Asymmetric Total Synthesis of (-)-Maldoxin, a Common Biosynthetic Ancestor of the Chloropupukeananin Family

Article abstract of DOI:10.1021/acs.orglett.8b01502

The total synthesis of pestheic acid based on an intramolecular S_NAr reaction without a nitro group and the asymmetric synthesis of (-)-maldoxin by a catalytic enantioselective oxidative dearomatization of pestheic acid are described. The reactivity of (-)-maldoxin as a diene in the Diels-Alder reaction is also investigated.

Full text of DOI:10.1021/acs.orglett.8b01502

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Total Synthesis of (−)-Maldoxin, a Common Biosynthetic
Ancestor of the Chloropupukeananin Family
Takahiro Suzuki,*,† Soichiro Watanabe,‡ Muhammet Uyanik,§ Kazuaki Ishihara,§
Susumu Kobayashi,# and Keiji Tanino*,†
†Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, 060-0816 Hokkaido, Japan
‡Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, 060-0816 Hokkaido, Japan
§Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603, Japan
#Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
S
* Supporting Information
ABSTRACT: The total synthesis of pestheic acid based on an intramolecular SNAr reaction without a nitro group and the
asymmetric synthesis of (−)-maldoxin by a catalytic enantioselective oxidative dearomatization of pestheic acid are described.
The reactivity of (−)-maldoxin as a diene in the Diels−Alder reaction is also investigated.
aldoxin (1, Figure 1) was originally isolated from the
Xylaria species collected in the Malaysian rain forest,1
lides A−G and chloropupukeanolides A−E from Pestalotiopsis
fici.3,4 These natural compounds contain the maldoxin unit as a
part of the bicyclo[2.2.2]octane skeleton that arises from an
intermolecular Diels−Alder reaction with various natural
products possessing alkenes. Since the stereocenter of the
acetal carbon of all these compounds has an (R)-configuration,
(R)-1 is presumed to be a biosynthetic intermediate for the
chloropupukeananin family.
M
Recently, Che and colleagues reported the isolation of (−)-1
from the extract of the fermentation broth of Pestalotiopsis theae
cultured on a potato dextrose agar medium.5 Interestingly,
maldoxin was not detected in the fermented rice culture of P.
theae, although chlorotheolides A (5) and B (6) were isolated,
along with its putative biosynthetic precursor, 1-undecene-2,3-
dicarboxylic acid. These results indicate that 1 is very reactive as
a diene and, hence, is difficult to isolate in the presence of other
secondary metabolites that act as dienophiles.
Because several maldoxin-containing natural products6 show
inhibitory activity against HIV-1 replication and/or cytotoxic
activity against human tumor cell lines, 1 is a potent
intermediate for not only biosynthetic but also bioactivity
studies. Although Yu and Snider have reported the total
synthesis of rac-1 and 2,7 the development of an effective and
robust synthesis of (−)-1 is an urgent task in order to achieve
the total synthesis of members of the chloropupukeananin
family and the SAR study of maldoxin-containing derivatives. In
this context, we have reported synthetic studies8 of 4 based on a
biomimetic strategy via chloropestolide C (7) and chloropu-
Figure 1. Maldoxin and related compounds.
along with dihydromaldoxin (2, also known as pestheic acid2a
and RES-1214-22b) and maldoxone (3). Since the optical
rotation of 1 was not reported, its absolute stereochemistry has
remained ambiguous. During the past decade, Che and
colleagues have reported the subsequent isolation of members
of the chloropupukeananin (4) family, including chloropesto-
Received: May 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01502
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
pukeanolide D (8) using model compounds of 1. We herein
report the subgram scale synthesis of (−)-1 based on an
intramolecular SNAr reaction without a nitro group and a
catalytic enantioselective oxidative dearomatization of pestheic
acid using chiral hypervalent iodine compounds.
