Total Syntheses of Lepadiformine Marine Alkaloids with Enantiodivergency, Utilizing Hg(OTf)2-Catalyzed Cycloisomerization Reaction and their Cytotoxic Activities

Article abstract of DOI:10.1002/chem.201701475

The enantioselective total syntheses of lepadiformine marine alkaloids, azatricyclic natural products isolated from marine tunicates, were completed. These alkaloids have a unique chemical structure characterized by the trans-1-azadecalin (AB ring system) fused with the spirocyclic ring (AC ring system). Here we found that a cycloisomerization reaction from functionalized linear substrates to a 1-azaspiro[4.5]decane framework corresponding to the AC ring in lepadiformines is promoted by a catalytic amount of mercury(II) triflate (Hg(OTf)₂). The total syntheses of (?)-lepadiformines A and B were achieved in 28 % and 21 % overall yields, respectively, through the novel cycloisomerization reaction. The syntheses of (+)- and (?)-lepadiformine C hydrochloride salts also enabled us to determine the absolute configuration of natural lepadiformine C. It has been found that a phenomenon of enantiodivergence occurs in lepadiformine alkaloids from a single species of marine tunicate, Clavelina moluccensis. The cytotoxic activities of synthesized lepadiformine hydrochloride salts and their synthetic intermediates were evaluated.

Full text of DOI:10.1002/chem.201701475

A Journal of
Accepted Article
Title: Total Syntheses of Lepadiformine Marine Alkaloids
with Enantiodivergency, Utilizing Hg(OTf)₂-Catalyzed
Cycloisomerization Reaction and their Cytotoxic Activities
Authors: Keisuke Nishikawa, Kengo Yamauchi, Seiho Kikuchi,
Shinnosuke Ezaki, Tomoyuki Koyama, Haruka Nokubo,
Kunihiro Matsumura, Takeshi Kodama, Momochika Kumagai,
and Yoshiki Morimoto
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the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201701475
Link to VoR: http://dx.doi.org/10.1002/chem.201701475
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Total Syntheses of Lepadiformine Marine Alkaloids with
Enantiodivergency, Utilizing Hg(OTf)2-Catalyzed
Cycloisomerization Reaction and their Cytotoxic Activities
Keisuke Nishikawa,[a] Kengo Yamauchi,[a] Seiho Kikuchi,[a] Shinnosuke Ezaki,[a] Tomoyuki Koyama,[a]
Haruka Nokubo,[a] Kunihiro Matsumura,[a] Takeshi Kodama,[a] Momochika Kumagai,[a, b]
and Yoshiki Morimoto*[a]
Abstract: The enantioselective total syntheses of lepadiformine
marine alkaloids, azatricyclic natural products isolated from marine
tunicates, were completed. These alkaloids have a unique chemical
structure characterized by the trans-1-azadecalin (AB ring system)
fused with the spirocyclic ring (AC ring system). Here we found that a
cycloisomerization reaction from functionalized linear substrates to a
1-azaspiro[4.5]decane framework corresponding to the AC ring in
lepadiformines is promoted by a catalytic amount of mercury(II) triflate
(Hg(OTf)2). The total syntheses of (–)-lepadiformines A and B were
achieved in 28% and 21% overall yields, respectively, through the
novel cycloisomerization reaction. The syntheses of (+)- and (–)-
lepadiformine C hydrochloride salts also enabled us to determine the
absolute configuration of natural lepadiformine C. It has been found
that a phenomenon of enantiodivergence occurs in lepadiformine
alkaloids from a single species of marine tunicate, Clavelina
moluccensis. The cytotoxic activities of synthesized lepadiformine
hydrochloride salts and their synthetic intermediates were evaluated.
1. All lepadiformines exhibit an effect on the cardiovascular
system and block the cardiac inward rectifying potassium
channel.[3] But cytotoxic activities with lepadiformines B and C
have not yet been reported. In addition, the absolute
configurations of (–)-1 and (–)-2 have been completely
determined through the total syntheses.[2i,4m] Although the
absolute configuration of lepadiformine C was assumed to be 3,
corresponding to that of (–)-1, some doubtful points have
remained according to Rychnovsky’s report.[4m] Establishing a
simple synthetic pathway for lepadiformine marine alkaloids is
important in elucidating their biological activities and determining
the absolute configuration of lepadiformine C.
Introduction
The compound (–)-lepadiformine A (1, Figure 1), an azatricyclic
marine alkaloid isolated by Biard et al. from the marine tunicate
Clavelina lepadiformis in 1994, exhibits moderate cytotoxic
activity against various cell lines [IC50: 9.20 μg mL–1 (KB), IC50:
0.75 μg mL–1 (HT29), IC50: 3.10 μg mL–1 (P388), IC50: 6.30 μg mL–
Figure 1. Chemical structures of lepadiformines A (1), B (2), and 3.
