Enantioselective 6-endo-trig Wacker-type cyclization of 2-geranylphenols: Application to a facile synthesis of (-)-cordiachromene

Article abstract of DOI:10.1016/j.tetasy.2010.04.060

An enantioselective intramolecular oxidative cyclization of 2-geranylphenols catalyzed by a Pd(II)-spiro bis(isoxazoline) complex is reported. The reaction proceeds in a 6-endo-trig manner to give chromene derivatives in reasonable yields and with moderate enantioselectivities. This transformation can be applied to a protecting-group-free total synthesis of naturally occurring cordiachromene.

Full text of DOI:10.1016/j.tetasy.2010.04.060

Tetrahedron: Asymmetry 21 (2010) 767–770
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Enantioselective 6-endo-trig Wacker-type cyclization of 2-geranylphenols:
application to a facile synthesis of (ꢀ)-cordiachromene
Kazuhiro Takenaka, Yugo Tanigaki, Mahesh L. Patil, C. V. Laxman Rao, Shinobu Takizawa, Takeyuki Suzuki,
*
Hiroaki Sasai
The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki, Osaka 567-0047, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective intramolecular oxidative cyclization of 2-geranylphenols catalyzed by a Pd(II)-spiro
bis(isoxazoline) complex is reported. The reaction proceeds in a 6-endo-trig manner to give chromene
derivatives in reasonable yields and with moderate enantioselectivities. This transformation can be
applied to a protecting-group-free total synthesis of naturally occurring cordiachromene.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 13 March 2010
Accepted 5 April 2010
Available online 1 June 2010
1. Introduction
cyclization product 2b was also formed in 11% yield, albeit with
a lower stereoselectivity. Effective chiral ligands for asymmetric
An intramolecular oxidative cyclization catalyzed by a palla-
dium complex, referred to as the Wacker-type cyclization, is one
of the most versatile methods for the preparation of heterocycles.1
Among them, reactions of 2-allylphenol substrates 1 have been
extensively investigated and developed to asymmetric synthesis.2
Such cyclizations usually proceed in a 5-exo-trig fashion to give
dihydrobenzofuran derivatives 2 (Scheme 1a). In contrast, there
are only a few examples of a 6-endo-trig Wacker-type cyclization
constructing a benzopyran (chromene) skeleton 3 (Scheme 1b).3
Chromenes are ubiquitous structural units found in physiologically
active compounds4 and are also useful intermediates in the synthe-
sis of natural products.5 Although enantioselective 6-endo-trig
Wacker-type cyclizations are expected to be a powerful tool for
the preparation of optically active chromenes, no such reports have
been published yet. Herein, we report an enantioselective synthe-
sis of chromene derivatives via a 6-endo-trig Wacker-type cycliza-
tion of 2-geranylphenols. This transformation can be applied to a
protecting-group-free total synthesis6 of cordiachromene 3a.
5-exo-trig cyclizations of 2-allylphenols, (S,S)-i-Pr-BOXAX 52b–e
and (ꢀ)-sparteine 6,2f,g did not promote the reaction enantioselec-
tively (entries 2 and 3). Pd complex 7, which is known to be a valu-
able catalyst for enantioselective Wacker-type cyclizations,2a gave
a trace amount of racemic 3b (entry 4). Furthermore, other chiral
ligands (R,R)-Bn-BOX 8 and (S)-BINAP 9 did not work under these
conditions (entries 5 and 6). When the reaction was conducted
without any chiral ligands, only 15% yield of 3b was obtained (en-
try 7). This background process would be a major pathway for the
formation of racemic 3b in entries 2–6. These results obviously
demonstrate the high utility of SPRIX for the enantioselective
6-endo-trig Wacker-type cyclization.
Cordiachromene 3a was first isolated from an American tree
Cordia alliodora,10 and later from Aplidium constellatum,11 Aplidium
antillense,12 and Aplidium multiplicatium.13 This chromene displays
H
a) 5-exo-trig
R
∗
O
2. Results and discussion
2
R
a)
Firstly, we examined several chiral ligands for an enantioselec-
tive Wacker-type cyclization using 2-geranylphenol 1b as a model
substrate (Table 1).7 We were pleased to find the formation of the
desired optically active chromene product 3b with a spiro bis(isox-
azoline) ligand (SPRIX).8,9 Thus, the reaction of 1b in the presence
of 10 mol % of Pd(OCOCF3)2, 11 mol % of (P,R,R)-i-Pr-SPRIX 4, and
4 equiv of p-benzoquinone in Cl2CHCHCl2 at 60 °C for 24 h afforded
3b in 55% yield with 54% ee (entry 1). In this reaction, 5-exo-trig
OH
b)
b) 6-endo-trig
∗
1
O
3
R
HO
O
cordiachromene 3a
* Corresponding author. Tel.: +81 6 6879 8465; fax: +81 6 6879 8469.
E-mail addresses: sasai@sanken.osaka-u.ac.jp, hsasai@mac.com (H. Sasai).
Scheme 1. Wacker-type cyclization of 2-allylphenol derivatives.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.060

