Catalytic enantioselective epoxidation of tertiary allylic and homoallylic alcohols

Article abstract of DOI:10.1021/ja401182a

An efficient and versatile method for the enantioselective epoxidation of both tertiary allylic and homoallylic alcohols catalyzed by Hf(IV)-bishydroxamic acid (BHA) complexes is described. Asymmetric epoxidation, kinetic resolution, and desymmetrization

Full text of DOI:10.1021/ja401182a

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Communication
Catalytic Enantioselective Epoxidation of
Tertiary Allylic- and Homoallylic alcohols
José Luis Olivares-Romero, Zhi Li, and Hisashi Yamamoto
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja401182a • Publication Date (Web): 13 Feb 2013
Downloaded from http://pubs.acs.org on February 17, 2013
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Journal of the American Chemical Society
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Catalytic Enantioselective Epoxidation of Tertiary Allylic- and
Homoallylic Alcohols
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José Luis OlivaresꢀRomero, Zhi Li and Hisashi Yamamoto*,†
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago Illinois 60637, United States
†Molecular Catalysis Center, Chubu University, 1200 Matsumoto, Kasugai, 487ꢀ8501, Japan
Supporting Information Placeholder
er center ion would provide more space around it.7,8 As a
consequence, less steric interaction between the subꢀ
strate and the complex would be anticipated, especially
ABSTRACT: An efficient and versatile method for the
enantioselective epoxidation of both tertiary allylicꢀ and
homoallylic
alcohols
catalyzed
by
Hf(IV)ꢀ
in the case of tertiary olefinic alcohols. This leads to
much higher reactivity of these previously unreactive
compounds. Herein, we would like to report a hafniꢀ
um(IV)ꢀcatalyzed enantioselective epoxidation of chalꢀ
lenging tertiary olefinic alcohols.
bishydroxamic acid (BHA) complexes is described.
Asymmetric epoxidation, kinetic resolution, and
desymmetrization have been developed demonstrating
the flexible nature of the system, Hf(IV)ꢀBHA. This is
the first report in which these substrates were obtained
with enantioselectivities up to 99%.
Table 1. Screening of Group IV metal catalysts
Ph
Enantioselective epoxidation of olefins presents a
powerful strategy for the synthesis of enantiomerically
enriched epoxides that are crucial building blocks for the
synthesis of natural products and biologically active
substances.1,2 Recently, our group has described efficient
protocols to perform the epoxidation not only for primaꢀ
ry and secondary allylic alcohols but also for Nꢀalkenyl
sulfonamides, and NꢀTosyl imines with excellent yields
and enantioselectivities.3,4 Nonetheless, the preparation
of enantioenriched tertiary 2,3ꢀepoxy alcohols is still a
longꢀstanding problem, especially when considering
they could be highly versatile building blocks containing
quaternary carbon centers. Unfortunately, the Sharpless
asymmetric epoxidation5 is not an efficient protocol to
prepare enantioꢀenriched tertiary epoxy alcohols from
corresponding tertiary allylic alcohols. Indeed, there are
only two (isolated) examples that show moderate yields
and suffer from low enantioselectivities using stoichioꢀ
metric chiral reagent6 and, no truly efficient and reliable
catalytic asymmetric epoxidation of tertiary olefinic alꢀ
cohols has been described. It is clear that development
of the catalytic enantioselective protocol for the epoxiꢀ
dation of tertiary olefinic alcohols remains urgent and
highly desirable.
