Total Synthesis of (?)-Perezoperezone through an Intermolecular [5+2] Homodimerization of Hydroxy p-Quinone

Article abstract of DOI:10.1002/anie.201911978

The first copper-catalyzed intermolecular [5+2] homodimerization of hydroxy p-quinone is presented, furnishing bicyclo[3.2.1]octadienone core structures in typically good yields and excellent diastereoselectivities. Applying this synthetic approach enables a concise nine-step total synthesis of (?)-perezoperezone from commercially available 3,5-dimethoxytoluene.

Full text of DOI:10.1002/anie.201911978

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Accepted Article
Title: Total Synthesis of (–)-Perezoperezone through an Intermolecular
[5+2] Homodimerization of Hydroxy p-Quinone
Authors: Yang Long, Yiming Ding, Hai Wu, Chunlei Qu, Hong Liang,
Min Zhang, Xiaoli Zhao, Xianwen Long, Shu Wang, Pema-
Tenzin Puno, and Jun Deng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911978
Angew. Chem. 10.1002/ange.201911978
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10.1002/anie.201911978
Angewandte Chemie International Edition
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Total Synthesis of (–)-Perezoperezone through an Intermolecular
[5+2] Homodimerization of Hydroxy p-Quinone
Yang Long+,[a],[b], Yiming Ding+,[b],[c], Hai Wu[b],[c], Chunlei Qu[b],[c], Hong Liang[b],[c], Min Zhang[b],[c], Xiaoli
Zhao[b],[c], Xianwen Long[b],[c], Shu Wang[a], Pema-Tenzin Puno[b] and Jun Deng*[b]
This paper is dedicated to Prof. Handong Sun on the occasion of his 80th birthday.
frequently applied by the organic community as witnessed by
completed synthetic approaches toward β-pipizol (1)[ 4 ] and
elisapterosin B (2)[ 5 ]. In contrast, the intermolecular [5+2]
cycloaddition of hydroxy p-quinone has attracted much less
attention, although it could potentially offer synthetic access to
the intriguing chemical scaffolds of perezoperezone (3),[ 6 ]
asperones A (5)[7] and taiwaniadduct F (6).[8]
Abstract: The first copper-catalyzed intermolecular [5+2]
homodimerization of hydroxy p-quinone is presented, furnishing
bicyclo[3.2.1]octadienone core structures in typically good yields and
excellent diastereoselectivities. Applying this synthetic approach
enables a concise nine-step total synthesis of (–)-perezoperezone
from commercially available 3, 5-dimethoxytoluene.
Bicyclo[3.2.1]octadienone[ 1 ] ring systems are present in a
variety of natural products and pharmaceutical molecules of both
biological relevance and structural beauty. Biogenetically, the
above motif is postulated to arise from a [5+2][2] cycloaddition of
Figure 1. Figure Caption. Selected natural products containing
bicycle[3.2.1]octadienone ring system.
a hydroxy quinone with a second double bound (Figure 1).[3] The
intramolecular [5+2] cycloaddition of hydroxy p-quinone, which is
also referred to as perezone type [5+2] cycloaddition had been
Scheme 1. Two types of intermolecular [5+2] dimerization of hydroxyl quinone
and their application in the total synthesis of natural products.
As part of our ongoing work toward structurally complex,
bicyclo[3.2.1]octadienone containing architectures based on
intermolecular [5+2] cycloadditions of hydroxy o-quinone with α,
β-unsaturated double bonds,[9] we were drawn to the idea of
developing a new approach to the bicyclo[3.2.1]octadienone
core through intermolecular [5+2] homodimerization of hydroxy
p-quinone. An intermolecular Michael addition of hydroxy p-
quinone and subsequent intermolecular Aldol or Michael
addition cascade reaction could hold the potential to facilitate the
construction of complex intermediates fueling synthetic routes to
a variety of natural products. As illustrated in Scheme 1, basic
conditions might initiate an intermolecular Michael addition of
hydroxy p-quinone (7) to α, β-unsaturated double bond giving
rise to intermediate 9, which in turn could further collapse to two
possible skeletons named path a and b. A sequence of a second
Michael addition followed by Aldol addition (path b) has been
[a]
[b]
