Concise asymmetric total synthesis of lycopodine and flabelliformine via cascade cyclization reaction

Article abstract of DOI:10.1016/j.tetlet.2018.12.007

The shortest asymmetric total synthesis of lycopodine (3) and the first asymmetric total synthesis of flabelliformine (4) were accomplished by a strategy that features a cascade cyclization of linear substrate (5) to construct tetracyclic structure (6).

Full text of DOI:10.1016/j.tetlet.2018.12.007

Accepted Manuscript
Concise asymmetric total synthesis of lycopodine and flabelliformine via cas-
cade cyclization reaction
Kentaro Wada, Noriyuki Kogure, Mariko Kitajima, Hiromitsu Takayama
PII:
S0040-4039(18)31439-4
https://doi.org/10.1016/j.tetlet.2018.12.007
TETL 50470
DOI:
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 November 2018
29 November 2018
3 December 2018
Please cite this article as: Wada, K., Kogure, N., Kitajima, M., Takayama, H., Concise asymmetric total synthesis
of lycopodine and flabelliformine via cascade cyclization reaction, Tetrahedron Letters (2018), doi: https://doi.org/
1
0.1016/j.tetlet.2018.12.007
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Concise asymmetric total synthesis of
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Kentaro Wada, Noriyuki Kogure, Mariko Kitajima, Hiromitsu Takayama

1
Tetrahedron Letters
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Concise asymmetric total synthesis of lycopodine and flabelliformine via cascade
cyclization reaction
Kentaro Wada, Noriyuki Kogure, Mariko Kitajima, Hiromitsu Takayama
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
—
——
ARTICLE INFO
ABSTRACT

Corresponding author. E-mail address: takayamah@faculty.chiba-u.jp (H. Takayama)
Article history:
Received
Received in revised form
Accepted
The shortest asymmetric total synthesis of lycopodine (3) and the first asymmetric total
synthesis of flabelliformine (4) were accomplished by a strategy that features a cascade
cyclization of linear substrate (5) to construct tetracyclic structure (6).
2
009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Lycopodium alkaloid
Lycopodine
Flabelliformine
Asymmetric total synthesis
Cascade reaction
Introduction
The Lycopodium alkaloids are a family of structurally diverse
and complex natural products. To date, more than 300
Lycopodium alkaloids have been isolated and characterized.1
Among them, huperzine A (1), which belongs to lycodine (2)
group (Fig. 1), showed potent activity in the reversible inhibition
of acetylcholinesterase and increased learning and memory
2
efficiency. Lycopodine (3), another representative Lycopodium
alkaloid, is a tetracyclic alkaloid in which all rings are six-
membered, similar to lycodine (2). The characteristic chemical
structure of 3, which includes five asymmetric centers, has Fig. 1.
fascinated synthetic chemists for a long time. Since its isolation
3
4
in 1881 and its structure elucidation in 1960, a number of total
5
and formal syntheses have been reported. The asymmetric total
syntheses by Carter in 20085n, 5o and by She in 2016 are notable.
5p
Carter reported the first enantioselective total synthesis via a
diastereoselective intramolecular Michael addition and
successive Mannich cyclization. Later, She developed
a
a
protecting-group-free, 12-step route to furnish (–)-lycopodine (3)
from commercially available (R)-(+)-pulegone. In the course of
6
our chemical studies on Lycopodium alkaloids, we have also
initiated the total synthesis of this historically and chemically
significant natural product. Herein, we describe the shortest total
synthesis of (–)-lycopodine (3) and its conversion into
flabelliformine (4). This synthesis features the cascade
cyclization of linear substrate 5 to construct tetracyclic structure
6
that has the same stereochemistry at C7, 12, and 13 as natural
lycopodine-type alkaloids.
Results and discussion

