
(–)-Galanthamine (
and (–)-Lycoramine (
)
5 g scale, >99% ee
1b
)
The catalytic asymmetric total syntheses of the biologically important and therapeutically valuable
Amaryllidaceae alkaloids (‒)-galanthamine and (‒)-lycoramine have been divergently achieved from
commercially available 3-butyn-1-ol. A newly developed spirocyclic pyrrolidine (SPD) catalyzed
enantioselective Robinson annulation rapidly constructs the key cis-hydrodibenzofuran core bearing an
all-carbon quaternary stereocenter of the target molecules with excellent stereoselective control.
Additionally, the current asymmetric synthetic strategy provides an alternative approach toward the
syntheses of (‒)-galanthamine and its analogues.
Galanthamine (1a), an Amaryllidaceae alkaloid isolated by Proskurnina from the Caucasian snowdrop in
1952, exhibits unique biological and pharmacological characterization1. As a competitive and reversible
acetylcholinesterase inhibitor, (‒)-galanthamine can effectively regulate the expression of nicotinic
acetylcholine receptor, so as to achieve the goal of significantly improving memory and cognitive functions
of the patients2. Consequently, (‒)-galanthamine has been approved by the Federal Drug Administration in
the USA for the early clinical treatment of Alzheimer’s disease (AD) in 20013. Structurally,
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galanthamine-type alkaloids contain a strained tetracyclic framework bearing a highly functionalized
cis-hydrodibenzofuran nucleus which includes a sterically congested all-carbon quaternary stereocenter
(Figure 1). As a key structural unit commonly existing in these alkaloids, how to rapidly and efficiently
construct such an ABC tricyclic skeleton is a major challenge. Over the past 50 years, extensive synthetic
studies towards galanthamine and its analogues1,4,5 have been carried out, and thus a variety of synthetic
strategies6-11 have also been developed to address the conflict between the increasing clinical demand for
(‒)-galanthamine and its limited supplies from natural sources. However, catalytic asymmetric total
syntheses of (‒)-galanthamine are still rather scarce9-10. Furthermore, to our best knowledge, no direct and
catalytic enantioselective approach to efficiently assemble the crucial cis-hydrodibenzofuran core bearing
all-carbon quaternary carbon from the racemic precursor in the asymmetric syntheses of (‒)-galanthamine
has been reported. Therefore, it remains important and challenging to develop an effective and asymmetric
synthetic strategy towards the Amaryllidaceae alkaloid (‒)-galanthamine.
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7
N
N
6
N
8
5
4
D
3
9
C
A
OH
B
10
OH
2
O
1
O
O
O
11
12
MeO
MeO
MeO
1b
(–)-Lycoramine (
)
1a
(–)-Galanthamine (
N
)
1c
(–)-Narwedine (
)
N
R2
OH
R1
O
OH
)
OH
O
O
HO
MeO
(–)-11-Hydroxylycoramine (
cis-Hydrodibenzofuran core
1d
1e
)
(–)-Sanguinine(
Figure 1. Representative galanthamine-type Amaryllidaceae alkaloids
During the past two decades, electrophile-induced semipinacol rearrangement has been extensively
investigated in our group12 for the efficient construction of the quaternary carbon centers and wide
application in the total syntheses of bioactive natural products13. Particularly, we have accomplished the
total syntheses of (±)-galanthamine and (±)-lycoramine using an NBS-mediated semipinacol rearrangement8
as the key step (Scheme 1a); however, no satisfactory results were obtained in the asymmetric synthesis of
(‒)-galanthamine based on the enantioselective Michael addition14. As a continuation of our ongoing project
centered on the exploration of novel chiral ligands or catalysts based on SPD (spirocyclic pyrrolidine) and
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SPA (spirocyclic amide) backbones15, very recently, we developed a novel SPD-catalyzed enantioselective
Robinson annulation to rapidly construct a cis-hydrodibenzofuran skeleton and achieved the asymmetric
total syntheses of (‒)-codeine and (‒)-morphine16 with high efficiency (Scheme 1b). Considering the
existence of the common cis-hydrodibenzofuran core in these two categories of alkaloids, together with
further investigation of the diversity-oriented synthetic application of the SPD-catalyzed Robinson
annulation, herein, we present our research results of the asymmetric total syntheses of (‒)-galanthamine (1a)
and (‒)-lycoramine (1b) (Scheme 1c).
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Our previous work
a) Total syntheses of racemic galanthamine and lycoramine (Ref. 8)
N
OH
O
NBS
steps
R'
OH
Semipinacol
rearrangement
OR
R'
O
OR
Br
MeO
OMe
MeO
()-Galanthamine
and ()-Lycoramine
b) Catalytic asymmetric total syntheses of (–)-codeine and (–)-morphine (Ref. 16)
OBn
BnO
N
O
H
O
N
H
steps
OTBDPS
SPD-catalyzed asymmetric
Robinson annulation
O
O
O
MeO
OH
OMe
O
RO
( >99% ee )
R = H, (–)-Morphine
R = Me, (–)-Codeine
4 steps from 3-butyn-1-ol
This work
c) Catalytic asymmetric total syntheses of (–)-galanthamine and (–)-lycoramine
N
BnO
O
O
steps
steps
OTBS
OH
O
O
O
MeO
MeO
MeO
( >99% ee )
1a
(–)-Galanthamine (
)
1b
and (–)-Lycoramine (
)
The common intermediate
Scheme 1. Studies on the total syntheses of galanthamine and morphine in our group
Our retrosynthetic analysis toward (‒)-galanthamine and (‒)-lycoramine is outlined in Scheme 2. The D ring
of target molecules 1a and 1b could be installed by an intramolecular Pictet-Spengler cyclization of
intermediate I, whereas the amide moiety in I would be introduced from the common advanced building
block II by a subsequent selective debenzylation/oxidation/radical-induced amidation procedure. We
expected that intermediate II could be prepared via a series of functional group conversions from
α,β-unsaturated ketone 2, which can be easily accessible from compound 3 via our newly developed
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SPD-catalyzed asymmetric Robinson annulation16 with excellent enantioselectivity (>99% ee). Similarly,
following the above-mentioned research results, the enone precursor 3 can also be efficiently synthetized
from commercially available 4 and 5 at a gram scale in just four steps.
