Total Syntheses of (?)-Strictosidine and Related Indole Alkaloid Glycosides

Article abstract of DOI:10.1002/anie.202005748

A collective synthesis of glycosylated monoterpenoid indole alkaloids is reported. A highly diastereoselective Pictet–Spengler reaction with α-cyanotryptamine and secologanin tetraacetate as substrates, followed by a reductive decyanation reaction, was developed for the synthesis of (?)-strictosidine, which is an important intermediate in biosynthesis. This two-step chemical method was established as an alternative to the biosynthetically employed strictosidine synthase. Furthermore, after carrying out chemical and computational studies, a transition state for induction of diastereoselectivity in our newly discovered Pictet–Spengler reaction is proposed. Having achieved the first enantioselective total synthesis of (?)-strictosidine in just 10 steps, subsequent bioinspired transformations resulted in the concise total syntheses of (?)-strictosamide, (?)-neonaucleoside A, (?)-cymoside, and (?)-3α-dihydrocadambine.

Full text of DOI:10.1002/anie.202005748

A Journal of the Gesellschaft Deutscher Chemiker
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International Edition
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Accepted Article
Title: Total Syntheses of (–)-Strictosidine and Related Indole Alkaloid
Glycosides
Authors: Hayato Ishikawa, Jukiya Sakamoto, Yuhei Umeda, Kenta
Rakumitsu, and Michinori Sumimoto
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10.1002/anie.202005748
Angewandte Chemie International Edition
RESEARCH ARTICLE
Total Syntheses of (–)-Strictosidine and Related Indole Alkaloid
Glycosides
Jukiya Sakamoto,[a] Yuhei Umeda,[a] Kenta Rakumitsu,[a] Michinori Sumimoto,[b] and Hayato
Ishikawa*[a], [c]
[a]
J. Sakamoto, Y. Umeda, K. Rakumitsu, Prof. Dr. H. Ishikawa
Department of Chemistry, Graduate School of Science and Technology
Kumamoto University
2-39-1, Kurokami, Chuo-ku, Kumamoto 860-8555, Japan
E-mail: h_ishikawa@kumamoto-u.ac.jp
Home page: http://www.sci.kumamoto-u.ac.jp/~ishikawa/ishikawa-lab/Top.html
Prof. Dr. M. Sumimoto
Graduate School of Science and Engineering
Yamaguchi University
2-16-1, Tokiwadai, Ube, Yamaguchi, 755-8611, Japan
Prof. Dr. H. Ishikawa
[b]
[c]
Faculty of Advanced Science and Technology
Kumamoto University
2-39-1, Kurokami, Chuo-ku, Kumamoto 860-8555, Japan
biological activity. Numerous synthetic studies of nonglycosylated
indole alkaloids have been reported, including total and
semisyntheses using biomimetic strategies. In addition, the
semisynthesis of historically important strictosidine and related
alkaloid glycosides located upstream in the biosynthetic scheme
have been reported by several groups.[4] Recently, Vincent and
Abstract: The collective synthesis of glycosylated monoterpenoid
indole alkaloids is reported. A highly diastereoselective Pictet–
Spengler reaction with a-cyanotryptamine and secologanin
tetraacetate as substrates, followed by a reductive decyanation
reaction, was developed for the synthesis of (–)-strictosidine, which is
an important intermediate in biosynthesis. This two-step protocol in a
flask was established as an alternative to the biosynthetically
employed strictosidine synthase. Furthermore, after carrying out
chemical and computational studies, the transition state to induce the
diastereoselectivity of our newly discovered Pictet–Spengler reaction
reported here is proposed. Having achieved the first enantioselective
total synthesis of (–)-strictosidine in just 10 steps, the subsequent
bioinspired transformations resulted in the concise total syntheses of
(–)-strictosamide, (–)-neonaucleoside A, (–)-cymoside, and (–)-3a-
dihydrocadambine.
coworkers reported the first asymmetric total synthesis of (–)-
6]
cymoside (5)[5,
using achiral secologanin aglycon prepared
following the synthetic protocol of Tietze et al.[7] On the other hand,
the enantioselective total synthesis of glycosylated
monoterpenoid indole alkaloids, including 1, has not been
Over 3000 nonglycosylated
monoterpenoid indole alkaloids
NH2
β-glucosidase
9
N
11
H
tryptamine
+
7
5
strictosidine
synthase
18
3S NH
H
OH
1 N
19
20
H
HO
H
OH
OH
10
14
O
H
8
O
O
21
OH
7
6
15
HO
O
OH
OH
1
O
5
MeO
O
22
9
16
17 (-)-strictosidine (1)
4
MeO
O
O
11
3
Introduction
O
(-)-secologanin (2)
Strictosidine-related alkaloid glycosides
Over 3000 monoterpenoid indole alkaloids have been isolated
from higher plants, including Rubiaceae, Loganiaceae, and
Apocynaceae species.[1] This vast number of monoterpenoid
indole alkaloids, which have highly complex structures and
diverse scaffolds, have occupied significant positions in natural
product chemistry and synthetic organic chemistry. In addition,
some of these alkaloids, such as vinblastine, camptothecin,
reserpine, quinine, and ajmaline, have been employed as
medicines, and several useful biological activities of this class of
compounds have also been reported. [1] As described in natural
product chemistry textbooks, (–)-strictosidine (1) acts as a
common biosynthetic intermediate for most of the monoterpenoid
indole alkaloids in nature.[2] (–)-Strictosidine (1) is biosynthesized
from (–)-secologanin (2) and tryptamine via enzymatic Pictet–
Spengler cyclization. Therefore, mechanistic studies of the
biosynthesis and application of the synthesis to monoterpenoid
indole alkaloids using strictosidine synthase have become major
focus areas in alkaloid chemistry.[3]
OH
HO
OH
OH
O
O
O
O
3S
N
O
N
H
H
3S
N
N
H
H
H
H
O
MeO
HO
OH
MeO
O
OH
OH
OH
HO
O
O
OH
OH
O
O
O
(-)-neonaucleoside A (4)
(-)-strictosamide (3)
H
OH
H
HO
H
H
OH
OH
O
N
O
3S
N
3S
N
H
O
H
H
OH
OH
O
MeO
O
H
H
HO
OH
OH
NH
O
O
CO2Me
O
(-)-cymoside (5)
(-)-3α-dihydrocadambine (6)
Monoterpenoid indole alkaloids have attracted the attention of
Figure 1. Structure and biosynthetic pathway of strictosidine and related
alkaloid glycosides.
synthetic chemists because of their divergent structure and
1
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10.1002/anie.202005748
Angewandte Chemie International Edition
RESEARCH ARTICLE
CN
reported, except for our previously reported total syntheses of (–)-
5-carboxystrictsidine and (–)-rubenine.[8] Although scientists
recognize that (–)-strictosidine (1) is a pivotal molecule in alkaloid
chemistry, total synthesis is not simple; (–)-secologanin (2), the
biosynthetic precursor of (–)-1, has not yet be obtained by
chemical synthesis.
