Enantioselective total synthesis of sagittacin e and related natural products

Article abstract of DOI:10.1039/c8cc03438a

The first enantioselective total synthesis of eremophilane-type sesquiterpenoids, sagittacin E and related natural products, was achieved. This synthesis features an asymmetric desymmetrization by Shi asymmetric epoxidation, intramolecular aldol-type cyclization, allylic oxidation of a 1,4-diene compound, and stereoselective epoxidation.

Full text of DOI:10.1039/c8cc03438a

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Enantioselective total synthesis of sagittacin E and
related natural products†
Cite this:DOI: 10.1039/c8cc03438a
ab
a
Hideki Abe,
*
Mitsuru Fujimaki,a Eri Nakagawa,a Toyoharu Kobayashi
and
Hisanaka Ito*a
Received 27th April 2018,
Accepted 23rd May 2018
DOI: 10.1039/c8cc03438a
rsc.li/chemcomm
The first enantioselective total synthesis of eremophilane-type
sesquiterpenoids, sagittacin E and related natural products, was
achieved. This synthesis features an asymmetric desymmetrization
by Shi asymmetric epoxidation, intramolecular aldol-type cyclization,
allylic oxidation of a 1,4-diene compound, and stereoselective
epoxidation.
Fig. 1 Structures of sagittacin E (1) and related natural products 2–4.
The genus Ligularia is an important member of the family
Compositae, which is a rich source of biologically active natural
products. This genus produces mainly eremophilane-type sesquiter- epoxidation. This desymmetrization technique is useful for the
penoids and pyrrolizidine alkaloids as secondary metabolites. asymmetric total syntheses of natural products. Thus, we
Sagittacin E (1), isolated from Ligularia sagitta by Gao and planned the asymmetric total synthesis of highly oxygenated
co-workers in 2014, is a highly oxygenated eremophilane-type eremophilane-type natural product sagittacin E and related
sesquiterpenoid that possesses mild cytotoxic activities against compounds based on our developed desymmetrization reaction.
three human tumor cell lines, HL-60, SMMC-7721, and HeLa
Herein, we describe the enantioselective total synthesis of
cells, and moderates antibacterial activities against E. coli and eremophilane-type sesquiterpenoids, sagittacin E and structurally
E. carotovora (Fig. 1).1 Three structurally similar sesquiterpenoids similar natural products, based on our asymmetric desym-
2–4 were isolated from Ligularia sagitta,1,2 Ligularia veitchana,2 metrization strategy.
and Senecio nemorensis.3 Although the antibacterial activity of 3
Our synthetic strategy for the target natural products is
against E. coli was reported, biological tests of 2 and 4 have outlined in Scheme 1. Sagittacin E (1) would easily be obtained by
not yet been performed. These four eremophilane-type natural deacetylation of 2. Likewise, 3 would be obtained by deacetylation of
products have very simple bicyclic skeletons, but highly oxygenated 4. The acetyl sagittacin E (2) would be synthesized from the bicyclic
frameworks. Consequently, there are few total syntheses or diene 9 via allylic oxidation and stereoselective epoxidation. On the
synthetic studies on them to date. Very recently, Liu reported other hand, natural compound 4 would be derived from 9 only by
the efficient total synthesis of five eremophilane-type natural allylic oxidation. The common intermediate 9 would be constructed
products in racemic form, including 3 and 4, by using Robinson by intramolecular aldol type condensation of nitrile 7 with a
annulation and Suzuki coupling.4
tethered aldehyde, followed by transformation of the nitrile group
We previously reported an asymmetric synthetic study of of the resulting bicyclic compound 8 to a methyl ketone. The
briarane-type diterpenoid pachyclavulide B using asymmetric precursor 7 would be synthesized in a multi-step operation
epoxidation.5 Our synthetic strategy featured desymmetrization from the optically active epoxide 6, which would be obtained by
of symmetric 1,4-cyclohexadiene derivatives by Shi asymmetric asymmetric desymmetrization of 1,1,2,6-tetrasubstituted cyclo-
hexadiene 5.
