Highly enantioselective Friedel-Crafts alkylation reaction catalyzed by rosin-derived tertiary amine-thiourea: Synthesis of modified chromanes with anticancer potency

Article abstract of DOI:10.1039/c1cc14379d

We present herein for the first time the synthesis and preliminary biological evaluation of various modified chromanes via a rosin-derived tertiary amine-thiourea-catalyzed highly enantioselective Friedel-Crafts alkylation reaction.

Full text of DOI:10.1039/c1cc14379d

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COMMUNICATION
Highly enantioselective Friedel–Crafts alkylation reaction catalyzed by
rosin-derived tertiary amine–thiourea: synthesis of modified chromanes
with anticancer potencywz
Xianxing Jiang,yab Lipeng Wu,yb Yanhong Xing,yb Long Wang,b Shoulei Wang,b
Zongyao Chenb and Rui Wang*ab
Received 20th July 2011, Accepted 1st November 2011
DOI: 10.1039/c1cc14379d
We present herein for the first time the synthesis and preliminary
biological evaluation of various modified chromanes via a rosin-
derived tertiary amine–thiourea-catalyzed highly enantioselective
Friedel–Crafts alkylation reaction.
hoped to extend the substrate scope to other functionalized
carbonyl compounds, such as b,g-unsaturated a-ketoesters,7
thereby contributing to the synthesis of potentially bioactive
chiral functionalized chromanes and providing a clue for the
further development of new types of agents through preliminary
biological studies. Herein, we first present the synthesis and
preliminary biological evaluation of various modified chromanes
via a rosin-derived tertiary amine–thiourea-catalyzed highly
enantioselective Friedel–Crafts alkylation reaction8 of
naphthols with a variety of b,g-unsaturated a-ketoesters.9
Our initial investigation began by screening rosin-derived
tertiary amine organocatalysts to evaluate their ability to
promote the Friedel–Crafts alkylation reaction of b,g-unsaturated
a-ketoester (2a) with naphthalen-1-ol (3a) in the presence of
10 mol% of ligand loading at 10 1C in dichloromethane. As
shown in Table 1, the rosin-derived thiourea catalyst 1a could
successfully catalyze the reaction and the process could afford
the desired adduct 4a in moderate yield and enantioselectivity
with 420 : 1 dr (entry 1). Further screening of other rosin-
derived thiourea catalysts 1b–1e indicated that catalyst 1d is
the best catalyst, furnishing the products in 61% yield and
52% ee (entry 4). Subsequently, a survey of other solvents was
carried out with catalyst 1d (entries 7–11). These results
indicated that a substantial change of the solvent has a
significant effect on the reaction. Among the solvents tested,
diethyl ether appeared to be the most suitable reaction media
in terms of chemical yield and enantioselectivity. To our
delight, the best result was observed when the reaction was
performed in diethyl ether at 25 1C by a further optimization
of reaction temperature (82% yield and 93% ee, entry 14).
In addition, a little decrease in the yield and enantioselectivity
was observed when 5.0 mol% ligand loading used (75%
yield and 82% ee, entry 16). It is worth noting that 1a could
also exhibit satisfactory catalytic activity with an opposite sense
of asymmetric induction at 25 1C (80% yield and 80% ee,
entry 17).
Function-oriented synthesis of chiral small molecules around
biologically relevant frameworks through a highly efficient and
convenient strategy is a key goal in modern organic chemistry.
Modified chromanes are important structural motifs in organic
synthesis1 and have been found as core structural elements
commonly present in many biological assays that have shown
potent biological and pharmaceutical activities, including
decreasing drug accumulation, aldose reductase and biosyn-
thesis inhibition.2 As a result of their importance and versatility,
optically active functionalized chromanes can not only be
directly contributed to drug-lead organic synthesis in medicinal
chemistry, but they can also be applied to the total synthesis of
biologically and pharmaceutically active compounds or natural
products.3 Therefore, the development of highly efficient
asymmetric synthetic methods to access these compounds is
particularly appealing. Moreover, the evaluation of chiral
chromanes and biological activities is scarce and remains a
great challenge. We recently developed a new class of thiourea
bifunctional catalysts4 based on rosin,5 which has successfully
been applied to several asymmetric transformation processes
of carbonyl compounds.6 Encouraged by these elegant advances
and on the basis of our recent efforts in expanding the
synthetic utility of this conceptually new catalytic system, we
a State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, China. E-mail: wangrui@lzu.edu.cn
b Key Laboratory of Preclinical Study for New Drugs of Gansu
Province, State Key Laboratory of Applied Organic Chemistry,
Institute of Biochemistry and Molecular Biology,
Lanzhou University, Lanzhou 730000, China.
