Divergent Entry to Gelsedine-Type Alkaloids: Total Syntheses of (-)-Gelsedilam, (-)-Gelsenicine, (-)-Gelsedine, and (-)-Gelsemoxonine

Article abstract of DOI:10.1021/jacs.8b08127

The gelsedine-type alkaloids possess a common oxabicyclo[3.2.2]nonane core and spiro-N-methoxyindolinone moiety along with a diversely functionalized heterocycle embedded in the compact framework. Herein we disclose a divergent entry to gelsedine-type alk

Full text of DOI:10.1021/jacs.8b08127

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Communication
Divergent entry to gelsedine-type alkaloids: Total syntheses of (-)-
gelsedilam, (-)-gelsenicine, (-)-gelsedine and (-)-gelsemoxonine
Pingluan Wang, Yang Gao, and Dawei Ma
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08127 • Publication Date (Web): 30 Aug 2018
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Divergent Entry to Gelsedine-type Alkaloids: Total Syntheses
of (–)-Gelsedilam, (–)-Gelsenicine, (–)-Gelsedine and (–)-
Gelsemoxonine
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†
Pingluan Wang , Yang Gao and Dawei Ma*
State Key Laboratory of Bioorganic & Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu,
Shanghai 200032, China
Supporting Information Placeholder
cloisomerization strategy to complete the first total synthesis of
gelsenicine (4). Soon after that, unified total synthesis of five
ABSTRACT: The gelsedineꢀtype alkaloids possess an common
10
oxabicyclo[3.2.2]nonane core and spiroꢀNꢀmethoxy indolinone
moiety, along with a diversely functionalized heterocycle embedꢀ
ded in the compact framework. Herein, we disclose a divergent
entry to gelsedineꢀtype alkaloids, which hinges on the rapid asꢀ
sembly of the common core by orchestrated application of asymꢀ
metric Michael addition, tandem oxidation/aldol cyclization and
pinacol rearrangement, and the structural diversity via a lateꢀstage
heterocyclization. The power of this strategy has been demonꢀ
strated through very short total syntheses of four gelsedineꢀtype
gelsedineꢀtype alkaloids was achieved by Fukuyama group from a
11
common intermediate. In addition, Zhao published a total synꢀ
thesis of gelsidilam by means of thiolꢀmediated conjugate addiꢀ
12
tionꢀaldol reaction. Despite these innovative strategies, efforts
toward more efficient route to this family have been scarce.
Moreover, given the fact that the comprehensive biological proꢀ
files of these alkaloids remain unclear, we seek to develop a more
efficient and divergent synthetic strategy, whereby large collecꢀ
tions of natural products or unnatural analogues could be rapidly
assembled for use as lead compounds or biological probes. Hereꢀ
in, we report the successful development of a divergent entry to
gelsedineꢀtype alkaloids, culminating in short, asymmetric total
syntheses of (–)ꢀgelsidilam (5), (–)ꢀgelsenicine (4), (–)ꢀgelsedine
alkaloids: gelsedilam, gelsenicine, gelsedine and gelsemoxonine
.
Treating human diseases by means of plant extracts has a rich
history in traditional medicine all around the world. Plants from
the genus Gelsemium, native to the subtropical and tropical Asia
and North America, are recognized as poisonous species and have
been widely used in traditional Asian medicine to treat skin ulꢀ
(
3) and (–)ꢀgelsemoxonine (6) without using protecting groups.
1
cers, dermatitis, and various ailments over a thousand years. Exꢀ
tensive phytochemical studies on Gelsemium plants have led to
2
the isolation of a series of structurally diverse alkaloids, some of
which exhibit a variety of promising therapeutic properties, inꢀ
cluding analgesic, antiꢀinflammatory, and immunomodulating
3
characteristics in addition to potent antitumor activity. Nevertheꢀ
less, the narrow therapeutic window of these alkaloids limits their
clinical use due to the lack of comprehensive biological profiling,
which was largely hampered by synthetic accessibility. Among
the five known classes of Gelsemium alkaloids, three subfamilies
possess a common spiroꢀindolinone motif, namely, gelsemineꢀ
type, humantenineꢀtype and gelsedineꢀtype (Figure 1).
The interesting biological activities displayed by Gelsemium
alkaloids and their denselyꢀpacked, polycyclic architectures have
received great attention from the synthetic community. Notably,
tremendous efforts have been devoted to the development of synꢀ
Figure 1. The Three Indolinone Subclasses of Gelsemium Alkaloids.