Recently, we accomplished the total synthesis of (–)-
secologanin (2) using an orgnocatalytic asymmetric Michael
reaction followed by thioester selective reduction/spontaneously
cyclization cascade as key step to construct an optically active
dihydropyran ring system.[8] Therefore, we were positioned to
consider the first enantioselective total synthesis of (–)-
strictosidine (1) and the collective synthesis[9] of strictosidine-
related alkaloid glycosides using biogenetically inspired
transformations.
diastereoselective
Pictet–Spengler
cyclization
NH2
CN
N
H
S or R-α-cyanotryptamine (8)
prepared from N-Cbz-tryptophan
(3 steps)
+
3S NH
N
H
H
H
O
D-Glc(OAc)4
MeO
O
O
H
O
O
D
-Glc(OAc)4
1) reductive
decyanation
2) hydrolysis
MeO
O
O
secologanin tetraacetate (7)
total 7 steps, total yield 25%
(-)-strictosidine (1)
Scheme 1. Synthetic strategy toward concise total synthesis of (–)-strictosidine.
Our discovery pertaining to the total synthesis of secologanin
tetraacetate (7) is summarized in Scheme 2.[8] Thioester
derivative 9, prepared as an E and Z mixture by Knoevenagel
condensation with commercially available 3-trimethylsilylpropanal
(81% yield), was employed in newly developed organocatalytic
anti-selective Michael reaction. Thus, thioester 9 and aldehyde 10
containing thioether were treated with 3 mol% of diphenylprolinol
trimethylsilyl ether catalyst to provide the optically active anti-
adduct selectively in excellent conversion and enantiomeric
excess (> 99% ee). Following the thioester selective
reduction/spontaneously cyclization cascade, we obtained our
desired dihydropyran compound 11 in excellent yield (76% from
9). Subsequent stereoselective Schmidt glycosylation, removal of
the TMS group, hydroboration/oxidation to construct an aldehyde
moiety, and final elimination of sulfoxide to form a terminal olefin
afforded our desired secologanin tetraacetate (7). The overall
yield of 7 from commercially available 3-trimethylsilylpropanal, via
a seven-step transformation, was 25%. Of particular importance
was that we could prepare around 8 g of this key intermediate 7
in a single synthetic sequence.
Herein, we describe the first practical enantioselective total
synthesis of (–)-strictosidine (1) in which we employ
diastereoselective Pictet–Spengler cyclization reaction using a-
cyanotryptamine (8), followed by reductive decyanation
a
a
sequence as the key steps. The total syntheses of glycosylated
monoterpenoid indole alkaloids (–)-strictosamide (3), (–)-
neonaucleoside
A
(4), (–)-cymoside (5), and (–)-3a-
dihydrocadambine (6) were achieved using bioinspired
transformations.
Results and Discussion
Development
cyclization using
of
diastereoselective
-cyanotryptamine and
Pictet–Spengler
reductive
a
a
decyanation reaction; total syntheses of (–)-strictosidine and
(–)-strictosamide.
In biosynthesis, strictosidine synthase is required to promote the
diastereoselective Pictet–Spengler cyclization reaction. The
newly generated C3 chiral center controls the S configuration
selectively. Several diastereo- and enantioselective Pictet–
Spengler reactions have been developed to reproduce the high
stereoselectivity achieved using strictosidine synthase in a
flask.[10] For example, Cook and coworkers achieved highly
diastereoselective Pictet–Spengler cyclization using N-benzyl-D-
tryptophan derivatives.[11] More recently, chiral phosphoric acid or
chiral thiourea catalysts were employed in the enantioselective
Pictet–Spengler cyclization reaction.[12] The enantioselective
catalytic Pictet–Spengler reaction has also been applied to
alkaloid synthesis.[13]
However, it remains difficult to apply the reported reaction
conditions to secologanin itself, as a substrate, in the total
synthesis of (–)-strictosidine (1). This is because, in the case of
Cook’s N-benzyl-D-tryptophan derivatives, it is necessary to
remove the carboxylic acid moiety using several chemical
conversions, and the removal of the benzyl group is difficult at the
late stage of total synthesis. Furthermore, it is difficult to use chiral
phosphoric acids or thiourea catalysts because secologanin
contains several hydrogen bonding donors and acceptors, such
as those in the sugar portion of a substrate. To achieve the
concise total synthesis of 1 in a minimum number of steps after
the Pictet–Spengler reaction, we aimed to develop a continuous
Ph
Ph
OTMS
3 mol%
SPh
N
H
TMS
TMS
Pd/C
Et3SiH
OH
PhS(CH2)3CHO (10)
MeO
SEt
MeO
O
THF
76%
(2 steps from 9)
Et2O
0 °C
O
O
O
9
E : Z = 1 : 1
11 (dr = 1 : 1)
> 99% ee
1)
OAc
AcO
OAc
OAc
O
O
H
Cl3C
O
O
D-Glc(OAc)4
NH
BF3·Et2O, MS 3Å, 87%
MeO
O
2) TBAT, quant.
3) cat. Cp2ZrHCl, 9-BBN; H2O2, 70%
4) PO(OMe)3, 68%
O
secologanin tetraacetate (7)
8 g scale
Scheme 2. Our concise total synthesis of secologanin tetraacetate.
With a sufficient quantity of secologanin tetraacetate (7) in
hand, we commenced with our experiments involving
diastereoselective Pictet–Spengler cyclization in the synthesis of
(–)-strictosidine (1). Since moderate diastereoselectivity had been
observed earlier when using L-tryptophan methyl ester
(quantitative yield, 3S:3R = 2.6:1; Table 1, entry 1),[8] (S)-a-
cyanotryptamine (S-8), prepared via a three-step transformation
from N-Cbz-L-tryptophan (see details in the Supporting
Information), was employed in an initial trial. Thus, secologanin
tetraacetate (7) and S-8 in CH2Cl2 were treated with trifluoroacetic
acid (TFA, 5 equiv) in the presence of MS 4Å at 0 °C. As a result,
when using S-8, which has the same stereochemistry as that of
L-tryptophan methyl ester, diastereoselectivity was decreased to
1.5:1 (quantitative yield; Table 1, entry 2).
diastereoselective
Pictet–Spengler
reaction
using
a-
cyanotryptamine (8) and a reductive decyanation reaction[14]
(Scheme 1).
2
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10.1002/anie.202005748
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RESEARCH ARTICLE
Then, since the NMR data of (–)-strictosidine (1) and
vincoside (a C3 epimer of 1) were very similar, we decided to
determine the absolute configuration of the C3 position more
clearly. Therefore, (–)-strictosamide (3), which is a tetracyclic
lactam compound, was synthesized, and its spectral data,
including ECD spectra,[15] were then compared with those of a
natural product. Strictosamide (3) has been isolated from several
species, such as Nauclea, Palicourea, Ophiorrhiza, Psychotria,
Triosteum, Strychnos, Vinca, and Sarcocephalus species.[16] In
addition, several useful biological activities have been reported,
Because this selectivity was not sufficient to advance the total
synthesis, the reaction was then carried out using the opposite
enantiomer, R-8. Surprisingly, the product was almost a single
isomer and, pleasingly, it was our desired C3S configuration
(3S:3R = >10:1, quantitative yield; Table 1, entry 3). On the other
hand, when D-tryptophan methyl ester was employed in the
Pictet–Spengler reaction under the same reaction condition, no
selectivity was observed (quantitative yield; Table 1, entry 3).