Y. Long, Dr. S. Wang
Department of Medicinal Natural Products, West China School of
Pharmacy, Sichuan University, Chengdu 610041, P.R. China
Y. Long, Y. Ding, H. Wu, C. Qu, H. Liang, X. Zhao, M. Zhang, X.
Long, Dr. P. Puno, Dr. J. Deng
State Key Laboratory of Phytochemistry and Plant Resources in
West China, and Yunnan Key Laboratory of Natural Medicinal
Chemistry, Kunming Institute of Botany, Chinese Academy of
Sciences.
132 Lanhei Road, Kunming, China
E-mail: dengjun@mail.kib.ac.cn
Y. Ding, H. Wu, C. Qu, X. Zhao, M. Zhang, X. Long
University of Chinese Academy of Sciences, Beijing 100049, China.
These authors contributed equally to this work
[c]
[+]
Supporting information for this article is given via a link at the end of
the document.
10
]
11
]
12 ]
reported by Tang,[
Ramachary[
and Suzuki[
in
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10.1002/anie.201911978
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naphthohydroquinone system. In addition both the laboratories
of Trauner[13] and Carreira[14] recently accomplised elegant total
rationalized that the major challenge for the envisioned
transformation lies both in stabilization and sufficient activation
of the short-lived intermediate 9 for subsequent cascade. Thus,
we speculated to surmount this problem by the addition of Cu (I)
catalysts in order to induce formation of a chelated
organocuprate complex.
syntheses of epicolatone (4) by using
intermolecular [5+2] cycloaddition strategy and
a
biomimetic,
[2+2]
a
[ 16 ]
photocycloaddition, followed by a cyclobutane ring expansion
strategy respectively. While path a type of [5+2] dimerization
have not been reported so far. We now present our discovery on
a copper-catalyzed intermolecular [5+2] homodimerization of
hydroxy p-quinone (path a) with typically good yields and
excellent diastereoselectivities and its application in the total
synthesis of (–)-perezoperezone (3).
To our delight, we discovered that Cu (I) was critical for this
dimerization (Table 1, entries 11-19) and 8aa was indeed
obtained in 70% yield when CuI was used (Table 1, entry 11)
and the loading of CuI could be as low as 5%. The use of other
Cu (I) proved to be less effective (Table 1, entries 13-16) and
oxygen (Table 1, entry 12) surpressed the dimerization
dramatically. With this excellent proof of concept in hand, we
turned to optimize the reaction for both yield and
diastereoselectivity. A quick solvent screen revealed THF as the
best solvent, both with respect to yield and conversion rate.
Additionally, no other diastereomer and regioisomer were
observed when keeping the reaction temperature below 120 ℃
(see Supporting Information for more details).
Table 1. Intermolecular [5+2] homodimerization of hydroxy p-quinone 7aa:
optimization of the reaction conditions.
Table 2. Substrate scope.
Entry[a]
Catalyst
Base
Solvent
Yield[b]
1
2
3
4
5
6
7
8
L-Proline
Quinine
-
-
-
BF3·OEt2
TiCl4
FeCl3
FeSO4·7H2O
K3Fe(CN)6
CuI
CuI/O2
CuCN
CuCl2·2H2O
Cu(OAc)2
Cu(OTf)2
CuI
-
-
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
ND[c]
ND[c]
ND[c]
ND[c]
ND[c]
De[d]
De[d]
ND[c]
ND[c]
ND[c]
70%
23%
63%
64%
21%
44%
79%
ND[c]
ND[c]
DABCO
Et3N
2,6-Lutidine
-
-
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
-
9
10
11
12
13
14
15
16
17
18
19
ZnCl2
CuI
DCM
DCM
[a] Reaction conditions: 7aa (0.3 mmol), cat. (0.015 mmol), base (0.3 mmol),
solvent (0.6 mL), 40 ℃. [b] Yield refers to the column-purified product. [c] Not
detected. DABCO = 1, 4-Diazabicyclo[2.2.2]octane, Et3N = Triethylamine,
DCM = Methylene chloride, THF = Tetrahydrofuran. [d] Decomposition.
