Asymmetric Total Synthesis of (-)-Guignardones A and B

Article abstract of DOI:10.1021/acs.orglett.0c00241

The asymmetric total synthesis of (-)-guignardones A (2) and B (1) has been accomplished. The highly oxidized 6-oxabicyclo[3.2.1]octane core was constructed from d-quinic acid via substitution/desulfurization reaction with thiophenol to forge the bridged ring scaffold, and a Pummerer rearrangement and 1,4-addition/elimination sequence was employed to install the β-carbonyl group at the congested C-1 position. A late-stage Knoevenagel condensation-6π-electrocyclization and directed hydrogenation formed (-)-guignardone B (1), which was subjected to dehydration to furnish (-)-guignardone A (2).

Full text of DOI:10.1021/acs.orglett.0c00241

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Letter
Asymmetric Total Synthesis of (−)-Guignardones A and B
Zhiming Yan, Chunbo Zhao, Jianxian Gong,* and Zhen Yang*
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ABSTRACT: The asymmetric total synthesis of (−)-guignardones A (2) and B (1) has been accomplished. The highly oxidized 6-
oxabicyclo[3.2.1]octane core was constructed from D-quinic acid via substitution/desulfurization reaction with thiophenol to forge
the bridged ring scaffold, and a Pummerer rearrangement and 1,4-addition/elimination sequence was employed to install the β-
carbonyl group at the congested C-1 position. A late-stage Knoevenagel condensation−6π-electrocyclization and directed
hydrogenation formed (−)-guignardone B (1), which was subjected to dehydration to furnish (−)-guignardone A (2).
he 6-oxabicyclo[3.2.1] octane framework was first found
in the natural products guignardones A−C, isolated by
these tetracyclic meroterpenes attracted our interest for
conducting the total synthesis of 2 and 1. Recently, Ito and
co-workers reported the first asymmetric total synthesis of
tricyclic guignardones H (6) and I (7) by employing
Knoevenagel condensation−6π-electrocyclization with the
unsaturated aldehyde 8 and a novel 1,3-cyclohexanedione 9,
followed by a chemo- and stereoselective directed hydro-
genation as the key steps and realized the construction of the
T
Tan and co-workers from the cultures of Guignardia mangiferae
IFB-GLP-4, which are associated with the normal Ilex cornuta
1
leaves, in 2010. (Figure 1) Other members of this family of
4
A/B/C ring of guignardones (Figure 2a). However, tetracyclic
Figure 1. 6-Oxabicyclo[3.2.1] octane core fragment and structures of
guignardones A (2) and B (1) and related natural products (3−5).
2
natural products were isolated and found to possess the 6-
oxabicyclo[3.2.1]octane core in common, which contains an
oxygen on the bridged carbon center. More than 12 types of
these tetracyclic meroterpenes have been isolated until now,
and some of them exhibited interesting bioactivities, such as
2
a,d
2b
antibacterial
and TLR3-regulating activities, cytotoxicity
2e
aginst MCF-7 cell lines, and inhibitory activity for Candida
albicans. Guignardone B (1) exhibited the most potent
inhibition of the growth of Candida albicans with an MIC
Figure 2. Total synthesis of guignardones.
Received: January 16, 2020
2d
value of 0.05 μM.
Structurally, guignardones A (2) and B (1) feature
tricycloalternarenes (TCAs) with an additional bridging
3
tetrahydrofuran ring D, which possesses a highly oxidized 6-
oxabicyclo[3.2.1]octane bearing a 1,3-diketone and a bridge-
head hydroxyl group. The relatively uncommon structure of
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c00241
A
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guignardones featuring the 6-oxabicyclo[3.2.1]octane core
fragment remain full of synthetic challenges, and no related
studies have been reported. Herein, we report the first
asymmetric total synthesis of (−)-guignardones A (2) and B
Scheme 1. Synthesis of 6-Oxabicyclo[3.2.1]octane 16 and
Enone 11
a
(
1).
