Bioinspired Total Synthesis of the Dimeric Indole Alkaloid (+)-Haplophytine by Direct Coupling and Late-Stage Oxidative Rearrangement

Article abstract of DOI:10.1002/anie.201609285

A bioinspired convergent total synthesis of (+)-haplophytine, a dimeric indole alkaloid with diazabicyclo[3.3.1]nonane and hexacyclic aspidosperma segments, is described. This synthesis involves the direct coupling of the two segments in a AgNTf₂-mediated Friedel–Crafts reaction and construction of the diazabicyclo[3.3.1]nonane skeleton through late-stage chemoselective aerobic oxidation of the 1,2-diaminoethene moiety and a sequential semipinacol-type rearrangement.

Full text of DOI:10.1002/anie.201609285

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Communications
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International Edition: DOI: 10.1002/anie.201609285
German Edition: DOI: 10.1002/ange.201609285
Natural Products Synthesis
Bioinspired Total Synthesis of the Dimeric Indole Alkaloid
(+)-Haplophytine by Direct Coupling and Late-Stage Oxidative
Rearrangement
Hitoshi Satoh, Ken-ichi Ojima, Hirofumi Ueda, and Hidetoshi Tokuyama*
Abstract: A bioinspired convergent total synthesis of (+)-hap-
lophytine, dimeric indole alkaloid with diazabicyclo-
after more than a half century since its isolation; this synthesis
a
was immediately followed by a further synthesis by the
[3.3.1]nonane and hexacyclic aspidosperma segments, is
described. This synthesis involves the direct coupling of the
two segments in a AgNTf2-mediated Friedel–Crafts reaction
and construction of the diazabicyclo[3.3.1]nonane skeleton
through late-stage chemoselective aerobic oxidation of the 1,2-
diaminoethene moiety and a sequential semipinacol-type
rearrangement.
Nicolaou/Chen group.[6b]
Despite these achievements, both synthetic routes remain
unsatisfactory in terms of convergency, and no synthesis based
on the biomimetic direct coupling of the two segments, as
proposed by Corey,[4c] has been described so far. Thus, each
À
total synthesis constructed the C15 C9’ linkage at the C9’
position through a coupling reaction of the precursor of the
left segment and a partial structure of the right segment
(+)-Haplophytine (1) is a dimeric indole alkaloid[1] (Scheme 2b,c). The characteristic diazabicyclo[3.3.1]nonane
isolated from the shrub Haplophyton cimicidum, which is
native to Central America;[2] its dried leaves have been used
as an insecticide since Aztec times. Alam and co-workers
found that several compounds isolated from this plant showed
inhibitory activity against acetylcholinesterase.[3] Structurally,
1 has a characteristic diazabicyclo[3.3.1]nonane skeleton in
the left segment; the right segment possesses an aspidosperma
skeleton: specifically, the structure of (À)-aspidophytine (2;
Scheme 1). This intriguing structure has inspired a number of
synthetic studies.[4] Following the landmark total synthesis of
(À)-aspidophytine (2) by Corey and co-workers,[5a] a number
of research groups established a route to 2.[5] Recently, we
completed the first total synthesis of (+)-haplophytine (1)[6a]
Scheme 2. Rearrangement reaction of (+)-1 and its application to total
synthesis. Cbz=benzyloxycarbonyl, Ms=methanesulfonyl, Fmoc=
9-fluorenylmethoxycarbonyl, mCPBA=m-chloroperbenzoic acid,
Bn=benzyl.
Scheme 1. (+)-Haplophytine and related compounds.
skeleton was then constructed by an oxidative skeletal
rearrangement on the basis of the semipinacol-type rear-
rangement of 1 reported by Cava, Yates, et al. (Scheme 2a).[2f]
For completion of the synthesis of 1, a further lengthy
sequence was necessary to construct the right segment and
manipulate the functional groups.
On the basis of a careful inspection of the structures of the
congeners of (+)-haplophytine (1) isolated from the same
plant,[2] including cimiciduphytine (3),[2h] (À)-cimiciphytine
[*] Dr. H. Satoh, K. Ojima, Dr. H. Ueda, Prof. Dr. H. Tokuyama
Graduate School of Pharmaceutical Sciences, Tohoku University
Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: tokuyama@mail.pharm.tohoku.ac.jp
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201609285.
