Kinetic resolution of racemic cyclic olefins via chiral dioxirane [12]

Full text of DOI:10.1021/ja9830039

7718
J. Am. Chem. Soc. 1999, 121, 7718-7719
Scheme 1
Kinetic Resolution of Racemic Cyclic Olefins via
Chiral Dioxirane
Michael Frohn,† Xiaoming Zhou,† Jian-Rong Zhang,†
Yong Tang, and Yian Shi*
Department of Chemistry, Colorado State UniVersity
Fort Collins, Colorado 80523
Scheme 2
ReceiVed August 21, 1998
Chiral dioxiranes have been shown to be effective reagents
for asymmetric epoxidation of olefins.1,2 Recently we reported a
highly enantioselective epoxidation method for trans- and trisub-
stituted olefins using a fructose-derived ketone 1 as catalyst and
Oxone as oxidant.3 The epoxidation has been shown to proceed
primarily through a well ordered spiro transition state A (Scheme
1).3b Since dioxiranes are expected to be sensitive to sterics, an
existing chiral center adjacent to the double bond provides the
possibility for kinetic resolution.4 Herein we wish to report our
preliminary studies in this area.
Scheme 3
Our initial studies have been focused on cyclic olefins with
the chiral center at the allylic position. The rigid conformation
and proximity of the chiral center to the olefin make them
promising candidates for kinetic resolution. Therefore, we began
the study with 1,6-disubstituted cyclohexenes (3) (Scheme 2).
Transition states B and C represent the spiro transition states for
the epoxidation of each enantiomer. Transition state C is expected
to be disfavored compared to transition state B due to the steric
interaction between R2 and one of the dioxirane oxygens.
Consequently one enantiomer would be epoxidized faster than
the other.
Scheme 4
* Corresponding author. Phone: 970-491-7424. Fax: 970-491-1801.
Email: yian@lamar.colostate.edu.
† M. F., X. Z., and J.R.Z. contributed equally to this work.
(1) For general leading references on dioxiranes see: (a) Murray, R. W.
Chem. ReV. 1989, 89, 1187. (b) Adam, W.; Curci, R.; Edwards, J. O. Acc.
Chem. Res. 1989, 22, 205. (c) Curci, R.; Dinoi, A.; Rubino, M. F. Pure Appl.
Chem. 1995, 67, 811. (d) Clennan, E. L. Trends Org. Chem. 1995, 5, 231. (e)
Adam, W.; Smerz, A. K. Bull. Soc. Chim. Belg. 1996, 105, 581.
(2) For leading references on asymmetric epoxidation mediated by chiral
ketones see: (a) Curci, R.; Fiorentino, M.; Serio, M. R. J. Chem. Soc., Chem.
Commun. 1984, 155. (b) Curci, R.; D’Accolti, L.; Fiorentino, M.; Rosa, A.
Tetrahedron Lett. 1995, 36, 5831. (c) Brown, D. S.; Marples, B. A.; Smith,
P.; Walton, L Tetrahedron 1995, 51, 3587. (d) Denmark, S. E.; Forbes, D.
C.; Hays, D. S.; DePue, J. S.; Wilde, R. G. J. Org. Chem. 1995, 60, 1391. (e)
Yang, D.; Yip, Y. C.; Tang, M. W.; Wong, M. K.; Zheng, J. H.; Cheung, K.
K. J. Am. Chem. Soc. 1996, 118, 491. (f) Yang, D.; Wang, X.-C.; Wong,
M.-K.; Yip, Y.-C.; Tang, M.-W. J. Am. Chem. Soc. 1996, 118, 11311. (g)
Song, C. E.; Kim, Y. H.; Lee, K. C.; Lee, S. G.; Jin, B. W. Tetrahedron:
Asymmetry 1997, 8, 2921. (h) Adam, W.; Zhao, C.-G. Tetrahedron: Asym-
metry 1997, 8, 3995. (i) Denmark, S. E.; Wu, Z.; Crudden, C. M.; Matsuhashi,
H. J. Org. Chem. 1997, 62, 8288. (j) Bergbreiter, D. E. Chemtracts: Org.
Chem. 1997, 10, 661. (k) Armstrong, A.; Hayter, B. R. Chem. Commun. 1998,
621. (l) Dakin, L. A.; Panek, J. S. Chemtracts: Org. Chem. 1998, 11, 531.
(m) Yang, D.; Wong, M.-K.; Yip, Y.-C.; Wang, X.-C.; Tang, M.-W.; Zheng,
J.-H.; Cheung, K.-K. J. Am. Chem. Soc. 1998, 120, 5943.