a School of Life Sciences, Tokyo University of Pharmacy and Life Sciences,
Our synthetic project started with the construction of an
asymmetric carbon via asymmetric desymmetrization with the
Shi epoxidation protocol as shown in Scheme 2. Symmetric 1,4-diene
derivative 12 having a quaternary carbon atom was synthesized from
2,6-dimethylbenzoic acid in a two-step procedure, i.e., reductive
methylation of 10 under Birch reduction conditions (78% yield),
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
b Department of Chemical and Biological Sciences, Faculty of Science, Japan
Women’s University, 2-8-1 Mejirodai, Bunkyo-ku, Tokyo 112-8681, Japan
† Electronic supplementary information (ESI) available. CCDC 1835801, 1835813
and 1843993. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c8cc03438a
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Scheme 1 Synthetic plan for sagittacin E (1) and related compounds.
Scheme 3 Synthesis of the nitrile derivative 8.
75% yield. The hydrogenation of 15 with platinum catalyst
proceeded from the same side of the primary alcohol, thus
the relative configuration of the two vicinal methyl groups was
syn. Regioselective epoxide ring opening of 16 was achieved
with DATMP (diethylaluminum 2,2,6,6-tetramethylpiperidine)10
developed by Yamamoto as a strong base to produce the exo-
methylene compound 17 in 76% yield. Extension of the side
chain at the C1 position was carried out in two steps: Johnson–
Claisen rearrangement of allyl alcohol 17, followed by reduction
of the resulting ester compound, to give the diol 18 in 78% yield
Scheme 2 Asymmetric desymmetrization of the symmetric 1,4-diene
derivative 12.
followed by esterification of the resulting symmetric diene for 2 steps. Transformation of the primary alcohol of 18 to a
derivative 11 (99% yield). Shi asymmetric epoxidation6,7 of 12 cyano group took place as a two-step operation, selective toluene-
with Shi ketone 13 prepared from D-fructose, and Oxones as the sulfonylation of the sterically less hindered primary alcohol
oxidant afforded the desymmetrized epoxide 14 in 49% yield, group of diol 18, followed by nucleophilic substitution of the
89% de, and 85% ee.8 Reduction of the benzyl ester of 14 with resulting monotoluenesulfonate 19 with sodium cyanide, to
DIBALH at À78 1C gave the alcohol 15 in 94% yield as a afford the nitrile 20 in 91% yield (2 steps). Parikh–Doering
crystalline compound. After recrystallization, the primary alcohol oxidation11 of 20 gave the aldehyde 7, the precursor of the
15 was obtained in enantiomerically pure form (99% ee).9
planned aldol-type condensation to construct the bicyclic frame-
With the desymmetrization of the symmetric 1,4-diene work, in high yield. Treatment of 7 with LHMDS in THF at
derivative achieved by Shi asymmetric epoxidation, we focused À60 1C furnished the bicyclic compound 21 as a separable
our efforts on the construction of the eremophilane skeleton mixture in a 1 : 1 ratio in quantitative yield. These compounds
(Scheme 3). After many attempts to hydrogenate the double were diastereomers related to the cyano group at the C7 position.
bond without opening the epoxide of 15, the use of platinum on Dehydration of 21 was executed in a single operation composed
carbon as a heterogeneous catalyst in AcOEt under hydrogen of a two-step reaction, acetylation of the hydroxyl group with
gave the best result to afford hydrogenated compound 16 in acetic anhydride, followed by deacetoxylation via deprotonation
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of the a proton of the cyano group with DBU, to afford the
a,b-unsaturated nitrile derivative 8 in 96% yield.
After construction of the bicyclic framework, we transformed
the nitrile to a methyl ketone group and performed the stereo-
selective introduction of the allyl alcohol unit on the bicyclic
skeleton (Scheme 4). Nucleophilic addition of methyl lithium to
the carbon atom of the nitrile group of 8, followed by treatment
with a Brønsted acid, afforded methyl ketone derivative 22 in
94% yield. Stereo- and chemoselective epoxidation of 22 with
mCPBA gave the epoxide 23 and its diastereoisomer 24 in 68%
and 16% yields, respectively. Many reaction conditions for
transformation of the epoxide to the allyl alcohol via epoxide
ring opening of 23 were attempted. As a result, use of p-toluene-
sulfonic acid as a Brønsted acid and sec-butyl alcohol as a solvent
afforded the desired allyl alcohol 25 in 62% yield. The stereo-
chemistry of 25 was confirmed by X-ray crystallographic analysis
of p-nitrobenzoate derivative 26,12 prepared from 25 with p-nitro-
benzoyl chloride and base. This result indicated that the stereo-
selective epoxidation of 22 occurred at the more electron-rich
olefin from the same face as the two methyl groups.
