Synthesis of Polycyclic Cyclohexadienone through Alkoxy-Oxylactonization and Dearomatization of 3′-Hydroxy-[1,1′-biphenyl]-2-carboxylic Acids Promoted by Hypervalent Iodine

Article abstract of DOI:10.1021/acs.joc.9b03012

Alkox-oxylactonization and dearomatization of 3′-hydroxy-[1,1′-biphenyl]-2-carboxylic acid simultaneously promoted by hypervalent iodine have been developed using stoichiometric PhI(OAc)₂ or a catalytic amount of chiral aryl-λ³-iodane generated in situ. This reaction provides a concise method to synthesize diverse polycyclic cyclohexadienones as potential inhibitors of DNA polymerase under mild reaction conditions.

Full text of DOI:10.1021/acs.joc.9b03012

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Article
Synthesis of Polycyclic Cyclohexadienone through the Alkoxy-
oxylactonization and Dearomatization of 3'-Hydroxy-[1,1'-
biphenyl]-2-carboxylic acids Promoted by Hypervalent Iodine
Qingfu Deng, Wen Xia, Muhammad Ijaz Hussain, Xiaohui Zhang, Wen Hu, and Yan Xiong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03012 • Publication Date (Web): 16 Jan 2020
Downloaded from pubs.acs.org on January 17, 2020
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Synthesis of Polycyclic Cyclohexadienone through the
Alkoxy-oxylactonization and Dearomatization of
3'-Hydroxy-[1,1'-biphenyl]-2-carboxylic acids Promoted by
Hypervalent Iodine
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Qingfu Deng, a,d Wen Xia,a,d Muhammad Ijaz Hussain,c Xiaohui Zhang,a Wen Hu,a
and Yan Xiong*,a,b
aSchool of Chemistry and Chemical Engineering, Chongqing University, Chongqing
401331, China. E-mail: xiong@cqu.edu.cn
bState Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin
300071, China
cDepartment of Chemistry, Ghazi University, Dera Ghazi Khan, Punjab 32200,
Pakistan
dThese authors contributed equally to this work
O
OH
important structural units:
- polycycle
R2
*
PhI(OAc)2, R2OH
R1
R1
O
O
OR
- dienone
COOH
Ar*-I, m-CPBA, R2OH
O
- lactone
yield: 21-90%
ee: 11-56%
- ketal
ABSTRACT
Hypervalent iodine simultaneously promoted alkoxy-oxylactonization and
dearomatization of 3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acid have been developed
using stoichiometric PhI(OAc)2 or a catalytic amount of chiral aryl-λ3-iodane
generated in situ. This reaction provides a concise method to synthesize diversely
polycyclic cyclohexadienones as potential inhibitors of DNA polymerase under mild
reaction conditions.
INTRODUCTION
Cyclohexadienones are acclaimed for their use in diverse biologically active
natural products and pharmaceuticals, in particular, dehydroaltenusin with
benzopyrolactone structure, found to be an effective inhibitor of DNA polymerase.1,2
Instances include the meds dexamethasone, (+)-puupehenone and dehydroaltenusin
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(Figure 1). Recently, aryliodine-catalyzed oxidative dearomatization reactions of
para-phenols have a time-honored intensifying interest as target synthesis with the
cyclohexadienones moiety as a key functional group.3 In addition, Kita reported the
synthesis of spirocyclohexanones from para-phenols following intramolecular
oxylactonizations of the carboxylic acids.4 For the time being, chiral iodine(III)
catalysts have been utilized to achieve asymmetric spirocyclizations of
ortho-substituted naphthol derivatives with high enantioselectivity.5 However, studies
on para-phenols alkoxy-oxylactonization reactions are relatively rare. The need for
aforesaid lactonized products has inspired the expansion of methodologies for their
synthesis. For a chemist, a low toxic synthetic approach utilizing metal-free reagents
such as hypervalent iodine reagents compared with metal-based reagents is a highly
fascinating means for accessing poly heterocycles.
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OH
O
O
OH
O
OH
OH
O
O
HO
O
H
OMe
F
H
HO
O
dehydroaltenusin
dexamethasone
(+)-puupehenone
Figure 1. Cyclohexadienone-containing natural products.
In recent years, hypervalent iodine reagents can be used for the alkoxylation or
hydroxylation of para-phenols6 and oxylactonizations of benzoic acids.7 For instance,
Martin and co-workers reported a synthesis of tricyclic benzolactones due to a big
energy gap between HOMO and LUMO frontier orbitals using catalytic amounts of
aryliodine and peracetic acid as terminal oxidant.7a And in 2013, Harned and
coworkers established a strategy to access para-quinols with low to moderate
enantioselectivity from oxidative dearomatization reactions of phenols utilizing a
newly designed 8-iodotetralone and tartaric acid based chiral aryl iodide catalyst.6a
According to Martin and Harned’s reports, it takes two steps to synthesize the
methoxy-cyclohexadienones. In defiance of these advances, some concerns still linger
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in this heartening field. Thereby, it is vitally important to explore new approaches to
scale up this area. To the best of our knowledge, there has been no single report of
using hypervalent iodine reagents for the construction of methoxy- cyclohexadienones
(2, Scheme 1). In the continuation of our ongoing lab interest8 and also premised on
the antecedent information, we report mild and user-friendly one-step synthesis
polycyclic cyclohexadienone from 3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acid by
utilizing PhI(OAc)2 (DIB) and MeOH (Scheme 1).
