Retro-biosynthetic construction of corynanthe alkaloid skeletons from rhynchophylline alkaloids

Article abstract of DOI:10.1039/c9ob01740b

Rhynchophylline alkaloids are bio-synthesized from corynanthe alkaloids via an oxidative rearrangement. We demonstrate here that corynanthe alkaloids could be generated from rhynchophylline alkaloids in a retro-biosynthetic manner via a Wagner-Meerwein rearrangement. A series of corynanthe analogues were afforded with good functional group tolerance and satisfactory yields.

Full text of DOI:10.1039/c9ob01740b

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DOI: 10.1039/C9OB01740B
COMMUNICATION
Retro-Biosynthetic Construction of Corynanthe Alkaloid Skeletons
from Rhynchophylline Alkaloids
Xiaogang Tong, Bingfei Shi, Qian Liu, Yanman Huo and Chengfeng Xia*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Rhynchophylline alkaloids are bio-synthesized from corynanthe comprise a new set of candidates for atypical antipsychotic as a
alkaloids via an oxidative rearrangement. We demonstrate here partial agonist of the dopamine and serotonin receptors.[7]
that corynanthe alkaloids could be generated from rhynchophylline
alkaloids in a retro-biosynthetical manner via Wagner–Meerwein
rearrangement. A series of corynanthe analogues were afforded
with good functional group tolerance and satisfactory yields.
N
N
N
N
N
N
H
H
H
H
H
H
H
H
H
H
H
H
MeO
MeO
MeO
CO2Me
CO2Me
CO2Me
Corynanthe alkaloids are characterized by
a tetracyclic
corynantheidine
hirsutine
corynantheine
tetrahydro--carboline motif (Figure 1). Biosynthetically,
corynanthe alkaloids are generated from tryptamine and iridoid
terpene secologanins under the catalysis of strictosidine
synthase (STR1) and strictosidine glucosidase (SG). Corynanthe
alkaloids are crucial progenitors for most of the monoterpene
indole alkaloids. They are converted to other kinds of complex
monoterpenoid indole alkaloids, including aspidosperma-,
iboga-, strychnos-, and yohimbs-type alkaloids, through
enzyme-catalyzed cleavage and/or formation of C–C bonds and
OMe
N
N
N
N
H
H
N
H
H
O
H
N
H
H
H
H
MeO2C
MeO2C
MeO
OH
CO2Me
geissoschizine
mitragynine
tetrahydroalstonine
Figure 1. Selected examples of corynanthe alkaloids.
Due to the importance of corynanthe alkaloids in
constructing monoterpenoid indole alkaloids, as well as their
significant biological activities, they have received considerable
attention from synthetic community. During the total synthesis
of hirsutine and antirhine, Brown, Takano, and Nakai groups
rearrangements.[1]
Rhynchophylline
alkaloids
are
biosynthesized from corynanthe alkaloids through an oxidative
rearrangement.[2] Inspired by the biosynthetic pathway, many
of the chemical synthesis of rhynchophylline alkaloids adopted
corynanthe alkaloid as the key intermediate followed by the
condensed tryptamine with secologanin analogues in
a
[4]
oxidative rearrangement using t-BuOCl[3] or OsO4
biomimetic manner.[8] The acid-catalyzed Pictet–Spengler
reaction was an extensive adopted strategy for the total
synthesis of corynanthe alkaloids.[9] Meanwhile, the amide-
derived Bischler−Napieralski cyclization was discovered to be an
elegant method for the construction of corynanthe skeleton.[10]
Here we reported the construction of corynanthe alkaloid
skeletons from rhynchophylline alkaloids via a suprafacial
Wagner–Meerwein rearrangement (scheme 1).[11] Previously,
we reported a transition metal-free intramolecular cross-
dehydrogenative coupling approach to efficiently assemble the
spirooxindole skeleton and to be converted to several
rhynchophylline alkaloids within five steps.[12] Jackson and
Smith reported that 3,3’-spirocyclic indole derivatives could
rearrange to -carbolines by reduction with LiAlH4 following by
treatment with HCl.[13] We speculated whether we could use
the oxindoles as starting materials to prepare corynanthe
.
