Asymmetric chroman synthesis via an intramolecular oxy-Michael addition by bifunctional organocatalysts

Article abstract of DOI:10.1039/c3ob41938j

Cinchona-alkaloid-urea-based bifunctional organocatalysts facilitate the catalytic asymmetric synthesis of chroman derivatives via an intramolecular oxy-Michael addition reaction. Phenol derivatives bearing an easily available (E)-α,β-unsaturated ketone or a thioester moiety are useful substrates for the title transformation. This method represents a facile synthesis of various optically active 2-substituted chromans in high yield. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob41938j

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Asymmetric chroman synthesis via an
intramolecular oxy-Michael addition by
bifunctional organocatalysts†
Cite this: Org. Biomol. Chem., 2014,
12, 119
Ryota Miyaji, Keisuke Asano* and Seijiro Matsubara*
Cinchona-alkaloid-urea-based bifunctional organocatalysts facilitate the catalytic asymmetric synthesis of
chroman derivatives via an intramolecular oxy-Michael addition reaction. Phenol derivatives bearing an
easily available (E)-α,β-unsaturated ketone or a thioester moiety are useful substrates for the title trans-
formation. This method represents a facile synthesis of various optically active 2-substituted chromans in
high yield.
Received 24th September 2013,
Accepted 29th October 2013
DOI: 10.1039/c3ob41938j
www.rsc.org/obc
Introduction
Chiral 2-substituted chromans are found in an extremely wide
range of bioactive compounds, as typified by vitamin E, and
their biological activities have attracted much attention
(Fig. 1).1 Thus, the enantioselective synthetic methods toward
chroman derivatives are in high demand; indeed, a number of
strategies have been reported, addressing this need.2–5 Among
them, the intramolecular oxy-Michael addition is a promising
method for constructing the desired framework from easily
available phenol derivatives bearing an α,β-unsaturated carbo-
nyl; the remaining carbonyl group in the product allows for
further structural modification, which may lead to the syn-
thesis of various pharmacological compounds. However, only
a few examples of such approaches have been reported to
date.4,5 In addition, most of these strategies display a signifi-
cant limitation in that the substrate, typically an α,β-unsatu-
rated ester moiety, must be in its (Z)-isomer form, and that the
(Z)-forms of more electron-deficient olefins (α,β-unsaturated
ketones and thioesters) are extremely difficult to prepare by
means of simple methods such as Wittig reactions using
stabilized ylides (Scheme 1). These problems must be solved to
expand the scope of synthetically accessible chromans.
Fig. 1 Representative 2-substituted chromans in bioactive compounds.
Scheme 1 Facile synthetic route to substrates 1.
We have recently established a useful strategy for the asym-
metric synthesis of five- or six-membered oxygen heterocycles
via an intramolecular oxy-Michael addition starting from
(E)-α,β-unsaturated carbonyl substrates (Scheme 2).6,7 This
Department of Material Chemistry, Graduate School of Engineering,
Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan.
E-mail: asano.keisuke.5w@kyoto-u.ac.jp, matsubara.seijiro.2e@kyoto-u.ac.jp;
Fax: +81 75 383 2438; Tel: +81 75 383 7571, +81 75 383 7130
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, analytical and spectroscopic data for synthetic compounds, copies of
NMR. CCDC 962820. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3ob41938j
Scheme 2 Asymmetric synthesis of 2-substituted THF and THP via an
intramolecular oxy-Michael addition by a bifunctional organocatalyst.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 119–122 | 119

View Article Online
Paper
Organic & Biomolecular Chemistry
method utilizes multipoint substrate recognition by bifunc- 10). However, the use of a smaller amount of catalyst (5 mol%)
tional organocatalysts through hydrogen bonding;8,9 the mild led to lower enantioselectivity, which was likely due to the
characteristics of activation through hydrogen bonding facilitate competing non-catalytic reaction (Table 1, entry 11). A time of
concerted catalysis efficient for obtaining high enantioselectivity 12 h was found to be sufficient for reaction completion, and
even in rapid intramolecular processes for cycloetherifica- higher enantioselectivity could be obtained (Table 1, entry 12).
