Asymmetric Synthesis of Dihydronaphthalene-1,4-Diones via Carbene-Catalyzed Stereodivergent Reaction

Article abstract of DOI:10.1002/adsc.201900506

2-Hydroxy-2,3-dihydronaphthalene-1,4-diones (HDNDs) are ubiquitous in natural products and bioactive molecules, but the rapid asymmetric construction of such scaffolds remains a significant challenge to date. Reported herein is the rapid construction of the above key units via carbene-catalyzed benzoin reaction. The resolution technique of divergent reaction on racemic mixture (divergent RRM) was employed, affording both isomers of HDNDs in a one-step fashion. Disubstituted substrates afford products with two contiguous quaternary stereocenters. A series of highly selective transformations on the products can be realized, and mechanistic studies indicate that the benzoin reaction is much faster than the racemization process and the aldol reaction. (Figure presented.).

Full text of DOI:10.1002/adsc.201900506

Title: Asymmetric Synthesis of Dihydronaphthalene-1,4-diones via
Carbene-Catalyzed Stereodivergent Reaction
Authors: Xinqiang Fang, Shuang Yang, Zhifei Zhao, Shouang Lan,
jinggong liu, and Shuhua Liu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900506
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10.1002/adsc.201900506
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Asymmetric Synthesis of Dihydronaphthalene-1,4-diones via
Carbene-Catalyzed Stereodivergent Reaction
Zhifei Zhao,a Shuang Yang,a Shouang Lan,a Jinggong Liu,c Shuhua Liu,b* and Xinqiang
Fanga*
a
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, University of
Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China. Email: xqfang@fjirsm.ac.cn
Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250014,
b
China. Email: liushuhuaosso@126.com
Orthopedics Department, Guangdong Provincial Hospital of Traditional Chinese Medicine, NO. 111 Dade Road,
c
Guangzhou 510120, China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
sets of reaction conditions or retrosynthetic plans,
Abstract. 2-Hydroxy-2,3-dihydronaphthalene-1,4-diones
(HDNDs) are ubiquitous in natural products and bioactive thus making the existing synthetic methods highly
costly and time-consuming.[3] Therefore, developing a
molecules, but the rapid asymmetric construction of such
scaffolds remains a significant challenge to date. Reported
herein is the rapid construction of the above key units via
carbene-catalyzed benzoin reaction. The resolution
technique of divergent reaction on racemic mixture
(divergent RRM) was employed, affording both isomers of
HDNDs in a one-step fashion. Disubstituted substrates
afford products with two contiguous quaternary
stereocenters. A series of highly selective transformations
on the products can be realized, and mechanistic studies
indicate that the benzoin reaction is much faster than the
racemization process and the aldol reaction.
concise approach to afford both diastereomers of
HDNDs still remains a formidable challenge to date.
Keywords: umpolung, cyclization, carbene, kinetic
resolution
2-Hydroxy-2,3-dihydronaphthalene-1,4-diones
(HDNDs) widely exist in naturally occurred
substances such as merochlorin D, nanaomycin B,
cardinalin 4, and cardinalin 5, and they display
promising bioactivities like antibacterial activity and
antimicrobial activity (Scheme 1a).[1] Noteworthy is
that cardinalin 4 and cardinalin 5 are diastereomeric
isomers and show different activities.[1h] However,
protocols that can rapidly construct chiral HDNDs
remain scarce. Asymmetric Diels-Alder reactions
between naphthalene-1,4-diones and 1,3-dienes have
been used to assemble cis-HDNDs, but the
regioselectivity of the reaction is hard to be
controlled when diene substituents are different, and
more steps are needed to introduce hydroxyl groups
(Scheme 1b).[2] Asymmetric Michael addition of a
nucleophile to substituted naphthalene-1,4-diones
constitutes a good choice to make HDNDs, but such
approach remains unknown to the best of our
knowledge (Scheme 1b). Furthermore, the synthesis
of cis- and trans-HDNDs usually employ different
Scheme 1. Background and Work Hypothesis.
