Synthesis of catechins via thiourea/AuCl3-catalyzed cycloalkylation of aryl epoxides

Article abstract of DOI:10.1021/jo8005649

(Chemical Equation Presented) A diversity-oriented approach for the synthesis of structurally diverse catechins was achieved in good yields via thiourea/AuCl₃/AgOTf-catalyzed annulations of aryl epoxides under mild conditions. This new protocol provides a highly efficient entry to a library of catechins-derived natural products, notably anti-HIV agent 8-C-ascorbyl-(-)-epigallocatechin.

Full text of DOI:10.1021/jo8005649

Synthesis of Catechins via Thiourea/AuCl3-Catalyzed
Cycloalkylation of Aryl Epoxides
Yongxiang Liu, Xiben Li, Guang Lin, Zheng Xiang, Jing Xiang, Mingzhe Zhao,
Jiahua Chen,* and Zhen Yang*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing
National Laboratory for Molecular Science (BNLMS), College of Chemistry, and Laboratory of Chemical
Genomics, Shenzhen Graduate School, and State Key Laboratory of Natural and Biomimetic Drugs, School
of Pharmaceutical Science, Peking UniVersity, Beijing 100871, China
jhchen@pku.edu.cn; zyang@pku.edu.cn
ReceiVed March 12, 2008
A diversity-oriented approach for the synthesis of structurally diverse catechins was achieved in good
yields via thiourea/AuCl3/AgOTf-catalyzed annulations of aryl epoxides under mild conditions. This new
protocol provides a highly efficient entry to a library of catechins-derived natural products, notably anti-
HIV agent 8-C-ascorbyl-(-)-epigallocatechin.
Introduction
in many herb medical formulations6 and thus in recent years
have attracted intensive research activity directed toward their
efficient syntheses.7
Several approaches have been developed for the syntheses
of catechin and eipgallocatechin-3-gallate, as well as their other
derivatives.7 However, the development of flexible strategy that
Catechin is a ubiquitous structural motif found in numerous
naturally occurring molecules, particularly those abundant in
green teas and red wines (Figure 1).1 The biological activities
of these compounds are very wide-ranging, including antioxi-
dative,2 anticarcinogenic,3 antiarteriosclerotic,4 and antibacterial
effects.5 These compounds have long served as key components
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J., Jr J. Org. Chem. 2003, 68, 1641. (m) Ohmori, K.; Hatakeyama, K.; Ohrui,
H.; Suzuki, K. Tetrahedron 2004, 60, 1365. (n) Ohmori, K.; Ushimaru, N.;
Suzuki, K. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12002. (o) Anderson, J. C.;
Headley, C.; Stapleton, P. D.; Taylor, P. W. Tetrahedron 2005, 61, 7703. (p)
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H.-J.; Kang, S.; Day, D. F.; Kim, D. J. Agric. Food Chem. 2006, 54, 1230. (q)
Hayes, C. J.; Whittaker, B. P.; Watson, S. A.; Grabowska, A. M. J. Org. Chem.
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10.1021/jo8005649 CCC: $40.75
Published on Web 05/23/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4625–4629 4625

Liu et al.
SCHEME 1. Au-Catalyzed Annulations
SCHEME 2
FIGURE 1. Catechin and its related natural products.
allows regio- and stereoselective construction of multisubstituted
catechins with the defined configuration at the C-2 and C-3
positions (Figure 1) employing versatile building blocks is highly
desirable.
the intermediate E could be prepared via a tosylate-mediated
cyclization reaction from diol F, which in turn could be readily
accessed through nucleophilic addition of phenol H to epoxide
G.13
The original catalytic reaction protocol, however, could not
be directly applied to the synthesis of catechins with regard to
the existence of the liable benzylic ether moiety (Scheme 2)
which might undergo decomposition when exposed to Lewis
acid AuCl3.14 Herein, we describe that thiourea is a unique
ligand that can moderate the Lewis acidity of AuCl3/AgOTf,
thereby realizing a concise route to generate catechins from
benzylic ether-based aryl epoxides. That method constitutes a
novel and complementary route to biologically important
catechins.
