Highly enantioselective CH oxidation of vic-diols with Shi's oxazolidinone dioxiranes

Article abstract of DOI:10.1021/ol060904a

Through an analogical study of the transition states of CH oxidation and asymmetric epoxidation of terminal alkenes, the first dioxirane-mediated catalytic highly enantioselective CH oxidation method was realized with Shi's oxazolidinone ketone derivatives. Very good enantioselectivity (up to 92% ee) may be obtained for both asymmetrization of meso vic-diols and kinetic resolution of racemic vic-diols.

Full text of DOI:10.1021/ol060904a

ORGANIC
LETTERS
2006
Vol. 8, No. 14
3013-3015
Highly Enantioselective CH Oxidation of
vic-Diols with Shi’s Oxazolidinone
Dioxiranes
Kavitha Jakka and Cong-Gui Zhao*
Department of Chemistry, UniVersity of Texas at San Antonio, One UTSA Circle,
San Antonio, Texas 78249-0698
cong.zhao@utsa.edu
Received April 13, 2006
ABSTRACT
Through an analogical study of the transition states of CH oxidation and asymmetric epoxidation of terminal alkenes, the first dioxirane-
mediated catalytic highly enantioselective CH oxidation method was realized with Shi’s oxazolidinone ketone derivatives. Very good
enantioselectivity (up to 92% ee) may be obtained for both asymmetrization of meso vic-diols and kinetic resolution of racemic vic-diols.
In the past decades, dioxirane has been shown to be a
powerful and highly selective oxidant, demonstrating excel-
lent chemoselectivity, regioselectivity, diastereoselectivity,
and enantioselectivity during the oxygen transfer.1 Moreover,
because dioxirane is normally obtained by the reaction of a
suitable ketone and potassium monoperoxysulfate (KHSO5),
the oxidation may be carried out in a catalytic manner under
in situ conditions. One of the highlights of the dioxirane
chemistry is its ability to oxidize the sp3-hybridized CH bond
with complete retention of configuration under mild condi-
tions.2,3 Although high regioselectivity and diastereoselec-
tivity have been achieved in the CH bond oxidation, it is
still a great challenge to achieve highly enantioselective CH
oxidation by using optically active dioxiranes.1,4 A few years
ago, Adam and co-workers demonstrated the feasibility of
enantioselective CH oxidation mediated by dioxirane with
Shi’s fructose-derived ketone 1 (Figure 1);5 however, the
enantioselectivity obtained was only mediocre (<65% ee in
most cases). Furthermore, ketone 1 is not stable under the
reaction conditions, such that an excessive amount of ketone
1 (3 equiv) is required to achieve reasonable conversions.
Herein, we wish to report the first catalytic and highly
(2) (a) Murray, R. W.; Jeyaraman, R.; Mohan, L. J. Am. Chem. Soc.
1986, 108, 2470-2472. (b) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R.
J. Am. Chem. Soc. 1989, 111, 6749-6757. (c) Adam, W.; Asensio, G.;
Curci, R.; Gonza´lez-Nun˜ez, M. E.; Mello, R. J. Org. Chem. 1992, 57, 953-
955. (d) Adam, W.; Curci, R.; D’Accolti, L.; Dinoi, A.; Fusco, C.;
Gasparrini, F.; Kluge, R.; Paredes, R.; Schulz, M.; Smerz, A. K.; Veloza,
L. A.; Weinko¨tz, S.; Winde, R. Chem.-Eur. J. 1997, 3, 105-109. (e) Curci,
R.; D’Accolti, L.; Detomaso, A.; Fusco, C.; Takeuchi, K.; Ohga, Y.; Eaton,
P.; Yip, Y.-C. Tetrahedron Lett. 1993, 34, 4559-4562. (f) D’Accolti, L.;
Detomaso, A.; Fusco, C.; Rosa, A.; Curci, R. J. Org. Chem. 1993, 58, 3600-
3601. (g) Bovicelli, P.; Sanetti, A.; Lupattelli, P. Tetrahedron 1996, 52,
10969-10978.
