Tungsten-catalyzed asymmetric epoxidation of allylic and homoallylic alcohols with hydrogen peroxide

Article abstract of DOI:10.1021/ja411379e

A simple, efficient, and environmentally friendly asymmetric epoxidation of primary, secondary, tertiary allylic, and homoallylic alcohols has been accomplished. This process was promoted by a tungsten-bishydroxamic acid complex at room temperature with the use of aqueous 30% H₂O₂ as oxidant, yielding the products in 84-98% ee.

Full text of DOI:10.1021/ja411379e

Communication
pubs.acs.org/JACS
Tungsten-Catalyzed Asymmetric Epoxidation of Allylic and
Homoallylic Alcohols with Hydrogen Peroxide
Chuan Wang† and Hisashi Yamamoto*,†,‡
†Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago Illinois 60637, United States
‡Molecular Catalyst Research Center, Chubu University, 1200 Matsumoto, Kasugai, Aichi 487-8501, Japan
S
* Supporting Information
of allylic and homoallylic alcohols,3 we initially investigated them
ABSTRACT: A simple, efficient, and environmentally
friendly asymmetric epoxidation of primary, secondary,
tertiary allylic, and homoallylic alcohols has been
accomplished. This process was promoted by a tung-
sten−bishydroxamic acid complex at room temperature
with the use of aqueous 30% H2O2 as oxidant, yielding the
products in 84−98% ee.
as ligands in the epoxidation reaction of cis-2-hexen-1-ol (1a)
using WO2(acac)2 as the tungsten source. Unfortunately, both
reactions gave the product 2a in moderate yields and low
enantioselectivities, while higher enantioselectivity was obtained
in the case of BHA-2 (Table 1, entries 1 and 2). For this reaction,
three other ligands, BHA-3−5, with modified ligand arms were
synthesized and studied on the basis of the scaffold of BHA-2
(Table 1, entries 3−5). The best results with respect to both yield
and enantioselectivity were achieved in the case of the BHA-5
(Table 1, entry 5). Furthermore, (−)-TADDOL was also
investigated as ligand, but the reaction gave only traces of
product after 8 h, indicating that the bishydroxamic acids were
essential for the outcome of this process (Table 1, entry 6). In all
the cases using BHA as ligand it was observed that the epoxide 2a
underwent a ring-opening reaction with H2O2 as nucleophile. In
order to halt this undesired reaction, we screened five different
alkali salts as additives.7m In the case of LiCl the side reaction was
totally blocked, but the epoxidation was also slowed down (Table
1, entry 7). When LiBr was employed, no reaction occurred, and
gas evolution was observed, suggesting the disproportion of
H2O2 (Table 1, entry 8). The use of LiF, Na2SO4, or NaCl as
additive afforded similar results, and all inhibited the ring-
opening reaction effectively, while the asymmetric induction of
epoxidation remained excellent (Table 1, entries 9−11).
Considering that Na2SO4 and toxic LiF are more expensive
than NaCl, we chose NaCl for further optimization. The
reactions were then conducted in toluene and THF, but there
were no better results (Table 1, entries 12, 13). Furthermore, the
commercially available WO2Cl2 was also tested and proved to be
less reactive (Table 1, entry 14). Reducing the catalyst loading to
2 mol % led to longer reaction time and lower yield (Table 1,
entry 15). Then we attempted to improve the catalytic activity by
adjusting the amount of additive used and substrate concen-
tration. By lowering the amount of NaCl to 0.5 equiv the reaction
time could be shortened to 8 h, and the yield improved to 87%
(Table 1, entry 16). When the concentration of the olefin 1a in
DCM was increased to 0.1 M, the reaction was completed within
3 h, affording the product in 92% yield and 95% ee (Table 1,
entry 17). Reducing the catalyst to 1 mol % resulted in a decrease
of the yield to 63% (Table 1, entry 18). Performing the reaction
with 0.25 equiv NaCl could improve the yield to 86%, but the ee
diminished to 79% (Table 1, entry 19). Finally, the reaction was
carried out on a scale of 10.0 mmol 1a, furnishing the product in
symmetric epoxidation is one of the most important
A
transformations in organic synthesis, since it provides a
straightforward access to various optically active epoxides, which
are highly useful chiral building blocks for the synthesis of natural
products and synthetic analogues with biological activities.1
Much progress has been achieved in this field since Sharpless et
al. reported the discovery of titanium-catalyzed asymmetric
epoxidation of allylic alcohols in the early 1980s.2 In recent years
our group developed a series of unique bishydroxamic acids
(BHA) and applied them successfully as ligands for highly
enantioselective epoxidation of allylic, homoallylic, and
bishomoallylic alcohols as well as N-alkenyl sulfonamides and
N-tosyl imines.3 However, all these reactions employ toxic alkyl
peroxide as the oxidant, functioning with low atom economy.