Recently, the development of C-H activation/C-C bond-
forming reactions catalyzed by transition metals has received
much attention.8 As a result, a wide range of metal-catalyzed
C-H cycloarylations has been applied to the syntheses of
structurally diverse scaffolds.9 In this context, the electronically
soft AuCl3 had been shown to be capable of forming arylgol-
d(III) complexes with aromatic groups under anhydrous condi-
tions,10 and this remarkable activity is presumably responsible
for the facile conversion of epoxide A into 3-chromanol B that
was discovered by Shi and He in 2004.11 Its mechanistic course
was conceived to involve an Au-mediated aryl C-H function-
alization.12
Inspired by the versatility of this Au-catalyzed cycloarylation,
we wished to use this annulation reaction to synthesize catechin
scaffold D from its precursor E (Scheme 1). Retrosynthetically,
Results and Discussion
We studied the Au-catalyzed annulation with 11 as a substrate
in which the two aromatic rings are electronically biased in such
a way that the more electronic-rich ring A should preferentially
interact with an incoming Au complex to initiate the desired
annulation process in a regioselective manner. The preparation
of 11 is illustrated in Scheme 3. Starting from benzaldehyde,
the epoxide 8 was synthesized in 68% yield via an olefination-
reduction-epoxidation sequence and was next combined with
phenol 9 to give diol 10 in 75% yield under sonication
conditions.15 Intramolecular displacement of the monotosylate
of 10 thus yielded cleanly 11 in 82% yield.
With substrate 11 in hand, we then set out to investigate its
Au-catalyzed annulation, and profiled its reaction under various
conditions. We found that in most of the cases the starting
material 11 underwent decomposition, and only complex
mixtures were obtained, presumably because of the liability of
benzylic ether moiety in the substrate toward the Au catalyst.
(8) (a) Dyker, G. Angew. Chem., Int. Ed. Engl. 1994, 33, 103. (b) Jia, C.;
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4626 J. Org. Chem. Vol. 73, No. 12, 2008

Synthesis of Structurally DiVerse Catechins
SCHEME 3. Synthesis of Compound 11 and Its
Au-Catalyzed Cycloalkylations
However, when the reaction was carried out in ClCH2CH2Cl at
50 °C for 4 h in the presence of AuCl3/AgOTf (5 mol %), the
expected product 12 with an endo-selectivity11 was indeed
obtained, but in merely 20% yield.
To improve the reactivity, we resort to electronic tuning of
the Au catalyst through its ligation with several ligands, such
as lutidine,12d Ph3P,16 PCy3, BINAP, bisoxazoline,17 and thio-
ureas A-C.18 The performance of these complexes was next
screened in a variety of solvents including THF, benzene,
toluene, DMF, DMSO, CH3CN, CH2Cl2, and ClCH2CH2Cl.
Gratifyingly, the best result was obtained when AuCl3/AgOTf/
thiourea A was utilized, and the desired product 12 was formed
in 65% yield (Scheme 3). It is worthwhile to note that the
complexes generated from AuCl3/AgOTf with thioureas B and
C gave the lower yields of product 12 (in 52% and 45% yields,
respectively), indicating that the oxazoline part of thiourea A
is essential to get the higher yield (Scheme 3).
We reasoned that the beneficial effect of ligand A on the
reaction could be derived from its steric effect and bidentate
coordination feature, which might stabilize the metal complexes
in ClCH2CH2Cl. Although CH2Cl2 shares the similar polarity
feature with ClCH2CH2Cl, its low boiling point prevents it from
being used at higher temperature. For other polar solvents (such
as THF, DMF, DMSO, CH3CN), the low yields in those
reactions might be due to their destabilizing effect on the
formation of metal complexes, which might cause the catalyst
precipitation.
With this promising initial result, we embarked on a
systematic evaluation of the catalytic system in a variety of
substituted aryl epoxides. To our delight, all the selected
substrates gave good yields and the reaction went to completion
at 50 °C in less than 24 h. The formation of catechins bearing
electron-withdrawing groups on the aryl B-ring proceeded in
high yields (entries 3-12). It is worthwhile to mention that the
products with halogens could be potentially used to generate
molecular complexity and diversity via metal-catalyzed coupling
reactions.