(3) For theoretical treatments, see: (a) Glukhovtsev, M. N.; Canepa, C.;
Bach, R. D. J. Am. Chem. Soc. 1998, 120, 10528-10533. (b) Houk, K. N.;
Du, X. J. Org. Chem. 1998, 63, 6480-6483. (c) Shustov, G. V.; Rauk, A.
J. Org. Chem. 1998, 63, 5413-5422. (d) Freccero, M.; Gandolfi, R.; Sarzi-
Amade´, M.; Rastelli, A. J. Org. Chem. 2003, 68, 811-823.
(1) For reviews, see: (a) Adam, W.; Curci, R.; Edwards, J. O. Acc. Chem.
Res. 1989, 22, 205-211. (b) Murray, R. W. Chem. ReV. 1989, 89, 1187-
1201. (c) Curci, R.; Dinoi, A.; Rubino, M. F. Pure Appl. Chem. 1995, 67,
811-822. (d) Adam, W.; Smerz, A. K. Bull. Soc. Chim. Belg. 1996, 105,
581-599. (e) Frohn, M.; Shi, Y. Synthesis 2000, 1979-2000. (f) Adam,
W.; Saha-Mo¨ller, C. R.; Zhao, C.-G. Org. React. 2002, 61, 219-516. (g)
Shi, Y. Acc. Chem. Res. 2004, 37, 488-496. (h) Adam, W.; Zhao, C.-G.;
Jakka, K. Org. React., submitted.
(4) For a recent review, see: Adam, W.; Zhao, C.-G. In Handbook of
CH Transformations: Applications in Organic Synthesis; Dyker, G., Ed.;
Wiley-VCH: Weinheim, 2005; Vol. 2, pp 507-516.
(5) (a) Adam, W.; Saha-Mo¨ller, C. R.; Zhao, C.-G. Tetrahedron:
Asymmetry 1998, 9, 4117-4122. (b) Adam, W.; Saha-Mo¨ller, C. R.; Zhao,
C.-G. J. Org. Chem. 1999, 64, 7492-7497.
10.1021/ol060904a CCC: $33.50
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Published on Web 06/16/2006

the CH bond (TSCH); and (3) in both cases, the steric and/or
electronic communications between the substrate and the
dioxirane are mainly coming from the more substituted end.
On the basis of this analysis, we hypothesized that the ketone
catalyst that induces high enantioselectivity in the epoxidation
of terminal alkenes should also induce high enantioselectivity
in CH bond oxidation.
Shi and co-workers have reported that oxazolidinone
ketones 2 and 3 are very good catalysts for the asymmetric
epoxidation of terminal alkenes such as styrenes.9 On the
basis of the recent theoretic work on the origin of the
enantioselectivity in this asymmetric epoxidation8d and our
above analogy, we reasoned that these catalysts should also
be good for CH oxidation of benzylic alcohols because in
both cases there is a phenyl group to interact with dioxirane
to direct the substrate approach.8d,9 By using a modified
procedure, we synthesized the known ketones 2 and 3 and
the new derivatives 4 and 5 and applied them for the
asymmetric CH oxidation of some benzylic Vic-diols. The
results are collected in Table 1.
To our pleasure, ketone 2 indeed yields a much improved
enantioselectivity in the asymmetrization of meso-hydroben-
zoin, and an ee value of 70% was obtained with 1 equiv of
the catalyst (Table 1, entry 1). For comparison, catalyst 1
yields only 45% ee of the product of this substrate.5 Ketone
3 is an even better catalyst for this oxidation, as a high ee
value of 87% was obtained and only 50 mol % of catalyst
loading was necessary (entry 2). This is the first example of
dioxirane-mediated asymmetric CH oxidation using a cata-
lytic amount of the ketone catalyst. The remote substituent
on the oxazolidinone ring was found to have a subtle
influence on the enantioselectivity of the reaction: with the
size of R reduced from t-Bu to Et or Me, the enantioselec-
tivity dropped slightly from 87% to 80% (entries 3 and 4).
On the basis of our preliminary screening, catalysts 3-5 are
comparable in reactivity, whereas catalyst 3 always yields a
slightly higher enantioselectivity than the other two.
