Asymmetric Total Syntheses of Aspidodasycarpine, Lonicerine, and the Proposed Structure of Lanciferine

Article abstract of DOI:10.1021/jacs.6b00764

Aspidodasycarpine and lonicerine are a pair of epimeric aspidophylline-type alkaloids bearing vicinal quaternary C7 and C16. The first and enantioselective total syntheses of these molecules are described here. A Ru-catalyzed asymmetric transfer hydrogenation established the first stereocenter. An Au-promoted Toste cyclization was exploited to assemble the bridged tetracyclic core and define the geometry of the exocyclic olefin; electron deficient (p-CF₃C₆H₄)₃P was a suitable ligand for this transformation. An aldol condensation followed by an intramolecular indole C3 alkylation constructed the adjacent quaternary C7 and C16 diastereoselectively, leading to a pentacyclic lactol as an advanced common intermediate for synthesizing both alkaloids. The proposed structure of lanciferine, a highly oxidized congener of aspidodasycarpine, was synthesized from the lactol by tuning the oxidation states of various carbons.

Full text of DOI:10.1021/jacs.6b00764

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Communication
Asymmetric Total Syntheses of Aspidodasycarpine,
Lonicerine, and the Proposed Structure of Lanciferine
Yong Li, Shugao Zhu, Jian Li, and Ang Li
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 10 Mar 2016
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Asymmetric Total Syntheses of Aspidodasycarpine, Lonicerine, and
the Proposed Structure of Lanciferine
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Yong Li,†,‡,§ Shugao Zhu,†,§ Jian Li,† and Ang Li*,†
†State Key Laboratory of Bioorganic and Natural Products Chemistry, Collaborative Innovation Center of
Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingꢀ
ling Road, Shanghai 200032, China
‡Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, Shaoxing University,
Shaoxing 312000, China
Supporting Information Placeholder
at a late stage through a radical/metal mediated conjugate
ABSTRACT: Aspidodasycarpine and lonicerine are a pair
addition that was hinted by Garg′s Heck cyclization.4 Durꢀ
of epimeric aspidophyllineꢀtype alkaloids bearing vicinal
ing studies of indole terpenoid synthesis,10 we realized that
quaternary C7 and C16. The first and enantioselective total
the reported synthetic strategies for aspidophyllineꢀtype
syntheses of these molecules are described here. A Ruꢀ
alkaloids, despite being concise and elegant, were perhaps
catalyzed asymmetric transfer hydrogenation established
limited to the targets carrying tertiary C16 (e.g. 2 and 3),
considering the challenge of homologation at C16 on a conꢀ
the first stereocenter. An Auꢀpromoted Toste cyclization
was exploited to assemble the bridged tetracyclic core and
gested bridged polycycle. Herein, we describe the first and
define the geometry of the exocyclic olefin; electron defiꢀ
asymmetric total syntheses of aspidodasycarpine (4) and
cient (pꢀCF3C6H4)3P was a suitable ligand for this transforꢀ
lonicerine (5) and the proposed structure of lanciferine (6)
mation. An aldol condensation followed by an intramolecuꢀ
bearing vicinal quaternary C7 and C16.11 Notably, right beꢀ
lar indole C3 alkylation constructed the adjacent quaternary
fore we submitted this manuscript, Garg et al. reported eleꢀ
C7 and C16 diastereoselectively, leading to a pentacyclic
lactol as an advanced common intermediate for synthesizꢀ
ing both alkaloids. The proposed structure of lanciferine, a
highly oxidized congener of aspidodasycarpine, was syntheꢀ
sized from the lactol by tuning the oxidation states of variꢀ
ous carbons.
gant asymmetric syntheses of (−)ꢀ2, (+)ꢀstrictamine, and
(−)ꢀ2(S)ꢀcathafoline;12 during the review process, Zhu and
Yang disclosed syntheses of (±)ꢀstrictamine and (−)ꢀ2,13
respectively.