Our
studies
commenced
by
investigating
the
homodimerization of quinone 7aa to probe both reactivity and
selectivety toward the desired bicyclo[3.2.1]octadienone in light
of the multiple possible reaction pathways. Quinones of type 7
were prepared through 3-5 step sequences involving
demethylation and subsequent oxidation of functionalized
toluene starting materials (see Supporting Information for more
details). Basd on the recent literature precedence for
naphthohydroquinones,[11] we initally screened the addition of a
variety of amines as facilitator for the desired transformations
(Table 1, entries 1-5; see Supporting Information for more
details). Unfortunately, the product 8aa was not detected under
these conditions. Contrary and in light of a literature-known
structurally related intramolecular perezone-type [5+2]
cycloaddition, exposure of 7aa to Lewis acids such as BF3•OEt2
and TiCl4 (Table 1, entries 6-7) resulted in decomposition to
intractable mixture. In addition, Fe (III)-based catalysts (Table 1,
entries 8-10) as recently developed by Liu and co-workers[15] for
intramolecular reactions proved not fruitful. At this point, we
[a] Reaction conditions: 7 (0.1 mmol), CuI (0.005 mmol), Et3N (0.1 mmol), THF
(0.5 mL), 40 ℃, 1h. [b] Yield refers to the column-purified product.
With optimized conditions in hand, the scope of the reaction
with respect to R1 and R2 substituents of hydroxy p-quinone was
explored. The reaction worked smoothly with both linear (8ae,
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8ca) and cyclic (Table 2, 8ba, 8bc, 8cd) substituents. Not
surprisingly, we observed that an increasing sterical demand of
the substituent (e.g. from methyl to cyclohexanyl) resulted in
slower reaction rates and lower conversion (Table 2, 8ca, 8cd,
8ba, 8bc). Next, we turned to aryl and heteroaryl substituents.
Gratifyingly, the developed methodology proved very robust and
gave rise to the corresponding dimmers. More precisely, both
electron-donating groups (Table 2, 8dc) and electron-
withdrawing groups (Table 2, 8ff) on the aryl side chain did not
have a profound effect on the yield. Furthermore, dimers with
heteroaryl substituent, such as indoles (8e and 8g) were also
obtained conveniently. However, when sterically hindered
groups were present in the side chain, a significant drop in yield
was observed. For example, diphenylmethanyl substituted
quinone led to corresponding products 8dj (10% yield) along
with a significant yield of recycled starting material. The
structures of some dimerized products (8ae, 8ba, 8ca, 8dc, 8ff)
were further confirmed by X-ray crystallographic analysis (Table
2). Generally, this intermolecular homodimerization was robust
and operationally simple; overall 36 bicyclo[3.2.1]octadienones
were synthesized in good yields (see Supporting Information for
more details). A general issue for this reaction was lower
conversion for sterically hindered substrates and some
dimerized products underwent retro-dimerization and afforded
monoquinone.
dimethoxytoluene 12 via a known three-step sequence.[17] With
ample amounts of toluene 13 in hand, mono-lithiation of 13
followed by trapping of the intermediate with trimethyl borate and
acid work-up yielded the sterically hindered boronic acid 14. The
second coupling partner, triflate 16 was readily accessed by
regioselective deprotonation of commercially available ketone 15
and quenching with Commin’s reagent.[18] Next, fragment-union
was accomplished by a standard Suzuki-Miyaura coupling[19] in
excellent yield. A subsequent chemo-selective hydrogenation
yielded compound 18 in 81% yield. At this point, we additionally
envisioned to render our route asymmetric. However, all
attempts to enable an enantioselective hydrogenation based on
chiral Ir and Rh catalysts remained unfruitful.[20]
Scheme 3. Control experiments and proposed reaction mechanism.