Therefore, from both economical and ecological viewpoints, it is
desirable to develop a catalytic epoxidation with broad substrate
scope using aqueous hydrogen peroxide (H2O2) as the oxidant,
which is safe, cheap, easy to handle and generates water as the
sole byproduct.4,5 Recently, Katsuki et al. described H2O2-
mediated epoxidation of allylic alcohols in highly enantiose-
lective manner using niobium−salem complexes as catalysts.6
Nonetheless, the substrate scope of this protocol is limited to
primary allylic alcohols. Over the last decades the use of
peroxotungstates as catalysts for the epoxidation with H2O2 has
attracted much attention as a result of their high capability for
oxygen transfers and low activity for disproportion of H2O2.7
Despite intensive research in this area, highly enantioselective
tungsten-catalyzed epoxidation remains still elusive. Recently,
Mizuno et al. developed dinuclear peroxotungstates, which could
catalyze the H2O2-mediated epoxidation of various allylic and
homoallylic alcohols efficiently;7g,k but no asymmetric induction
was reported in these two contexts. Herein, we report a tungsten-
catalyzed asymmetric epoxidation of both primary, secondary,
and tertiary allylic as well as homoallylic alcohols with aqueous
H2O2 as oxidant by using our W-BHA catalyst system.
Since BHA-1 and BHA-2 showed high catalytic activity and
Received: November 7, 2013
selectivity in the vanadium- and hafnium-catalyzed epoxidation
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
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After optimizing the reaction conditions we started to evaluate
the substrate scope of this reaction. We first investigated a variety
of allylic alcohols with different substituted patterns; see Chart 1
Table 1. Ligand, Additive, and Solvent Screening for the
Asymmetric Epoxidation
a
a b c d e f
,
8
, , , , ,
Chart 1. Asymmetric Epoxidation of Allylic Alcohols
b
c
entry
ligand
solvent
additive
t (h) yield (%)
ee (%)
1
1
2
3
4
5
d
5
5
5
5
5
5
5
5
5
5
5
5
5
5
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
toluene
THF
−
−
−
−
−
−
LiCl
LiBr
NaCl
LiF
2.5
2.5
2.5
2.5
2.5
8
38
54
−12
37
2
3
69
49
4
71
41
5
84
94
e
6
traces
81
n.d.
93
7
24
24
2.5
8
0
−
96
95
95
93
55
92
94
95
95
9
91
10
11
12
13
14
15
16
17
2.5
2.5
92
Na2SO4
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
92
24
83
24
24
24
8
49
f
DCM
DCM
DCM
DCM
DCM
DCM
DCM
51
g
g
73
a
,
h
Unless otherwise stated, reactions were performed on a 0.50 mmol
scale of allylic alcohols 1 using 2.0 equiv; 30% aqueous H2O2, 2 mol %
WO2(acac)2, 2.4 mol % BHA ligand, and 0.5 equiv NaCl at rt in 5 mL
87
g,h,i
3
92
62
h
,
j
e
18
19 ,
24
24
3
n.d.
