Arabinose-derived ketones as catalysts for asymmetric epoxidation of alkenes

Article abstract of DOI:10.1021/jo050928f

Readily available arabinose-derived ketones, containing a tunable butane-2,3-diacetal as the steric blocker, displayed increasing enantioselectivity (up to 90% ee) with the size of the acetal alkyl group in catalytic asymmetric epoxidation of trans-disubstituted and trisubstituted alkenes. The stereochemical communication between our ketone catalysts and the alkene substrates is mainly due to steric effect, and electronic effect involving π-π interaction between phenyl groups of substrate and of catalyst did not appear to be operative in our system.

Full text of DOI:10.1021/jo050928f

Arabinose-Derived Ketones as Catalysts for Asymmetric
Epoxidation of Alkenes
Tony K. M. Shing,* Gulice Y. C. Leung, and To Luk
Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong, China
tonyshing@cuhk.edu.hk
Received May 10, 2005
Readily available arabinose-derived ketones, containing a tunable butane-2,3-diacetal as the steric
blocker, displayed increasing enantioselectivity (up to 90% ee) with the size of the acetal alkyl
group in catalytic asymmetric epoxidation of trans-disubstituted and trisubstituted alkenes. The
stereochemical communication between our ketone catalysts and the alkene substrates is mainly
due to steric effect, and electronic effect involving π-π interaction between phenyl groups of
substrate and of catalyst did not appear to be operative in our system.
Introduction
ketones, have become promising reagents for asymmetric
epoxidation of unfunctionalized alkenes.4 The pioneering
asymmetric epoxidation using chiral ketone catalysts was
reported by Curci et al. in 1984.5 Subsequently, elegant
11-membered C2 symmetry biaryl ketones developed by
the Yang group6 afforded impressive enantioselectivity
results that then have encouraged worldwide investiga-
tion on the subject. Now, many research groups,7 includ-
ing Adam,8 Armstrong,9 Denmark,10 Shi,11 and Solladie´-
Cavallo,12 have achieved attractive results using different
chiral ketone/oxone systems. A notable application of this
epoxidation protocol has been described recently, using
Yang’s 11-membered C2 symmetry binaphthyl ketone6 as
Catalytic asymmetric epoxidation of alkenes is a
versatile synthetic method to induce chirality into organic
molecules, and many natural products contain epoxide
units for their biological activities.1 Catalytic enantiose-
lective epoxidation based on transition metal-containing
complexes is well developed, and chiral epoxides could
be obtained from allylic alcohols2 and unfunctionalized
cis-alkenes3 with high enantioselectivity. In recent years,
chiral dioxiranes, generated in situ from Oxone and chiral
* Tel: +852-2609 6344. Fax: +852-2603 5057.
(1) (a) Jose, M. C.; Maria, T. M.; Shazia, A. Chem. Rev. 2004, 104,
2857-2900. (b) Li, C.; Johnson, R. P.; Porco, J. A., Jr. J. Am. Chem.
Soc. 2003, 125, 5095-5106. (c) Altmann, K. H.; Bold, G.; Caravatti,
G.; Denni, D.; Florsheimer, A.; Schmidt, A.; Rihs, G.; Wartmann, M.
Helv. Chim. Acta 2002, 85, 4086-4110. (d) Valluri, M.; Hindupur, R.
M.; Bijoy, P.; Labadie, G.; Jung, J. C.; Avery, M. A. Org Lett. 2001, 3,
3607-3609. (e) Nicoloau, K. C.; Sarabia, F.; Ninkovic, S,; Finlay, M.
R. V.; Boddy, C. N. C. Angew. Chem., Int. Ed. 1998, 37, 81-84.
(2) (a) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1-299. (b)
Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: New York, 1993; Chapter 4.1. (c) Katsuki, T.;
Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 464-465. (d) Katsuki,
T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-5976.
(3) (a) Mukaiyama T. Aldrichimica Acta 1996, 29, 59. (b) Palucki,
M.; McCormick, G. J.; Jacobsen, E. N. Tetrahedron Lett. 1995, 36,
5457-5460. (c) Katsuki, T. Coord. Chem. Rev. 1995, 140, 189-214.
(d) Deng, L.; Jacobsen, E. N. J. Org. Chem. 1992, 57, 4320-4323. (e)
Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am.
Chem. Soc. 1991, 113, 7063-7064. (f) Lee, N. H.; Muci, A. R.; Jacobsen,
E. N. Tetrahedron Lett. 1991, 32, 5055-5058.
(4) For reviews, see: (a) Yang, D. Acc. Chem. Res. 2004, 37, 497-
505. (b) Shi, Y. Acc. Chem. Res. 2004, 37, 488-496. (c) Frohn, M.; Shi,
Y. Synthesis 2000, 14, 1979-2000.
(5) (a) Curci, R.; D’Accolti, L.; Fiorentino, M.; Rosa, A. Tetrahedron
Lett. 1995, 36, 5831-5834. (b) Curci, R.; Florentino, M.; Serio, M. R.
J. Chem. Soc., Chem. Commun. 1984, 155-156.
(6) (a) Yang, D.; Jiao, G.-S.; Yip, Y.-C.; Lai, T.-H.; Wong, M.-K. J.
Org. Chem. 2001, 66, 4619-4624. (b) Yang, D.; Jiao, G. S. Chem.-
Eur. J. 2000, 6, 3517-3521. (c) Yang, D.; Jiao, G. S.; Yip, Y. C.; Wong,
M. K. J. Org. Chem. 1999, 64, 1635-1639. (d) 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, 5943-5952. (e) Yang, D.; Yip, Y. C.; Chen,
J.; Cheung, K. K. J. Am. Chem. Soc. 1998, 120, 7659-7660. (f) Yang,
D.; Yip, Y. C.; Tang, M. W.; Wong, M. K.; Cheung, K. K. J. Org. Chem.
1998, 63, 9888-9894. (g) Yang, D.; Yip, Y. C.; Jiao, G. S.; Wong, M. K.
J. Org. Chem. 1998, 63, 8952-8956. (h) Yang, D.; Yip, Y. C.; Tang, M.
W.; Wong, M. K.; Zheng, J. H.; Cheung, K. K. J. Am. Chem. Soc. 1996,
118, 491-492. (i) Yang, D.; Wang, X. C.; Wong, M.-K.; Yip, Y. C.; Tang,
M.-W. J. Am. Chem. Soc. 1996, 118, 11311-11312.
10.1021/jo050928f CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/10/2005
J. Org. Chem. 2005, 70, 7279-7289
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Shing et al.
19
SCHEME 1.
Syntheses of Chiral Ketones from L-Arabinosea
a Reagents and conditions: (a) BnOH, AcCl (0.6 equiv), room temperature (rt), 5 d, 87%; (b) 2,2,3,3-tetramethoxybutane (1.2 equiv),
CH(OMe)3 (4 equiv), (()-CSA (0.1 equiv), reflux, 12 h, 76% for 2; 2,2,3,3-tetraethoxybutane (1.2 equiv), CH(OEt)3 (4 equiv), (()-CSA (0.1
equiv), reflux, 12 h, 50% for 3; (c) 2-methyl-1-propanol (4 equiv), p-TsOH, PhH, Dean-Stark trap, reflux, 12 h, 85%; (d) PDC (1.5 equiv),
3 Å MS, CH2Cl2, rt, 12 h, 90% for 5, 85% for 6, 95% for 7.