We next examined the dependence of the reaction yield and
regioselectivity on substrates bearing an asymmetrically sub-
stituted A-ring. The reaction mechanistic scenario suggests that
a decreased electron density on the A-ring would weaken the
splitting of C-H on the Au center and thus retard the reaction
progress. In fact, when eight additional substrates 11m-11t with
no or only one alkoxy group on the A-ring were selected and
annulated in this process, the reaction speed decreased substan-
tially and little product was formed under conditions employed
previously in Table 1, although more product could be obtained
at higher temperature and/or with longer time (Table 2). In all
cases, the cycloalkylation occurred preferentially at less-hindered
aryl ring site.
significant ligand effect on tuning the reactivity of the catalysts.
Noticing scarce studies on the ligand effect in the Au(III)-
catalyzed reactions, we hope our results can benefit other types
of Au(III)-catalyzed reactions applied in complex natural product
syntheses. Moreover, the constructed catechins are endowed with
suitable functionalities that are amenable for further structural
elaboration toward more complex molecules with useful bio-
logical activities. Integration of this robust method in the
asymmetric synthesis of a library of 8-C-ascorbyl-(-)-epigal-
locatechin19 from chiral epoxides generated by Sharpless
epoxidation20 is currently underway in our laboratory and will
be reported in due course.
Experimental Section
Additional information regarding the synthesis is provided in
Supporting Information.
General Procedure for the Syntheses of Epoxides 11a-3 to
11i-3. To a suspension of sodium hydride (0.96 g, 60% in mineral
oil, 24 mmol) in anhydrous THF (15 mL) was added triethyl
phosphonoacetate (4.0 mL, 20 mmol) dropwise at 0 °C under N2,
and the mixture was stirred at the same temperature for 30 min.
To above solution was added a solution of aldehyde (20 mmol) in
THF (10 mL) via a cannula, and the reaction mixture was warmed
to room temperature and stirred for 4.0 h. The reaction was worked
up by addition of a saturated aqueous NaHCO3 solution (50 mL),
the formed organic layer was separated, and the aqueous layer was
then extracted with EtOAc (3 × 50 mL). The combined organic
layer was washed with brine (3 × 30 mL) and dried over anhydrous
In summary, we have reported here for the first time the Au-
catalyzed cycloalkylation of aryl epoxides to generate a variety
of catechins in the presence of thiourea A and demonstrated
(16) (a) Woehrle, G. H.; Warner, M. G.; Hutchison, J. E. J. Phys. Chem. B
2002, 106, 9979. (b) Bartlett, P. A.; Bauer, B.; Singer, S. J. J. Am. Chem. Soc.
1978, 100, 5085.
(17) Guan, B.; Xing, D.; Cai, G.; Wan, X.; Yu, N.; Fang, Z.; Yang, L.; Shi,
Z. J. Am. Chem. Soc. 2005, 127, 18004.
(19) (a) Hashimoto, F.; Nonaka, G-I.; Nishioka, I. Chem. Pharm. Bull. 1989,
37, 3255. (b) Hashimoto, F.; Kashiwada, Y. F.; Nonaka, G-I.; Nishioka, I.;
Nohara, T.; Cosentino, L. M.; Lee, K-H. Bioorg. Med. Chem. Lett. 1996, 6,
695–700.
(18) (a) Armer, B.; Schmidbaur, H. Angew. Chem., Int. Ed. Engl. 1970, 9,
101. (b) Schmidbaur, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 728. (c) Dai,
M.; Liang, B.; Wang, C.; Chen, J.; Yang, Z. Org. Lett. 2004, 6, 221. (d) Liang,
B.; Liu, J.; Gao, Y.; Wongkhan, K.; Shu, D.; Lan, Y.; Li, A.; Batsanov, A. S.;
Howard, J. A. H.; Marder, T. B.; Chen, J.; Yang, Z. Organometallics 2007, 26,
4756.