1
(P388 doxorubicin-resistant), and IC50: 6.10 μg mL–1 (NSCLS-
N6)].[1] Although a chemical structure that was different from 1
was first proposed based on spectroscopic and chemical
methods,[1a] the original structure was revised to (–)-1 through
studies on the total synthesis by Kibayashi’s, Weinreb’s, and
Pearson’s groups.[2] Lepadiformines B (2) and C were also
isolated by Sauviat’s group from another marine tunicate
Clavelina moluccensis off Djibouti waters in 2006, along with (–)-
As regards its structural features, (–)-1 has a unique skeleton
characterized by the trans-1-azadecalin AB ring system fused
with the AC spirocyclic ring, four asymmetric centers including a
nitrogen-containing stereogenic tetrasubstituted carbon, and a B-
ring as a boat form produced by a bulky n-hexyl side chain. The
core skeleton of (–)-1 is conserved in (–)-2, but the aliphatic side
chain at C13 is shortened from an n-hexyl group to an n-butyl
group. And 3 has the same framework as (–)-2 without a
hydroxymethyl group at C2. The unique molecular architecture of
lepadiformine alkaloids has attracted considerable attention from
the organic synthesis community.[2,4] In a previous letter,[5] our
laboratory described the enantioselective total synthesis of (–)-1
via an Hg(OTf)2-catalyzed cycloisomerization reaction from a
[a]
Dr. K. Nishikawa, K. Yamauchi, S. Kikuchi, S. Ezaki, T. Koyama, H.
Nokubo, K. Matsumura, Dr. T. Kodama, M. Kumagai, Prof. Dr. Y.
Morimoto
Department of Chemistry, Graduate School of Science, Osaka City
University
functionalized linear substrate to
a 1-azaspiro[4.5]decane
Sumiyoshi-ku, Osaka 558-8585 (Japan)
E-mail: morimoto@sci.osaka-cu.ac.jp
M. Kumagai
skeleton as a key reaction. We then successfully synthesized (–)-
2 and 3 to examine the structure-activity relationships of
lepadiformine alkaloids. In this full article, we describe the
development of the metal-catalyzed cycloisomerization reaction,
the full details of the total syntheses of (–)-1, (–)-2, and (–)- and
(+)-3, the determination of the absolute configuration of
[b]
Japan Food Research Laboratories
Ibaraki-shi, Osaka 567-0085 (Japan)
Supporting information for this article is given via a link at the end of
the document.
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lepadiformine C, and the evaluation of their cytotoxic activities
against Hela, HT-29, and P388 cell lines.
such a metal-catalyzed cycloisomerization reaction proceeds was
investigated using designed linear substrates (Tables 1−4).
First, the reaction of ynone 18 possessing a hydroxy group at
Results and Discussion
Our laboratory focused on the construction of a spirocyclic
skeleton, which is embedded in several complex alkaloids.
Especially, a 1-azaspiro[4.5]decane framework represents not
only the AC spirocyclic ring system of lepadiformines, but also the
core skeleton of many alkaloids, such as cylindricines 4−11,[6]
polycitorol A (12),[7] FR901483 (13),[8] and Kopsia alkaloids 14−17
(Figure 2).[9] It was envisioned that the desired spirocyclic
compounds, such as 1-heterospiro[4.5]decane frameworks 20
and 21, could be produced from designed acyclic ynones 18 and
19, respectively, in one step if 6-exo-dig oxymetalation followed
by ketalization of the substrates with metal catalysis and Ferrier-
type cyclization[10] proceeded as outlined in Scheme 1. Concretely,
a 6-exo-dig intramolecular oxymetalation initiated by coordination
of a catalyst to the alkyne π-electron and nucleophilic addition of
the heteroatom to the carbonyl carbon would produce spiroketal
A. The intermediate A would be cleaved by protonation of the
enol ether to afford oxonium or iminium ion B. The spirocyclic
product could be obtained by reforming a carbocycle via Ferrier-
type cyclization with regeneration of a catalyst. Whether
Scheme 1. Novel metal-catalyzed cycloisomerization reaction.
Table 1. Examination of the metal-catalyzed cycloisomerization reaction of
linear substrate 18.
yield (%)[a]
entry
catalyst
solvent
CH2Cl2
time (h)
20
22
23
18
1
2
AuCl
2
−
4
26
9
35
29
AuCl3
MeCN
17
7
39
/CH2Cl2
3
4
5
Ph3PAuOTf[b]
Toluene
CH2Cl2
THF
6
23
17
26
−
20
−
−
17
−
42
63
21
[b,c]
Ph3PAuBF4
PtCl4
−
16
6
7
8
Pd(TFA)2
PdCl2
CH2Cl2
CH2Cl2
CH2Cl2
3
8
3
−
−
5
−
−
11
−
37
quant.
