Chiral Lewis base-assisted Bronsted acid (LBBA)-catalyzed enantioselective cyclization of 2-geranylphenols

Article abstract of DOI:10.1021/ol201032t

Chiral Lewis base-assisted Bronsted acids (Chiral LBBAs) have been designed as new organocatalysts for biomimetic enantioselective cyclization. A salt of a chiral phosphonous acid diester with FSO₃H catalyzes the enantioselective cyclization of

Full text of DOI:10.1021/ol201032t

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3130–3133
Chiral Lewis Base-Assisted Brønsted
Acid (LBBA)-Catalyzed Enantioselective
Cyclization of 2-Geranylphenols
Akira Sakakura, Masayuki Sakuma, and Kazuaki Ishihara*
EcoTopia Science Institute, Graduate School of Engineering, and JST, CREST, Nagoya
University, Furo-cho, Chikusa, Nagoya, 464-8603, Japan
ishihara@cc.nagoya-u.ac.jp
Received April 18, 2011
ABSTRACT
Chiral Lewis base-assisted Brønsted acids (Chiral LBBAs) have been designed as new organocatalysts for biomimetic enantioselective
cyclization. A salt of a chiral phosphonous acid diester with FSO3H catalyzes the enantioselective cyclization of 2-geranylphenols to give the
desired trans-fused cyclized products with high diastereo- and enantioselectivities (up to 98:2 dr and 93% ee).
Biomimetic polyenecyclization ofisoprenoids isa highly
powerful method for constructing polycyclic structures of
terpenoids. Considerable effort has been focused on the
development of enantioselective polyene cyclizations using
a chiral artificial cyclase. Since the pioneering work on
Lewis acid-assisted Brønsted acid (LBA) catalysis by
Yamamoto and Ishihara,1ꢀ3 some elegant studies on en-
antioselective polyene cyclizations have been reported.4
We recently developed a chiral Lewis base-promoted
enantioselective iodocyclization of isoprenoids.5,6 The
(1) (a) Uyanik, M.; Ishihara, K.; Yamamoto, H. Bioorg. Med. Chem.
2005, 13, 5055. (b) Uyanik, M.; Ishibashi, H.; Ishihara, K.; Yamamoto,
H. Org. Lett. 2005, 7, 1601. (c) Ishibashi, H.; Ishihara, K.; Yamamoto,
H. J. Am. Chem. Soc. 2004, 126, 11122. (d) Kumazawa, K.; Ishihara, K.;
Yamamoto, H. Org. Lett. 2004, 6, 2551. (e) Ishihara, K.; Ishibashi, H.;
Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 3647. (f) Ishihara, K.;
Ishibashi, H.; Yamamoto, H. J. Am. Chem. Soc. 2001, 123, 1505.
(g) Nakamura, S.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc.
2000, 122, 8131. (h) Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am.
Chem. Soc. 1999, 121, 4906.
(2) For reports on asymmetric catalysis by chiral LBAs, see:
(a) Cheon, C. H.; Imahori, T.; Yamamoto, H. Chem. Commun. 2010,
46, 6980. (b) Repka, L. M.; Ni, J.; Reisman, S. E. J. Am. Chem. Chem.
2010, 132, 14418. (c) Upar, K. B.; Mishra, S. J.; Nalawade, S. P.; Singh,
S. A.; Khandare, R. P.; Bhat, S. V. Tetrahedron: Asymmetry 2009, 20,
1637. (d) Rauniyar, V.; Zhai, H.; Hall, D. G. J. Am. Chem. Soc. 2008,
130, 8481. (e) Yanagisawa, A.; Touge, T.; Arai, T. Angew. Chem., Int.
Ed. 2005, 44, 1546. (f) Ishihara, K.; Nakashima, D.; Hiraiwa, Y.;
Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 24. (g) Nakamura, S.;
Kaneeda, M.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122,
8120. (h) Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H.
J. Am. Chem. Soc. 1996, 118, 12854. (i) Ishihara, K.; Kaneeda, M.;
Yamamoto., H. J. Am. Chem. Soc. 1994, 116, 11179.
(4) (a) Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132,
5027. (b) Knowles, R. R.; Lin, S.; Jacobsen, E. N. J. Am. Chem. Soc.
2010, 132, 5030. (c) Zhao, Y.-J.; Li, B.; Tan, L.-J. S.; Shen, Z.-L.; Loh,
T.-P. J. Am. Chem. Soc. 2010, 132, 10242. (d) Mullen, C. A.; Campbell,
A. N.; Gagne, M. R. Angew. Chem., Int. Ed. 2008, 47, 6011. (e) Yang, D.;
Gu, S.; Yan, Y.-L.; Zhao, H.-W.; Zhu, N.-Y. Angew. Chem., Int. Ed.
2002, 41, 3014.
ꢀ
(5) (a) Sakakura, A.; Shomi, G.; Ukai, A.; Ishihara, K. Heterocycles
2011, 82, 249. (b) Sakakura, A.; Ishihara, K. Chimica Oggi-Chemistry Today
2007, 25, 9. (c) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900.
(6) For enantioselective halocyclizations, see: (a) Zhou, L.; Chen, J.;
Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc. 201110.1021/ja201627h.
€
(b) Hennecke, U.; M€uller, C. H.; Frohlich, R. Org. Lett. 2011, 13, 860.
(c) Jaganathan, A.; Garzan, A.; Whitehead, D. C.; Staples, R. J.; Borhan,
B. Angew. Chem., Int. Ed. 2011, 50, 2593. (d) Murai, K.; Matsushita, T.;
Nakamura, A.; Fukushima, S.; Shimura, M.; Fujioka, H. Angew. Chem.,
Int. Ed. 2010, 49, 9174. (e) Veitch, G. E.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2010, 49, 7332. (f) Denmark, S. E.; Burk, M. T. Proc. Natl. Acad. Sci.
2010, 107, 20655. (g) Snyder, S. A.; Treitler, D. S.; Schall, A. Tetrahedon
2010, 66, 4796. (h) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan,
B. J. Am. Chem. Soc. 2010, 132, 3298. (i) Zhang, W.; Zheng, S.; Liu, N.;
Werness, J. B.; Guzei, I. A.; Tang, W. J. Am. Chem. Soc. 2010, 132, 3664.
(j) Kwon, H. Y.; Park, C. M.; Lee, S. B.; Youn, J. H.; Kang, S. H. Chem.
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(3) For reviews of combined acids, see: (a) Yamamoto, H.; Futatsugi,
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Yamamoto, H. Chem. Rec. 2002, 2, 177.
r
10.1021/ol201032t
Published on Web 05/19/2011
2011 American Chemical Society