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Scheme 1. Previous Work and Methoxy-oxylactonization
Martin et. al.
O
O
OH
4-MeC6H4I, AcOOH, HFIP
40-99%
R1
O
R1
R2
R2
O
Harned et. al.
R1
R1
OH
m-CPBA, Ar*I
R2
MeCN/H2O
HO R3
R2
R3
yield%:20-79
ee%:6-60
this work:
O
OH
MeOH
DIB
O
O
COOH
O
2
1
RESULTS AND DISCUSSION
To
investigate
our
supposition,
we
primarily
chose
3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acid (1a) as a model substrate. The
efficiencies of various hypervalent iodine reagents in the MeOH solvent were
examined to explore various reaction conditions. Selected findings from this
investigation are itemized in Table 1. To our delight, the desired product 2a could be
synthesized in 16% and 31% yields with the use of PhIO and DIB, respectively, while
ABX and CBX did not respond to produce the desired product (Table 1, entries 1-4).
When the experiment was conducted in a less polar medium such as DCM instead of
methanol, a lactonization product 2aa without dearomatization was obtained in 11%
yield (Table 1, entry 5). After that concentration effect of DIB and MeOH were tested
(Table 1, entries 6-12), the best result of 72% yield was obtained when added 2.8 eq.
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DIB and 1mL MeOH. Subsequently, the effects of reaction time and temperature were
investigated. Both raising and lowering time and temperature resulted in the decreased
yield correspondingly (Table 1, entries 13-17). Thereafter, different additives and
their amounts were subjected to the rection in order to get improved yield (Table 1,
entries 18-26). Among these, 5 Å of molecular sieve as an additive provided the best
yield in 78%.
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Table 1. Optimization of Reaction Conditionsa
OH
O
OH
oxidant, additives
+
MeOH, T oC, t h
O
O
O
COOH
O
O
1a
2a
2aa
O
O
O
I
AcO
I
OAc
O
O
I
I
NC
3b
HO
3d
: PhIO
3a
: ABX
: CBX
3c
: DIB
Oxidant
(equiv)
MeOH
Additivesb
T (°C)
Yieldc (% )
Entry
(mL)
1
1
2
ABX(1.2)
CBX(1.2)
PhIO(1.2)
DIB(1.2)
DIB(1.2)
DIB(1.8)
DIB(2.2)
DIB(2.5)
DIB(2.8)
DIB(3.0)
DIB(2.8)
DIB(2.8)
DIB(2.8)
DIB(2.8)
DIB(2.8)
DIB(2.8)
DIB(2.8)
DIB(2.8)
DIB(2.8)
DIB(2.8)
DIB(2.8)
20
20
20
20
20
20
20
20
20
20
20
20
0
0
1
0
3
1
16
31
11
40
61
69
72
67
68
57
65
69
58
61
56
78
71
69
0
4
5 d
1
1
6
1
7
1
8
1
9
1
10
11
12
13
14
15
16e
17f
18
19
20
21
1
0.5
1.5
1
1
30
50
20
20
20
20
20
20
1
1
1
1
5Å MS
4 Å MS
3 Å MS
Et3N
1
1
1
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DIB(2.8)
DIB(2.8)
DIB(2.8)
DIB(2.8)
1
1
1
1
Na2CO3
CF3COOH
CH3COOH
FeCl3
20
20
20
20
35
31
26
47
9
a Conditions: 1a (0.3 mmol), oxidant (specified) in MeOH for 10 h. b 20 wt% of additives. c Yield
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1
d
e
determined by H-NMR using anisole ether as an internal standard. DCM replaced MeOH.
Reaction for 5 h. f Reaction for 15 h.
With the optimal conditions for alkoxy-oxylactonization and dearomatization in
hand, the scope of the reaction was investigated. An inspection of the differently
substituted substrates disclosed that all 3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acid
derivatives underwent alkoxy-oxylactonization and dearomatization to generate 2a–k
in moderate to high yields ranging from 48% to 80%. Results depicted in Table 2
reveal that this reaction is highly sensitive to the size of the aliphatic part of alcohol.
Increasing the size of R2OH had a negative effect (2a-d), and no products were
obtained in the cases of 2e and 2f. The effects of both electrons donating and
withdrawing group on various position of phenyl ring were also studied. For
electron-withdrawing groups, para-nitro showed a high yield of 72% (2h) compared
to para-fluorine (2g). In the case of an inductively electron-donating methyl group,
meta-position was found to be more favourable than that of ortho-position (2i and 2j).
In addition, this method can also be employed successfully to synthesize the mother
core (2k) of dehydroaltenusin in moderate yield.
Table 2. Scope of 3'-Hydroxy-[1,1'-biphenyl]-2-carboxylic Acidsa
O
O
O
OH
DIB, R2OH
R2
R1
R1
O
5 Å MS, 20 °C, 10 h
R
O
COOH
O
O
1
2a-j
, R = H
2k
, R = Me
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O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
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2a, 78%b
2b, 69%
2c, 65%
2d, 48%
O
O
O
O
O
O
O
O
CF3
O
O
O
O
O
F
O2N
O
O
O
2e, 0%
2f, 0%
2g, 49%
2h, 72%
O
O
O
O
O
O
O
O
O
O
O
2k, 75%c
2i, 69%
2j, 80%
a Conditions: 1 (0.3 mmol), 20 wt% 5 Å MS and DIB (0.84 mmol) in R2OH (1 mL) at 20oC for 10
h. b Isolated yield by silica gel column chromatography. c DCM replaced MeOH.