From a structural standpoint, gelsedineꢀtype alkaloids possess a
common oxabicyclo[3.2.2]nonane core and spiroꢀNꢀmethoxy inꢀ
dolinone moiety, along with a diversely functionalized heterocyꢀ
cle (such as pyrrolidine, pyrroline, pyrrolidinone or azetidine ring)
embedded in the compact framework (3-6; Figure 1). Our retroꢀ
synthetic analysis for these molecules is depicted in Scheme 1.
We envisioned that the synthetic diversity of these natural prodꢀ
ucts could be realized through tetracyclic nitroꢀcompound 8 or 9
via a lateꢀstage heterocyclization process. Specifically, gelsemoxꢀ
onine (6), a unique azetidineꢀcontaining alkaloid, could be derived
thetic approaches toward
gelsemine (1, Figure 1), the flagship
4
member of this family, resulting in nine total syntheses in the
past two decades. Gelsedineꢀtype alkaloids, as the largest subfamꢀ
ily of the Gelsemium alkaloids (>60 members isolated to date),
5
have received relatively less attention and only a handful of
6
7ꢀ12
semiꢀsyntheses and total syntheses
have been reported to date.
Of particular note are Fukuyama’s landmark synthesis of gelseꢀ
moxonine (6) featuring a divinylcyclopropaneꢀcycloheptadiene
rearrangement to assemble the spiroꢀquaternary center connected
13
from epoxide 7 through a biomimetic cyclization. The pyrroliꢀ
8
to the oxabicyclo[3.2.2]nonane core skeleton, and Carreira’s eleꢀ
dine and pyrroline, meanwhile, were expected to be formed by inꢀ
tramolecular condensation and reduction from ethyl ketone 8.
Likewise, the pyrrolidinone core in 5 could be accessed by reducꢀ
tion of the nitro group and the alkene in ester 9 followed by lacꢀ
gant synthesis of the same target molecule, wherein a novel ring
9
contraction was utilized to furnish the unique azetidine moiety.
Very recently, Ferreira and coꢀworkers adopted a catalyzed cyꢀ
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tamization. Compound 8 or 9 was anticipated to be derived from a
would be more favorable, leading to the cyclization product with
the matched configuration to natural products. Furthermore, the
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versatile intermediate 10 by a general acylation strategy at the αꢀ
position of ketone followed by a series of functional group maꢀ
nipulations. The oxabicyclo[3.2.2]nonane skeleton of 10 could be
constructed by a key oxonium ionꢀinduced pinacol rearrangeꢀ
17
stabilizing hydrogenꢀbonding interactions between the nitro
group and the hydroxyl group would also favor intermediate 21a.
Much to our delight, treatment of Nꢀchlorosuccinimide (NCS) and
water allowed for the formation of oxindole through hydrolysis of
14
ment of a greatly simplified oxabicyclo[3.3.1]nonane 11. The
18
quaternary stereocenter of the indolinone moiety in 11 could be
built through a tandem oxidation/aldol cyclization of tricyclic 12,
which would be further divided in half via asymmetric Michael
addition to deliver two simple known compounds 13 and 14.
the corresponding 2ꢀchloroindole, which underwent a concomiꢀ
tant aldol cyclization to exclusively produce oxabicyclo[3.3.1]ꢀ
nonane 17 as a single isomer in 90% yield. To the best of our
knowledge, this oxidationꢀcyclization cascade reaction represents
one of the few examples of ketone aldol reaction of 3ꢀsubstituted
Scheme 1. Retrosynthetic Analysis of Gelsedineꢀtype Alkaloids.
19
oxindoles. It was worth noting that quenching with silica gel and
triethylamine was essential for complete epimerization of nitro
group to form the more thermodynamically stable isomer 17,
whose absolute configuration and structural assignment was conꢀ
firmed by Xꢀray crystallographic analysis (Scheme 2).
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Scheme 2. Construction of the Key Intermediates 17 and 20.