E-mail: wangrui@lzu.edu.cn; Fax: (86)-931-8911255
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: CCDC
834600. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1cc14379d
The results of experiments under the optimized conditions
that probed the scope of the reaction are summarized in Table 2.
The catalytic Friedel–Crafts alkylation reaction of naphthalen-1-ol
with b,g-unsaturated a-ketoesters in the presence of 10 mol%
1d was performed. A variety of b,g-unsaturated a-ketoesters
y These authors contributed equally to this work.
c
446 Chem. Commun., 2012, 48, 446–448
This journal is The Royal Society of Chemistry 2012

Table 1 Catalyst screening and optimization of reaction conditionsa
Table 2 The synthesis of modified chromanes by the reaction of
naphthalen-1-ol with a variety of b,g-unsaturated a-ketoestersa
Entry
R1
R2
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Ph
2-naphthyl
4-FPh
4-ClPh
4-BrPh
4-F3CPh
2-FPh
2-ClPh
2-F, 5-BrPh
2-Br, 5-FPh
3-MePh
2-furyl
2-thienyl
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
4a, 82 (80)
4b, 80 (81)
4c, 84 (83)
4d, 82 (83)
4e, 84 (78)
4f, 86 (79)
4g, 83 (85)
4h, 81 (76)
4i, 82 (80)
4j, 82 (82)
4k, 80 (78)
4l, 81 (84)
4m, 82 (83)
4n, 79 (80)
4o, 80 (78)
93 (ꢀ80)d
82 (ꢀ96)
93 (ꢀ80)
91 (ꢀ85)
94 (ꢀ86)
95 (ꢀ83)
92 (ꢀ78)
96 (ꢀ80)
ꢀ96 (92)
ꢀ93 (91)
90 (ꢀ79)
ꢀ86 (80)
ꢀ91 (85)
82 (ꢀ80)
87 (ꢀ90)
Entry
Cat.
Solvent
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
MeCN
Et2O
Toluene
THF
m-xylene
Et2O
Et2O
50
61
59
61
65
54
58
63
60
Trace
61
46
79
82
87
75
80
ꢀ50d
40
9e
10e
11
12
13
14
15
ꢀ45
52
40
55
62
74
65
n.d.
71
62
88
93
83
82
ꢀ80
9
Ph
Bn
10
11
12e
13f
14g
15h
16i
17j
a
Unless otherwise noted, the reaction was conducted with
(0.10 mmol) and 3a (0.20 mmol) for 36 h and products were observed
2
b
c
with 420 : 1 dr. Isolated yield. The ee values were determined by
HPLC and the configuration was assigned by comparison of HPLC
Et2O
Et2O
Et2O
Et2O
d
data and X-ray crystal data of 4e. Values in parentheses are the
results obtained using 1a. 5 : 1 dr was determined by 1H NMR and
HPLC.
e
a
Unless noted, the reaction was conducted with 2a (0.10 mmol) and
3a (0.20 mmol) for 36 h at 10 1C and products were observed with
the desired products in high yields (86–89%, entries 1–3)
and almost the same high enantioselectivities (86–91% ee,
entries 1–3).
b
c
420 : 1 dr. Isolated yield. The ee values were determined by HPLC
and the configuration was assigned by a comparison of the HPLC data
d
and X-ray crystal data of 4e. The opposite configuration. The
e
f
g
h
The proposed possible model to account for the high
enantioselectivity is shown in Fig. 1. In light of the experi-
mental results described above and recent studies, the tertiary
amine–thiourea 1d would act in a bifunctional fashion. The
a-carbon atom of naphthols could be activated by an inter-
action between the neighboring tertiary amine moiety of
the catalyst and hydroxy group of naphthols, alongside
b,g-unsaturated a-ketoesters are fixed and activated by the
two thiourea hydrogen atoms through weak hydrogen bonds.
Subsequently, the attack of the incoming nucleophiles to the
si-face of b,g-unsaturated a-ketoesters takes place and then
undergoes a hemiketal cyclization to afford desired product,
reaction was conducted at 0 1C for 64 h. At 20 1C. At 25 1C. At
35 1C. 5 mol% ligand loading at 25 1C. At 25 1C.
i
j
including those bearing electron-withdrawing and electron-
donating substituents on the aryl ring, heterocyclic was
examined. In general, the results showed that all reactions
with aromatic b,g-unsaturated a-ketoesters underwent reactions
affording the desired products in good yields (80–86% yields,
entries 1–11) and high to excellent enantioselectivities (82–96% ee,
entries 1–11) with excellent diastereoselectivities. The enantio-
selectivity was found to be insensitive to the position of the
substituent on the phenyl group of b,g-unsaturated a-ketoesters.