8
9
Pictet-Spengler
7
N
10
11
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BnO
MeHN
cyclization
6
Amidation
OR
8
O
5
4
D
3
9
C
OR
A
B
10
OH
2
1
O
11
O
O
12
MeO
MeO
MeO
I
II
1a)
1b)
(–)-Galanthamine (
or (–)-Lycoramine (
Enone
functionalization
OBn
O
BnO
Catalytic asymmetric
Robinson annulation
O
Br
Ref. 16
+
OH
4 steps
O
O
OMe
OH
MeO
OMe
O
5
2
4
3
Scheme 2. Retrosynthetic analysis of (‒)-galanthamine and (‒)-lycoramine
Our synthetic route commenced with the preparation of 9 on a gram scale from the optically pure tricyclic
compound 2 (>99% ee), which was readily available from 3-butyn-1-ol 5 through our recently reported
six-step protocol featuring a Pd-catalyzed Suzuki coupling reaction and an SPD-catalyzed asymmetric
Robinson annulation16 (Scheme 3). To this end, the first key issue that needed to be addressed was the
construction of C2 stereocenter and adjustments of the enone group in compound 2. According to the
classical Rubottom oxidation reaction17, we successfully achieved the introduction of C2 hydroxyl group
through a three-step procedure in high yield. Starting from compound 2, selective conjugate reduction of the
enone with L-selectride afforded ketone 6, which was able to be efficiently converted into silyl enol ether
with TMSOTf and Et3N in excellent regioselectivity17c. In this reaction, attempts to trap the enolate
intermediate generated in situ by one-pot conjugate reduction/silylation proved to be difficult and
no satisfying outcome was achieved. Subsequently, the above crude silylether intermediate was directly
treated with dimethyl dioxirane18 (DMDO), followed by an acid-mediated epoxide cleavage to furnish the
α-hydroxy ketone 7 in high diastereoselectivity, whose stereochemical structure was confirmed by NOESY
experiments. It is presumed that the epoxidation of the double bond of silyl enol ether could highly
selectively proceed on the less-hindered face, leading to deliver the α-hydroxy ketone 7 as a single isomer.
Then, under the standard conditions, the protection of the hydroxy group of 7 with TBSOTf produced the
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silylether 8 in 96% yield, which was treated with NaHMDS and Tf2NPh, followed by a Pd-catalyzed
reduction reaction19, giving the desired key building block 9 in 90% yield over two steps. Notably, all of the
above-mentioned chemical transformations performed well even on the gram scale.
8
9
BnO
BnO
b) TMSOTf, Et3N, DCM, 0 ºC
c) DMDO, DCM, 0 ºC
then NaHSO3, HOAc
10
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a) L-selectride,
THF, –78 ºC
O
O
Ref. 16
2
6 steps
[gram scale]
91%
[gram scale]
76%
[gram scale]
O
O
2
OH
MeO
MeO
6
5
(>99% ee)
BnO
BnO
BnO
e) NaHMDS, THF,
–78 °C, then PhNTf2
f) Pd(OAc)2, HCOOH
Et3N, DMF, 50 °C
O
O
d) TBSOTf, Et3N,
DCM, 0 °C
OTBS
OH
OTBS
2
96%
88%
O
O
O
[gram scale]
MeO
MeO
[gram scale]
MeO
7
8
9
Scheme 3. Preparation of compound 9 on a gram scale
With ample amounts of key intermediate 9 on hand, then we focused our attentions on the asymmetric
total synthesis of the important clinical drug (‒)-galanthamine (1a) (Scheme 4). Selective debenzylation of 9
with DDQ, followed by Dess-Martin oxidation of the resulting primary alcohol, furnished the aldehyde 10.
The structure of 10 was similar to that of the key intermediate in our previously reported synthesis of
(±)-galanthamine8b. Therefore, these practical protocols guided our late-stage synthetic steps in the current
asymmetric synthesis. The free radical-induced oxidation reaction8,20 of 10 in the presence of NBS and a
catalytic amount of AIBN furnished acyl bromide, without further purification, which was directly reacted
with an excess of dry methylamine gas to deliver the desired amide 11 in 72% yield. Subsequently, in order
to build the seven-membered N-containing heterocycle of 1a, the Pictet-Spengler reaction8,21 of 11 with
paraformaldehyde and TFA was conducted to readily afford the lactam 12 in 81% yield, in which the TBS
protecting group was simultaneously removed under acidic conditions. At this stage, the inversion of the
configuration of C2-OH and selective reduction of amide group could furnish the asymmetric total synthesis
of (‒)-galanthamine. To this end, allylic alcohol 12 was first oxidized with Dess-Martin periodinane to
produce enone 13 (Zhou’s intermediate9d,22), which was then treated subsequently with L-selectride and
LiAlH4 in a one-pot procedure to efficiently afford the target molecule (‒)-galanthamine (1a). All
spectroscopic data of our synthetic (‒)-galanthamine were in agreement with the ones reported in the
literatures10.
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9
O
O
N
N
N
f) L-selectride,
THF, –78 ºC
then LiAlH4, 60 °C
e) DMP, NaHCO3,
DCM, 0 °C
2
2
OH
OH
93%
O
O
71%
O
O
MeO
MeO
12
MeO
13
1a)
(–)-Galanthamine (
d) (HCHO)n, TFA,
DCE, rt, 81%
BnO
O
MeHN
10
11
12
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c) NBS, AIBN,
CCl4, 95 °C, then
CH NH2 (g), 0 °C
3
O
a) DDQ, H2O, PhCl,
45 ºC, 94% (brsm)
OTBS
OTBS
OTBS
O
b) DMP, NaHCO3,
DCM, 0 °C, 86%
72%
MeO
O
O
9
MeO
10
MeO
The common intermediate
11
O
N
a') H2, Pd/C, MeOH, 35 ºC, then
DMP, NaHCO3, DCM, 0 °C
Perform
same steps
OTBS
OH
81%
O
O
MeO
(–)-Lycoramine (
MeO
14
1b
)
Scheme 4. Catalytic asymmetric total syntheses of (‒)-galanthamine (1a) and (‒)-lycoramine (1b)
To further explore the synthetic diversity, our efforts toward the total synthesis of (‒)-lycoramine were
continued. Starting from the common building block 9, catalytic hydrogenolysis in the presence of Pd/C
resulted in the reduction reaction of the double bond as well as the removal of the benzyl group to provide a
primary alcohol, which was directly treated with Dess-Martin periodinane to afford aldehyde 14 in 81%
yield. Subsequently, according to the above-mentioned similar synthetic approach toward (‒)-galanthamine,
a four-step protocol involving radical-mediated amidation8,20, Pictet-Spengler reaction8,21, Dess-Martin
oxidation, and one-pot reduction reaction smoothly proceeded and afforded (‒)-lycoramine (1b) with high
efficiency. In addition, the spectral data of synthetic (‒)-lycoramine were identical to those of the previous
reports10.