−
[d]
Hg(OTf)2
16
−
[a] Isolated yield. [b] These catalysts were prepared in situ from Ph3PAuCl
Figure 2. Chemical structures of complex alkaloids having
a
1-
and AgOTf or AgBF4 (Ref. 12). [c] 1 mol %. [d] 10 mol %.
azaspiro[4.5]decane skeleton.
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the terminal position was investigated (Table 1). To retain dry
conditions, 4 Å molecular sieves (MS4A) were added to the
reaction. Gold catalysts known as good ynophiles[11] were
examined. Although the reaction using AuCl provided only two
byproducts, diketone 22, which was hydrated in the alkyne moiety
and dimerized ketal 23 (entry 1), the use of AuCl3 afforded the
desired spirocyclic compound 20 albeit in low yield (7%) along
with 22 and 23 (entry 2). The reaction using Ph3PAuOTf improved
the yield of 20 (26%) (entry 3),[13] but the use of Ph3PAuBF4
spirocyclic compound 21 albeit in modest yields (53% and 47%,
respectively) (entries 3 and 4). Only the use of AgOTf, which was
required for the preparation of Ph3PAuOTf, resulted in recovery
of 19 (entry 5). PtCl4 afforded 21 in low yield (22%) along with
diketone 24 (entry 6). Pd(TFA)2 also generated 24 (entry 7), and
[17]
PdCl2 gave a complex mixture (entry 8). [Ir(cod)Cl]2
Rh2(TFA)4
and
[18]
were ineffective catalysts and led only to the
recovery of 19 (entries 9 and 10). Finally, mercury catalysts were
examined (Table 3). Unfortunately, Hg(OAc)2 and Hg(TFA)2
resulted in recovery of 19 (entries 1 and 2). To our delight, it was
found that Hg(OTf)2 effected the cycloisomerization reaction in
resulted in the production of 23 and recovery of the starting
[14]
material (entry 4). The use of PtCl4
afforded the alkyne
hydration product 22 without the desired 20 (entry 5). Pd(TFA)2
also generated 22 and 23 (entry 6), and the use of PdCl2 resulted
in no reaction (entry 7).[15] Finally, mercury(II) triflate (Hg(OTf)2), a
good ynophile developed by Nishizawa et al.,[16] was tested.
Hg(OTf)2 afforded only the desired 20 in lower yield (16%) than
that with Ph3PAuOTf (entry 8). From these results, it was
concluded that ynone 18 was not a good substrate for the
cycloisomerization reaction.
Next, we investigated ynone 19 bearing an NHBoc group at
the terminal position (Tables 2 and 3). Although the reaction using
AuCl and AuCl3 resulted in recovery of the starting material 19
(entries 1 and 2), it was found that Ph3PAuOTf and Ph3PAuBF4
brought about the desired cycloisomerization reaction to provide
Table 3. Examination of the mercury-catalyzed cycloisomerization reaction
of 19[a]
.
yield (%)[b]
entry
catalyst
solvent
MeCN
time (h)
21
24
19
1
2
Hg(OAc)2
Hg(TFA)2
17
2
−
−
89
57
MeCN
CH2Cl2
MeCN
24
16
−
3
4
Hg(OTf)2
Hg(OTf)2
Hg(OTf)2
Hg(OTf)2
TfOH
0.7
0.7
1
71
74
64
61
−
−
10
−
5
Toluene
MeCN
33
−
Table 2. Examination of the metal-catalyzed cycloisomerization reaction of
19.
6[c]
7
0.4
2
−
MeCN
−
24
[a] The reaction in Table 3 is the same as that in Table 2. [b] Isolated yield.
[c] MS4A (100 wt %) was added to the reaction.
yield (%)[a]
Table 4. Examination of the metal-catalyzed cycloisomerization reaction of
25.
entry
catalyst
AuCl
solvent
time (h)
21
24
19
1
2
MeCN
MeCN
14
22
−
−
−
−
65
57
AuCl3
3
4
5
6
7
8
PPh3AuOTf[b]
CH2Cl2
MeCN
0.5
30
23
42
13
8
53
47
−
−
−
[b]
PPh3AuBF4
−
−
yield (%)[a]
AgOTf
MeCN
−
73
−
entry
catalyst
Hg(OTf)2
solvent
CH2Cl2
Toluene
MeCN
time (h)
26
46
60
65
31
27
19
11
26
49
[c]
PtCl4
Toluene
MeCN
22
−
23
12
−
1
2
3
4
1
2
1
2
Pd(TFA)2
PdCl2
21
−
Hg(OTf)2
Hg(OTf)2
CH2Cl2
−
9
[Ir(cod)Cl]2
Rh2(TFA)4
MeCN
MeCN
14
1
−
−
−
−
43
31
Ph3PAuOTf[b]
MeCN
10
[a] Isolated yield. [b] This catalyst was prepared in situ from Ph3PAuCl and
AgOTf (Ref. 12).