As expected, heterocyclic b,g-unsaturated a-ketoesters have
also proven to be suitable substrates for this asymmetric
process (entries 12, 13). Notably, when the substrate scope
was extended to different substituents on the ester moiety, good
enantioselectivities and yields were still obtained (82–87% ee
and 79–80% yields, entries 14, 15). In addition, The reactions
employing 1a were examined next. Gratifyingly, all of the
reactions could also provide the opposite enantiomeric products
with good yields (78–85% yields, in parentheses) and good to
excellent enantioselectivities (ꢀ78–ꢀ96% ee, in parentheses).
With the successful synthesis of various functionalized
chromanes using naphthalen-1-ol, as described above,
naphthalen-2-ol was next tested under the asymmetric protocol
established (Table 3). Gratifyingly, While 3 : 1 dr was observed
in entries 1 and 3, the reactions proceeded smoothly, affording
Table 3 The test for the asymmetric reaction with naphthalen-2-ola
Entry
R1
R2
Yield (%)b
ee (%)c
1d
2
Ph
3-MePh
2-thienyl
Me
Me
Me
90 (5a)
89 (5b)
86 (5c)
91
91
ꢀ86
3d
a
Unless noted, the reaction was conducted with 2 (0.10 mmol) and 3b
b
(0.20 mmol) for 36 h. Isolated yield. The ee values were determined
c
d
by HPLC. 3 : 1 dr was determined by H NMR and HPLC.
1
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 446–448 447

levels of enantio- and diastereoselectivity (up to 96% ee, and
420 : 1 dr) via the rosin-derived tertiary amine–thiourea-catalyzed
enantioselective Friedel–Crafts alkylation reaction of
naphthols with a variety of b,g-unsaturated a-ketoesters for
the first time. In addition, several of the new chromanes
showed promising anticancer potency through preliminary
biological studies. The current study provides a clue for the
further development of new types anticancer agents. Further
investigation is ongoing in our laboratories.
We are grateful for the grants from the National Natural
Science Foundation of China (Nos. 20932003 and 90813012), the
Key National S&T Program ‘‘Major New Drug Development’’
of the Ministry of Science and Technology of China
(2009ZX09503-017) and the Fundamental Research Funds for
the Central Universities of China (860618).
Fig. 1 The proposed model of the reaction transition state.
which is consistent with the experimental results. In recent
studies,5,6a we also tried to explain the role of structural
features of rosin derived thiourea catalysts in obtaining high
enantioselectivity by carrying out reactions with catalysts
bearing different configurations of the chiral scaffold moiety.
We disclosed that the two chiral moieties of the thiourea are
mutually reinforcing for the high efficacy of the catalyst. The
relative and absolute configurations of the products were
determined by X-ray crystal structure analysis of 4e (see the
Supporting Informationz).
Notes and references
1 (a) G. P. Ellis and I. M. Lockhart in Chromans and Tocopherols,
Wiley-Interscience, New York, 1981; (b) E. E. Schweizer and
O. Meeder-Nycz, in Chromenes, Chromanes, Chromones, ed.
G. P. Ellis, Wiley-Interscience, New York, 1977, pp. 11–139.
2 For examples, see: (a) R. Hiessbock, C. Wolf, E. Richter,
M. Hitzler, P. Chiba, M. Kratzel and G. Ecker, J. Med. Chem.,
1999, 42, 1921; (b) C. A. Lipinski, C. E. Aldinger, T. A. Beyer,
J. Bordner, D. F. Burdi, D. L. Bussolotti, P. B. Inskeep and
T. W. Siegel, J. Med. Chem., 1992, 35, 2169; (c) N. Cohen,
G. Weber, B. L. Banner, R. J. Lopresti, B. Schaer, A. Focella,
G. B. Zenchoff, A. Chiu, L. Todaro, M. O’Donnell, A. F. Welton,
D. Brown, R. Garippa, H. Crowley and D. W. Morgan, J. Med.
Chem., 1989, 32, 1842.