The akuammiline (1, Figure 1) indole alkaloids have held
the attention of synthetic chemists because of their molecuꢀ
lar structures and biological properties.1 In the last decade,
a number of syntheses of vincorine2 and scholarisine A3
were accomplished with various elegant strategies. Aspidoꢀ
phylline A (2) represents a large subfamily of akuammiline
alkaloids (including
1 itself) which share an indoꢀ
line/indolenine fused azabicyclo[3.3.1]nonane system.1 In
2011, Garg et al. made a breakthrough in the synthesis camꢀ
paign toward the aspidophylline subfamily,1 by accomplishꢀ
ing the first total synthesis of (±)ꢀaspidophylline A.4 They
assembled the bridged ring system via a Heck annulation5
connecting a geometryꢀdefined alkenyl iodide with an α,βꢀ
unsaturated ester, and then developed a creative strategy of
interrupted Fisher indole synthesis6 to build the quaternary
C7. Recently, the same team disclosed the first synthesis of
(±)ꢀpicrinine (3),7 an aspidophylline congener with a higher
oxidation state. In late 2013, the groups of Zhu8 and Ma9
simultaneously reported two independent syntheses of (±)ꢀ
aspidophylline A. The former featured a beautiful desymmeꢀ
trization strategy to establish the chiral C7, and the latter
relied on a signature intramolecular oxidative coupling
strategy of the team. These endeavors strategically simpliꢀ
fied the problem of synthesizing aspidophyllineꢀtype alkaꢀ
loids into two parts: a, the construction of a tetracyclic fuꢀ
roindoline, and b, the assembly of the bridged ring system
Figure 1. Selected akuammiline alkaloids from the aspidoꢀ
phylline subfamily.
Through the retrosynthetic analysis (Scheme 1), the synthetꢀ
ic challenge of aspidodasycarpine (4) is separated into the
following problems: a, introducing the first stereocenter; b,
assembling the 2ꢀazabicyclo[3.3.1]nonane unit with an exoꢀ
cyclic C═C bond; c, constructing the adjacent quaternary C7
and C16. The natural product is first traced back to an adꢀ
vance intermediate 7; lactol reductive opening may spontaꢀ
neously furnish furoindoline motif. Disconnection at C6−C7
bond gives indole derivative 8. A diastereoselective cyclizaꢀ
tion would secure the configuration of quaternary C7 based
on the stereochemistry at C16. Compound 8 is simplified to
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aldehyde 9, the benzylic quaternary center of which could
We then direct our attention to constructing the vicinal
1
2
3
4
5
6
7
8
be built via an aldol condensation. Nitrile 10 and ketone 11
are then envisioned as intermediates in our synthetic route.
Inspired by our synthesis of daphenylline,14 we plan to use
Toste cyclization15 for constructing the bridged ring system
from a simple precursor 12. The geometry of the trisubstiꢀ
tuted exocyclic olefin should be defined by a trans alkyne
activation mode of Au(I) catalysis.16 The initial stereocenter
would be introduced by asymmetric reductive amination,
which leads to a pair of known compounds 13 and 14. Noꢀ
tably, lactol 7 can serve as a common intermediate for synꢀ
thesizing lonicerine (5) and lanciferine (6). The flexibility of
tuning the lactol oxidation state enables us to assemble the
oxidized furoindoline moiety of 6, although a lateꢀstage
diastereoselective epoxidation could be a challenge as well.
quaternary C7 and C16 (Scheme 3). Ketone 18 was convertꢀ
ed to nitrile 22 with good overall efficiency, through a twoꢀ
step sequence of homologation10d (NaBH4 reduction and
BF3•OEt2 promoted cyanation). DIBALꢀH reduction of 22
Scheme 2. Assembly of a Bridged Tetracycle
Me
a) MgSO4, 4 Å MS
O
HN
15
b) , HCO2Na,
NH2
Bu4NBr, 68% (2 steps)
HN
+
HN
9
Me
10
11
12
13
14
15
16
17
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Me
Me
Me
Cl
Ru
16
13
14
(95% ee)
Ts
N
NH2 15
c) TsCl, Et3N,
83%
Scheme 1. Retrosynthetic Analysis of 4
Ph
Ph
t-Bu
d) DDQ, 93%
e) o-NsCl, Et3N,
4-DMAP, 70%
N
N
18
ORTEP of
H
t-Bu
t-Bu
21
Ts
Me
f) TIPSOTf, Et3N, 94%
g) (p-CF3Ph)3PAuCl,
21
AgSbF6, , 4 Å MS
N
Ts
N
o-Ns
o-Ns
Me
N
N
H
O
O
18
17
Table 1. Studies of the Toste cyclization.