[a] Isolated yield. [b] These catalysts were prepared in situ from Ph3PAuCl
and AgOTf or AgBF4 (Ref. 12). [c] 10 mol %.
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better yields (61–74%) than gold catalysts (entries 3–6). As the
alkyne hydration byproduct 24 was observed (entries 3 and 5),
the reaction was conducted in the presence of MS4A; however,
the yield of 21 could not be improved (entry 6). Treatment with
TfOH afforded only the starting material 19, demonstrating that
TfOH does not catalyze this cycloisomerization reaction (entry 7).
The cycloisomerization reaction of ynone 25 possessing an
aromatic ring was also investigated (Table 4). Among the solvents
examined, MeCN was the solvent of choice in terms of the yield
of spirocyclic product 26 (65%) (entries 1–3). The reaction with
Ph3PAuOTf resulted in a lower yield (31%) than with Hg(OTf)2
(entry 4). Thus, our laboratory could develop the novel Hg(OTf)2-
catalyzed cycloisomerization reaction from linear substrates to a
1-azaspiro[4.5]decane framework frequently occurring in the
aforementioned alkaloids. With this reaction in hand, we
embarked on the total syntheses of lepadiformine marine
alkaloids.
moiety in 36, acylation of an α-anion of sulfone 32 with 31 followed
by SmI2-mediated desulfonylation[21] afforded the desired
cyclization precursor 30 in high yield (78% in 3 steps).
Our first-generation retrosynthetic analysis of (–)-1 is depicted
in Scheme 2. The spirocyclic ring 28 could be converted into (–)-
1 via B-ring formation followed by the introduction of an n-hexyl
group according to the synthesis of (–)-1 reported by Kim et al.[4d]
We planned to construct the AC spirocyclic ring by applying the
Hg(OTf)2-catalyzed cycloisomerization reaction to linear
substrate 30. The precursor 30 would be prepared by acylation of
sulfone 32 with pyrrolidinone 31, which was derived from L-
glutamic acid (33) by the use of a known method.[19] Sulfone 32
would be synthesized by alkylation of a lithium acetylide of alkyne
35[20] with commercially available 1,3-diiodopropane (34).
Scheme 3. Synthesis of cyclization precursor 30.
We examined the Hg(OTf)2-catalyzed cycloisomerization
reaction of precursor 30 (Table 5). Firstly, the cycloisomerization
reaction in MeNO2 afforded the desired spirocylic product 29 as
Table 5. Examination of the cycloisomerization reaction of linear substrate
30.
entry
solvent
MeNO2
temperature
time (h)
yield (%)[a]
1
2
3
4
5
6
rt
rt
3
8
Toluene
THF
20
19
17
12
10
52
74
rt
CH2Cl2
MeCN
MeCN
rt
3
Scheme 2. Our first-generation retrosynthetic analysis of (–)-lepadiformine A
(1).
rt
0.5
0.75
0 oC
The total synthesis commenced with the known alkyne 35,
prepared by TBDPS protection of commercially available 4-
pentyn-1-ol[20] (Scheme 3). The alkylation of a lithium acetylide of
35 with 34 afforded monoiodide 36. After sulfonylation of the iodo
[a] Isolated yield.
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Scheme 4. Proposed mechanism for the cycloisomerization reaction of 30.
a single diastereomer albeit in low yield (entry 1). Among various
solvents examined at room temperature, MeCN was still the
solvent of choice (52%) (entries 1–5). The reaction at 0 oC
improved the yield (74%) (entry 6). The stereochemistry of 29 was
clearly assigned based on the NOESY spectrum; see the
Supporting Information (SI).
and II with steric repulsion between benzyloxymethyl and
TBDPSO-containing alkyl groups would be less stable than I
without such steric repulsion. Like transition state III, transition
states with the bulky TBDPSO-containing alkyl group in an axial
position in II, IV, and V should also be disfavored due to steric
hindrance. Thus, the desired 29 would be selectively obtained as
a single diastereomer via transition state I.