O
Me
Me
Me
MeO
O
O
Me
1
5
N
Me
O
O
Me
NO2
Cs2CO3, Et2O
+
95%
O
dr = 1:1
1
6
NO2
Me
NCS, H2O
THF
N
Me
Me
Me
13 OMe
O
O
O
O
HO
OMe
N
O
O
Me
N
Me
OMe
O
O
N
H
O2N
21b (disfavor)
Me
Me
O
21a (favor)
Me
Me
Me
O
O
O
O
O
OMe
N
HO
HO
N
Me
OMe
O
O N
2
silica gel
Et3N 90% 22a (major)
NO
2
22b (minor)
Me
Me
AlCl3 Me
toluene
Me
AlCl3
With the above analysis in mind, we first investigated the
asymmetric Michael addition, as shown in Scheme 2. Taking inꢀ
O
O
O
Et2O
O
O
o
1
5
95
C
O
spiration from Varela’s seminal work, we decided to choose (–)ꢀ
mentholꢀderived enone 15 (readily accessible from Lꢀarabinose in
four steps, dr> 98:2) as the Michael acceptor, in the hope of acꢀ
cessing serviceable stereocontrol. Initial attempts to treat indole
HO
O
N
OMe
Me
N
Me
N
OMe
OMe
H
O
O
O
NO2
19
NO2
NO
2
17
18
16
86%
fragment 13 (easily prepared from gramine in three steps) and
dihyropyranone 15 with a variety of organic bases all met with
failure, leading to decomposition of both coupling partners in
most cases. Exhaustive experiments revealed that inorganic bases
drastically promoted the asymmetric Michael addition, providing
the desired adduct 16 in 95% yield as an 1:1 diastereoisomeric
mixture under the optimized condition. Careful structural analysis
confirmed that the dr value originated from the αꢀposition of nitro
group, which in turn indicated the chiral center at the anomeric
position fully controlled the other newly formed stereocenter.
Moving forward, we sought to establish the quaternary stereoꢀ
center of the spiroꢀNꢀmethoxy indolinone via a tandem oxidation
and aldol cyclization sequence. A stereochemical question regardꢀ
ing the configuration of the pivotal quaternary center should be
addressed and two possible transition states (21a and 21b) were
envisioned for this key cyclization. We speculated that there was
considerable steric repulsion between the nitro group and the benꢀ
zene ring in transition state 21b, whereas the transition state 21a
O
O
N
OMe
O
NO2
20
ORTEP of 17
ORTEP of 20
With ample quantities of 17 in hand, the stage was set to exploit
the pivotal pinacol rearrangement. Myriad Lewis acid and
Brønsted acid were evaluated and we were pleased to find out that
adding pꢀtoluenesulfonic acid (pꢀTsOH) to 17 in toluene solution
and heating the mixture at reflux successfully affect the oxonium
20
ionꢀinduced pinacol rearrangement to give the key intermediate
20 in 54% isolated yield, whose structure was unambiguously deꢀ
termined by Xꢀray crystallographic analysis. However, this proceꢀ
dure suffered from poor reproducibility especially at large scales
which affected the ensuing divergent synthesis. After extensive
optimization, we ultimately found that heating the mixture of
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aluminum chloride (AlCl ) and 17 in toluene/Et O (10:1, v/v) at
study the key acylation by changing every conceivable variable
3
2
1
2
3
4
5
6
7
8
9
reflux dramatically promoted the yield (86%) on a 30 mmol scale
with excellent reproducibility, providing ketone 20 (8.6 g) in a
including the base used to deprotonate, the acylation reagent, solꢀ
vent, and temperature. Emerging from this exhaustive study was
the finding that treatment 20 with KHMDS and freshly distilled
propionyl cyanide led to 1,3ꢀdiketone 26 as a single isomer in
single pass. AlCl /ether complex, mainly used in the field of oleꢀ
3
21
22
fin polymerization and aromatic alkylation , was particularly
effective for this transformation, presumably owing to its mild
22
43~55% yield after quenching with 1 M HCl. Despite the modꢀ
Lewis acidity, since the employment of AlCl alone led to total
est yield, this sequence successfully introduced the requisite acyl
unit in a straightforward fashion and validated the critical acylaꢀ
tion strategy of our synthetic design. Employment of a slight modꢀ
ification of the twoꢀstep procedure used in synthesis of gelsidilam
furnished the desired α,βꢀunsaturated ethyl ketone 28 in 47% yield
over 2 steps, thus setting the stage for the lateꢀstage heterocyclizaꢀ
tion. Selective reduction of alkene and nitro group without disꢀ
turbing the ketone group was accomplished by the combination of
NiCl2 and NaBH4 under low temperature, delivering (–)ꢀ
gelsenicine (4) in 7 steps and 6.6% overall yield from 13 and 15.
Catalytic hydrogenation of 4 with Adam’s catalyst in the hydroꢀ
3
decompostion of 17. Furthermore, structurally related Lewis acid
Al(OEt) Cl and Al(OEt)Cl , possibly produced by heating AlCl
2
2
3
and ether, were also tested for the crucial pinacol rearrangement.
Interestingly, the former kept 17 intact while the latter was able to
partially accelerate the transformation.
1
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Scheme 3. End Game of the Total Synthesis of (–)ꢀGelsedilam (5).
O
KHMDS
NCCOOMe
HO
O
O
Tf2O, DIPEA
N
11
_78 o
C
OMe 81%
N
O
gen atmosphere following the precedent reports furnished (–)ꢀ
OMe
7
3%
O
gelsedine (3) smoothly.
