Total Syntheses of (+)-Aquatolide and Related Humulanolides

Article abstract of DOI:10.1002/anie.201904404

The short, efficient total synthesis of (+)-aquatolide was achieved by a biomimetic transannular [2+2] photocycloaddition, and provides the first example of constructing a 5/5/4/8-ring system from asteriscunolides. Furthermore, the reaction leading to a 5/4/4/7-ring system, the originally proposed structure of aquatolide, was also developed. This strategy achieved syntheses of five more humulanolides, (?)-asteriscunolides A, C, D, and I, and (+)-tetradehydroasteriscanolide.

Full text of DOI:10.1002/anie.201904404

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Accepted Article
Title: Total Syntheses of (+)-Aquatolide and Related Humulanolides
Authors: Ken-ichi Takao, Hirotaka Kai, Ai Yamada, Yuuki Fukushima,
Daisuke Komatsu, Akihiro Ogura, and Keisuke Yoshida
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201904404
Angew. Chem. 10.1002/ange.201904404
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10.1002/anie.201904404
Angewandte Chemie International Edition
COMMUNICATION
Total Syntheses of (+)-Aquatolide and Related Humulanolides
Ken-ichi Takao,*[a] Hirotaka Kai,[a] Ai Yamada,[a] Yuuki Fukushima,[a] Daisuke Komatsu,[a]
Akihiro Ogura,[a] and Keisuke Yoshida[b]
A)
Abstract: The short, efficient total synthesis of (+)-aquatolide was
achieved by a biomimetic transannular [2+2] photocycloaddition,
which provides the first example of constructing a 5/5/4/8-ring
system from asteriscunolides. Furthermore, the reaction leading to a
5/4/4/7-ring system, the originally proposed structure of aquatolide,
was also developed. This strategy achieved syntheses of five more
humulanolides, (–)-asteriscunolides A, C, D, and I, and (+)-
tetradehydroasteriscanolide.
O
O
9
10
2
O
3
H
H
H
O
O
O
O
O
O
(–)-asteriscunolide A (1) (–)-asteriscunolide B (2) (–)-asteriscunolide C (3)
O
O
O
H
H
O
H
O
H
H
Sesquiterpenes contained in Asteriscus (Compositae) have
attracted considerable attention from the community. (–)-
Asteriscunolide A (1), isolated from Asteriscus aquaticus along
with cis-trans isomers (–)-asteriscunolides B–D (2–4), is the first
H
O
H
H
O
O
O
(+)-tetradehydro-
asteriscanolide (6)
(–)-asteriscunolide D (4) (+)-asteriscanolide (5)
elucidated sesquiterpene lactone containing
a
humulane
HO
H
skeleton, known as a humulanolide[1] (Figure 1A). The same
plant also afforded tricyclic (+)-asteriscanolide (5),[2] and its
tetradehydro- analog (+)-tetradehydroasteriscanolide (6) was
isolated from A. graveolens.[3] In 1989, San Feliciano found a
new humulanolide called aquatolide in A. aquaticus.[4] The
structure of (+)-aquatolide was originally assigned mainly by
NMR analysis as 7a, which consists of a tetracyclic 5/4/4/7-ring
system with an unusual embedded [2]-ladderane motif. Later, its
structure was revised based on quantum chemical NMR
calculations and X-ray crystallography of the re-isolated sample
by Shaw and Tantillo.[5] Revised structure 7b possesses an
unprecedented, intricate 5/5/4/8-ring system containing five
O
H
H
O
10H
10
H
O
9
9
2
H
O
H
2
H
3
O
3
O
H
O
O
7a
O
(+)-aquatolide (7b)
originally proposed
structure of aquatolide
(–)-asteriscunolide I (8)
B)
“parallel”
“crossed”
[2+2] cycloaddition
[2+2] cycloaddition
7a
3
7b
C2–C10
C3–C9
C2–C9
C3–C10
contiguous
stereogenic
centers.
In
particular,
a
R2
R3
HO
C)
bicyclo[2.1.1]hexane core is uncommon in natural products. The
proposed biosynthesis of 7b involves a transannular crossed
[2+2] cycloaddition of 3, in which the C2–C9 and C3–C10 bonds
are formed (Figure 1B). Although the alternative parallel
cycloaddition leading to originally proposal 7a seems likely, such
a closure has not been discovered so far in A. aquaticus.