Table 1. Pictet–Spengler reaction using secologanin tetraacetate and
tryptophan methyl ester or a-cyanotryptamine[a]
including
antiplasmodial,
antiviral,
antiproliferative,
anticarcinogenic, acetyl-/butyrylcholinesterase inhibiting, anti-
inflammatory, antidiabetic, and antioxidative activities.[16m, 17]
R
5
The semisynthesis of 3 from naturally occurring (–)-
R
NH2
TFA
MS 4Å
strictosidine (1) has already been reported; therefore, 1 was
treated with 5% aqueous Na2CO3 solution (a known protocol).[2f]
However, in our hands, the desired (–)-3 was obtained in only
36% yield, and undesired deglycosylated natural products,
vallesiachotamine (16%) and isovallesiachotamine (4%), were
generated under basic conditions.[18]
Thus, we considered an alternative synthetic pathway from
strictosidine tetraacetate 13. When the key intermediate 13 was
heated in toluene under neutral conditions (48 h), tetracyclic
lactam 14 was obtained in excellent yield (92%). Then, after
hydrolysis, the first total synthesis of (–)-strictosamide (3) was
achieved in 75% yield. A total of 11 steps was required to
complete the synthesis of 3 from commercially available materials.
The total yield was 14%. All spectral data of 3 were carefully
analyzed, including its ECD spectra.
3S
NH
H
N
N
H
H
H
O
tryptophan derivative
CH2Cl2
0 °C, time
D-Glc(OAc)4
+
MeO
O
secologanin
tetraacetate (7)
O
Time
3 h
Tryptophan
derivatives
Yield[b]
[%]
Product ratio[c]
Entry
CO2Me
S
1
NH2
quant
3S:3R = 2.6:1
N
H
CN
S
2
3
4
3 min
3 min
3 h
quant
quant
quant
3S:3R = 1.5:1
3S:3R = >10:1
3S:3R = 1:1.8
NH2
N
S-8
H
CN
R
NH2
R-8
TFA
CN
3S NH
N
H
R-8
CO2Me
O
H
R
MS 4Å
N
O
H
H
H
D
-Glc(OAc)4
NH2
O
N
D-Glc(OAc)4
MeO
O
H
MeO
O
O
7
[a] Reaction conditions: 7 (0.009 mmol), tryptophan derivative (0.018
mmol), TFA (0.045 mmol), and MS 4Å (10 mg) in CH2Cl2 (0.18 mL) were
stirred at 0 °C (see details in the Supporting Information). [b] Isolated yield
as diastereomer mixture. [c] The diastereomeric ratio was determined by
1H-NMR analysis of the crude product.
O
12
85% (2 steps)
NaBH3CN
AcOH
K2CO3
MeOH
91%
3S
NH
N
H
These results indicated that the products were obtained
through a different transition state in each case of the tryptophan
methyl ester and a-cyanotryptamine (8) as substrates.
Furthermore, in the case of a-cyanotryptamine (8), it is strongly
suggested that it is not only the stereochemistry of the cyano
group on tryptamine, but also the asymmetric environment of
secologanin tetraacetate (7) that influences this remarkable
diastereoselectivity. Before delving into the details of the reaction
mechanism, we proceeded with the total synthesis of (–)-
strictosidine (1) through reductive decyanation (Scheme 3).
OH
3S NH
H
N
H
H
HO
O
OH
OH
H
H
O
O
D-Glc(OAc)4
MeO
O
MeO
O
O
O
strictosidine tetraacetate (13)
(-)-strictosidine (1)
Total 20% over 10 steps
5% Na2CO3
36%
toluene
92%
/ H2O
65 °C
Since the developed Pictet–Spengler cyclization proceeded
with excellent diastereoselectivity, a mixture of the coupling
product 12 and a trace amount of its isomer were employed in the
following reductive decyanolation reaction. Thus, the mixture of
products was treated with sodium cyanoborohydride (20 equiv) in
the presence of acetic acid (MeOH, rt, 2.5 days). We obtained our
desired strictosidine tetraacetate (13) as a single isomer in very
good yield (85% over two steps). The developed two-step
sequence was carried out on the gram scale; finally, > 1.3 g of
compound 13, which is a key intermediate of the bioinspired
collective synthesis of monoterpenoid indole alkaloids, was
obtained. In addition, the total number of steps was only nine. The
removal of four acetyl groups on the sugar moiety using standard
methanolysis conditions proceeded smoothly. The first
enantioselective total synthesis of (–)-strictosidine (1) was thus
completed. The total yield of 1 was 20% from commercially
available 3-trimethylsilylpropanal via a 10-step transformation.
3S
N
O
K2CO3
MeOH
N
N
O
N
H
H
H
H
H
75%
H
O
O
OH
HO
OH
OH
O
O
O
D-Glc(OAc)4
strictosamide tetraacetate (14)
(-)-strictosamide (3)
Total 14% over 11 steps
Scheme 3. Total syntheses of strictosidine and strictosamide.
3
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10.1002/anie.202005748
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RESEARCH ARTICLE
Mechanistic insight into the diastereoselective Pictet–
a
Spengler cyclization using -cyanotryptamine.
Table 2. Pictet-Spengler reaction using secologanin derivatives and a-
cyanotryptamine.[a]
In the discovered diastereoselective Pictet–Spengler reaction, we
investigated which of the functional groups of secologanin affect
the induction of the diastereoselectivity. First, in efforts to examine
how the sugar chain and the double bond contained in
secologanin affect the reaction, corresponding substrates 15, 16
were synthesized (Scheme S1a; see details in Supporting
Information). Next, in an effort to investigate the influence of the
b-acrylate residue of secologanin on the diastereoselectivity in the
CN
NH2
5
CN
R1
N
H
TFA
NH
H
3S
N
H
R-8 (1.0 equiv)
MS 4Å
H
O
21
+
20
Me
15
CH2Cl2
secologanin
derivative
(1.0 equiv)
O
0 °C, 1 h
R2
22
Secologanin
derivatives
Yield[b]
[%]
Product ratio[c]
Pictet–Spengler reaction,
a
derivative 17 in which
a
Entry
1
methoxycarbonyl group was converted to a methyl group was
synthesized (Scheme S1b; see details in Supporting Information).
Furthermore, we carried out an enantioselective synthesis of the
5,9-trans derivatives 18 to investigate the effect of the
stereochemistry at the C9 position of secologanin (Scheme S2;
O
H
1
OMe
5
9
quant
quant
3S:3R = >10:1
MeO 11
O
O
15a
10
see details in Supporting Information).
O
H
8
Then, we carefully examined what structural factors of
secologanin influence the C3 diastereoselectivity. When
secologanin aglycon (15a) was employed in our Pictet–Spengler
reaction here, excellent selectivity was maintained (1 equiv of R-
8, 0.5 equiv. of TFA, 0 °C; Table 2, entry 1). Thus, the sugar
moiety of secologanin (2) had no effect on stereoselectivity. Next,
when the reaction was carried out using compound 16a, which
has a saturated ethyl group on C9, similar excellent selectivity
was observed (Table 2, entry 2). We also found that the
stereochemistry of the acetal at the C1 position did not affect this
selectivity (Table 2, entries 2 and 3). Furthermore, no decrease in
selectivity was observed with compounds 18a and 18b, in which
the stereochemistry at the C9 position was inverted (Table 2,
entries 4 and 5).
We therefore recognized that the stereochemistry of C1 and
C9 generally did not affect the expression of selectivity. When
performing the reaction with the synthesized ent-18a, no great
diastereoselectivity was observed (Table 2, entry 6). Although, it
was expected from the result from that useful diastereoselectivity
was not induced when the reaction was carried out using
secologanin and (S)-a-cyanotryptamine (S-8) as a substrate
(Table 1, entry 2).