In summary, we have developed a highly efficient and catalytic asymmetric synthetic approach toward
(‒)-galanthamine and (‒)-lycoramine based on an SPD-catalyzed enantioselective Robinson annulation as a
key step. Significantly, these results described here not only further exhibit the distinctive superiorities of
our SPD catalyst in the construction of the all-carbon quaternary stereocenter but also explore an alternative
synthetic methodology for the preparation of the other galanthamine-type alkaloids and their analogues,
which could be potentially used for syntheses of a series of lead compounds for pharmaceutical screening.
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Additionally, the current study represents the first example of the syntheses of (‒)-galanthamine and
(‒)-lycoramine through direct and catalytic enantioselective construction of the key ABC ring system from
the racemic precursor. Efforts toward the asymmetric syntheses of other biologically important natural
products based on SPD-catalyzed tandem reactions are currently underway in our laboratory.
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EXPERIMENTAL SECTION
General Information. All moisture or oxygen-sensitive reactions were carried out under argon atmosphere with dry and
freshly distilled solvents in oven-dried flasks. Unless otherwise noted, all reagents were analytically pure and used without
further purification. All reactions were monitored by thin-layer chromatography (TLC), and the products were purified by
flash column chromatography on silica gel (200−300 mesh). NMR spectra were recorded in CDCl3 solution on Bruker
AM-400 MHz or Varian Mercury-600 MHz instruments. Chemical shifts (δ) were calibrated by using residual undeuterated
1
solvent CHCl3 (7.26 ppm) or tetramethylsilane (0.00 ppm) as internal references for H NMR and the deuterated solvent
CDCl3 (77.0 ppm) as internal standard for 13C NMR. High-resolution mass spectra (HRMS) were measured by the
electrospray ionization (ESI) technique on a Fourier-transform ion cyclotron resonance mass analyzer. IR spectra were
recorded on a Nicolet FT-170SX spectrometer. Optical rotations were measured with a RUDOLPH A21202-J APTV/GW
polarimeter. The compound 2 was readily prepared from commercially available 3-butyn-1-ol 6 through our recently
reported six-step protocol16, and for the more synthetic details, also please see the supporting information.
(4aS,9bS)-9b-(2-(benzyloxy)ethyl)-6-methoxy-3,4,4a,9b-tetrahydrodibenzo[b,d]furan-2(1H)-one (6). To a stirred solution
of 2 (1.00 g, 2.86 mmol, 1 equiv) in dry THF (50 mL) at −78 ºC, L-selectride (2.71 mL, 2.71 mmol, 1 mol/L, 0.95 equiv)
was slowly added. After stirring at 78 ºC for 10 min, the reaction mixture was quenched with saturated NH4Cl solution,
and extracted with EtOAc. The combined organic extract was washed with saturated NH4Cl solution and brine, dried with
Na2SO4, and concentrated in vacuum. The crude product was purified by column chromatography on silica gel (petroleum
25
1
ether : EtOAc = 8:1) to afford product 6 (916 mg, 91%) as a colorless oil. [α]D = +40 (c = 0.20, CHCl3); H NMR (400
MHz, CDCl3) δ 7.35–7.26 (m, 5H), 6.81 (t, J = 7.8 Hz, 1H), 6.73 (d, J = 7.3 Hz, 1H), 6.60 (dd, J = 7.5, 1.0 Hz, 1H), 5.17 (t,
J = 3.5 Hz, 1H), 4.41 (s, 2H), 3.87 (s, 3H), 3.56–3.44 (m, 2H), 2.74 (d, J = 15.5 Hz, 1H), 2.64 (d, J = 15.5 Hz, 1H), 2.37–
2.32 (m, 1H), 2.26–2.22 (m, 2H), 2.19–2.06 (m, 2H), 2.04–1.95 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 210.6, 147.4,
144.0, 137.9, 132.5, 128.4, 127.7, 127.6, 121.7, 115.3, 111.5, 85.8, 73.2, 66.6, 55.8, 48.4, 48.2, 40.8, 33.1, 26.4; HRMS
(ESI) calcd for C22H24O4Na [M+Na]+: 375.1567, found: 375.1561; IR (neat): 2926, 1716, 1619, 1592, 1493, 1460, 1276,
1203, 1094, 734, 700 cm-1; EI MS m/z (%): 91 (100), 161 (20), 217 (38), 261 (9), 352 (64).
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(3S,4aS,9bS)-9b-(2-(benzyloxy)ethyl)-3-hydroxy-6-methoxy-3,4,4a,9b-tetrahydrodibenzo[b,d]furan-2(1H)-one (7). To a
stirred solution of 6 (1.75 g, 4.97 mmol, 1 equiv) in dry DCM (40 mL) at 0 ºC, Et3N (2.77 mL, 19.88 mmol, 4 equiv) and
TMSOTf (1.62 mL, 8.95 mmol, 1.8 equiv) were added sequentially. The reaction mixture was slowly warmed to room
temperature and stirred for 0.5 h. Then, the reaction mixture was quenched with saturated NaHCO3 solution, and extracted
with EtOAc. The combined organic layer was washed with saturated NaHCO3 solution and brine, dried with Na2SO4, and
concentrated in vacuum. Without purification, the above crude product was dissolved in dry DCM (70 mL) at 0 ºC and the
fresh-made DMDO (75 mL, 0.08 mol/L, 5.96 mmol, 1.2 equiv) was added slowly. After stirring at 0 ºC for 15 min, the
mixture was quenched with NaHSO3 (783 mg, 7.45 mmol, 1.5 equiv) and HOAc (426 uL, 7.45 mmol, 1.5 equiv). After
stirring at 0 ºC for an additional 10 min, the reaction was extracted with EtOAc. The combined organic layer was washed
with brine, dried with Na2SO4, and concentrated in vacuum. The crude product was purified by column chromatography on
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silica gel (petroleum ether : EtOAc = 3:1) to afford product 7 (1.39 g, 76% yield) as a colorless oil. [α]D = ‒5 (c = 0.20,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.35–7.25 (m, 5H), 6.86 (t, J = 8.0 Hz, 1H), 6.79 (dd, J = 8.1, 0.9 Hz, 1H), 6.62 (dd,
J = 7.4, 1.1 Hz, 1H), 4.97 (t, J = 2.8 Hz, 1H), 4.39 (s, 2H), 4.27 (ddd, J = 12.8, 6.0, 2.9 Hz, 1H), 3.90 (s, 3H), 3.53–3.45 (m,
2H), 3.26 (d, J = 3.0 Hz, 1H), 2.85 (ddd, J = 14.7, 6.1, 2.3 Hz, 1H), 2.78 (d, J = 16.5 Hz, 1H), 2.68 (d, J = 16.4 Hz, 1H),
2.12–1.98 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 210.0, 146.9, 144.6, 137.7, 134.6, 128.4, 127.7, 127.6, 122.0,
114.4, 111.8, 86.1, 73.1, 69.8, 66.2, 55.9, 49.9, 46.7, 38.2, 35.6; HRMS (ESI) calcd for C22H24O5Na [M+Na]+: 391.1516,
found: 391.1513; IR (neat): 3500, 2851, 1715, 1620, 1592, 1493, 1459, 1365, 1267, 1204, 1100, 943, 750, 733 cm-1; EI MS
m/z (%): 57 (100), 97 (82), 236 (35), 313 (23), 353 (13), 368 (85).
