Asymmetric Synthesis and Structure Revision of Guignardone H and I: Development of a Chiral 1,3-Diketone Possessing C2 Symmetry

Article abstract of DOI:10.1021/acs.orglett.9b00486

A novel chiral 1,3-diketone possessing C₂ symmetry was synthesized and utilized in the asymmetric synthesis of guignardone H and I by employing sequential condensation-6?-electrocyclization reactions with the novel 1,3-diketone followed by ster

Full text of DOI:10.1021/acs.orglett.9b00486

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Synthesis and Structure Revision of Guignardone H and
I: Development of a Chiral 1,3-Diketone Possessing C2 Symmetry
Toyoharu Kobayashi,† Iori Takizawa,† Ayumu Shinobe,† Yuichiro Kawamoto,† Hideki Abe,‡
and Hisanaka Ito*,†
†School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
‡Department of Chemical and Biological Sciences, Faculty of Science, Japan Women’s University, 2-8-1 Mejirodai, Bunkyo-ku,
Tokyo 112-8681, Japan
S
* Supporting Information
ABSTRACT: A novel chiral 1,3-diketone possessing C2 symmetry was synthesized and utilized in the asymmetric synthesis of
guignardone H and I by employing sequential condensation−6π-electrocyclization reactions with the novel 1,3-diketone
followed by stereoselective hydrogenation as key steps. Although the synthetic compounds differed from natural guignardone H
and I, we realized that the C4-epimers of the proposed structures for guignardone H and I were the actual structures.
he guignardones are a family of tricycloalternarene-type
meroterpenoids, first isolated from cultures of Guignardia
these compounds include three consecutive stereocenters on a
cyclopentane ring and a trans-1,3-disubstituent on a cyclo-
hexenone ring. When guignardone I (2) was discovered to
possess antibacterial activity against MRSA, related compounds
such as guignardone J (3), L (4), and S (5) were isolated and
shown to have biological activities.1f,h Although members of the
guignardone family show structural diversity and interesting
bioactivity, no total synthesis or synthetic studies of these
guignardones have been reported. The structural features and
biological activities of these compounds prompted a synthetic
study of guignardone H (1) and I (2) with a goal to develop an
efficient synthetic procedure to access the guignardone family
and other tricycloalternarene-type meroterpenoids, such as
coibanols.2 Herein, we report the first asymmetric total synthesis
and structure revision of guignardone H and I, involving the
sequential condensation−6π-electrocyclization reaction3 be-
tween a novel chiral 1,3-diketone possessing C2 symmetry and
an unsaturated aldehyde followed by highly stereoselective
hydrogenation of the resulting tricyclic compound, and the
determination of the absolute configuration of guignardone I
and related natural products.
T
mangiferae IFB-GLP-4 associated with normal Ilex cornuta leaves
by Tan and co-worker in 2010.1 More than 20 types of these
compounds exist, some of which exhibit interesting bioactivity,
such as antibacterial activity,1d,g TLR3-regulating activity,1e and
cytotoxicity for MCF-7 cell lines.1h Guignardone H (1) and I
(2) were isolated from the endophytic fungus of the mangrove
plant Scyphiphora hydrophyllaceae in 2012 by Dai and co-
workers (Figure 1).1d
The structures of 1 and 2 were established through 2D NMR
spectral analysis, including COSY, HMBC, and ROESY
experiments, although the absolute configurations of compound
1 and 2 had not yet been determined. The structural features of
The synthetic strategy for guignardone H (1) and I (2) is
outlined in Scheme 1.
Guignardone H (1) could be synthesized from tricyclic
compound 6 via formation of an exo-olefin moiety and
deprotection of the TBS group; guignardone I (2) would be
obtained from 6 by deprotection of the TBS group. The
common intermediate 6 would be derived from compound 7 via
Figure 1. Structures of guignardone H (1) and I (2) and related natural
products 3−5.