Further study with catalyst 3 reveals that very good ee
values may be obtained for the asymmetrization of var-
ious meso-4,4′-disubstituted hydrobenzoins (g76% ee,
entries 5-9). However, the dependence of the enantioselec-
tivity on the electronic nature of the para substituents that
has been observed for catalyst 15 did not happen in the case
of catalyst 3.
Figure 1. Ketone catalysts utilized for CH oxidation.
enantioselective CH oxidation protocol for the oxidation of
Vic-diols.
Although ketone 1 is an excellent catalyst for the asym-
metric epoxidation of trans- and trisubstituted alkenes,6 the
asymmetric induction is considerably lower in CH bond
oxidation.5 The reason for this is probably due to totally
different steric requirements for these two oxidations.
Through the comparison of the transition state (TS) of CH
oxidation7 with those of epoxidation of different alkene
substrates, we found that these distinct TSs3,8 achieve the
closest resemblance of each other in the cases of CH
oxidation and epoxidation of the terminal alkene (Figure 2):
Figure 2. Transition states for the epoxidation of terminal alkene
(TSE) and the CH oxidation (TSCH).
(1) Both TSs are asynchronous spiro; (2) in the terminal
alkene cases (TSE), the terminal CH2 group is small and not
differentiated in space (regarding the left and right sides of
the forming oxirane plane), as is the hydrogen atom end of
(6) (a) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806-
9807. (b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Shi, Y. J. Org. Chem. 1997, 62,
2328-2329. (c) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J.
Am. Chem. Soc. 1997, 119, 11224-11235. (d) Frohn, M.; Dalkiewicz, M.;
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948-2953. (e)
Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425-
4428. (f) Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 3099-3104. (g)
Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64, 7646-7650. (h)
Frohn, M.; Zhou, X.; Zhang, J.-R.; Tang, Y.; Shi, Y. J. Am. Chem. Soc.
1999, 121, 7718-7719. (i) Lorenz, J. C.; Frohn, M.; Zhou, X.; Zhang, J.-
R.; Tang, Y.; Burke, C.; Shi, Y. J. Org. Chem. 2005, 70, 2904-2911.
(7) As one reviewer pointed out, the most recent theoretic work by Sarzi-
Amade´ and co-workers described a perpendicular radicaloid transition state
for this oxidation; however, as the authors conceded, such a mechanism
cannot explain the high selectivity data obtained experimentally (ref 3d).
(8) (a) Houk, K. N.; Liu, J.; DeMello, N. C.; Condroski, K. R. J. Am.
Chem. Soc. 1997, 119, 10147-10152. (b) Crehuet, R.; Anglada, J. M.;
Cremer, D.; Bofill, J. M. J. Phys. Chem. A 2002, 106, 3917-3929. (c)
Bach, R. D.; Dmitrenko, O.; Adam, W.; Schambony, S. J. Am. Chem. Soc.
2003, 125, 924-934. (d) Singleton, D. A.; Wang, Z. J. Am. Chem. Soc.
2005, 127, 6679-6685.
The kinetic resolution of racemic hydrobenzoins was also
studied with catalyst 3. Again, improved enantioselectivity
was observed as compared with catalyst 1. For example, with
3 as catalyst, an ee value of 87% was obtained for the product
of rac-hydrobenzoin, whereas the reported result with catalyst
1 was only 65% ee.5 In most cases, the racemic substrates
yield better enantioselectivities of the products than their
meso counterparts (entries 10-15). For example, the fluoro-
substituted racemic diol generates an ee value of 90% for
the product (entry 12), whereas the corresponding meso diol
(9) (a) Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc.
2000, 122, 11551-1152. (b) Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett.
2001, 3, 1929-1931. (c) Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org.
Chem. 2002, 67, 2435-2446. (d) Shu, L.; Wang, P.; Gan, Y.; Shi, Y. Org.
Lett. 2003, 5, 293-296.