(3S,4aS,9bS)-9b-(2-(benzyloxy)ethyl)-3-((tert-butyldimethylsilyl)oxy)-6-methoxy-3,4,4a,9b-tetrahydrodibenzo[b,d]furan-
2(1H)-one (8). To a stirred solution of 7 (1.38 g, 3.75 mmol, 1 equiv) in dry DCM (35 mL) at −10 ºC, Et3N (2.09 mL, 15
mmol, 4 equiv) and TBSOTf (1.29 mL, 5.63 mmol, 1.5 equiv) were added sequentially. The reaction mixture was slowly
warmed to room temperature and stirred for 0.5 h. Then, the reaction was quenched with saturated NaHCO3 solution, and
extracted with EtOAc. The combined organic layer was washed with brine, dried with Na2SO4, and concentrated in vacuum.
The crude product was purified by column chromatography on silica gel (petroleum ether : EtOAc = 20:1) to afford product
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8 (1.73 g, 96% yield) as a colorless oil. [α]D = ‒28 (c = 0.60, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.34–7.25 (m, 5H),
6.85 (t, J = 8.0 Hz, 1H), 6.78 (d, J = 7.3 Hz, 1H), 6.63 (dd, J = 7.4, 1.0 Hz, 1H), 4.99 (t, J = 3.5 Hz, 1H), 4.39 (s, 2H), 4.23
(dd, J = 11.7, 5.5 Hz, 1H), 3.90 (s, 3H), 3.53–3.44 (m, 2H), 2.68 (s, 2H), 2.60 (ddd, J = 14.7, 5.5, 3.1 Hz, 1H), 2.31–2.23 (m,
1H), 2.11–1.99 (m, 2H), 0.86 (s, 9H), 0.08 (s, 3H), -0.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 207.8, 146.9, 144.5,
137.9, 134.4, 128.4, 127.6, 121.9, 114.7, 111.7, 86.3, 73.1, 71.1, 66.4, 55.9, 49.8, 47.5, 38.3, 36.7, 25.7, 18.3, -4.7, -5.5;
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HRMS (ESI) calcd for C28H38O5SiNa [M+Na]+: 505.2381, found: 505.2373; IR (neat): 2929, 2856, 1732, 1492, 1459, 1257,
1202, 1127, 838, 780, 735 cm-1; EI MS m/z (%): 91 (100), 129 (28), 143 (22), 205 (10), 295 (74), 334 (5), 425 (18).
(((3S,4aS,9bS)-9b-(2-(benzyloxy)ethyl)-6-methoxy-3,4,4a,9b-tetrahydrodibenzo[b,d]furan-3-yl)oxy)(tert-butyl)dimethylsil
ane (9). Under argon atmosphere, to a stirred solution of 8 (1.60 g, 3.32 mmol, 1 equiv) in dry THF (90 mL) at −78 ºC,
NaHMDS (2.27 mL, 4.32 mmol, 1.9 mol/L, 1.3 equiv) was slowly added. After stirring at −78 ºC for 50 min, PhNTf2 (1.66
g, 4.65 mmol, 1.4 equiv) was added. Then, the reaction was warmed to room temperature (about 10 min) under argon and
stirred for an additional 1 h. The mixture was quenched with saturated NH4Cl solution, and extracted with EtOAc. The
combined organic layer was washed with brine, dried with Na2SO4, and concentrated in vacuum. Without purification, the
resulting crude product was dissolved in dry DMF (35 mL), and Pd(OAc)2 (74 mg, 0.33 mmol, 0.1 equiv),
1,3-bis(diphenylphosphino)propane (dppp, 165 mg, 0.40 mmol, 0.12 equiv), Et3N (1.39 mL, 9.96 mmol, 3 equiv) and
HCOOH (250 μL, 6.64 mmol, 2 equiv) were added sequentially. After stirring at 60 °C for 1 h, the mixture was quenched
with H2O (1 mL), and extracted with EtOAc. The combined organic layer was washed with brine, dried with Na2SO4, and
concentrated in vacuum. The residue was purified by column chromatography on silica gel (petroleum ether : EtOAc = 20:1)
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to afford product 9 (1.36 g, 88% yield) as a colorless oil. [α]D = ‒60 (c = 0.40, CHCl3); H NMR (400 MHz, CDCl3) δ
7.34–7.25 (m, 5H), 6.82 (t, J = 8.0 Hz, 1H), 6.72 (dd, J = 11.5, 7.4 Hz, 2H), 5.74 (d, J = 10.2 Hz, 1H), 5.46 (d, J = 10.2 Hz,
1H), 4.93 (brs, 1H), 4.49–4.47 (m, 1H), 4.45 (d, J = 1.0 Hz, 2H), 3.86 (s, 3H), 3.60–3.52 (m, 2H), 2.60–2.53 (m, 1H), 2.17–
2.08 (m, 2H), 1.85–1.78 (m, 1H), 0.89 (s, 9H), 0.07 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.9, 144.6, 138.1, 134.8,
132.8, 130.3, 128.3, 127.54, 127.52, 121.3, 115.3, 111.1, 85.8, 73.0, 67.0, 63.0, 55.8, 47.3, 37.5, 33.7, 25.8, 18.1, -4.55,
-4.63; HRMS (ESI) calcd for C28H38O4SiNa [M+Na]+: 489.2432, found: 489.2434; IR (neat): 2929, 2856, 1493, 1459, 1281,
1203, 1090, 876, 837, 776, 733 cm-1; EI MS m/z (%): 91 (100), 199 (20), 331 (6), 466 (16).
2-((5aS,7S,9aS)-7-((tert-butyldimethylsilyl)oxy)-4-methoxy-6,7-dihydrodibenzo[b,d]furan-9a(5aH)-yl)ethan-1-ol (9-1).