Received: February 5, 2019
© XXXX American Chemical Society
A
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using Shi ketone 16, prepared from D-fructose and oxone as the
oxidant, afforded diepoxide 10. After several attempts at acid-
catalyzed epoxide opening of 10 with various acids, TBSOTf was
selected as the Lewis acid. Thus, treatment of diepoxide 10 with
a catalytic amount of TBSOTf (10 mol %) in THF at −78 °C
provided the desired chiral diketone (+)-9 in 62% yield for two
steps. 1,3-Diketone (+)-9 was determined to have 97% ee6 after
transformation into the methyl enol ether (+)-14 using
Zubaidha’s protocol.7 The absolute configuration of 1,3-
diketone (+)-9 was determined as 4R,6R using single-crystal
X-ray crystallographic analysis after conversion to compound
(+)-15.8
Scheme 1. Retrosynthetic Analysis of 1 and 2
With the synthesis of 1,3-diketone (+)-9 in hand, we next
focused on construction of the tricyclic skeleton of the
guignardones via sequential condensation−6π-electrocycliza-
tion reaction and chemo- and stereoselective hydrogenation
(Scheme 3).
Ozonolysis of (−)-limonene (17) followed by intramolecular
aldol condensation of the resulting keto aldehyde afforded
a
Scheme 3
chemo- and stereoselective hydrogenation and chemoselective
methylation of the secondary alcohol. Compound 7 would be
constructed by Knoevenagel condensation of the 1,3-diketone 9
possessing C2 symmetry and unsaturated aldehyde 8 and
followed by 6π-electrocyclization. Chiral 1,3-diketone 9 could
be obtained by acid-catalyzed epoxide-opening of known
diepoxide 10,4 which was developed by Myers and co-workers
from resorcinol (12) via Shi asymmetric epoxidation of
compound 11.
The synthetic study began with the development of the chiral
1,3-diketone 9, as shown in Scheme 2.
According to Myers’ protocol,4 chiral diepoxide 10 was
prepared from resorcinol (12). Thus, TBS protection of 12 and
Birch reduction of resulting compound 13 afforded compound
11 in 98% yield for two steps. Shi asymmetric epoxidation5 of 11
a
Scheme 2
a
Reagents and conditions: (a) O3, CH2Cl2-MeOH, −78 °C, then
Me2S, RT, 93%; (b) piperidinium acetate, benzene, reflux, quant.; (c)
NCS, t-BuOH-H2O, RT; (d) LAH, THF, 0 °C, 50% (2 steps); (e)
MnO2, CH2Cl2, RT, 90%; (f) piperidinium acetate, MS 4 Å, Et2O,
RT, 53% 20 (dr 1:1), 24% 21 (dr 2:1); (g) p-TsOH, THF-H2O, 50
°C, 40% (brsm 96%); (h) H2, Crabtree’s catalyst, CH2Cl2, RT, 96%,
single isomer; (i) MeI, Ag2O, MS 4 Å, Et2O, reflux, 98%; (j) 4 M
HCl, THF, RT, quant.; (k) Burgess reagent, benzene, reflux; (l) 3 M
HCl, THF, RT, 50% (2 steps).
a
Reagents and conditions: (a) TBSCl, imidazole, DMF, 0 °C, 99%;
(b) Li, t-BuOH, liq. NH3, reflux, 99%; (c) Shi ketone 16, oxone,
K2CO3, MeCN-buffer, 0 °C; (d) TBSOTf (10 mol %), THF, − 78
°C, 62% (2 steps); (e) I2, MeOH, RT, 37%; (f) 4-bromobenzoyl
chloride, Et3N, CH2Cl2, 0 °C, 85%.
B
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known compound (−)-18.9 The chlorohydrination of (−)-18
with NCS in t-BuOH-H2O, followed by reduction with LAH,
provided diol (−)-19 in 50% yield for two steps. Treatment of
compound (−)-19 with MnO2 gave unsaturated aldehyde (−)-8
in 90% yield. The sequential condensation−6π-electrocycliza-
tion reaction with 1,3-diketone (+)-9 was investigated in detail.