OMe
OMe
OMe
OMe
OMe
2
3S:3R = >10:1
MeO
O
O
16a
O
H
1
3
4
5
6
7
quant
quant
quant
quant
98%
3S:3R = >10:1
3S:3R = >10:1
3S:3R = 6.7:1
3S:3R = 1.1:1
3S:3R = 2.7:1
MeO
O
O
16b
O
H
1
5
9
MeO
O
18a
O
O
H
1
5
9
MeO
O
O
18b
O
H
1
5
9
MeO
O
O
ent-18a
O
H
OMe
The above results indicated that the relative stereochemistry
O
Me
between the cyano group on tryptamine and the C5 position of
secologanin is important for the diastereoselective Pictet–
Spengler reaction here. Furthermore, one of the important
findings in the experiments was the significant decrease in
selectivity with compound 17 with a reduced b-acrylate residue
(Table 2, entry 7). This result suggests that the methoxycarbonyl
group at the C11 position of secologanin is very important for the
induction of stereoselectivity. The absolute configuration of newly
generated C3 in the products obtained in the above experiments
(Tables 1 and 2) was determined from 1D and 2D NMR, NOEDF,
and ECD spectra after derivatization.
11
17
[a] Reaction conditions: secologanin derivative (0.03 mmol), R-8 (0.03
mmol), TFA (0.015 mmol), and MS 4Å (40 mg) in CH2Cl2 (0.6 mL) were
stirred at 0 °C (see details in the Supporting Information). [b] Isolated yield
as diastereomer mixture. [c] Diastereomeric ratio was determined by 1H-
NMR analysis of the crude product.
Then, the structure of the transition state in the Pictet–Spengler
reaction was determined by computational studies,[19] because,
despite the difference in the C5 stereochemistry of (R)-a-
cyanotryptamine (R-8) and L(S)-tryptophan methyl ester, the
generated C3 position is identical to S configuration. The
theoretical calculations were performed using the PBE1PBE
method (see details in the Supporting Information). The results
showed a clear hydrogen bond between the methoxycarbonyl
group of the secologanin and the proton of the iminium ion when
the transition state was estimated when using (R)-a-
cyanotryptamine (R-8) as a substrate (Figure 2). The resulting
transition state including the unique eight-membered ring
predominantly produces the 3S isomer (difference in energy, 4.2
kcal/mol). The results clearly indicated that the hydrogen bonding
ability of the methoxycarbonyl group in secologanin and the
relative stereochemistry of the CN group at the C5 and C15 chiral
centers (C5 in secologanin) are crucial to induce excellent
diastereoselectivity.
4
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10.1002/anie.202005748
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RESEARCH ARTICLE
Total synthesis of (–)-neonaucleoside A and stereochemistry
reassignment of (–)-bahienosides A and B.
In 2003, neonaucleoside A, comprising two secologanin units
and
a tryptamine moiety, was isolated from Neonauclea
sessilifolia by Tanahashi and coworkers (Scheme 4).[20] The
structure of neonaucleoside A was determined by 2D NMR
analysis and semisynthesis from naturally occurring (–)-
secologanin (2) and (–)-strictosidine (1); the stereochemistry of
C3 was determined as the S configuration. At almost the same
time, Maxwell and coworkers isolated two diastereomers having
the same plane structure as neonaucleoside A from Psychotria
bahiensis; they named these bahienosides
A
and B,
respectively.[21] They concluded that bahienosides A and B were
diastereomers at the C3 position; bahienoside B was assigned
C3S according to the rules of thumb of ECD spectra and NMR
analysis. Thus, it was proposed that neonaucleoside A and
bahienoside B had the same structure. However, the optical
rotations of neonaucleoside A and bahienoside B have opposite
signs and different value (neonaucleoside A, [a]D = –133;
bahienoside B, [a]D = +65). In addition, all reported spectral data,
including the rotation value of neonaucleoside A (proposed C3S
configuration, [a]D = –133), were identical for bahienoside A
(proposed C3R configuration, [a]D = –128). As a result, it was
necessary to reconfirm the stereochemistry at the C3 position of
neonaucleoside A and/or bahienosides A and B by total synthesis.
TS to major 3S isomer (Table 2, entry 1)
0.0 kcal/mol
N
5R
C
N
H
N
H
H
H
O
Me
O
O
OMe
To synthesize C3S neonauleoside
A (4), strictosidine
tetraacetate (13) was treated with 1 equiv of secologanin
tetraacetate (7) in the presence of NaBH3CN. The aminated
product was obtained in excellent yield (79%). The final hydrolysis
proceeded smoothly, and the desired C3S neonauleoside A (4)
was obtained in 74% yield. The optical rotation of the synthesized
product 4 was [a]D = –128.4, and all spectral data identified the
isolated neonauleoside A and bahienoside A. Thus, the structure
of Tanahashi’s proposed neonaucleoside A (4), including the C3
stereochemistry, was confirmed; the C3 stereochemistry of
bahienoside A was revised from the R to S configuration. In
addition, the above results also suggested that the
stereochemistry of bahienoside B at the C3 position was the R
configuration. In summary, the first efficient total synthesis of (–)-
TS to minor 3R isomer (Table 2, entry 1)
+4.2 kcal/mol
Figure 2. Calculated transition state to form major 3S isomer and minor 3R
isomer using (R)-a-cyanotryptamine.
On the other hand, when L-tryptophan methyl ester was used
as a substrate, the hydrogen bonds forming the eight-membered
ring, when using (R)-a-cyanotryptamine, were not observed in the
calculated transition state to a major 3S product (Figure 3).
Interestingly, a clear hydrogen bond was observed between the
methoxycarbonyl group at the C5 position and the proton of the
iminium ion in the transition state that induces the major 3S
product; it inhibits the hydrogen bonding to form the eight-
membered ring through the methoxycarbonyl group in
secologanin. The energy difference between the two transition
states was 3.8 kcal/mol, suggesting that the 3S isomer is
preferentially formed (similar to the experimental results). To
summarize the mechanistic study, the different steric induction
mechanisms are dependent on the hydrogen bonding abilities of
the C5 substituents (–CN vs –CO2Me) and the methoxycarbonyl
group of secologanin, and reaction proceeds via obviously
different transition states.
D-Glc
O
D-Glc
O
O
O
3R
3S
N
N
N
N
H
H
O
H
O
H
H
H
MeO
MeO
MeO
O
MeO
O
O
O
D-Glc
O
O
D-Glc
reported structure of
(–)-bahienoside A ([α]D = –128)
reported structure of
(-)-neonaucleoside A ([α]D = –133)
or (+)-bahienoside B ([α]D = +65)
All spectral data of isolated (-)-neonaucleoside A and (–)-
bahienoside A were almost identical.
1) 7, NaBH3CN
AcOH, MS 4Å
MeOH, 79%
3S NH
N
H
H
H
2) K2CO3, MeOH
74%
O
D-Glc(OAc)4
MeO
O
O
0.0 kcal/mol
strictosidine tetraacetate (13)
TS to major 3S isomer (ref. Table 1, entry 1)
OH
HO
O
OH
OH
O
O
O
3S
N
N
H
The synthetic product
was identified as (-)-
neonaucleoside A and
(–)-bahienoside A.