To a stirred solution of 9 (470 mg, 1.01 mmol, 1 equiv) in chlorobenzene (45 mL, about 10 mg/mL) at room temperature,
DDQ (688 mg, 3.03 mmol, 3 equiv) and H2O (4.5 mL) were added. Then, the reaction was sealed in argon and stirred at
45 °C for 15 h. After being cooled to room temperature, the reaction mixture was diluted with DCM, quenched with
saturated NaHCO3 solution, and extracted with DCM. The combined organic layer was washed with saturated NaHCO3
solution, dried with Na2SO4, and concentrated in vacuum. The residue was purified by column chromatography on silica gel
(petroleum ether : EtOAc = 5:1) to afford product 9-1 (152 mg, 40%) as a colorless oil, together with recovered starting
material 9 (255 mg, 54%). [α]D25 = ‒90 (c = 0.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.86–6.82 (m, 1H), 6.75–6.71 (m,
2H), 5.81 (dd, J = 10.1, 2.4 Hz, 1H), 5.60 (d, J = 10.1 Hz, 1H), 5.02 (t, J = 4.4 Hz, 1H), 4.46–4.42 (m, 1H), 3.87 (s, 3H),
3.76 (t, J = 6.6 Hz, 2H), 2.41 (dt, J = 10.5, 5.0 Hz, 1H), 2.08–2.00 (m, 2H), 1.95–1.90 (m, 1H), 1.88 (brs, 1H), 0.90 (s, 9H),
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0.09 (s, 3H), 0.08 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.7, 144.8, 134.7, 131.9, 130.7, 121.4, 115.2, 111.3, 85.3,
63.3, 59.4, 55.9, 47.6, 40.9, 34.2, 25.8, 18.1, -4.66, -4.71; HRMS (ESI) calcd for C21H32O4SiNa [M+Na]+: 399.1962, found:
399.1955; IR (neat): 3427, 2927, 2855, 2376, 1619, 1510, 1460, 1281, 1252, 1203, 1088, 875, 837, 776, 733 cm-1; EI MS
m/z (%): 199 (11), 214 (29), 244 (64), 331 (8), 376 (3).
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2-((5aS,7S,9aS)-7-((tert-butyldimethylsilyl)oxy)-4-methoxy-6,7-dihydrodibenzo[b,d]furan-9a(5aH)-yl)acetaldehyde (10).
To a stirred solution of alcohol 9-1 (175 mg, 0.465 mmol, 1 equiv) in dry DCM (20 mL) at 0 ºC, NaHCO3 (195 mg, 2.325
mmol, 5 equiv) and DMP (296 mg, 0.698 mmol, 1.5 equiv) were added. The reaction mixture was slowly warmed to room
temperature and stirred for 1 h. Then, the reaction was quenched with saturated NaS2O3 solution, and extracted with EtOAc.
The combined organic layer was washed with brine, dried with Na2SO4, and concentrated in vacuum. The crude product
was purified by column chromatography on silica gel (petroleum ether : EtOAc = 6:1) to afford product 10 (150 mg, 86%
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yield) as a colorless oil. [α]D = ‒160 (c = 0.20, CHCl3); 1H NMR (600 MHz, CDCl3) δ 9.78 (t, J = 2.6 Hz, 1H), 6.86 (t, J =
7.8 Hz, 1H), 6.77 (d, J = 7.7 Hz, 2H), 5.80 (dd, J = 10.1, 2.2 Hz, 1H), 5.66 (d, J = 10.1 Hz, 1H), 4.88 (t, J = 3.8 Hz, 1H),
4.49–4.47 (m, 1H), 3.87 (s, 3H), 2.81 (d, J = 2.6 Hz, 2H), 2.53 (dt, J = 14.0, 5.0 Hz, 1H), 1.86 (ddd, J = 13.9, 9.0, 3.2 Hz,
1H), 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 200.4, 146.9, 145.0, 133.0, 128.8, 121.9,
115.2, 111.9, 85.3, 62.8, 55.9, 50.9, 46.5, 33.3, 25.8, 18.0, -4.61, -4.65; HRMS (ESI) calcd for C21H30O4SiNa [M+Na]+:
397.1806, found: 397.1801; IR (neat): 2928, 2855, 2372, 1722, 1492, 1460, 1286, 1252, 1202, 1092, 875, 837, 776 cm-1; EI
MS m/z (%): 75 (100), 199 (85), 225 (6), 273 (7), 317 (8), 374 (2).
2-((5aS,7S,9aS)-7-((tert-butyldimethylsilyl)oxy)-4-methoxy-6,7-dihydrodibenzo[b,d]furan-9a(5aH)-yl)-N-methylacetamid
e (11). To a stirred solution of 10 (148 mg, 0.396 mmol, 1 equiv) in dry CCl4 (15 mL), AIBN (3.2 mg, 0.02 mmol, 0.05
equiv) and NBS (85 mg, 0.475 mmol, 1.2 equiv) were added sequentially. The flask was then placed in an oil-bath
preheated at 95 °C, and the heterogeneous mixture was stirred for about 10 min. Then the crude reaction mixture was cooled
to 0 °C and bubbled by CH3NH2 gas, which was freshly prepared in situ from MeNH2•HCl and NaOH solid and dried by a
basic NaOH drying tower. Keeping on the continuous MeNH2 bubble, the suspension was stirred at room temperature for an
additional 10 min. After removal of CCl4 in vacuum at ambient temperature, the residue was rapidly purified by column
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chromatography on silica gel (petroleum ether : EtOAc = 1:1) to afford the amide 11 (114 mg, 72%) as a white foam. [α]D
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= ‒117 (c = 0.30, CHCl3); H NMR (400 MHz, CDCl3) δ 6.84–6.77 (m, 2H), 6.73 (dd, J = 7.7, 1.6 Hz, 1H), 5.73 (dd, J =
10.2, 0.9 Hz, 1H), 5.61–5.57 (m, 1H), 5.53 (brs, 1H), 4.98 (t, J = 3.2 Hz, 1H), 4.66–4.43 (m, 1H), 3.84 (s, 3H), 2.72 (d, J =
4.8 Hz, 3H), 2.65 (d, J = 14.1 Hz, 1H), 2.60 (d, J = 14.1 Hz, 1H), 2.58–2.50 (m, 1H), 1.82 (ddd, J = 14.1, 9.4, 3.0 Hz, 1H),
0.86 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.8, 146.8, 144.8, 133.9, 133.1, 129.1, 121.6,
115.2, 111.6, 85.4, 63.0, 55.8, 46.8, 44.8, 33.1, 26.3, 25.8, 18.0, -4.6, -4.7; HRMS (ESI) calcd for C22H33NO4SiNa [M+Na]+:
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426.2071, found: 426.2075; IR (neat): 3311, 2954, 2930, 2857, 1739, 1648, 1561, 1493, 1461, 1254, 1204, 1092, 877, 838,
777 cm-1; EI MS m/z (%): 130 (35), 148 (45), 199 (47), 272 (35), 346 (28), 403 (2).