N-heterocyclic
carbene
(NHC)-catalyzed
asymmetric benzoin reaction has proven to be a
powerful approach to produce α-hydroxyketones via
C-C bond formation.[4] A recent increasing research
interest has been paid to the development of methods
leading to benzoin products with multiple
stereocenters, as reported by Ema and Johnson’s
groups.[5] During the past three years, we have
employed the idea of group addition-kinetic
resolution (GAKR) to systematically study the
1
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10.1002/adsc.201900506
Advanced Synthesis & Catalysis
benzoin reactions using racemic substrates. In more
details, through rational additions of substituted
groups into the nonchiral/prochiral benzoin reaction
substrates, and running the corresponding catalytic
kinetic resolutions, we were able to provide a series
of tetralones, rotenoids, chromanones, and flavanones
with multiple stereocenters in a one-step fashion.[6]
Classical kinetic resolution (KR), dynamic kinetic
resolution (DKR), and divergent RRM were all
tolerated by the above benzoin reactions, and all these
have extended greatly the applications of this named
reaction, and a series of new insights have also been
disclosed. As the last work of this series, we report
herein the rapid access to both stereoisomers of
HDNDs via benzoin reaction-mediated divergent
RRM using 2-substituted 1,3-diketones with a
formylphenyl group (Scheme 1c).
promote the enantioselectivities to an excellent level
without increasing the amount of aldol product (Table
1, entry 14). Under the optimal conditions, catalyst
E[4y] was also surveyed but only resulted in the
formation of 2a’ (Table 1, entry 15).
Table 1. Optimization of the Reaction Conditions[a]
base (equiv),
solvent
yield (%) ee (%)
2a/3a/2a’ 2a/3a
22/30/35 85/69
28/32/21 87/73
16/50/15 72/18
17/18/51 87/80
16/57/14 60/17
entry cat.
1
2
3
4
5
K2CO3 (1.0), THF
K2CO3 (0.2), THF
K2CO3 (0.2), THF
K2CO3 (0.2), THF
K2CO3 (0.2), THF
A
A
B
C
D
We commenced by selecting rac-1a as the model
substrate. Catalyst A[7a] and stoichiometric K2CO3
were used initially (Table 1, entry 1). However, aldol
product 2a’ was obtained in 35% yield and two
diastereomeric products 2a and 3a were obtained in
22% and 30% yields with 85% and 69% ee,
respectively (Table 1, entry 1). Somewhat to our
surprise, the result did not support a DKR pathway,[8]
and divergent RRM was applicable. Although the
yield is 50% theoretically, the technique of divergent
RRM is advantageous in providing diversified
products and shortening the synthetic routes.[9]
Selected applications of this technique can be found
in the total synthesis of (-)-cyanthiwigin G/(+)-
cyathin A3,[10a] rotigotine/(S)-8-OH-DPAT,[10b] (+)-
erogorgiaene/(-)-colombiasin A,[10c-d] and sanggenon
C/sanggenon O,[10e] etc. In all these cases, the
technique of divergent RRM proved to be the best
choices in making the above structurally related pairs
of natural products. To our pleasure, in our reaction
both stereoisomeric products are easily separable and
this method provides an approach for the rapid
synthesis of both cis- and trans-isomers of HDNDs,
which will be useful in making both isomers of
related bioactive molecules.[1h] Then we tried to
suppress the aldol side product, a perennial problem
among intramolecular benzoin reaction-related
studies in the past decades.[11] Similar results with
that in entry 1 were observed when catalytic amount
of K2CO3 was used (Table 1, entry 2), and catalysts
B,[7b] C, and D[7c] all led to the generation of aldol
product together with two diastereomeric products
with various yields and ee values (Table 1, entries
35). Using catalyst A, we surveyed a series of bases.