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(4), and (À)-norcimiciphytine (5),[2g] we hypothesized that
1 could be biosynthesized via related intermediates through
oxidation and subsequent skeletal rearrangement, as shown in
Scheme 2a. With this proposed biosynthesis in mind, we
designed a convergent route to 1 through the direct coupling
of advanced precursors of the left and the right segments and
entry 1). However, the reaction resulted in the recovery of the
b-carboline derivative 13, and the desired coupling product
trans-16 was not obtained at all. After extensive investigation,
we found that the order of mixing of the substrates was crucial
for successful coupling. Thus, iodoindolenine 14 was initially
treated with AgOTf at À108C, and then 15 was added to the
reaction mixture (procedure B) to provide the coupling
product trans-16 in 14% yield along with cis-17 (entry 2).
We also observed that the choice of the silver salt was
important for reproducibility and a high-yielding reaction.
Extensive studies with various silver salts revealed that
a
late-stage oxidation and rearrangement cascade
(Scheme 3). Thus, the coupling of 10 and 11[6a] should give
the fully elaborated compound 12 after formation of the
lactam ring, and 12 could be readily converted into haplo-
phytine (1) through the challenging late-stage chemoselective
oxidation of the 1,2-diaminoethene moiety and a semipinacol-
type rearrangement.
[7]
AgNTf2 significantly improved the reaction, and the reac-
tion in CH2Cl2 at 08C furnished the desired coupling product
in approximately 69% combined yield (trans-16/cis-17 2.8:1),
whereas AgBF4, AgPF6, and AgSbF6 gave only a trace
amount of 16.
We then converted the coupling product 16 into lactam 18
and examined the late-stage oxidative skeletal rearrangement
to construct the characteristic diazabicyclo[3.3.1]nonane
skeleton (Scheme 5). After chromatographic separation of
Scheme 3. Retrosynthesis of 1 featuring a late-stage oxidation/
rearrangement cascade and direct coupling of the two segments.
PG=protecting group.
At the outset, the direct coupling of the left and right
segments was investigated by the use of tetrahydro-b-carbo-
line 13[6a] and the aspidosperma segment 15[5h] as the
substrates (Scheme 4). Thus, after the conversion of 13 into
the corresponding iodoindolenine 14, a silver-mediated
Friedel–Crafts alkylation with the right aspidosperma seg-
ment 15 was examined by modification of the previously
established conditions.[6a] First, AgOTf was added to a mixture
of iodoindolenine 14 and indoline 15 at À108C (procedure A,
Scheme 5. Attempted oxidative skeletal rearrangement of the fully
elaborated 1,2-diaminoethene 18. DBU=1,8-diazabicyclo[5.4.0]undec-
7-ene, DMDO=dimethyldioxirane.
Scheme 4. Direct coupling of the two segments by AgNTf2-mediated Friedel–Crafts alkylation. [a] The reaction was carried out with 2 equivalents
of the silver salt relative to 14. [b] The reaction was carried out with 1.5 equivalents of the silver salt relative to 14. [c] Including a small amount of
an inseparable side product. NIS=N-iodosuccinimide, Tf=trifluoromethanesulfonyl.
2
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Table 1: Optimization of the cascade reaction.
trans-16, saponification of the sterically less hindered methyl
ester and lactamization via the acid chloride provided 18. To
our disappointment, however, all oxidative conditions tested
generated a complex mixture instead of the expected
oxidative rearrangement product 19, possibly as result of
the undesired oxidation of sensitive functional groups, such as
the tertiary amines, the electron-rich aromatic ring, and the
alkene.
In order to realize the formidable chemoselective oxida-
tion of the fully elaborated dimeric substrate, which has
several oxidation-sensitive functionalities, we tried to
enhance the reactivity of the 1,2-diaminoethene moiety by
removing the Cbz protecting group. We examined this idea by
using a model substrate (Scheme 6). First, the Cbz group of
20[8] was cleaved by hydrogenolysis or treatment with BBr3.
However, hydrogenolysis provided imine 21 instead of the
corresponding 1,2-diaminoethene 22. The expected oxidation
of imine 21 under various conditions did not proceed at all.
We next tested the Ns-protected substrate 24a.[4d] Surpris-
ingly, upon removal of the Ns group of 24a under the standard
conditions with a combination of thiophenol and cesium
carbonate,[9] the diazabicyclo[3.3.1]nonane product 23a was
obtained in 38% yield along with a trace amount of imine 21,
thus indicating that oxidation followed by skeletal rearrange-
ment somehow proceeded after removal of the Ns group.
Entry Substrate R1
R2
Atmosphere t1 [h] t2 [h] Yield[a] [%]
1
2
3
4
5
6
7
24a
24a
24a
24b
24c
24d
24e
H
H
H
Me
Me
Me
Ar
O2
air
air
air
air
air
6
38
19
46
25
50
73
57
0.5
0.5
2.0
1.5
1.5
0.5
23.5
23.5
22.0
22.5
22.5
23.5
OTs Me
OMe Me
OMe Ts
OTs Boc
[a] Yield of the isolated product. Boc=tert-butoxycarbonyl, Ts=
p-toluenesulfonyl.
possibly owing to suppression of the undesired oxidation of
the electron-rich benzene ring. Finally, the synthetically more
useful substrate 24e bearing readily removable TsO and Boc
groups gave the product in acceptable yield (Table 1, entry 7).