H
H
MeO
HO
OH
MeO
O
OH
OH
O
O
O
(-)-neonaucleoside A (4)
(also called (–)-bahienoside A)
Total 13% over 11 steps
+3.8 kcal/mol
TS to minor 3R isomer (ref. Table 1, entry 1)
Scheme 4. Total synthesis of (–)-neonaucleoside A and stereochemistry
reassignment of (–)-bahienosides A.
Figure 3. Calculated transition state to form major 3S isomer and minor 3R
isomer using L(S)-tryptophan methyl ester.
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202005748
Angewandte Chemie International Edition
RESEARCH ARTICLE
neonaucleoside
A (4) was accomplished via bioinspired
underwent the domino formal [3+2] cycloaddition to construct a
hexacyclic core, affording the cage molecule 20. The O–C bond
formation at the C7 hydroxy group and C17, and C–C bond
formation at C16 and C2, proceeded spontaneously.
transformation, with a total yield of 13% over 11 steps.
Total synthesis of (–)-cymoside.
We were therefore successful in proceeding with the oxidation
reaction, which simultaneously builds four asymmetric centers,
with cyclization, in 42% yield. Furthermore, this protocol
proceeded favorably, without the requirement for any protection
on the secondary amine. The decyanation reaction of 20, followed
by methanolysis of the acetyl groups on the sugar moiety,
proceeded smoothly under our established conditions. The
product (–)-cymoside (5) was obtained in 61% yield over two
steps. The total yield of the synthesis was 7% over only 11 steps.
(–)-Cymoside (5) was isolated from Chimarrhis cymosa
(Rubiaceae) in 2015.[5] This unusual monoterpenoid indole
alkaloid 5 has a hexacyclic skeleton that includes a propellan-type
structure, and eight asymmetric centers, including three
continuous quaternary chiral centers other than a sugar moiety,
are densely present. Grougnet and coworkers, who isolated and
determined the structure of 5, proposed a continuous oxidative
ring-closing reaction from (–)-strictosidine (1) as a biosynthetic
pathway. In 2020, Vincent and coworkers reported the first total
synthesis of (–)-cymoside (5) using achiral secologanin aglycon
via elegant bioinspired cyclization reaction.[6]
Total synthesis of (–)-3 -dihydorocadambine.
a
To establish the construction of a hexacyclic skeleton,
diastereoselective oxidative hydroxy group insertion at the C7
position was required. In the oxidation step, our additional
intention was to proceed with the total synthesis, without
protection of the secondary amine (N4), to reduce the number of
steps. We initially screened several oxidants, such as
(–)-3a-Dihydrocadambine (6) was isolated from Uncaria,
Anthocephalus, Nauclea, and Emmenopterys species that are
used as traditional medicines.[25] Its structure was determined by
careful analysis of spectroscopic data and the degradation
reaction reported by Brown and coworkers and McLean and
coworkers, independently, in 1974[25a–c]; it was finally determined
by McLean and coworkers and reported in 1982 using a
pioneering semisynthesis from naturally occurring secologanin
(2).[26] Furthermore, (–)-3a-isodihydrocadambine (21), which is
biosynthetically related to (–)-3a-dihydrocadambine (6), has been
found in plants of similar origin.[27] The hypotensive action,
antioxidant activity, COX-2 inhibitory activity, and agonistic effects
against the 5-HT1A receptor of (–)-3a-dihydrocadambine (6) have
been reported.[28] Compound 22, which is epoxidized at positions
C8 and C10 of secologanin (2), was used in our earlier synthesis
of rubenine (see details in Ref 8; Scheme 6).
dimethyldioxirane,[22]
N-sulfonyloxaziridines,[6]
and
[bis(trifluoroacetoxy)iodo]benzene,[23] to oxidize compound 12
with a cyano group remaining, under neutral conditions. However,
we were unsuccessful¾we were unable to obtain our desired
oxidative cyclized product. The reactions yielded complex
products, including b-carboline-type compounds, derived from
undesirable secondary amine oxidation.
We then conceived the idea that the desired oxidation
reaction could be performed after in situ protection of the
secondary amine as a salt under strong acidic conditions
(Scheme 5). After screening of the oxidation reaction, with various
acids, we found that m-CPBA oxidation in the presence of TFA
offered suitable oxidation conditions to introduce stereoselective
C7 oxidation.[24] Thus, after dissolving compound 12 in CH2Cl2,
TFA (10 equiv) was added under low-temperature conditions (0
°C, CH2Cl2) to achieve salt formation, and subsequently, m-CPBA
(1.05 equiv) was added. After a b-hydroxyl group was introduced
at the C7 position, the generated indoline intermediate 19
Thus, compound 22 was synthesized from secologanin
tetraacetate (7) via a three-step transformation. The Pictet–
Spengler cyclization reaction in the presence of TFA was carried
out using R-8 to construct the C3 stereocenter of (–)-3a-
dihydrocadambine (6). The product most predominantly
CN
O
10
O
H
O
8
R-8, TFA
MS 4Å
NH
H19
18
H
O
N
O
H
H
H
D-Glc(OAc)4
O
OH
CN
D-Glc(OAc)4
MeO
–
mCPBA
TFA
7
CN
NH
CF3CO2
MeO
O
2
NH2
H
O
N
N
H
22
O
42%
O
H
H
H
23
D
-Glc(OAc)4
O
D
-Glc(OAc)4
16
MeO
O
NaBH3CN
AcOH
MeO
O
17
O
19
O
12
–
CF3CO2
18
H
H
N
H
19
H
N
18
19
N
N
H
OH
O
N
H
H
N
H
H
H
H
H
+
H
H
O
O
O
D
H
NC
D
-Glc(OAc)4
-Glc(OAc)4
OH
O
NC
D-Glc(OAc)4
16
MeO
O
H
H
O
O
2
MeO
O
NH
O
17
7
H
O
D-Glc(OAc)4
N
O
H
CO2Me
CO2Me
19
25 (15%, 2 steps)
24 (37%, 2 steps)
20
K2CO3, MeOH
K2CO3, MeOH
72%
87%
1) NaBH3CN, AcOH, 73%
2) K2CO3, MeOH, 84%
3S
N
N
H
N
H
OH
N
OH
OH
H
N
H
HO
H
H
H
OH
OH
OH
H
H
H
O
O
HO
O
OH
OH
O
OH
O
MeO
O
H
H
HO
O
OH
OH MeO
O
H
O
O
O
NH
O
CO2Me
Total 7% over 11 steps
(-)-3α-dihydrocadambine (6)
Total 3% over 13 steps
(-)-3α-isodihydrocadambine (21)
(-)-cymoside (5)
Scheme 6. Syntheses of (–)-3a-dihydrocadambine and (–)-3a-
Scheme 5. Total synthesis of (–)-cymoside.
isodihydrocadambine.
6
This article is protected by copyright. All rights reserved.