The retrosynthetic analysis for the total synthesis of
−)-guignardones A (2) and B (1) is delineated in Figure
b. (−)-Guignardone A (2) could be obtained from
(
2
(
−)-guignardone B (1) by dehydration. We also envisioned
that the B ring of (−)-guignardone B (1) could be formed
5
through Knoevenagel condensation−6π-electrocyclization
4
with the known unsaturated aldehyde 8 and the 1,3-
cyclohexanedione 10, followed by a chemo- and stereoselective
4
directed hydrogenation. On the other hand, 1,3-cyclo-
hexanedione 10 could be obtained from enone 11 by α-
6
hydrogen elimination type Pummerer rearrangement and 1,4-
addition/elimination for installing the β-carbonyl group at the
7
congested C-1 position. We envisioned access to enone 11
8
9
through reduction, substitution, and desulfurization of
lactone 12. Finally, lactone 12 could be derived from the
1
0
a
commercially available chiral pool
lactonization.
D-quinic acid by
Reagents and conditions: (a) 2,2-dimethylpropane (4.0 equiv),
PTSA·H O (0.1 equiv), acetone, reflux, 7 h, 92%; (b) imidazole (2.0
2
equiv), TMSCl (1.5 equiv), DCM, rt, 6 h, 95%; (c) DIBAL-H (1.1
equiv), DCM, −78 °C, 1 h; then AcOH (20 equiv), −78 °C to rt,
DMAP (1.0 equiv), H O (10 equiv), overnight; then Et N (30 equiv),
Our synthetic studies began with the preparation of lactone
3 by lactonization and cis diol protection of D-quinic acid in
11
1
2
3
the presence of PTSA·H O, followed by the protection of the
2
Ac O (8.0 equiv), 3 h, 63%, dr = 10:1; (d) PhSH (1.1 equiv), BF ·
2
3
tertiary alcohol with a trimethylsilyl group, to afford 13 in 76%
yield. The lactone 13 was subjected to DIBAL-H reduction in
toluene at low temperature and was quenched with AcOH to
OEt (1.2 equiv), MeCN, 0 °C to rt, 6 h, 46%, dr = 10:1; (e) Raney-
2
Ni (50 μm in H O, excess), EtOH, 50 °C, 5 h, 78%; (f) TFA (20.0
2
equiv), CHCl3, 0 °C to rt, 5 h, 89%; (g) Mattock’s bromide (2.0
equiv), dry MeCN, 0 °C to rt, 3.5 h, 59%; (h) DBU (2.5 equiv),
12
remove the trimethylsilyl group. Bisacetylation delivered 14,
which upon treatment with thiophenol in the presence of 1
MeCN, rt to reflux, 5 h, 67%; (i) Mg(OMe)
4 h; (j) DMP (1.6 equiv), DCM, rt, 2 h, 60% two steps. PTSA·H
2
(8.0 equiv), MeOH, rt,
O =
8
equiv of BF ·Et O afforded the thiosemiacetal 15 in 46% yield
2
3
2
p-toluenesulfonic acid monohydrate, DCM = dichloromethane,
DIBAL-H = diisobutylaluminum hydride, TMS = trimethylsilyl,
DMAP = 4-dimethylaminopyridine, TFA = trifluoroacetic acid,
Mattock’s bromide = 1-bromo-2-methyl-1-oxopropan-2-yl acetate,
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, DMP = Dess−Martin
periodinane.
as a 10:1 diastereomeric mixture. Subsequent desulfurization of
5 by treatment with Raney nickel in ethanol at 50 °C
9a
1
proceeded smoothly to provide the precursor 6-
oxabicyclo[3.2.1]octane 16 in moderate yield. Deprotection
of 16 in the presence of excess TFA provided diol 17 in 89%
13
yield, and the use of excess Mattock’s bromide in dry MeCN
converted the cis diol group to trans bromoacetate 18, which
upon treatment with DBU in hot MeCN led to the elimination
of bromide, providing allylic diacetate 19 in good yield. With
the carbonyl group of 20 with ethane-1,2-diol was required to
prevent the occurrence of elimination in the next step,
involving H O (30% in H O) for the conversion of 21
21,6d
1
9 in hand, in order to afford the unprotected secondary allylic
2 2 2
14
alcohol, magnesium methoxide was used to chemoselectively
remove the acetyl group from the secondary allylic hydroxyl,
rather than from the tertiary hydroxyl group. Finally, Dess−
Martin oxidation was employed to achieve the allylic
oxidation for preparing the desired enone 11 (Scheme 1).
The strategy for constructing the corresponding cyclic 1,3-
diketone derivatives starting from cyclic substrates was proven
to be difficult in congested bridged or spiro ring systems.