the catalyst, in a practical synthesis methyl (2R,3S)-3-
(4-methoxyphenyl)glycidate, a key intermediate for cal-
cium antagonist diltiazem hydrochloride.13 Our long-term
interest in the application of carbohydrates in asym-
metric synthesis has prompted us to search for a readily
prepared ketone catalyst to induce chirality with high
ee in asymmetric epoxidation. The abundance of arabi-
nose in the chiral pool and its commercial availability in
large quantities for both enantiomers have made it the
first choice for our studies. Over the years, we had
described the use of arabinose-derived alcohols as chiral
auxiliaries in asymmetric Diels-Alder reaction14 and in
asymmetric Hosomi-Sakurai reaction.15 Our efforts to-
ward enantioselective epoxidation of alkenes have fur-
nished chiral ketone catalysts derived from D-glucose16
as well as 2-uloses and 3-uloses derived from L-arabi-
nose.17 Recently, we reported in a communication that
readily available arabinose-derived 4-uloses 5-7, con-
taining a tunable butane-2,3-diacetal18 as the steric
blocker and using Oxone as oxidant, displayed increasing
enantioselectivity with the size of the acetal alkoxy group
in catalytic asymmetric epoxidation of trans-disubstitut-
ed and trisubstituted alkenes.19 These sugar ketones 5-7
were readily prepared from L-arabinose in three (for 5
and 6) or four steps (for 7), involving Fischer glycosida-
tion, transacetalization, and oxidation reactions (Scheme
1).19 According to this protocol, the methoxy substituents
in bis-acetal 2 have now been exchanged to different
alkoxy groups by transacetalization20 under acidic condi-
tions, and ketones with various acetals, such as an
isopropyl group, an isopentyl, a neopentyl, a benzyl
group, and a cyclohexylmethyl group, have been synthe-
sized. The enantioselectivities displayed by these ketones
721 and 13-17 in catalytic asymmetric epoxidation of
olefins are reported in this article.
(7) (a) Matsumoto, K.; Tomioka, K. Tetrahedron Lett. 2002, 43, 631-
633. (b) Klein, S.; Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 2002,
2686-2691. (c) Stearman C. J.; Behar V. Tetrahedron Lett. 2002, 43,
1943-1946. (d) Seki, M.; Furutani T.; Hatsuda M.; Imashiro, R.
Tetrahedron Lett. 2000, 41, 2149-2152. (e) Carnell, A. J.; Johnstone,
R. A. W.; Parsy, C. C.; Sanderson, W. R. Tetrahedron Lett. 1999, 40,
8029-8032. (f) Dakin, L. A.; Panek, J. S. Chemtracts: Org. Chem. 1998,
11, 531. (g) Bergbreiter, D. E. Chemtracts: Org. Chem. 1997, 10, 661.
(h) Song, C. E.; Kim, Y. H.; Lee, K. C.; Lee, S. G.; Jin, B. W.
Tetrahedron: Asymmetry 1997, 8, 2921-2926.
(8) (a) Adam, W.; Saha-Moller, C. R.; Zhao, C.-G. Tetrahedron:
Asymmetry 1999, 10, 2749-2755. (b) Adam, W.; Zhao, C.-G. Tetrahe-
dron: Asymmetry 1997, 8, 3995-3998.
(9) (a) Armstrong, A.; Ahme, G.; Dominguez-Fernandez, B.; Hayter,
B. R.; Wailes, J. S. J. Org. Chem. 2002, 67, 8610-8617. (b) Armstrong,
A.; Moss, W. O.; Reeves, J. R. Tetrahedron: Asymmetry 2001, 12, 2779-
2781. (c) Armstrong, A.; Hayter, B. R.; Moss, W. O.; Reeves, J. R.;
Wailes, J. S. Tetrahedron: Asymmetry 2000, 11, 2057-2061. (d)
Armstrong, A.; Hayter, B. R. Chem Commun. 1998, 621-622.
(10) (a) Denmark, S. E.; Wu, Z.; Crudden, C. M.; Matsuhashi, H. J.
Org. Chem. 1997, 62, 8288-8289. (b) Denmark, S. E.; Forbes, D. C.;
Hays, D. S.; DePue, J.; Wilde, R. G. J. Org. Chem. 1995, 60, 1391-
1407.
(11) (a) Lorenz, J. C.; Frohn, M.; Zhou, X. M.; Zhang, J. R.; Tang,
Y.; Burke, C.; Shi, Y. J. Org. Chem. 2005, 70, 2904-2911. (b) Shu, L.;
Shi, Y. Tetrahedron Lett. 2004, 45, 8115-8117. (c) Shu, L.; Wang, P.;
Gan, Y.; Shi, Y. Org. Lett. 2003, 5, 293-296. (d) Shu, L.; Shen, Y.-M.;
Burke, C.; Goeddel, D.; Shi, Y. J. Org. Chem. 2003, 68, 4963-4965.
(e) Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792-
8793. (f) Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002,
67, 2435-2446. (g) Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3,
1929-1931. (h) Tian, H.; She, X.; Shi, Y. Org. Lett. 2001, 3, 715-718.
(i) Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem.
2001, 66, 521-530. (j) Shu, L.; Shi, Y. Tetrahedron 2001, 57, 5213-
5218. (k) Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc.
2000, 122, 11551-11552. (l) Warren, J. D.; Shi, Y. J. Org. Chem. 1999,
64, 7675-7677. (m) Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999,
64, 7646-7650. (n) Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y.
J. Org. Chem. 1999, 64, 6443-6458. (o) Frohn, M.; Dalkiewicz, M.;
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948-2953. (p)
Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39,
4425-4428. (q) Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998,
39, 7819-7822. (r) Wang, Z. X.; Shi, Y. J. Org. Chem. 1997, 62, 8622-
8623. (s) Tu, Y.; Wong, Z. X.; Shi, Y. J. Am. Chem. Soc. 1996, 118,
9806-9807.
(14) (a) Shing, T. K. M.; Chow; H.-F.; Chung, I. H. F Tetrahedron
Lett. 1996, 37, 3713-3716. (b) Shing, T. K. M.; Lloyd-Williams, P. J
Chem. Soc., Chem. Commun. 1987, 423-424.
(15) Shing, T. K. M.; Li, L.-H. J. Org. Chem. 1997, 62, 1230-1233.
(16) Shing, T. K. M.; Leung, G. Y. C. Tetrahedron 2002, 58, 7545-
7552.
(17) Shing, T. K. M.; Leung; Y. C.; Yeung, K. W. Tetrahedron 2003,
59, 2159-2168.
(18) For a review on 1,2-diacetals, see: Ley, S. V.; Baeschlin, D. K.;
Dixon, D. J.; Foster, A. C.; Ince, S. J.; Priepke, W. M. H.; Reynolds, D.
J. Chem. Rev. 2001, 101, 53-80.
(19) Shing, T. K. M.; Leung; Y. C.; Yeung, K. W. Tetrahedron Lett.
2003, 44, 9225-9228.
(20) Isidor, J. L.; Carlson, R. M. J. Org. Chem. 1973, 38, 554-556.
(21) Entries 1, 5, 9, 13, 29, 33, and 37 in Table 2 and entries 1, 3, 5,
7, 9, and 11 in Table 5 were reported in a communication; see ref 19.
(22) Chang, H.-T.; Sharpless, K. B. J. Org. Chem. 1996, 61, 6456-
6457.
(12) (a) Solladie´-Cavallo, A.; Jierry, L.; Lupattelli, P.; Bovicelli, P.;
Antonioletti, R. Tetrahedron 2004, 60, 11375-11381. (b) Solladie´-
Cavallo, A.; Jierry, L.; Klein, A.; Schmitt, M.; Welter, R. Tetrahedron:
Asymmetry 2004, 15, 3891-3898. (c) Solladie´-Cavallo, A.; Jierry, L.;
Norrousi-Arasi, H.; Tahmassebi, D. J. Fluorine Chem. 2004, 125,
1371-1377. (d) Solladie´-Cavallo, A.; Jierry, L.; Klein, A. C. R. Chim.
2003, 6, 603-606. (e) Solladie´-Cavallo, A.; Boue´rat, L.; Jierry, L. Eur.