To sum up, the key cycloisomerization reaction enabled us to
conduct the diastereocontrolled construction of the 1-
azaspiro[4.5]decane framework. The mechanism and the
diastereoselectivity of the reaction that we propose at present are
summarized in Scheme 4. The aminoketal C would be generated
through a 6-exo-dig type intramolecular oxymercuration initiated
by coordination of Hg(OTf)2 to the alkyne π-electron followed by
nucleophilic addition of the nitrogen function. C could be cleaved
by protonation with generated TfOH to give iminium ion
intermediate D. Although an α-mercury carbonyl in D would be in
equilibrium with the enolate form E, we presumed that D would
predominate due to the stability of the C−Hg bond.[22] In addition,
although the stereochemistry of the aminoketal C and the face
selectivity of the protonation in C were unknown, we think that the
intermediate D can have both (R) and (S) configurations of the
C−Hg bond via E. The construction of a carbocycle via Ferrier-
type cyclization would result in production of the desired product
29 and regeneration of an Hg(OTf)2 catalyst. Considering chair-
like transition states I−V in the re-cyclization, I−III could be more
stable than IV and V because in IV and V a bulky NBoc iminium
moiety is disposed in an axial position. In transition states I−III, III
with a bulky TBDPSO-containing alkyl group in an axial position
After a ketone moiety in the synthesized 29 was converted into
a tosylhydrazone group, NaBH3CN reduction to a methylene
group[23] afforded Kim’s synthetic intermediate 28[4d] (Scheme 5).
The spectral characteristics (1H and 13C NMR) of synthetic 28
were identical to those of Kim’s reported sample.[4d] The optical
rotation of (−)-28, [α]D20 −41.0 (c 1.06, CHCl3), was similar to that
Scheme 5. Synthesis of Kim’s intermediate 28.
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19
of the reported sample, [α]D −39.8 (c 1.08, CHCl3).[4d] The
synthesis of (−)-1 by Kim et al. was a formal total synthesis
wherein 28 was led to Weinreb’s synthetic intermediate 39[2g,h]
(Scheme 6). But in the transformation from 39 to (−)-1, the
stereoselectivity was not sufficient to attach an n-hexyl group to
the B-ring (40:41 = 3:1). To resolve this problem, we tried to carry
out the key cycloisomerization reaction with a new linear substrate
having all the carbon atoms required for the total synthesis of (−)-
1.
arise from the key Hg(OTf)2-catalyzed cycloisomerization reaction
of functionalized cyclization precursor 43 bearing all the carbon
numbers required for the total synthesis of (−)-1. Precursor 43
could be prepared by acylation of sulfone 44 with the known 31.
Compound 44 would be synthesized through Wittig olefination of
the known lactol 45[24] with ylide 46 followed by alkylation of a
lithium acetylide of 35.
Our second-generation total synthesis started with Wittig
olefination of the known optically active lactol 45[24] to
stereoselectively yield Z-olefin 47 (Scheme 8). The
heterogeneous hydrogenation of 47 for 3.5 h provided the desired
alcohol 48 in low yield (30%), along with the TBS-migrated
byproduct 49 (33%). But shortening the reaction time (15 min)
selectively afforded 48 in high yield (87%). After iodination of 48,
alkylation of a lithium acetylide of 35 with iodide 50 followed by
selective deprotection of a TBDPS group using TBAF[25] gave
alcohol 51 (Scheme 9), which was transformed to the cyclization
precursor 43 in a 4-step reaction sequence: (1) iodination of a
hydroxy group, (2) sulfonylation, (3) acylation of an α-anion of
sulfone 44 with 31, and (4) desulfonylation by SmI2-mediated
radical reduction.
Scheme 6. Formal synthesis of (−)-1 by Kim et al.
Our second-generation retrosynthetic analysis of (−)-1 is
shown in Scheme 7. Deoxygenation of the spirocyclic compound
42 followed by B-ring formation according to Kibayashi’s and
Zhao’s method[4c,j] would generate (−)-1. Compound 42 could
Scheme 8. Synthesis of iodide 50.
The key Hg(OTf)2-catalyzed cycloisomerization reaction of
precursor 43 was performed under various reaction conditions
(Table 6). As expected, the reaction proceeded in
a
stereoselective manner to furnish the desired spirocyclic
compound 42 in 39% isolated yield as a sole diastereomer, when
43 was allowed to react with Hg(OTf)2 (10 mol %) at −40 oC (entry
1). We supposed that the spirocyclic product 42 would be
selectively produced through transition state VI corresponding to
I in Scheme 4. Increasing the catalyst loading to 20 mol % gave a
better yield of 42 (52%), along with a minor diastereomer 54 (6%)
through transition state VII (entry 2). Raising the reaction
temperature resulted in a gradual increase in the yield of 42
(entries 3−5). In addition, the reaction time for disappearance of
the starting material was gradually shortened as the temperature
increased. Entry 5 indicates the best temperature conditions (−20
Scheme 7. Our second-generation retrosynthetic analysis of (−)-1.