Table 1. Enantioselective Cyclization of 2-Geranylphenol (2a)
Catalyzed by Chiral LBBAs 1 Tf2NH
3
entry
1 [R1, R2]
yield (%)
trans/cis
ee (%)a
1
1a [OPh, H]
1b [OCy, H]
1c [Ph, H]
1c [Ph, H]
1d [i-Pr, H]
61
42
28
59
15
93
85:15
95:5
0
0
2
3
93:7
22
52
14
;
4b
5
91:9
Figure 1. Chiral Lewis base-assisted Brønsted acids (Chiral
LBBAs, 1 HX) and proposed catalytic cycle for the LBBA-
catalyzed cyclization of 2-geranylphenols 2.
3
89:11
79:21
6c
a Ee of trans-3a. Determined by HPLC analysis. b Reaction was
conducted in the presence of 1c (40 mol %) and Tf2NH (10 mol %)
at ꢀ40 °C. c Reaction was conducted in the absence of 1.
chiral nucleophilic phosphoramidite, prepared from
a binaphthol bearing triphenylsilyl groups at the 3,30-
positions, reacts with N-iodosuccinimide (NIS) to gener-
ate the corresponding phosphonium salt as an active
species. This chiral Lewis base-promoted method can also
be applied to the Brønsted acid-induced cyclization of
isoprenoids. Thus, we pursued the design of new chiral
Brønsted acids: Lewis base-assisted Brønsted acids
(LBBAs), phosphonium salts7 prepared from a chiral
phosphorus(III) compound 1 with an achiral Brønsted
acid (HX) (Figure 1). We report here the chiral LBBA-
catalyzed enantioselective cyclization of 2-geranylphenols.
The Brønsted acidity of the chiral LBBAs should
strongly depend on the structure of 1. For example, the
Brønsted basicities of phosphorous acid triesters are higher
than those of corresponding triaryl- and trialkylpho-
sphines [pKa values of conjugate acids: P(OPh)3 ꢀ2.0,
P(OMe)3 2.6, PPh3 2.7, and PMe3 8.7].8 We first examined
the catalytic activities of chiral LBBAs prepared from 1
with Tf2NH. The cyclization of 2-geranylphenol 2a was
carried out in the presence of 1 (20 mol %) and Tf2NH (20
mol %) in toluene at ꢀ78 °C (Table 1). The reaction
preferentially gave the corresponding trans-fused product
3a (trans/cis = ca. 9:1). Based on the high trans selectivity,
these reactions might proceed through concerted cycliza-
tion. Although chiral LBBAs prepared from phosphorous
acid triesters 1a (R1 = OPh) and 1b (R1 = OCy) showed
good catalytic activities (yields of 61 and 42%), the ob-
tained trans-3a was racemic (entries 1 and 2). Due to the
lower basicity of 1a, the corresponding LBBA was thermo-
dynamically unstable, and racemic product was obtained
via a background reaction catalyzed by an achiral
Brønsted acid (entry 1). LBBA 1b Tf2NH, which was
less acidic than 1a Tf2NH, improved the diastereoselectiv-
3
3
ity, although it did not have enough stability to control the
enantioselectivity (entry 2). On the other hand, the use of
chiral phosphonous acid diesters 1c (R1 = Ph) and
1d (R1 = i-Pr), which are more basic than 1a and 1b,
successfully induced enantioselectivity (22 and 14% ees),
albeit the yields of 3a were low (entries 3 and 5). The
absolute stereochemistry of the obtained trans-3a was as-
signed to be (4aR).1g Further investigation revealed that
when the reaction was conducted using 1c (40 mol %) and
Tf2NH (10 mol %) at ꢀ40 °C, both the yield and enantios-
electivity were improved (entry 4). The use of excess 1c
should promote rapid regeneration of the phosphonium salt
in the catalytic cycle and prevent the background reaction.
When the reaction was conducted in the absence of 1, 3a was
obtained in 93% yield with moderate diastereoselectivity
(79:21 dr, entry 6). This result suggested that use of Lewis
base 1 controlled not only reactivity and enantioselectivity
but also diastereoselectivity.
Next, we investigated Brønsted acids (HX) in chiral
LBBAs for the cyclization of 2a (Table 2). The reaction
was conducted in CHCl3, since the use of CHCl3 as a solvent
generally gave 3a in higher yield and enantioselectivity than
with toluene when sulfonic acids were used as Brønsted
acids.9 As a result of our investigation of various Brønsted
acids, we found that the enantioselectivity depended on the
steric bulkiness as well as the acidity of Brønsted acids
(entries 1ꢀ4). The low enantioselectivity of the 1c Tf2NH-
3
(7) For the use of triphenylphosphonium triflate as a Brønsted acid
catalyst, see: Iwahashi, H.; Oka, T.; Abiko, A. Chem. Lett. 2008, 37, 708.
(8) Rahman, Md. M.; Liu, H.-Y.; Eriks, K.; Prock, A.; Giering, W. P.
Organometallics 1989, 8, 1.
(9) The low yield and enantioselectivity in the reaction using Tf2NH
in CHCl3 (entry 1) can be attributed to the rapid decomposition of 1c due
to the high acidity of Tf2NH.
Org. Lett., Vol. 13, No. 12, 2011
3131