J. Org. Chem. 2001, 23, 4557-4560. (f) Solladie´-Cavallo, A.; Jierry,
L.; Boue´rat, L.; Taillasson, P. Tetrahedron: Asymmetry 2001, 12, 883-
891. (g) Solladie´-Cavallo, A.; Boue´rat, L. Tetrahedron: Asymmetry 2000,
11, 935-941. (h) Solladie´-Cavallo, A.; Boue´rat, L. Org. Lett. 2000, 2,
3531-3534.
(23) Brandes, B. D.; Jacobsen, E. N. J. Org. Chem. 1994, 59, 4378-
4380.
(24) Witkop, B.; Foltz, C. M. J. Am. Chem. Soc. 1957, 79, 197-201.
(25) Rossiter, B. E.; Sharpless, K. B. J. Org. Chem. 1984, 49, 3707-
3711.
(26) Betti, G.; Macchia, B.; Macchia, F.; Monti, L. J. Org. Chem.
1968, 33, 4045-4049.
(27) Harada, T.; Nakamura, T.; Kinugasa, M.; Oku, A. Tetrahedron
Lett. 1999, 40, 503-506.
(13) Imashiro, R.; Seki, M. J. Org. Chem. 2004, 69, 4216-4226.
7280 J. Org. Chem., Vol. 70, No. 18, 2005

Ketones as Catalysts for Epoxidation of Alkenes
SCHEME 2. Preparation of Chiral Ketones via Transacetalizationa
a Reagents and conditions: (a) 2-propanol (4 equiv), p-TsOH, PhH, Dean-Stark trap, reflux, 12 h, 70% for 8; 3-methyl-1-butanol (4
equiv) p-TsOH, PhH, Dean-Stark trap, reflux, 12 h, 80% for 9; neopentyl alcohol (7 equiv), p-TsOH, PhH, Dean-Stark trap, reflux, 12
h, 87% for 10; benzyl alcohol (3.5 equiv), p-TsOH, PhH, Dean-Stark trap, reflux, 12 h, 80% for 11; cyclohexylmethyl alcohol (4 equiv),
p-TsOH, PhH, Dean-Stark trap, reflux, 12 h, 76% for 12; (b) PDC (1.5 equiv), 4 Å MS, CH2Cl2, rt, 12 h, 87% for 13, 89% for 14, 96% for
15, 84% for 16, 92% for 17.
FIGURE 1. X-ray structure of alcohol 12 (ORTEP view).
Results and Discussion
stereochemistry of bis-acetals 8-12 resulted from the
thermodynamically controlled formation of a stable trans-
decalin structure.18 The constitution of alcohol 12 was
confirmed by X-ray crystallography (Figure 1). Oxidation
of the free alcohol in bis-acetals 8-12 with pyridinium
dichromate (PDC) gave the respective ketones 13-17 in
good yields. The relative stereochemistry of ketone 16
was also confirmed by X-ray crystallography (Figure 2).
Ketones 13-17 had steric blockers, that is, the acetal
alkoxy groups, of different sizes that might induce
different degrees of enantioselectivity in catalytic epoxi-
dation of alkenes.
With the new catalysts in hand, we began to study the
effect of chain length of the branching carbon in the
acetal on enantioselectivity of the catalytic epoxidation.
Ketones 13 (isopropyl acetal, branching R to oxygen), 7
(isobutyl acetal, branching â to oxygen), and 14 (isopentyl
acetal, branching γ to oxygen) had steric blockers with
the same bulkiness at the termini but with different
carbon chain length. The results are summarized in Table
1. As the carbon chain of the steric blockers became
longer (from isopropyl group to isobutyl to isopentyl),
enantioselectivity first increased and then decreased.
Design of Ketones for Better Chiral Induction
Capabilities in Asymmetric Epoxidation. Initially,
we prepared ketones 5-7 to test our design of catalysts.19
On the basis of the established spiro transition states6i,11h
for chiral dioxirane epoxidation and of our previous
studies,16,17 we reasoned that the enantioselectivity should
be sensitive to the size of the acetal steric blocker. Indeed,
ketone 7 with a more bulky isobutyl acetal group
consistently displayed better chiral induction than meth-
yl acetal 5 (e.g., the ee with trans-stilbene could be
improved from 42 to 65%).19 Encouraged by these results,
we therefore synthesized ketones with various acetals
and investigated their chiral induction capabilities. Ke-
tones 13-17 were readily accessible from dimethyl acetal
2 via a reaction sequence involving transacetalization and
oxidation in good overall yields (Scheme 2). Thus, the
methoxy groups in dimethyl acetal 2 were exchanged
with 2-propanol, isopentanol, neopentanol, benzyl alcohol,
and cyclohexylmethyl alcohol under acidic conditions to
give diisopropyl acetal 8, diisopentyl acetal 9, dineopentyl
acetal 10, dibenzyl acetal 11, and dicyclohexylmethyl
acetal 12 in 70, 80, 87, 80, and 76%, respectively. The
J. Org. Chem, Vol. 70, No. 18, 2005 7281

Shing et al.
FIGURE 2. X-ray structure of ketone 16 (ORTEP view).
This means that steric blockers of appropriate carbon
chain length could induce higher enantioselectivity.
Ketone 7 performed better selectivity than ketones 13
and 14 (Table 1, entries 2, 5, 8, 11, and 14). Ketone 7
gave the highest 85% ee in the reaction with triphenyl-
ethylene (Table 1, entry 14). However, the enantioselec-
tivities toward trans-disubstituted alkenes are still poor
(Table 1, entries 2, 5, and 8).
dation of cinnamates, a conclusion different from Seki’s13
findings which employed Yang’s catalyst, and demon-
strated that the more bulky tert-butyl esters gave higher
ee than the corresponding methyl esters (Table 2, entries
25-32).
In the asymmetric epoxidation of trisubstituted alkenes
(Table 2, entries 33-48), the enantioselectivity remained
high for ketones 7 and 15. Interestingly, ketone 7
performed even better in two cases (entries 37 and 41,
with triphenylethylene, its ee was 90%, the highest ee
reported for this series of arabinose-derived ketones).
Ketones 16 and 17 were prepared to study the elec-
tronic effect of our asymmetric epoxidation. It was
interesting to find that, in our ketone-catalyzed epoxi-
dation system, no significant π-π interaction was ob-
served between the phenyl group of the alkene and the
benzyl moiety in ketone 16 for both trans-disubstituted
and trisubstituted alkenes. In some cases (Table 2,
entries 7, 8; 11, 12; 35, 36; and 43, 44), ketone 16
containing a benzyl acetal group afforded higher ee than
ketone 17 with a cyclohexylmethyl group, whereas in
other cases (entries 15, 16; 19, 20; 27, 28; and 39, 40),
ketone 16 gave lower ee values. Our results are in
contrast to Shi’s findings11c that the attractive interaction
between the phenyl group of the alkene and the oxazo-
lidinone of the catalyst is important for ketone-catalyzed
epoxidation. It is noteworthy that our ketones could be
recovered in no less than 95% yield after workup and the
recovered catalyst did not undergo epimerization.
With the best catalyst 15 for disubstituted alkenes in
hand, we studied the effect of alcohol protecting group
on enantioselectivity in the asymmetric epoxidation of
(E)-hex-3-en-1-ol, and the results are summarized in
Table 3. The enantioselectivity enhanced with the size
of the protecting group, and hence the alkene bearing
the most sterically demanding trityl group furnished the
highest ee of 55% (Table 3, entry 4). It was surprising
that the ee observed from using a TBS protecting group
(Table 3, entry 3) was lower than that from using a benzyl
The above findings led us to prepare ketones 15-17,
all with acetal branching â to oxygen of the alkoxy group.