Inspired from the our afore substrate generality, next, observations were
designed to approach enantioselective alkoxy-oxylactonization and dearomatization
of 3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acid by utilizing a series of chiral
iodoarenes as a catalyst with m-CPBA in MeOH at 20 oC, respectively, and results are
tabulated in Table 3. Initially, oxygen and nitrogen moieties based chiral iodoarenes
3a-d were subjected to this transformation. Gratifyingly, we found that the chiral
iodoarene 3d, incorporating a bulky phenyl group and as various H-bond donor,
afforded better enantioselectivity. Next, alternative chiral iodoarene precursors
possessing different substituted groups of phenylamide were considered (3e-h). It is
worth noting that introducing an electron-donating group such as -Me, on the phenyl
appears more beneficial for enantioselectivity than that of electron-withdrawing
groups such as -F, -Cl, or -CF3. Encouraged by this result, a variety of chiral
iodoarenes, possessing different methyl substitution on phenylamide, were prepared
(3i-n) and their effects on this changeover under afore mentioned reaction conditions
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were analyzed. Among these, 3l provided the highest level of enantioselectivity.
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Table 3. Optimization of the Chiral Organoiodinea
8
9
O
OH
O
I
O
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3,
m-CPBA
O
O
*
X
X
O
MeOH
O
COOH
3
O
1
4a
3a (X = OEt): 22% yieldb, 4% eec
3b (X = OH): 18% yield, 10% ee
3h (X = NHNap): 14% yield, 31% ee
3i (X = NH(3,5-Me2-Ph)): 18% yield, 40%
ee
3c (X = NHPr: 20% yield,11% ee
3d (X = NHPh): 13% yield, 36% ee
3e (X = NH(4-CF3-Ph)): 17% yield,
31% ee
3j (X = NHMes): 15% yield, 15% ee
3k (X = NH(2-Me-Ph)): 17% yield, 23% ee
3l (X = NH(4-Me-Ph)): 22% yield, 41% ee
3f (X = NH(2,3-F-Cl-Ph)): 17% yield,
25% ee
3m (X = NH(3,4,5-Me3-Ph)): 17% yield,
41% ee
3g (X = NH(2,3-Me-F-Ph)): 11%
yield, 38% ee
3n (X = NH(4-iPr-Ph)): 20% yield, 37 %
ee
a Conditions: 1a (0.3 mmol), 3 (specified, 20 mol%) and m-CPBA (0.45 mmol) in MeOH (1 mL)
at 20oC for 10 hours. b Yield determined by 1H-NMR using anisole ether as an internal standard. c
By HPLC analysis (chiralpack AD-H).
After screening of catalysts, tricyclic aryl iodide 3l as a lead structure, efforts
were made to investigate its optimal conditions for this catalytic asymmetric oxidative
dearomatization and results are detailed in Table 4. Initially, catalyst uploading was
investigated using 3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acid 1a with 1.5 equiv of
m-CPBA in MeOH for 10 hours and the best result of 22% yield with 41% ee was
obtained in the presece of 0.2 equiv of 3l (Table 4, entries 1-5). Subsequently, the
effects of amounts of m-CPBA and reaction time were tested (Table 4, entries 6-12).
As the amount of m-CPBA decreases, an improvement in ee value along with a fall in
the yield was observed (Table 4, entry 7). An increase in reaction output resulted in
the foremost result of 58% yield with 43% ee at 30 hours (Table 4, entry 11).
Lowered the temperature, both the yield and ee dropped correspondingly (Table 4,
entries 13-15). After that, different additives were subjected to the afore optimal
reaction conditions to improve both ee and yield. Unfortunately, all additives resulted
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in a negative impact (Table 4, entries 16-22). Basic additive such as Et3N found
quencher to the reaction while a negative effect was noticed for either acidic or
neutral additives. From these experimental data, we determined the optimized
conditions to be using 3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acid 1a as a model
substrate, 1.5 equiv m-CPBA as an oxidant and 0.2 equivalents of tricyclic aryl iodide
3l as a catalyst in MeOH for 30 hours.
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Table 4. Optimization of Reaction Conditionsa
O
OH
3l,
m-CPBA
*
O
MeOH
O
COOH
O
1
4a
m-CPBA
Additives
Entry
1
3l (equiv)
0.05
0.1
(equiv)
1.5
1.5
1.5
1.5
1.5
1
(0.2 equiv)
t (h)
10
10
10
10
10
10
10
10
10
20
30
40
30
30
30
30
30
30
30
30
30
30
eeb (%)
34
38
39
41
40
36
43
38
37
42
43
39
40
41
39
0
Yield (%)
15
17
18
22
27
6
2
3
0.15
0.2
4
5
0.3
6
0.2
7
0.2
1.2
1.8
2
14
23
25
30
58
55
40
24
16
0
8
0.2
9
0.2
10
11
12
13d
14e
15f
16
17
18
19
20
21
22
0.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
0.2
0.2
0.2
0.2
0.2
0.2
Et3N
3Å
0.2
38
37
36
37
34
35
40
43
55
47
49
53
0.2
4Å
0.2
5Å
0.2
H2O
0.2
Na2SO4
CH3COOH
0.2
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a Conditions: 1a (0.3 mmol), 3l (specified, 20 mol%) and m-CPBA (specified) in MeOH (1 mL) at
20 oC. b By HPLC analysis (chiralpack AD-H). c Yield determined by 1H-NMR using anisole ether
as an internal standard. d Reaction at 0 oC. e Reaction at -10 oC. f Reaction at -30 oC.