Cs2CO3 and K3PO4 resulted in more than 20% yield
of aldol product (Table 1, entries 6 and 7), and
weaker base of KHCO3 delivered less 2a’ (Table 1,
entry 8). Organic bases such as DBU and Et3N were
not good choices (Table 1, entries 9 and 10), but
iPr2NEt proved suitable considering both the yields
and ee of the two products (Table 1, entry 11). While
the solvent of toluene was not superior (Table 1,
entry 12), CH2Cl2 could further diminish the
formation of 2a’ (Table 1, entry 13). Finally we
6
7
Cs2CO3 (0.2), THF
K3PO4 (0.2), THF
28/28/24 80/78
22/43/23 95/72
A
A
8
KHCO3 (0.2), THF
DBU (0.2), THF
Et3N (0.2), THF
iPr2NEt (0.2), THF
26/40/15 98/67
34/40/12 91/77
25/42/15 91/56
A
A
A
A
A
9
10
11
12
38/38/6
93/90
iPr2NEt (0.2), toluene 31/45/10 87/75
13
14
15
iPr2NEt (0.2), CH2Cl2 36/43/4
98/85
A
A
E
iPr2NEt (0.8), CH2Cl2
37/40/3
-/-/96
95/91
iPr2NEt (0.8), CH2Cl2
N.D.[b]
[a] Reaction conditions: 1a (0.1 mmol), NHC (0.015 mmol),
solvent (1.5 mL), −20 °C, under argon atmosphere. All
yields are isolated yields and were based on 1a; ee
values were determined via HPLC analysis on a chiral
stationary phase. [b] Not determined.
[a] Reaction conditions: rac-1 (0.1 mmol), A (0.015 mmol),
CH2Cl2 (1.5 mL), −20 °C, under argon atmosphere. All
yields are isolated yields and were based on rac-1; ee
values were determined via HPLC analysis on a chiral
stationary phase.
Scheme 2. Substrate Scope of Monosubstituted
i
Diketones.[a]
found that increasing the amount of Pr2NEt can
2
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10.1002/adsc.201900506
Advanced Synthesis & Catalysis
Having established the optimal conditions, we then
checked a series of mono-substituted diketone
substrates. The replacement of Me group in 2a by Bn
did not affect the results (Scheme 2, 2b/3b), and 2-
allyl diketone was also tolerated (Scheme 2, 2c/3c).
We then tested differently substituted phenyl ketones,
and found that the annulation products were produced
in good yields with good to excellent
enantioselectivities (Scheme 2, 2d/3d, and 2e/3e).
Furthermore, aliphatic ketone also worked well
considering the stereoselectivity, albeit with moderate
total yield (Scheme 2, 2f/3f). The configuration of 2a
was confirmed via single crystal X-ray structure
analysis (Figure 1).[12]
Furthermore, we studied substrates with fully
substituted carbon centers. As shown in Scheme 3,
Bn/Me-disubstituted diketones worked well under
slightly modified conditions (using Et3N instead of
iPr2NEt), affording the corresponding stereoisomers
in moderate to good yields with 82‒94% ee (Scheme
3, 5a/6a, 5b/6b, and 5c/6c). The absolute
configuration of 5c was determined via single crystal
X-ray structure analysis (Figure 1).[12] We then
studied
a
series of substrates with allyl/Me
[a] Reaction conditions: rac-4 (0.1 mmol), A (0.015 mmol),
CH2Cl2 (1.5 mL), −20 °C, under argon atmosphere. All
yields are isolated yields and were based on rac-4; ee
values were determined via HPLC analysis on a chiral
stationary phase.
substituents. Phenyl-substituted diketone could
release 5d and 6d with good ee values (Scheme 3, 5d
and 6d), and the introduction of electron-rich 3-Me or
4-OMe substituents into the phenyl group had no
influence on the outcomes (Scheme 3, 5e/6e, and
5f/6f). The phenyl ketone bearing electron-neutral
phenyl group worked well to deliver the two isomers
in good yields with high to excellent ee values
(Scheme 3, 5g/6g). Additionally, substrates with
electron-poor Cl or Br group underwent smooth
annulations to generate the corresponding products
with 87‒95% ee (Scheme 3, 5h/6h and 5i/6i).
Aliphatic ketones with cyclopropyl group or ethyl
group were also tolerated in this reaction, producing
5j/6j and 5k/6k in good total yield, albeit with
moderate to excellent enantioselectivities (Scheme 3,
5j/6j and 5k/6k).
Scheme 3. Substrate Scope of 2,2-Disubstituted Diketones.
Figure 1. X-ray Structures of 2a and 5c.
Gram-scale reaction proved possible using 1e (1.5
g) as the example, without obvious erosion of yields
and ee values of the products (Scheme 4a). Making
all four isomers of a molecule with multiple
stereocenters is highly needed in drug discovery since
different physiological and pharmacological activities
might be derived from different isomers.[13] In this
work, using divergent RRM, all four stereoisomers of
the products can be easily accessed using A and ent-
A as the catalysts through two reactions (Scheme 4b).