The epoxidation reactions were carried out at 0 °C with
0.1 mmol of alkene and 10 mol % of catalyst in aqueous
CH3CN at almost neutral conditions (pH 7-7.5). The
catalytic and chiral induction properties of 721 and 15-
17 with trans-disubstituted and trisubstituted alkenes
were studied, and the results are summarized in Table
2. In all cases, the epoxides were isolated in high chemical
yields (81-99% yield), indicating that all the ketones are
efficient catalysts. In the enantioselective epoxidation of
trans-disubstituted alkenes (Table 2, entries 5-32),
ketone 15 with a more bulky neopentyl acetal group
consistently displayed the best chiral induction (62-86%
ee) among the ketones except for entries 1-4. The
neopentyl group was thus demonstrated to be a good
steric blocker to induce high degree of enantioselectivity
in asymmetric epoxidation. A high ee of 86% was
obtained with (E)-tert-butyl cinnamate (Table 2, entry
18). A high ee of 81% was also observed for (E)-tert-butyl
4-methoxycinnamate (Table 2, entry 26), which was
better than Seki’s result13 (77% ee, using Yang’s 11-
membered C2 symmetry binaphthyl ketone6 as the cata-
lyst). However, the ee for the asymmetric epoxidation of
methyl p-methoxycinnamate (MPC) (Table 2, entry 30)
was a moderate 62%. The resultant chiral epoxide,
methyl (2R,3S)-3-(4-methoxyphenyl)glycidate, was a key
intermediate for synthesizing diltiazem hydrochloride, a
drug for the treatment of angina and hypertension.13 Our
results showed that the bulkiness of the ester moiety
could affect the enantioselectivity in asymmetric epoxi-
7282 J. Org. Chem., Vol. 70, No. 18, 2005

Ketones as Catalysts for Epoxidation of Alkenes
TABLE 1. Effect of Acetal Alkoxy Chain Length on Asymmetric Epoxidation of Alkenes Catalyzed by Ketones 7, 13,
and 14
entrya
catalysts
substrates
yield (%)b
ee (%)c
configurationd
1
2
13
7
14
13
7
14
13
7
14
13
7
a
a
a
b
b
b
c
c
c
i
91
92
87
92
93
94
90
90
94
95
95
93
87
96
95
56
68
56
51
65
54
59
67
57
82
83
68
69
85
80
(-)-(S,S)23
(-)-(S,S)23
(-)-(S,S)23
(-)-(S,S)22
(-)-(S,S)22
(-)-(S,S)22
(-)-(S,S)
3
4
5
6
7
8
(-)-(S,S)
9
(-)-(S,S)
10
11
12
13
14
15
(-)-(S,S)24
(-)-(S,S)24
(-)-(S,S)24
(+)-(S)24
i
14
13
7
i
j
j
(+)-(S)24
14
j
(+)-(S)24
a All epoxidations were carried out at room temperature with substrate (0.1 mmol), ketone (0.01 mmol), Oxone (1 mmol), and NaHCO3
(3.1 mmol) in CH3CN/4 × 10-4 M aqueous EDTA (5:1, v/v) for 12 h. b Isolated yield. c Enantioselectivity was determined by 1H NMR
analysis of the epoxide products directly with shift reagent Eu(hfc)3. d The absolute configurations were determined by comparing the
measured optical rotations with the reported ones.
protecting group (Table 3, entry 2) since the silyl group
should be more bulky. Nevertheless, the ee of the
asymmetric epoxidation of (E)-hex-3-en-1-ol could be
improved from 16 to 55% by means of a trityl protecting
group.
methoxy group at the anomeric center, was synthesized
(Scheme 3). trans-Diol protection of methyl â-L-ara-
binopyranoside17 gave dimethyl acetal 18. The methoxy
groups in dimethyl acetal 18 were exchanged with
isobutanol to give diisobutyl acetal 19, which was oxi-
dized to ketone 20. The catalytic and chiral induction
properties of methyl glycoside 20 with trans-disubstituted
and trisubstituted alkenes were studied and compared
with those of benzyl glycoside 7.21 The results are
summarized in Table 5. Like the catalysts described
earlier, methyl glycoside 20 also afforded good chemical
yields of epoxides (87-97% yield). However, the change
of the blocking group at the anomeric center from benzyl
to methyl caused no appreciable change in enantioselec-
tivity (Table 5). This indicated that the blocking group
at the anomeric carbon of our system is not a controlling
factor for enantioselectivity in asymmetric epoxidation.
Thus the argument of a possible π-π interaction between
the OBn group of ketone catalyst and the phenyl groups
of alkene substrates was not substantiated.
On the other hand, we found that when the double
bond was closest to the protecting group, the ee would
be the highest. We investigated the effect of the double
bond position in the alkene substrate on enantioselec-
tivity of (E)-hexenyl benzyl ethers, and the results are
shown in Table 4. As the double bond was positioned
gradually away from the protecting group, as shown in
the benzyl ethers of (E)-hex-2-en-1-ol, (E)-hex-3-en-1-ol,
and (E)-hex-4-en-1-ol, the ee of the asymmetric epoxida-
tion would gradually decrease from 67 to 34%. On the
basis of our results, the stereochemical communication
between our ketone catalysts and the alkenes substrates
is mainly due to steric effect.
To further investigate the possibility of π-π interaction
in our system, ketone 20, which has a nonaromatic
J. Org. Chem, Vol. 70, No. 18, 2005 7283

Shing et al.
TABLE 2. Asymmetric Epoxidation of Alkenes Using Ketones 7, 15, 16, and 17 as Catalysts at 0 °C
entrya catalysts substrates yield (%)b ee (%) configurationg entrya catalysts substrates yield (%)b ee (%) configurationg
1
2
7
15
16
17
7
15
16
17
7
15
16
17
7
15
16
17
7
15
16
17
7
15
16
17
a
a
a
a
b
b
b
b
c
83
90
90
80
97
91
97
84
93
94
94
86
85
85
93
92
88
90
92
84
78
87
81
82
69c
69c
72c
72c
76d
83d
77d
67d
77c
82c
77c
62c
75f
81f
68f
79f
81c
86c
66c
77c
68e
77e
47e
56e
(-)-(S,S)23
(-)-(S,S)23
(-)-(S,S)23
(-)-(S,S)23
(-)-(S,S)22
(-)-(S,S)22
(-)-(S,S)22
(-)-(S,S)22
(-)-(S,S)
(-)-(S,S)
(-)-(S,S)
(-)-(S,S)
(-)-(S,S)11r,11s
(-)-(S,S)11r,11s
(-)-(S,S)11r,11s
(-)-(S,S)11r,11s
(-)
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
7
15
16
17
7
15
16
17
7
15
16
17
7
15
16
17
7
15
16
17
7
15
16
17
g
g
g
g
h
h
h
h
i
96
92
89
93
91
93
88
91
93
84
97
81
99
96
98
89
92
80
94
81
85
88
93
85
80c
81c
63c
72c
61d
62d
42d
59d
87d
88d
83d
80d
90d
88d
82d
85d
85c
77c
79c
60c
56h
58h
48h
48h
(-)-(2R,3S)13
(-)-(2R,3S)13
(-)-(2R,3S)13
(-)-(2R,3S)13
(-)-(2R,3S)13
(-)-(2R,3S)13
(-)-(2R,3S)13
(-)-(2R,3S)13
(-)-(S,S)24
(-)-(S,S)24
(-)-(S,S)24
(-)-(S,S)24
(+)-(S)24
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
c
i
c
c
i
i
d
d
d
d
e
e
e
e
f
j
j
(+)-(S)24
j
(+)-(S)24
j
(+)-(S)24
k
k
k
k
l
(-)-(S,S)25,26
(-)-(S,S)25,26
(-)-(S,S)25,26
(-)-(S,S)25,26
(-)
(-)
(-)
(-)
(-)
f
(-)
l
(-)
f
(-)
l
(-)
f
(-)
l
(-)
a All epoxidations were carried out with substrate (0.1 mmol), ketone (0.01 mmol), Oxone (1 mmol), and NaHCO3 (3.1 mmol) in CH3CN/4
× 10-4 M aqueous EDTA (5:1, v/v) for 12 h. b Isolated yield. c ee was determined by 1H NMR analysis of the epoxide products directly
with shift reagent Eu(hfc)3. d ee was determined by HPLC using Chiralcel OD-H column. e ee was determined by 1H NMR analysis of the
derived acetate with Eu(hfc)3. f ee was determined by HPLC using Chiralcel OD-H column after desilylation with TBAF. g The absolute
configurations were determined by comparing the measured optical rotations with the reported ones. h ee was determined by 1H NMR
analysis of the derived acetate with Eu(hfc)3.