b
c
DCM. Yields of the isolated products. Determined by HPLC on a
chiral stationary phase on the corresponding benzoates. Determined
by HPLC on a chiral stationary phase. 5 mol % WO2(acac)2 and 5.5
mol % BHA-5 were used. Reaction time: 24 h Determined by GC on
jk
86
79
96
d
g
,h,i,l
20
89
e
a
f
Unless otherwise stated, reactions were performed on a 0.25 mmol
scale of cis-2-hexen-1-ol (1a) using 2.0 equiv; 30% aqueous H2O2, 5
a chiral stationary phase.
mol % WO2(acac)2, 5.5 mol % BHA ligand, and 1.0 equiv additive at rt
b
c
in 5.0 mL solvent. Yields of isolated products. Determined by HPLC
d
on a chiral stationary phase on the corresponding benzoate. (−)-
TADDOL was used as ligand. Not determined. WO2Cl2 was used
instead of WO2(acac)2. 2.0 mol % WO2(acac)2 and 2.4 mol % BHA-5
were used. 0.5 equiv NaCl was used. Reaction was performed in 2.5
mL DCM. Reactions were performed on 1.0 mol % WO2(acac)2, 1.2
mol % BHA-5 in 0.5 mL DCM. 0.25 equiv NaCl was used. The
for summarized results. Excellent results in terms of both yield
and enantioselectivity were obtained in the case of aliphatic cis
and trans disubstituted allylic alcohols 1a−1e. Cinnamyl alcohol
1f and its fluorinated analogue 1g turned out to be less reactive.
In both cases the reactions were carried out with 5 mol % catalyst
furnishing the products 2f and 2g in 87 and 72% yields and 94
and 86% ee, respectively. Two α-substituted cinnamyl alcohols
1h and 1i were employed as substrates for the epoxidation
reaction, giving the products 2h and 2i in good yields (87 and
79%) and 84 and 86% ee. Symmetric β,β-disubstituted allylic
alcohol 1j was also a suitable substrate for this method, giving the
product 2j in 86% yield and 92% ee. The reaction using nerol, 1k,
farnesol, 1l, and its derivative, 1m, as precursors proceeded
smoothly with high regioselectivities under the optimized
conditions, giving the products 2k−m in 84−96% yields and
84−90% ee. A tertiary allylic alcohol 1n was also subjected to the
epoxidation reaction, requiring longer reaction time and higher
catalyst loading (5 mol %), and the product 2n was obtained in a
86% yield and 90% ee.
e
f
g
h
i
j
k
l
reaction was performed on a scale of 10.0 mmol 1a.
89% yield and 96% ee (Table 1, entry 20). In this case BHA-5
could be recycled through column chromatography with 92%
yield in analytically pure form. Importantly, all the reactions were
conducted under air and needed no anhydrous solvents or
additional preparation of the BHA-W complexes prior to the
epoxidation reaction. The olefin 1a and H2O2 could be added to
the mixture of BHA-5 and WO2(acac)2 immediately, giving the
product 2a with excellent ee. In addition, conducting the reaction
in the absence of BHA gave only traces of epoxide after 3 h,
indicating that the BHA ligand is crucial not only for the
stereoselectivity but also for the catalytic activity.
B
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Journal of the American Chemical Society
Communication
that of the geometry of the olefins on the reactivity of the
substrates. Hopefully, Tables 2 and 3 will provide at least some
Chart 2. Asymmetric Epoxidation of Homoallylic
Alcohols
a b c d e f g 8
, , , , , , ,
Table 2. Investigation of the Chemoselectivity of Various
a
9
,
Allylic Alcohols
1o
1q
1r
1t
b
1b
1e
1k
1s
−
84/25
82/7
79/7
71/5
−
−
90/35
−
86/10
a
Unless otherwise stated, reactions were performed on a 0.50 mmol
scale of homoallylic alcohols 3 using 2.0 equiv; 30 % aqueous H2O2, 2
mol % WO2(acac)2, 2.4 mol % BHA-5, and 0.5 equiv NaCl at rt in 5
−
9/69
−
−
−
−
b
c
mL DCM. Yields of the isolated products. Determined by HPLC on
a
Reactions were performed with a 1:1 mixture of two allylic alcohols
a chiral stationary phase on the corresponding benzoates.