9
On the basis of the reaction conditions optimized in Table 4, the substrate
generality of the asymmetric alkoxy-oxylactonization and dearomatization reaction
was explored. Initially, the effect of the nucleophilic organic moiety of alchol was
probed. An increase in the size of R2OH demonstrated a considerable steric effect. A
prominent decrease in yield from 58% to 21% along with moderate level of
enantioselectivities ranging from 40% to 50% ee caused when sterically hindered
alcohols were investigated (Table 5, 4a-d). After that, effects of position and
substituents were examined. Electron-donating groups such as methyl both at meta-
and ortho- positions provided close enantioselectivities while electron-withdrawing
groups such as para-fluorine that enhance the nucleophilic character of carboxylate
anion showed a considerable increase in yield and ee (Table 5, 4e-g). When DCM
replaced MeOH, methyl substituted substrate led to formation of 4h in yield of 61%
with 13% ee as well.
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Table 5. Scope of of 3'-Hydroxy-[1,1'-biphenyl]-2-carboxylic Acidsa
O
O
OH
R2
3l,
R2OH
m-CPBA
*
*
R1
R1
O
R
O
O
COOH
O
O
1
4a-g
, R = H
4h
, R = Me
O
O
O
O
*
O
*
*
*
O
O
O
O
O
O
O
O
O
O
O
4a, 58% yieldb,
4b, 55% yield,
4c, 27% yield,
4d, 21% yield,
43% eec
52% ee
50% ee
40% ee
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O
O
O
O
5
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*
*
*
*
O
O
O
O
O
O
O
F
9
O
O
O
O
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4e, 42% yield,
4f, 31% yield,
4g, 42% yield,
4h, 61% yieldd,
15% ee
11% ee
23% ee
13% ee
a Conditions: 1 (0.3 mmol), 3l (0.06 mmol) and m-CPBA (0.36 mmol) in R2OH (1 mL) at 20 C
for 30 h. b Isolated yield by silica gel column chromatography. c By HPLC analysis (chiralpack
AD-H). d DCM replaced MeOH.
o
Controlled investigations were made to explore the reaction mechanism and to
confirm the reaction intermediate. The alkoxy-dearomatization of lactone phenol
resulted in both higher enantioselectivity and yield (4a, 56% ee, 87% yield) than the
corresponding 3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acid which confirms that
reaction proceeds via lactone phenol intermediate. The 6-hydroxy-4-methylcoumarin
substrate was also examined leading to the corresponding product in good yield (4i,
31% ee, 90% yield) that further strengthen our hypothesis (Scheme 2).
Scheme 2. Alkoxy-dearomatization of Lactone Phenols
O
OH
conditionsa
*
O
O
O
O
O
87%yeildb,
56%eec
2aa
4a
O
OH
conditionsa
*
O
O
O
O
O
90%yeild,
31%ee
2ab
4i
a Conditions: 1 (0.3 mmol), 3l (0.06 mmol) and m-CPBA (0.36 mmol) in MeOH (1 mL) at 20 C
o
b
for 30 h. Isolated yield by silica gel column chromatography. c By HPLC analysis (chiralpack
AD-H).
1
In an effort to glean insights into the mechanism, H NMR analysis was
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employed to detect the interaction of electron-deficiency iodine(III) and substrates.
N-acyl aniline have been reported interacting with hypervalent iodine(III) at the
para-carbon of aniline by Nicolaou9 and the hypervalent iodide has been separated
successfully. Similarly, for this electron-rich phenol, two nucleophilic sites were
considered, i.e. basic oxygen of hydroxyl and para-carbon of phenol. In starting
material structure (1a), the three aryl hydrogen atoms of phenol appeared multiplet
signal peaks in displace of 6.72-6.75 ppm (Figure 2, 1). When we mixed starting
material 1a and DIB, the 1H NMR spectrum showed three new signal peaks very soon
which correspond to three aryl hydrogen atoms of phenol moieties: H1 singlet peak of
6.70 ppm; H2 doublet peak of 6.63 ppm with coupling constant J = 7.5 Hz; H3 doublet
peak of 6.82 ppm with coupling constant J = 7.5 Hz. No interaction with aryl carbon
of phenol was observed. Thus, the adduct of starting materials and DIB was
speculated to form as in line 2 of Figure 2. The sample was tested again after ten
minutes, and the hydrogen content of hydroxyl signal significantly reduced (Figure 2,
3). Ten hours later, the adduct disappeared (Figure 2, 4) and the lactone 2aa was
generated, which was confirmed by comparing the 1H NMR spectra.
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OH
H1
H2
H2
H1
O
2aa
O
Ph
OAc
I
H3
H1
H2
O
H1
H2
H3
COOH
OH
3H
H1
H2
H3
1a
COOH
Figure 2. 1H NMR analysis for mechanism insight. (1) 1a; (2) mixing 1a and DIB, no
wait; (3) mixing 1a and DIB for 10 min; (4) mixing 1a and DIB for 10 h.