was increased to 84% ee without any decrease in the yield of
3a (entry 7). On the other hand, the introduction of a
trifluoromethyl group at the phenyl moiety decreased the
yield and enantioselectivity of 3a (entry 8). The electron-
withdrawing substituent of 1f did not decrease the decom-
position of 1, but increased the acidity of the corresponding
LBBA.
Table 2. Optimization of the Reaction Conditions
With the optimized reaction conditions in hand, we next
examined the enantioselectivecyclization of 2-geranylphe-
nol derivatives 2 using 1e FSO3H as a catalyst (Table 3).
entry
1 [R1, R2]
1c [Ph, H]
HX
yield (%) trans/cis ee (%)a
1
Tf2NH
TfOH
30
77
69
42
60
86
86
62
97:3
19
75
76
81
81
78
84
49
3
2
1c [Ph, H]
1c [Ph, H]
1c [Ph, H]
1c [Ph, H]
1e [Ph, Br]
1e [Ph, Br]
90:10
94:6
The introduction of both electron-donating and electron-
withdrawing groups at the 4- and 5-positions (R1 and R2)
did not affect the enantioselectivity (87ꢀ93% ee), albeit
the yields of 3 were decreased (entries 1ꢀ4). In contrast,
the introduction of a substituent at the 3-position (R3)
slightly decreased the diastereo- and enantioselectivities
(entries 5ꢀ7). Interestingly, substrate 2i bearing a hydro-
xyl group at the 3-position showed high diastereoselec-
tivity (93:7 dr, entry 8). The C2 symmetry of 2i might be
suitable for the high-level induction of diastereoselectiv-
ity. The use of 100 mol % of 1e and 20 mol % of FSO3H
increased the yield of 3i without a loss of enantioselectivity
(60% yield, entry 9).
3
ClSO3H
FSO3H
FSO3H
FSO3H
FSO3H
4
98:2
5b
6
97:3
85:15
90:10
92:8
7c
8
1f [4-CF3C6H4, H] FSO3H
a Ee of trans-3a. Determined by HPLC analysis. b One-hundred
molar percent of 1c was used. c Reaction was conducted at ꢀ55 °C for
3 days.
catalyzed reaction would be attributed to the background
reaction caused by strongly acidic Tf2NH (entry 1). The use
of sterically less-hindered FSO3H as a Brønsted acid gave the
highest enantioselectivity (81% ee), albeit the yield of 3a was
moderate (42%, entry 4). The moderate yield of 3a could
mainly be attributed to the fact that 1c gradually decomposed
under the reaction conditions. Thus, the use of 100 mol % of 1c
improved the yield of 3a (60%, entry 5). The use of 1e bearing
two bromine atoms at the 6,60-positions also increased the
yield of 3a without a significant loss of enantioselectivity
(86%, 78% ee, entry 6). Importantly, the introduction of
electron-withdrawing substituents at the 6,60-positions re-
duced the decomposition of 1 under the acidic reaction
Scheme 2. Synthesis of 4a-epi-Ugonstilbene B (6)
conditions. When the 1e FSO3H-catalyzed cyclization of
2a was conducted at ꢀ55 °C for 3 days, the enantioselectivity
3
Table 3. Enantioselective Cyclization of 2-Geranylphenol De-
rivatives 2 Catalyzed by Chiral LBBA 1e FSO3H
3
Cyclized products 3 were useful chiral building blocks
forthesynthesisof variousbioactivenaturalcompounds.10
Thus, after protection of the hydroxyl group of trans-3i
with MOM, DDQ oxidation of the MOM group11 at the
4-position gave aldehyde 4 in 71% yield (Scheme 2).12
A subsequent HornerꢀEmmonsꢀWadsworth reaction
of 4 with phosphonate 513 followed by the removal of
MOM groups gave 4a-epi-ugonstilbene B (6)14 in 55%
yield.
entry
2 [R1, R2, R3]
yield (%)
trans/cis
ee (%)a
1
2
3
4
5
6
7
8
9b
2b [H, Me, H]
64
43
48
44
80
65
57
36
60
90:10
96:4
93
88
87
88
72
79
74
70
69
We propose the following mechanism to explain the
absolute stereopreference we observed. Structure A in
2c [H, OMe, H]
2d [H, I, H]
97:3
2e [OCH2O, H]
2f [Me, H, Me]
2g [OMe, H, OMe]
2h [MOM, H, OMe]
2i [MOM, H, OH]
2i [MOM, H, OH]
91:9
88:12
65:35
80:20
93:7
(10) For selected recent examples, see: (a) Snyder, S. A.; Treitler,
D. S.; Brucks, A. P. J. Am. Chem. Soc. 2010, 132, 14303. (b) Surendra,
K.; Corey, E. J. J. Am. Chem. Soc. 2009, 131, 13928.
(11) Lee-Ruff, E.; Ablenas, F. J. Can. J. Chem. 1989, 67, 699.
(12) Topczewski, J. J.; Neighbors, J. D.; Wiemer, D. F. J. Org. Chem.
2009, 74, 6965.
89:11
(13) Gester, S.; Pietzsch, J.; Wuest, F. R. J. Label. Compd. Radio-
pharm. 2007, 50, 105.
(14) Chen, C.-C.; Huang, Y.-L.; Yeh, P.-Y.; Ou, J.-C. Planta Med.
2003, 69, 964.
a Ee of trans-3. Determined by HPLC analysis. b One-hundred molar
percent of 1e and 20 mol % of FSO3H were used in CHCl3 (0.02 M).
3132
Org. Lett., Vol. 13, No. 12, 2011