768
K. Takenaka et al. / Tetrahedron: Asymmetry 21 (2010) 767–770
Table 1
Screening of catalyst systems in the enantioselective intramolecular Wacker-type cyclization of 1ba
H
R
Pd(OCOCF3)2 (10 mol %)
chiral ligand (11 mol %)
p-benzoquinone (4 equiv)
∗
O
2b
+
R
Cl2CHCHCl2 (0.3 M)
OH
1b
60 ºC, 24 h
in the dark
∗
O
R
3b
R =
Entry
Chiral ligand
Conv.b (%)
Yieldb (%)
eec (%)
2b
3b
2b
3b
1
2
3
4
5
6
7
4
5
100
48
58
79
24
36
61
11
5
7
0
0
55
19
19
5
15
17
15
18
<5
<5
–
–
–
54
rac
rac
rac
rac
rac
–
6
7d
8
9
0
0
None
–
O
N
P
i-Pr
i-Pr
N
O
H
R
R
H
N
N
i-Pr
i-Pr
i-Pr
i-Pr
N
N
O
O
(P,R,R)-i-Pr-SPRIX 4
(S,S)-i-Pr-BOXAX 5
(—)-sparteine 6
PPh2
PPh2
O
O
OAc
Pd
N
N
2
Bn
Bn
7
(R,R)-Bn-BOX 8
(S)-BINAP 9
a
All reactions were carried out in the presence of 10 mol % of Pd(OCOCF3)2, 11 mol % of chiral ligand, and 4 equiv of p-benzoquinone at 60 °C for 24 h in Cl2CHCHCl2 (0.3 M)
under a nitrogen atmosphere in the dark.
b
Determined by 1H NMR spectroscopy.
Determined by HPLC analysis.
10 mol % of chiral complex 7 was used instead of Pd(OCOCF3)2.
c
d
antibacterial activity against Staphylococcus aureus12 and anti-
inflammatory activity.14 The asymmetric total synthesis of 3a has
been achieved by utilizing the Sharpless enantioselective epoxida-
tion15 or lipase-catalyzed kinetic resolution of racemic acetates.16
Both of these strategies provided the target product in reasonable
yields with high enantiomeric purities, but they required a lengthy
synthetic sequence. Toward an application of the Pd-catalyzed oxi-
dative 6-endo-trig cyclization for the facile synthesis of 3a, we
examined a variety of hydroquinone substrates protecting one hy-
droxy group. Representative results are shown in Table 2.17 In spite
of moderate chemical yields and enantioselectivities, products
3c–e having an ether group were obtained (entries 1–3). Acetal
functionality was tolerated as a protecting group for the phenol
component to produce 3f (entry 4). Reactions of ester-substituted
substrates 1g–j furnished the corresponding chromenes 3g–j in
30–52% yields (entries 5–8). 2-Geranylphenol 1k bearing a bromo
moiety convertible to a hydroxy group18 also participated in this
cyclization to give 3k in 46% yield with 55% ee (entry 9).
however, have proven to racemize under acidic and basic19 as well
as photochemical conditions.7,20 To avoid such a racemization, we
attempted to execute a protecting-group-free asymmetric synthe-
sis of cordiachromene, namely, direct conversion of non-protected
substrate 1a to 3a (Scheme 2).21 The precursor 1a was readily pre-
pared from hydroquinone and geraniol in the presence of BF3ꢁEt2O
in 34% yield.22 Disappointingly, we could not obtain 3a in an
acceptable yield under the catalytic conditions, due to an inevita-
ble oxidation of 1a into 2-geranylbenzoquinone.23 A stoichiometric
use of the Pd salt was eventually found to be operative for the
cyclization. Thus, 3a with 54% ee was isolated in 42% yield when
1a was treated with 1 equiv of Pd(OCOCF3)2 and 1.1 equiv of
(P,R,R)-4 at 60 °C for 2 h (Scheme 2).24 The absolute configuration
of the resulting 3a was assigned to be (R) by comparison of the sign
of the specific rotation with the reported value.15,16
This enantioselective 6-endo-trig cyclization of 1 seems to pro-
ceed through a general catalytic cycle of Wacker-type reaction,
that is, an initial coordination of the olefin to Pd(II), a subsequent
intramolecular attack of the nucleophile, and a final b-hydride
elimination producing chromenes 3. From the results shown in
As shown in Table 2, the synthetic precursors 3c–k of cordia-
chromene were obtained in an optically active form. Chromenes,