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Based on the isolated intermediate 2aa and above NMR-identification, a
plausible mechanism pathway for this catalytic dearomatization of
alkoxy-oxylactonizations process as well as asymmetric inductivity is proposed
(Figure 3). At first, oxygen of phenolic hydroxyl attacks the iodine of DIB in a
nucleophilic way to give adduct A, and para-position of phenol therefore gets reactive
to permit the σ-bond shift from carboxyl, which leads to cleavage of OAc group,
reduction of iodine(III) and formation of dienone. Then, a flash rearomatization
process undergoes to form 2aa through 1,5-H shift. Repeatedly, oxygen of phenolic
hydroxyl attacks again by the iodine(III) and RO- exchanges subsequentially to give
rise to the final product with release of PhI and HOAc. Enantioselectively, with
m-CPBA and chiral aryl iodine instead of DIB, a similar process could experience to
reach enantiomer excessive product. The ee values of the enantioselective conversion
are generally low in all cases, similar to asymmetric para-dearomatization of phenols
(up to 60% ee).7a One possible reason might be that the prochiral center of starting
materials is far away from the chiral center of hypervalent iodine species.
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Ph
OAc
OH
I
OH
O
O
O
- PhI
- HOAc
1,5-H shift
DIB
- HOAc
OH
H
O
O
O
O
OH
O
B
A
2aa
Ph
O
*Ar
O
OAc
OR
I
I
O
OHAc
O
- PhI
- HOAc
- Ar*I
- ROH
DIB, ROH
- HOAc
*
OR
OR
O
O
O
O
O
OR
OR
O
H
H
O
O
Figure 3. Proposed reaction mechanism.
CONCLUSION
In summary, we have developed an alkoxy-oxylactonization and dearomatization
reaction of 3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acid derivatives under optimized
conditions in which DIB acts as a double Umpolung reagent to promote
dioxygenation of electron-rich aryl carbon. We have described a polycyclic
cyclohexadienone derivatives one-step synthesis using DIB. We also have described
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an enantioselective reaction using a catalytic amount of chiral hypervalent iodine
precursors. Moreover, we found alkoxy-dearomatization of lactone phenols reaction
gave higher enantioselectivity. This method provides an efficient access to various
interesting enantioenriched cyclohexadienone in acceptable yields and moderate
enantioselectivity. The further improvement of enantiomer excess and applications of
this strategy using other nucleophile are underway.
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EXPERIMENTAL SECTION
General Information. 1H- and 13C-NMR spectra were recorded in CDCl3 solution on
1
a Bruker Avance 500 spectrometer at 20~25 °C. H NMR spectra were reported in
parts per million using tetramethylsilane TMS (δ = 0.00 ppm) as an internal standard.
The data of 1H NMR are reported as follows: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (J, Hz), and
13
integration. C NMR spectra were reported in parts per million using solvent CDCl3
(δ = 77.2 ppm) as an internal standard, The data of 13C NMR are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet), and coupling constants (J, Hz). High resolution mass spectra (HRMS)
were obtained with a Q-TOF MS spectrometer. High-performance liquid
chromatography (HPLC) analysis was performed, equipped with a UV/Vis detector
employing chiral columns. Reactions were monitored by TLC and column
chromatography was performed using silica gel. Commercially available reagents
were used without further purification unless otherwise specified.
General Procedure for Synthesis of 1.10
For starting materials: 3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acid,
3'-hydroxy-5-methyl-[1,1'-biphenyl]-2-carboxylic
3'-hydroxy-6-methyl-[1,1'-biphenyl]-2-carboxylic
5'-hydroxy-2'-methyl-[1,1'-biphenyl]-2-carboxylic acid.
acid,
and
acid
(i) To a solution of bromobenzoate (10 mmol), 2 N Na2CO3 (10 mL, 2 equiv) and
(3-hydroxyphenyl)boronic acid (10 mmol, 1 equiv) in toluene (50 mL) was added
Pd(dppf)Cl2 (0.5 mmol, 5 mol %) under argon. After stirring for 14 h, the solvent was
removed by vacuum and the mixture was purified by silica-gel column
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chromatography (10:1 petroleum ether: EtOAc) to give colourless oil liquid
biphenyl-carboxylate (90% yield). (ii) To a solution of biphenyl-carboxylate (9 mmol)
in THF (25.0 mL) and MeOH (25.0 mL) was added 2 N NaOH (25 mL, 5.6 equiv)
and stirred overnight at room temperature. The reaction mixture was cooled to 0 °C,
quenched with 1 N HCl until pH reached to 2, and extracted with EtOAc (30 mL × 3).
The organic layers were dried over anhydrous MgSO4 and the solvents were removed
in vacuo to give pure solid biphenyl-carboxylic acid with quantative yield.
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For starting materials: 5-fluoro-3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acid and
3'-hydroxy-5-nitro-[1,1'-biphenyl]-2-carboxylic acid.
(i) To a solution of bromobenzoate (10 mmol), t-BuOK (20 mmol, 2 equiv) and
(3-hydroxyphenyl)boronic acid (10 mmol, 1 equiv) in THF (50 mL) was added
Pd2(dba)3 (0.5 mmol, 5 mol %) under argon. After stirring for 14 h, the solvent was
removed by vacuum and the mixture was purified by chromatography (10:1
petroleum ether: EtOAc) to give colourless oil liquid biphenyl-carboxylate (80%
yield). (ii) To a solution of biphenyl-carboxylate (8 mmol) in THF (25.0 mL) and
MeOH (25.0 mL) was added 2 N NaOH (25.0 mL, 6.2 equiv) and stirred overnight at
room temperature. The reaction mixture was cooled to 0 °C, quenched with 1 N HCl
until pH reached to 2 and extracted with EtOAc (30 mL × 3). The organic layers were
dried over anhydrous MgSO4 and the solvents were removed in vacuo to give pure
solid biphenyl-carboxylic acid with quantative yield.