Figure 2 is the Newman projection of the chiral LBBA
1c FSO3H viewed along the HꢀP bond. The substrate
3
should approach the active proton of A with the terminal
dimethyl group away from the triphenylsilyl groups,
avoiding their steric hindrance. As shown in structure C,
the reaction at the si-face would be disfavored because of
steric repulsion with the triphenylsilyl group. Therefore,
the re-face of the terminal isoprenyl group of the substrates
would preferentially approach the active proton (B) to give
(4aR)-3 selectively.
In conclusion, we have developed chiral Lewis base-
assisted Brønsted acids (LBBAs) as new chiral Brønsted
acid catalysts for the enantioselective cyclization of 2-ger-
anylphenols. Chiral phosphonium salt of 1e with FSO3H
catalyzed the cyclization of 2-geranylphenols to give the
corresponding trans-fused cyclized products with high
diastereo- and enantioselectivities.
Acknowledgment. Financial support for this project
was provided by JSPS.KAKENHI (20245022 and
23350039) and the Global COE Program of MEXT.
Supporting Information Available. Experimental pro-
cedures, spectroscopic data for all new compounds,
NMR spectra, and HPLC charts. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Figure 2. Proposed transition-state assemblies.
Org. Lett., Vol. 13, No. 12, 2011
3133