K. Takenaka et al. / Tetrahedron: Asymmetry 21 (2010) 767–770
769
Table 2
Effect of substituents on the aromatic ring in the enantioselective intramolecular Wacker-type cyclization of 1a
R'
H
R
Pd(OCOCF3)2 (10 mol %)
(P,R,R)-4 (11 mol %)
p-benzoquinone (4 equiv)
∗
O
R'
R
2
+
ClCH2CH2Cl (0.3 M)
OH
R'
60 ºC, 24 h
1
in the dark
∗
O
R
R =
3
Entry
1
R0
Yieldb (%)
Ratio 2/3c
ee of 3d (%)
1
2
3
4
5
6
7
8
9
1c
1d
1e
1f
1g
1h
1i
BnO
MeO
TBSO
MOMO
PivO
BzO
BocO
TsO
Br
45 (24)
42 (19)
26 (15)
61 (33)
57 (35)
46 (37)
68 (52)
41 (30)
63 (46)
1/1.6
1/1.5
1/1.4
1/2.1
1/2.2
1/4.1
1/3.0
1/4.1
1/4.7
34
48
49
37
52
44
47
42
55
1j
1k
a
All reactions were carried out in the presence of 10 mol % of Pd(OCOCF3)2, 11 mol % of (P,R,R)-4, and 4 equiv of p-benzoquinone at 60 °C for 24 h in ClCH2CH2Cl (0.3 M)
under a nitrogen atmosphere in the dark. In each case, the starting material was almost consumed at the end of the reaction.
b
Combined yield determined by 1H NMR spectroscopy. Isolated yields for 3 are given in parentheses.
c
Determined by 1H NMR.
d
Determined by HPLC analysis.
HO
(4 equiv)
HO
HO
HO
BF3·Et2O (4 equiv)
1,4-dioxane (0.2 M)
rt, 6 h
OH
OH
1a
34%
Pd(OCOCF3)2 (100 mol %)
(P,R,R)-4 (110 mol %)
Cl2CHCHCl2 (0.1 M)
O
60 ºC, 2 h
in the dark
(R)-cordiachromene 3a
42%, 54% ee
Scheme 2. Asymmetric protecting-group-free short total synthesis of 3a.
icantly because of its strong Lewis acidity.9c A positive charge
X
X
induced on the C–C double bond is more stabilized at the carbon
atom possessing the two alkyl chains (Scheme 3). The nucleophilic
attack of the phenolic hydroxy group, therefore, takes place prefer-
entially at this carbon, leading to a 6-endo-trig cyclization.3a
N
N
∗
∗
X
X
Pd
Pd
N
N
δ+
R
R
OH
OH
unfavorable
5-exo-trig
3. Conclusion
favorable
In conclusion, we have developed an enantioselective 6-endo-trig
Wacker-type cyclization of 2-geranylphenols, where the SPRIX
ligand plays a crucial role for obtaining optically active chromene
derivatives. This reaction can be extended to a protecting-group-
free asymmetric synthesis of a natural product. (R)-Cordiachromene
was prepared in 14% overall yield over two steps from commercially
availableand cheap reagents. Further improvement of conditions for
this enantioselective Wacker-type cyclization is currently ongoing
in our group.
6-endo-trig
3
2
Scheme 3. Plausible description of the regioselectivity.
Table 1, the use of ligand 4 is essential for promoting this cycliza-
tion. Presumably, the Pd–SPRIX complex activates the olefin signif-