We propose that this cascade reaction is initiated by
nucleophilic addition of a thiolate anion to the Ns group to
give the amidosulfurous acid anion 25 via a Meisenheimer
complex (Scheme 7).[9] At this point, 25 would be oxidized in
a single-electron-transfer (SET) process to a thiyl radical
generated from the thiolate anion through aerobic oxida-
tion[11] to afford the radical species 26. Extrusion of SO2
should provide the aminyl radical 27, which would be trapped
by molecular oxygen. Then, hydroperoxide 29 would be
reduced by the thiolate anion,[12] and subsequent semipinacol-
type rearrangement should furnish 23, which has
a diazabicyclo[3.3.1]nonane skeleton.
Scheme 6. Oxidation after cleavage of the protecting group on the
nitrogen. Ns=2-nitrobenzenesulfonyl.
Considering the possibility that the thiolate anion and/or
thiyl radical species participate in the oxidation/reduction
This unexpected result prompted us to optimize the
reaction conditions as well as the structure of the substrate
(Table 1). Initially, the argon atmosphere was replaced with
oxygen after the removal of the Ns group; however, the yield
of 23a decreased to 19% (Table 1, entry 2).[10] Conversely, the
yield of 23a was improved to 46% upon the replacement of
the argon atmosphere with air (entry 3). We observed
substantial effects of substituents on the two benzene rings.
The reaction of substrate 24c bearing an electron-donating
methoxy group at the C14’ position provided the desired
product 23c in higher yield (50%) than that observed with the
tosyloxy substrate 24b (Table 1, entries 4 and 5). These results
can be explained by the influence of the C14’ substituents on
the electron density of the 1,2-diaminoethene moiety. We
discovered that the substituent on the aniline nitrogen atom
was also important. Substrate 24d, which has a tosyl group
instead of one of the two methyl groups on the nitrogen atom,
provided the product 23d in higher yield (73%, entry 6)
Scheme 7. Plausible mechanism of the cascade reaction.
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Table 2: Effect of thiophenol substituents on the cascade reaction.
elaborated dimeric substrate protected with a Ns group and
examined the feasibility of the cascade process (Scheme 8).
The aspidosperma compound 31[5h] was reduced under Luche
conditions[15] to give a secondary amine, which was allylated
to give 32. Iodoindolenine 35, the precursor of the left
segment, was readily prepared from indole 33[6a] by conver-
sion into optically active tetrahydro-b-carboline 34[16] and
treatment with NIS. As expected, the direct coupling of 32
and 35 under the AgNTf2-mediated Friedel–Crafts alkylation
conditions proceeded quite smoothly to furnish the dimeric
compounds cis-36 and trans-37 (ca. 2.4:1) in 57% combined
yield. Notably, in contrast to the Cbz-protected substrate 14,
the Ns-protected substrate 35 preferentially provided cis-
36.[17] After the separation of cis-36, the lactam ring was
formed by selective hydrolysis with Me3SnOH[18] and lactam-
ization. For the problematic deallylation of 38, we devised
novel conditions involving the use of [Pd(PPh3)4] in the
presence of PPTS and dimethyl malonate. Finally, the
secondary amine was protected with a Boc group to give 39,
ready for the key one-pot aerobic oxidation/skeletal rear-
rangement cascade. Gratifyingly, the expected cascade reac-
tion proceeded smoothly to give the desired diazabicyclo-
[3.3.1]nonane 40 with the oxidant-sensitive groups
untouched.[19]
Entry
X
t1 [h]
t2 [h]
Yield[a] [%]
1
2
3
4
5
H
1.5
0.5
0.25
0.5
2.0
22.5
23.5
23.75
23.5
22.0
73
41
70
70
89
4-MeO
4-Cl
3-Cl
2-Cl
[a] Yield of the isolated product.
process,[13] we tested various thiophenols for the oxidation/
rearrangement process (Table 2) and observed substantial
substituent effects. Thus, 4-methoxythiophenol accelerated
the removal of the Ns group; however, the oxidation/
rearrangement step was considerably slower, which led to
a decrease in the yield of 23d (Table 2, entry 1 versus 2).
Conversely, acceleration of the oxidation/rearrangement step
was observed with 4-, 3-, and 2-chlorothiophenol (entry 1
versus 3–5). 2-Chlorothiophenol gave the desired product 23d
in the highest yield (89%). These results suggested that
thiophenol, which has a higher redox potential,[14] accelerated
the oxidation process.