2
Tetrahedron Letters
8
9
In 2014, we developed a strategy for the concise asymmetric
2 3 2
iodide 13 in the presence of Zn and 5 mol% PdCl (PPh ) gave
6
e
total synthesis of lycodine (2) by capitalizing on a hint gained
ketone 14 in good yield. On the other hand, enone 17 was also
9
prepared by the Fukuyama coupling using thioester 15 prepared
1
0
11
from crotonic acid and iodide 16. Thus-obtained ketone 14
and enone 17 were subjected to olefin cross metathesis reaction
using a second-generation Hoveyda-Grubbs catalyst to give
desired linear substrate 5.
With linear substrate 5 in hand, we thoroughly examined the
reaction conditions for the key cascade cyclization step. Although
the chemical yield needed improvement, we were able to obtain
desired compound 6a in 11% yield together with diastereomeric
isomer 6b in 28% yield, when
5 was treated with
methanesulfonic acid in methanol at 40 °C. The structures of 6a
and 6b were elucidated by X-ray crystallographic analysis after
conversion into 3,5-dinitrobenzamide derivatives 18a (CCDC
Scheme 1. Previous work by our group.
1
878845) and 18b (CCDC 1878846), respectively.
Starting from tetracyclic intermediate 6a, we completed the
from the biosynthetic pathway of Lycopodium alkaloids (Scheme
total synthesis of lycopodine (3) and flabelliformine (4) as
7
1
). Treatment of linear substrate 7 under the acidic condition
5f
follows. Referring to Heathcock’s work, treatment of 6a with
gave tetracyclic lycodine skeleton (8) via cascade conjugate
addition reactions that mimics the proposed biosynthesis of
lycodine (2). By further developing this strategy, we expected
that a similar cascade reaction starting from linear substrate 5
would occur to produce tetracyclic compound 6 (Scheme 2). The
dihydropyran ring in 6 would be incorporated by the conjugate
addition of oxonium intermediate 9, and 9 would be generated
when we substitute an oxygen atom for the nitrogen atom on the
right end of compound 7. Thus-obtained tetracyclic compound 6
HBr in AcOH at r.t. gave the ammonium bromide salt, which was
then basified with NaOH to give lycopodine (3) in 80% yield by
pyrrolidine ring formation. 6b was also converted into 21, which
corresponds to 15-epi-ent-lycopodine, by the same procedure
used for the conversion of 6a into lycopodine (3). Further, α-
12
13
hydroxylation of the ketone in 3 gave flabelliformine (4) in
6% yield, thereby realizing the first asymmetric total synthesis
of this alkaloid. The synthetic 3 and 4 were respectively identical
4
would be directly converted into lycopodine (3) by referring to
Heathcock’s approach.5f
O
Me
O
Boc2N
OTBDPS
5
Our synthesis began with the preparation of linear substrate 5
for the cascade cyclization reaction (Scheme 3). The Hosomi-
Sakurai allylation of commercially available crotonamide (10)
furnished 11 in high yield and excellent diastereoselectivity, and
MsOH
MeOH
0 °C
4
Me
1
5
15
8
8
7
Me 14
1
1 had the same stereochemistry at C15 as (–)-lycopodine (3).
14
H
7
1
3
12
Removal of Evans’s oxazolidinone moiety in 11 with lithium
12
13
O 4 5 HN
NH 5
O
4
Me
H
H
Me
H
O
O
H
H
H
NH
HN
6a
6b
y. 11%
y. 28%
Et3N
3
,5-Dinitrobenzoyl chloride
CH2Cl2
Me
H
H
Me
H
O
O
H
H
H
O
O
N
N
O2N
NO2
O2N
NO2
1
8a
18b
quant.
y. 63%
Scheme 3. Synthesis of linear substrate 5.
Scheme 2. Synthetic plan in this work.
thiolate gave thioester 12 in 88% yield. Next, coupling of 12 with
Scheme 4. Cascade cyclization.

3
in all respects with the natural products, which were isolated
In conclusion, we have completed the shortest asymmetric
from Lycopodium clavatum in our laboratory.
total synthesis of lycopodine (3) (in 7 steps from commercially
available 10) and the first asymmetric total synthesis of
flabelliformine (4), via a novel cascade cyclization reaction as the
key step. Further studies are underway in our laboratory to
optimize the reaction conditions of the key cyclization step and to
examine the application of this strategy to the synthesis of other
lycopodine-type alkaloids.
Scheme 5. Synthesis of lycopodine (3) and flabelliformine (4).
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Highlights

4
Tetrahedron
The shortest-step asymmetric total synthesis of
lycopodine was accomplished.
The first asymmetric synthesis of flabelliformine was
achieved.
The strategy includes a novel cascade cyclization to
construct tetracyclic structure.