Organocatalytic synthesis of enantioenriched β-arylsplitomicins

Article abstract of DOI:10.1055/s-0031-1290303

By employing a chiral bifunctional thiourea-tertiary amine as catalyst, domino Michael-type Friedel-Crafts alkylation/cyclization of -naphthols with akylidene Meldrum's acids was realized. The reactions afforded various enantioenriched -arylsplitomicins with good yields (up to 99%) in moderate enantioselectivities (up to 79%). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290303

796▌
LETTER
Letter
Organocatalytic Synthesis of Enantioenriched β-Arylsplitomicins
Enantioenriched β-Arylsplitomicins
Ji-Yu Wang,a,b Hui Zhang,a,b Yu-Hua Liao,a,b Wei-Cheng Yuan,a Yu-Jun Feng,*a Xiao-Mei Zhang*a
a
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Fax +86(28)85257883; E-Mail: xmzhang@cioc.ac.cn
b
Graduate School of Chinese Academy of Sciences, Beijing 100049, P. R. of China
Received: 02.12.2011; Accepted: 09.01.2012
lyzed cyclization of β-naphthols with cinnamic acids.1g
Kitamura et al. employed triflic acid to promote cycliza-
tion of β-naphthols with cinnamic acid esters to give β-
arylsplitomicins in high yields.2a Yuan and co-workers
Abstract: By employing a chiral bifunctional thiourea–tertiary
amine as catalyst, domino Michael-type Friedel–Crafts alkyla-
tion/cyclization of β-naphthols with akylidene Meldrum’s acids
was realized. The reactions afforded various enantioenriched β-aryl-
splitomicins with good yields (up to 99%) in moderate enantio- synthesized β-phenylsplitomicin through solid acid cata-
selectivities (up to 79%).
lyzed tandem esterification–Friedel–Crafts alkylation of
β-naphthol and cinnamoyl chloride under microwave irra-
diation.2b Yao et al. reported TBAF catalyzed multicom-
ponent reactions of aldehydes, β-naphthol and Meldrum’s
acid to give various β-arylsplitomicins in good yields.2c
However, synthesis of enantioenriched β-arylsplitomicins
has been rarely explored. Manfred Jung and co-workers
employed a chiral rhodium catalyst to catalyze the conju-
gated addition of arylboronic acids to 8-methyl-3H-
benzo[f]chromen-3-one to generate β-phenyl-8-methyl-
splitomicin (2) and β-para-tolyl-8-methylsplitomicin (3)
in excellent enantioselectivities (up to 99% ee) but with
very poor yields (18%).1g Jeffry W. Bode and co-workers
demonstrated an enantioselective annulation of 3-phenyl-
propiolaldehyde and 2-naphthol promoted by a chiral N-
heterocyclic carbene catalyst. The reaction gave β-phe-
nylsplitomicin in moderate yield with moderate ee value
and there was only one example.3 To our knowledge, sys-
tematic research of asymmetric synthesis of β-arylsplito-
micins has not been reported and is worth exploration in
view of the great importance of this kind of compounds.
Key words: domino reaction, alkylation, cyclization, phenols, or-
ganocatalysis, asymmetric catalysis
Splitomicin analogues are important inhibitors of sirtu-
ins.1 Splitomicin was also proved to suppress human
platelet aggregation via inhibition of cyclic AMP phos-
phodiesterase and intracellular Ca++ release.1h Splitomicin
(1, Figure 1) itself is inhibitor of yeast sirtuins. However,
it does not inhibit human sirtuin subtypes and is prone to
hydrolysis in aqueous medium. Recently, several β-aryl-
splitomicins such as β-phenyl-8-methylsplitomicin (2)
and β-para-tolyl-8-methylsplitomicin (3) were found to
inhibit recombinant SIRT 2 and exhibit antiproliferative
properties and tubulin hyperacetylation in MCF7 breast
cancer cells.1g In addition, the instability of the lactone can
be overcome by β-arylsplitomicins.1i Thus they are prom-
ising candidates for further optimization as potential anti-
cancer drugs.1g Notably, the stereochemistry at the
substituted β-carbon atom is of great importance. Com-
pounds (R)-2 and (R)-3 were found to be much more ac-
tive than (S)-enantiomers.1g,i
Recently, chiral bifunctional organocatalysts were ap-
plied successfully in promoting Friedel–Crafts alkylations
of electron-rich phenols.4 Among these phenols, naph-
thols were frequently subjected to organocatalyzed asym-
metric reactions with various electrophiles.4a–d,f Hence,
we envisioned that chiral bifunctional organocatalysts
would catalyze enantioselective Michael-type Friedel–
Crafts alkylation of β-naphthols with alkylidene Mel-
drum’s acids5 followed by intramolecular cyclization to
generate enantioenriched β-substituted splitomicins as
outlined in Scheme 1.