Entry
Conditions
18 (%)
55
20 (%)
a
1
2
3
4
5
Ph3PAuCl, AgSbF6
8
27
43
6
a
iPrAuCl, AgSbF6
[JohnPhosAu(MeCN)]SbF6
61
The synthesis commenced with assembling the bridged
tetracyclic core of the natural products (Scheme 2). Condenꢀ
sation of ketone 14 with amine 13 (MgSO4, 4 Å MS) affordꢀ
ed the corresponding imine, which was subjected to modiꢀ
fied Deng conditions17 (Noyori catalyst 15, HCO2Na,
Bu4NBr) to give amine 16 (68% yield for the two steps, 95%
ee), along with a small amount of the benzylic alcohol. A
sequence of amine tosylation, DDQ oxidation, and indole Nꢀ
protection with oꢀNs gave compound 17 with good overall
efficiency. The benzylic carbonyl facilitated the nosylation
reaction under mild basic conditions. This indole Nꢀ
protection was essential for the success of the next enol
ether formation. To construct bridge tetracycle 18, we had
to activate ketone 17 as silyl enol ether 19 (94% yield) beꢀ
fore the Toste cyclization. In Table 1 was briefly summarized
the results of the cyclization studies. The standard condiꢀ
tions (entry 1) gave a reasonable yield of the desired 6ꢀexoꢀ
dig cyclization product 18, together with a small portion of
7ꢀendoꢀtrig cyclization product 20.12 Alkyne hydration was
a severe side reaction under these conditions. Bulky, elecꢀ
tronꢀrich ligands18,19 enhanced the overall yields of cyclizaꢀ
tion products but resulted in poor exo/endo ratio (entries 2
and 3). In contrast, (pꢀCF3C6H4)3P improved this ratio to ca.
10:1 (entry 4). Furthermore, pyrimidine20 21 suppressed
acidꢀpromoted desilylation of 19, and 4 Å MS inhibited the
alkyne hydration process; thus, 18 was obtained in 86%
yield on decagram scale, albeit with prolonged reaction
times (entry 5). Its structure was verified by Xꢀray crystalloꢀ
graphic analysis (Scheme 3).
a
45
a
(pꢀCF3C6H4)3PAuCl, AgSbF6
(pꢀCF3C6H4)3PAuCl, AgSbF6, 21, 4 Å MS b
62
86
9
a 5 mol% of [Au], MeOH/toluene (1:10), 3 h. b 3 mol% of [Au], 10 mol%
of 21, 4 Å MS, iꢀPrOH/CH2Cl2 (7:100), 3 d.
followed by aldol condensation with HCHO gave βꢀ
hydroxyaldehyde 23 (54% for the two steps) as a single diaꢀ
stereomer, which indicated a steric bias arising from the Nꢀ
containing ridge. Compound 23 underwent benzylation,
reduction, and Ns deprotection to reach alcohol 24 in 75%
overall yield, the structure of which was confirmed by Xꢀray
crystallographic analysis (Scheme 3). Notably, basic benꢀ
zylation conditions resulted in retroꢀaldol type decomposiꢀ
tion of 23, and Cl3C(C═NH)OBn suffered selfꢀinstability
issues against acid promoters. Yamada−Yu reagent 25 in
the presence of TfOH was optimal for the benzyl protection
in this case.21 Building the quaternary C7 proved to be chalꢀ
lenging, even when powerful intramolecular metalꢀ
carbenoid and allylic substitution reactions were used. Inꢀ
spired by our syntheses of anominine and epoxyeujindole A,
we prepared iodides such as 26 (ca. 1:1 dr at C5) from readiꢀ
ly available vinyl ethers and 24. Although Ueno−Stork radiꢀ
cal cyclization was fruitless in this case, Magnus′ elegant
synthesis of codeine22 reminded us of the dearomatizing
alkylation3a,b of such substrates. Under optimized condiꢀ
tions [tꢀBuOLi, DMSO, 120 °C (microwave)], cyclization of
26 proceeded with high facial selectivity to give the desired
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product (73% yield, a single diastereomer at C7 with a ca.
