Total synthesis of (-)-aplaminal by Buchwald-Hartwig cross-coupling of an aminal

Article abstract of DOI:10.1039/c9nj04743c

The concise total synthesis of an unusual alkaloid, aplaminal, has been accomplished. The synthetic feature is the Buchwald-Hartwig cross-coupling between a novel triazabicyclo[3.2.1]octane core and an aromatic bromide. The practicality of our approach provides aplaminal analogs and preliminary structure-cytotoxicity relationships of an aromatic moiety were achieved.

Full text of DOI:10.1039/c9nj04743c

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Total synthesis of (À)-aplaminal by
Buchwald–Hartwig cross-coupling of an aminal†
Cite this: New J. Chem., 2019,
43, 18442
Takayuki Ohyoshi, * Kei Akemoto, Ayaka Taniguchi, Takuma Ishihara and
Received 17th September 2019,
Accepted 5th November 2019
Hideo Kigoshi
*
DOI: 10.1039/c9nj04743c
rsc.li/njc
The concise total synthesis of an unusual alkaloid, aplaminal, has
been accomplished. The synthetic feature is the Buchwald–Hartwig
cross-coupling between a novel triazabicyclo[3.2.1]octane core and
an aromatic bromide. The practicality of our approach provides
aplaminal analogs and preliminary structure–cytotoxicity relation-
ships of an aromatic moiety were achieved.
Fig. 1 Structure of aplaminal (1).
Natural product synthesis and synthetic methodology may
produce synergistic effects with each other. When a chemical
reaction is developed, chemists study the synthesis of useful
compounds by using the reaction and improve it by clarifying
its scope and limitations by optimizing the reaction conditions.
For example, cross-coupling reactions are used not only in
natural product synthesis but also in a wide range of fields such
as bioconjugations, material sciences, and process chemistry.1
Among them, the Buchwald–Hartwig coupling reaction2 is used
in many syntheses involving nitrogen nucleophiles as one of the
coupling partners and their application range is wide. Many
ligands for this reaction have been developed.3
moiety via a cross-coupling reaction at a late stage of the
synthesis for the structure–activity relationships study. Although
Buchwald–Hartwig cross coupling involves amides or amines,
there have been no reports on the use of an aliphatic aminal to
date.6 Therefore, we decided to establish the adaptable synthetic
route of 1 by using the Buchwald–Hartwig cross-coupling reaction
of an aliphatic aminal as a key step.
The retrosynthetic pathway of aplaminal (1) is shown in
Scheme 1. Aplaminal (1) was synthesized by a Buchwald–Hartwig
cross-coupling of the bicyclic core 2 and an aromatic halide.
This plan would be suitable for the synthesis of its analogs.
Aplaminal (1), isolated from the Japanese sea hare Aplysia
kurodai by our group in 2008, has an unusual triazabicyclo-
[3.2.1]octane skeleton (Fig. 1).4 Owing to its unique structural
feature, aplaminal (1) has attracted the attention of synthetic
organic chemists. Smith and co-worker achieved the first elegant
total synthesis and assignment of the absolute configuration of
aplaminal.5 However, the previous biological study on aplaminal
(1) was limited to its cytotoxicity against HeLa S3 cells.4 There-
fore, we started to develop an adaptable and a scalable synthetic
route of aplaminal (1) for a structure–activity relationships study
and chemical probe development. By focusing on the aromatic
ring of aplaminal (1), we envisioned the introduction of an aryl
Department of Chemistry, Graduate School of Pure and Applied Sciences,
University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, Japan.
E-mail: ohyoshi@chem.tsukuba.ac.jp, kigoshi@chem.tsukuba.ac.jp
† Electronic supplementary information (ESI) available: Experimental protocols, char-
acterization data and NMR spectra of all new compounds. See DOI: 10.1039/c9nj04743c
Scheme 1 Retrosynthetic pathway of aplaminal (1).
18442 | New J. Chem., 2019, 43, 18442--18444 This journal is ©The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019