O
O
O
*
*
O
O
O
1
2
3
Figure 1 Representative examples of splitomicin analogues
Herein we would like to describe the organocatalytic
domino Michael-type Friedel–Crafts alkylation/cycliza-
tion of β-naphthols with alkylidene Meldrum’s acids,
through which a variety of enantioenriched β-arylsplito-
micins were obtained with moderate to good yields in
moderate enantioselectivities.
First, various chiral bifunctional organocatalysts 4a–k6
(Figure 2) were tested in the domino Michael-type
Friedel–Crafts alkylation/cyclization of 2-naphthol 5a
with 4-nitrobenzylidene Meldrum’s acid 6a in dichloro-
methane at 20 °C for 24 hours. Because of the poor reac-
Therefore, synthesis of enantioenriched β-arylsplitomi-
cins is important for further structure–activity studies and
development of new pharmaceuticals. Up to now, synthe-
sis of racemic β-arylsplitomicin derivatives has been well
developed.1g,2 Manfred Jung and co-workers synthesized
a series of racemic β-arylsplitomicins by the acid-cata-
SYNLETT 2012, 23, 796–800
Advanced online publication: 16.02.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290303; Art ID: ST-2011-W0741-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioenriched β-Arylsplitomicins
797
Following investigation of solvents demonstrated that
several chlorinated solvents such as dichloromethane,
1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform
and chlorobenzene resulted in good yields in which di-
chloromethane and 1,2-dichloroethane gave the best ee
values (Table 1, entries 12–14, 17). Meanwhile tetrachlo-
romethane, toluene and α,α,α-trifluorotoluene only af-
forded low to moderate yields, perhaps due to the poor
solubility of 4-nitrobenzylidene Meldrum’s acid 6a in
these solvents (Table 1, entries 15, 16 and 18). Afterward,
when the reaction temperature was lowered to 0 °C, the
reaction proceeded sluggishly to provide dramatically de-
creased ee value as well as poor yield even for prolonged
reaction time (Table 1, entry 19). Therefore we tried to
conduct the reaction at higher temperatures in 1,2-dichlo-
roethane and evident increases in ee values were observed
at 30 and 40 °C (Table 1, entries 20 and 21). Further en-
hancing the temperature did not improve the enantioselec-
tivity any more (Table 1, entry 22). Addition of 4 Å MS in
the reaction mixture gave rise to a slight increase in ee val-
ue (Table 1, entry 23).
chiral backbone
X
O
*
N
H
Me
Me
O
R
O
O
O
H
O
O
OH
O
O
R
R
O
*
O
Scheme 1 Proposed domino Michael-type Friedel–Crafts alkyl-
ation/cyclization of β-naphthols with alkylidene Meldrum’s acids
tivity, benzylidene Meldrum’s acid was not selected as the
standard substrate. As can be seen in Table 1, several cin-
chona alkaloids cinchonidine 4a, qinine 4b and cupreine
4c6a resulted in very poor ee values (Table 1, entries 1–3).
Cinchona alkaloids derived thiourea–tertiary amine cata-
lysts 4d6b,c and 4e6b,c also gave low enantioselectivities
(Table 1, entries 4 and 5). Better results were observed
with 4f6b,c and 4g6b,c (Table 1, entries 6 and 7). (1R,2R)-
1,2-Diphenyl-1,2-diamine-derived catalyst 4h6d gave
only moderate yield and enantioselectivity (Table 1, entry
8). Screen of the thiourea–tertiary amine catalysts, which
were derived from (1R,2R)-cyclohexane-1,2-diamine, re-
vealed that 4i6e,f turned out to be the optimal catalyst in
terms of yield and enantioselectivity (Table 1, entries
9–11).
In order to further improve the enantioselectivity, several
bulkier 4-nitrobenzylidene Meldrum’s acids 6b–f were
subjected to the reaction with 2-naphthol 5a promoted by
catalyst 4i with 4 Å MS as additive in 1,2-dichloroethane
at 40 °C for 20 hours. The results are summarized in Table
2. To our delight, cyclohexyl 4-nitrobenzylidene Mel-
drum’s acid 6d and adamantyl 4-nitrobenzylidene Mel-
drum’s acid 6f provided 7a in good yields and obviously
higher ee values (Table 2, entries 4 and 6). Therefore, cy-
clohexyl alkylidene Meldrum’s acids were determined to
be employed in the following investigations.
