Synthesis of (±)-Lasubine II Using N-Methoxyamines

Article abstract of DOI:10.1002/asia.201501143

The synthesis of (±)-lasubine II has been achieved through a three-component allylation capitalizing on the unique properties of N-methoxyamines. This reaction enabled the installation of all the carbon atoms of lasubineII in a single operation. The N-met

Full text of DOI:10.1002/asia.201501143

DOI: 10.1002/asia.201501143
Communication
Total Synthesis
Synthesis of (Æ)-Lasubine II Using N-Methoxyamines
Takashi Yokoyama, Yutaro Fukami, Takaaki Sato,* and Noritaka Chida*[a]
Abstract: The synthesis of (Æ)-lasubine II has been ach-
ieved through a three-component allylation capitalizing
on the unique properties of N-methoxyamines. This reac-
tion enabled the installation of all the carbon atoms of la-
subine II in a single operation. The N-methoxy group was
efficiently used for the subsequent nitrone formation. A
single-step cyclization of isoxazolidines or N-methoxya-
mines to form functionalized piperidine rings was also de-
veloped.
Lasubine II (1) is the most well-known member of the Lythra-
ceae alkaloids, isolated from the leaves of Lagerstroemia sub-
costata Koehne by Fuji and co-workers in 1978 (Scheme 1A).[1]
Although no biological activity of lasubine II (1) has been re-
ported to date, the Lythraceae alkaloids have been shown to
possess a range of biological activities.[2] Structurally, lasubine II
(1) possesses an arylquinolizidine structure, which is embed-
ded in a number of the Lythraceae alkaloids as a common scaf-
fold. This widely distributed structure has received considera-
ble attention from the synthetic chemists to demonstrate the
utility of new methods.[3–5]
Our research group has been engaged in a program devot-
ed to the efficient total synthesis of natural products by taking
advantage of unique properties of hetero atom–hetero atom
bonds.[6] In this context, we envisioned the synthetic approach
to (Æ)-lasubine II (1), whose key step is the three-component
allylation of N-methoxyamine 5[7,8] (Scheme 1B). Condensation
of 5 with aldehyde 6[9] in the presence of an acid would pro-
duce N-oxyiminium ion 7,[10] which would subsequently under-
go allylation to afford a-substituted N-methoxyamine 8. This
multi-component reaction could install all carbon atoms em-
bedded in lasubine II (1) in a single operation. The key to suc-
cess is based on the unique reactivities derived from the N-me-
thoxy group.[6c,d,7] In the condensation step, N-methoxyamine 5
showed high nucleophilicity even in the presence of the acid
without forming an unreactive salt. On the other hand, we pre-
Scheme 1. (A) Representative Lythraceae alkaloids. (B) Synthetic plan for la-
subine II (1) using a three-component allylation with N-methoxyamine 5.
viously reported that the resulting N-oxyiminium ion 7 had
a higher electrophilicity than that of ordinary alkyl iminium
ions. These two properties would promote the high-yielding
three-component coupling reaction. Furthermore, the N-me-
thoxy group in 8 could be used as a trigger for further trans-
formations.
Our synthesis of lasubine II (1) commenced with condensa-
tion of 3,4-dimethoxybenzaldehyde with N-methoxyamine
(Scheme 2). The resulting oxime ether was then reduced with
NaBH3CN and HCl in a one-pot sequence to give N-methoxya-
mine 5 in 96% yield. The three-component reaction of 5
smoothly took place with known aldehyde 6 in the presence
of Gd(OTf)3 (30 mol%).[11] It is noteworthy that an undesired al-
lylation of an aldehyde with allyltributylstannane prior to the
[a] T. Yokoyama, Y. Fukami, Dr. T. Sato, Prof. Dr. N. Chida
Department of Applied Chemistry
Faculty of Science and Technology
Keio University
3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522 (Japan)
E-mail: takaakis@applc.keio.ac.jp
chida@applc.keio.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201501143.
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Communication
guishable from reported spectral data including 1H NMR,
13C NMR, HRMS and IR.
During the course of our synthesis of lasubine II (1), we dis-
covered the single-step formation of the quinolizidine from
the isoxazolidine ring derived from the [3+2]cycloaddition
(Scheme 2, 12!13). We considered that this transformation
could also be applied to N-methoxyamines instead of isoxazoli-
dines, rendering our synthetic strategy based on the three-
component reaction more useful (Scheme 3). Indeed, transfor-
Scheme 3. Control experiments in single-step cyclization of N-alkoxyamines.
mations of N-methoxyamines are much less explored than