Transition States in Asymmetric Epoxidation.
The preponderant formation of the (S,S)-enantiomer may
be rationalized by the spiro6g,i,11h,o transition state re-
sulted from a minimum steric interaction between the
steric blocker and the alkene substrate, using (E)-1-tert-
butyldimethylsilyloxy-3-phenyl-2-propene as an example.
First, equatorial attack of the alkene on the equatorial
oxygen in dioxirane should be preferred because the axial
approach of the alkene would be significantly more
hindered by the axial proton of the pyran ring (Figure
3). Second, Figure 4 shows that the steric repulsion
between the phenyl group and the acetal alkyl group in
transition state (spiro-2) is absent in (spiro-1). On the
basis of steric ground, transition state (spiro-4) is the
7284 J. Org. Chem., Vol. 70, No. 18, 2005

Ketones as Catalysts for Epoxidation of Alkenes
TABLE 3. Blocking Group Effect in Asymmetric
TABLE 4. Effect of Double Bond Position in
Epoxidation of (E)-Hex-3-en-1-ol
Asymmetric Epoxidation of (E)-Hexenyl Benzyl Ether
entrya
substrates
yield (%)b
ee (%)c
configuratione
entrya
substrates
yield (%)b
ee (%)c
configuratione
1
2
3
a
b
c
89
88
82
67
(-)-(S,S)27
(-)-(S,S)27
(-)-(S,S)f
45d
34
1
2
3
4
a
b
c
88
88
87
95
16
45d
36
55
(-)-(S,S)11s
(-)-(S,S)27
(-)-(S,S)11s
(-)-(S,S)f
a All epoxidations were carried out with substrate (0.1 mmol),
ketone (0.01 mmol), Oxone (1 mmol), and NaHCO3 (3.1 mmol) in
CH3CN/4 × 10-4 M aqueous EDTA (5:1, v/v) for 12 h. b Isolated
yield. c Enantioselectivity was determined by HPLC using Chiral-
cel OD-H column. d Enantioselectivity was determined by 1H NMR
analysis of the corresponding benzoate with Eu(hfc)3. e The abso-
lute configurations were determined by comparing the measured
optical rotations with the reported ones. f The absolute configu-
ration was tentatively assigned by analogy based on the spiro
reaction mode.
d
a All epoxidations were carried out with substrate (0.1 mmol),
ketone (0.01 mmol), Oxone (1 mmol), and NaHCO3 (3.1 mmol) in
CH3CN/4 × 10-4 M aqueous EDTA (5:1, v/v) for 12 h. b Isolated
yield. c Enantioselectivity was determined by 1H NMR analysis
of the derived acetate with Eu(hfc)3. d Enantioselectivity was
determined by 1H NMR analysis of the corresponding benzoate
with Eu(hfc)3. e The absolute configurations were determined by
comparing the measured optical rotations with the reported ones.
f The absolute configuration was tentatively assigned by analogy
based on the spiro reaction mode.
were similar, electronic effect involving π-π interaction
between phenyl groups of alkene substrates and the
benzyl group in ketone catalyst 16 did not appear to be
operative in our system. The change of the blocking group
at the anomeric center from benzyl (7) to methyl (20)
caused no appreciable change in enantioselectivity, in-
dicating that the anomeric aglycone of our system is not
a controlling factor for enantioselectivity. The possibility
of π-π interaction between the anomeric OBn group of
ketone catalysts and the phenyl groups of alkene sub-
strates was not substantiated. The stereochemical com-
munication of our ketone catalysts with alkene substrates
was attributed to steric effect, and the most sterically
demanding trityl protecting group afforded the highest
ee of 55% in the epoxidation of protected (E)-hex-3-en-
1-ols. When the double bond in the alkene substrate was
positioned closest to the protecting group, the steric effect
was most significant.
least favored and transition state (spiro-3) is less favored
than (spiro-1) because the TBS group is sterically more
demanding than the phenyl group. We have also readily
prepared the enantiomer of 15 from D-arabinose, and ent-
15 displayed almost identical conversion yields and ee
values for the (R,R)-enantiomer.
Conclusion
In summary, ketones 7, 13-17, and 20, easily prepared
from L-arabinose in four steps, afforded excellent chemi-
cal yields (78-99%) of epoxides in catalytic asymmetric
epoxidation of alkenes. Steric blockers 7 and 15-17 with
branching â to the acetal oxygen exhibited good stereo-
chemical communication toward trans-disubstituted and
trisubstituted alkenes, and the enantioselectivity in-
creased with the size of the blocker (up to 90% ee). For
trans-disubstituted alkenes, ketone catalyst 15, bearing
the neopentyl blocking group, was shown to display the
best chiral induction power. A high ee of 81% was
observed for the formation of tert-butyl (2R,3S)-3-(4-
methoxyphenyl)glycidate, amenable for a chiral synthesis
of calcium antagonist diltiazem hydrochloride. The excel-
lent catalytic property of 15 was demonstrated by the
epoxidation/recovery cycle without loss of activity. In
asymmetric epoxidation of trisubstituted alkenes, both
ketones 7 and 15 induce good enantioselectivity and
complement each other.
It is noteworthy that the benzyl aglycone in ketone 15
is amenable for elaboration into a polymer support and
hence opens an avenue for the development of solid-phase
catalysis. Research in this direction is also under active
investigation.
Experimental Section17
General in Situ Epoxidation Procedure at 0 °C. To a
stirred solution of trans-stilbene (0.1 mmol), ketone (10 mol
%), and n-Bu4NHSO4 (0.5 mg) in CH3CN (10 mL) was added
an aqueous a buffer (5 mL, 4 × 10-4 M aqueous EDTA). The
resulting solution was cooled to 0 °C (bath temperature). A
solution of Oxone (307 mg, 0.5 mmol) in aqueous EDTA (5 mL,
4 × 10-4 M) and a solution of NaHCO3 (260 mg, 3.1 mmol) in
Since the enantioselectivities displayed by benzyl ac-
etal ketone 16 and cyclohexylmethyl acetal ketone 17
J. Org. Chem, Vol. 70, No. 18, 2005 7285

Shing et al.
SCHEME 3. Preparation of Chiral Ketones from Methyl â-L-Arabinopyranosidea
a Reagents and conditions: (a) 2,2,3,3-tetramethoxybutane (1.5 equiv), CH(OMe)3 (4 equiv), (()-CSA (0.1 equiv), reflux, 12 h, 69%; (b)
2-methyl-1-propanol (4 equiv), p-TsOH, PhH, Dean-Stark trap, reflux, 12 h, 87%; (c) PDC (1.5 equiv), 3 Å MS, CH2Cl2, rt, 12 h, 94%.