Results showed that piperidinium acetate is essential for this
reaction. Treatment of compounds (−)-8 and (+)-9 with
piperidinium acetate in Et2O at room temperature afforded
tricyclic compound 20 in 53% and 21 in 24% yield as an
inseparable diastereomeric mixture. Selective TBS group
deprotection of compound 20 using p-TsOH led to compound
21 in 40% yield (brsm 96% yield). Surprisingly, after many
attempts at chemo- and stereoselective hydrogenation of
diastereomeric mixture 21, the desired compound (−)-22 was
obtained in excellent yield as a single isomer. Thus, treatment of
diastereomeric mixture 21 with Crabtree’s catalyst10 in CH2Cl2
at room temperature afforded the desired (−)-22 in 96% yield as
a single isomer. The stereochemistry of the two newly formed
stereocenters of (−)-22 were confirmed by X-ray crystallo-
graphic analysis of (−)-1. Then, selective methylation of
secondary alcohol (−)-22 provided compound (+)-6 in 98%
yield. The TBS deprotection of (+)-6 gave (−)-2 (proposed
structure of guignardone I) in quantitative yield. Furthermore,
dehydration of compound (+)-6 with Burgess reagent,11
followed by TBS deprotection, afforded (−)-1 (proposed
structure of guignardone H) in 50% yield over two steps. The
structure of compound (−)-1 was confirmed unambiguously by
X-ray crystallographic analysis.
Thus, the asymmetric syntheses of the proposed structures of
guignardone H (1) and I (2) were achieved. However, the 1H
and 13C NMR spectra of synthetic 1 and 2 were not identical to
those of naturally occurring guignardone H and I.1d Especially,
in the spectra of 1 and 2, the chemical shift of the cyclohexenone
moiety was different from the reported chemical shift of the
guignardones.12 Therefore, the diastereomers of 1 and 2 with
different stereochemistry of the cyclohexenone moiety are the
real structures of guignardone H and I. Based on this
assumption, a literature search was conducted to determine
whether naturally occurring products with these spectra had
been reported. Fortunately, the NMR spectra of two naturally
occurring products, tricycloalternarene F (24)1b and guignar-
enone C (25),13 were identical with those of naturally occurring
guignardone H. Tricycloalternarene F (24) has same planar
structure as guignardone H; however, the stereochemistry of the
cyclohexenone moiety was not determined.1b Guignarenone C
(25) has cis-1,3-disubstituents on the cyclohexenone ring and an
angular methyl group, isopropenyl group, and substituents on
the cyclohexenone ring also in a cis-orientation. Therefore, the
actual structures of guignardone H and I were predicted to be
compounds 26 and 27, respectively, which are C4-epimers of
(−)-1 and 2, respectively. The syntheses of 26 and 27 were
conducted using compound (−)-2 as a starting material
(Scheme 4).
Thus, Mitsunobu reaction of (−)-2 with p-bromobenzoic acid
led to compound (−)-28 in 83% yield. Solvolysis of (−)-28
provided desired compound (−)-27 in 58% yield. Dehydration
of compound (−)-28 with Burgess reagent, followed by the
solvolysis, afforded compound (−)-26 in 48% for two steps. The
1H and 13C NMR spectra of both (−)-26 and (−)-27 were
A proposed reaction mechanism for the chemo- and
stereoselective hydrogenation (from 21 to (−)-22) is shown
in Figure 2.
a
Scheme 4
Figure 2. Proposed reaction mechanism for the chemo- and
stereoselective hydrogenation of diastereomeric mixture 21.
It is proposed that Crabtree’s catalyst can coordinate to the
secondary or tertiary alcohols to direct the hydrogenation of
compound 21. For β-21, the hydroxyl groups would direct
hydrogenation to the more sterically hindered concave face,
which is disfavored and does not proceed. In contrast, hydroxyl
groups would direct hydrogenation to the convex face of α-21,
so hydrogenation can proceed to give (−)-22. It is hypothesized
that an equilibrium exists between α-21 and β-21 via the 6π-
electrocyclization of dienone A, which enables the hydro-
genation reaction to converge the diastereomeric mixture
exclusively to (−)-22.
a
Reagents and conditions: (a) p-bromobenzoic acid, PPh3, DEAD,
THF, RT, 83%; (b) 2 M NH3 in MeOH, RT, 58%; (c) Burgess
reagent, benzene, reflux, 56%; (d) 2 M NH3 in MeOH, 60 °C, 85%.