General Procedure for Synthesis of 2.
To a round-bottom flask was charged with 1 (0.3 mmol), ROH (1 mL), 20 wt% 5
Å MS and DIB (0.84 mmol, 2.8 equiv) in sequence successively. Then the resulting
mixture was stirred under closed conditions at 20 oC (water bath temperature) for 10 h.
The reaction was quenched with saturated solution of Na2S2O3 (1 mL). The organic
phase was separated, and the aqueous layer was extracted with DCM (5 mL × 3). The
combined organic solution was dried with Mg2SO4 and concentrated in vacuo. The
resulting residue was purified by a column chromatography (20:1 petroleum ether:
EtOAc) to give racemic 2.
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General Procedure for Synthesis of 3.11,8d
5
6
7
8
To a solution of 2-iodoresorcinol (2.36 g, 10.0 mmol), PPh3 (6.56 g, 25.0 mmol)
and (-)-lactic acid ethylester (2.95 g, 25.0 mmol) in THF (50 mL) was added slowly
diisopropyl azodicarboxylate (DIAD, 1.9 M in toluene, 13.2 mL, 25.0 mmol) at 0°C.
The reaction mixture was allowed to warm to room temperature. After stirring for 6 h,
the resulting mixture was concentrated in vacuo. The residue was purified by flash
silica-gel column chromatography (30:1 petroleum ether: EtOAc) to give colorless oil
3a (3.93 g, 9.0 mmol) in 90% yield. To a solution of 3a (3.93 g, 9.0 mmol) in THF
(25.0 mL) and MeOH (25.0 mL) was added 2N NaOH (25 mL) and stirred overnight
at room temperature. The reaction mixture was cooled to 0 °C, quenched with 1 N
HCl and extracted with EtOAc (30 mL × 3). The organic layers were dried over
anhydrous MgSO4 and the solvents were removed in vacuo to give pure white solid
3b (3.42 g, 9.0 mmol) in 99% yield. To a solution of 3b (0.87 g, 2.29 mmol) in DCM
(10 mL) and DMF (1 drop) was added SOCl2 (1.32 mL, 18.32 mmol, 8 equiv) and the
mixture was stirred overnight under argon. The resulting mixture was concentrated
under vacuum. Then the residue was dissolved in DCM (6 mL) at 0 °C and amine
derivative (4.17 mmol, 1.8 equiv) was added. After 0.5 h, Et3N (1.16 mL, 8.34 mmol)
was added. Stirring continued overnight, and the reaction mixture was poured into
aqueous HCl (1 M, 20 mL) and extracted with brine and DCM (10 mL × 2). The
organic layers were dried with MgSO4, filtered and the solvent was removed under
vacuum to give solid product 3c-n.
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General Procedure for Synthesis of 4.
To a round-bottom flask was charged with 1 or lactone phenols (0.3 mmol),
ROH (1 mL), 20 % 3l and m-CPBA (0.36 mmol, 1.2 equiv) in sequence successively.
o
Then the resulting mixture was stirred under closed conditions at 20 C (water bath
temperature) for 30 h. The reaction was quenched with saturated solution of Na2S2O3
(1 mL). The organic phase was separated, and the aqueous layer was extracted with
DCM (5 mL × 3). The combined organic solution was dried with Mg2SO4 and
concentrated in vacuo. The resulting residue was purified by a column
chromatography (20:1 petroleum ether: EtOAc) to give optically active 4.
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1H- and 13C-NMR Analytical Data
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8
2-Hydroxy-6H-benzo[c]chromen-6-one (2aa):7a 7.03 mg, 0.033 mmol, 11% yield,
mp 195-196 °C yellowish solid; 1H NMR (500 MHz, DMSO-d6 ) δ 9.74 (s, 1H), 8.26
(m, 2H), 7.93 (t, J = 8 Hz, 1H), 7.67 (t , J = 8 Hz, 1H), 7.61 (s, 1H), 7.27 (d, J = 9 Hz,
1H), 7.00 (d, J = 9 Hz, 1H); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H9O3
213.0546; Found 213.0539.
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4a-Methoxy-6H-benzo[c]chromene-2,6(4aH)-dione (2a and 4a). 2a: 56.9 mg,
0.234 mmol, 78% yield, yellowish solid, mp 145-146 °C; 4a: 42.3 mg, 0.174 mmol,
20
58% yield, 43% ee, [α]
+66.5 (c 0.16, CHCl3); 4a: 63.4 mg, 0.261 mmol,87%
D
20
yield, 56% ee from 2aa, [α]
+118.1 (c 0.21, CHCl3), chiralpack AD-H,
D
hexane/i-PrOH = 92/8, flow rate = 1.0 mL/min, 254nm, major isomer : tR = 26.052
1
min, minor isomer : tR = 30.415 min; H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 7.5
Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.65 (t , J = 7.5 Hz, 1H),
7.06 (d, J = 10 Hz, 1H), 6.70 (s, 1H), 6.47 (d, J = 10 Hz, 1H), 3.36 (s, 3H), 2.04 (s,
3H); 13C{1H} NMR (125 MHz,CDCl3) δ 184.6, 162.3, 145.1, 140.3, 134.9, 133.0,
131.7, 130.7, 124.5, 124.1, 95.3, 52.1, 18.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C14H11O4 243.0652; Found 243.0659.