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(4aS,6S,8aS)-6-hydroxy-3-methoxy-11-methyl-4a,5,11,12-tetrahydro-6H-benzo[2,3]benzofuro[4,3-cd]azepin-10(9H)-one
(12). To a stirred solution of 11 (102 mg, 0.253 mmol, 1 equiv) in dry DCE (15 mL) at room temperature,
paraformaldehyde (30 mg, 1.55 mmol, 4 equiv) and CF3CO2H (283 μL, 3.80 mmol, 15 equiv) were added sequentially. The
reaction mixture was stirred for 1.5 h. Then, the mixture was quenched with saturated aqueous NaHCO3 (10 mL), and
extracted with DCM. The combined organic phase was washed with brine, and dried with Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified by column chromatography on silica gel (DCM : MeOH = 20:1) to
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afford the product 12 (62 mg, 81%) as a white foam. [α]D = ‒117 (c = 0.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.69
(d, J = 8.2 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 5.84 (d, J = 10.2 Hz, 1H), 5.45 (dt, J = 10.2, 1.8 Hz, 1H), 4.71–4.66 (m, 2H),
4.50 (d, J = 15.9 Hz, 1H), 4.23 (d, J = 15.9 Hz, 1H), 3.85 (s, 3H), 2.98 (s, 3H), 2.85 (s, 2H), 2.83–2.77 (m, 1H), 2.09 (d, J =
6.7 Hz, 1H), 1.84–1.77 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.1, 147.7, 144.6, 131.8, 131.6, 128.9, 125.4, 119.4,
111.7, 87.6, 62.6, 56.1, 52.0, 43.4, 42.8, 35.7, 31.0; HRMS (ESI) calcd for C17H19NO4Na [M+Na]+: 324.1206, found:
324.1201; IR (neat): 3404, 2922, 1631, 1618, 1433, 1278, 1050, 803, 734 cm-1; EI MS m/z (%): 115 (33), 197 (32), 229
(25), 258 (9), 282 (12), 301 (100).
(4aS,8aS)-3-methoxy-11-methyl-4a,5,11,12-tetrahydro-6H-benzo[2,3]benzofuro[4,3-cd]azepine-6,10(9H)-dione (13).
To a stirred solution of alcohol 12 (31 mg, 0.103 mmol, 1 equiv) in dry DCM (10 mL) at 0 ºC, NaHCO3 (43 mg, 0.515
mmol, 5 equiv) and DMP (65 mg, 0.155 mmol, 1.5 equiv) were added. The reaction mixture was slowly warmed to room
temperature and stirred for 2 h. Then the reaction was quenched with saturated NaS2O3 solution and extracted with EtOAc.
The combined organic layer was washed with brine, dried with Na2SO4, and concentrated in vacuum. The crude product
was purified by column chromatography on silica gel (petroleum ether : EtOAc = 1:2) to afford product 13 (28.5 mg, 93%
yield) as a colorless oil. (All spectroscopic data of our synthetic compound 13 were in agreement with the ones reported in
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the literature9d.) [α]D = ‒106 (c = 0.30, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.76–6.73 (m, 2H), 6.39 (dd, J = 10.2, 2.3
Hz, 1H), 6.06 (d, J = 10.2 Hz, 1H), 4.85 (q, J = 2.8 Hz, 1H), 4.50 (d, J = 16.2 Hz, 1H), 4.41 (d, J = 16.2 Hz, 1H), 3.86 (s,
3H), 3.17 (dd, J = 17.9, 2.9 Hz, 1H), 3.06 (s, 3H), 3.02 (d, J = 13.9 Hz, 1H), 2.96 (d, J = 13.8 Hz, 1H), 2.82 (dd, J = 17.9,
3.2 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 193.5, 170.0, 147.8, 145.0, 144.6, 129.9, 127.8, 124.9, 120.2, 112.9, 87.1,
56.3, 52.0, 43.9, 40.7, 36.4, 36.0; HRMS (ESI) calcd for C17H17NO4Na [M+Na]+: 322.1050, found: 322.1053; IR (neat):
3404, 2924, 2368, 1686, 1639, 1439, 1284, 1164, 1119, 1069, 738 cm-1; EI MS m/z (%): 115 (29), 214 (21), 227 (50), 271
(29), 299 (100).
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(‒)-galanthamine (1a). To a stirred solution of 13 (25 mg, 0.084 mmol, 1 equiv) in dry THF (6 mL) at −78 ºC,
L-selectride (168 μL, 0.168 mmol, 1 mol/L, 2 equiv) was slowly added. After stirring for 10 min, LiAlH4 (29 mg, 0.756
mmol, 9 equiv) at –78 ºC was added slowly. Then, the reaction mixture was stirred at 60 ºC for 2 h. After being cooled to
room temperature, the reaction was carefully quenched with NaOH aqueous solution (3mol/L, 4 mL), and extracted with
EtOAc. The combined extracts was dried over K2CO3, and concentrated in vacuum. The residue was purified by column
chromatography on silica gel (DCM : MeOH = 15:1) to afford (‒)-galanthamine (1a) (17 mg, 71%). [α]D25 = ‒93 (c = 0.30,
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CHCl3); (lit.10a: []D = –91.3 (c = 1.0, CHCl3)); H NMR (400 MHz, CDCl3) δ 6.67 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 8.2
Hz, 1H), 6.07–5.99 (m, 2H), 4.62 (s, 1H), 4.15–4.11 (m, 2H), 3.84 (s, 3H), 3.72 (d, J = 15.1 Hz, 1H), 3.31 (t, J = 13.1 Hz,
1H), 3.08 (d, J = 14.6 Hz, 1H), 2.69 (dd, J = 15.7, 3.4 Hz, 1H), 2.43 (s, 3H), 2.10 (td, J = 13.5, 3.1 Hz, 1H), 2.01 (ddd, J =
15.7, 5.0, 2.4 Hz, 1H), 1.61 (dd, J = 13.8, 2.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 145.9, 144.3, 133.0, 127.8,
126.6, 122.2, 111.3, 88.7, 62.0, 60.4, 55.9, 53.7, 48.1, 41.7, 33.5, 29.9; HRMS (ESI) calcd for C17H22NO3 [M+H]+:
288.1594, found: 288.1595; IR (neat): 3369, 2924, 1624, 1593, 1508, 1439, 1282, 1167, 1068, 1047, 921, 731 cm-1; EI MS
m/z (%): 115 (53), 128 (31), 174 (40), 216 (41), 244 (31), 270 (15), 286 (100), 287 (81).