Recently, another congener, (–)-asteriscunolide I (8), was
isolated from A. graveolens.[6] With prominent cycotoxicity of
humulanolides including 1 and 4,[7,8] the development of a
practical synthesis of 7b and related compounds might allow the
discovery of new antitumor agents.
transannular
[2+2]
cycloaddition
R1
R4
(+)-aquatolide (7b)
H
O
H
O
O
O
9
R1-4 = H or functional groups
10
intramolecular
NHTK reaction
CHO
ROM/RCM/CM
CHO
I
I
O
O
O
O
12
11
[a]
[b]
Prof. Dr. K. Takao, H. Kai, A. Yamada, Y. Fukushima, D. Komatsu,
Dr. A. Ogura
Department of Applied Chemistry
Keio University
Hiyoshi, Kohoku-ku, Yokohama 223-8522 (Japan)
E-mail: takao@applc.keio.ac.jp
Dr. K. Yoshida
Faculty of Pharmacy
Meijo University
150 Yagotoyama, Tempaku-ku, Nagoya 468-8503 (Japan)
Figure 1. (A) (+)-Aquatolide and related humulanolides. (B) Proposed
biosynthesis of (+)-aquatolide. (C) Retrosynthetic analysis of (+)-aquatolide.
Owing to their fascinating structure, these humulanolides
have been exciting synthetic targets.[9] Five groups have
published total syntheses of 5.[10-14] The structurally related
naupliolide[15] was also synthesized by Ito and co-workers.[16]
With regard to asteriscunolides, total syntheses of 3 and 4 were
achieved by Fernandes[17] and Trost,[18] respectively. Eventually,
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201904404
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COMMUNICATION
Dess–Martin
periodinane
NaHCO3
Li’s group reported an elegant collective synthesis of
compounds 1–6.[19] The total synthesis of the challenging
revised structure of aquatolide 7b has been completed by two
groups. Hiemstra and co-workers accomplished the first total
synthesis of racemic (±)-7b through intramolecular [2+2]
photocycloaddition of an allenic pentenolide in 16 steps (longest
linear chain) with 2.2% overall yield.[20] Zhang and Gu’s group
synthesized (±)-7b using the Wolff rearrangement of
bicyclo[2.2.1]heptane in 22 steps with 0.8% overall yield.[21] In
both syntheses, the strained bicyclo[2.1.1]hexane skeleton was
constructed at an earlier stage, and biomimetic transannular
[2+2] cycloaddition of an asteriscunolide-type compound has not
been reported. Here, we report a concise, high-yielding synthetic
route towards the natural enantiomer of (+)-aquatolide (7b) by
the biomimetic transannulation strategy. This approach allowed
the total syntheses of six natural products, (–)-asteriscunolides A,
C, D, and I (1, 3, 4, and 8), (+)-tetradehydroasteriscanolide (6),
and 7b. Furthermore, the originally proposed structure of
aquatolide (7a) was also synthesized for the first time.
O
ref 26
OH
HO
O
CH2Cl2, RT
OMPM
81% in 3 steps
96%
14
D-(–)-pantolactone (13)
CrCl3, LiAlH4
DDQ
CHI3
O
I
THF/1,4-dioxane
RT, 90%
H2O/CH2Cl2
RT, 98%
OMPM
OMPM
15
16
2nd Grubbs cat.
methacrolein
I
LiHMDS, 18
I
O
OH
THF, –78 °C
90%
toluene, 65 °C
60%
17
O
12
HO
H
CHO
NiCl2, CrCl2
I
DMSO, RT
96%
Our retrosynthetic analysis of 7b is shown in Figure 1C. Li
and co-workers reported that irradiation of (–)-asteriscunolide D
(4) afforded the cis-trans isomers including (–)-asteriscunolide C
(3), a putative biosynthetic precursor of (+)-aquatolide, but that
7a or 7b were not formed in the reaction.[19] Given our
experience with biomimetic total synthesis,[22] we expected that
the [2+2] cycloaddition could be achieved by tuning the structure
of the substrate. An asteriscunolide-type precursor 9 would be
derived from humulene lactone 10, the common intermediate for
the divergent synthesis of related natural products. To form the
11-membered ring, an intramolecular Nozaki–Hiyama–Takai–
Kishi (NHTK) reaction of iodoalkene–aldehyde 11 would be used
because this reaction gave good results in some difficult
cyclizations.[23,24] The disubstituted g-butenolide skeleton would
be constructed by a ring-opening/ring-closing/cross-metathesis
(ROM/RCM/CM) reaction from cyclobutenecarboxylate 12 and
methacrolein, which is an extension of our ring-opening/ring-
closing metathesis (ROM/RCM) of cyclobutenecarboxylate
derivatives for concise access to g-butenolides.[25]
O
O
O
O
11
10
N
N
Mes
Mes
Ph
O
Cl
Ru
O
O
Cl
PCy3
2nd Grubbs cat.
