Electronic probing of ketone catalysts for asymmetric epoxidation. Search for more robust catalysts

Article abstract of DOI:10.1021/ol000385q

Equation presented Ketones with a fused oxazolidinone were synthesized and investigated to determine the electronic effect of the substituents at α-positions of ketone catalysts on the Baeyer-Villiger oxidation and catalytic properties for asymmetric epoxidation. These new ketones give high yields and ee's with only 1 5 mol % catalyst. The current studies further show that the electronic effect is very important for the kitone-catalyzed epoxidation.

Full text of DOI:10.1021/ol000385q

ORGANIC
LETTERS
2001
Vol. 3, No. 5
715-718
Electronic Probing of Ketone Catalysts
for Asymmetric Epoxidation. Search for
More Robust Catalysts
Hongqi Tian, Xuegong She, and Yian Shi*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
yian@lamar.colostate.edu
Received December 19, 2000
ABSTRACT
Ketones with a fused oxazolidinone were synthesized and investigated to determine the electronic effect of the substituents at r-positions of
ketone catalysts on the Baeyer−Villiger oxidation and catalytic properties for asymmetric epoxidation. These new ketones give high yields and
ee’s with only 1−5 mol % catalyst. The current studies further show that the electronic effect is very important for the ketone-catalyzed
epoxidation.
Asymmetric epoxidation using chiral dioxiranes generated
in situ from chiral ketones has received intensive interest in
recent years.1-4 During the course of our studies, the fructose-
derived ketone (1) has provided high enantioselectivities for
a wide range of trans- and trisubstituted olefins (Scheme
1).4 One drawback of this ketone is that it decomposes under
the oxidative reaction conditions, thus requiring relatively
high catalyst loading (typically 20-30%). It has been
postulated that the Baeyer-Villiger reaction is the likely
decomposition pathway, although corresponding lactones
(1a or 1b) have not been isolated or detected from the
reaction mixture, presumably as a result of the facile
hydrolysis of the lactones under the aqueous reaction
conditions.
* Ph: 970-491-7424. Fax: 970-491-1801.
(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. (f) Denmark, S. E.; Wu, Z. Synlett 1999, 847. (g) Frohn, M.; Shi,
Y. Synthesis 2000, 1979.
(2) For examples of in situ generation of dioxiranes, see: (a) Edwards,
J. O.; Pater, R. H.; Curci, R.; Di Furia, F. Photochem. Photobiol. 1979, 30,
63. (b) Curci, R.; Fiorentino, M.; Troisi, L.; Edwards, J. O.; Pater, R. H. J.
Org. Chem. 1980, 45, 4758. (c) Gallopo, A. R.; Edwards, J. O. J. Org.
Chem. 1981, 46, 1684. (d) Cicala, G.; Curci, R.; Fiorentino, M.; Laricchiuta,
O. J. Org. Chem. 1982, 47, 2670. (e) Corey, P. F.; Ward, F. E. J. Org.
Chem. 1986, 51, 1925. (f) Adam, W.; Hadjiarapoglou, L.; Smerz, A. Chem.
Ber. 1991, 124, 227. (g) Kurihara, M.; Ito, S.; Tsutsumi, N.; Miyata,
N. Tetrahedron Lett. 1994, 35, 1577. (h) Denmark, S. E.; Forbes, D. C.;
Hays, D. S.; DePue, J. S.; Wilde, R. G. J. Org. Chem. 1995, 60, 1391. (i)
Yang, D.; Wong, M. K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887. (j)
Denmark, S. E.; Wu, Z.; Crudden, C. M.; Matsuhashi, H. J. Org. Chem.
1997, 62, 8288. (k) Denmark, S. E.; Wu, Z. J. Org. Chem. 1997, 62, 8964.
(l) Boehlow, T. R.; Buxton, P. C.; Grocock, E. L.; Marples, B. A.;
Waddington, V. L. Tetrahedron Lett. 1998, 39, 1839. (m) Denmark, S. E.;
Since the migratory trend of Baeyer-Villiger oxidations
could be influenced by electronic factors,5,6 it was envisioned
that the Baeyer-Villiger oxidation of ketone 1 could pos-
sibly be reduced by increasing the electron deficiency of
the R-carbons via decreasing the electron density of
the oxygen attached, thus providing more stable ketone
catalysts. As part of our efforts to further understand the
factors affecting the ketone stability, some close analogues
Wu, Z. J. Org. Chem. 1998, 63, 2810. (n) Frohn, M.; Wang, Z.-X.; Shi, Y.
J. Org. Chem. 1998, 63, 6425. (o) Yang, D.; Yip, Y.-C.; Jiao, G.-S.;
Wong, M.-K. J. Org. Chem. 1998, 63, 8952. (p) Yang, D.; Yip, Y.-C.;
Tang, M.-W.; Wong, M.-K.; Cheung, K.-K. J. Org. Chem. 1998, 63,
9888.
10.1021/ol000385q CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/15/2001