Further transformations based on product 2e can also
be easily realized (Scheme 4c). For instance, selective
reduction of 2e using NaBH4 afforded 7a in 84%
yield with 97% ee, and the full reduction of 2e
produced 7b with four contiguous stereocenters.
Additionally, nucleophilic attack of 2e by vinyl
magnesium bromide allowed access to diol 7c
without erosion of the ee value.[14]
Scheme 4. Synthetic Applications.
3
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10.1002/adsc.201900506
Advanced Synthesis & Catalysis
To further demonstrate the mechanistic details of
disclosed that the benzoin process is much faster than
the racemization step, and an irreversible aldol
reaction was also demonstrated. We have shown that
the idea of group addition-kinetic resolution (GAKR)
is useful in further promoting the applications and
values of benzoin reaction. More utilities of GAKR in
other named reactions will be conducted.
this process, especially the reactions using mono-
substituted 1,3-diketones, we conducted further
studies. First, thoroughly different to the prior DKR
reaction,[6b] the aldol product 2a’ could not be
converted to benzoin product via reversible process
(Scheme 5a). Moreover, no isomerization of 2a to 3a
occurred under the standard conditions (Scheme 5b).
Noteworthy is that 95% yield of the aldol product
was formed without NHC catalyst (Scheme 5c),
showing that the deprotonation-racemization process
can occur. However, when enantioenriched substrate
1e was put under the standard conditions, 3e was
obtained in 93% yield with 97% ee, indicating that
the benzoin process happens much faster than the
racemization step (Scheme 5d). It’s a surprising
observation because aldol type side reactions have
been really difficult to be suppressed using easily
enolizable substrates,[11] and 1,3-diketone type
substrates have been widely used in DKR reactions.[8]
Summarily, a plausible mechanism was proposed in
Scheme 5e. In the whole process, the benzoin
reaction happens much faster than the racemization
and aldol process, and both aldol and benzoin
reactions are irreversible. This mechanism is sharply
different to the previous reports.[6b]
Experimental Section
General procedure for benzoin reaction of rac-1: To a
dried 10 mL Schlenk tube equiped with a tiny magnetic stir
bar, catalyst A (7.2 mg, 15 mol%), rac-1 (0.1 mmol), and
DIPEA (0.08 mmol, 13.2 uL) were added together. The
flask was then evacuated and refilled with dry argon. To
this mixture, CH2Cl2 (1.5 mL) was added and the resulting
solution was stirred at −20 ºC for 3−5 h. After completion
of the reaction, solvent was evaporated and the resulting
crude products were purified through a short column
chromatography on silica gel with ethyl acetate and
petroleum ether as eluent to afford the desired product 2
and 3.
General procedure for benzoin reaction of rac-4: To a
dried 10 mL Schlenk tube equiped with a tiny magnetic stir
bar, catalyst A (7.2 mg, 15 mol%), rac-4 (0.1 mmol), and
Et3N (0.08 mmol, 11.1 uL) were added together. The flask
was then evacuated and refilled with dry argon. To this
mixture, CH2Cl2 (1.5 mL) was added and the resulting
solution was stirred at −20 ºC for 3−7 h. After completion
of the reaction, solvent was evaporated and the resulting
crude products were purified through a short column
chromatography on silica gel with ethyl acetate and
petroleum ether as eluent to afford the desired product 5
and 6.
Acknowledgements
This work was supported by NSFC (21871260, 21502192 and
21402199), the strategic priority research program of the
Chinese Academy of Sciences (XDB20000000), Fujian Natural
Science Foundation (2018J05035), and China Postdoctoral
Science Foundation (2018M630734). We thank Professor
Daqiang Yuan for the X-ray data analysis.
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10.1002/adsc.201900506
Advanced Synthesis & Catalysis
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10.1002/adsc.201900506
Advanced Synthesis & Catalysis
COMMUNICATION
Asymmetric Synthesis of Dihydronaphthalene-1,4-
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Adv. Synth. Catal. Year, Volume, Page – Page
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6
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