tions.6d The efficiency of this protocol prompted us to explore In this reaction, the urea catalyst 3a was revealed to be more
the use of bifunctional organocatalysts for the intramolecular efficient than the corresponding thiourea catalyst 3b (Table 1,
oxy-Michael addition from phenol derivatives bearing an (E)- entries 12 and 13).7a Further screening of urea catalysts
α,β-unsaturated carbonyl moiety.5,10 In this study, we present a showed that quinine-derived 3d was an efficient catalyst for
novel enantioselective synthesis of 2-substituted chromans via obtaining the opposite enantiomer of 2a with good enantio-
an intramolecular oxy-Michael addition using cinchona-alka- selectivity (Table 1, entry 15).
loid-urea-based bifunctional organocatalysts.
With catalyst 3a and optimized reaction conditions identi-
fied, we next investigated the reactions of substrates bearing
Results and discussion
Table 2 Scope of α,β-unsaturated ketonesa
We initiated our investigation using substrate 1a with 10 mol%
quinidine-derived bifunctional aminourea catalyst 3a in
CH2Cl2 at 25 °C over 24 h; chroman product 2a was obtained
with moderate enantioselectivity (Table 1, entry 1). Solvent
screening revealed that THF was effective for both enantio-
selectivity and yield (Table 1, entry 9). A decrease in reaction Entry
temperature improved the enantioselectivity (Table 1, entry
Product (2)
Yieldb (%)
95
ee (%)
84
1
2a
2b
Table 1 Optimization of conditionsa
2
81
84
3
2c
95
95
84
70
Entry
Catalyst
Solvent
Yieldb (%)
ee (%)
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
CH2Cl2
Benzene
Pyridine
DMSO
Et2O
t-BuOMe
CPMEc
1,4-Dioxane
THF
THF
THF
THF
THF
99
87
99
88
91
99
93
96
99
99
99
95
95
86
98
86
63
60
58
25
69
55
63
72
72
81
76
84
75
82
−80
−78
4
5
6
2d
2e
2f
99
66
83
72
9
10d
11d,e
12d, f
13d, f
14d, f
15d, f
16d, f
THF
THF
THF
7
8
2g
2h
64
86
36
74
a Reactions were run using 1a (0.1 mmol) and the catalyst (0.01 mmol)
in the solvent (0.2 mL). b Isolated yields. c CPME = cyclopentyl methyl
ether. d Reactions were run at 0 °C. e Reaction was run using 5 mol% of
3a (0.005 mmol). f Reactions were run for 12 h.
9
2i
68
65
a Reactions were run using 1 (0.1 mmol) and 3a (0.01 mmol) in THF
(0.2 mL). b Isolated yields.
120 | Org. Biomol. Chem., 2014, 12, 119–122
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Notes and references
1 For reviews, see: (a) Chromenes, Chromanones, and
Chromones, ed. G. P. Ellis, Wiley-Interscience, New York,
1977; (b) Comprehensive Heterocyclic Chemistry II, ed.
A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon,
Oxford, 1996.
Scheme 3 Reaction of α,β-unsaturated thioester.
2 For reviews, see: (a) H. C. Shen, Tetrahedron, 2009, 65,
3931; (b) M. Núñez, P. García, R. F. Moro and D. Díez, Tetra-
hedron, 2010, 66, 2089.
other (E)-Michael-acceptor moieties.11 Electron-rich substrates
were also effective, providing the chroman products in high
yield and comparable enantioselectivity (Table 2, entries 2
and 3). A starting material bearing an electron-withdrawing
group afforded the corresponding product in high yield,
although the enantiomeric excess was slightly lower (Table 2,
entry 4). A substrate with a p-bromophenyl substituent yielded
the corresponding product quantitatively in high enantio-
selectivity (Table 2, entry 5); however, a 2-naphthyl-substituted
enone gave the resultant product in lower yield and stereo-
selectivity (Table 2, entry 6). Unfortunately, a methylketone
proved to be an unsuccessful substrate (Table 2, entry 7). Sub-
stituents on the phenol moiety were also investigated, and a
substrate with a methoxy group gave the corresponding
product in good yield with moderate enantioselectivity
(Table 2, entry 8), although a phenol derivative with a bromo
group resulted in lower yield and stereoselectivity (Table 2,
entry 9). To our delight, an α,β-unsaturated thioester partici-
pated in the cyclization reaction, yielding a chroman derivative
suitable for various subsequent transformations, demonstrat-
ing the synthetic utility of our method (Scheme 3). The abso-
lute configuration of 2e was determined as (R) using X-ray
analysis (see ESI† for details), and the configurations of all
other examples were assigned accordingly.
