Catalytic Asymmetric Total Synthesis of (+)- and (-)-Paeoveitol via a Hetero-Diels-Alder Reaction

Article abstract of DOI:10.1021/acs.orglett.6b03801

The first catalytic asymmetric total synthesis of (+)- and (-)-paeoveitol has been accomplished in 42% overall yield via a biomimetic hetero-Diels-Alder reaction. The chiral phosphoric acid catalyzed hetero-Diels-Alder reaction showed excellent diastereo-

Full text of DOI:10.1021/acs.orglett.6b03801

Letter
pubs.acs.org/OrgLett
Catalytic Asymmetric Total Synthesis of (+)- and (−)-Paeoveitol via a
Hetero-Diels−Alder Reaction
Tian-Ze Li, Chang-An Geng, Xiu-Juan Yin, Tong-Hua Yang, Xing-Long Chen, Xiao-Yan Huang,
Yun-Bao Ma, Xue-Mei Zhang, and Ji-Jun Chen*
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of
Sciences, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming 650201, China
S
* Supporting Information
ABSTRACT: The first catalytic asymmetric total synthesis of
(+)- and (−)-paeoveitol has been accomplished in 42% overall
yield via a biomimetic hetero-Diels−Alder reaction. The chiral
phosphoric acid catalyzed hetero-Diels−Alder reaction showed
excellent diastereo- and enantioselectivity (>99:1 dr and 90%
ee); two rings and three stereocenters were constructed in a
single step to produce (−)-paeoveitol on a scale of 452 mg.
This strategy enabled us to selectively synthesize both
paeoveitol enantiomers from the same substrates by simply
changing the enantiomer of the catalyst.
he root of Paeonia veitchii, well-known as Chuan-Chi-Shao
in China, is an important crude drug in traditional
Xie’s group reported a seven-step total synthesis of
( )-paeoveitol in 26% overall yield using a similar hetero-
Diels−Alder cycloaddition reaction as a key step.6 Herein, we
report the first enantioselective total synthesis of (+)- and
(−)-paeoveitol in six steps with 42% overall yield.
Structurally, paeoveitol consists of a unique 6,5,6,6-fused
tetracyclic ring system with three contiguous stereogenic
centers, one of which is a quaternary carbon. The structural
correlation between paeoveitol and 2 inspired us to develop a
biomimetic strategy for the synthesis of paeoveitol. Biogeneti-
cally, paeoveitol may arise from 2 via an oxo-Diels−Alder
reaction with in situ generated o-quinone methides (o-QMs)
(Scheme 1). o-QMs are highly efficient intermediates in organic
T
Chinese medicine and used as a sedative, analgesic, and
cardiovascular agent.1 Chuan-Chi-Shao is also included in the
composition of many traditional formulas (such as Sini-San and
Xiaoyao-Wan) used to treat mental illness.2 To clarify the
antipsychotic components of this plant, our previous chemical
investigation led to the isolation of six new natural products,3
including a pair of structurally novel norditerpene paeoveitol
enantiomers (1) and two benzofuran constituents paeoveitols
D and E (2 and 3) (Figure 1). Preliminary biological assays of
Scheme 1. Proposed Biosynthesis of Paeoveitol
Figure 1. Structures of (+)-paeoveitol (1a), (−)-paeoveitol (1b), and
paeoveitols D and E (2 and 3).