18
Scheme 1. Construction of the asteriscunolide skeleton. MPM
= 4-
methoxyphenylmethyl, THF tetrahydrofuran, DDQ 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone, LiHMDS = lithium bis(trimethylsilyl)amide, DMSO
= dimethylsulfoxide.
=
=
With this retrosynthetic analysis in mind, we first investigated
the construction of the asteriscunolide skeleton (Scheme 1).
According to a known three-step procedure, D-(–)-pantolactone
(13) was converted into alcohol 14.[26] Oxidation of 14 with the
Dess–Martin reagent provided aldehyde 15, which was
subjected to Takai–Utimoto olefination[27,28] to afford alkenyl
iodide 16 with high E-selectivity. Removal of the MPM group
from 16 provided allylic alcohol 17, which was acylated with acid
anhydride 18[25] to provide cyclobutenecarboxylate 12. After
optimization of the reaction conditions, we found that the
ROM/RCM/CM reaction of 12 proceeded in a cascade manner
to produce desired (E)-a,b-unsaturated aldehyde 11 directly in a
good yield (60%). In this reaction, the iodoalkene moiety
remained intact. The cascade ROM/RCM/CM reaction
substantially improved the yield of 11 and provided an
operationally simple method. The next stage of the synthesis
involved construction of the 11-membered carbocycle. The
intramolecular NHTK reaction of 11 achieved efficient cyclization
and key intermediate 10 was obtained as a single diastereomer
in excellent yield.[29] We attribute this high diastereoselectivity to
the general tendency of NHTK reaction to afford
a
pseudoequatorial hydroxyl group.[23,24] Considering the highly
strained structure of the 11-membered ring, the high yield of 10
was remarkable.
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COMMUNICATION
A)
hν
Dess–Martin
periodinane
NaHCO3
HO
H
O
high-pressure
Hg lamp
O
+
2 + 3 (1:1 mixture, 39%)
acetone, RT
42% for 1
CH2Cl2, RT
91%
H
O
H
O
O
O
isomerization
O
O
10
(–)-asteriscunolide D (4)
(–)-asteriscunolide A (1)
B)
hν
Dess–Martin
periodinane
NaHCO3
hν
O
HO
HO
H
HO
H
high-pressure
Hg lamp
high-pressure
Hg lamp
H
m-CPBA
O
10
H
acetone, RT
acetone, RT
CH2Cl2, RT
61%
CH2Cl2, RT
O
H
O
H
O
42% for 19
27% for rec. 10
21% for 21
64% for rec. 20
100%
O
O
21
O
19
20
partial isomerization
parallel [2+2] cycloaddition
O
O
H
H
O
H
O
1) NaI, TFA, MeCN, RT
2) TFAA, Et3N,
CH2Cl2, RT
Dess–Martin
periodinane
NaHCO3
H
H
O
H
H
H
19
O
O
CH2Cl2, RT
79%
H
3) NaI, DMF, 60 °C
63%
O
O
O
22
7a
(–)-asteriscunolide C (3)
C)
O
hν
H O
H
H O
H
H
H
OMe
high-pressure
Hg lamp
BF3·OEt2
BF3·OEt2
H
H
4
O
O
acetone, RT
CH2Cl2, 35 °C
64%
MeOH, RT
74%
OMe
H
O
37% for 24
35% for rec. 23
O
O
O
24
(+)-aquatolide (7b)
23
crossed [2+2] cycloaddition
Scheme 2. (A) Syntheses of (–)-asteriscunolides D (4) and A (1).(B) Syntheseis of the originally proposed structure of aquatolide (7a) and (–)-asteriscunolides C
(3). (C) Total synthesis of (+)-aquatolide (7b). m-CPBA = m-chloroperbenzoic acid, TFA = trifluoroacetic acid, TFAA = trifluoroacetic anhydride, DMF = N,N-
dimethylformamide.