(20) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless,
K. B. J. Am. Chem. Soc. 1987, 109, 5765.
J. Org. Chem. Vol. 73, No. 12, 2008 4627

Liu et al.
TABLE 1. Syntheses of Type-I Catechins
TABLE 2. Syntheses of Type-II Catechins
mixture was then stirred at the same temperature until the reaction
was completed. The reaction was worked up by careful addition
of a saturated aqueous solution of Rochelle salt (100 mL), and the
formed mixture was stirred until two phases became clear. The
aqueous layer was first extracted with EtOAc (3 × 50 mL), then
washed with brine (3 × 30 mL), and finally dried over anhydrous
Na2SO4. The solvent was removed under vacuum, and the residue
was then dissolved in CH2Cl2. To this solution was added m-CPBA
(6.9 g, 30 mmol) in a portion-wise manner at 0 °C, and the mixture
was stirred at the same temperature for 3 h. The reaction was
worked up by addition of a solution of NaHCO3 (30% aqueous
solution, 100 mL), and the formed aqueous phase was first extracted
with EtOAc (3 × 50 mL). The combined organic phase was first
washed with brine (3 × 30 mL) and then dried over anhydrous
Na2SO4. The solvent was removed under vacuum, and the residue
was purified by a flash chromatography on silica gel to give the
desired product.
Na2SO4. The solvent was removed under vacuum, and the residue
was used in the next step without further purification.
To a solution of the ester (20 mmol) generated above in dry
CH2Cl2 (25 mL) was added DIBAL-H (50 mL, 1.0 M in hexane,
50 mmol) in a dropwise manner at -78 °C under N2, and the
Synthesis of rac-(2S,3S)-3-(3-Methoxyphenyl)-oxiran-2-yl
Methanol (11a-3). The residue was purified by a flash chroma-
tography on silica gel (petroleum ether/ethyl acetate ) 3/1) to give
product 11a-3 (2.95 g) in 82% yield; 1H NMR (300 MHz, CDCl3)
4628 J. Org. Chem. Vol. 73, No. 12, 2008

Synthesis of Structurally DiVerse Catechins
δ 7.27 (t, J ) 7.8 Hz, 1H), 6.78-6.91 (m, 3H), 4.06 (dd, J1 ) 2.1
Hz, J2 ) 1.6 Hz, 1H), 3.92 (d, J ) 2.1 Hz, 1H), 3.83 (s, 3H), 3.22
(dd, J1 ) 3.9 Hz, J2 ) 2.4 Hz, 1H), 2.10 (br, 1H); 13C NMR (75
MHz, CDCl3) δ 159.5, 138.1, 129.3, 117.9, 113.7, 110.5, 62.4, 61.1,
55.4, 54.9; MS (EI) calcd for C10H12O3 (M+) 180, found 180.
General Procedure for the Syntheses of Diols 11a-4 to
11t-4. To a solution of phenol (12 mmol) in CH2Cl2 (20 mL) and
H2O (5 mL) was added sodium hydroxide (0.48 g, 12 mmol) and
tetrabutyl ammonium chloride (0.56 g, 2.0 mmol) at room tem-
perature, and the mixture was stirred at the same temperature for
0.5 h. To the mixture was added a solution of epoxides 11a-3 to
11i-3 (10 mmol) in CH2Cl2 (10 mL), and the mixture was then
stirred at 65 °C for 6 h. After cooling to room temperature, the
reaction was quenched by addition of brine (25 mL), and the formed
mixture was extracted with EtOAc (3 × 40 mL). The combined
organic phase was washed with water (2 × 30 mL) and dried over
anhydrous Na2SO4. The solvent was removed under vacuum, and
the residue was purified by a flash chromatography on silica gel to
give the desired product.
General Procedure for the Syntheses of Catechins 12,
12a-12i, 12ma-12ta, 12mb-12rb. A mixture of thiourea A (0.06
mmol), AgOTf (0.15 mmol), and AuCl3 (0.05 mmol) in
ClCH2CH2Cl (3 mL) was stirred at room temperature under N2 for
1 h. A solution of aryl epoxide (1.0 mmol) in ClCH2CH2Cl (2 mL)
was added, and the reaction was warmed to 50 °C and stirred until
completion. The mixture was then concentrated, and the residue
was filtered through a pad of silica gel and washed with EtOAc.