The synthetic strategies for pestheic acid and (−)-maldoxin
are illustrated in Scheme 1. Normally, a nitro group is present
hydroxyl group of fragment 11 was then achieved, providing
benzoate 12 in 79% yield. After several experiments,12 we found
that treatment of benzoate 12 with Cs2CO3 in DMSO (0.05 M,
80 °C, 65 h) provided diaryl ether 16 in 51% yield, along with
hydrolysates 10 (20%) and 11 (15%). Ether 16 was formed by
the intramolecular SNAr and successive hydrolysis of 7-
membered lactone 15. Removal of the Bn group was
accomplished by treatment with a mixture of TFA and
thioanisole13 to give pestheic acid 2 in quantitative yield. All
the spectral data of our synthetic 2 were identical to those of
natural 2.2
Scheme 1. Synthetic Strategy toward (−)-Maldoxin
We next focused on the asymmetric oxidative dearomatiza-
tion of pestheic acid (2) to (−)-maldoxin (1). At first, oxidation
of 2 with stoichiometric amounts of chiral hypervalent
organoiodine(III) reagents 17a and 17b14 was attempted
(Table 1). Oxidation of 2 with lactate-derived iodine(III) 17a
Table 1. Stoichiometric Oxidative Dearomatization Using
Chiral Organoiodine(III) Reagents
in the electrophilic substrates of an SNAr reaction, i.e., Sanger’s
reagent (1-fluoro-2,4-dinitrobenzene), to accelerate the reac-
tion effectively. However, removal of the nitro group requires a
stepwise reduction and decreases the convergency of the
synthesis. Thus, we planned an intramolecular SNAr reaction
without nitro groups for the diaryl ether formation, as reported
in the recent work of Ohmori and Suzuki.9 We envisioned that
the intramolecular SNAr reaction of ester 12 would give 2
directly via the hydrolysis of 3. Once a large amount of 2 was in
hand, catalytic asymmetric oxidative dearomatization10 would
be attempted. Ester 12 can be easily prepared from benzoic acid
10 and catechol 11 by a site-selective esterification. In addition,
preparation of catechol 11 has been reported in our previous
studies.8
We commenced the total synthesis of pestheic acid 2 with
the preparation of fragment 10 (Scheme 2) according to a
procedure similar to the preparation of benzoic acid 14,11 in
which lithiation of 3,5-difluorotoluene (13) and subsequent
carboxylation provided benzoic acid 14. The intermolecular
SNAr reaction with KOBn in THF gave Bn-protected 6-fluoro-
4-methylsalicylic acid 10 in quantitative yield. Regioselective
esterification via benzoyl chloride with the less hindered
reagent
(equiv)
temp
(°C)
time
(h)
yield
(%)
ee
(%)
a
entry
solvent
b
1
2
3
4
5
6
7
17a (2.0)
17a (2.0)
17a (2.0)
17a (2.0)
17a (2.0)
17a (2.0)
17b (1.5)
CH2Cl2/HFIP
toluene
CCl4
0
25
5
15
15
8
47
50
51
59
57
59
67
76
85
77
90
99
25
CHCl3
0
CH2Cl2
CHCl3
0
8
c
−10
−20
50
59
CHCl3
15
b
61
a
All reactions were carried out at 0.01 mmol scale. CH2Cl2/HFIP =
2/1. Starting material 2 (5%) was recovered.
c
gave (−)-1 in moderate yield (entries 1−5), and the best
enantioselectivity was observed when CHCl3 was used as the
solvent (entry 4). The enantioselectivity was improved further
at lower temperature; however, the reaction did not complete,
even after a long reaction time (entry 6). On the other hand,
and to our delight, both the reaction rate and enantioselectivity
could be improved by the use of the much more conforma-
tionally flexible organoiodine(III) 17b,14c and enantiomerically
pure (−)-1 was obtained (entry 7). The X-ray crystallographic
analysis of (−)-1 confirmed the absolute stereochemistry of
(−)-maldoxin as an (R)-configuration (Figure 2). The
spectroscopic data of our synthetic (−)-maldoxin were in
good agreement with those of natural (−)-maldoxin.1,4,15
Scheme 2. Total Synthesis of Pestheic Acid (2)
Figure 2. ORTEP drawing of (−)-maldoxin.
B
DOI: 10.1021/acs.orglett.8b01502
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Organic Letters
Letter
Next, we investigated the oxidative dearomatization of
pestheic acid under catalytic conditions using organoiodine
18 and m-CPBA as a co-oxidant (Table 2). Treatment of 2 with
Table 3. Diels−Alder Reaction of (−)-Maldoxin with Typical
Dienophiles 19a−c
Table 2. Catalytic Oxidative Dearomatization Using Chiral
Organoiodine 18
temp
(°C)
time
(h)
yield
(%)
ratio
20:21
entry
R
solvent
1
2
3
OEt (19a)
Ph (19b)
CH2Cl2
CH2Cl2
toluene
25
25
80
8
20
25
99
7.5:1
7.8:1
4.8:1
scale
18
MeOH
(equiv)
time
(h)
yield
(%)
ee
95
entry
(mmol)
(mol %)
(%)
CO2Me
(19c)
quant
1
2
3
4
5
6
7
0.01
0.01
0.01
0.01
0.01
0.01
0.01
1.0
20
20
20
20
20
20
20
20
10
-
8
14
6
65
71
75
76
75
61
36
86
93
96
98
98
99
99
98
87
99
99
10
a
1
The ratio was determined by H NMR analysis.
