Asymmetric Total Syntheses of Kopsia Indole Alkaloids

Article abstract of DOI:10.1002/anie.201700831

The asymmetric total syntheses of a group of structurally complex Kopsia alkaloids, (?)-kopsine, (?)-isokopsine, (+)-methyl chanofruticosinate, (?)-fruticosine, and (?)-kopsanone, has been achieved. The key strategies for the construction of the molecular complexity in the targets included an asymmetric Tsuji–Trost rearrangement to set the first quaternary carbon center at C20, an intramolecular cyclopropanation by diazo decomposition to install the second and third quaternary carbon centers at C2 and C7, respectively, and a SmI₂-promoted acyloin condensation to assemble the isokopsine core. A radical decarboxylation of an isokopsine-type intermediate results in a thermodynamic partial rearrangement to give N-decarbomethoxyisokopsine and N-decarbomethoxykopsine, two key intermediates for the syntheses of Kopsia alkaloids with different subtype core structures.

Full text of DOI:10.1002/anie.201700831

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201700831
German Edition: DOI: 10.1002/ange.201700831
Natural Product Synthesis
Asymmetric Total Syntheses of Kopsia Indole Alkaloids
Lingying Leng, Xiaohan Zhou, Qi Liao, Falu Wang, Hao Song,* Dan Zhang, Xiao-Yu Liu, and
Yong Qin*
Abstract: The asymmetric total syntheses of a group of
structurally complex Kopsia alkaloids, (À)-kopsine, (À)-
isokopsine, (+)-methyl chanofruticosinate, (À)-fruticosine,
and (À)-kopsanone, has been achieved. The key strategies
for the construction of the molecular complexity in the targets
included an asymmetric Tsuji–Trost rearrangement to set the
first quaternary carbon center at C20, an intramolecular
cyclopropanation by diazo decomposition to install the
second and third quaternary carbon centers at C2 and C7,
respectively, and a SmI2-promoted acyloin condensation to
assemble the isokopsine core. A radical decarboxylation of an
isokopsine-type intermediate results in a thermodynamic par-
tial rearrangement to give N-decarbomethoxyisokopsine and
N-decarbomethoxykopsine, two key intermediates for the
syntheses of Kopsia alkaloids with different subtype core
structures.
K
opsia indole alkaloids[1] (Figure 1, 1–12) are isolated from
various Kopsia (Apocynaceae) species, which are mainly
distributed in Southeast Asia, India, and China. These
alkaloids show several impressive types of biological activity,
including cholinergic, antirheumatism, and anti-inflammation
effects.[2] Although they have a long history in terms of
isolation and identification,[3,4] kopsine (1) and kopsanone
(12) were only obtained synthetically in the 1980s, when
Magnus et al. reported their total syntheses in racemic forms
using an intramolecular Diels–Alder reaction as a key step.[5]
The first asymmetric total synthesis of 12 was reported by
MacMillan et al. in 2011 using organocatalysis, an intermo-
lecular Diels–Alder reaction, and thermodynamic rearrange-
ment of kopsinic acid as key steps.[6] The asymmetric total
synthesis of methyl N-decarbomethoxychanofruticosinate (9)
was recently described by Ma et al. using an anion oxidative
coupling as a key step.[7] To the best of our knowledge,
however, the total syntheses of fruticosine (10) and isokop-
sine (5) have not been reported.
Figure 1. Structures of the representative kopsine-related alkaloids.
challenge, these alkaloids feature a rigid and cagelike
polycyclic skeleton as well as multiple stereogenic centers,
including three all-carbon-substituted quaternary carbon
centers, the construction of which is considered to be one of
the most difficult challenges in synthetic organic chemistry.[8]
Herein, we report the asymmetric total syntheses of repre-
sentatives of all four subfamilies of these alkaloids, namely,
kopsine (1), isokopsine (5), methyl chanofruticosinate (7),
fruticosine (10), and kopsanone (12).
Our retrosynthetic analysis is outlined in Figure 2. Based
on previous semisynthetic studies it found that switching
between the kopsine and isokopsine core skeletons was
possible under basic conditions,[4b] and we reasoned that if an
isokopsine intermediate such as 13 could be efficiently
assembled, then we should be able to generate N-decarbo-
methoxyisokopsine (15) by direct radical decarbonylation. N-
Decarbomethoxykopsine (16) then should be readily pre-
pared from 15 by an acyloin rearrangement. Protection of the
nitrogen atom in 15 and 16 could afford 5 and 1, respectively.