10.1002/anie.202005748
Angewandte Chemie International Edition
RESEARCH ARTICLE
generated, 23, was quite unstable. The crude materials
containing 23 were directly employed in a reductive decyanation
reaction under optimized conditions. The crude product mixture of
the decyanation reaction was separated by employing silica gel
column chromatography. The desired pentacyclic seven-
membered ring-closed product 24 and the six-membered ring-
closed product 25 were obtained in yields of 37% and 15%,
respectively, over three steps (Pictet–Spengler cyclization
/reductive decyanation/cyclization reaction, via an epoxide ring-
opening reaction). After methanolysis to remove all acetyl groups
on the sugar moiety, (–)-3a-dihydrocadambine (6) and (–)-3a-
isodihydrocadambine (21) were obtained in yields of 87% and
72%, respectively. The structure of the synthesized product 6 was
assigned after careful 2D NMR analysis; the spectroscopic data
of 6 and 21 were identical to the reported data. Hence, the first
total synthesis of (–)-3a-dihydrocadambine (6) was accomplished,
over 13 steps, from commercially available materials, in a total
yield of 3%.
Chemistry of Heterocyclic Compounds, Indoles Part 4, The monoterpen-
oid Indole Alkaloids (Ed.: J. E. Saxton), Wiley, New York, 1983; e) The
Chemistry of Heterocyclic Compounds, Supplement to Volume 25, Part
4, The Monoterpenoid Indole Alkaloids, (Ed.: J. E. Saxton), Wiley, New
York, 1994; f) J. E. Saxton, Nat. Prod. Rep. 1997, 14, 559–590; g) J. Leonard,
Nat. Prod. Rep. 1999, 16, 319–338; h) G. A. Cordell, M. L. Quinn-Beattie, N. R.
Farnsworth, Phytother. Res. 2001, 15, 183–205; i) S. E. O’Connor, J. J. Maresh,
Nat. Prod. Rep. 2006, 23, 532–547; j) L. B. Pickens, Y. Tang, Y.-H. Chooi, Annu.
Rev. Chem. Biomol. Eng. 2011, 2, 211–236; k) V. Amirkia, M. Heinrich,
Phytochem. Lett. 2014, 10, xlviii–liii.
[2]
[3]
a) G. N. Smith, Chem. Commun. 1968, 912–913; b) R. T. Brown, G. N.
Smith, K. S. J. Stapleford, Tetrahedron Lett. 1968, 9, 4349; c) K. T. D.
De Silva, G. N. Smith, K. E. H. Warren, Chem. Commun. 1971, 905–906;
d) J. Stöckigt, M. H. Zenk, J. Chem. Soc., Chem. Commun. 1977, 646–
648; e) Á. Patthy-Lukáts, L. Károlyházy, L. F. Szabó, B. Podányi, J. Nat.
Prod. 1997, 60, 69–75; f) Á. Patthy-Lukáts, Á. Kocsis, L. F. Szabó, B.
Podányi, J. Nat. Prod. 1999, 62, 1492–1499.
a) A. Geerlings, F. J. Redondo, A. Contin, J. Memelink, R. van der
Heijden, R. Verpoorte, Appl. Microbiol. Biotech. 2001, 56, 420–424; b) S.
Chen, M. C. Galan, C. Coltharp, S. E. O’Connor, Chemistry & Biology
2006, 13, 1137–1141; c) M. C. Galan, E. McCoy, S. E. O’Connor, Chem.
Commun. 2007, 3249–3251; d) E. A. Loris, S. Panjikar, M. Ruppert, L.
Barleben, M. Unger, H. Schübel, J. Stöckigt, Chemistry & Biology 2007,
14, 979–985; e) J. J. Maresh, L.-A. Giddings, A. Friedrich, E. A. Loris, S.
Panjikar, B. L. Trout, J. Stöckigt, B. Peters, S. E. O’Connor, J. Am. Chem.
Soc. 2008, 130, 710–723; f) L. Yang, H. Zou, H. Zhu, M. Ruppert, J.
Gong, J. Stöckigt, Chemistry & Biodiversity 2010, 7, 860–870; g) F. Wu,
H. Zhu, L. Sun, C. Rajendran, M. Wang, X. Ren, S. Panjikar, A.
Cherkasov, H. Zou, J. Stöckigt, J. Am. Chem. Soc. 2012, 134, 1498–
1500; h) A. M. Ehrenworth, S. Sarria, P. Peralta-Yahya, ACS Synth. Biol.
2015, 4, 1295–1307; i) E.-M. Fischereder, D. Pressnitz, W. Kroutil, ACS
Catal. 2016, 6, 23–30; j) Y. Cai, H. Zhu, Z. Alperstein, W. Yu, A.
Cherkasov, H. Zou, ACS Chem. Biol. 2017, 12, 3086–3092; k) Y. Cai, N.
Shao, H. Xie, Y. Futamura, S. Panjikar, H. Liu, H. Zhu, H. Osada, H. Zou,
ACS Catal. 2019, 9, 7443–7448; l) E. Eger, A. Simon, M. Sharma, S.
Yang, W. B. Breukelaar, G. Grogan, K. N. Houk, W. Kroutil, J. Am. Chem.
Soc. 2020, 142, 792–800.
Conclusion
In conclusion, we accomplished the total syntheses of (–)-
strictosidine (1), (–)-strictosamide (3), (–)-neonaucleoside A (4),
(–)-cymoside (5), (–)-3a-dihydrocadambine (6), and (–)-3a-
isodihydrocadambine (21) in £ 13 steps. (–)-Strictosidine (1) is a
very important molecule, not only in our proposed collective total
synthesis, but also in the biosynthetic study of monoterpenoid
indole alkaloids; 1 is a common intermediate from which > 3000
alkaloids are derived, in biosynthesis. With our established
protocol, this key intermediate 1 could be prepared on a gram
scale (total 10 steps, 20% overall yield). In addition, the newly
discovered diastereoselective Pictet–Spengler cyclization
reaction to prepare 1 is recognized to proceed via a unique cyclic
transition state induced by hydrogen bonding. As a result, our new
[4]
a) R. T. Brown, D. M. Duckworth, C. A. M. Santos, Tetrahedron Lett.
1991, 32, 1987–1990; b) N. Aimi, H. Seki, S. Sakai, Chem. Pharm. Bull.
1992, 40, 2588–2590; c) O. Ohmori, H. Takayama, M. Kitajima, N. Aimi,
Chem. Pharm. Bull. 1999, 47, 1512–1513; d) R. T. Brown, M.
Kandasamy, Tetrahedron Lett. 2000, 41, 3547–3550; e) R. T. Brown, S.
B. Pratt, P. Richards, Tetrahedron Lett. 2000, 41, 5627–5630; f) F. Binns,
R. T. Brown, B. E. N. Dauda, Tetrahedron Lett. 2000, 41, 5631–5635; g)
R. T. Brown, B. E. N. Dauda, S. B. Jameson, C. A. M. Santos,
Tetrahedron Lett. 2000, 41, 8861–8865; h) R. T. Brown, B. E. N. Dauda,
S. B. Pratt, P. Richards, Heterocycles 2002, 56, 51–58; i) A. Friedrich, S.
Bräse, S. E. O’Connor, Tetrahedron Lett. 2009, 50, 75–76.
two-step
protocol
(Pictet–Spengler
reaction/reductive
decyanation reaction) is a very concise and useful alternative to
the biosynthetically employed strictosidine synthase used in
enzymatic synthesis. Furthermore, subsequent derivatization to
more complex natural products 3–6 was achieved in just a few
steps by bioinspired transformations from strictosidine
derivatives: (–)-strictosamide (3, total 11 steps, 14% overall yield),
(–)-neonaucleoside A (4, total 11 steps, 13% overall yield), (–)-
cymoside (5, total 11 steps, 7% overall yield), and (–)-3a-
dihydrocadambine (6, total 13 steps, 3% overall yield). Further
bioinspired synthetic and biological studies on glycosylated
monoterpenoid indole alkaloids are underway.