O2N
O2N
TfO
O
O
OMe
2
0
23
Scheme 4. Completion of the Divergent Total Syntheses of Gelsedineꢀtype Alꢀ
kaloids.
Pd(PPh3)4, DIPEA
Et3SiH, DMF, 70 o
O
C
O
KHMDS, NCCOEt
8 oC to rt
O
N
N
Tf O
O
2
OMe
8
0%
OMe
_7
O
O
O
DIPEA
65%
OMe
O2N
O
2
O N
O
25
N
N
OMe
OMe
OMe then 1 N HCl
43-55%
2
4
O
O N
O
20
O
2
O N
2
O
26
NiCl2, NaBH4
_1
0 oC to rt
O
N
O
PdCl (PPh ) , DIPEA,
2 3 2
then silica gel,
rt to 40 o
7%
OMe
TfO
Et3SiH, DMF
C
NH O
N
O
N
70 oC, 73%
O
6
(_)-gelsedilam (5)
O
OMe
OMe
O N
O
2
7
steps from known
O2N
O
28
compounds 13 and 15
24% overall yield
27
ORTEP of 5
O
N
O
NiCl , NaBH ,
Having achieved rapid assembly of common tetracyclic scafꢀ
fold in a highly efficient manner, we were positioned to test the
feasibility of the divergent synthesis and the total synthesis of (–)ꢀ
gelsidilam was first pursued (Scheme 3). Thus, treatment of 20
with potassium hexamethyldisilazide (KHMDS) and Mander’s reꢀ
2
4
_7
8 oC to rt
PtO2/H2
N
N
H
OMe
OMe
85%
44%
O
NH O
)-gelsedine (3)
8 steps from known
compounds 13 and 15
5.6% overall yield
(_
)-gelsenicine ( )
7 steps from known
compounds 13 and 15
4
(_
23
agent (methyl cyanoformate) introduced a carbomethoxy group
at the αꢀposition of the ketone group in 73% yield. An inconseꢀ
quential epimerization at the αꢀposition of the nitro group was alꢀ
so observed during the procedure, leading to the formation of 23
as a 1:1 diastereomeric mixture. Next, the enol mixture 23 was
converted to corresponding enol triflate 24 under conditions of triꢀ
6
.6% overall yield
O
O
Zn
AcOH
mCPBA, NaHCO3
O
N
56% (74% brsm)
N
N
O
O
O
OMe
OMe
fluoromethanesulfonic anhydride (Tf O) and Hünig’s base. Subꢀ
O N
O
O
2
2
O N
2
29
sequent reductive removal of the triflate group was achieved by
28
8
a
treatment with Pd(PPh ) and triethylsilane (Et SiH) to furnish
3 4
3
O
penultimate α,βꢀunsaturated methyl ester 25. We found that the
base and elevated temperature were essential for the complete
epimerization to produce more thermodynamically stable isomer
EtOH, reflux
O
HO
O
78% (2 steps)
O
N
OMe
OMe
H
O
N
O
Et
2
5. Finally, the synthetic route was completed by nickel boronhyꢀ
NH2
30
H
_
( )-gelsemoxonine (6)
drideꢀmediated reduction of the alkene and the nitro group to give
an uncyclized intermediate, which, delivered enantioenriched (–)ꢀ
9
steps from known compounds 13 and 15
.6% overall yield
6
o
gelsedilam (5) upon heating with silica gel at 40 C in only 7 steps
and 24% overall yield from 13 and 15.
Our attention was then turned to achieving a different lateꢀstage
heterocyclization to deliver (–)ꢀgelsenicine (4) and (–)ꢀgelsedine
Finally, we further extended our strategy of divergent synthesis
to a total synthesis of (–)ꢀgelsemoxonine (6). Starting from adꢀ
vanced intermediate 28, the ensuing epoxidation turned out to be
nontrivial because the wellꢀestablished alkaline conditions for α,βꢀ
unsaturated carbonyl compound all suffered from inevitable epiꢀ
merization of the αꢀposition of nitro group. After some experiꢀ
mentation, we found that the stereoselective epoxidation of 28
promoted by mCPBA gave epoxide 29 in 56% yield, along with
24% recovered 28. Subsequent reduction of the nitro group with
zinc powder and acetic acid (AcOH), followed by biomimetic cyꢀ
(
3) (Scheme 4). One overarching problem to be solved was how
to introduce an 1ꢀpropanoyl group at the αꢀcarbon of the ketone
group in 20 in a direct manner. This seemingly simple conversion
proved to be remarkably difficult. Indeed, after extensive efforts
on direct introduction of the 1ꢀpropanoyl motif were met with
failure, Fukuyama and coꢀworkers developed a fiveꢀstep sequence
8
to circumvent this obstacle. Not to be deterred, we set out to
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8
a
clization rendered synthetic (–)ꢀgelsemoxonine (6) in 78% yield
Commun. 1994, 765. (c) Newcombe, N. J.; Ya, F.; Vijn, R. J.; Hiꢀ
emstra, H.; Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994,
1
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over two steps and completed the entire route in only 9 steps and
.6% overall yield from 13 and 15.