In turn, 7 and 10 could be obtained by either direct cleavage
of the C16–C22 bond in 5 or by reduction of the ketone in 5
first, then cleavage of the C16–C22 bond, followed by an
intramolecular aldol addition of the aldehyde 17. Meanwhile,
12 could be easily generated by dehydroxylation from 16. We
envisioned that a critical nitrile intermediate (18) could be
generated by forming the C16–C22 bond by a SmI2 promoted
acyloin condensation of 19.[9] Forming the substituted pyrro-
lidine ring in 19 from 20 was envisioned by opening of the
cyclopropyl ring by a cyano anion at C2, that is, a Strecker-
type reaction, followed by a Mannich reaction. We planned to
The core skeletons of the kopsine family can be catego-
rized into four subtypes: kopsine, isokopsine, chanofrutico-
sine, and fruticosine. The latter three types are most likely
biogenetically derived from the first type by rearrangement
and fragmentation (Figure 1). In terms of the synthetic
[*] L. Leng, X. Zhou, Q. Liao, F. Wang, Dr. H. Song, Dr. D. Zhang,
Dr. X.-Y. Liu, Prof. Y. Qin
Key Laboratory of Drug Targeting and Drug Delivery Systems
of the Ministry of Education, West China School of Pharmacy
and State Key Laboratory of Biotherapy, Sichuan University
Chengdu 610041 (P.R. China)
E-mail: songhao@scu.edu.cn
yongqin@scu.edu.cn
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201700831.
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Scheme 1. Preparation of the diazo 21. Reagents and conditions:
a) (Boc)2O, DMAP, DCM, RT, 15 min, 96%; b) LiHMDS, THF, À788C,
30 min, then allyl carbonochloridate, À788C to RT, 1.5 h, 83%; c) 3-
bromo-5-(bromomethyl) isoxazole, K2CO3, acetone, reflux, 16 h, 86%;
d) [Pd2(dba)3] 25, PhMe, RT, 30 min, then reflux, 3 h, 91%, 94% ee;
e) benzo[d][1,3,2]dioxaborole, [RhCl(PPh3)3], THF, RT, 30 min, then
NaBO3·H2O, THF/H2O (v/v 4:1), 858C 92%; f) MsCl, TEA, DCM, 08C,
15 min; g) NaN3, DMF, 608C, 3 h, 95% over two steps; h) PPh3, THF/
H2O (V/V 5:1), reflux, 3 h, 91%; i) NaBH4, EtOH/THF (V/V 3:1), RT,
16 h, 27 (85%), 28 (5%); j) TrocCl, Na2CO3, DCM/H2O (V/V 1:1), RT,
1 h, 94%; k) FeCl2, CH3CN, reflux, 20 min, (l) 1H-imidazole-1-sulfonyl
azide, pyridine, RT, 3 h, 91% over two steps. dba=dibenzylideneace-
tone, DCM=dichloromethane, DMAP=4-(N,N-dimethylamino)pyri-
dine, DMF=N,N-dimethylformamide, HMDS=hexamethyldisilazide,
Ms=methanesulfonyl, TEA=triethylamine, THF=tetrahydrofuran.
Figure 2. Retrosynthetic analysis of kopsine-related alkaloids. Boc=
tert-butoxycarbonyl, Troc=2,2,2-trichloroethoxycarbonyl.
ring with FeCl2 in 29 and diazotation of the resultant b-
ketone-a-diazo intermediate furnished 21 in 86% yield.
With diazo 21 available, we then evaluated the efficiency
of various metal salts as catalysts for the intramolecular
cyclopropanation reaction (Table 1). Initial experiments on
the diazo decomposition of 21 in CH2Cl2 with [Rh(OAc)2],
Rh(C3F7CO2)2, CuOTf, Cu(OTf)2, and Cu(TBS)2 as catalysts
generate the cyclopropyl ring in 20 by a metal-salt-catalyzed
diazo decomposition of 21, a strategy that we used to
efficiently construct the quaternary carbon centers at C2
and C7 in previous indole alkaloid syntheses.[10] The diazo 21
could be generated from 22 by opening the isoxazole ring and
diazotation. The first quaternary carbon center at C20 could
be constructed from 23 by an asymmetric Tsuji–Trost
rearrangement.[11,12] The intermediate 23 could be pre-
pared from the commercially available tetrahydrocarbazo-
lone 24.
As depicted in Scheme 1, we started our synthesis with 24.
Installation of a Boc group on the indole nitrogen atom,
followed by two steps, a-acylation and a-alkylation, yielded
23 in 69% yield. Application of an asymmetric Tsuji–Trost
rearrangement[11,12] with the oxazole (S)-25 as a catalyst
provided 22 in 91% yield and 94% ee. This rearrangement
was readily implemented on a 50 gram scale without loss of
either the yield or the enantioselectivity. Three steps of
converting the terminal olefin into an azide group were
realized to afford 26 in 87% yield by subsequent borohydra-
tion, mesylation, and azide replacement. Transformation of
the azide in 26 into an amine with Ph3P in aqueous THF at
608C concomitantly resulted in formation of an imine group
at C21, which was then diastereoselectively reduced with
NaBH4 in a mixture of EtOH/THF (3:1) to give 27 and 28 in
82% combined yield and a 17:1 ratio over two steps.