Meanwhile, many of corynanthe alkaloids possess excellent
biological activities. Hirsutine has antihypertensive,
antiarrhythmic, and anti-influenza effects.[5] The EC50 value of
hirsutine for inhibiting the growth of influenza A virus is 0.40–
0.57 μg/mL (subtype H3N2), which is 10–20 times more potent
than the clinically used drug ribavirin.[5d] Geissoschizine methyl
ether (GM) showed reversible and non-competitive AChE
inhibition activity at concns. of 3.7 ± 0.3 μg/mL.[6] As the third-
generation antipsychotic medicine (aripiprazole), GM may
Key Laboratory of Medicinal Chemistry for Natural Resource (Ministry of
Education and Yunnan Province), School of Chemical Science and Technology,
Yunnan University, Kunming 650091, China
Email: xiacf@ynu.edu.cn
† Electronic Supplementary Information (ESI) available: Experimental details and
spectral data for new compounds. See DOI: 10.1039/x0xx00000x
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alkaloids in a retro-biosynthetic manner. However, the vigorous no rearrangement occurred when the amino-acetal
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DOI: 10.1039/C9OB01740B
reaction conditions of Jackson and Smith’s method are not intermediate derived from Ts-protected oxindole substrate was
compatible with sensitive functional groups during the subjected (Table 1, entry 1). We reasoned that the iminium
synthesis. We predicted that conversion of oxindole to imide could be difficultly generated from the Ts-protected substrate.
would facilitate the reduction under mild conditions.
The less electron-withdrawing Ac-protected amino-acetal was
then subjected to acidic conditions. However, we still did not
detect any rearrangement products (Table 1, entry 2). To our
delight, the Boc-protected 3-spirooxindole 1a afforded the
rearranged product 2a in 85% yield (Table 1, entry 3). Moreover,
the Boc protecting group was removed in the rearranged
product 2a. Meanwhile, when the substrate was protected with
other carbamate protecting groups (such as Cbz, -CO2Me, -
CO2Ph and Troc), no reaction was observed (Table 1, entry 4,
where the carbamate protecting group was Cbz). The
introducing a carbonyl or sulphonyl protecting group on the N-
1 position was to facilitate the reduction of amide to amino-
CHO
Br
R
H
OGlc
+
+
NH2
O
H
N
H
N
N
O
MeO2C
H
typtamine
secologanin
constructing tetracyclic
3-spirooxindole
by CDC approach
STR1
SG
biosynthetic
transformation
N
N
O
N
H
N
H
retro-biosynthetic
transformation
corynanthe alkaloid
skeleton
rhynchophylline alkaloid
skeleton
NOBoc
H
N
N
N
H
H
H
CO2Me
CO2Me
b)
H
H
O
O
O
N
N
N
N
N
H+
Boc
1h
Boc
Boc
1a
1c
a)
OH
d)
H
OH
O
N
H
N
S
S
N
N
N
H
H
O
H
c)
e)
f)
Scheme 1. Biosynthetic pathway for corynanthe alkaloids and rhynchophylline alkaloids,
O
O
and proposed retro-biosynthetic transformation.
N
H
N
N
3
1f
4
H
Boc
3 steps
S
S
The rearrangement substrate 3-spirooxindoles 1 with
different protecting groups were prepared according to our
reported method.[12a] As shown in Table 1, the protected
oxindoles 1 were reduced with NaBH4 to provide the
corresponding amino-acetal intermediates. Then the crude
amino-acetals were investigated for Wagner–Meerwein
rearrangement catalyzed by trifluoroacetic acid. We found that
N
O
O
H
Br
H
CO2Me
OMe
O
H
O
N
CO2Me
N
N
N
H
Boc
1i
3 steps
O
OH
N
OH
g)
N
OMe
h)
N
H
H
H
O
O
O
Table 1. Optimization of Wagner–Meerwein rearrangement.a
N
Boc
N
N
H
Boc
1e
5
1g
i)
O
O
N
N
N
H
CO2Me
N
OMe
N
i) NaBH4, MeOH
ii) acid, solvent
H
H
H
j)
O
OMe
H
N
N
CO2Me
H
O
O
PG
PG
N
N
1
2
Boc 1d
Boc 1b
Entry
Protecting group
Acid
Solvent
Yield 2
(%)b
NRc
NRc
85
Scheme 2. Procedures for synthesis of 3-spirooxindole substrates. Reagents and
conditions: a) i) trimethyl orthoacetate (5.0 equiv.), propanoic acid (0.3 equiv.), dioxane,
(PG)
Ts
Ac
1
2
3
4
5
6
7
8
9
TFA
TFA
TFA
TFA
CSA
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
PhMe
MeCN
DCE
sealed, 120 ℃, 20 h; ii) Boc2O (1.05 equiv.), DMAP (1.5 equiv.), MeCN, rt, 30 min, 54%
over 2 steps; b) PtO2 (0.1 equiv.), H2 balloon, MeOH, rt, 6 h, 67%; c) DMP (1.2 equiv.),
DCM, rt, 2 h, 74%; d) i) NH2OH.HCl (1.2 equiv.), NaOAc (1.5 equiv.), EtOH, 80 ℃, 1 h; ii)
Boc
Cbz
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
NRc
30
Boc2O (2.1 equiv.), DMAP (3.0 equiv.), MeCN, rt, 1 h, 42% over 2 steps; e) i) 1,2-
ethanedithiol (20.0 equiv.), BF3·Et2O (10.0 equiv.), DCM, rt, 8 h; ii) Boc2O (1.05 equiv.),
DMAP (1.5 equiv.), MeCN, rt, 30 min, 57% over 2 steps; f) i) dimethyl malonate (5.0
p-TsOH.H2O
CF3SO3H
TMSOTf
TFA
75
74
68
83
76
84
80
.