The total synthesis of (+)-haplophytine (1) was completed
by the endgame sequence without event. Thus, after removal
of the Boc group under thermal conditions, reductive
methylation of the two secondary amino groups provided
41. Finally, one-pot removal of the tosyl group, saponification
of the methyl ester, and oxidative formation of the lactone
ring[5a] afforded (+)-haplophytine (1).[20]
Having successfully established a one-pot aerobic oxida-
tion/skeletal rearrangement cascade for the formation of the
diazabicyclo[3.3.1]nonane skeleton, we prepared the fully
Scheme 8. Bioinspired total synthesis of (+)-haplophytine (1). PPTS=pyridinium p-toluenesulfonate, TFA=trifluoroacetic acid.
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1891; c) S. Sumi, K. Matsumoto, H. Tokuyama, T. Fukuyama,
In summary, we have completed the total synthesis of the
dimeric indole alkaloid (+)-haplophytine (1) on the basis of
a convergent strategy inspired by the presumed biosynthetic
pathway. Our convergent route relies on two key reactions:
1) the highly effective AgNTf2-mediated direct coupling of
two polycyclic indole segments, and 2) a highly chemoselec-
tive late-stage aerobic oxidation/rearrangement cascade of
the fully elaborated dimeric compound.
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[8] For the preparation of 20, see the Supporting Information.
[9] T. Kan, T. Fukuyama, Chem. Commun. 2004, 353.
[10] The decrease in the yield of 23a under an oxygen atmosphere
was possibly due to the generation of a diaryl disulfide, which
would interfere with the desired single-electron oxidation of 25
and/or reduction of 29.
Acknowledgments
This research was supported by JSPS KAKENHI Grants
JP16H01127 in Middle Molecular Strategy, JP16H00999 in
Precisely Designed Catalysts with Customized Scaffolding,
and JP10J06322, Grants-in-Aid for Scientific Research (A)
(26253001) and Young Scientists (B) (26860004), the Emer-
gency Fund of Astellas Foundation for Research on Meta-
bolic Disorders, a Banyu Foundation Research Grant, the
Shorai Foundation for Science and Technology, the Platform
Project for Supporting in Drug Discovery and Life Science
Research(Platform for Drug Discovery, Informatics, and
Structural Life Science)from the MEXT and AMED. We
thank Professor Tohru Fukuyama (Nagoya University) for
valuable discussions.
[11] F. Dꢀnꢃs, M. Pichowicz, G. Povie, P. Renaud, Chem. Rev. 2014,
114, 2587.
Keywords: alkaloids · Friedel–Crafts reaction · oxidation ·
rearrangement · total synthesis
[12] In contrast to results reported by Fukuyama and co-workers
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[13] We could not exclude the conventional autoxidation mechanism:
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[16] For a preparation of 34, see: Supporting Information.
[17] The stereoselectivity of this coupling reaction may be controlled
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[18] K. C. Nicolaou, A. A. Estrada, M. Zak, S. H. Lee, B. S. Safina,
Angew. Chem. Int. Ed. 2005, 44, 1378; Angew. Chem. 2005, 117,
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[19] A substrate bearing a methoxy group at the C14’ position
provided the corresponding product in 90% yield (for the
preparation of the substrate and the key reaction, see the
Supporting Information). However, the preparation of this
substrate required deprotection, methylation, and demethyla-
tion reactions at the C14’ position, which decreased the
efficiency of the total synthesis.
[20] The efficiency of the total synthesis (33 step longest linear
sequence in 0.59% overall yield) is higher than that of our
previous synthesis (29 step longest linear sequence in 0.11%
overall yield). Notably, the efficiency of this synthesis after the
coupling reaction is much higher (11.2% yield over 10 steps)
than that of the previous synthesis (0.79% yield over 16 steps).
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Received: September 22, 2016
Published online: && &&, &&&&
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Communications
Natural Products Synthesis
H. Satoh, K. Ojima, H. Ueda,
H. Tokuyama*
&&&& — &&&&
Bioinspired Total Synthesis of the Dimeric
Indole Alkaloid (+)-Haplophytine by
Direct Coupling and Late-Stage Oxidative
Rearrangement
Direct and to the point: In a bioinspired
convergent total synthesis of the dimeric
indole alkaloid (+)-haplophytine, the two
segments were coupled directly in a Frie-
del–Crafts reaction mediated by AgNTf2.
Another key step was the construction of
the diazabicyclo[3.3.1]nonane skeleton by
a highly chemoselective late-stage aero-
bic oxidation/skeletal rearrangement
cascade (see scheme).
6
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