Hence, various cyclohexyl alkylidene Meldrum’s acids
were investigated in the titled reaction. The results are
summarized in Table 3. As can be seen in Table 3,all of
the alkylidene Meldrum’s acids derived from para- or
meta-substituted benzyl aldehydes afforded high yields of
the corresponding products with moderate ee values (Ta-
ble 3, entries 1, 3, 4, 6, 7, 9–13, 17). Meanwhile benzyli-
dene Meldrum’s acid 6g exhibited much lower reactivity
which gave the product 7b with only moderate yield, how-
ever, in superior enantioselectivity (Table 3, entry 2). The
absolute configuration of 7b was determined as S by com-
parison of its optical rotation value with the literature da-
ta.5 It is very interesting that either electron-donating
substituents or electron-withdrawing substituents at para
or meta position of the phenyl group improve the reactiv-
ity significantly. Additionally, ortho substitution at the
phenyl group caused dramatic drops in ee values (Table 3,
entries 5 and 8). Moreover, reaction of ortho-bromo sub-
strate 6m afforded the corresponding product in obviously
lower yield (Table 3, entry 8). Apparently, the ortho sub-
stitution at the phenyl group made the substrates more ste-
rically hindered so that they exhibited lower reactivity as
well as enantioselectivity. Owing to the same reason, re-
action of 1-naphthyl derivative 6t provided the product
with inferior yield and very poor ee value (Table 3, entry
15). 2-Thienyl derivative 6s resulted in lower yield but ac-
N
N
H
N
H
CF3
N
OH
R
R
S
CF3
N
N
4a R = H
4b R = OMe
4c R = OH
4d R = H
4e R = OMe
CF3
N
H
N
H
Ph
Ph
N
CF3
HN
S
Me2N
HN
R
S
CF3
CF3
4h
N
4f R = H
4g R = OMe
CF3
HN
F
HN
Me2N
HN
R
N
HN
S
S
R
CF3
4i R = Me
4j R = Bn
4k
Figure 2 Bifunctional organocatalysts evaluated in this study
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 796–800

798
J.-Y. Wang et al.
LETTER
Table 1 Enantioselective Domino Michael-Type Friedel–Crafts Alkylation/Cyclization of 2-Naphthol 5a with 4-Nitrobenzylidene Mel-
drum’s Acid 6a
O2N
O
Cat* 4
OH
O
*
O
(0.1 equiv)
+
O
O
O
O2N
5a
6a
7a
Entrya
Yield (%)b
ee (%)c
Cat*
Solvent
T (°C)
Time (h)
1
4a
4b
4c
4d
4e
4f
4g
4h
4i
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
0
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
48
20
20
18
20
55
94
82
47
86
42
88
66
99
34
38
99
97
88
25
66
94
60
53
99
99
88
99
8
2
28
0
3
4
25
17
-35
-45
42
45
7
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4j
4k
4i
32
46
42
41
21
33
37
40
22
52
55
56
57
ClCH2CH2Cl
Cl2CHCHCl2
CHCl3
4i
4i
4i
CCl4
4i
toluene
4i
C6H5Cl
4i
C6H5CF3
4i
CH2Cl2
4i
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
30
40
50
40
4i
4i
23d
4i
a Unless specified otherwise, reactions were carried out with 0.3 mmol of 5a, 0.2 mmol of 6a and 0.02 mmol of catalyst in 4 mL of solvent.
b Yield based on 6a.
c The ee values were determined using chiral HPLC.
d With 30 mg of 4 Å MS as additive.
Synlett 2012, 23, 796–800
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioenriched β-Arylsplitomicins
799
Table 3 Enantioselective Domino Michael-Type Friedel–Crafts
Alkylation/Cyclization of 2-Naphthols 5a and 5b with Alkylidene
Meldrum’s Acids 6d,g–u7,8
Table 2 Enantioselective Domino Michael-Type Friedel–Crafts
Alkylation/Cyclization of 2-Naphthol 5a with 4-Nitrobenzylidene
Meldrum’s Acids 6a–f
OH
OH
O2N
R1
R2
O
*
O
5a
*
5a,b
+
Cat* 4i (0.1 equiv)
Cat* 4i (0.1 equiv)
+
O
O
O
O
ClCH2CH2Cl, 4 Å MS
40 °C, 20 h
ClCH2CH2Cl, 4 Å MS
40 °C, 20 h
R1
O
O
R
7a–p
R2
O
O
O2N
7a
R
6a–f
O
O
Entrya
Yield (%)b
ee (%)c
6
R, R
6d,g–u
Entrya R1 (5)
R2 (6)
Yield (%)b ee (%)c
1
2
3
4
5
6
6a
Me, Me
Bn, Bn
99
94
91
94
63
97
57
44
58
64
59
64
7
6b
6c
6d
6e
6f
1
H (5a) 4-O2NC6H4 (6d)
H (5a) Ph (6g)
7a
7b
7c
7d
7e
7f
94
62
91
99
99
99
99
80
95
99
99
99
64
-(CH2)4-
-(CH2)5-
-(CH2)6-
79 (S)d
69
2
3
H (5a) 4-FC6H4 (6h)
H (5a) 4-ClC6H4 (6i)
H (5a) 2-ClC6H4 (6j)
H (5a) 4-BrC6H4 (6k)
H (5a) 3-BrC6H4 (6l)
H (5a) 2-BrC6H4 (6m)
H (5a) 4-F3CC6H4 (6n)
H (5a) 4-NCC6H4 (6o)
H (5a) 4-MeC6H4 (6p)
H (5a) 4-MeOC6H4 (6q)
4
64
5
39
6
60
a Unless specified otherwise, reactions were carried out with 0.3 mmol
of 5a, 0.2 mmol of 6, 0.02 mmol of 4i and 30 mg of 4 Å MS in 4 mL
of 1,2-dichloroethane at 40 °C for 20 hours.
