Enantioselective Synthesis of 4-Hydroxy-dihydrocoumarins via Catalytic Ring Opening/Cycloaddition of Cyclobutenones

Article abstract of DOI:10.1021/acs.orglett.9b00670

A highly diastereo- and enantioselective ring-opening/cycloaddition reaction of cyclobutenones with 2-hydroxyacetophenones or salicylaldehyde was achieved by employing a chiral N,N′-dioxide-scandium(III) complex as the catalyst. It provided various 3-phen

Full text of DOI:10.1021/acs.orglett.9b00670

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Synthesis of 4‑Hydroxy-dihydrocoumarins via
Catalytic Ring Opening/Cycloaddition of Cyclobutenones
Hang Zhang, Yao Luo, Dawei Li, Qian Yao, Shunxi Dong, Xiaohua Liu,* and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, China
S
* Supporting Information
ABSTRACT: A highly diastereo- and enantioselective ring-opening/cycloaddition reaction of cyclobutenones with 2-
hydroxyacetophenones or salicylaldehyde was achieved by employing a chiral N,N′-dioxide-scandium(III) complex as the
catalyst. It provided various 3-phenylvinyl-4-hydroxy-dihydrocoumarins in good yields (up to 92%), high enantioselectivities
(up to 93% ee), and excellent diastereoselectivities (>19:1 dr). Moreover, a possible catalytic cycle was proposed based on the
control experiments and previous reports.
yclobutenones, readily available unsaturated cyclic
Ccompounds with high ring strain, have proven valuable
in organic synthesis.1 The unique core skeleton provides them
with multiple reactive patterns, depending on the nature of the
reaction partners,2 the activation modes of different catalysts,3
and the reaction conditions as well.1b Of the patterns reported
to date, distinctive ring opening/cycloaddition has attracted
considerable interest.1b,4 In this regard, most of the
enantioselective reactions were promoted by either transition
metal catalyst5 or nucleophilic organocatalyst3b−d (Scheme
1a). In addition, photolysis and thermolysis of cyclobutenones
could afford the important vinylketene intermediates which
possess multiple reactive patterns similar to disubstituted
ketenes.6 Previous reports mainly focused on the nucleophilic
addition2f−h or formal [2 + 2] cycloadditions with electron-rich
alkenes and alkynes.2a−e Recently, we disclosed that chiral
Lewis acids could activate cyclobutenones to generate the
aforementioned vinylketene intermediates under mild con-
ditions, which subsequently acted as electron-rich dienes6a in
formal [4 + 2] cycloaddition reaction with β,γ-unsaturated α-
ketoesters (Scheme 1b).7 Despite that these vinylketene
intermediates are potentially useful in the rapid construction
of structurally attractive and biologically important mole-
cules,2e such kinds of multiple transformations are still rare.1b,2f
3,4-Dihydrocoumarins are core structures of various bio-
logically active compounds and natural products.8 They are
also widely used as important intermediates in organic
synthesis.9 In the past decade, many efforts have been devoted
to their enantioselective synthesis.10 Among them, only a few
examples were related to the synthesis of optically active 4-
hydroxy-chroman-2-one.10a We hypothesized that the reaction
of ketenes with 2-hydroxyacetophenones or salicylaldehyde
might provide a new access to optically active dihydrocoumar-
in derivatives via a formal [2 + 4] process. Mechanistically, in
the presence of a Lewis acid, cyclobutenone is activated to
generate a vinylketene intermediate, which is subsequently
captured by the hydroxyl group of 2-hydroxyacetophenone to
afford a Lewis-acid-bonded dienolate intermediate. If a
stereoselective intramolecular nucleophilic addition of a
dienolate intermediate with the carbonyl group occurs, chiral
4-hydroxy-3,4-dihydrocoumarins could be readily provided.
Scheme 1. Multiple Reactive Patterns of Cyclobutenones
Received: February 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00670
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Herein, we demonstrate our contribution to this area. The
chiral N,N′-dioxide−scandium(III) complex11 developed by
our group was found to be a suitable catalyst to promote the
titled cascade reaction, furnishing enantioenriched dihydro-
coumarin derivatives in good to excellent results (>19:1 dr, up
to 92% yield, and 93% ee).
Initially, the cycloaddition of cyclobutenone 2a with 2-
hydroxyacetophenone 1a was selected as the model reaction to
optimize the reaction conditions (Table 1). A variety of metal
Sc(OTf)3/L-PrPr2 in anhydrous methanol, decreasing the