C
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identical to those of naturally occurring guignardone H and I,
respectively. These results suggest that the relative stereo-
chemistry of some guignardones (guignardones J, K, L, R, and
S1f,h) might be incorrect because it was determined based on the
relative stereochemistry of guignardone H and I. The optical
rotations of synthetic (−)-27 had the same rotation as that
reported for natural guignardone I [synthetic 27: [α]D −35.7 (c
0.37, MeOH); guignardone I: [α]D −32 (c 0.24, MeOH),1d so
the absolute stereochemistries were determined as depicted in
Scheme 4. However, the optical rotation of synthetic (−)-26 had
the reverse rotation with a very different absolute value than that
reported for natural guignardone H.1d Therefore, to confirm the
absolute value of compound 26, the synthesis of (+)-26 was
conducted (Scheme 5).
(+)-31 in 36% yield as single isomer, respectively. Treatment of
(+)-30 with Crabtree’s catalyst provided the desired (+)-32 in
91% yield as a single isomer. Selective TBS group deprotection
of (+)-32 led to compound (+)-33. The stereochemistry of
compound (+)-33 was confirmed using X-ray crystallographic
analysis. Mitsunobu reaction of (+)-33 with formic acid,
followed by solvolysis provided desired compound (+)-34 in
65% yield over two steps. The secondary alcohol selective
methylation of (+)-34 afforded compound (+)-35 in 93% yield.
Finally, dehydration of compound (+)-35 with Burgess reagent,
followed by TBS deprotection, provided compound (+)-26 in
45% yield for two steps. The optical rotation absolute values of
(+)- and (−)-26 were similar, suggesting that the isolated
guignardone H is a racemic mixture or includes impurities.
Additionally, the optical rotations of synthetic 26, (−)-tricy-
cloalternarene F (24),1b and (+)-guignarenone C (25)13 were
compared, and the absolute stereochemistries were determined
as shown in Scheme 5. The result indicates that tricycloalternar-
ene F and guignarenone C are enantiomers.
In conclusion, a chiral diketone (+)-9 was developed and
utilized in the first asymmetric synthesis of proposed
guignardone H (1) and (2) in 11 and 10 linear steps from
(−)-limonene (17). The syntheses featured the sequential
condensation−cyclization reaction of unsaturated aldehyde
(−)-8 and diketone (+)-9 to construct the tricyclic skeleton of
guignardones, and chemo- and stereoselective hydrogenation
with Crabtree’s catalyst utilized the equilibrium involving
compound 21 via 6π-electrocyclization. Although synthetic 1
and 2 were different from naturally occurring guignardone H
and I, compounds 26 and 27, which were C4-epimers of 1 and 2,
were demonstrated to be the true structures of guignardone H
and I. In addition, the absolute stereochemistry of guignardone I
and guignarenone C and the relative and absolute stereo-
chemistry of tricycloalternarene F were determined. This
methodology can be extended to the synthesis of other
guignardones and structurally related meroterpenoids. Further
investigations are now in progress.
Sequential condensation−6π-electrocyclization reaction with
unsaturated aldehyde (+)-8, prepared from (+)-limonene
through an established procedure (Scheme 3), and diketone
(+)-9 afforded tricyclic compound (+)-30 in 45% yield and
a
Scheme 5
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00486.
General methods; detailed experimental studies; exper-
1
imental procedures and spectral data; H and 13C NMR
spectra (PDF)
Accession Codes
CCDC 1884504−1884505 and 1884515 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: itohisa@toyaku.ac.jp.
ORCID
a
Reagents and conditions: (a) piperidinium acetate, MS 4 Å, Et2O,
RT, 45% (+)-30 (single isomer), 36% (+)-31 (single isomer); (b)
(+)-33, H2, Crabtree’s catalyst, CH2Cl2, RT, 91%, single isomer; (c)
0.5 M HCl, THF, RT, 66%; (d) formic acid, PPh3, DEAD, RT; (e)
5% NH3 in H2O, RT, 65% (2 steps); (f) MeI, Ag2O, MS 4 Å, Et2O,
reflux, 93%; (g) Burgess reagent, benzene, 50 °C; (h) 3 M HCl, THF,
RT, 45% (2 steps).
Toyoharu Kobayashi: 0000-0002-7362-1129
Yuichiro Kawamoto: 0000-0003-1245-2090
Hideki Abe: 0000-0002-3608-7123
D
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Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Platform for Drug Discovery,
Informatics, and Structural Life Science of the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
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