TABLE 5. Effect of Blocking Group at Anomeric Center on Asymmetric Epoxidation of Alkenes Catalyzed by Ketones
7 and 20
entrya
catalysts
substrates
yield (%)b
ee (%)c
configurationd
1
2
7
20
7
20
7
20
7
20
7
20
7
20
7
20
a
a
b
b
c
c
d
d
i
83
95
97
97
93
94
85
87
93
96
99
97
92
89
69
70
76
82
77
80
75
74
87
89
90
89
85
87
(-)-(S,S)23
(-)-(S,S)23
(-)-(S,S)22
(-)-(S,S)22
(-)-(S,S)
3
4
5
6
(-)-(S,S)
7
(-)-(S,S)11r,11s
(-)-(S,S)11r,11s
(-)-(S,S)24
(-)-(S,S)24
(+)-(S)24
8
9
10
11
12
13
14
i
j
j
k
k
(+)-(S)24
(-)-(S,S)25,26
(-)-(S,S)25,26
a All epoxidations were carried out at 0 °C with substrate (0.1 mmol), ketone (0.01 mmol), Oxone (1 mmol), and NaHCO3 (3.1 mmol)
in CH3CN/4 × 10-4 M aqueous EDTA (5:1, v/v) for 12 h. b Isolated yield. c Enantioselectivity was determined by 1H NMR analysis of the
epoxide products directly with shift reagent Eu(hfc)3. d The absolute configurations were determined by comparing the measured optical
rotations with the reported ones.
H2O (5 mL) were added dropwise concomitantly via two
dropping funnels. The pH of the mixture was maintained at
about 7-7.5 over a period of 12 h. The reaction mixture was
then poured into water (10 mL), extracted with Et2O (3×),
dried with anhydrous magnesium sulfate, and filtered. The
filtrate was concentrated under reduced pressure to give a
residue that was purified by flash column chromatography to
give the epoxide.
Diisobutyl Acetal 4. A solution of dimethyl acetal 2 (228
mg, 0.64 mmol) in benzene (20 mL) containing 2-methyl-1-
propanol (190 mg, 2.56 mmol) and p-TsOH (5 mg) was heated
under reflux with a Dean-Stark trap for 12 h. The cooled
reaction mixture was then treated with saturated aqueous
NaHCO3 and extracted with Et2O (3 × 20 mL). The combined
organic extracts were dried over anhydrous MgSO4 and
filtered. The filtrate was concentrated under reduced pressure.
The crude residue was purified by flash column chromatog-
raphy to afford diisobutyl acetal 4 as a syrup (240 mg, 85%):
Rf 0.22 (hexanes-Et2O, 2.5:1); [R]23 +13.6 (c 1.2, CHCl3); IR
D
(thin film) 3449 (OH) cm-1; 1H NMR (CDCl3) δ 7.40-7.26 (5H,
m), 4.99 (1H, d, J ) 3 Hz), 4.79 (1H, d, J ) 12.3 Hz), 4.64 (1H,
d, J ) 12.3 Hz), 4.24 (2H, m), 3.90 (1H, d, J ) 1.5 Hz), 3.81
(1H, dd, J ) 11.7, 1.2 Hz), 3.74 (1H, dd, J ) 12.6, 1.5 Hz),
3.25-3.15 (4H,m), 2.29 (1H, brs), 1.87-1.82 (2H, m), 1.33 (3H,
s), 1.32 (3H, s), 0.95-0.92 (12H, m); 13C NMR (CDCl3) δ 138.0,
128.1, 127.2, 127.0, 100.3, 100.2, 98.0, 69.5, 68.6, 66.1, 65.9,
65.6, 63.5, 29.0, 20.1, 19.9, 18.9; MS (EI) m/z (relative intensity)
7286 J. Org. Chem., Vol. 70, No. 18, 2005

Ketones as Catalysts for Epoxidation of Alkenes
1
IR (thin film) 3455 (OH) cm-1; H NMR (CDCl3) δ 7.41-7.28
(5H, m), 4.98 (1H, s), 4.77 (1H, d, J ) 12.3 Hz), 4.64 (1H, d, J
) 12.3 Hz), 4.22-4.21 (2H, m), 3.90 (1H, s), 3.81 (1H, dd, J )
12.9, 1.5 Hz), 3.72 (1H, dd, J ) 12.9, 1.8 Hz), 3.49-3.43 (4H,
m), 2.17 (1H, brs), 1.78-1.68 (2H, m), 1.49-1.45 (4H, m) 1.36
(3H, s), 1.32 (3H, s), 0.92-0.86 (12H, m); 13C NMR (CDCl3) δ
138.5, 128.6, 127.7, 127.6, 100.4, 101.1, 98.0, 69.6, 68.6, 66.0,
65.6, 63.4, 59.1, 58.9, 39.2, 39.1, 25.7, 25.4, 23.2, 23.1, 22.9,
18.9; MS (EI) m/z (relative intensity) 378 (100); Anal. Calcd
for C26H42O7: C, 66.93; H, 9.07. Found: C, 66.82; H, 9.19.
Dineopentyl Acetal 10. A solution of dimethyl acetal 2
(125 mg, 0.35 mmol) in benzene (20 mL) containing neopentyl
alcohol (239 mg, 2.7 mmol) and p-TsOH (5 mg) was heated
under reflux with a Dean-Stark trap for 12 h. The cooled
reaction mixture was then treated with saturated aqueous
NaHCO3 and extracted with Et2O (3 × 20 mL). The combined
organic extracts were dried over anhydrous MgSO4 and
filtered. The filtrate was concentrated under reduced pressure.
The crude residue was purified by flash column chromatog-
raphy to afford dineopentyl acetal 10 as a white solid (141 mg,
FIGURE 3. Approach of alkene substrates based on steric
effect.
364 (M+ - C4H10O, 23), 291 (10); Anal. Calcd for C24H38O7: C,
65.73; H, 8.73. Found: C, 65.68; H, 9.20.
Diisobutyl Ketone 7. To a solution of alcohol 4 (170 mg,
0.39 mmol) in dry CH2Cl2 (10 mL) were added slowly PDC (177
mg, 0.47 mmol) and powdered 3 Å molecular sieves (170 mg).
The mixture was stirred at room temperature for 12 h. The
mixture was suction filtered through a pad of silica gel, and
the filtrate was concentrated under reduced pressure. The
crude residue was purified by flash column chromatography
to afford diisobutyl ketone 7 as a syrup (161 mg, 95%). Rf 0.35
(Et2O-hexane, 3:7); [R]23D +12.2 (c 1.4, CHCl3); IR (thin film)
87%): Rf 0.28 (hexanes-Et2O, 4:1); mp 112-113 °C; [R]20
D
-0.58 (c 1.44, CHCl3); IR (thin film) 3454 (OH) cm-1; 1H NMR
(CDCl3) δ 7.38-7.25 (5H, m), 4.99 (1H, d, J ) 2.4 Hz), 4.79
(1H, d, J ) 12.3 Hz), 4.61 (1H, d, J ) 12.3 Hz), 4.27 (2H, m),
3.90 (1H, brs), 3.83 (1H, d, J ) 12.6 Hz), 3.79 (1H, dd, J )
12.6, 1.5 Hz), 3.13-3.04 (4H, m), 1.90 (1H, brs), 1.34 (3H, s),
1.33 (3H, s), 0.95 (9H, s), 0.94 (9H, s); 13C NMR (CDCl3) δ
138.5, 128.5, 127.6, 127.3, 100.3, 100.1, 98.2, 70.7, 69.5, 68.6,
65.9, 63.5, 32.1, 27.4, 18.8; MS (FAB) m/z (relative intensity)
489 ([M + Na]+, 18), 379 (34), 91 (100), 71 (76); HRMS (FAB)
calcd for C26H42O7 [M + Na]+ 489.2823, found 489.2846.