Having rapidly assembled the asteriscunolide skeleton, we
turned to the transannular [2+2] photocycloaddition to construct
the bicyclo[2.1.1]hexane core.[30] First, alcohol 10 was oxidized
to 4 (Scheme 2A). Thus we achieved the total synthesis of 4 in
10 steps from 13 with a 32% overall yield. Compared with
previous routes,[18,19] our approach gave a yield of 4 that was
several times higher. With substrate 4 in hand, we used a high-
pressure Hg lamp (100 W) emitting over a wide range of
wavelengths to irradiate 4 through Pyrex glass. The results were
similar to those obtained previously with a UV lamp (10 W, 254
nm)[19] and only isomerization of the olefins occurred. As a major
product, (–)-asteriscunolide A (1) was isolated in 42% yield (an
overall yield of 14% in 11 steps).
resulting epoxide 22 via iodohydrin,[32] provided the originally
proposed structure of aquatolide (7a).[29] Remarkably, the 1H and
1
13C NMR chemical shifts and the H–1H coupling constants for
synthetic 7a matched those calculated by Shaw and Tantillo’s
group quite well.[5,33] Thus we succeeded in synthesizing a non-
natural product 7a. On the other hand, oxidation of 19 gave (–)-
asteriscunolide C (3) (11 total steps, 13% overall yield).
As an alternative strategy, we examined a 1,4-addition of
alcohol to 4 to mask the olefin (Scheme 2C). The reaction using
acids in methanol regio- and stereoselectively provided 1,4-
adduct 23 as a single isomer.[29] Fortunately, the transannular
crossed [2+2] photocycloaddition of 23 proceeded to construct
the bicyclo[2.1.1]hexane core, giving desired cycloadduct 24 in
37% yield (57% brsm). This is the first example of a biomimetic
transannular [2+2] cycloaddition of an asteriscunolide-type
compound being used to form the aquatolide skeleton. The
elimination of methanol from 24 proceeded under acidic
conditions and the first total synthesis of the natural enantiomer
of (+)-aquatolide (7b) was completed. Our synthetic route was a
total of 13 steps from 13 with an overall yield of 5.7%, and was
more concise and efficient than the previous racemic
syntheses.[20,21] The results of this experiment suggested that
1,4-adducts of 3 or 4 with alcohols or thiols in the plant may
The irradiation of dienol 10, instead of dienone 4,
chemoselectively isomerized the trisubstituted olefin to the Z-
configuration to produce compound 19 in 42% yield (67% based
on recovered starting material [brsm]),[31] but the ensuing [2+2]
cycloaddition failed (Scheme 2B). We suspected that the olefin
would require masking. Therefore, 19 was treated with m-CPBA.
The epoxidation chemo- and stereoselectively gave single
isomer 20.[29] As expected, the [2+2] photocycloaddition of 20
proceeded. However, the cycloaddition mode was parallel and
20 was converted into [2]-ladderane adduct 21 in 21% yield
(58% brsm). Oxidation of 21, followed by deoxygenation of
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10.1002/anie.201904404
Angewandte Chemie International Edition
COMMUNICATION
O
O
contribute to the assembly of the aquatolide skeleton in
nature.[34]
n-Bu3P
H
H
O
We verified the clear-cut regioselectivity in the transannular
[2+2] photocycloadditions of 20 and 23 by conformational
analysis of substrates using calculations (Scheme 3).[35] In the
most stable conformer of 20, H-2 and H-10 adopt a b-orientation
and H-9 adopts an a-orientation. The [2+2] cycloaddition of 20 to
form a [2]-ladderane structural unit is the likely preferred path to
21. The alternative path to form a bicyclo[2.1.1]hexane structure
apparently does not occur. In contrast to 20, the most stable
conformer of 23 contains trans H-2 and H-10. Therefore, C2–
C10/C3–C9 closure would produce an unrealistic trans-fused
[2]-ladderane structure, but C2–C9/C3–C10 closure would
proceed in accordance with the rule of five[36] to assemble the
aquatolide skeleton. Consequently, we reasoned that the
conformation of substrates controlled the regioselectivity
(parallel or crossed) of the [2+2] photocycloaddition.