3 For selected examples, see: (a) Y. Uozumi, K. Kato and
T. Hayashi, J. Am. Chem. Soc., 1997, 119, 5063;
(b) E. Mizuguchi and K. Achiwa, Chem. Pharm. Bull., 1997,
45, 1209; (c) B. M. Trost and F. D. Toste, J. Am. Chem. Soc.,
1998, 120, 9074; (d) B. M. Trost and N. Asakawa, Synthesis,
1999, 1491; (e) B. M. Trost, H. C. Shen and J.-P. Surivet,
Angew. Chem., Int. Ed., 2003, 42, 3943; (f) B. M. Trost,
H. C. Shen, L. Dong and J.-P. Surivet, J. Am. Chem. Soc.,
2003, 125, 9276; (g) B. M. Trost, H. C. Shen, L. Dong,
J.-P. Surivet and C. Sylvain, J. Am. Chem. Soc., 2004, 126,
11966; (h) J.-R. Labrosse, C. Poncet, P. Lhoste and D. Sinou,
Tetrahedron: Asymmetry, 1999, 10, 1069; (i) K. Ishihara,
S. Nakamura and H. Yamamoto, J. Am. Chem. Soc., 1999,
121, 4906; ( j) S. Nakamura, K. Ishihara and H. Yamamoto,
J. Am. Chem. Soc., 2000, 122, 8131; (k) H. Ishibashi,
K. Ishihara and H. Yamamoto, J. Am. Chem. Soc., 2004, 126,
11122; (l) L. F. Tietze, K. M. Sommer, J. Zinngrebe and
F. Stecker, Angew. Chem., Int. Ed., 2005, 44, 257;
(m) L. F. Tietze, F. Stecker, J. Zinngrebe and K. M. Sommer,
Chem.–Eur. J., 2006, 12, 8770; (n) K. Liu, A. Chougnet and
W.-D. Woggon, Angew. Chem., Int. Ed., 2008, 47, 5827;
(o) Y. K. Chung and G. C. Fu, Angew. Chem., Int. Ed., 2009,
48, 2225; (p) L.-Q. Lu, F. Li, J. An, J.-J. Zhang, X.-L. An,
Q.-L. Hua and W.-J. Xiao, Angew. Chem., Int. Ed., 2009, 48,
9542; (q) X.-F. Wang, Q.-L. Hua, Y. Cheng, X.-L. An,
Q.-Q. Yang, J.-R. Chen and W.-J. Xiao, Angew. Chem., Int.
Ed., 2010, 49, 8379; (r) X.-F. Wang, J. An, X.-X. Zhang,
F. Tan, J.-R. Chen and W.-J. Xiao, Org. Lett., 2011, 13, 808;
(s) L.-Q. Lu, Z.-H. Ming, J. An, C. Li, J.-R. Chen and
W.-J. Xiao, J. Org. Chem., 2012, 77, 1072; (t) X.-G. Song,
S.-F. Zhu, X.-L. Xie and Q.-L. Zhou, Angew. Chem., Int. Ed.,
2013, 52, 2555; (u) H. Wu, Y.-P. He and L.-Z. Gong,
Org. Lett., 2013, 15, 460; (v) W. Yang, Y. Yang and D.-M. Du,
Org. Lett., 2013, 15, 1190; (w) Z.-X. Jia, Y.-C. Luo,
X.-N. Cheng, P.-F. Xu and Y.-C. Gu, J. Org. Chem., 2013, 78,
6488.