equiv.), NaOMe (0.5 equiv.), MeOH, rt, 12 h; ii) 1,2-ethanedithiol (20.0 equiv.), BF3 OEt2
(10.0 equiv.), DCM, rt, 8 h; iii) Boc2O (1.05 equiv.), DMAP (1.5 equiv.), MeCN, rt, 30 min,
26% over 3 steps; g) i) DIBAL (2.0 equiv.), DCM, -78 ℃, 1.5 h; ii) Boc2O (1.05 equiv.),
DMAP (1.5 equiv.), MeCN, rt, 30 min, 41% over 2 steps; h) i) allylmagnesium bromide
(5.0 equiv.), CuI (1.1 equiv.), Me2S (3.0 equiv.), THF, 0 ℃, 1 h; ii) Boc2O (1.05 equiv.),
10
11
12
TFA
TFA
TFA
CHCl3
DMAP (1.5 equiv.), MeCN, rt, 30 min, 55% over 2 steps; i) Boc2O (1.05 equiv.), DMAP (1.5
equiv.), MeCN, rt, 30 min, 74%; j) NH(OMe)Me.HC (1.05 equiv.), i-PrMgCl (3.0 equiv.),
ai) 1 (1.0 equiv.), NaBH4 (1.5 equiv.), MeOH, 0 ℃, 1.5 h; ii) acid (10.0 equiv.), DCM,
25 ℃, 12 h. bisolated yield by chromatography. cNo reaction.
THF, -20 ℃, 3 h, 73%. DMAP = 4-dimethylaminopyridine, DMP = 1,1,1-triacetoxy-1,1-
dihydro-1,2-benziodoxol-3(1H)-one, DIBAL = diisobutylaluminum hydride.
2 | J. Name., 2012, 00, 1-3
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Table 2. Investigate the substrate scope.a
were also a suitable reagents and moderate yield was obtained
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(Table 1, entry 8). Screening the solveDnOtsI: r1e0.v1e03a9le/Cd9OthBa0t174th0Be
reaction was compatible in different aprotic solvents (Table 1,
entries 9–12), and DCM was the optimal one.
N
N
R
i) NaBH4, MeOH
O
R
N
H
ii) TFA, DCM
N
To investigate the scope of the reaction, different Boc-
protected tetracyclic 3-spirooxindole substrates were
synthesized (Scheme 2). Following our previous procedures, the
alcohol 3 was efficiently prepared in three steps from
commercial available 3-(2-bromoethyl)indolin-2-one and 3-
acetylpyridine.[12a] The allyl alcohol 3 was converted to the
oxindole 1a by Johnson-Claisen rearrangement followed with
Boc protecting. Hydrogenation of the double bond catalyzed by
PtO2 afforded the substrate 1h. Oxidation of the alcohol by
periodinane gave the ketone 4, which was further converted to
oxime 1c and thioketal 1f by simple reactions. The substrate 1i
was obtained from the ketone 4 in three steps including one
Michael addition and two protecting sequences. Meanwhile,
methyl niconate was also selected for synthesis of another
general intermediate 5. Reduction by DIBAL or treatment with
allylmagnesium bromide, the intermediate 5 was efficiently
converted to the Boc-protected alcohols 1e and 1g,
respectively. Finally, Weinreb amide 1b was prepared by an
ester-amide exchange reaction in the presence of i-PrMgCl from
the Boc-protected 1d.