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Table 6. Optimization of the Hg(OTf)2-catalyzed cycloisomerization
reaction of cyclization precursor 43.
yield (%)[a]
selectivity
entry
Hg(OTf)2
(mol %)
temper-
ature
(oC)
time
(min)
42
54
43
42 : 54
1
2
3
10
20
20
−40
−40
−30
60
40
40
39
52
60
N.D.[b]
−
6
−
−
6
5
8.9 : 1
12.0 : 1
Scheme 9. Synthesis of cyclization precursor 43.
4
5
6
20
20
30
−20
−20 to 0
0
15
5
77
78
47
12
6
−
−
4
6.4 : 1
13.0 : 1
11.8 : 1
oC to 0 oC) in terms of the yield and the diastereoselectivity.
Increasing the catalyst loading to 30 mol % led to a decrease in
the yield of 42 (47%) (entry 6). The stereochemistry of 42 and 54
was apparently assigned based on their NOESY spectra.[5] With
regard to the generation of diastereomer 54, the thermodynamic
10
4
[a] Isolated yield. [b] N.D. = Not Determined.
and
kinetic
experiments
for
the
Hg(OTf)2-catalyzed
cycloisomerization reaction were compared. Treatment of the
spirocyclic product 42 under the same reaction conditions as
those employed for the cycloisomerization of 43 resulted in
recovery of the starting material in quantitative yield. And
treatment of the diastereomer 54 also resulted in recovery of the
starting material. Therefore, we think that the above
cycloisomerization reaction is under kinetic control.
(Scheme 10, synthetic pathway a) to furnish 55 in low yield (23%
in 3 steps from 42) along with the recovered 56. As a result of this
examination, it was found that Barton-McCombie’s deoxygenation
method[27] (Scheme 10, synthetic pathway b) provided the desired
55 in high yield (76% in 3 steps from 42). In the NaBH4 reduction
of 42, an equatorial hydride attack could predominate as a result
1
of avoiding the axial alkyl group at C5. In the H NMR spectrum
We synthesized Kibayashi’s synthetic intermediate 59[4c] from
42 (Scheme 10). For deoxygenation of the carbonyl group, we
applied the previous method via a tosylhydrazone to yield the
desired methylene 55. But the method resulted in a modest yield
(44% in 2 steps) and poor reproducibility. Instead, Markó-Lam’s
deoxygenation method utilizing SmI2-HMPA[26] was employed
after the diastereocontrolled reduction to axial alcohol 56
of a major rotamer of 56, the coupling pattern of C9−H at 4.12
ppm was observed as a doublet with J = 2.2 Hz showing an
equatorial proton. Removal of both Boc and TBS protecting
groups in 55 with TFA afforded the amino alcohol 59. The spectral
30
characteristics (1H and 13C NMR) and the optical rotation, [α]D
−35.3 (c 0.76, MeOH), of synthetic 59 were identical to those of
Kibayashi’s reported sample.[4c]
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We performed the enantioselective total synthesis of (−)-
lepadiformine B (2) in a similar manner in order to explore the
structure-activity relationships of lepadiformine marine alkaloids
(Scheme 12; see the SI for details). Iodide 63 was prepared
through a 3-step synthesis including Wittig olefination of 45 with
propyltriphenylphosphorane.[28] The corresponding cyclization
precursor 64 was synthesized from pyrrolidinone 31, alkyne 35,
and synthesized 63 by the same synthetic procedure as that of 1.
The Hg(OTf)2-catalyzed cycloisomerization reaction of 64
afforded the desired spirocyclic compound 65 (dr = 12:1).
Compound 65 was converted to (−)-2 via Barton-McCombie’s
deoxygenation and construction of the B-ring. The total synthesis
of (–)-2 was also achieved in 16 steps from the known lactol 45
with 21% overall yield. The spectral characteristics (1H and 13C
NMR) of synthetic (−)-lepadiformine B hydrochloride salt 66 were
identical to those of the authentic sample.[3, 4m] The optical rotation
of synthetic 66, [α]D27 +2.7 (c 0.40, CHCl3), was similar to that of
the authentic sample, [α]D22 +3.2 (c 0.30, CHCl3).[4m]
Scheme 10. Synthesis of Kibayashi’s intermediate 59.
The total synthesis of (–)-lepadiformine A was completed from
59 as outlined in Scheme 11. Compound 59 was subjected to
Kibayashi’s and Zhao’s procedure[4c,j] to give an azatricyclic ring
system 60 via B-ring formation accompanied by inversion of
configuration. Finally, deprotection of a Bn group in 60 afforded
(–)-lepadiformine A (1). The total synthesis of (–)-1 was achieved
in 16 steps from the known lactol 45 with 28% overall yield. The
spectral data (1H and 13C NMR) and the optical rotation of
synthetic 1, [α]D30 −14.6 (c 0.38, MeOH), were in agreement with
20
those reported previously, [α]D −15 (c 0.45, MeOH).[2h] We
confirmed that the spectral data and the optical rotation of the
30
hydrochloride salt 61, [α]D +2.2 (c 0.70, CHCl3), are also
comparable to those reported for the authentic sample, [α]D20 +2.5
(c 0.51, CHCl3).[2h]
Scheme 12. Synthesis of (−)-lepadiformine B (2).