Scheme 5
To test this hypothesis, we used (()-1-phenyl-6-(trimethyl-
siloxy)cyclohexene (4) as our initial substrate. When the epoxi-
dation was carried out with 35% ketone 1 at -10 °C for 2.5 h, a
49% conversion was obtained as judged by H NMR assay of
1
1
the crude reaction mixture (Scheme 3). The H NMR spectra
showed that the trans epoxide was formed predominantly (trans/
cis > 20:1).5 Analysis of the unreacted substrate using HPLC on
a chiral support (Chiralcel OD) showed a 96% ee. The fact that
the major epoxide product was trans and the recovered olefin
was enriched in the S isomer supports the above transition state
analysis.
(3) (a) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
(b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc.
1997, 119, 11224. (c) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi,
Y. J. Org. Chem. 1998, 63, 2948. (d) Wang, Z.-X.; Shi, Y. J. Org. Chem.
1998, 63, 3099. (e) Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron
Lett. 1998, 39, 4425. (f) Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett.
1998, 39, 7819. (g) Tu, Y.; Wang, Z.-X.; Frohn, M.; He, M.; Yu, H.; Tang,
Y.; Shi, Y. J. Org. Chem. 1998, 63, 8475.
(4) Many excellent kinetic resolution methods have been developed. For
leading references on kinetic resolution by asymmetric epoxidation see: (a)
Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless,
K. B. J. Am. Chem. Soc. 1981, 103, 6237. (b) Johnson, R. A.; Sharpless, K.
B. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993;
Chapter 4.1. (c) Vander Velde, S. L.; Jacobsen, E. N. J. Org. Chem. 1995,
60, 5380. (d) Noguchi, Y.; Irie, R.; Fukuda, T.; Katsuki, T. Tetrahedron Lett.
1996, 37, 4533.
(5) The trans configuration of the major isomer was assigned on the basis
of the following comparison: Epoxide 5 was desilylated with TBAF. The 1H
NMR analysis showed that the resulting epoxy alcohol matched the minor
isomer (trans epoxide) of the epoxidation products of 2-phenyl-2-cyclohexenol
with m-CPBA. It is known that the epoxidation of an allylic alcohol with
m-CPBA gives the cis epoxide as a major product due to the directing effect
of the hydroxy group. For a leading reference on this subject see: Hoveyda,
A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
10.1021/ja9830039 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/06/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 33, 1999 7719
Table 1. Kinetic Resolution of Representative Olefins by Ketone 1
of 1,3-disubstituted cyclohexenes (6) (Scheme 4). The kinetic
resolution efficiency would be dependent on the energy difference
between repulsive interactions a and b. Subjecting the TBS ether
of 3-phenyl-2-cyclohexenol (7)6 to the typical reaction conditions
(with 40% ketone catalyst 1 at -10 °C for 1.5 h) led to a 70%
conversion of the substrate (Scheme 5). The product was a 4:1
mixture of trans and cis epoxides (8) favoring the trans isomer.7
This result demonstrates that transition state D is favored over
E, suggesting that the interaction b is greater than the interaction
a.8 The enantiomeric excess of the unreacted substrate was
determined to be 99%.
Catalyzed Asymmetric Epoxidationa
recov’d
temp con. SM ee epoxide epoxide
(°C) (%)b (%)c ee (%) (trans/cis)d (kf/ks)
trans
e
krel
entry
substrate
1f
2i
3l
R ) TMS
R ) Me
-10 49 96g (S)h
-10 65 99j (S)
95g
85k
88j
97j
>20
6
>100
16
R ) COMe
0
54 96m (S)
12
39
4n,o R ) COOEt -10 51 94g (S)
>20
70
Encouraged by the result obtained for compound 7, we prepared
and investigated a number of 1,3-disubstituted cyclohexenes
(Table 1, entries 6-12). The resolution efficiency for these
substrates is reasonably good. On the basis of the reaction model
presented in Scheme 4, the unreacted substrates presented in
entries 5-10 and 12 are likely to have R configurations. To
confirm the configuration, the pivaloate in entry 12 was converted
to 3-tert-butylcyclohexanone by hydrolysis (NaOMe-MeOH). The
resulting ketone was determined to indeed have the R configu-
ration by comparing the measured optical rotation with the
reported value for the ketone.9
5p R ) TBS
-10 70 99g (R)
-10 61 95g (R)
81q
nd
4
6
11
14
6r
R ) Me
7r
0
72 81m (R)
nd
1.7
4
In summary, we have shown that the kinetic resolution of 1,3
and 1,6-disubstituted cyclohexenes via chiral dioxirane is feasible.
High-resolution efficiency was obtained for a number of trisub-
stituted cyclic olefin substrates,10 which provides a valuable way
to prepare certain chiral intermediates in a straightforward manner.