1.6:1 dr at C5), indicating that one epimer of 26 performed
better than the other in this reaction. Notably, the Li base
was superior to the counterpart. Treatment with
[Ir(cod)(MePPh2)2]PF6 caused the terminal C═C bond miꢀ
gration to afford acidꢀlabile enol ether,23 hydrolysis of which
gave lactol 27 in 74% overall yield as a single epimer at C5
(stereochemistry determined by NOE studies), which was
presumably the thermodynamically more favored one.
1
2
3
4
5
6
7
K
8
9
Scheme 3. Construction of a Common Intermediate
Ts
Ts
a) NaBH4, 90%
b) BF3 OEt2,
TMSCN, 76%
10
11
12
13
14
15
16
17
18
19
20
21
22
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N
N
H
H
o-Ns
o-Ns
Me
Me
N
N
H
H
CN
O
22
18
Ph
c) DIBAL-H
d) HCHO,
aq. Na2CO3
54%
(2 steps)
N
e) 25, TfOH
f) NaBH4,
then aq. NaOH,
thioglycolic acid
63% (2 steps)
F3C
OBn
Ts
25
Ts
N
N
H
H
o-Ns
Me
Me
H
HN
N
H
OBn
OH
OH
Scheme 5. Completion of the Synthesis of the Pro-
posed Structure of Lanciferine
O
23
24
Ts
Ts
O
N
g) allyl vinyl ether,
NIS, NaHCO3
ORTEP of 24
N
a) TPAP, NMO, 86%
b) aq. LiOH, 94%
94%
H
H
O
HN
Me
Me
H
N
H
Ts
Ts
N
H
h) t-BuOLi, 120 oC, 73%
N
OBn
OBn
i) [Ir(cod)(MePPh2)2]PF6,
then aq. HClO4, 74%
OH
31
O
Me
Me
HN
N
H
H
27
32
OH
7
OBn
c) AZADO,
NaClO2
d) I2, NaHCO3
OBn
91%
(2 steps)
O
5
ORTEP of ( )-
Ts
5
O
I
OH
27
O
Ts
O
O
N
26
O
H
N
I
e) Na2CO3, MeOH
79%
O
HN
O
HN
We further converted the common intermediate 27 into
aspidodasycarpine and lonicerine (4 and 5, Scheme 4), reꢀ
spectively. Reductive opening of the lactol followed by sponꢀ
taneous aminal formation provided furoindoline 28 in 90%
yield. AZADO oxidation24 and TMSCHN2 methylation gave
ester 29 smoothly. Removal of Bn with BBr3 and reductive
desulfonation with Na naphthalenide2a,9 afforded 4 with
good overall efficiency. We then swapped the reaction seꢀ
quence to synthesize 5. Debenzylation of 28 furnished diol
30 (65% yield). This compound was exposed to TPAP to
form the βꢀhydroxyaldehyde (ca. 3:1 dr at C16, chromatoꢀ
Me
O
O
Me
OBn
OMe
O
OBn
33
32
f) Na naphthalenide
g) HCHO, H2, Pd/C
50% (2 steps)
Me
O
N
O
H
Me
O
h) 4-DMAP, py
N
O
O
HN
Ph
Me
cinnamic anhydride
O
HN
Me
O
H
graphically
inseparable),
which
underwent
Lindꢀ
O
OMe
OH
OMe
79%
O
gren−Krauss−Pinnick oxidation followed by esterification to
give N4ꢀTsꢀ4 in 65% isolation yield for the three steps,
along with 11% of N4ꢀTsꢀ3. Final detosylation rendered 4.