770
K. Takenaka et al. / Tetrahedron: Asymmetry 21 (2010) 767–770
15. Bouzbouz, S.; Goujon, J.-Y.; Deplanne, J.; Kirschleger, B. Eur. J. Org. Chem. 2000,
Acknowledgment
3223.
16. Goujon, J.-Y.; Zammattio, F.; Kirschleger, B. Tetrahedron: Asymmetry 2000, 11,
We thank the technical staff of the Comprehensive Analysis
Center of ISIR for their assistance.
2409.
17. Typical experimental procedure for the Pd-catalyzed oxidative cyclization of 1
(Table 2): Under a nitrogen atmosphere, a solution of Pd(OCOCF3)2 (2.5 mg,
10 mol %) and (P,R,R)-4 (3.1 mg, 11 mol %) in ClCH2CH2Cl (0.125 mL) was
stirred at 25 °C for 2 h. To the solution was added a solution of p-benzoquinone
(32.4 mg, 0.30 mmol) and 1 (17.3 mg, 0.075 mmol) in ClCH2CH2Cl (0.125 mL).
The reaction mixture was stirred at 60 °C for 24 h in the dark. After complete
consumption of 1, the resulting mixture was subjected to short column
chromatography on silica gel (eluent: ethyl acetate) and concentrated under
vacuum in the dark. Crude yield was determined by 1H NMR spectrum using p-
hydroxyacetophenone as an internal standard. The residue was purified by
preparative TLC in the dark to give dihydrobenzofuran 2 and chromene 3.
18. (a) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am. Chem. Soc.
2006, 128, 10694; (b) Gallon, B. J.; Kojima, R. W.; Kaner, R. B.; Diaconescu, P. L.
Angew. Chem., Int. Ed. 2007, 46, 7251; (c) Schulz, T.; Torborg, C.; Schäffner, B.;
Huang, J.; Zapf, A.; Kadyrov, R.; Börner, A.; Beller, M. Angew. Chem., Int. Ed.
2009, 48, 918; (d) Zhao, D.; Wu, N.; Zhang, S.; Xi, P.; Su, X.; Lan, J.; You, J. Angew.
Chem., Int. Ed. 2009, 48, 8729.
19. (a) Konoike, T.; Matsumura, K.; Yorifuji, T.; Shinomoto, S.; Ide, Y.; Ohya, T. J.
Org. Chem. 2002, 67, 7741; (b) Goujon, J.-Y.; Zammattio, F.; Chretien, J.-M.;
Beaudet, I. Tetrahedron 2004, 60, 4037.
20. We indeed observed photoracemization of the products 3b–k: for example, for
3k, 55% ee was diminished to 45% ee after 24 h upon irradiation with a (room)
light.
21. Pd-catalyzed non-enantioselective transformation of 1a to 3a has already been
reported. Racemic 3a was obtained in 18% yield by using PdCl2 (3 mol %) and
CuCl2 (10 mol %) under an O2 atmosphere. see: Iyer, M.; Trivedi, G. K. Synth.
Commun. 1990, 20, 1347.
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24. Experimental procedure for the synthesis of cordiachromene 3a (Scheme 2):
Under a nitrogen atmosphere, a solution of Pd(OCOCF3)2 (4.2 mg, 100 mol %)
and (P,R,R)-4 (5.2 mg, 110 mol %) in Cl2CHCH2Cl (0.06 mL) was stirred at 25 °C
for 6 h. To the solution was added a solution of 1a (3.1 mg, 0.0125 mmol) in
Cl2CHCHCl2 (0.06 mL). The reaction mixture was stirred at 60 °C for 2 h in the
dark. After complete consumption of 1a, the resulting mixture was directly
passed through a short pad of silica gel, which was rinsed with ethyl acetate.
The filtrate was evaporated to dryness in the dark. The crude product was
purified by preparative TLC (hexane/ethyl acetate = 10/1) in the dark to give
1.3 mg (42%) of (R)-3a as a yellow oil. The enantiomeric excess was determined
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[Chiralpak AD-H, hexane/i-PrOH = 40/1, flow rate = 0.5 mL/min, k = 335 nm:
52.0 min (minor) and 68.9 min (major)]. Analytical data for 3a: 1H NMR
(400 MHz, CDCl3): d 1.36 (s, 3H), 1.57 (s, 3H), 1.66 (s, 3H), 1.61–1.75 (m, 2H),
2.00–2.17 (m, 2H), 4.31 (br, 1H), 5.09 (t, J = 6.9 Hz, 1H), 5.60 (d, J = 9.9 Hz, 1H),
6.28 (d, J = 9.9 Hz, 1H), 6.48 (d, J = 2.9 Hz, 1H), 6.57 (dd, J = 8.7, 2.9 Hz, 1H), 6.64
(d, J = 8.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 17.6, 22.7, 25.7, 26.0, 40.9,
78.1, 112.8, 115.4, 116.7, 122.0, 122.6, 124.1, 131.0, 131.7, 147.0, 149.2. IR
(film): 422, 475, 659, 715, 815, 862, 922, 1078, 1200, 1333, 1384, 1456, 1486,
2350, 2863, 2923, 2968, 3359 cmꢀ1. HRMS (ESI): calcd for C32H40NaO4: m/z
13. Kim, I. K.; Park, S. K. Magn. Reson. Chem. 1993, 31, 788.
14. Benslimane, A. F.; Ponchus, Y. F.; Verbist, J. F.; Petit, J.-Y.; Brion, J. D.; Welin, L. J.
Clin. Pharmacol. 1995, 35, 298.
511.2824 ([2 M+Na]+), found: m/z 511.2838. ½a 2D5
ꢂ
¼ ꢀ58:1 (c 0.04, CHCl3) {lit16
½aꢂD ¼ ꢀ109:1 (c 0.95, CHCl3, 95% ee)}.