With the prepared tetracyclic 3-spirooxindole substrates in
hand, we next examined the retro-biosynthetic pathway to
generate corynanthe derivatives via Wagner–Meerwein
rearrangement. As illustrated in Table 2, the rearrangements
were successfully conducted regardless of the substitution
pattern and electronic properties of the piperidine ring system.
The substrate with a Weinreb amide group, which facilitated
the further transformation to ketone, was smoothly converted
to the corresponding corynanthe 2b in 52% yield. The
substrates with oxime, ester, hydroxyl, and ethylene thioketal
groups were discovered to be tolerated in the acidic-mediated
rearrangement and afforded the compounds 2c – 3f in good
yields (Table 2, entries 2–5). Meanwhile, a sterically hindered
tertiary alcoholic substrate 1g was also subjected to the
sequential reaction, giving the rearranged product 2g in 72%
yield (entry 6). In addition, two rhynchophylline-type alkaloids
with tetra–substituted piperidine moieties were also suitable to
this transformation, affording the corresponding corynanthe
derivatives 2h and 2i in 78% and 67% yields, respectively
(entries 7 and 8). The relative configuration of 2i was assigned
via NOESY experiments. The ROESY correlations of H-3/H-16, H-
16/H-20, and H-15/H3-18 confirmed the relative configuration
of 2i as shown in Table 2. Consequently, the retro-biosynthetic
rearrangement offered an alternative method to synthesize the
corynanthe alkaloids. For examples, after desulfurating by
Raney-Ni, the tetracyclic tetrahydro-β-carboline product 2i
could be easily delivered into (±)-hirsutine in two steps
following the known procedures.[14]
Boc
1
2
Yield
(%)b
Entry
1
Substrate
Product
O
O
N
N
N
N
OMe
H
52
83
N
H
H
2b
O
MeO
N
1b
Boc
NOBoc
NOH
N
N
H
2
N
H
H
O
2c
N
1c
Boc
O
O
N
N
OMe
OH
H
3
4
5
71
72
75
OMe
N
H
H
2d
O
N
1d
Boc
N
N
H
OH
S
O
N
H
H
N
2e
1e
Boc
S
S
S
N
N
H
N
H
H
2f
O
N
1f
Boc
OH
OH
N
N
H
6
7
72
78
N
H
H
O
2g
N
1g
Boc
H
H
S
N
N
H
CO2Me
H
N
H
H
O
CO2Me
H
N
2h
1h
Boc
S
S
N
S
N
3
H
H
20
H
15
CO2Me
8c
18CH3
67
H
N
H
16 CO2Me
H
O
H
H
CO2Me
MeO2C
N
2i
1i
Boc
aUnless otherwise noted, the reactions were performed as following: i) 1 (1.0
equiv.), NaBH4 (1.5 equiv.), MeOH, 0 ℃, 1.5 h; ii) TFA (10.0 equiv.), DCM, 25 ℃, 12
h. bisolated yield by chromatography. ckey ROESY correlations.
acetal. Since only the Boc-protected substrate could undergo
Wagner–Meerwein rearrangement, and the Boc group was
found to be removed in the product, we proposed that the de-
protecting procedure was crucial for the following
rearrangement. With the preliminary results in hand, we then
evaluated the efficiency of different acids. It was discovered
that most of the protonic acids could catalyze the
rearrangement reaction, while the stronger acid resulted in
higher yield (Table 1, entries 5 -7). Lewis acids, such as TMSOTf,
In summary, we have developed an efficient and simple two-
step process for the constructing of corynanthe skeleton from
corresponding 3-spirooxindole via a suprafacial Wagner–
Meerwein rearrangement. This methodology was also
successfully employed in synthesis of a series of tetracyclic
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Chem. 2005, 4179-4186; d) N. Sydorenko, C. A. Zificsak, A.
tetrahydro--carboline derivatives with good functional group
tolerance, which promised the preparation of different
corynanthe natural products and derivatives in a retro-
biosynthetic manner.
This work was financially supported by the National Natural
Science Foundation of China (21602194 and 21871228), and the
Program for Changjiang Scholars and Innovative Research Team
in University (IRT_17R94). We are grateful to the Advance
Analysis and Measurement Center of Yunnan University for the
helps on NMR experiments.
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Conflicts of interest
There are no conflicts to declare.
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