4a-Ethoxy-6H-benzo[c]chromene-2,6(4aH)-dione (2b and 4b). 2b: 53.2 mg, 0.207
mmol, 69% yield, yellowish solid, mp 149-151 °C; 4b: 42.4 mg, 0.165 mmol, 55%
20
yield, 52% ee, [α]
+55.8 (c 0.12, CHCl3), chiralpack AD-H, hexane/i-PrOH =
D
92/8, flow rate = 1.0 mL/min, 254nm, major isomer : tR = 19.286 min, minor isomer :
tR = 22.435 min; 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 7.5 Hz, 1H), 7.73 (t, J =
7.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.06 (d, J = 10 Hz, 1H), 6.67 (s, 1H), 6.42 (d, J
13
= 10 Hz, 1H), 3.78-7.72 (m, 1H), 3.56-3.51 (m, 1H), 1.03 (t, J = 7 Hz, 3H); C{1H}
NMR (125 MHz,CDCl3) δ 184.6, 162.4, 145.5, 140.9, 134.8, 133.1, 131.6, 130.5,
130.4, 124.5, 124.1, 123.8, 95.0, 60.6, 15.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C15H13O4 257.0808; Found 257.0807.
4a-Propoxy-6H-benzo[c]chromene-2,6(4aH)-dione (2c and 4c). 2c: 52.8 mg,
0.195 mmol, 65% yield, yellowish oil; 4c: 21.9 mg, 0.081 mmol, 27% yield, 50% ee,
[α] 20 +78.9 (c 0.14, CHCl3), chiralpack AD-H, hexane/i-PrOH = 92/8, flow rate =
D
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1.0 mL/min, 254nm, major isomer : tR = 16.968 min, minor isomer : tR = 19.522 min;
1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 8 Hz, 1H), 7.73-7.68 (m, 2H), 7.60 (t, J =
10 Hz, 1H), 7.03 (t, J = 10 Hz, 1H), 6.66 (s, 1H), 6.40 (d, J = 10 Hz, 1H), 3.64-3.60
(m, 1H), 3.41-3.37 (m, 1H), 1.40-1.36 (m, 2H), 0.63 (t, J = 7 Hz, 3H); 13C{1H} NMR
(125 MHz,CDCl3) δ 184.6, 162.4, 145.5, 141.0, 134.8, 133.0, 131.6, 130.4, 130.4,
124.6, 124.1, 123.7, 94.9, 66.3, 22.8, 10.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C16H15O4 271.0965; Found 271.0962.
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4a-Butoxy-6H-benzo[c]chromene-2,6(4aH)-dione (2d and 4d). 2d: 41.1 mg,
0.144 mmol, 48% yield, yellowish oil; 4d : 17.9 mg, 0.063 mmol, 21% yield, 40% ee,
[α] 20 +66.3 (c 0.178, CHCl3), chiralpack AD-H, hexane/i-PrOH = 92/8, flow rate =
D
1.0 mL/min, 254nm, major isomer: tR = 14.996 min, minor isomer: tR = 16.645 min;
1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 7.5 Hz, 1H), 7.74-7.69 (m, 2H), 7.63 (t, J
= 7.5 Hz, 1H), 7.05 (d, J = 10 Hz, 1H), 6.68 (s, 1H), 6.43 (d, J = 10 Hz, 1H),
3.71-3.67 (m, 1H), 3.47-3.43 (m, 1H), 1.41-1.35 (m, 2H), 1.11-1.07 (m, 2H), 0.73 (t, J
13
= 7 Hz, 3H)); C{1H} NMR (125 MHz,CDCl3) δ 184.7, 162.5, 145.6, 141.0, 134.8,
133.1, 131.6, 130.4, 30.4, 124.6, 124.2, 123.8, 95.0, 64.5, 31.5, 18.9, 13.6; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H17O4 285.1121; Found 285.1113.
8-Fluoro-4a-methoxy-6H-benzo[c]chromene-2,6(4aH)-dione (2g and 4g). 2g:
38.4 mg, 0.147 mmol, 49% yield, yellowish solid, mp 163-165 °C; 4g: 32.9 mg, 0.126
20
mmol, 42% yield, 23% ee, [α]
+47.9 (c 0.146, CHCl3), chiralpack AD-H,
D
hexane/i-PrOH = 92/8, flow rate = 1.0 mL/min, 254nm, major isomer: tR = 23.070
1
min, minor isomer : tR = 30.656 min; H NMR (500 MHz, CDCl3) δ 8.24 (dd, J = 8
Hz, 5.5 Hz, 1H), 7.37 (dd, J = 8 Hz, 2 Hz, 1H), 7.32 (dt, J = 8 Hz, 2 Hz, 1H), 7.07 (d,
J = 10 Hz, 1H), 6.66 (d, J = 1.5 Hz, 1H), 6.47 (dd, J = 10 Hz, 1.5 Hz, 1H), 3,38 (s,
13
3H); C{1H} NMR (125 MHz,CDCl3) δ 184.2, 166.6 (d, J = 256 Hz), 161.4, 144.1,
140.2, 135.8 (d, J = 10 Hz), 133.9 (d, J = 10 Hz), 130.9, 124.8, 120.5, 119.2 (d, J = 22
Hz), 111.6 (d, J = 24 Hz), 95.3, 52.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C14H10FO4 261.0558; Found 261.0551.