Protection of the amine in 27 with Troc under basic
conditions, followed by two steps of opening of the isoxazole
À
gave very disappointing results. In these cases, only the C H
insertion byproduct 30 was obtained in low yields rather than
the desired product 20 (entries 1–5). The absolute configu-
ration of 30 was determined by its X-ray crystallographic
analysis. To our delight, diazo decomposition of 21 with
20 mol% of either [Cu(acac)2], [Cu(tfacac)2], or [Cu-
(hfacac)2] in 1,2-dichloroethane (DCE) at 808C provided 20
in 10–22% yields and 30 in 12–15% yields (entries 6–8).
Using [Cu(hfacac)2] afforded 20 with the highest yield of 22%
(entry 8). To improve the yield of 20, [Cu(hfacac)2] was then
used as the catalyst in further screening of the solvent and
temperature. The yield of 20 was enhanced to 38% when
microwave irradiation conditions (1208C) were applied in
DCE (entry 9). Further screening revealed that chloroben-
zene was the best solvent for the cyclopropanation reaction
when heating at 1208C for 30 minutes (entries 10–14). Diazo
decomposition of 21 on a 5 gram scale with 20 mol% of
[Cu(hfacac)2] provided 20 in an acceptable 52% yield and 30
in 13% yield (entry 12). Successful preparation of 20 by
cyclopropanation allowed us to build up two other quaternary
carbon centers at C2 and C7, thus propelling us forward
toward the target alkaloids.
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Table 1: Optimization of cyclopropanation reactions.[a]
Entry
Catalyst
Solvent
T [8C]/t
Yield [%]
20
30
1
2
3
4
5
6
7
8
[Rh(OAc)2]
Rh(C3F7CO2)2
CuOTf
Cu(OTf)2
Cu(TBS)2
[Cu(acac)2]
[Cu(tfacac)2]
[Cu(hfacac)2]
[Cu(hfacac)2]
[Cu(hfacac)2]
[Cu(hfacac)2]
[Cu(hfacac)2]
[Cu(hfacac)2]
[Cu(hfacac)2]
DCM
DCM
DCM
DCM
DCE
DCE
DCE
DCE
25/3 h
25/3 h
25/3 h
25/3 h
80/2 h
80/2 h
80/2 h
80/2 h
120/5 min
80/2 h
100/1 h
120/30 min
130/15 min
150/10 min
trace
none
trace
none
none
10
17
22
38
40
16
23
22
18
15
15
12
13
12
5
9[b]
10
11
12
13
14
DCE
benzene
chlorobenzene
chlorobenzene
chlorobenzene
1,2-dichloro-
benzene
45
52
49
34
17
13
15
13
Scheme 2. Asymmetric approach to the core structure.[15] Reagents and
conditions: a) Zn, EtOH/THF/AcOH (v/v/v 15:15:1), RT, 30 min;
b) CH2O (30% aq.), EtOH, reflux, 6 h, 55% over two steps;
c) CF3CO2H, DCM, 08C to RT, 1 h, d) TMSCN, AlCl3, DCM, RT, 16 h,
74% over two steps; e) SmI2 (0.1m in THF), THF, RT, 15 min, 74%;
f) HCl (concentrated), 1008C, 16 h, 81%; g) EDCI, DMAP, DCM, RT,
3 h; h) AIBN, Bu3SnH, benzene, reflux, 1 h, 35 (11%), 15 (36%), 16
(30%); j) DMP, DCM, RT, 30 min, 36%; k) 1.0m NaOH aq./1,4-
dioxane (v/v 1:1), RT, 5 min, 15 (20.6%), 16 (79.4%); l) 1.0m NaOH
aq./1,4-dioxane (v/v 1:1), RT, 5 min, 16 (84.5%), 15 (15.5%).
TMSCN=trimethylsilyl cyanide, EDCI=1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride, DMAP=4-dimethylaminopyridine,
AIBN=azodiisobutyronitrile.
[a] All reactions were performed with 20 mol% catalyst in 0.005m
concentration in freshly dried and argon-sparged solvent.[15] [b] Heating
by microwave. acac=acetylacetonyl, hfacac=hexafluoroacetylacetone,
TBS=tert-butyldimethylsilyl, Tf=trifluoromethanesulfonyl, tfacac=tri-
fluoroacetylacetone.