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e (14). To a stirred solution of 9 (300 mg, 0.64 mmol, 1 equiv) in MeOH (15 mL), Pd/C (30 mg) was added. The reaction
was stirred at 35 °C under H2 atmosphere (1 atm) for 5 h. Then, the reaction mixture was concentrated in vacuum, and the
dry DCM (20 mL), NaHCO3 (188 mg, 2.24 mmol, 3.5 equiv), and DMP (407 mg, 0.96 mmol, 1.5 equiv) were added
sequentially at 0 °C. After stirring at room temperature for 1 h, the mixture was quenched with saturated Na2S2O3 solution,
and extracted with EtOAc. The combined organic layer was dried with Na2SO4, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (petroleum ether : EtOAc = 10:1) to afford product 14
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(195 mg, 81% yield) as a colorless oil. [α]D = ‒33 (c = 0.30, CHCl3); 1H NMR (600 MHz, CDCl3) δ 9.71 (s, 1H), 6.88 (t, J
= 7.8 Hz, 1H), 6.79 (t, J = 6.6 Hz, 2H), 4.72 (t, J = 5.6 Hz, 1H), 4.01 (brs, 1H), 3.87 (s, 3H), 2.71 (dd, J = 15.4, 2.7 Hz, 1H),
2.63 (dd, J = 15.4, 2.0 Hz, 1H), 2.04–1.93 (m, 3H), 1.89–1.85 (m, 1H), 1.55–1.47 (m, 2H), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s,
3H); 13C{1H} NMR (150 MHz, CDCl3) δ 201.1, 146.5, 145.4, 134.4, 121.7, 115.1, 111.9, 87.0, 65.9, 55.9, 51.2, 45.9, 35.2,
29.5, 29.3, 25.8, 18.0, -4.8; HRMS (ESI) calcd for C21H32O4SiNa [M+Na]+: 399.1962, found: 399.1958; IR (neat): 2929,
2856, 1721, 1491, 1456, 1289, 1255, 1098, 1064, 1043, 872, 837, 775 cm-1; EI MS m/z (%): 201 (100), 275 (61), 319 (5),
376 (5).
2-((5aS,7R,9aR)-7-((tert-butyldimethylsilyl)oxy)-4-methoxy-6,7,8,9-tetrahydrodibenzo[b,d]furan-9a(5aH)-yl)-N-methylac
etamide (15). To a stirred solution of 14 (181 mg, 0.48 mmol, 1 equiv) in dry CCl4 (18 mL), AIBN (3.9 mg, 0.024 mmol,
0.05 equiv) and NBS (103 mg, 0.58 mmol, 1.2 equiv) were added sequentially. The flask was placed in an oil-bath
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preheated at 95 °C, and the heterogeneous mixture was stirred for about 10 min. Then, the reaction mixture was cooled to
0 °C and bubbled with dry CH3NH2 gas for 5 min, which was freshly prepared in situ from MeNH2•HCl and NaOH solid,
and dried with a basic NaOH drying tower. After removal of CCl4 in vacuum, the residue was rapidly purified by column
chromatography on silica gel (petroleum ether : EtOAc = 1:1) to afford the product amide 15 (157 mg, 81%) as a white
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foam. [α]D = ‒23 (c = 0.30, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.85–6.82 (m, 1H), 6.79–6.77 (m, 1H), 6.77–6.75 (m,
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1H), 5.35 (m, 1H), 4.73 (t, J = 5.3 Hz, 1H), 3.98–3.95 (m, 1H), 3.85 (d, J = 2.5 Hz, 3H), 2.65 (dd, J = 4.8, 2.2 Hz, 3H),
2.51–2.46 (m, 2H), 2.08–2.00 (m, 2H), 1.92–1.91 (m, 1H), 1.82–1.78 (m, 1H), 1.51–1.44 (m, 2H), 0.86 (s, 9H), 0.03 (s, 3H),
0.02 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 170.4, 146.6, 145.2, 135.4, 121.3, 115.2, 111.7, 87.4, 66.0, 55.9, 46.4,
44.4, 35.3, 29.8, 29.3, 26.1, 25.8, 18.0, -4.77, -4.78; HRMS (ESI) calcd for C22H35NO4SiNa [M+Na]+: 428.2228, found:
428.2223; IR (neat): 3312, 2932, 2857, 1740, 1647, 1491, 1458, 1255, 1096, 1067, 873, 836, 776, 734 cm-1; EI MS m/z (%):
201 (28), 260 (11), 275 (100), 333 (9), 348 (20), 405 (3).
(4aS,6R,8aR)-6-hydroxy-3-methoxy-11-methyl-4a,5,7,8,11,12-hexahydro-6H-benzo[2,3]benzofuro[4,3-cd]azepin-10(9H)
-one (16). To a stirred solution of 15 (157 mg, 0.388 mmol, 1 equiv) in dry DCE (15 mL), paraformaldehyde (47 mg, 1.55
mmol, 4 equiv) and CF3CO2H (434 μL, 5.82 mmol, 15 equiv) were added sequentially at room temperature. The reaction
mixture was stirred at ambient temperature for 1.5 h. Then the reaction was quenched with saturated aqueous NaHCO3 (10
mL), and extracted with DCM. The combined organic phase was washed with brine, and dried with Na2SO4. After removal
of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (DCM : MeOH =
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20:1) to afford the product 16 (97 mg, 83%) as a white amorphous solid. [α]D = ‒70 (c = 0.30, CHCl3); H NMR (600
MHz, CDCl3) δ 6.66 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 8.2 Hz, 1H), 4.46 (brs, 1H), 4.38 (d, J = 16.1 Hz, 1H), 4.30 (d, J =
16.1 Hz, 1H), 4.10–4.02 (m, 1H), 3.86 (s, 3H), 3.01 (s, 3H), 2.89 (d, J = 14.1 Hz, 1H), 2.86 (d, J = 14.0 Hz, 1H), 2.68–2.65
(m, 1H), 1.86 (d, J = 12.5 Hz, 1H), 1.77 (d, J = 14.2 Hz, 1H), 1.70 (ddd, J = 14.8, 11.2, 3.6 Hz, 1H), 1.60 (t, J = 14.2 Hz,
1H), 1.46 (dd, J = 25.2, 12.5 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 171.9, 146.3, 144.7, 136.3, 124.7, 119.1, 111.5,
90.9, 66.4, 56.1, 52.0, 41.5, 40.2, 36.1, 34.3, 33.4, 30.1; HRMS (ESI) calcd for C17H22NO4 [M+H]+: 304.1543, found:
304.1548; IR (neat): 3394, 2924, 2853, 1738, 1627, 1460, 1377, 1245, 1187, 1081, 970, 739 cm-1; EI MS m/z (%): 70 (100),
188 (36), 230 (43), 231 (35), 303 (79).