4a-Methoxy-8-nitro-6H-benzo[c]chromene-2,6(4aH)-dione (2h): 62.2 mg, 0.216
1
mmol, 72% yield, yellow solid, mp 186-187 °C; H NMR (500 MHz, CDCl3) δ 9.03
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(s, 1H), 8.59-8.56 (dd, J = 8.5 Hz, 2 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 10
Hz, 1H), 6.79 (s, 1H), 6.52 (d, J = 10 Hz, 1H), 3.42 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 183.8, 160.5, 149.6, 142.9, 139.8, 138.4, 131.2, 129.2, 126.3, 126.3, 125.9,
125.6, 95.4, 52.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H10NO6 288.0503;
Found 288.0501.
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4a-Methoxy-10-methyl-6H-benzo[c]chromene-2,6(4aH)-dione (2i and 4f). 2i:
53.2 mg, 0.207 mmol, 69% yield, yellowish solid, mp 154-156 °C; 4f: 23.9 mg, 0.093
20
mmol, 31% yield, 11% ee, [α]
+12.5 (c 0.08, CHCl3), chiralpack AD-H,
D
hexane/i-PrOH = 97/3, flow rate = 1.0 mL/min, 254nm, major isomer: tR = 31.945
1
min, minor isomer: tR = 33.547 min; H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.5
Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 10 Hz, 1H),
13
6.58 (s, 1H), 6.47 (d, J = 10 Hz, 1H), 3.32 (s, 3H), 2.58 (s, 3H); C{1H} NMR (125
MHz,CDCl3) δ 184.6, 162.6, 144.5, 140.5, 137.8, 136.5, 131.8, 130.4, 130.3, 128.9,
128.4, 125.1, 94.9, 51.9, 21.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H13O4
257.0808; Found 257.0814.
4a-Methoxy-9-methyl-6H-benzo[c]chromene-2,6(4aH)-dione (2j and 4e). 2j:
61.7 mg, 0.24 mmol, 80% yield, yellowish solid, mp 156-156 °C; 4e: 32.4 mg, 0.126
20
mmol, 42% yield, 15% ee, [α]
+26.6 (c 0.128, CHCl3), chiralpack AD-H,
D
hexane/i-PrOH = 95/5, flow rate = 1.0 mL/min, 254nm, major isomer: tR = 28.596
min, minor isomer: tR = 37.726 min; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7 Hz,
1H), 7.48 (s, 1H), 7.43 (d, J = 7 Hz, 1H), 7.04 (d, J = 10 Hz, 1H), 6.66 (s, 1H), 6.44 (d,
13
J = 10 Hz, 1H), 3.34 (s, 3H), 2.49 (s, 3H); C{1H} NMR (125MHz,CDCl3) δ 184.6,
162.3, 146.2, 145.3, 140.4, 132.9, 132.7, 130.8, 130.7, 124.9, 123.8, 121.4, 95.2, 52.1,
22.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H13O4 257.0808; Found
257.0800.
4a-Methyl-6H-benzo[c]chromene-2,6(4aH)-dione (2k and 4h). 2k (DCM as
solvent): 51.1 mg, 0.225 mmol, 75% yield, yellowish solid, mp 138-140 °C; 4h (DCM
as solvent): 41.5 mg, 0.183 mmol, 61% yield, 13% ee, [α] 20 +48.6 (c 0.122, CHCl3),
D
chiralpack AD-H, hexane/i-PrOH = 92/8, flow rate = 1.0 mL/min, 254nm, minor
isomer : tR = 26.134 min, major isomer : tR = 33.090 min; 1H NMR (500 MHz, CDCl3)
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δ 8.22 (d, J = 7.5 Hz, 1H), 7.78 - 7.72 (m, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.11 (d, J =
10 Hz, 1H), 6.67 (s, 1H), 6.33 (d, J = 10 Hz, 1H), 1.68 (s, 3H); 13C{1H} NMR
(125MHz,CDCl3) δ 184.8, 162.7, 150.1, 147.8, 135.0, 133.7, 131.9, 130. 9, 127.8,
124.5, 123.9, 123.2, 76.9, 29.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H11O3
227.0703; Found 227.0699.
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8a-Methoxy-4-methyl-2H-chromene-2,6(8aH)-dione (4i): 55.9 mg, 0.270 mmol,
20
90% yield, 31% ee, yellowish solid, mp 74-76 °C, [α]
+33.9 (c 0.18, CHCl3),
D
chiralpack AD-H, hexane/i-PrOH = 96/4, flow rate = 1.0 mL/min, 254nm, minor
isomer : tR = 24.617 min, major isomer : tR = 25.619 min; 1H NMR (500 MHz, CDCl3)
δ 7.04 (d, J = 10 Hz, 1H), 6.40 (m, 2H), 6.10 (s, 1H), 3.40 (s, 3H), 2.18 (s, 3H);
13C{1H} NMR (125 MHz,CDCl3) δ 184.7, 161.4, 147.7, 145.8, 141.5, 130.4, 125.8,
120.9, 94.8, 52.2, 17.81; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H11O4
207.0652; Found 207.0645.
ASSOCIATED CONTENT
Supporting Information
Supporting Information is available free of charge on the ACS Publications website at
1H-NMR Spectra for Mechanism Insight; HPLC, 1H-NMR, 13C-NMR and HRMS
spectra for 2 and 4
ACKNOWLEDGMENTS
We gratefully acknowledge funding from the National Natural Science Foundation
of China (No. 21372265) and the Natural Science Foundation Project of CQ CSTC
(cstc2018jcyjAX0155).
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