Scheme 1
of ketone 1 were prepared to investigate the electronic
lactone 1a was detected as the major product by the 1H NMR
effects on catalyst stability. Herein we wish to report such
studies.
of the crude reaction mixture (Scheme 2), indicating that
When the Baeyer-Villiger reaction of ketone 1 was
carried out using mCPBA under anhydrous conditions,
Scheme 2
(3) For leading references on asymmetric epoxidation mediated in situ
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) Denmark, S. E.; Forbes,
D. C.; Hays, D. S.; DePue, J. S.; Wilde, R. G. J. Org. Chem. 1995, 60,
1391. (d) Brown, D. S.; Marples, B. A.; Smith, P.; Walton, L. Tetrahedron
1995, 51, 3587. (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: Asymmetry 1997, 8, 3995. (i) Denmark, S. E.; Wu, Z.;
Crudden, C. M.; Matsuhashi, H. J. Org. Chem. 1997, 62, 8288. (j) Wang,
Z.-X.; Shi, Y. J. Org. Chem. 1997, 62, 8622. (k) Armstrong, A.; Hayter,
B. R. Chem. Commun. 1998, 621. (l) 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. (m) Yang, D.; Yip, Y.-C.; Chen, J.; Cheung, K.-K.
J. Am. Chem. Soc. 1998, 120, 7659. (n) Adam, W.; Saha-Moller, C. R.;
Zhao, C.-G. Tetrahedron: Asymmetry 1999, 10, 2749. (o) Wang, Z.-X.;
Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 1999, 64, 6443.
(p) Carnell, A. J.; Johnstone, R. A. W.; Parsy, C. C.; Sanderson, W.
R. Tetrahedron Lett. 1999, 40, 8029. (q) Armstrong, A.; Hayter, B.
R. Tetrahedron 1999, 55, 11119. (r) Armstrong, A.; Hayter, B. R.;
Moss, W. O.; Reeves, J. R.; Wailes, J. S. Tetrahedron: Asymmetry
2000, 11, 2057. (s) Solladie-Cavallo, A.; Bouerat, L. Org. Lett. 2000, 2,
3531.
C4 in ketone 1 is more prone to migrate than C2 in the
Baeyer-Villiger reaction. Increasing the electron defi-
ciency of C4, therefore, became our initial focus. To maintain
the high enantioselectivity of the epoxidation, our studies
focused on ketones with minimal skeletal change from 1.
Our initial target was ketone 2, where the fused ketal in 1
was replaced with an electron-withdrawing cyclic carbonate
(Scheme 3). C4 should be less likely to migrate in the
Baeyer-Villiger oxidation, resulting in a more robust ketone.
(4) For examples of asymmetric epoxidation mediated in situ by fructose-
derived ketones, see: (a) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc.
1996, 118, 9806. (b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Shi, Y. J. Org. Chem.
1997, 62, 2328. (c) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y.
J. Am. Chem. Soc. 1997, 119, 11224. (d) Frohn, M.; Dalkiewicz, M.; Tu,
Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948. (e) Wang, Z.-X.;
Shi, Y. J. Org. Chem. 1998, 63, 3099. (f) Cao, G.-A.; Wang, Z.-X.; Tu,
Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425. (g) Zhu, Y.; Tu, Y.; Yu, H.;
Shi, Y. Tetrahedron Lett. 1998, 39, 7819. (h) Tu, Y.; Wang, Z.-X.; Frohn,
M.; He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998, 63, 8475. (i)
Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64, 7646. (j) Warren,
J. D.; Shi, Y. J. Org. Chem. 1999, 64, 7675. (k) Frohn, M.; Zhou, X.; Zhang,
J.-R.; Tang, Y.; Shi, Y. J. Am. Chem. Soc. 1999, 121, 7718. (l) Shu, L.;
Shi. Y. Tetrahedron Lett. 1999, 40, 8721.
Scheme 3
(5) For a recent review of the Baeyer-Villiger oxidation, see: Krow,
G. R. Org. React. 1993, 43, 251.
716
Org. Lett., Vol. 3, No. 5, 2001