With the requisite enone 11 in hand, we investigated an
epoxidation/ring-opening sequence strategy
to the sulfoxide 22 (86% yield). The sulfoxide 22 was then
treated with pyridine and trifluoroacetic anhydride (TFAA),
which led to the almost exclusive formation of the6
corresponding vinyl sulfide by α-hydrogen elimination,
which was followed by the HCl-mediated 1,2-diol deprotection
to afford the vinyl sulfide carbonyl compound 23 in 95% yield.
Next, we needed to oxidize the sulfur group to the sulfoxide to
increase its ability to undergo a displacement, which was
achieved by treatment with LiH in cold MeOH followed by
acidification and delivered the target 1,3-cyclohexanedione 6-
oxabicyclo[3.2.1]octane 10 via the Michael addition of
1
5
16,17
5d,18
and studied
the typical silyl conjugate addition−Tamao oxidation ap-
7
,19
16
7
proaches and allylic oxidation strategy to introduce the β-
carbonyl group. However, none of those conditions were
successful, probably due to the instability of enone 11 under
strongly alkaline conditions and the high steric congestion at
methoxide and the elimination of sulfoxide followed by the
deprotection. Overall, the asymmetric construction of 6-
oxabicyclo[3.2.1]octane 10 was completed with this synthetic
sequence (Scheme 2).
In the latter stage of the synthetic route, we first investigated
various hetero-Diels−Alder conditions for the reaction of 1,3-
cyclohexanedione 10, formaldehyde, and the simple unac-
tivated olefins (1-methylcyclopent-1-ene derivatives), such as
the use of L-proline catalysis, hydroquinone catalysis, and
Cu(OAc) catalysis, to construct the B ring of guignardone
B (1). Unfortunately, 1,3-cyclohexanedione 10 decomposed
7
the C-1 position. We considered that the C-1 position could
be oxidized by an efficient rearrangement based on a previous
report that carried out the conversion of a sulfoxide to a vinyl
sulfide utilizing the α-hydrogen elimination type Pummerer
6
22a
22b
rearrangement. The thiocarbonyl compound 20 could be
22c
obtained by Michael addition between the enone 11 and
2
20
thiophenol in the presence of a weak base. The protection of
B
https://dx.doi.org/10.1021/acs.orglett.0c00241
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
2
0
Scheme 2. Synthesis of 1,3-Cyclohexanedione 6-
Oxabicyclo[3.2.1]octane 10
isolated (+)-guignardone B (1), [α] = +67, c = 0.76 in
D
a
1
4,24
acetone). Finally, Burgess reagent-mediated dehydration of
(
7
−)-guignardone B (1) delivered (−)-guignardone A (2) in
2
5
3% yield ([α] = −35, c = 0.30 in acetone; isolated
D
2
0
1
(
+)-guignardone A (1), [α] = +42, c = 0.30 in acetone).
D
In conclusion, we completed the asymmetric total synthesis
of (−)-guignardones A (2) and B (1). The key features of
convergent synthetic approach included (i) construction of the
highly oxidized 6-oxabicyclo[3.2.1]octane core fragment by a
substitution/desulfurization reaction with thiophenol; (ii)
installation of the β-carbonyl group at the congested C-1
position utilizing α-hydrogen elimination type Pummerer
rearrangement and 1,4-addition/elimination in the 6-
oxabicyclo[3.2.1]octane; and (iii) Knoevenagel condensa-
tion−6π-electrocyclization and chemo-/stereoselective direc-
ted hydrogenation to afford (−)-guignardone B (1), followed
by dehydration to prepare (−)-guignardone A (2). On the
basis of this synthetic approach, total syntheses of other
guignardones and related challenging molecules are currently
underway in our laboratory.
a
Reagents and conditions: (a) PhSH (1.1 equiv), Et N (1.2 equiv),
3
CHCl , rt, 3 h, 82%; (b) ethane-1,2-diol (10 equiv), PTSA·H O (0.1
equiv), benzene, reflux, 5 h, 89%; (c) H O (2.0 equiv, 30 ω% in
H O), HFIP, rt, 2 h, 86%; (d) pyridine (10.0 equiv), TFAA (5.0
equiv), DCM, rt, 2 h; then 4 N HCl, 95%; (e) m-CPBA (1.1 equiv, ω
3
2
2
2
2
=
85%), DCM, −40 °C to rt, 4 h; (f) LiH (5.0 equiv), dry MeOH, 0
°C, 3 h; then 4 N HCl, 0 °C to rt, 40% two steps. HFIP = 1,1,1,3,3,3-
hexafluoro-2-propanol, Py = pyridine, TFAA = trifluoroacetic
anhydride, m-CPBA = 3-chloroperoxybenzoic acid.