Since the dioxirane-mediated resolution is expected to rely largely
on steric interactions, this process could potentially be applied to
olefins with a variety of substituents. Extension of this resolution
to other classes of substrates is currently under study. In addition
to the synthetic value, such a study will yield useful mechanistic
information.
8r
9r
R ) TBS
R ) TBS
-10 49 75s (R)
nd
nd
13
8
18
11
20 66 96s (R)
10n R ) OTMS -10 61 91m (R)
76k
85k
84k
4
8
>20
11
15
61
11t
12i
R ) iPr
R ) tBu
-10 59 93m (S)
-10 54 99m (R)u
a All reactions were carried out with substrate (1 equiv), ketone
(0.25-0.75 equiv), Oxone (2.3 equiv), and K2CO3 (9.5 equiv) in
CH3CN-DMM-0.05 M Na2B4O7‚10H2O in aqueous EDTA (4 × 10-4
M) solution (1:2:2, v/v/v). Oxone was added over 2.5 h except for entry
5 and entry 6 (1.5 h). b Conversion was determined by 1H NMR of the
crude reaction mixture after workup. In cases where the ee of the
epoxide was determined and one diastereomer of the epoxide was
formed predominately (entries 1, 4, and 12), the conversion could be
cross-checked applying the ee’s of the olefin and epoxide to the
following equation: ee(olefin)/ee(epoxide) ) C/(1 - C). In these cases
the meassured conversion was consistent with the calculated conversion.
c The absolute configuration was tentatively assumed on the basis of
the spiro reaction mode unless otherwise noted. d The ratio of trans
Acknowledgment. We are grateful to the generous financial support
from the Beckman Young Investigator Award Program, the General
Medical Sciences of the National Institutes of Health (GM55704-01),
the Camille and Henry Dreyfus New Faculty Award Program, Alfred P.
Sloan Foundation, and Colorado State University.
Supporting Information Available: Experimental procedure for the
kinetic resolution reaction and the characterization data of the compounds
in Table 1 along with the HPLC and NMR spectral data for the
determination of the enantiomeric excess of the unreacted substrates and
the epoxide products. This material is available free of charge via the
Internet at http://pubs.acs.org.
and cis epoxides was determined by H NMR. e The relative rate was
1
calculated using the equation krel ) kf/ks ) ln[(1 - C)(1 - ee)]/ln[(1
- C)(1 + ee)], where C is the conversion and ee is the percent
enantiomeric excess of the recovered starting material (ref 12). f 0.35
equiv of ketone used. g Enantioselectivity was determined by chiral
HPLC (Chiralcel OD). h The configuration was determined by compar-
ing the measured optical rotation with the known alcohol after
desilylation (ref 11). i 0.45 equiv of ketone used. j Enantioselectivity
was determined by chiral HPLC (Chiralcel AD). k Enantioselectivity
was determined by 1H NMR shift analysis using Eu(hfc)3. l 0.50 equiv
of ketone used. m Enantioselectivity was determined by chiral HPLC
(Chiralcel OJ). n 0.60 equiv of ketone used. o 2.8 equiv of Oxone used.
p 0.40 equiv of ketone used. q Enantioselectivity was determined by
chiral HPLC (Chiralcel AD) of the corresponding benzoate. r 0.25 equiv
of ketone used. s Enantioselectivity was determined by chiral HPLC
(Chiralcel OD) after desilylation with TBAF. t 0.75 equiv of ketone
used. u The configuration was determined by comparing the measured
optical rotation with the known ketone after hydrolysis (ref 9).
JA9830039
(6) For kinetic resolution of related systems using asymmetric dihydroxy-
lation see: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2503.
(7) The trans configuration was assigned as epoxide 5.
(8) In addition to the spiro transition state (C or E), the epoxidation of the
less reactive enantiomer of the substrate could proceed via an alternative planar
transition state to give the trans epoxide, particularly when R2 is large (e.g.,
Table 1, entry 12) (for further discussion of the effects of sterics on the
transition state, see ref 3b).
(9) Dieter, R. K.; Tokles, M. J. Am. Chem. Soc. 1987, 109, 2040.
(10) For a Zr-catalyzed kinetic resolution of cyclic allylic ethers see: (a)
Visser, M. S.; Harrity, J. P. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1996, 118,
3779. (b) Harrity, J. P. A.; Visser, M. S.; Gleason, J. D.; Hoveyda, A. H. J.
Am. Chem. Soc. 1997, 119, 1488.
(11) Allen, J. V.; Williams J. M. J. Tetrahedron Lett. 1996, 37, 1859.
(12) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
The feasibility of the kinetic resolution of (()-2-phenyl-2-
cyclohexenol derivatives led us to investigate the kinetic resolution