O
6
: the proposed
structure of lanciferine
34
The H and 13C NMR spectra and optical rotation direction
1
oxidation of 31 gave the corresponding carboxylic acid,
which underwent a sequence of iodolactonization, transꢀ
esterification, and SN2ꢀtype epoxide formation to reach
compound 32, with the intermediacy of iodide 33.25 The
structure of 32 was secured by Xꢀray crystallographic analyꢀ
sis of a racemic sample (Scheme 5). Ts was swapped with
Me via desulfonation and hydrogenative reductive aminaꢀ
tion, during which Bn was removed as well; alcohol 34 was
furnished in 50% overall yield. Treatment of 34 with cinꢀ
namic anhydride and 4ꢀDMAP delivered 6 in 79% yield.
and values of the synthetic 3 and 4 were consist with those
of the authentic samples isolated by Kam et al.11e
The proposed structure of lanciferine (6) was synthesized
from the common intermediate 27 as well (Scheme 5). Oxiꢀ
dation with TPAP/NMO followed by saponification of the
resultant lactone with aq. LiOH afforded oxofuroindoline 31
with good overall efficiency. The presumed carboxylate inꢀ
termediate generated during the hydrolysis should be inꢀ
stantaneously trapped by the imine. The epoxidation of the
trisubstituted olefin from the sterically more hindered face
took advantage of an internal directing effect. AZADO
1
However, the H NMR chemical shift of C18 methyl of synꢀ
thetic 6 (δ = 1.4) drastically differed from that reported for
natural lanciferine (δ = 1.2).11c Thus, we ended up with a
synthesis of the proposed structure of lanciferine. The strucꢀ
tural reassignment attempts were hampered by the ambiguꢀ
Scheme 4. Completion of the Syntheses of 4 and 5
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1
ous and incomplete H NMR data (13C NMR data not even
available) reported in the isolation paper.11c Uncovering the
structural mystery of lanciferine has to rely on reꢀisolation
of the sample from nature.
(7) (a) Smith, J. M.; Moreno, J.; Boal, B. W.; Garg, N. K. J. Am.
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1
2
3
4
5
6
7
8
9
In summary, we accomplished enantioselective syntheses
of aspidodasycarpine, lonicerine, and the proposed strucꢀ
ture of lanciferine (3−5). A versatile common intermediate
was constructed by using an asymmetric imine hydrogenaꢀ
tion, a Toste cyclization, a diastereoselective aldol condenꢀ
sation, and an indole dearomatizing cyclization as key steps.
An iodolactonization furnished the epoxide moiety of 5 at a
late stage. These endeavors toward synthesis of akuamꢀ
miline alkaloids with the vicinal quaternary C7 and C16 may
facilitate their biological studies.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and compound characterization
(cif, pdf). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
(12) Moreno, J.; Picazo, E.; Morrill, L. A.; Smith, J. M.; Garg, N. K.
J. Am. Chem. Soc. 2016, 138, 1162.
Corresponding Author
ali@sioc.ac.cn
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Author Contributions
§Y.L. and S.Z. contributed equally.
ACKNOWLEDGMENT
This article is dedicated to the memory of Chaochao Gao.
We thank Prof. TohꢀSeok Kam for providing the authentic
1H and 13C NMR spectra and data and optical rotation direcꢀ
tion and values of 4 and 5, and Dr. Zhanchao Meng for proꢀ
cessing some NMR data. Financial support was provided by
Ministry of Science & Technology (2013CB836900), Naꢀ
tional Natural Science Foundation of China (21525209,
21290180, 21172235, 21222202), and Shanghai Science and
Technology Commission (15JC1400400).
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H
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Me
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OMe
CO2Me
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the proposed
structure of lanciferine
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aspidodasicarpine
lonicerine
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