Conclusions
In summary, we have presented a novel asymmetric chroman
synthesis via an intramolecular oxy-Michael addition employ-
ing bifunctional aminourea catalysts. In this method, sub-
strates bearing an easily available (E)-Michael acceptor
including α,β-unsaturated ketones and thioesters could be
used, thereby leading to a facile and versatile approach to opti-
cally active chromans. Further studies on the expansion of the
substrate scope and the application of this methodology
toward other heterocyclic scaffolds are currently underway in
our laboratory and will be reported in due course.
4 (a) A. Merschaert, P. Delbeke, D. Daloze and G. Dive, Tetra-
hedron Lett., 2004, 45, 4697; (b) N. Saito, A. Ryoda,
W. Nakanishi, T. Kumamoto and T. Ishikawa, Eur. J. Org.
Chem., 2008, 2759.
5 Analogous intramolecular oxy-Michael additions to form
chromans from (E)-substrates by a bifunctional organocata-
lyst have been recently reported, and the utility is specific
to slow reactions from α,β-unsaturated amides, see:
Y. Kobayashi, Y. Taniguchi, N. Hayama, T. Inokuma and
Y. Takemoto, Angew. Chem., Int. Ed., 2013, 52, 11114.
Acknowledgements
We thank Professor Takuya Kurahashi (Kyoto University) for
X-ray crystallographic analysis. This work was supported finan-
cially by the Japanese Ministry of Education, Culture, Sports,
Science and Technology.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 119–122 | 121

View Article Online
Paper
Organic & Biomolecular Chemistry
6 (a) K. Asano and S. Matsubara, J. Am. Chem. Soc., 2011, 133,
16711; (b) K. Asano and S. Matsubara, Org. Lett., 2012, 14,
1620; (c) T. Okamura, K. Asano and S. Matsubara, Chem.
Commun., 2012, 48, 5076; (d) Y. Fukata, R. Miyaji,
T. Okamura, K. Asano and S. Matsubara, Synthesis, 2013, 1627.
7 For our related works on intramolecular aza-Michael
addition by bifunctional organocatalysts, see: (a) R. Miyaji,
K. Asano and S. Matsubara, Org. Lett., 2013, 15, 3658;
(b) Y. Fukata, K. Asano and S. Matsubara, Chem. Lett., 2013,
(e) S. J. Connon, Chem.–Eur. J., 2006, 12, 5418; (f) J.-L. Zhu,
Y. Zhang, C. Liu, A.-M. Zheng and W. Wang, J. Org. Chem.,
2012, 77, 9813.
9 For reviews on asymmetric catalysis based on hydrogen
bonding, see: (a) Hydrogen Bonding in Organic Synthesis, ed.
P. M. Pihko, Wiley-VCH, Weinheim, 2009; (b) A. G. Doyle
and E. N. Jacobsen, Chem. Rev., 2007, 107, 5713;
(c) M. S. Taylor and E. N. Jacobsen, Angew. Chem., Int. Ed.,
2006, 45, 1520.
355; (c) Y. Fukata, K. Asano and S. Matsubara, J. Am. Chem. 10 For an example of endo-cyclization via an asymmetric intra-
Soc., 2013, 135, 12160.
molecular oxy-Michael addition from phenol derivatives
mediated by bifunctional organocatalyst, see:
M. M. Biddle, M. Lin and K. A. Scheidt, J. Am. Chem. Soc.,
2007, 129, 3830.
8 (a) T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc.,
2003, 125, 12672; (b) T. Okino, Y. Hoashi, T. Furukawa,
X. Xu and Y. Takemoto, J. Am. Chem. Soc., 2005, 127, 119;
a
(c) B. Vakulya, S. Varga, A. Csámpai and T. Soós, Org. Lett., 11 Although reactions from β-disubstituted α,β-unsaturated
2005, 7, 1967; (d) A. Hamza, G. Schubert, T. Soós and
ketones were also examined, they were less reactive in this
I. Pápai, J. Am. Chem. Soc., 2006, 128, 13151;
catalytic process. See ESI for details (Scheme S1†).
122 | Org. Biomol. Chem., 2014, 12, 119–122
This journal is © The Royal Society of Chemistry 2014