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Org. Lett., Vol. 8, No. 14, 2006

epoxidation of cis-alkenes with ketone 3,8d the phenyl group
has to be aligned roughly parallel with the oxazolidinone
ring to lower the energy of the transition state. On the basis
of this and the theoretical work on the CH oxidations,3a-c
the following TSs were proposed to account for these results
(Figure 3).
Table 1. Enantioselective C-H Oxidation of Vic-Diolsa
diol
time yield
(h)
ee
entry
X
config catalyst
(%)b
(%)c configd
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H
H
H
H
meso
meso
meso
meso
meso
2e
3
4
5
3
3
3
3
3
3
3
3
3
3
3
1.5
1.8
1.8
1.3
1.5
1.8
1.8
1.8
1.8
1.5
1.3
1.3
1.3
1.3
2.0
60
80
90
85
85
60
65
80
74
48
42
45
38
40
10i
70
87
80
80
77
76
87
77f
76f
87g
85g
90g
84f,g
84f,g
92g
R
R
R
R
R
R
R
R
R
S
S
S
S
S
S
Me
Figure 3. Transition states for the asymmetric CH oxidation.
OMe meso
F
meso
meso
meso
rac
rac
rac
rac
rac
rac
Cl
Br
H
Me
F
Cl
Br
CNh
When the substrate is using its S-configured center to
approach the dioxirane, the favored TS may be achieved
(Figure 3, left), as the smaller hydroxy group will interact
directly with the oxazolidinone ring. If the R-configured
center is used, then the large secondary alcohol group will
have to interact with the oxazolidinone ring (Figure 3, right),
which will cause the energy of the TS to increase. Therefore,
the S-configured center will be preferably oxidized to
generate the R-product for the meso substrate (from S,R) and
the S-product for the racemic substrate (from S,S).
In summary, on the basis of the transition state analogy
hypothesis, we have developed the first dioxirane-mediated
highly enantioselective CH oxidation method with Shi’s
oxazolidinone ketone catalyst 3. Although the catalytic
efficiency of the ketone is still to be improved, very good
enantioselectivity may be obtained for both asymmetrization
of meso Vic-diols and kinetic resolution of racemic Vic-diols.
These new results demonstrate the potential of chiral
dioxiranes in highly enantioselective CH oxidations.
a Unless otherwise specified, all reactions were carried out with the diol
(0.10 mmol), the ketone catalyst (0.05 mmol, 50 mol %) and Bu4NHSO4
(4 µmol) in CH3CN (1.5 mL) and Na2B4O7 (0.5 mL)/K2CO3 buffer at 0-5
°C. For asymmetrization of meso-diols, Oxone (0.15 mmol, in 1.0 mL of
4 × 10-4 M aq solution of Na2EDTA) and K2CO3 (0.63 mmol) were used;
for kinetic resolution of rac-diols, Oxone (0.12 mmol, in 1.0 mL of 4 ×
10-4 M aq solution of Na2EDTA) and K2CO3 (0.58 mmol) were used.
b Yield of isolated product after chromatography. c Determined by HPLC
analyses. d Determined by comparison of the measured optical rotation with
the reported data (ref 5). e 0.10 mmol (100 mol %) of catalyst was used.
f Determined on the basis of its acetate. g The ee values of the remaining
diols were not determined. h 0.20 mmol of Oxone and 0.72 mmol of K2CO3
were used. i Conversion.
gives a slightly inferior 87% value (entry 7). Racemic 4,4′-
dicyanohydrobenzoin produces the highest ee value of 92%
(entry 15). The low conversion obtained in this case was
probably due to the low solubility of this substrate in such
a reaction medium.5
Acknowledgment. The authors thank the NIH-MBRS
program (Grant No. S06 GM 08194) for the generous
financial support of this project.
In the asymmetrization of meso-diols, the R-configured
R-hydroxy ketones were obtained as the major products, and
in the kinetic resolution of racemic diols, the S-configured
ones were obtained (Table 1). The results indicate that in
both cases the S-configured center is preferably oxidized.
According to the recent theoretical work on the asymmetric
Supporting Information Available: Experimental pro-
cedures, NMR spectra for all new compounds, and HPLC
analysis data. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL060904A
Org. Lett., Vol. 8, No. 14, 2006
3015