With these novel functionalized chromanes in hand, we
decided to evaluate their preliminary biological activities. A
summary of the IC50 values is shown in Table 4. At first,
chromane (2R,4S)-4a was prepared to test the cytotoxic
activity against six different types of tumor cell lines by using
the MTT assay. Excitingly, the results showed that (2R,4S)-4a
displayed some cytotoxic effect against six different types of
tumor cell lines (IC50: 46.852–60.233 mM Lꢀ1). We questioned
whether other substituted analogues would show a more powerful
anticancer effect. Subsequently, four other representative functio-
nalized chromanes 4d, 4e, 4i and 4j with the same configuration
were synthesized in the presence of catalyst 1d. The results of the
cytotoxic activity evaluation were quite revealing in that although
4j showed the weaker inhibitory activity with IC50 values of
38.128 mM Lꢀ1 and 40.056 mM Lꢀ1 on Hela and HepG-2,
respectively, the moderate anticancer potencies on PC-3 (IC50:
19.103 mM Lꢀ1) and Jurkat (IC50: 18.389 mM Lꢀ1) were still
observed. In addition, the opposite enantiomers of corresponding
compounds also were tested (see the Supporting Informationz).
In conclusion, we have disclosed the synthesis of various
potentially bioactive chiral functionalized chromanes with high
3 G. W. Burton and K. U. Ingold, Acc. Chem. Res., 1986, 19, 194, and
references therein.
4 For reviews concerning amine–thiourea catalysis, see: (a) A. G. Doyle
and E. N. Jacobsen, Chem. Rev., 2007, 107, 5713; (b) S. J. Connon,
Chem.–Eur. J., 2006, 12, 5418; (c) M. S. Taylor and E. N. Jacobsen,
Angew. Chem., Int. Ed., 2006, 45, 1520; (d) Y. Takemoto, Org. Biomol.
Chem., 2005, 3, 4299.
5 For rosin-derived thiourea, see: X. X. Jiang, Y. F. Zhang,
A. S. C. Chan and R. Wang, Org. Lett., 2009, 11, 153.
6 (a) X. X. Jiang, Y. M. Cao, Y. Q. Wang, L. P. Liu, F. F. Shen and
R. Wang, J. Am. Chem. Soc., 2010, 132, 15328; (b) X. X. Jiang,
D. Fu, G. Zhang, Y. M. Cao, L. P. Liu and R. Wang,
Chem. Commun., 2010, 46, 4294; (c) X. X. Jiang, G. Zhang,
D. Fu, Y. M. Cao, F. F. Shen and R. Wang, Org. Lett.,
2010, 12, 1544; (d) X. X. Jiang, Y. F. Zhang, X. Liu, G. Zhang,
L. H. Lai, L. P. Wu, J. N. Zhang and R. Wang, J. Org. Chem., 2009,
74, 5562.
7 For selected examples of b,g-unsaturated a-ketoesters in reactions,
see: (a) Z. Xu, L. Liu, K. Wheeler and H. Wang, Angew. Chem., Int.
Ed., 2011, 50, 3484; (b) F. Gallier, H. Hussain, A. Martel,
A. Kirschning and G. Dujardin, Org. Lett., 2009, 11,
3060; (c) R. P. Herrera, D. Monge, E. Martin-Zamora,
R. Fernandez and J. M. Lassaletta, Org. Lett., 2007, 9, 3303;
(d) G. Gaulon, R. Dhal, T. Chapin, V. Maisonneuve and
G. Dujardin, J. Org. Chem., 2004, 69, 4192; (e) K. Juhl and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2003, 42, 1498;
(f) A. Arbore, G. Dujardin and C. Maignan, Eur. J. Org. Chem.,
2003, 4118; (g) N. Halland, T. Velgaard and K. A. Jørgensen,
J. Org. Chem., 2003, 68, 5067.
8 For recent reviews of the Friedel–Crafts alkylation reaction, see:
(a) T. B. Poulsen and K. A. Jørgensen, Chem. Rev., 2008, 108, 2903;
(b) M. Bandini, A. Melloni, S. Tommasi and A. Umani-Ronchi,
Synlett, 2005, 1199; (c) M. Bandini, A. Melloni and A. Umani-Ronchi,
Angew. Chem., Int. Ed., 2004, 43, 550; (d) K. A. Jørgensen, Synthesis,
2003, 1117.
9 Selected examples of b,g-unsaturated a-ketoesters in Friedel–
Craft-type reactions, see: Supplementary reference 3z.
Table 4 In vitro anticancer activity of functionalized chromanes
IC50(mM)a
4a
4d
4e
4i
4j
Comp.
HELA
HepG-2
U251
MDA-MB-231
PC-3
Jurkat
60.233
56.250
50.023
52.231
49.026
46.852
53.256
41.589
48.052
48.013
42.105
40.029
43.422
37.569
35.041
36.230
30.125
26.257
40.352
43.024
26.782
35.563
26.120
24.756
38.128
40.056
30.032
30.125
19.103
18.389
IC50 (mM Lꢀ1) is 50% inhibitory concentration and values are the
means of three experiments each done in duplicate.
a
c
448 Chem. Commun., 2012, 48, 446–448
This journal is The Royal Society of Chemistry 2012