using 2.0 equiv; 30% aqueous H2O2, 1 or 2 mol % WO2(acac)2, 1.2 or
d
e
Determined by HPLC on a chiral stationary phase. Reaction was
performed at 0 °C using 1.0 equiv NaCl; reaction time 8 h.
b
2.4 mol % BHA-5 and 0.5 equiv NaCl in DCM. Conversions were
1
determined by H NMR spectroscopy of the reaction mixtures. The
f
g
Determined by GC on a chiral stationary phase. 5 mol %
conversions were given in form of a/b with a as conversion of the
compound shown in the first column and b as conversion of the
compound shown in the top of the respective row.
WO2(acac)2 and 5.5 mol % BHA-5 were used; reaction time: 24 h.
Being similar to their allylic analogues, primary cis and trans
disubstituted homoallylic alcohols 3a−f were excellent substrates
for this epoxidation method, and the corresponding products
4a−f were obtained in high yields (80−92%) with good to
excellent asymmetric induction (88−97% ee). In the case of
cyclic olefin 3g the reaction was conducted at 0 °C using 1.0
equiv NaCl as additive to prevent the undesired side reaction.
Under this condition the product 4g was afforded in 72% yield
and 96% ee. In contrast, the tertiary homoallylic alcohol 3h
underwent an epoxidation/intramolecular ring-opening cascade
reaction giving a tetrasubstituted tetrahydrofuran 4h as product
in 75% yield, >98% de, and 90% ee.
Table 3. Investigation of the Chemoselectivity of Various
Homoallylic Alcohols
a
9
,
The method was also applied to the kinetic resolution of
racemic α-vinylbenzyl alcohol (rac-5) furnishing both the allylic
alcohol 5 and the epoxide 6 with high ee’s (Chart 3).
3h
3i
3j
3k
b
3d
92/3
89/5
81/27
64/21
a
Reactions were performed with a 1:1 mixture of two homoallylic
Chart 3. Kinetic Resolution of α-Vinylbenzyl Alcohol
alcohols using 2.0 equiv; 30% aqueous H2O2, 2 mol % WO2(acac)2, 2.4
b
mol % BHA-5, and 0.5 equiv NaCl in DCM. Conversions were
1
determined by H NMR spectroscopy of the reaction mixtures. The
conversions are given in form of a/b: where a = conversion of 3d and
b = conversion of 3h−k.
basic information. The results obtained show the following trend
of the reactivity of different substrates: (a) primary alcohols ≫
tertiary alcohols and phenyl-substituted secondary alcohols; (b)
cis- or trans-disubstituted olefins ≈ trisubstituted olefins >
geminal disubstituted olfefins.
Last, two farnesol derivatives 1u and 1v bearing three olefins
and two alcohol moieties were employed as precursors of the
epoxidation reaction. To our delight, the corresponding products
2u and 2v were furnished in almost complete regioselectivities,
85 and 74% yields, and 88−92% ee (Chart 4).
Since our W-catalyst exhibits not only excellent stereo-
selectivity but also distinct reactivity for various types of alcohols,
our method could be used not only for the synthesis of a simple
chiral pool but also as a late-stage oxidation for the synthesis of
complex molecules. However, we have to provide more
information about the influence of the anchor groups as well as
C
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Journal of the American Chemical Society
Communication
(2) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
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Chart 4. Regioselective Epoxidation of the Farnesol
Derivatives 1u and 1v
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Y.; Liu, X.; Li, W.; Hu, X.; Lin, L.; Feng, X. Chem. Sci. 2012, 3, 1996.