Table 1. Asymmetric Epoxidation of Olefins by Ketones 3a
a All reactions were carried out at 0 °C with substrate (1 equiv), ketone (0.01-0.05 equiv), Oxone (1.49-2.13 equiv), and K2CO3 (3.12-4.45 equiv) in
(2:1:2, v/v) DMM/CH3CN/buffer (0.2 M K2CO3/HOAc, pH 8.0). For 5 h reaction, 1.49 equiv of Oxone and 3.12 equiv of K2CO3 were used. For 7 h
reaction, 2.13 equiv of Oxone and 4.45 equiv of K2CO3 were used. b The epoxides were purified by flash chromatography and gave satisfactory spectroscopic
characterization. c The number is the conversion that is determined by GC. d Enantioselectivity was determined by chiral GC (Chiraldex G-TA column).
e Enantioselectivity was determined by chiral HPLC (Chiralcel OD column). f The absolute configurations were determined by comparing the GC and HPLC
chromatograms with the reported ones.
Attempts to synthesize ketone 2 were unsuccessful as a result
of hydrolysis of the carbonate. Subsequently, ketone 3,
containing a hydrolytically more stable oxazolidinone, was
investigated. Ketones 3a-c were prepared from D-fructose
as outlined in Scheme 4. These ketones exist largely in
hydrate forms, indicating that the carbonyl groups are quite
electrophilic.
high yields and ee’s were obtained in these cases using 5
mol % ketone 3c. In one case (entry 9), the catalyst loading
could be reduced as low as 1 mol %, still giving a good
yield and high ee.
By adjusting the electron nature of the R carbons, the
catalyst loading can be lowered from 20-30% for ketone 1
to 1-5 mol % for ketone 3c while the yields and ee’s are
maintained. Upon the basis of the absolute configuration of
the epoxide products, the epoxidation appears to occur via
the spiro transition state similar to ketone 1.4c The enanti-
oselectivity obtained with ketone 3c is very similar to that
With ketones 3a-c in hand, their catalytic properties for
epoxidation were investigated using trans-â-methylstyrene
as the test substrate. These ketones were indeed found to be
active catalysts (Table 1, entries 1-3), with high conversions
obtained when 5 mol % ketone was used.7 The substituent
on the nitrogen showed some effect on both conversion and
enantioselectivity, with ketone 3c giving the best results.
Encouraged by this, additional olefins were then investigated
for the epoxidation. As shown in Table 1 (entries 4-10),
(7) Representative Procedure for Asymmetric Epoxidation. To a
stirred solution of phenylcyclohexene (0.079 g, 0.50 mmol) in DMM/CH3-
CN (2:1 v/v) (7.5 mL) were added buffer (0.2 M K2CO3/AcOH, pH )
8.0) (5 mL), Bu4NHSO4 (7.5 mg, 0.020 mmol), and ketone 3c (0.004 g,
0.01 mmol). The mixture was cooled to 0 °C via an ice bath. A solution
of Oxone (0.458 g, 0.744 mmol) in aqueous Na2EDTA (4 × 10-4 M, 3.5
mL) and a solution of K2CO3 (0.215 g, 1.558 mmol) in water (3.5 mL)
were added dropwise simultaneously through two separate syringes via
syringe pump over a period of 5 h. Upon quenching with hexane and
water, the reaction mixture was extracted with hexane (3 × 30 mL), washed
with brine, dried (Na2SO4), filtered, concentrated, and purified by flash
chromatography [the silica gel was buffered with 1% Et3N in hexane;
hexanes/ether (1:0 to 10:1 v/v) was used as eluent] to afford phenylcyclo-
hexne oxide as a colorless liquid (0.081 g, 93% yield, 97% ee) (Table 1,
entry 9).
(6) For leading references on the regioselective Baeyer-Villiger reaction
of polyhydroxycyclohexanone derivatives, see: (a) Chida, N.; Yamada, E.;
Ogawa, S. J. Carbohydr. Chem. 1988, 7, 555. (b) Chida, N.; Suzuki, M.;
Suwama, M.; Ogawa, S. J. Carbohydr. Chem. 1989, 8, 319. (c) Chida,
N.; Tanikawa, T.; Tobe, T.; Ogawa, S. J. Chem. Soc., Chem. Commun.
1994, 1247. (d) Chida, N.; Tobe, T.; Ogawa, S. Tetrahedron Lett. 1994,
35, 7249.
Org. Lett., Vol. 3, No. 5, 2001
717