The filtrate was concentrated, and the residue was purified by silica
gel flash chromatography.
Synthesis of rac-(2R,3S)-5,7-Dimethoxy-2-(3-methoxy-phen-
yl)-chroman-3-ol (12a). The residue was purified by a flash
chromatography on silica gel (petroleum ether/ethyl acetate ) 5/1)
1
to give product 12a (0.158 g) in 50% yield; H NMR (300 MHz,
CDCl3) δ 7.32 (t, J ) 7.8 Hz, 1H), 7.02 (d, J ) 7.8 Hz, 1H), 6.99
(m, 1H), 6.90 (ddd, J1 ) 8.1 Hz, J2 ) 2.7 Hz, J3 ) 0.9 Hz, 1H),
6.15 (d, J ) 2.4 Hz, 1H), 6.11 (d, J ) 2.4 Hz, 1H), 4.75 (d, J )
8.1 Hz, 1H), 4.07-4.11 (m, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.76
(s, 3H), 3.01 (dd, J1 ) 16.5 Hz, J2 ) 5.7 Hz, 1H), 2.62 (dd, J1 )
16.5 Hz, J2 ) 8.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 159.7,
159.5, 158.6, 154.9, 139.7, 129.6, 119.2, 113.9, 112.4, 101.3, 92.8,
91.7, 81.4, 67.9, 55.3, 55.2, 55.1, 27.1; HRMS (EI) calcd for
C18H20O5 (M+) 316.1311, found 316.1314.
Synthesis of rac-(2S,3R)-3-(3,5-Dimethoxyphenoxy)-3-(3-
methoxyphenyl)-propane-1,2-diol (11a-4). The residue was puri-
fied by a flash chromatography on silica gel (petroleum ether/ethyl
1
acetate ) 1/1) to give product 11a-4 (2.00 g) in 60% yield; H
Syntheses of rac-(2R,3S)-2-(3,5-Bis(benzyloxy)-phenyl)-7-
methoxychroman-3-ol (12ma) and rac-(2R,3S)-2-(3,5-Bis(ben-
zyloxy)-phenyl)-5-methoxy chroman-3-ol (12mb). The reaction
was carried out at 80 °C for 24 h, and the residue was purified by
a flash chromatography on silica gel (petroleum ether/ethyl acetate
) 7/1) to give product 12ma (0.192 g) in 41% yield and compound
NMR (300 MHz, CDCl3) δ 7.30 (d, J ) 7.8 Hz, 1H), 6.97 (d, J )
7.8 Hz, 1H), 6.92 (t, J ) 2.4 Hz, 1H), 6.84 (ddd, J1 ) 8.4 Hz, J2
) 2.7 Hz, J3 ) 0.9 Hz, 1H), 6.03 (s, 3H), 2.22 (d, J ) 5.7 Hz,
1H), 2.05 (t, J ) 5.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 161.3,
159.9, 159.3, 139.3, 129.9, 119.0, 113.5, 112.3, 94.7, 93.4, 80.6,
74.7, 62.8, 55.2, 55.1; MS (EI) calcd for C18H22O6 (M+) 334, found
334.
1
12mb (0.042 g, 9% yield). For compound 12ma: H NMR (300
MHz, CDCl3) δ 7.31-7.43 (m, 10H), 7.00 (d, J ) 8.4 Hz, 1H),
6.69 (d, J ) 2.1 Hz, 2H), 6.62 (t, J ) 2.1 Hz, 1H), 6.49-6.54 (m,
2H), 5.03 (s, 4 H), 4.73 (d, J ) 7.8 Hz, 1H), 4.07 (dt, J1 ) 5.1 Hz,
J2 ) 8.4 Hz, 1H), 3.77 (s, 3H), 3.01 (dd, J1 ) 15.6 Hz, J2 ) 5.1
Hz, 1H), 2.82 (dd, J1 ) 15.6 Hz, J2 ) 8.7 Hz, 1H), 1.82 (br, 1H);
13C NMR (75 MHz, CDCl3) δ 160.1, 159.2, 154.4, 140.4, 136.5,
130.4, 128.5, 128.0, 127.5, 111.8, 108.0, 106.0, 102.0, 101.1, 81.1,
70.0, 68.0, 55.2, 31.9; HRMS (EI) calcd for C30H28O5 (M+)
General Procedures for the Syntheses of Epoxides 11a-11t.