25
37.5
50
6
6
75
7
the biomimetic synthesis of chloropupukeananin using
(−)-maldoxin and (+)-iso-A82775C18 will be reported in due
course.
100
37.5
20
13
5
a
8
a
9
0.10
18
a
The reactions were carried out at 0 °C.
ASSOCIATED CONTENT
* Supporting Information
■
S
20 mol % of 18 and 1.5 equiv of m-CPBA at room temperature
resulted in a slight decrease in the enantiomeric excess
compared to stoichiometric oxidation at low temperature
(Table 2, entry 1 versus Table 1, entry 7). The additional effect
of an alcohol14c−e was then examined under catalytic oxidation
conditions (entries 2−7). The yield and enantioselectivity of
the reaction improved with the use of an excess of methanol
(10 to 50 equiv, entries 2−5). Moreover, the use of a large
excess of methanol resulted in lower yield and enantioselectivity
(entries 6 and 7). These results are very consistent with the
previous findings.14c−e The best results with respect to chemical
yield and enantioselectivity were obtained with the use of 37.5
equiv of methanol (entry 4). Importantly, the reaction
proceeded much more efficiently at 0 °C on a 1.0 mmol
scale, and optically pure (−)-1 was obtained in 86% yield
(entry 8). Furthermore, the yield and enantioselectivity were
maintained (93% yield, 99% ee) when the loading amount of
the catalyst was lowered to 10 mol % (entry 9).
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01502.
Detailed experimental procedures, spectroscopic data, 1H
and 13C NMR spectra, and X-ray crystallographic data of
new compounds (PDF)
Accession Codes
CCDC 1829379 and 1833157 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Finally, we were interested in the reactivity of (−)-maldoxin
as a diene in the Diels−Alder reaction with the typical
dienophiles ethyl vinyl ether 19a, styrene 19b, and methyl
acrylate 19c (Table 3). A reaction with 19a and 19b (entries 1
and 2) proceeded smoothly at room temperature to give the
corresponding cycloadducts 20 and 21 in excellent yields with
good diastereoselectivity;16 however, the reaction with 19c
required relatively harsh conditions (entry 3, 80 °C, 25 h).
These results reveal that (−)-maldoxin is a good substrate for
reverse-electron-demand Diels−Alder reactions.17
In conclusion, we have achieved the total synthesis of
pestheic acid based on an intramolecular SNAr reaction without
a nitro group (9-step longest linear sequence (LLS) from
commercial 5-methoxysalicylic acid) and the subgram scale
synthesis of (−)-maldoxin by catalytic enantioselective
oxidative dearomatization (overall 10% yield, 10-step LLS,
99% ee). This synthesis demonstrates usefulness of the catalytic
enantioselective oxidative dearomatization using chiral organo-
iodine compound 18. Moreover, we revealed the reactivity of
(−)-maldoxin as a diene with simple alkenes. Studies toward
*E-mail: takahiro-suzuki@sci.hokudai.ac.jp (T.S.).
*E-mail: ktanino@sci.hokudai.ac.jp (T.K).
ORCID
Takahiro Suzuki: 0000-0002-3842-1025
Muhammet Uyanik: 0000-0002-9751-1952
Kazuaki Ishihara: 0000-0003-4191-3845
Keiji Tanino: 0000-0002-0580-0125
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported in part by JSPS KAKENHI Grant
Numbers JP15H05842 in Middle Molecular Strategy and
24790025 in Grant-in-Aid for Young Scientists (B). We thank
the Naito Foundation, the Uehara Memorial Foundation, the
Kurata Memorial Hitachi Science and Technology Foundation,
and the Research Foundation for Pharmaceutical Sciences for
financial support.
C
DOI: 10.1021/acs.orglett.8b01502
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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DOI: 10.1021/acs.orglett.8b01502
Org. Lett. XXXX, XXX, XXX−XXX