With the desired allyl alcohol in hand, we were on track to
achieve our goal for the synthesis of the eremophilane-type
target molecules (Scheme 5). After acetylation of 25, many conditions
for allylic oxidation of the resulting 27 were examined. Although
manganese acetate-catalyzed,13 or palladium-catalyzed14 allylic
oxidations failed, giving a complex mixture or recovered 27,
respectively, allylic oxidation using 3,5-dimethylpyrazole–chromium
trioxide complex15 in dichloromethane at 0 1C afforded the oxidized
product 416 in 52% yield. Alternatively, the combination of tert-butyl
hydroperoxide and copper iodide17 caused sequential allylic
oxidation and stereoselective epoxidation of 27 to give the
epoxide 2 in 44% yield. Finally, removal of the acetoxy group of
the resulting oxidized products 4 and 2 quantitatively produced
the corresponding alcohols 3 and 1, respectively. Both 1H and
Scheme 5 Asymmetric synthesis of sagittacin E (1) and related natural
products.
13C NMR spectra of the synthetic compounds 1–4 were identical
with those of natural sagittasin E (1) and related natural products
2–4.1,2 The optical rotation of the synthetic 1 had the same rotation
as that reported for the natural product [synthetic 1: [a]D +104.5
(c 0.5, MeOH); natural product 1: [a]D +90.0 (c 0.5, MeOH)1]. Therefore,
we determined the absolute configuration of naturally occurring
sagittasin E as 1R,4S,5R,6R and 7S (natural product numbering).
Optical rotations of synthetic alcohol 3 and its acetate 4 also had the
same rotations as those reported [synthetic 3: [a]D À43.3(c 1.0,
CHCl3); natural product 3: [a]D À36.0 (c 0.6, CHCl3)2] and [synthetic
4: [a]D À33.3 (c 0.5, CHCl3); natural product 4: [a]D À34.6 (c 0.5,
CDCl3)2]. The absolute configurations of natural products 3 and 4
were determined as 1R,4S and 5S, respectively. However, interest-
ingly, the optical rotation of the synthetic epoxide 2 was different
from the reported value of the natural product [synthetic 2: [a]D
+52.1 (c 0.4, CHCl3); natural product 2: [a]D À11.6 (c 0.4, CHCl3)2].
Fortunately, we were able to obtain a single crystal of 2 by
recrystallization from hexane. The stereochemistry of 2 was con-
firmed by the X-ray crystallographic analysis of 218 to be the same
configuration as that of sagittasin E (1). Since natural product 2 was
isolated along with 3 and 4,2 the optical rotation value of our
synthetic sample 2 must be the correct value for natural product 2.
Scheme 4 Synthesis of the allyl alcohol 25 and its benzoate 26.
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The first enantioselective total synthesis of (+)-sagittacin E
and three related natural products was achieved. This synthesis
features an asymmetric desymmetrization of a symmetric 1,4-
cyclohexadiene derivative having a quaternary carbon by Shi
asymmetric epoxidation, intramolecular aldol-type cyclization of a
nitrile compound to construct the bicyclic skeleton, allylic oxidation
of a 1,4-diene compound, and stereoselective epoxidation.
This work was supported by the Platform for Drug Discovery,
Informatics, and Structural Life Science from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
6 Y. Shi, Acc. Chem. Res., 2004, 37, 488–496.
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8 The enantiomeric excess of compound 14 was determined by chiral
HPLC [AD-H column, hexane–isopropanol (150 : 1), 8.8 min for the first
eluted isomer (minor) and 9.7 min for the second eluted isomer (major)].
9 The enantiomeric excess of 15 was determined for the benzoate
derivative prepared from 15 with benzoyl chloride by chiral HPLC.
See ESI†.
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12 CCDC 1835801 (26)†.
Conflicts of interest
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There are no conflicts to declare.
Notes and references
16 CCDC 1843993 (4)†.
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18 CCDC 1835813 (2)†.
Chem. Commun.
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