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Compound 2 was conveniently assembled from amine 3 by
lactamization. Because Smith reported that the hydrogenation
of a benzyl group could not succeed in the presence of an
aminal moiety,5 we decided to use an o-nitrobenzyl (oNB) group
as the protecting group on the amino functionality. The third
nitrogen functional group was introduced in aminal 4 by a
Mitsunobu reaction. Aminal 4 was then constructed by condensation
between diamine 6 and dimethyl 2-oxomalonate (5). Diamine 6 was
synthesized from commercially available Boc-L-Asn.
The starting point for this work was the synthesis of bicyclic
core 2 (Scheme 2). The known Boc-L-Dap-OH was synthesized
from Boc-L-Asn by a Hofmann rearrangement.7 Borane reduction
of the carboxylic acid moiety to a hydroxy group and the Boc
group to a methyl group followed by Boc protection of both
amino groups gave alcohol 7. Aminal 8 was obtained from
alcohol 7 by a sequence of reactions: protection of the primary
hydroxy group, removal of both Boc groups, and condensation
with oxo-malonate 5. Removal of the TBDPS group in 8 afforded
the precursor 4 for the Mitsunobu reaction. Next, we attempted
the Mitsunobu reaction8 with o-nitrobenzyl nosylamide to give the
desired compound 3 in 32% yield. After removal of the Ns
group by PhSH, lactamization gave the protected bicyclic core 9.
Removal of the oNB group with 365 nm irradiation afforded
bicyclic core 2, one of the desired coupling partners of the
Buchwald–Hartwig cross-coupling.
With the coupling partner 2 in hand, we examined the
Buchwald–Hartwig cross-coupling reaction (Scheme 3). The
Buchwald–Hartwig cross-coupling of 2 was carried out using
Pd(dba)2 and SPhos,9 a widely used phosphine ligand for this
reaction. However, aplaminal (1) could not be obtained, instead
compound 10 in which the reaction proceeded at the amide moiety
was obtained. Also, Goldberg amination10 and Chan–Lam–Evans
Scheme 3 Total synthesis of aplaminal (1).
coupling11 did not produce aplaminal (1). Therefore, we next tried
the coupling reaction with 9, in which the amide moiety was
protected. The bicyclic core 9 underwent the Buchwald–Hartwig
cross-coupling reaction of the aminal moiety. Finally, removal of the
oNB group with 365 nm irradiation afforded aplaminal (1). The
spectroscopic data of the synthesized aplaminal (1) were in full
agreement with those of the natural sample.4
Thus, total synthesis of aplaminal (1) was achieved. However,
the overall yield was low (9% yield) because of the low-yielding
Mitsunobu reaction. Therefore, we reconsidered the synthetic
route for compound 3. We thought that the instability of the
aminal moiety caused the low yield of the Mitsunobu reaction.
Therefore, the Mitsunobu reaction was performed with compound
7, but the reaction did not proceed. Alternatively, we tried to
introduce a nitrogen function by reductive amination (Scheme 4).
Dess–Martin oxidation of alcohol 7 followed by reductive amination
of the resultant aldehyde with oNBNH2 gave amine 12. After
protection of the amino group, removal of both the Boc groups
and condensation with oxo-malonate 5 gave aminal 3. In this way,
the net yield for the conversion of alcohol 7 to aminal 3 could be
improved about three times over that of the Mitsunobu reaction
route, and the overall yield of aplaminal (1) was also significantly
improved to 33%.
Thus, since the optimal synthetic route for a structure–activity
relationship was established, several analogs were synthesized
(Table 1). Interestingly, the coupling reaction proceeded with aryl
halides having an electron withdrawing group (entries 1, 2, 4, and
5), but the reaction did not occur with aryl halides having electron
donating groups (entries 7 and 8) or fluorine (entry 6). Even with a
carbomethoxy group, the ortho compound failed in the reaction
perhaps because of steric hindrance (entry 3). Although various