1743, 1736 (CdO) cm-1 1H NMR (CDCl3) δ 7.43-7.26 (5H,
;
m), 5.11 (1H, d, J ) 3 Hz), 5.02 (1H, d, J ) 10.8 Hz), 4.85 (1H,
d, J ) 12.3 Hz), 4.77 (1H, d, J ) 12.3 Hz), 4.17 (1H, d, J )
15.6 Hz), 4.11 (1H, dd, J ) 7.8, 3.0 Hz), 3.92 (1H, d, J ) 15.0
Hz), 3.27-3.16 (4H, m), 1.86-1.80 (2H, m), 1.40 (3H, s), 1.36
(3H, s), 0.93-0.89 (12H, m); 13C NMR (CDCl3) δ 200.9, 137.3,
128.7, 128.07, 127.7, 100.5, 99.9, 97.6, 71.3, 70.6, 70.3, 67.6,
67.5, 67.3, 29.0, 20.1, 19.9, 19.8, 18.8, 18.7; MS (EI) m/z
(relative intensity) 362 (M+ - C4H10O, 100), 288 (8). Anal.
Calcd for C24H36O7: C, 66.03; H, 8.31. Found: C, 66.19; H,
8.38.
Dibenzyl Acetal 11. A solution of dimethyl acetal 2 (100
mg, 0.28 mmol) in benzene (20 mL) containing benzyl alcohol
(121 mg, 1.12 mmol) and p-TsOH (10 mg) was heated under
reflux with a Dean-Stark trap for 12 h. The cooled reaction
mixture was then treated with saturated aqueous NaHCO3
and extracted with Et2O (3 × 20 mL). The combined organic
extracts were dried over anhydrous MgSO4 and filtered. The
filtrate was concentrated under reduced pressure. The crude
residue was purified by flash column chromatography to afford
dibenzyl acetal 11 as a syrup (115 mg, 80%): Rf 0.35 (hexanes-
Et2O, 1:1); [R]23D +17.0 (c 1.4, CHCl3); IR (thin film) 3462 (OH)
cm-1; 1H NMR (CDCl3) δ 7.41-7.22 (15H, m), 5.04 (1H, d, J )
3.0 Hz), 4.81 (1H, d, J ) 12.3 Hz), 4.70-4.58 (5H, m), 4.41
(1H, dd, J ) 10.5, 3.0 Hz), 4.35 (1H, dd, J ) 10.5, 3.0 Hz) 3.91
(1H, s), 3.90 (1H, dd, J ) 12.6, 1.2 Hz), 3.77 (1H, dd, J ) 12.6,
1.5 Hz), 2.11 (1H, brs), 1.51 (3H, s), 1.50 (3H, s); 13C NMR
(CDCl3) δ 139.0, 128.8, 128.7, 127.6, 127.3, 126.8, 100.8, 97.9,
69.8, 68.5, 66.4, 65.9, 63.5, 62.9, 62.4, 19.5; MS (EI) m/z
(relative intensity) 398 (M+ - C7H8O, 15), 91 (100); Anal. Calcd
for C30H34O7: C, 71.13; H, 6.76. Found: C, 71.17; H, 6.86.
Diisopropyl Acetal 8. A solution of dimethyl acetal 2 (50
mg, 0.14 mmol) in benzene (20 mL) containing 2-propanol (33.6
mg, 0.56 mmol) and p-TsOH (5 mg) was heated under reflux
with a Dean-Stark trap for 12 h. The cooled reaction mixture
was then treated with saturated aqueous NaHCO3 and ex-
tracted with Et2O (3 × 20 mL). The combined organic extracts
were dried over anhydrous MgSO4 and filtered. The filtrate
was concentrated under reduced pressure. The crude residue
was purified by flash column chromatography to afford diiso-
propyl acetal 8 as a syrup (40 mg, 70%): Rf 0.35 (hexanes-
EtOAc, 2:1); [R]23D +27 (c 1.0, CHCl3); IR (thin film) 3476 (OH)
1
cm-1; H NMR (CDCl3) δ 7.41-7.28 (5H, m), 4.94 (1H, d, J )
1.5 Hz), 4.79 (1H, d, J ) 12.3 Hz), 4.67 (1H, d, J ) 12.3 Hz),
4.41 (2H, m), 4.11 (2H, m), 3.88 (1H, d, J ) 1.2 Hz), 3.76 (1H,
dd, J ) 12.6, 1.2 Hz), 3.72 (1H, dd, J ) 12.6, 1.2 Hz), 2.26
(1H, brs), 1.37 (3H, s), 1.34 (3H, s), 1.25 (3H, 6 Hz), 1.21 (3H,
6 Hz), 1.19 (3H, 6 Hz), 1.16 (3H, 6 Hz); 13C NMR (CDCl3) δ
138.5, 128.6, 127.7, 127.6, 101.3, 101.1, 97.8, 69.3, 68.6, 66.2,
65.7, 64.4, 64.3, 63.5, 24.8, 24.4, 24.3, 20.1, 20.0; MS (EI) m/z
(relative intensity) 350 (M+ - i-PrOH, 25), 91 (100); Anal.
Calcd for C22H34O7: C, 64.37; H, 8.35. Found: C, 64.00; H,
8.21.
Dicyclohexylmethyl Acetal 12. A solution of dimethyl
acetal 2 (100 mg, 0.28 mmol) in benzene (30 mL) containing
cyclohexylmethyl alcohol (128 mg, 1.12 mmol) and p-TsOH (10
mg) was heated under reflux with a Dean-Stark trap for 12
h. The cooled reaction mixture was then treated with saturated
aqueous NaHCO3 and extracted with Et2O (3 × 20 mL). The
combined organic extracts were dried over anhydrous MgSO4
and filtered. The filtrate was concentrated under reduced
pressure. The crude residue was purified by flash column
chromatography to afford dicyclohexylmethyl acetal 12 as
white crystals (110.3 mg, 76%): Rf 0.58 (hexanes-Et2O, 1:1)
mp 119-120 °C; [R]23D +8.4 (c 1.1, CHCl3); IR (thin film) 3429
Diisopentyl Acetal 9. A solution of dimethyl acetal 2 (100
mg, 0.28 mmol) in benzene (30 mL) containing 3-methyl-1-
butanol (98 mg, 1.12 mmol) and p-TsOH (5 mg) was heated
under reflux with a Dean-Stark trap for 12 h. The cooled
reaction mixture was then treated with saturated aqueous
NaHCO3 and extracted with Et2O (3 × 20 mL). The combined
organic extracts were dried over anhydrous MgSO4 and
filtered. The filtrate was concentrated under reduced pressure.
The crude residue was purified by flash column chromatog-
raphy to afford diisopentyl acetal 9 as a syrup (104.3 mg,
80%): Rf 0.47 (hexanes-Et2O, 3:1); [R]23D +5.4 (c 1.2, CHCl3);
1
(OH) cm-1; H NMR (CDCl3) δ 7.40-7.26 (5H, m), 4.99 (1H,
d, J ) 1.8 Hz), 4.78 (1H, d, J ) 12.3 Hz), 4.62 (1H, d, J ) 12.3
Hz), 4.22 (2H, s), 3.90 (1H, s), 3.83 (1H, d, J ) 12.6 Hz), 3.74
(1H, dd, J ) 12.6, 1.2 Hz), 3.26-3.20 (4H, m), 2.17 (1H, brs),
1.81-1.65 (12H, m), 1.26 (3H, s), 1.23 (3H, s), 0.98-0.93 (10H,
m); 13C NMR (CDCl3) δ 138.5, 128.6, 127.6, 127.4, 100.3, 100.1,
98.1, 69.6, 68.6, 66.1, 65.9, 65.6, 63.5, 38.5, 38.4, 30.8, 30.6,
27.0, 26.3, 18.9; MS (EI) m/z (relative intensity) 404 (M+
-
J. Org. Chem, Vol. 70, No. 18, 2005 7287

Shing et al.