b Yield based on 6.
c The ee values were determined using chiral HPLC.
7
7g
7h
7i
63
8
32
9
60
10
11
12
13
14
15
16
17
7j
58
ceptable enantioselectivity (Table 3, entry 14). Cyclohex-
ylidene Meldrum’s acid 6u was found to be almost
inactive in this reaction system (Table 3, entry 16). Fur-
thermore, 6-bromo-2-naphthol 5b was also subjected to
the reaction with 4-nitrobenzylidene Meldrum’s acid 6d
to afford product 7p in good yields with moderate ee value
(Table 3, entry 17).
7k
7l
68
66
H (5a) 3,4-(MeO)2C6H3 (6r) 7m 89
61
H (5a) 2-thienyl (6s)
H (5a) 1-naphthyl (6t)
H (5a) C6H11 (6u)
7n
7o
–
71
70
In summary, an organocatalytic domino Michael-type
Friedel–Crafts alkylation/cyclization of 2-naphthols with
alkylidene Meldrum’s acids was developed. Through this
transformation, a variety of chiral β-arylsplitomicins were
prepared with good yields (up to 99%) in moderate enan-
tioselectivities (up to 79%). The absolute configuration of
product 7b was determined as S by comparison of the op-
tical rotation value with the literature data.
70
4
trace
95
n.d.
59
Br (5b) 4-O2NC6H4 (6d)
7p
a Unless specified otherwise, reactions were carried out with 0.3 mmol
of 5, 0.2 mmol of 6, 0.02 mmol of 4h and 30 mg of 4 Å MS in 4 mL
of 1,2-dichloroethane at 40 °C for 20 hours.
b Yield based on 6.
c The ee values were determined using chiral HPLC.
d The absolute configuration was determined by comparison of the op-
tical rotation value of 7b with the literature data.5
Acknowledgment
We are grateful for the financial support from Sichuan Youth Sci-
ence & Technology Foundation.
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Synlett 2012, 23, 796–800

800
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LETTER
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conducted at 40 °C for 20 hours, the mixture was subjected
to flash chromatography on silica gel with petroleum ether–
ethyl acetate as the eluent to give the pure product 7. The ee
value was determined using established HPLC techniques
with chiral stationary phases.
(8) 1-(4-Nitrophenyl)-1H-benzo[f]chromen-3(2H)-one (7a)
White solid, mp 55–56 °C. This product was obtained in
94% yield after flash chromatography and in 64% ee as
determined by HPLC [Daicel Chirapak AD-H, n-hexane–
i-PrOH = 70:30, 1.0 mL/min, λ = 254 nm]: tR = 9.65
(major), 14.21 (minor) min. []D25 +4.7 (c 0.6, CHCl3);
1H NMR (300 MHz, CDCl3): δ = 8.14 (d, J = 8.7 Hz, 2 H),
7.94–7.88 (m, 2 H), 7.68 (d, J = 7.1 Hz, 1 H), 7.51–7.46 (m,
2 H), 7.38 (d, J = 8.9 Hz, 1 H), 7.31 (d, J = 8.7 Hz, 2 H),
5.07 (d, J = 6.8 Hz, 1 H), 3.31 (dd, J1 = 7.3 Hz, J2 = 16.0 Hz,
1 H), 3.17 (dd, J1 = 1.8 Hz, J2 = 15.9 Hz, 1 H). 13C NMR (75
MHz, CDCl3): δ = 166.18, 149.81, 147.75, 147.22, 131.05,
130.62, 130.53, 128.92, 128, 127.79, 125.53, 124.4, 122.39,
117.47, 115.95, 37.25, 36.83. ESI-HRMS Calcd for
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Synlett 2012, 23, 796–800
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