[5]
Isolation of (–)-cymoside; C. Lémus, M. Kritsanida, A. Canet, G. Genta-
Jouve, S. Michel, B. Deguin, R. Grougnet, Tetrahedron Lett. 2015, 56,
5377–5380.
[6]
[7]
[8]
[9]
Total synthesis of cymoside by Vincent et. al.; Y. Dou, C. Kouklovsky, V.
Gandon, G. Vincent, Angew. Chem., Int. Ed. 2020, 59, 1527–1531.
a) L. F. Tietze, H. Meier, H. Nutt, Chem. Ber. 1989, 122, 643–650. b) L.
F. Tietze, H. Meier, H. Nutt, Liebigs Ann. Chem. 1990, 253–260.
K. Rakumitsu, J. Sakamoto, H. Ishikawa, Chem. Eur. J. 2019, 25, 8996–
9000.
Acknowledgements
We gratefully acknowledge financial support through a Grant-in-
Aid for Scientific Research (B) (17H03059) from JSPS and the
Uehara Memorial Foundation.
Review of collective synthesis of natural products; a) L. Li, Z. Chen. X.
Zhang, Y. Jia, Chem. Rev. 2018, 118, 3752–3832; b) Z. Xu, Q. Wang, J.
Zhu, Chem. Soc. Rev. 2018, 47, 7882–7898.
[10]
Review of diastereo- and enantioselective Pictet-Spengler reaction; a)
E. L. Larghi, M. Amongero, A. B. J. Bracca, T. S. Kaufman, ARKOVIC
2005, 98–153; b) J. Stöckigt, A. P. Antonchick, F. Wu, H. Waldmann,
Angew. Chem., Int. Ed. 2011, 50, 8538–8564; c) R. Nishanth, B. Maiti, K.
Chanda, ACS Comb. Sci. 2017, 19, 199–228; d) M. M. Heravi, V.
Zadsirjan, M. Malmir, Molecules 2018, 23, 943.
Keywords: monoterpenoid indole alkaloid • bioinspired reaction
• Pictet-Spengler reaction • collective synthesis • strictosidine
[1]
a) G. A. Cordell, Introduction to Alkaloids: A Biogenetic Approach, Wiley-
Interscience; New York, 1981; b) S. W. Pelletier in The Alkaloids:
Chemical and Biological Perspectives, Vol. 1 (Ed.: S. W. Pelletier), Wiley,
New York, 1983; c) Indoles and Biogenetically Related Alkaloids (Eds.:
J. D. Phillipson, M. H. Zenk), Academic Press, London, 1980; d) The
[11] a) L. Zhang, J. M. Cook, Heterocycles 1988, 27, 2795–2802; b) L. Zhang,
Y.-Z. Bi, F.-X. Yu, G. Menzia, J. M. Cook, Heterocycles 1992, 34, 517–
7
This article is protected by copyright. All rights reserved.

10.1002/anie.202005748
Angewandte Chemie International Edition
RESEARCH ARTICLE
547; c) J. Li, J. M. Cook, J. Org. Chem. 1998, 63, 4166–4167; d) P. Yu,
J. M. Cook, J. Org. Chem. 1998, 63, 9160–916.
[12] a) M. S. Taylor, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 10558−
10559; b) J. Seayad, A. M. Seayad, B. List, J. Am. Chem. Soc. 2006,
128, 1086−1087; c) M. J. Wanner, R. N. S. van der Haas, K. R. de Cuba,
J. H. van Maarseveen, H. Hiemstra, Angew. Chem., Int. Ed. 2007, 46,
7485−7487; d) N. V. Sewgobind, M. J. Wanner, S. Ingemann, R. de
Gelder, J. H. van Maarseveen, H. Hiemstra, J. Org. Chem. 2008, 73,
6405−6408; e) R. S. Klausen, E. N. Jacobsen, Org. Lett. 2009, 11,
887−890; f) N. Mittal, D. X. Sun, D. Seidel, Org. Lett. 2014, 16,
1012−1015; g) D. Huang, F. Xu, X. Lin, Y. Wang, Chem. Eur. J. 2012,
18, 3148−3152; h) N. Glinsky-Olivier, S. Yang, P. Retailleau, V. Gandon,
X. Guinchard, Org. Lett. 2019, 21, 9446–9451; review see; h) D. Kampen,
C. M. Reisinger, B. List, Top. Curr. Chem. 2009, 291, 395−456.
NH
H
5% Na2CO3
H2O
N
N
N
H
H
17
21
O
H
20
H
D-Glc
CO2Me
MeO
O
20
17
CHO
21
O
(–)-strictosidine (1)
isomerization
N
N
H
17
R1 = CH3, R2 = H; vallesiachotamine
R1 = H,R2 = CH3; isovallesiachotamine
H
CO2Me
CHO
20
21
R1
[13] a) D. J. Mergott, S. J. Zuend, E. N. Jacobsen, Org. Lett. 2008, 10, 745–
748; b) I. P. Kerschgens, E. Claveau, M. J. Wanner, S. Ingemann, J. H.
van Maarseveen, H. Hiemstra, Chem. Commun. 2012, 48,
12243−12245; c) C. Piemontesi, Q. Wang, J. Zhu, J. Am. Chem. Soc.
2016, 138, 11148−11151; d) I. T. Raheem, P. S. Thiara, E. A. Peterson,
E. N. Jacobsen, J. Am. Chem. Soc. 2007, 129, 13404−13405; e) J. J.
Badillo, A. Silva-García, B. H. Shupe, J. C. Fettinger, A. K. Franz,
Tetrahedron Lett. 2011, 52, 5550−5553; f) S. Duce, F. Pesciaioli, L.
Gramigna, L. Bernardi, A. Mazzanti, A. Ricci, G. Bartoli, G. Bencivenni,
Adv. Synth. Catal. 2011, 353, 860–864; g) M. J. Wanner, R. N. A. Boots,
B. Eradus, R. de Gelder, J. H. van Maarseveen, H. Hiemstra, Org. Lett.
2009, 11, 2579−2581; h) B. Herlé, M. J. Wanner, J. H. van Maarseveen,
H. Hiemstra, J. Org. Chem. 2011, 76, 8907−8912; see review; i) H.
Ishikawa, S. Shiomi, The Alkaloids, 2018, 79, 1–70.
R2
Isolation and structure elucidation see; P. G. Waterman, S. Zhong,
Planta Med. 1982, 45, 28–30.
[19] C. Zheng, Z.-Li. Xia, S.-L. You, Chem 2018, 4, 1952–1966.
[20]
A. Itoh, T. Tanahashi, N. Nagakura, T. Nishi, Phytochemistry 2003, 62,
359–369.
[21] J. H. A. Paul, A. R. Maxwell, W. F. Reynolds, J. Nat. Prod. 2003, 66, 752–
754.
[22] J. Éles, G. Kalaus, A. Lévai, I. Greiner, M. Kajtár-Peredy, P. Szabó, L.
Szabó, C. Szántay, J. Heterocyclic Chem. 2002, 39, 767–771.