O
Ph
N
OH
BHA (11 mol%)
Group IV metal (X mol%)
OH
OH
OH
N
*
Ph
MgO (20 mol%),
CHP (2 eq), toluene, 48h
O
O
1
Ph
BHA-1
time
(h)
Group IV
metal
temp
(˚C)
entry
% yielda
% eeb
1
2
3
[Hf] (10mol%)
[Zr] (10 mol%)
[Ti] (10 mol%)
rt
rt
rt
12
12
12
99
96
98
96
91
30
4
5
[Hf] (10mol%)
[Hf] (5 mol%)
[Hf] (3 mol%)
[Hf] (1 mol%)
0
0
0
0
0
48
96
96
96
96
99
84
71
76
78
98
98
87
74
80
6
7
8c
[Hf] (1 mol%)
The major problem with these substrate classes is their
extremely low reactivity, probably due to steric hinꢀ
drance, which diminishes the coordinating ability with
the metal center. This drawback can be solved using anꢀ
other approach. For instance, Zr and Hf have longer
metalꢀoxygen bonds than titanium, and the use of a largꢀ
aIsolated yields. Enantiomeric excess values were determined by
chiral gas chromatography. The reaction was carried out at 0.4
M. [Hf] = Hf(OtꢀBu)4, [Zr] = Zr(OtꢀBu)4, [Ti] = Ti(OiꢀPr)4
b
c
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Scheme 1. Enantioselective Epoxidation of Tertiary Allylic
Alcoholsa,b,11
Scheme 2. Enantioselective Epoxidation of Tertiary
Homoallylic Alcoholsa,b,11
1
2
3
4
5
6
7
8
9
OH
OH
4b
OH
O
O
O
4a
4c
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BHA-1: 87% ee, 92% yield
BHA-2: 62% ee, 89% yield
BHA-1: 99% ee, 84% yield
BHA-1: 99% ee, 93% yield
OH
OH
O
OH
O
O
4fc
4d
4e
BHA-1: 60% ee, 95% yield
BHA-1: 97% ee, 87% yield
BHA-1: 99% ee, 89% yield
OH
O
OH
O
OH
O
4gc
4h
4i
O
BHA-1: 74% ee, 92% yield
BHA-1: 97% ee, 87% yield
BHA-1: 96% ee, 84% yield
OH
OH
OH
O
O
O
Ph Ph
Ph Ph
Ph Ph
4j
4l
4k
BHA-1: 58% ee, 76% yield
BHA-2: 27% ee, 80% yield
BHA-1: 97% ee, 79% yield
BHA-1: 86% ee, 74% yield
b
aIsolated yields. Enantiomeric excess values were determined by
b
aIsolated yields. Enantiomeric excess values were determined by
c
chiral HPLC or chiral gas chromatography. Enantiomeric excess
values were determined by 1H NMR in the presence of Eu(hfc)3.
chiral HPLC or chiral gas chromatography.
The studies were initiated by the examination of Hf,
Zr, and Ti. Compared with the Zr(IV)ꢀBHA system,
Hf(IV) gave a higher selectivity (Table 1, entries 1 and
2). As expected, the same reaction based on the Ti(IV)ꢀ
BHA system gave poor selectivity (Table 1, entry 3).
Temperature, concentration, and catalyst loading were
examined, and the optimum reaction conditions were
found to be with 10 mol% catalyst loading at 0˚C (Table
1, entries 4ꢀ8).
CPh3
Cα
Ph
Cα
O
O
O
O
Ph
N
N
N
N
OH
OH
OH
OH
Ph
CPh3
Ph
BHA-1
BHA-2
Figure 1. Chiral bishydroxamic acids.
To our delight, the selectivity was improved dramatiꢀ
cally using BHAꢀ2 (99% vs. 55% ee for 2d). The extra
methylene group at Cα position released sterical congesꢀ
tions and provided a larger pocket, allowing for higher
selectivity (Figure 1).
With these optimized reaction conditions, the asymꢀ
metric epoxidation of various tertiary allylic alcohols
was performed and the results are summarized in
Scheme 1. Initially the oxidation of the α,α’ꢀgemꢀ
dimethyl, and 2ꢀmethylꢀα,α’ꢀgemꢀdimethyl alcohols
were carried out, with high yields and enantioselectiviꢀ
ties up to 99% (2a and 2b). Unfortunately, when a series
of different tertiary allylic alcohols containing different
substitution patterns (1c to 1h) were oxidized using
BHAꢀ1, they gave moderate enantioselectivities. For
instance, the epoxidation of E and Z tertiary alcohols
gave 55 and 23% ee, respectively (2d and 2e).
It was found that the reaction was more enantioselecꢀ
tive for Eꢀsubstituted olefins than Zꢀolefins, 99% ee and
84% ee, respectively (2d and 2e). Encouraged by these
results, the epoxidation of aromatic and cyclic tertiary
olefins was also performed. Gratifyingly, the enantioseꢀ
lectivities were improved significantly: the selectivity
using 1h was enhanced from 35 to 90% ee (2h), also the
cyclic one was superior up to 96% ee (2i). Substrates
bearing α,α’ꢀgemꢀdicyclopropyl or α,α’ꢀgemꢀdiethyl
could also be oxidized with highest enantioselectivities
up to 93% (2j and 2k).
The enantioselectivity was compared with even more
sterically demanding tertiary allylic alcohols using
BHAꢀ2.
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Table 2. Kinetic Resolution of Tertiary Olefinic Alcohols
Table 3. Desymmetrization of Meso-Tertiary Olefinic Al-
cohols
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conv.