Scheme 2. Total synthesis of (–)-perezoperezone.
The synthesis of (±)-perezone was completed by oxidation of
18 with cerium (Ⅳ) ammonium nitrate(CAN) and subsequent
demethylation with LiI. In order to avoid the diastereomerically
mismatched intrermolecular 5+2 dimerization, perezone need to
be prepared in enantiopure form. To this end, enantiopure (–)-
was obtained exploting chiral-phase column
chromatography. Next we were excited to probe our optimized
reaction conditions and the key dimerization occurred smoothly
To showcase the practical utility of this new dimerization in a
complex setting, we embarked on the total synthesis of (–)-
perezoperezone (Scheme 3), the sole isolated homodimerized
hydroxy p-quinone natural product to the best of our
knowledge.[6] Our synthesis commenced with a stereospecific
construction of perezone monomer 18. Toluene 13 was
prepared in 90% yield starting from commercially available 3, 5-
21
]
perezone[
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10.1002/anie.201911978
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providing (–)-perezoperezone 3 in 51% yield, forging two
carbon-carbon bonds and setting four stereogenic centers in a
single step. The physical data of our synthesized (–)-
perezoperezone 3 are identical to those reported in the literature.
Thus, we achieved the total synthesis of (–)-perezoperezone 3
in only nine steps (longest linear sequence) with 15% overall
yield from commercially available 3, 5-dimethoxytoluene 12.
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In order to gain more insight into the reaction mechanism, we
subsequently turned our focus to control experiments. The
homodimerization of 7aa was conducted in the presence of
radical scavengers, such as TEMPO and BHT, without
observation of significant decrease in yield or any detected
radical trapping adducts (Scheme 3a). When quinone 7bc
bearing a cyclopropyl ring as a radical clock was tested in the
reaction, the standard condition afforded dimerized 8bc in
moderate yield (Scheme 3b). In addition, sterically hindered
dimerized product 8dc underwent retro-dimerization under the
standard condition and afforded monoquinone 7dc (Scheme 3c).
Based on these findings, a radical pathway appears to be
unlikely and we propose that the homodimerization proceeds
through double Michael addition process of chelated
organocuprate complex 20 (Scheme 3d). We speculate that the
role of Cu (I) was to stabilize and activate the organocuprate
complex 20 both as Michael addition donor and acceptor and
the short-lived intermediate 21 for subsequent cascade. Further
programs in our laboratory will be initiated to shed more light
onto our proposal and clarify the role of Cu (I) safeguarding both
the reactivity and the selectivity of the discovered methodology.
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In summary, the work described herein disclosed the first
copper-catalyzed intermolecular [5+2] homodimerization of
hydroxy p-quinone, furnishing bicyclo[3.2.1]octadienone core
structures with typically good yields and excellent
diastereoselectivities. The resulting method enabled us to
accomplish the total synthesis of (–)-perezoperezone in only
nine steps from commercially available 3, 5-dimethoxytoluene 9.
The application of this methodology to the synthesis of cross-
dimerized quinone natural products such as asperones A and B
is subject to further research in our laboratory and will be
reported in due course.
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Acknowledgements
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We thank two anonymous reviewers and Dr. Daniel Hog (Bayer
AG) for insightful comments and very helpful discussions, Xinru
Du and Yashi Xu for technical contributions, and Dr. Xiaonian Li
for X-ray crystallographic analysis. Financial support from CAS
Pioneer Hundred Talents Program (No. 2017-022), National
Natural Science Foundation of China (21871278) and Start up
funding of Kunming Institute of Botany are gratefully
acknowledged.
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Keywords: 5+2 cycliaddition • dimerization • total synthesis •
natural products • perezoperezone
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21 The Optical rotation of (－)-perezoperezone was disclosed by Cuevas and
co-workers, see: G. R. Pérez, B. Quiróz, M. Aguilar-Martínez, C. Frontana, A.
Solano, I. González, J. A. Bautista-Martínez, J. Jiménez-Barbero, G. Cuevas,
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