chemistry that are widely used in the key step of the synthesis
of various natural products.7 However, the fleeting nature of o-
QMs leads to difficulties in the stereocontrol of reactions, and
only one example of the utilization of o-QMs in the catalytic
asymmetric total synthesis of natural products has been
documented.8 With the development of asymmetric Brønsted
acid catalysis, enantioselective reactions that involve o-QMs
have been reported in the recent literature.9 Inspired by this, we
paeoveitol explored its interaction with 5-HT1A and 5-HT2C
receptors in vitro, but no meaningful agonistic activities were
observed.3a Intensive investigations of its biological activity are
hampered by the limited availability of this natural product. As
the chirality of a natural product is crucial to its bioactivity,4 the
development of a synthetic strategy that can provide both
enantiomers in adequate amounts is clearly important for
further investigation of its biological activity. Recently, Zhao
and co-workers completed the first total synthesis of paeoveitol
in racemic form through hetero-Diels−Alder cycloaddition
from methylhydroquinone in 24% overall yield over four steps.5
Received: January 4, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03801
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
envisioned that the enantioselective total synthesis of
paeoveitol could be realized if chiral phosphoric acid could
promote the asymmetric hetero-Diels−Alder reaction between
paeoveitol D and o-QMs. In this design, three stereocenters
could be constructed in a single step, and by changing only the
enantiomer of the catalyst, both paeoveitol enantiomers could
be synthesized from the same prochiral substrates.
enantiomeric excess of the asymmetric [4 + 2] addition. The
subsequent screening of different BINOL-derived CPAs (Table
1, entries 1−5) revealed that catalyst C2 bearing a bulky SiPh3
Table 1. Optimization of the Brønsted Acid Catalyzed [4 +
a
2] Hetero-Diels−Alder Reaction
Our synthesis commenced with the preparation of paeoveitol
D from commercially available 4-methoxy-3-methylbenzalde-
hyde (Scheme 2). According to the reported procedure, 4 was
a
Scheme 2. Synthesis of Paeoveitol D
b
c
entry
solvent
CH3CN
cat.
time (d)
yield (%)
ee (%)
1
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C9
C9
C9
C9
C9
C9
C9
C9
C9
C11
2
72
51
34
57
52
14
27
48
80
63
92
68
2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
4
3
4
59
4
3
72
5
3.5
4
68
6
58
7
3.5
4
62
8
74
9
3
66
10
11
12
13
14
15
16
17
3
67
5
trace
trace
trace
85
THF
5
EtOAc
5
toluene
CH2Cl2
CHCl3
2.5
3
68
90
90
90
90
a
95
Reagents and conditions: (a) m-CPBA (1.7 equiv), CH2Cl2, 0 °C to
3
93
rt, 2 h; (b) K2CO3 (2.0 equiv), MeOH, 0 °C, 15 min, 72% (two steps);
(c) (CHO)n (5.0 equiv), MgCl2 (1.5 equiv), Et3N (4.0 equiv), THF,
reflux, 8 h, 93%; (d) N2CHCO2Et (3.0 equiv), HBF4·Et2O (0.1 equiv),
0 °C to rt, 30 min, then H2SO4 (1 mL), rt, 30 min, 82%; (e) BBr3 (1.5
equiv), CH2Cl2, − 78 to 0 °C, 1 h, 97%; (f) DIBAL-H (3.0 equiv),
CH2Cl2, − 78 to 0 °C, 1 h, 85%.
ClCH2CH2Cl
CH2Cl2
CH2Cl2
CH2Cl2
3
92
d
18
6
67
e
f
19
e
3
92
90 (96)
g
20
3
93
89
a
Unless stated otherwise, the reactions were performed with 5 mol %
of catalyst, 0.1 mmol of paeoveitol D, and 0.11 mmol of 11 (1.1 equiv)
b
converted into the phenol 5 through Baeyer−Villiger
oxidation/saponification in 72% yield.10 Substituted salicylalde-
hyde 6 was easily obtained by the magnesium chloride
mediated ortho-specific formylation of 5 in good yield.11
Treatment of 6 with ethyl diazoacetate produced 7 in 82%
yield.12 Removal of the methoxyl group with BBr3, followed by
DIBAL-H reduction furnished paeoveitol D in 45% overall
yield.
in 2 mL of solvent at room temperature. Yield of the isolated product.