[23] H. Takayama, H. Ishikawa, M. Kurihara, M. Kitajima, N. Aimi, D. Ponglux,
F. Koyama, K. Matsumoto, T. Moriyama, L. T. Yamatomo, K. Watanabe,
T. Murayama, S. Horie, J. Med. Chem. 2002, 45, 1949–1956.
[24] C. Piemontesi, Q. Wang, J. Zhu, Angew. Chem., Int. Ed. 2016, 55, 6556–
6560.
[14] Similar decyanation strategy was recently reported in Snyder’s total
synthesis of (+)-Arborisidine; Z. Zhou, A. X. Gao, S. A. Snyder, J. Am.
Chem. Soc. 2019, 141, 7715–7720.
[25] a) R. T. Brown, S. B. Fraser, Tetrahedron Lett. 1974, 23, 1957–1959; b)
G. I. Dimitrienko, D. G. Murray, S. McLean, Tetrahedron Lett. 1974, 23,
1961–1964; c) S. McLean, G. I. Dmitrienko, A. Szakolcai, Can. J. Chem.
1976, 54, 1262–1277; d) F. Hotellier, P. Delaveau, J. L. Pousset, Planta
Med. 1979, 35, 242–246; e) H. Takayama, S. Tsutsumi, M. Kitajima, D.
Santiarworn, B. Liawruangrath, N. Aimi, Chem. Pharm. Bull. 2003, 51,
232–233; f) X.-D. Wu, L. Wang, J. He, X.-Y. Li, L.-B. Dong, X. Gong, X.
Gao, L.-D. Song, Y. Li. L.-Y. Peng, Q.-S. Zhao, Hel. Chim. Acta 2013, 96,
2207–2213; g) Q. Guo, X. Si, Y. Shi, H. Yang, X. Liu, H. Liang, P. Tu, Q.
Zhang, J. Nat. Prod. 2019, 82, 3288–3301.
[15]
O. Ohmori, H. Takayama, M, Kitajima, N. Aimi, in Towards Natural
Medicine Research in the 21st Century (Proceedings of the International
Symposium on Natural Medicines) 1998, 573–582.
[16] a) R. T. Brown, C. L. Chapple, A. G. Lashford, Phytochemistry 1977, 16,
1619–1620; b) M. Zeches, B. Richard, L. Gueye-M’Bahia, L. Le Men-
Olivier, C. Delaude, J. Nat. Prod. 1985, 48, 42–46; c) H. Morita, Y.
Ichihara, K. Takeya, K. Watanabe, H. Itokawa, M. Motidome, Planta Med.
1989, 55, 288–289; d) C. A. J. Erdelmeier, A. D. Wright, J. Orjala, B.
Baumgartner, T. Rali, O. Sticher, Planta Med. 1991, 57, 149–152; e) Z.
Zhang, H. N. ElSohly, M. R. Jacob, D. S. Pasco, L. A. Walker, A. M. Clark,
J. Nat. Prod. 2001, 64, 1001–1005; f) M. Kitajima, S. Yoshida, K.
Yamagata, M. Nakamura, H. Takayama, K. Saito, H. Seki, N. Aimi,
Tetrahedron 2002, 58, 9169–9178; g) M. Kitajima, N. Fujii, F. Yoshino,
H. Sudo, K. Saito, N. Aimi, H. Takayama, Chem. Pharm. Bull. 2005, 53,
1355–1358; h) E. O. Faria, L. Kato, C. M. A. de Oliveira, B. G. Carvalho,
C. C. Silva, L. S. Sales, I. T. A. Schuquel, E. P. Silveira-Lacerda, P. G.
Delprete, Phytochemistry Lett. 2010, 3, 113–116; i) X. Huang, Y. Li, Y.
Su, X. Chai, S. Yan, Phytochemistry Lett. 2014, 7, 30–34; j) Z.-J. Zhang,
R.-N. Du, J. He, X.-D. Wu, Y. Li, R.-T. Li, Q.-S. Zhao, Helv. Chim. Acta
2016, 99, 157–160; k) H. Jiang, Y.-B. Liu, Y. Li, L. Li, S.-G. Ma, J. Qu,
S.-S. Yu, Tetrahedron 2016, 72, 1276–1284; l) A. Berger, E. Tanuhadi,
L. Brecker, J. Schinnerl, K. Valant-Vetschera, Phytochemistry 2017, 143,
124–131.
[26] a) G. N. Saunders, R. G. Hamilton, S. McLean, Tetrahedron Lett. 1982,
23, 2359–2360; b) R. G. Hamilton, G. N. Saunders, S. McLean, Can. J.
Chem. 1983, 61, 284–287.
[27] R. T. Brown, S. B. Fraser, J. Banerji, Tetrahedron Lett. 1974, 37, 3335–
3338.
[28] a) K. Aisaka, Y. Hattori, T. Kihara, T. Ishihara, K. Endo, H. Hikino, Planta
Med. 1985, 424–427; b) M. Chandel, M. Kumar, U. Sharma, B. Singh, S.
Kaur, Chem. Biodiversity 2017, 14, e1600376; c) D. P. Mishra, M. A.
Khan, D. K. Yadav, A. K. Rawat, R. K. Singh, T. Ahamad, M. K. Hussain,
M. Saquib, M. F. Khan, ChemistrySelect 2018, 3, 8468–8472.
[17] a) K. Mesia, R. K. Cimanga, L. Dhooghe, P. Cos, S. Apers, J. Totté, G.
L. Tona, L. Pieters, A. J. Vlietinck, L. Maes, J. Ethnopharmacol. 2010,
131, 10–16; b) Z. Li, Z. Li, Y. Lin, Z. Meng, G. Ding, L. Cao, N. Li, W.
Liu, W. Xiao, X. Wu, J. Xu, Chem. Biol. Drug Des. 2015, 86, 523–530;
c) V. Kuete, L. P. Sandjo, A. T. Mbaveng, J. A. Seukep, B. T. Ngadjui,
T. Efferth, BMC Complement. Altern. Med. 2015, 15, 309; d) S. Y.
Liew, K. Y. Khaw, V. Murugaiyah, C. Y. Looi, Y. L. Wong, M. R.
Mustafa, M. Litaudon, K. Awang, Phytomedicine 2015, 22, 45–48; e) D.
Li, J. Chen, J. Ye, X. Zhai, J. Song, C. Jiang, J. Wang, H. Zhang, X.
Jia, F. Zhu, J. Ethnopharmacol. 2017, 196, 66–74.
[18] The structure and synthetic pathway of vallesiachotamine and
isovallesiachotamine.
8
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10.1002/anie.202005748
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
OH
HO
OH
OH
O
O
O
N
N
H
H
O
H
MeO
HO
OH
MeO
OH
O
O
OH
O
O
(-)-neonaucleoside A
H
OH
H
HO
H
H
OH
OH
O
N
NH
H
O
OH
N
H
HO
O
H
OH
OH
O
H
O
O
MeO
O
NH
CO2Me
O
(-)-strictosidine
(-)-cymoside
N
N
H
H
OH
OH
MeO
H
H
HO
OH
OH
O
O
O
O
(-)-3α-dihydrocadambine
The collective synthesis of glycosylated monoterpenoid indole alkaloids is reported. A highly diastereoselective Pictet–Spengler
reaction with a-cyanotryptamine and secologanin tetraacetate, followed by a reductive decyanation reaction, was developed for the
synthesis of strictosidine. The subsequent bioinspired transformations resulted in the concise total syntheses of strictosamide,
neonaucleoside A, cymoside, and 3a-dihydrocadambine.
9
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