In summary, the replacement of the fused ketal of ketone
1 with an oxazolidinone creates a more stable and reactive
catalyst for asymmetric epoxidation. Presumably the en-
hanced stability of ketone 3 is due to the reduction of
Baeyer-Villiger decomposition.8,9 The ketones synthesized
are highly active, giving good yields and enantioselectivities
for a variety of olefin substrates. The catalyst loading can
be reduced to 5 mol % and even 1 mol % in some cases.
Generally speaking, developing catalysts using small loading
is still one of the challenges for the chiral ketone-catalyzed
asymmetric epoxidation. The information gained from this
study is helpful for the further understanding of the ketone-
catalyzed epoxidation and for the design of more efficient
catalysts in the future.
Scheme 4a
Acknowledgment. We are grateful for generous financial
support from the General Medical Sciences of the National
Institutes of Health (GM59705-02), the Arnold and Mabel
Beckman Foundation, the Camille and Henry Dreyfus
Foundation, the Alfred P. Sloan Foundation, DuPont, Eli
Lilly, GlaxoWellcome, and Merck.
a Reaction conditions: (a) 2,2-dimethoxypropane, acetone, HClO4,
0 °C, 53% (ref 4c). (b) PhCOCl, Et3N, CH2Cl2, rt, 93%. (c) DDQ
(0.1 equiv), CH3CN/H2O, rt, 24 h, 92%. (d) PPh3, imidazole, I2,
Zn, 79%. (e) K2CO3, MeOH, rt, 12 h, 68%. (f) TBSCl, Et3N,
DMAP, CH2Cl2, rt, 24 h, 100%. (g) K2OsO6H4, chloramine-T
trihydrate, CH3CN/H2O, rt, overnight, 91%. (h) triphosgene, pyri-
dine, CH2Cl2, 0 °C, 84%. (i) Li, NH3(l), THF, -78 °C, overnight,
64%. (j) for 9a, NaH, MeI, THF, rt, 2 h, 93%; for 9b, NaH, BnBr,
THF, rt, 2 h, 70%; for 9c, NaH, t-BuO2CCH2Br, THF, rt, 96%. (k)
TBAF, THF, rt, 91-96%. (l) PCC, 3 Å MS, CH2Cl2, rt, 3-12 h,
73-93%.
Supporting Information Available: The preparation and
characterization of ketones 3a-c. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL000385Q
(8) The Baeyer-Villiger reactions of ketones 3a-c with mCPBA were
attempted. However, the results were not conclusive since the NMR spectra
of the reaction mixture were not clean, partly as a result of the hydration
of the ketones.
(9) The recovery of ketones 3a-c was found to be difficult partly because
of the low catalyst loading and high water solubility of the ketones (highly
hydrated).
of ketone 1, indicating that the configuration of the ketone
was not greatly changed by changing the electronic nature
of C4.
718
Org. Lett., Vol. 3, No. 5, 2001