their construction. For example, cleavage of the methoxy
group under reductive conditions is known to produce secon-
dary amines. As we demonstrated in the synthesis, oxidation
of N-methoxyamines to nitrones is another practical approach.
However, there are few examples of direct formation of tertiary
amines from N-methoxyamines. Our findings could be a solu-
tion to overcome this limitation. Therefore, the feasibility of
the reaction was evaluated using model compound 15, which
was prepared by the three-component allylation of N-benzyl-
N-methoxyamine 14. As we expected, piperidine 16 was effi-
ciently produced in 75% yield upon treatment of N-methoxya-
mine 15 with activated zinc in 2m aqueous HCl at 408C. To
elucidate the mechanistic pathway of this reaction, N-methoxy-
amine 15 was converted into two possible intermediates: sec-
ondary amine 17 and aldehyde 18, which were exposed to the
optimized conditions. While the reaction of aldehyde 18 gave
piperidine 16 in only 43% yield, use of secondary amine 17
led to results similar to N-methoxyamine 15. These control ex-
periments indicated that cleavage of the methoxy group took
place faster than hydrolysis of the acetal. Furthermore, pro-
longed exposure of the aldehyde to these reductive conditions
led to decomposition.
Scheme 2. Synthesis of (Æ)-lasubine II (1).
condensation with an amino group often becomes problemat-
ic in this type of three-component coupling. However, the re-
action gave the a-substituted N-methoxyamine 8 in 93% yield
without any detectable byproduct.
Having all carbon atoms needed for lasubine II (1) installed,
we turned our attention to the construction of the quinolizi-
dine framework (Scheme 2). The N-methoxyamino group in 8
was converted to the nitrone upon treatment with meta-chlor-
operoxybenzoic acid (mCPBA) at À208C, thus providing 10 in
79% yield with complete regioselectivity.[12] A solution of ni-
trone 10 and toluene was then heated to 1308C in a sealed
tube, resulting in stereoselective formation of isoxazolidine 12
in 74% yield through the transition state 11, along with two
other diastereomers in 10% yield.[13] Surprisingly, reduction of
isoxazolidine 11 with activated zinc in aqueous HCl induced
not only cleavage of the nitrogen–oxygen bond, but also the
subsequent cyclization to provide known quinolizidine 13[4d] in
a single-step. The resulting hydroxy group was inverted under
Mitsunobu conditions, followed by methanolysis to afford (Æ)-
lasubine II (1). Our synthetic sample was found to be indistin-
A plausible reaction pathway in the cyclization of N-me-
thoxyamines was proposed on the basis of the above control
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Scheme 4. Plausible mechanism for single-step cyclization of N-alkoxy-
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experiments (Scheme 4). The initial step is reductive cleavage
of the nitrogen–oxygen bond through single electron transfer
with activated zinc. The acetal group in 17 is then hydrolyzed
under aqueous acidic conditions to generate aldehyde 19,
which readily forms iminium ion 20. Finally, the resulting imini-
um ion 20 is efficiently reduced with activated zinc to produce
piperidine 16. These four processes are well orchestrated, and
enable single-step access to piperidine rings from N-methoxya-
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In conclusion, the synthesis of (Æ)-lasubine II (1) was ach-
ieved in 7 steps with an overall yield of 39%. The synthesis in-
volved a three-component allylation of N-methoxyamines capi-
talizing on the N-methoxy group as a reactivity control ele-
ment. In addition, a single-step cyclization of N-alkoxyamines
(isoxazolidines and N-methoxyamines) broadened the utility of
our synthetic strategy. The unified total synthesis of the Lythra-
ceae alkaloids using the developed strategy is now in progress
in our laboratory.
Acknowledgements
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lated three-component reaction, see; b) S. Pramanik, P. Ghorai, Chem.
Commun. 2012, 48, 1820–1822.
This research was supported by a Grant-in-Aid for Scientific Re-
search (C) from MEXT (15K05436).
[8] For selected examples on the three-component reaction with an alde-
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Keywords: allylation · amines · lasubine · multicomponent
reactions · total synthesis
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Manuscript received: October 17, 2015
Accepted Article published: November 19, 2015
Final Article published: November 30, 2015
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