Finally, we successfully synthesized (–)-3 from the synthetic
intermediate 67 during the synthesis of (–)-2 (Scheme 13). The
starting material 67 was transformed to carboxylic acid 68 through
deprotection of a benzyl group, Dess-Martin oxidation, and
Pinnick oxidation. A carboxy group in 68 was removed by applying
photodecarboxylation using acridine, as developed by Okada et
al.,[29] to provide methylene 69 in modest yield (72%).
Deprotection of a TBS group with TBAF afforded Rychnovsky’s
synthetic intermediate 70.[4m] The spectral characteristics (1H and
Scheme 11. Synthesis of (–)-lepadiformine A (1).
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13C NMR) of synthetic 70 were identical to those of Rychnovsky’s
23
sample.[4m] The optical rotation of (–)-70, [α]D –28.9 (c 0.13,
22
CHCl3), was similar to previous data, [α]D –29.2 (c 0.90,
CHCl3).[4m]
Scheme 15. Synthesis of (+)-lepadiformine C (ent-3).
Scheme 13. Synthesis of Rychnovsky’s intermediate 70.
Rychnovsky et al. suggested that the optical rotation reported for
the natural product, [α]D +11.0 (c 1.00, CHCl3), was that of the free
base 3 and not of the HCl salt 71,[4m] the optical rotation of our
25
The total synthesis of 3 was completed from 69 as outlined in
Scheme 14. Compound 69 was subjected to Kibayashi’s and
Zhao’s procedure[4c,j] to provide 3 in modest yield (75% in 2 steps).
The spectral characteristics (1H and 13C NMR) of synthetic (−)-
lepadiformine C hydrochloride salt 71 were identical to those of
the authentic sample.[3,4m] But the optical rotations of our and
synthetic free base 3 was [α]D −32.7 (c 0.46, CHCl3) (Scheme
14). Thus, the authors suggest that the absolute configuration of
natural lepadiformine C should be shown as ent-3. To further
confirm our suggestion, the measurement of the optical rotation
of a natural lepadiformine C free base would be necessary.
Recently,
a
phenomenon of enantiodivergence was
Rychnovsky’s synthetic 71, [α]D24 −13.3 (c 0.80, CHCl3) and [α]D
22
uncovered as a new biosynthetic paradigm for natural products.[30]
This was found in pyrrole-imidazole alkaloids isolated from
different species of marine sponges. In the case of lepadiformine
marine alkaloids, it is a further interesting phenomenon that
lepadiformines A−C (1, 2, and ent-3) have been isolated from a
single species of marine tunicate, Clavelina moluccensis.[31] How
should we consider this enantiodivergence of lepadiformines?
Our hypothetical biogenesis of lepadiformines is shown in
Scheme 16. We speculated the formation of an azatricyclic ring
system common to lepadiformines and related marine alkaloids
through (1) polyketide extension using amino acids as starter
units, (2) Schiff base formation, (3) an intramolecular Mannich
reaction, and (4) an intramolecular Michael reaction.[32] In
lepadiformines A (1) and B (2) with a hydroxymethyl group at C2,
an intramolecular Mannich reaction would proceed from the Re
face of an iminium ion in chair-like transition state IX with an enol
moiety in an equatorial disposition. At that time, cylindricines 4−11
from a different species and polycitorol A (12) from a different
family would be produced via the same Re face attack on chair-
like transition state X with an enol moiety in an axial disposition.
On the other hand, in lepadiformine C (ent-3) without a
hydroxymethyl group at C2, the Si face attack would predominate
in transition state XIV due to interaction with an enzyme.
−13.9 (c 0.33, CHCl3),[4m] respectively, were opposite in sign to
that of the natural product, [α]D +11.0 (c 1.00, CHCl3).[3] Therefore,
we also synthesized (+)-lepadiformine C (ent-3), which was
enantiomeric to 3, from pyrrolidinone ent-31, iodide ent-63, and
alkyne 35 by the same synthetic procedure as that of 3 (Scheme
25
15). The optical rotation of ent-71, [α]D +13.5 (c 0.85, CHCl3),
was identical to that of the natural product.[3] Although
Scheme 14. Synthesis of 3.
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Scheme 16. Hypothetical biogenesis of lepadiformine alkaloids.
Figure 3. Cytotoxic activities of lepadiformine hydrochloride salts (61, 66, 71,
and ent-71).
Figure 4. Cytotoxic activities of synthetic intermediates (59 and 72−75).