THF/H2O, 50 °C
98%
H
H
O
O
O
(+)-tetradehydroasteriscanolide (6)
4
HO
H
HO
O
m-CPBA
CH2Cl2, RT
73%
H
O
O
O
O
10
(–)-asteriscunolide I (8)
Scheme 4. Syntheses of (+)-tetradehydroasteriscanolide (6) and (–)-
asteriscunolide I (8).
In summary, we have achieved the total synthesis of (+)-
aquatolide (7b) by using a biomimetic transannular [2+2]
photocycloaddition. To synthesize
a
substrate for the
H
HO
9
10
9
H
10
cycloaddition, the asteriscunolide skeleton was efficiently
constructed through a cascade ROM/RCM/CM reaction and an
intramolecular NHTK reaction. Our strategy provided a divergent
route to six humulanolides, including 7b, 6, and (–)-
asteriscunolides A, C, D, and I (1, 3, 4, and 8) in 10–13 steps
with good efficiency. In addition, the originally proposed
structure of aquatolide (7a) was also synthesized, which
suggests that a 5/4/4/7-ring system humulanolide may also
occur naturally in Asteriscus. Future studies will focus on
applying this strategy to the synthesis of humulanolide
derivatives as well as investigating their bioactivity.
parallel
O
H
H
2
3
2
O
3
O
21
20
Computed structure, B3LYP/6-31G(d)
H O
H
9
10
9
crossed
2
10
3
H
H
O
2
3
OMe
O
23
Computed structure, B3LYP/6-31G(d)
24
Acknowledgements
Scheme 3. Regioselectivity of transannular [2+2] photocycloadditions of 20
and 23.
This work was supported by JSPS KAKENHI Grant Number
15K05504 and the Naito Foundation.
Having proved that asteriscunolide-type compounds
underwent irradiation to form a 5/4/4/7- or 5/5/4/8-ring system,
we then turned our attention to the formation of asteriscanolide
skeleton, namely a tricyclic 5/5/8-ring system. We considered
that a one-step formation of (+)-tetradehydroasteriscanolide (6)
from 4 could be performed by the intramolecular Rauhut–Currier
(vinylogous Morita–Baylis–Hillman) reaction.[37,38] Compound 4
was treated with n-Bu3P to construct the 5/5/8-ring system and
synthesis of 6 was thus directly achieved efficiently (11 total
steps, 32% overall yield) (Scheme 6). Finally, the synthesis of (–
)-asteriscunolide I (8), a new congener, was carried out.
Epoxidation of 10 with m-CPBA gave 8 as a single product. This
is the first total synthesis of 8 (10 total steps, 26% overall yield).
Keywords: biomimetic synthesis • cycloaddition • metathesis •
terpenoids • total synthesis
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COMMUNICATION
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10.1002/anie.201904404
Angewandte Chemie International Edition
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Author(s), Corresponding Author(s)*
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Title
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COMMUNICATION
HO
H
O
H
H
O
Ken-ichi Takao,* Hirotaka Kai, Ai
Yamada, Yuuki Fukushima, Daisuke
Komatsu, Akihiro Ogura, and Keisuke
Yoshida
H
“parallel”
[2+2]
cycloaddition
“crossed”
[2+2]
cycloaddition
10
10
H
9
9
9
2
H
O
H
10
H
2
3
2
3
O
3
C2–C10
C3–C9
C2–C9
C3–C10
O
originally proposed
structure of aquatolide
H
O
(+)-Aquatolide
O
O
Page No. – Page No.
Total Syntheses of (+)-Aquatolide and
Related Humulanolides
The short, efficient total synthesis of (+)-aquatolide was achieved by a biomimetic
transannular [2+2] photocycloaddition, which provides the first example of
constructing a 5/5/4/8-ring system from asteriscunolides. Furthermore, the reaction
leading to a 5/4/4/7-ring system, the originally proposed structure of aquatolide, was
also developed. This strategy achieved syntheses of five more humulanolides.
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