(4aS,8aR)-3-methoxy-11-methyl-4a,5,7,8,11,12-hexahydro-6H-benzo[2,3]benzofuro[4,3-cd]azepine-6,10(9H)-dione (17).
To a stirred solution of alcohol 16 (97 mg, 0.32 mmol, 1 equiv) in dry DCM (10 mL) at 0 ºC, NaHCO3 (134 mg, 1.60 mmol,
5 equiv) and Dess-Martin periodinane (203 mg, 0.48 mmol, 1.5 equiv) were added. The reaction mixture was slowly
warmed to room temperature and stirred for 2 h. Then, the reaction was quenched with saturated NaS2O3 solution, and
extracted with EtOAc. The combined organic layer was washed brine, dried with Na2SO4, and concentrated in vacuum. The
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crude product was purified by column chromatography on silica gel (petroleum ether : EtOAc = 1:2) to afford product 17
(85 mg, 88% yield) as a colorless oil. (At this point, we had completed the asymmetric formal synthesis of (‒)-lycoramine
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and all spectroscopic data of our synthetic compound 17 were in agreement with the ones reported in the literature9d.) [α]D
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= ‒120 (c = 0.25, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.70 (dd, J = 18.4, 8.2 Hz, 2H), 4.83 (t, J = 3.0 Hz, 1H), 4.42 (dd,
J = 25.2, 16.8 Hz, 2H), 3.85 (s, 3H), 3.06–3.02 (m, 1H), 3.02 (s, 3H), 2.99 (d, J = 13.8 Hz, 1H), 2.85 (d, J = 13.8 Hz, 1H),
2.73 (dd, J = 17.6, 2.9 Hz, 1H), 2.39–2.34 (m, 1H), 2.30–2.24 (m, 1H), 2.04–2.01 (m, 2H); 13C{1H} NMR (150 MHz,
CDCl3) δ 207.3, 171.3, 146.9, 144.5, 132.6, 124.9, 120.0, 112.5, 88.4, 56.3, 52.1, 43.6, 42.3, 39.4, 36.2, 35.8, 32.7; HRMS
(ESI) calcd for C17H19NO4Na [M+Na]+: 324.1206, found: 324.1206; IR (neat): 3399, 2956, 2919, 2851, 1721, 1639, 1509,
1460, 1439, 1285, 1186, 1075, 969 cm-1; EI MS m/z (%): 115 (18), 188 (23), 204 (28), 229 (29), 245 (21), 301 (100).
(‒)-lycoramine (1b). To a stirred solution of 17 (23 mg, 0.076 mmol, 1 equiv) in dry THF (6 mL) at −78 ºC, L-selectride
(152 μL, 0.152 mmol, 1 mol/L, 2 equiv) was added slowly. After stirring for 10 min, LiAlH4 (26 mg, 0.684 mmol, 9 equiv)
at –78 ºC was added slowly. The reaction mixture was stirred at 60 ºC for 2 h. After being cooled to room temperature, the
reaction was carefully quenched with NaOH aqueous solution (3 mol/L, 4 mL), and extracted with EtOAc. The combined
extract was dried with K2CO3, and concentrated in vacuum. The residue was purified by column chromatography on silica
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gel (DCM : MeOH = 15:1) to afford (‒)-lycoramine (1b) (16 mg, 73%). [α]D = ‒83 (c = 0.35, EtOH) (lit.10b: []D = –
89.3 (c = 0.35, EtOH)); 1H NMR (600 MHz, CDCl3) δ 6.66 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 8.2 Hz, 1H), 4.38 (s, 1H), 4.09
(s, 1H), 4.05 (d, J = 15.0 Hz, 1H), 3.86 (s, 3H), 3.67 (d, J = 15.0 Hz, 1H), 3.26 (t, J = 13.5 Hz, 1H), 3.08 (d, J = 14.3 Hz,
1H), 2.51 (d, J = 16.1 Hz, 1H), 2.40 (s, 3H), 2.01–1.95 (m, 1H), 1.93–1.88 (m, 1H), 1.87–1.80 (m, 1H), 1.79–1.75 (m, 1H),
1.74–1.67 (m, 2H), 1.60–1.54 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 146.1, 144.3, 136.2, 127.9, 122.0, 111.0, 89.9,
65.4, 60.2, 55.9, 54.0, 46.7, 41.5, 31.6, 31.1, 27.7, 23.8; HRMS (ESI) calcd for C17H24NO3 [M+H]+: 290.1751, found:
290.1752; IR (neat): 3360, 2955, 2922, 2851, 1743, 1460, 1377, 1240, 1188, 1082, 969 cm-1; EI MS m/z (%): 115 (14), 187
(8), 202 (10), 232 (8), 288 (100), 289 (67).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: XXXXX
Copies of 1H and 13C NMR spectra of all new compounds and HPLC chromatograms of compound 2 (PDF)
NMR spectral data comparison of compound 13, compound 17, galanthamine (1a), and lycoramine (1b) (PDF)
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AUTHOR INFORMATION
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Corresponding Author
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*E-mail: tuyq@lzu.edu.cn; tuyq@sjtu.edu.cn.
*E-mail: zhangfm@lzu.edu.cn.
ORCID
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Fu-Min Zhang: 0000-0001-5578-1148
Shao-Hua Wang: 0000-0002-4347-8245
Xiao-Ming Zhang: 0000-0002-9294-9672
Yong-Qiang Tu: 0000-0002-9784-4052
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by the National Natural Science Foundation of China (Nos. 21971095, 21772076,
21502080, 21772071, 21702136, and 21871117), National Science and Technology Major project of the Ministry of
Science and Technology of China (2018ZX09711001-005-002), and the ‘111’ Program of MOE.
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(19) Yoshida, K.; Itatsu, Y.; Fujino, Y.; Inoue, H.; Takao, K.-i. Enantioselective organocatalytic construction of
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data of our synthetic compound 13 (Zhou’s intermediate) were in agreement with the ones reported in the literatures9d.
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