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With these synthetic lepadiformine hydrochloride salts 61, 66,
71, and ent-71 in hand, we evaluated their cytotoxic activities
along with those of the synthetic intermediates 59, 73, 74, and
hydrochloride salts 72 and 75. The biological activities were
evaluated, in terms of IC50 (half maximal (50%)
inhibitory concentration) values against Hela, HT-29, and P388
cell lines exposed to each compound for 72 h. These results are
shown in Figures 3 and 4. The (−)-lepadiformine A hydrochloride
salt 61 inhibited P388 cells at 19 μM, which was similar to the
value (9.4μM, 3.10 μg mL−1) reported by Biard et al. (Figure 3).[1a]
But the cytotoxic activity of 61 against HT-29 cells (33μM) was
about ten times lower than indicated by the previous data (2.3μM,
0.75 μg mL−1).[1a] In addition, 61 showed inhibitory activity against
Hela cells at 40 μM and (−)-lepadiformine B hydrochloride salt 66,
71, and (+)-lepadiformine C hydrochloride salt ent-71 inhibited
P388 cells at 19 μM, 51 μM, and 89 μM, respectively, which
indicated similar activity to 61. However, 66, 71, and ent-71 did
not show any activity against Hela and HT-29. These
experimental results suggested that a hexyl side chain at C13 is
important in increasing the cytotoxicity against Hela and HT-29
cells. In addition, the cytotoxic activities of 71 and ent-71 against
all three lines were about the same, suggesting that the absolute
configuration of lepadiformine C hydrochloride salt plays a minor
role in the cytotoxic activity. Interestingly, the synthetic
intermediates for (−)-lepadiformine A, such as amino alcohol 59
and hydrochloride salt 72, were more potent than 61 with cytotoxic
activities against all three cell lines (3.1–6.1 μM). This may be due
to hydrophobic groups (benzyl group) increasing cell permeability
and cytotoxicity. The synthetic intermediates for lepadiformine B,
such as amino alcohol 73, benzyl ether 74, and the hydrochloride
salt 75, showed similar levels of cytotoxic activities against HT-29
and P388 cells to 59 and 72, although the activity of 75 was
slightly less than that of 72. But 73, 74, and 75 showed lower
activities against Hela cells than 59 and 72, indicating that the
shortening of the aliphatic side chain from an n-hexyl group to an
n-butyl group decreased the potency of the inhibitory activity
against Hela cells. Lepadiformine alkaloids have been reported to
exhibit cardiovascular effects and are expected to lead to the
development of antiarrhythmic drugs.[1b,3] These fundamental
findings with respect to cytotoxicity may be useful for further
exploitation of lepadiformine alkaloids.
lepadiformines
A
(1) and
B
(2). This enantiodivergent
phenomenon is of great interest with respect to the isolation of
lepadiformines A−C from a single species of marine tunicate
Clavelina moluccensis, because the first occurrence of
enantiodivergence was found in natural products isolated from
different species.[30a] We evaluated the cytotoxic activities of
hydrochloride salts of lepadiformine alkaloids and some synthetic
intermediates against Hela, HT-29, and P388 cell lines and
revealed that hydrophobic factors such as the alkyl chain length
and benzyl protection increase the cytotoxic activities. These
findings, coupled with the development of a short and high
yielding synthetic route to lepadiformine alkaloids, lay the
groundwork for further investigation of biological properties.
Experimental Section
1
Experimental procedures, spectroscopic data, and copies of H
and 13C NMR spectra are available in the SI.
Acknowledgements
This work was financially supported by the Astellas Foundation
and the JGC-S Scholarship Foundation (Nikki Saneyoshi
Scholarship). We particularly thank Prof. Dr. Keiji Okada for
providing a medium-pressure mercury lamp. We also thank Dr.
Matsumi Doe for NMR analysis of synthetic compounds.
Keywords: natural products • total synthesis • alkaloids • spiro
compound • cytotoxicity
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A phenomenon of
K. Nishikawa, K. Yamauchi, S. Kikuchi,
S. Ezaki, T. Koyama, H. Nokubo,
K. Matsumura, T. Kodama,
enantiodivergence was found in
lepadiformine alkaloids isolated from a
single species marine tunicate
M. Kumagai, Y. Morimoto*
Clavelina moluccensis through their
syntheses. The enantioselective total
syntheses have been achieved by a
key mercury(II) triflate-catalyzed
cycloisomerization reaction developed
in our laboratory (see Scheme), and
cytotoxic activities of synthesized
compounds were also evaluated.
Page No. – Page No.
Total Syntheses of Lepadiformine
Marine Alkaloids with
Enantiodivergency, Utilizing
Hg(OTf)2-Catalyzed
Cycloisomerization Reaction and
Their Cytotoxic Activities
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