To conclude, we have developed a tungsten-catalyzed
asymmetric epoxidation with the following advantages and
breakthroughs: (1) the first highly enantioselective epoxidation
using tungsten catalyst; (2) the use of environmentally benign
aqueous H2O2 as oxidant instead of toxic organic alkyl peroxides;
(3) simple conditions: reactions are performed under air and in
most cases at RT requiring no anhydrous solvent or preparation
of metal−catalyst complex prior to the catalytic process; (4)
broad substrate scope, i.e. both primary, secondary, and tertiary
allylic as well as homoallylic alcohols are successfully employed as
precursors for this epoxidation reaction furnishing the products
in high ee’s; (5) good chemoselectivities for primary alcohols
over secondary and tertiary alcohols, promising the use of this
method in late-stage, complex molecule synthesis.
(c) Lifchits, O.; Mahlau, M.; Reisinger, C. M.; Lee, A.; Fares
̀
, C.; Polyk,
I.; Gopakumar, G.; Thiel, W.; List, B. J. Am. Chem. Soc. 2013, 135, 6677.
(d) Berkessel, A.; Gunther, T.; Wang, Q.; Neudorfl, J.-M. Angew. Chem.,
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Int. Ed. 2013, 52, 8467. (e) Cusso,
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O.; Garcia-Bosch, I.; Ribas, X.; Lloret,
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(7) For examples of tungsten-catalyzed epoxidation of olefins:
(a) Herrmann, W. A.; Haider, J. J.; Fridgen, J.; Lobmaier, G. M.;
Spiegler, M. J. Organomet. Chem. 2000, 603, 69. (b) Xi, Z.; Zhou, N.;
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es, V.; Plusquellec, D. Chem. Commun. 2001, 37, 2460.
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Rozner, D.; Zhang, R. Synlett 2002, 34, 2011. (e) Adam, W.; Alsters, P.
̈
ASSOCIATED CONTENT
* Supporting Information
Experimental details; characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
L.; Neumann, R.; Saha-Moller, C. R.; Slobada-Rozner, D.; Zhang, R. J.
̈
■
Org. Chem. 2003, 68, 1721. (f) Wang, X.-Y.; Shi, H.-C.; Sun, C.; Zhang,
Z.-G. Tetrahedron 2004, 60, 10993. (g) Kamata, K.; Yamaguchi, K.;
Mizuno, N. Chem.Eur. J. 2004, 10, 4728. (h) Maheswari, P. U.; de
Hoog, P.; Hage, R.; Gamez, P.; Reedijk, J. Adv. Synth. Catal. 2005, 347,
1759. (i) Sartorel, A.; Carraro, M.; Bagno, A.; Scorrano, G.; Bonchio, M.
Angew. Chem., Int. Ed. 2007, 46, 3255. (j) Kamata, K.; Kotani, M.;
Yamaguchi, K.; Hikichi, S.; Mizuno, N. Chem.Eur. J. 2007, 13, 639.
(k) Kamata, K.; Hirano, T.; Kuzuya, S.; Mizuno, N. J. Am. Chem. Soc.
2009, 131, 6997. (l) Kamata, K.; Yonehara, K.; Sumida, Y.; Hirata, K.;
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(m) Hachiya, H.; Kon, Y.; Ono, Y.; Takumi, K.; Sasagawa, N.; Ezaki, Y.;
Sato, K. Synlett 2012, 44, 1672.
(8) Absolute stereochemistries of 2a, 2c, 2f, 2h, 2i, 2k, 2l, 4c, 4e, 5, and
6 were assigned by comparison with known compounds (see the
Supporting Information). Hence, 2b, 2d, 2e, 2g, 2j, 2m, 2n, 2u, 2v, 4a,
4b, 4d, 4f, 4g, and the epoxide precursor of 4h were assigned by analogy,
assuming a common reaction pathway. The absolute configuration of
the tetrahydrofuran 4h was assigned by assuming that the ring-opening
reaction proceeds in an SN-2-type reaction.
S
AUTHOR INFORMATION
Corresponding Author
yamamoto@uchicago.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (NIH) for financial
support (2R01GM068433). C.W. thanks the Alexander von
Humboldt Foundation for his postdoctoral fellowship. We also
thank Dr. Antoni Jurkiewicz and Dr. Jin Qin for their respective
expertise in NMR spectroscopy and mass spectrometry.
(9) For detailed reaction conditions, see the SI.
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