c
The enantiomeric ratio (ee) was determined by HPLC analysis on a
Daicel Chiralpak AD-H column (n-hexane/EtOH = 85/15, 1.0 mL/
d
e
min. The catalyst loading of C9 was 2 mol %. The reaction was
f
performed on a 1.5 mmol scale. The data in parentheses were
obtained after one recrystallization from a mixture of acetone−hexane
g
(1:4, v/v). The opposite enantiomer of 1b was obtained.
substituent slightly improved the ee value to 57%, albeit with a
minor decrease in yield (47%). We resorted to the chiral acids
C7−C10 with a spirocyclic backbone that were structurally
more rigid (Figure 2).14 The highest selectivity was eventually
obtained with phosphoric acid C9, which delivered (−)-paeo-
veitol in 66% yield and 92% ee. Next, the solvent effect was
investigated. The reaction became sluggish in EtOH, THF, and
EtOAc (Table 1, entries 11−13). The stereoselectivity
decreased when toluene was used as the solvent (Table 1,
entry 14). The reaction proceeded well in chlorinated solvents
such as CH2Cl2, CH3Cl3, and ClCH2CH2Cl (Table 1, entries
15−17). Using CH2Cl2 as the solvent, the reaction yield was
enhanced to 95% while maintaining excellent enantioselectivity
(90% ee). Reducing the catalyst loading from 5 to 2 mol % led
to a significant decrease in the yield with retained
enantioselectivity, and only 67% yield was achieved after
stirring for 6 d (Table 1, entry 18 vs 15).
As depicted in Scheme 3 for the construction of coupling
partner 11, the ketone 10 was prepared from the commercially
Scheme 3. Synthesis of the o-QM Precursor
available 2-methylhydroquinone 9 in a reported two-step
process13 and was then reduced with NaBH4 to provide the
o-QM precursor 11 in 82% yield.
With paeoveitol D and 11 in hand, attention was turned to
the crucial asymmetric [4 + 2] cycloaddition. The initial
experiment to test our hypothesis commenced with the
reaction of paeoveitol D and 11 in CH3CN catalyzed by 5
mol % of C1. The desired natural product could be obtained in
72% yield with 34% ee as a single diastereomer. The reaction
conditions were investigated to improve the yield and
Under the optimal reaction conditions, a large-scale synthesis
using 1.5 mmol of paeoveitol D also provided excellent yield
(92%, 452 mg) and enantioselectivity (90% ee, entry 19). The
B
DOI: 10.1021/acs.orglett.6b03801
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chenjj@mail.kib.ac.cn.
ORCID
Chang-An Geng: 0000-0001-9834-0756
Ji-Jun Chen: 0000-0001-5781-7511
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Dr. Yu-Rong Yang (Kunming Institute of
Botany) for suggestions and discussions. We are grateful for the
financial support from the Hundred Talents Program of the
Chinese Academy of Sciences, the Program of Yunling
Scholarship, the West Light Foundation of CAS (Western
Youth Scholars “A”), the China Postdoctoral ScienceFounda-
tion (2015M580801), and the China Postdoctoral Science
Foundation−Chinese Academy of Sciences joint grant.
Figure 2. Structures of the chiral phosphoric acid compounds.
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(−)-paeoveitol was completed in six steps and 42% overall
yield. The most significant tactical feature of this synthesis
involves the chiral acid-catalyzed asymmetric hetero-Diels−
Alder reaction, which enabled us to selectively synthesize both
paeoveitol enantiomers from the same substrates by simply
changing the catalyst’s stereochemistry. Efforts to expand the
application of this key transformation in the asymmetric total
synthesis of other benzopyran-containing natural products are
ongoing in our laboratory.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03801.
Experimental details of chemical synthesis, compound
characterizations (PDF)
X-ray crystallographic data for compound 1b (CIF)
C
DOI: 10.1021/acs.orglett.6b03801
Org. Lett. XXXX, XXX, XXX−XXX