To a solution of the diol (5 mmol) in dry pyridine (10 mL) was
added p-toluenesulfonyl chloride (0.95 g, 5 mmol) in a portionwise
manner at 0 °C, and the resulted mixture was stirred at room
temperature overnight. The reaction was worked up by addition of
aqueous HCl solution (1 M, 50 mL), and the aqueous phase was
extracted with EtOAc (3 × 20 mL). The combined organic phase
was sequentially washed with brine (2 × 20 mL), 30% aqueous
solution of NaHCO3 (2 × 20 mL), and brine (2 × 20 mL) and
finally dried over anhydrous Na2SO4. The solvent was removed
under vacuum, and the residue was dissolved in dry methanol (15
mL). To this solution was added K2CO3 (0.83 g, 6.0 mmol), and
the formed mixture was stirred at room temperature for 4 h. The
reaction was worked up by addition of water, and the formed
aqueous phase was extracted with ether (3 × 20 mL). The combined
organic phase was washed with brine (3 × 15 mL) and dried over
anhydrous Na2SO4. The solvent was removed under vacuum, and
the residue was purified by a flash chromatography to give the
product.
1
468.1937, found 468.1941. For compound 12mb: H NMR (300
MHz, CDCl3) δ 7.29-7.43 (m, 10H), 7.12 (t, J ) 8.1 Hz, 1H),
6.70 (d, J ) 2.1 Hz, 2H), 6.58-6.62 (m, 2H), 6.48 (d, J ) 8.1 Hz,
1H), 5.03 (s, 4H), 4.68 (d, J ) 8.4 Hz, 1H), 4.05-4.07 (m, 1H),
3.84 (s, 3H), 3.08 (dd, J1 ) 16.8 Hz, J2 ) 5.7 Hz, 1H), 2.66 (dd,
J1 ) 16.8 Hz, J2 ) 9.0 Hz, 1H), 1.73 (d, J ) 3.6 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 160.2, 159.3, 154.5, 140.3, 136.5, 130.4,
128.6, 128.1, 127.6, 111.8, 108.2, 106.0, 102.2, 101.2, 81.8, 70.1,
68.2, 32.0; HRMS (EI) calcd for C30H28O5 (M+) 468.1937, found
468.1943.
Acknowledgment. We gratefully acknowledge financial
support by the National Science Foundation of China (Grants
20672004, 20521202). We also thank Professor David Zhigang
Wang of the Laboratory of Chemical Genomics of Peking
University for useful discussion.
Synthesis of rac-(S)-(2-(R)-(3,5-dimethoxyphenoxy)-(3-meth-
oxyphenyl)-methyl)-oxirane (11a). The residue was purified by a
flash chromatography on silica gel (petroleum ether/ethyl acetate
) 5/1) to give product 11a (0.885 g) in 56% yield; 1H NMR (300
MHz, CDCl3) δ 7.28 (t, J ) 8.1 Hz, 1H), 6.95-7.00 (m, 1H), 6.85
(dd, J1 ) 8.4 Hz, J2 ) 2.7 Hz, 1H), 6.03-6.06 (m, 1H), 5.06 (d,
J ) 4.2 Hz, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.32 (dd, J1 ) 7.2 Hz,
J2 ) 3.3 Hz, 1H), 2.83 (d, J ) 3.0 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 161.2, 159.7, 159.3, 138.9, 129.6, 118.9, 113.6, 112.2,
94.8, 93.4, 78.8, 55.1, 55.0, 54.2, 44.9; MS (EI) calcd for C18H20O5
(M+) 316, found 316.
Supporting Information Available: Experimental procedure
and 1H NMR and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO8005649
J. Org. Chem. Vol. 73, No. 12, 2008 4629