ASSOCIATED CONTENT
■
*
sı Supporting Information
under these heating conditions. Next, we synthesized the
known unsaturated aldehyde 8 from (−)-limonene in five
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00241.
4
steps and employed intermolecular Knoevenagel condensa-
tion to combine the aldehyde 8 and 1,3-cyclohexanedione 10,
which set the stage for the key 6π-electrocyclization (Scheme
Experimental procedures and characterization data for
all new compounds (PDF)
3
). The resulting crude tetracyclic compound 24 was refluxed
Accession Codes
Scheme 3. Asymmetric Total Synthesis of
a
CCDC 1969699 contains the supplementary 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(−)-Guignardones A (2) and B (1)
AUTHOR INFORMATION
■
Corresponding Authors
Jianxian Gong − State Key Laboratory of Chemical
Oncogenomics, Key Laboratory of Chemical Genomics, Peking
University Shenzhen Graduate School, Shenzhen 518055,
China; orcid.org/0000-0003-4331-0976; Email: gongjx@
pku.edu.cn
Zhen Yang − State Key Laboratory of Chemical Oncogenomics,
Key Laboratory of Chemical Genomics, Peking University
Shenzhen Graduate School, Shenzhen 518055, China; Key
Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education and Beijing National Laboratory for
Molecular Science (BNLMS), and Peking-Tsinghua Center for
Life Sciences, Peking University, Beijing 100871, China;
orcid.org/0000-0001-8036-934X; Email: zyang@
pku.edu.cn
a
Reagents and conditions: (a) 10 (1.0 equiv), 8 (1.2 equiv),
piperidinium acetate (1.0 equiv), benzene, reflux with Dean−Stark
apparatus under argon atmosphere, 4 h; (b) Crabtree’s catalyst (0.5
equiv), H , DCM, rt, 5 h, 30% in two steps from 10; (c) Burgess
reagent (2 equiv), benzene, 50 °C, 3 h, 73%. Crabtree’s catalyst =
2
(
1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(I)
hexafluorophosphate, Burgess reagent = (methoxycarbonylsulfamoyl)-
triethylammonium hydroxide inner salt.
under Dean−Stark conditions in benzene, in the presence of
piperidinium acetate, to remove the generated water. Next, the
chemo- and stereoselective directed hydrogenation of com-
pound 24, directed using the tertiary alcohol of the left wing,
Authors
Zhiming Yan − State Key Laboratory of Chemical
Oncogenomics, Key Laboratory of Chemical Genomics, Peking
University Shenzhen Graduate School, Shenzhen 518055,
China
Chunbo Zhao − State Key Laboratory of Chemical
Oncogenomics, Key Laboratory of Chemical Genomics, Peking
4
,23
was carried out using Crabtree’s catalyst
in DCM at room
temperature and successfully afforded (−)-guignardone B (1)
in 30% yield in two steps from 1,3-cyclohexanedione 10. The
structure of the prepared 1 was verified by X-ray crystallog-
raphy, and optical rotation ([α] = −65, c = 0.76 in acetone;
2
5
D
C
https://dx.doi.org/10.1021/acs.orglett.0c00241
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
University Shenzhen Graduate School, Shenzhen 518055,
pubs.acs.org/OrgLett
Letter
(c) Zhang, P.-P.; Yan, Z.-M.; Li, Y.-H.; Gong, J.-X.; Yang, Z. J. Am.
Chem. Soc. 2017, 139, 13989. (d) Han, Y.-X.; Jiang, Y.- L.; Li, Y.; Yu,
H.-X.; Tong, B.-Q.; Niu, Z.; Zhou, S.-J.; Liu, S.; Lan, Y.; Chen, J.-H.;
Yang, Z. Nat. Commun. 2017, 8, 14233.
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00241
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was supported by the National Key Research and
Development Program of China (Grant No.
2
2
018YFC0310905), National Science Foundation of China
(
(Grant Nos. 21772008, 21632002 and 21871012), Guangdong
4
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and 2017TQ04R032), and Shenzhen Basic Research Program
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