7
67. (d) Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426. (e)
6
Atarashi, S.; Choi, J.ꢀK.; Ha, D.ꢀC.; Hart, D. J.; Kuzmich, D.; Lee, C.ꢀ
S.; Ramesh, S.; Wu, S. C. J. Am. Chem. Soc. 1997, 119, 6226. (f) Maꢀ
din, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp,
M. J. Angew. Chem. Int. Ed. 1999, 38, 2934. (g) Yokoshima, S., Toꢀ
kuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, 473. (h)
Ng, F. W.; Lin, H.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124,
In brief, we developed and implemented a divergent route to
gelsedineꢀtype alkaloids, which culminated in total syntheses of (–
ꢀgelsedilam, (–)ꢀgelsedine, (–)ꢀgelsenicine and (–)ꢀ
)
gelsemoxonine in 7ꢀ9 steps from known fragments 13 and 15
without using any protecting group. These synthetic routes feature
a number of key elements, including an asymmetric Michael addiꢀ
tion and a tandem oxidation/aldol cyclization for the introduction
of quaternary center in spiroꢀNꢀmethoxy indolinone moiety, an
unprecedented oxonium ionꢀinduced pinacol rearrangement to
construct the common oxabicyclo[3.2.2]nonane core, and a lateꢀ
stage heterocyclization process for structural diversity. The above
endeavor represents the shortest synthetic routes of gelsedineꢀtype
alkaloids to date. The versatility of the advanced intermediate 20
would facilitate the total synthesis of a diverse set of structurally
related alkaloids as well as unnatural analogues, which should acꢀ
celerate further investigations on pharmacological action and
structureꢀactivity relationships.
9
2
812. (i) Zhou, X.; Xiao, T.; Iwama, Y.; Qin, Y. Angew. Chem., Int. Ed.
012, 51, 4909. (j) Chen, X.; Duan, S.; Tao, C.; Zhai, H.; Qiu, F. G.
Nat. Commun. 2015, 6, 7204.
5) For earlier synthetic studies, see: (a) Baldwin, S. W.; Doll, R. J.
(
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ASSOCIATED CONTENT
Supporting Information.
Experimental procedures and compound characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
8) (a) Shimokawa, J.; Harada, T.; Yokoshima, S.; Fukuyama, T. J.
Am. Chem. Soc. 2011, 133, 17634. (b) Shimokawa, J.; Harada, T.; Yoꢀ
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6084.
AUTHOR INFORMATION
Corresponding Author
(
10) Newcomb, E. T.; Knutson, P. C.; Pedersen, B. A.; Ferreira, E.
M. J. Am. Chem. Soc. 2016, 138, 108.
(11) Harada, T.; Shimokawa, J.; Fukuyama, T. Org. Lett. 2016, 18,
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(12) Huang, Y.ꢀM.; Liu, Y.; Zheng, C.ꢀW.; Jin, Q.ꢀW.; Pan, L.; Pan,
R.ꢀM.; Liu, J.; Zhao, G. Chem. Eur. J. 2016, 22, 18339.
*
madw@sioc.ac.cn
Author Contributions
†
P.W. and Y.G. contributed equally.
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13) Kitajima, M.; Kogure, N.; Yamaguchi, K.; Takayama, H.; Aimi,
N. Org. Lett. 2003, 5, 2075.
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ACKNOWLEDGMENT
The authors are grateful to Chinese Academy of Sciences (supꢀ
ported by the Strategic Priority Research Program, grant
XDB20020200 & QYZDJꢀSSWꢀSLH029) and the National Natuꢀ
ral Science Foundation of China (grant 21132008 & 21831009)
for their financial support.
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arrangements in Organic Synthesis; Rojas, C. M., Ed.; John Wiley &
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NO2
O
RO
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7-9 steps
N OMe
+
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H
N
O
NH
_
OMe
O
( )-gelsedilam
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O
O
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H
N
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N OMe
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H
H
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N
H
N
_
_
Et _
H
(
)-gelsenicine
( )-gelsedine
( )-gelsemoxonine
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