amount of 4 Å molecular sieves, and performing the reaction
under N2 atmosphere for 72 h, the product 3aa could be
obtained in a higher yield (entry 9 vs entry 6; 72% yield).
Using an excessive amount of cyclobutenone 2a (1.5 equiv)
could further increase the yield to 84% (entry 10). Finally, the
adjustment of the reaction concentration and the reaction
temperature (from 50 to 60 °C) resulted in the optimal
conditions, and the product 3aa was isolated in 91% yield, 91%
ee, and >19:1 dr (entry 11).
Table 1. Optimization of the Reaction Conditions
Under the optimized reaction conditions, the substrate
scope was then investigated (Table 2). With respect to the
substrate 1, the effect of different group R1 was first examined.
Table 2. Substrate Scope with Respect to the 2-
Hydroxyacetophenones
a
b
c
entry
metal salt
ligand
yield (%)
ee (%)
1
Mg(OTf)2
La(OTf)3
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
L-PrPr2
L-PrPr2
L-PrPr2
L-PrPr2
L-PiPr2
L-RaPr2
L-RaPr2
L-RaPr2
L-PrPr2
L-PrPr2
L-PrPr2
43
44
72
58
46
55
18
24
72
84
91
0
0
9
2
3
4
5
6
7
8
90
70
90
45
65
91
91
91
d
e
fg
9 ,
fg h
,
10 ,
fg hi
, ,
11 ,
a
Reactions were performed with 1a (0.10 mmol), 2a (0.10 mmol), 4
Å MS (50 mg), and ligand/metal salt (1:1, 10 mol %) in
b
ClCH2CH2Cl (1.0 mL) at 50 °C for 48 h. Yield of the isolated
c
d
product. Determined by chiral HPLC analysis. With 3-
e
ClC6H4COOH (10 mol %). With PhCH2CH2COOH (10 mol %).
The catalyst L-PrPr2/Sc(OTf)3 (1:1) was prepared in CH3OH.
Performed with 1a (0.15 mmol), 2a (0.15 mmol), 4 Å MS (30 mg),
f
g
and catalyst L-PrPr2/Sc(OTf)3 (10 mol %) in ClCH2CH2Cl (1.5
h
mL) at 50 °C under N2 atmosphere for 72 h. 2a (1.5 equiv).
i
ClCH2CH2Cl (1.2 mL) and at 60 °C for 72 h.
salts were examined by coordinating with L-proline-derived
N,N′-dioxide L-PrPr2 in ClCH2CH2Cl at 50 °C. It was found
that the complexes of Mg(OTf)2, La(OTf)3, or Yb(OTf)3
could promote the reaction smoothly with low enantioselec-
tivity (entries 1−3). In sharp contrast, the use of Sc(OTf)3/L-
PrPr2 was able to achieve high enantioselectivity (entry 4; 90%
ee). We next chose Sc(OTf)3 as the central metal to screen
chiral N,N′-dioxide ligands. It was found that both the chiral
backbones and the amine moieties in ligands displayed an
obvious effect on the enantioselectivity of the reaction (for
details, see SI). L-PrPr2 and L-RaPr2 were superior to L-PiPr2
derived from L-pipecolic acid in terms of enantioselectivity
(entries 4−6). In addition, we investigated other commercially
available ligands, such as chiral Box ligand, Pybox ligand, and
Salen ligand, while no better results were obtained (see SI for
details). It was worth noting that some acidic byproducts were
detected by HRMS which might inhibit this reaction (see SI
and entries 7−8). Finally, after preparing the catalyst
a
Reactions were performed with 1 (0.15 mmol), 2a (0.23 mmol), 4 Å
MS (30 mg), and catalyst L-PrPr2/Sc(OTf)3 (10 mol %) in
ClCH2CH2Cl (1.2 mL) at 60 °C for 72 h. Yield of the isolated
product. Determined by chiral HPLC analysis. 4 Å MS (50 mg) and
b
c
d
e
L-PrPr2/Sc(OTf)3 (15 mol %). At 50 °C.
B
DOI: 10.1021/acs.orglett.9b00670
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
All the alkyl-substituted ketones, ethynyl ketone, and α-ketone
ester could be converted into the corresponding products
3aa−3ga in 54−91% yields and 85−93% ee (entries 1−7).
When R1 was a phenyl group, the product 3ha was obtained in
90% yield with only 20% ee, which might be due to the steric
hindrance (entry 8). Next, various C4-, C5-, and C6-
substituted 2-hydroxyacetophenones were tested, and all the
reactions proceeded smoothly and gave the desired products
3ia−3ra in moderate to good yields with high enantioselectiv-
ities (entries 9−18; 51−92% yield and 87−92% ee). When 3,5-
dimethyl-2-hydroxyacetophenone was used, the product 3sa
was given in lower ee value (entry 19). In addition, 1-(2-
hydroxynaphthalen-1-yl)ethan-1-one was also tolerated well in
this reaction, providing 3ta in 80% yield with 91% ee value
(entry 20).
Scheme 2. Reactions of Cyclobutenone with Aldehydes
To evaluate the synthetic potential of the catalytic system, a
gram-scale synthesis of 3oa was carried out. As shown in
Scheme 3, 4.5 mmol of 1o reacted smoothly with 6.8 mmol of
Subsequently, we turned our attention to the generality of
cyclobutenones 2. As shown in Table 3, all the reactions
Scheme 3. Gram-Scale Synthesis of the Product 3oa and Its
Transformation
Table 3. Substrate Scope for Cyclobutenones
a
a
a
entry
R1; R2; R3
yield (%)
ee (%)
1
2
3
4
5
6