As shown in Scheme 2, the total synthesis was continued
using 20 as the starting material. Treatment of 20 with Zn dust
in a mixture of EtOH/THF/AcOH resulted in removal of the
Troc group and simultaneous opening of the cyclopropane
ring to form an iminium cation at C2, which was immediately
captured by ethanol to afford the amine 31. The amine 31 was
unstable under chromatography conditions because the
secondary amine in 31 was prone to forming an aminal
functional group with the carbonyl group at C22. As a result,
crude 31 was used directly in the following Mannich step, and
afforded the hexacyclic 32 in 55% yield over two steps.
Removal of the Boc group in 32 with CF3CO2H and
subsequent cyanation[13] with TMSCN and AlCl3 provided
19 in 74% overall yield over two steps. All efforts to
hydrolyze the cyano group into either an ester group or to
protect the indoline nitrogen atom as a methoxycarbonyl
group failed at this stage. The cyano group at C2 was very
unstable to both acidic and basic conditions. Based on the
strategy developed by Wei,[14] SmI2-mediated acyloin con-
densation of 19 was employed, and it proceeded smoothly at
room temperature in THF to give 18 in 74% yield. The
structures of 18 and 32 were unambiguously confirmed by
their X-ray crystallographic analyses.[15] After hydrolysis of
the cyano group in 18, the resultant carboxylic acid in 13 was
condensed with 33 to give the ester 34. Without purification,
the crude 34 was subjected to radical decarboxylation
conditions to afford the diol 35 in 11% yield and 15 in 36%
yield, both with an isokopsine skeleton, as well as 16 in 30%
yield with a kopsine skeleton. The relative configuration of
the hydroxy group at C16 in 35 was confirmed based on the
NOE correlations observed between OH-16 and H-19, and H-
6 and H-16. Oxidation of 35 with DMP provided 15 in 36%
yield. The compound 16 was believed to be an acyloin
rearrangement product of 15, which was confirmed by heating
pure 15 in benzene for 1 hour, after which time a mixture of 15
and 16 in a 1:1 ratio was detected. In accordance with
literature,[4b] when pure 15 was stirred in a mixture of 1m
NaOH and 1,4-dioxane (v/v 1:1) for 5 minutes at room
temperature, approximately four-fifths of 15 was converted
into 16. A similar result was observed when pure 16 was
stirred in the same reaction mixture, that is, about one-fifth
was converted into 15 (Scheme 2).
The late stages of the syntheses of the Kopsia family
alkaloids are illustrated in Scheme 3. Treating 15 with
triphosgene and pyridine followed by heating the reaction
mixture with absolute MeOH provided 36. Without purifica-
tion, directly heating 36 with pyridine in aqueous MeOH for
16 hours resulted in selective removal of the methoxycarbon-
ate group at C18 to give (À)-isokopsine [(À)-5][4b] in 64%
yield over two steps (Scheme 3A). Cleavage of the C16–C22
bond in 5 with Pb(OAc)4 afforded (+)-methyl chanofrutico-
sinate [(+)-7][4d] in 65% yield. (À)-Kopsine [(À)-1][5e] was
synthesized from 16 by treating 16 with triphosgene and
pyridine in CH2Cl2 and then heating the resultant cyclic
carbamate 37 in absolute MeOH for 16 hours, and it afforded
38 in 47% yield and (À)-1[4j,5e] in 42% yield (Scheme 3B).
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Acknowledgments
We are grateful for financial support from the National
Natural Science Foundation of China (21572140 and
21132006).
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkaloids · diazo compounds · natural products ·
rearrangements · total synthesis
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Scheme 3. Syntheses of Kopsia alkaloids. Reagents and conditions:
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In summary, the asymmetric total syntheses of a group of
Kopsia alkaloids [i.e., (À)-1, (À)-5, (+)-7, (À)-10, and (À)-12]
which belong to four subfamilies has been accomplished
within 23 steps. Construction of the molecular complexity in
the targets mainly relied on an asymmetric Tsuji–Trost
rearrangement, a metal-salt-catalyzed intramolecular cyclo-
propanation, and a SmI2-promoted acyloin condensation. A
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subtype core structures for the synthesis of the individual
alkaloids.
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supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
[12] For related examples in indole alkaloid syntheses, see: a) C. J.
Gartshore, D. W. Lupton, Angew. Chem. Int. Ed. 2013, 52, 4113;
Manuscript received: January 24, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Natural Product Synthesis
L. Leng, X. Zhou, Q. Liao, F. Wang,
H. Song,* D. Zhang, X.-Y. Liu,
Y. Qin*
&&& — &&&
Asymmetric Total Syntheses of Kopsia
Indole Alkaloids
Targeting the core: Asymmetric total
syntheses of a group of structurally
complex Kopsia alkaloids have been
achieved by employing a unified synthetic
strategy. Key to the success was an
intramolecular cyclopropanation, a SmI2-
promoted acyloin condensation, as well
as a radical-based rearrangement pro-
cess.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!