Scheme 2 Synthesis of bicyclic core 2, a coupling partner of Buchwald–
Hartwig cross-coupling.
Scheme 4 Improved synthesis of aminal 3.
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Table 1 Syntheses of aplaminal analogs
involving an aliphatic aminal and an aromatic bromide. Further-
more, we synthesized aplaminal analogs and investigated their
cytotoxicity, revealing that an electron withdrawing group at the
para position of the phenyl group is essential for the cytotoxicity. A
detailed structure–activity relationship study based on this syn-
thetic strategy is ongoing in our laboratory.
Entry
R
Yield (2 steps) (%)
Product
Conflicts of interest
1a
2b
3
p-CO2Me
m-CO2Me
o-CO2Me
p-Cl
p-CN
p-F
p-OMe
p-Me
H
60
13
0
6
3
0
0
0
0
Aplaminal (1)
14
15
16
17
18
19
20
21
There are no conflicts to declare.
4b
5b
6
Acknowledgements
7
8
This work was supported by Grants-in-Aid for Scientific
Research (Grant Number JP26242073) from the Japan Society
for the Promotion of Science (JSPS).
9c
a
b
c
CF3CH2OH was used. MeCN/H2O was used. PhBr and PhI were
used, respectively.
Notes and references
Table 2 Cytotoxicity of aplaminal (1) and its analogs
1 C. C. C. Johansson-Seechurn, M. O. Kitching, T. J. Colacot
and V. Snieckus, Angew. Chem., Int. Ed., 2012, 51, 5062.
2 (a) F. Paul, J. Patt and J. F. Hartwig, J. Am. Chem. Soc., 1994,
116, 5969; (b) A. S. Guram and S. L. Buchwald, J. Am. Chem.
Soc., 1994, 116, 7901.
Compound
Cytotoxicity against HeLa S3 cells IC50 values (mM)
1 (natural)
1 (synthetic)
2
10
14
16
17
29
23
41000
41000
41000
41000
72
3 D. S. Surry and S. L. Buchwald, Angew. Chem., Int. Ed., 2008,
47, 6338.
4 T. Kuroda and H. Kigoshi, Org. Lett., 2008, 10, 489.
5 A. B. Smith III and Z. Liu, Org. Lett., 2008, 10, 4363.
6 P. Ruiz-Castillo and S. L. Buchwald, Chem. Rev., 2016, 116, 12564.
7 R. S. Chhabra, A. Mahajan and C. W. Chan, J. Org. Chem.,
2002, 67, 4017.
conditions such as ligands, bases, and solvent were examined
using bromobenzene or iodobenzene, the reaction still did not
proceed (entry 9).12
Cytotoxicity against HeLa S3 cells of aplaminal (1) and its
analogs was evaluated (Table 2). As a result, synthetic aplaminal
(1) showed moderate cytotoxicity as did the natural sample. On
the other hand, compounds 2 and 10 showed no cytotoxicity,
revealing that an aromatic ring on the aminal nitrogen atom is
important for cytotoxicity. Also, the m-carbomethoxy analog 14
and chloro analog 16 showed no cytotoxicity. On the other
hand, nitrile analog 17 exhibited a slightly weaker cytotoxicity than
1. From these results, analogs with a strong electron withdrawing
group at the para position show cytotoxicity, thus supposing that the
nature and position of the substituent on the benzene moiety is
important for the interaction with the target protein.
8 T. Tsunoda, J. Otsuka, Y. Yamamiya and S. Ito, Chem. Lett.,
1994, 539.
9 T. E. Barder, S. D. Walker, J. R. Martinelli and S. L. Buchwald,
J. Am. Chem. Soc., 2005, 127, 4685.
10 (a) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003,
42, 5400; (b) I. P. Beletskaya and A. V. Cheprakov, Coord.
Chem. Rev., 2004, 248, 2337.
11 (a) D. M. T. Chan, K. L. Monaco, R.-P. Wang and M. P.
Winteres, Tetrahedron Lett., 1998, 39, 2933; (b) D. A. Evans,
J. L. Katz and T. R. West, Tetrahedron Lett., 1998, 39, 2937;
(c) P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters,
D. M. T. Chan and A. Combs, Tetrahedron Lett., 1998, 39,
2941.
12 We tried XPhos, DavePhos, JohnPhos, and BINAP as
ligands, tBuOK as a base, and DMF and xylene as solvents,
and under microwave condition. However, coupling product
could not be obtained.
Conclusions
We have accomplished a concise total synthesis of aplaminal (1). A
key step in the synthesis was the Buchwald–Hartwig cross-coupling
18444 | New J. Chem., 2019, 43, 18442--18444 This journal is ©The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019