7
8
H; H; 3-MeC6H4
H; H; 2-FC6H4
H; H; 3-FC6H4
92 (3ab)
80 (3ac)
86 (3ad)
89 (3ae)
68 (3nf)
88 (3ng)
68 (3ah)
64 (3ai)
91
92
89
90
91
90
59
53
H; H; 4-FC6H4
5-MeO; H; 4-MeC6H4
5-MeO; H; 4-MeOC6H4
H; Cl; 4-MeC6H4
H; Cl; 3-MeC6H4
2a under the optimized reaction conditions, delivering the
corresponding product 3oa in 85% yield (1.37g) with 91% ee.
Furthermore, the absolute configuration of 3oa was
determined to be (3S,4R) by the X-ray crystallographic
analysis. In addition, 3,4-dihydrocoumarin 3oa (96% ee)
could also be oxidized by m-CPBA to generate the expected
epoxide 7oa as a single diastereomer with maintained ee value
(70% yield, 97% ee).
b
a
Unless otherwise stated, all reactions were the as same as the
footnote in Table 2. 4 Å MS (50 mg) and L-PrPr2/Sc(OTf)3 (15
mol %, 1:1).
b
proceeded smoothly and gave the 3-vinyl-substituted dihy-
drochromans 3ab−3nf in moderate to good yields with high
enantioselectivities (entries 1−5; 68−92% yields and 89−92%
ee). When R3 was replaced by an electron-rich aryl group, for
instance, 4-MeOC6H4, a lower yield of 3ng was obtained. This
issue could be addressed by increasing the loading of the
catalyst and molecular sieve (entry 6; 88% yield with 90% ee).
The reaction was also applicable to cyclobutenones 2h and 2i
(R2 = Cl), and the desired products 3ah and 3ai were obtained
in moderate yields but with moderate ee values (entries 7 and
8).
Salicylaldehyde 4a was also tolerated in this ring-opening/
cycloaddition process after slight modification of reaction
conditions, and the desired product 5aa was isolated as the
major product in 40% yield with 88% ee (Scheme 2a). It was
worth mentioning that a trace amount of oxa-Diels−Alder
reaction product 6aa was detected where cyclobutenone
participated in the reaction as a diene. When aldehydes as
4b and 4c without a hydroxyl group were employed, racemic
β,γ-unsaturated δ-lactones 6ba and 6ca were produced in
moderate yields under the standard catalytic conditions. After
the newly optimized reaction conditions by the use of L-
RaPr2-Y(OTf)3 as the catalyst, the oxa-Diels−Alder products
could be delivered in good yields with moderate enantiose-
lectivities (Scheme 2b).
To get insight into the mechanism of this catalytic reaction,
we carried out several control experiments (see SI for details).
Only a trace amount of the product 3ga was detected if
Sc(OTf)3 or ligand L-PrPr2 was absent (Scheme 4a).
Furthermore, the ring-opening product 8ga was not detected
1
by H NMR at different reaction time under the catalytic
conditions (Scheme 4b). Based on these experiments and the
reaction of aldehydes (Scheme 2), we proposed a possible
catalytic cycle to explain the catalytic activation process
(Scheme 4c). Originally, the N,N′-dioxide−scandium(III)
complex could promote ring opening of cyclobutenone 2a to
generate the vinylketene A, which underwent a nucleophilic
addition of the hydroxyl group of 1g to give the dienolate
intermediate B. From the absolute configuration of the product
3oa, we speculated that a bidentate dienolate intermediate C
was formed via coordination with the scandium catalyst in six-
membered cyclic transition states. As the steric hindrance of
one amide subunit of the ligand shielded the styryl group (see
TS1), an intramolecular α-nucleophilic addition occurred via
the transition state TS2 from the Re−Re faces, and then the
chiral product 3ga was generated after protonation procedure
accompanied with the regeneration of the catalyst.
In summary, we have developed an efficient asymmetric
catalytic synthesis of 4-hydroxy-dihydrocoumarins via ring-
opening/cycloaddition reaction of cyclobutenones with 2-
C
DOI: 10.1021/acs.orglett.9b00670
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ORCID
Scheme 4. Control Experiments and Proposed Mechanism
Shunxi Dong: 0000-0002-3018-3085
Xiaohua Liu: 0000-0001-9555-0555
Xiaoming Feng: 0000-0003-4507-0478
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We appreciate the National Natural Science Foundation of
China (Nos. 21890723 and 21801175), the National Program
for Support of Top-Notch Young Professionals, for financial
support.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00670.
Experimental details and analytical data (NMR, HPLC,
HRMS) (PDF)
Accession Codes
CCDC 1884906 and 1884908 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
■
*E-mail: liuxh@scu.edu.cn.
*E-mail: xmfeng@scu.edu.cn.
D
DOI: 10.1021/acs.orglett.9b00670
Org. Lett. XXXX, XXX, XXX−XXX

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