(%)
entry
R
time
% ee,a
% ee,a
sc
d.r.
% ee
entry
R
yield
(% yield)b
(% yield)b
(anti/syn) (anti)
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H
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97:3
90
87
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2
H
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50
80 (46)
90 (47)
84 (49%)
90 (50%)
24
58
CH3
60:40
Me
aEnantiomeric excess values were determined by chiral HPLC.
bIsolated yields. The selectivity factor s was calculated as s =
c
ln[(1ꢀC)(1ꢀee)]/ln[(1ꢀC)(1+ee)]. C represents conversion.
d.r.
% ee
Next, the epoxidation of the tertiary homoallylic alcoꢀ
hols under the optimized conditions was tested, and the
results are shown in Scheme 2. The reaction of α,α’ꢀ
gemꢀdimethyl homoallylic alcohol proceeded with high
yield and good enantioselectivity (4a). With the incorpoꢀ
ration of the methyl group at the Cꢀ3 position, the epoxꢀ
idation took place with up to 99% ee (4b). Substrates
containing α,α’ꢀgemꢀdicyclopropyl and α,α’ꢀgemꢀdiethyl
furnished the desired epoxy alcohols with excellent enꢀ
antioselectivities (4c and 4d). Tertiary olefinic alcohols
bearing cyclic moiety in the α,α’ꢀgemꢀposition also furꢀ
nished the epoxides with enantioselectivities up to 97%
(4eꢀ4i). The epoxidation was accomplished with up to
97% ee for α,α’ꢀgemꢀdiphenyl substrates (4j and 4l).
The epoxidation of 3a and 3j using BHAꢀ2 gave lower
enantioselectivity. In general, tertiary olefinic alcohols
having exo methylenes were the best substrates for the
reaction.
entry
R
yield
(anti/syn) (anti)
1
2
H
63
74
99:1
99
95
CH3
75:25
In conclusion, we have successfully applied our Hafꢀ
nium/BHA catalyst system to the enantioselective epoxꢀ
idation, kinetic resolution, and desymmetrization of terꢀ
tiary olefinic alcohols. To the best of our knowledge, this
is the first general protocol for the catalytic enantioselecꢀ
tive epoxidation of tertiary alcohol substrates. Further
studies on hafnium/bishydroxamic acid catalyzed
asymmetric oxidation toward other applications are onꢀ
going.
ASSOCIATED CONTENT
Supporting Information. Representative experimental
procedures and necessary characterization data for all new
compounds are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
With the successful results of the asymmetric epoxidaꢀ
tion of tertiary allylicꢀ and homoallylic alcohols in hand,
this catalyst system was applied to the kinetic resolution
of aromatic tertiary olefinic alcohols (Table 2). Amazꢀ
ingly, both the starting allylic alcohol and epoxy alcohol
were obtained with up to 90% of enantiopurity (s >15).10
AUTHOR INFORMATION
Corresponding Author
yamamoto@uchicago.edu
Finally, the scope of the reaction was further expanded
to the desymmetrization of meso tertiary bisallylicꢀ and
bishomoallylic alcohols. The combination of lower temꢀ
perature and 10 mol% catalyst loading provided the
epoxy alcohols with high diastereoselectivities and exꢀ
cellent enantioselectivities (Table 3).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The National Institutes of Health (NIH) is greatly appreciꢀ
ated for providing financial support (2R01GM068433).
J.L.O.ꢀR. thanks CONACYT (México) for his postdoctoral
fellowship (184749). We would also like to thank Dr. Anꢀ
toni Jurkiewicz, Dr. Ian Steele, and Dr. Jin Qin for their
expertise in NMR, Xꢀray crystallography, and mass specꢀ
trometry, respectively.
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(9) Lubben, T. V.; Wolczanski, P. T. J. Am. Chem. Soc. 1987, 109,
424.
(10) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.;
Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237.
(11) Absolute stereochemistry of compounds 2a and 4a was asꢀ
signed by comparison with known compounds (see supporting inforꢀ
mation). Hence, the remaining tertiary alcohols were assigned by
analogy assuming a common reaction pathway.
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8
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Journal of the American Chemical Society
For TOC Only
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Hf(IV)-BHA system
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R4 OH
OH R2
CPh3
Ph
R1
R1
R2
R3
O
O
R1
R3
Ph
R1
R4
N
N
N
N
OH
OH
OH
OH
R4 OH
R1
R1
OH R2
Ph
R3
O
R1
O
R3
9
O
R1
O
CPh3
Ph
R2
R4
up to 99% ee
BHA-1
BHA-2
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CHP
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