FIGURE 4. Four spiro transition states for 1-tert-butyldimethylsilyloxy-3-phenyl-2-propene epoxidation catalyzed by ketone 15.
C7H14O, 79), 290 (30); Anal. Calcd for C30H46O7: C, 69.47; H,
8.94. Found: C, 69.54; H, 9.08.
(M+ - C5H12O, 100). Anal. Calcd for C26H40O7: C, 67.22; H,
8.68. Found: C, 67.18; H, 8.60.
Diisopropyl Ketone 13. To a solution of alcohol 8 (70 mg,
0.17 mmol) in dry CH2Cl2 (10 mL) were added slowly PDC (77
mg, 0.20 mmol) and powdered 4 Å molecular sieves (170 mg).
The mixture was stirred at room temperature for 12 h. The
mixture was suction filtered through a pad of silica gel, and
the filtrate was concentrated under reduced pressure. The
crude residue was purified by flash column chromatography
to afford diisopropyl ketone 13 as a syrup (60 mg, 87%). Rf
Dineopentyl Acetal 15. To a solution of alcohol 10 (56 mg,
0.12 mmol) in dry CH2Cl2 (10 mL) were added slowly PDC (55
mg, 0.15 mmol) and powdered 4 Å molecular sieves (60 mg).
The mixture was stirred at room temperature for 12 h. The
mixture was suction filtered through a pad of silica gel, and
the filtrate was concentrated under reduced pressure. The
crude residue was purified by flash column chromatography
to afford dineopentyl ketone 15 as a syrup (53 mg, 96%): Rf
0.28 (hexanes-Et2O, 1:1); [R]20D -5.7 (c 2.83, CHCl3); IR (thin
film) 1743 (CdO) cm-1; 1H NMR (CDCl3) δ 7.41-7.26 (5H, m),
5.12 (1H, d, J ) 3.0 Hz), 5.05 (1H, d, J ) 10.8 Hz), 4.84 (1H,
d, J ) 12.3 Hz), 4.75 (1H, d, J ) 12.3 Hz), 4.16 (1H, d, J )
15.6 Hz), 4.07 (1H, dd, J ) 8.1, 3.3 Hz), 3.92 (1H, d, J ) 15.0
Hz), 3.14-3.02 (4H,m), 1.40 (3H, s), 1.36 (3H, s), 0.92 (9H, s),
0.91 (9H, s); 13C NMR (CDCl3) δ 201.0, 137.7, 128.7, 128.0,
127.6, 100.5, 99.9, 97.7, 71.3, 71.0, 70.8, 70.6, 70.4, 67.6, 32.1,
27.3, 27.2, 18.7, 18.6; MS (FAB) m/z (relative intensity) 487
([M + Na]+, 2), 377 (14), 91 (100), 71 (80); HRMS (FAB) calcd
for C26H40O7 [M + Na]+ 487.2666, found 487.2680; Anal. Calcd
for C26H40O7: C, 67.22; H, 8.68. Found: C, 67.31; H, 8.31.
Dibenzyl Ketone 16. To a solution of alcohol 11 (310 mg,
0.61 mmol) in dry CH2Cl2 (10 mL) were added slowly PDC (275
mg, 0.73 mmol) and powdered 4 Å molecular sieves (270 mg).
The mixture was stirred at room temperature for 12 h. The
mixture was suction filtered through a pad of silica gel, and
the filtrate was concentrated under reduced pressure. The
crude residue was purified by flash column chromatography
to afford dibenzyl ketone 16 as white crystals (258 mg, 84%):
Rf 0.37 (hexanes-Et2O, 1:1); mp 174-176 °C; [R]23D +20 (c 3.4,
CHCl3); IR (thin film) 1743, 1729 (CdO) cm-1; 1H NMR (CDCl3)
δ 7.41-7.24 (15H, m), 5.15 (1H, d, J ) 2.7 Hz), 5.12 (1H, d, J
) 10.8 Hz), 4.87 (1H, d, J ) 12.3 Hz), 4.79 (1H, d, J ) 12.3
Hz), 4.70-4.66 (2H, m), 4.63-4.59 (2H, m), 4.25 (1H, dd, J )
10.8, 3.0 Hz), 4.15 (1H, d, J ) 15.0 Hz), 3.87 (1H, d, J ) 15.0
Hz), 1.57 (3H, s), 1.55 (3H, s); 13C NMR (CDCl3) δ 200.1, 138.7,
138.6, 137.5, 128.8, 128.7, 128.6, 128.2,128.1, 127.7, 127.6,
0.45 (hexanes-Et2O, 1:1); [R]23 +23 (c 1.2, CHCl3); IR (thin
D
film) 1750 (CdO) cm-1; 1H NMR (CDCl3) δ 7.43-7.26 (5H, m),
5.17 (1H, d, J ) 10.8 Hz), 5.07 (1H, d, J ) 3 Hz), 4.83 (1H, d,
J ) 12.6 Hz), 4.78 (1H, d, J ) 12.6 Hz), 4.34 (1H, dd, J )
10.8, 3.0 Hz), 4.19-4.03 (3H, m), 3.87 (1H, d, J ) 15 Hz), 1.39
(3H, s), 1.37 (3H, s), 1.28-1.13 (12H, m); 13C NMR (CDCl3) δ
200.9, 137.3, 128.7, 128.07, 127.7, 101.5, 100.7, 97.6, 71.3, 70.6,
70.3, 67.6, 64.9, 64.7, 24.7, 24.4, 24.3, 19.7, 19.6; MS (EI) m/z
(relative intensity) 408 (M+, 10), 366 (100). Anal. Calcd for
C22H32O7: C, 64.69; H, 7.90. Found: C, 64.45; H, 7.78.
Diisopentyl Ketone 14. To a solution of alcohol 9 (140 mg,
0.3 mmol) in dry CH2Cl2 (10 mL) were added slowly PDC (135
mg, 0.36 mmol) and powdered 4 Å molecular sieves (130 mg).
The mixture was stirred at room temperature for 12 h. The
mixture was suction filtered through a pad of silica gel, and
the filtrate was concentrated under reduced pressure. The
crude residue was purified by flash column chromatography
to afford diisopentyl ketone 14 as a syrup (124 mg, 89%). Rf
0.45 (hexanes-Et2O, 1:1); [R]23D +15.2 (c 2.2, CHCl3); IR (thin
1
film) 1743, 1729 (CdO) cm-1; H NMR (CDCl3) δ 7.43-7.26
(5H, m), 5.11 (1H, d, J ) 3 Hz), 4.97 (1H, d, J ) 11.1 Hz), 4.83
(1H, d, J ) 12.3 Hz), 4.77 (1H, d, J ) 12.3 Hz), 4.14 (1H, d, J
) 14.4 Hz), 4.10 (1H, dd, J ) 11.3, 3 Hz), 3.90 (1H, d, J )
14.4 Hz), 3.52-3.41 (4H, m), 1.75-1.68 (2H, m), 1.52-1.41
(4H, m), 1.39 (3H, s), 1.36 (3H, s), 0.91-0.84 (12H, m); 13C
NMR (CDCl3) δ 200.8, 137.7, 128.7, 128.1, 127.7, 100.6, 100.0,
97.6, 71.4, 70.6, 70.3, 67.6, 59.3, 39.1, 38.9, 25.4, 23.2, 23.1,
22.8, 22.7, 18.8, 18.7; MS (EI) m/z (relative intensity) 376
7288 J. Org. Chem., Vol. 70, No. 18, 2005

Ketones as Catalysts for Epoxidation of Alkenes
127.3, 127.0, 126.6, 100.9, 100.4, 97.3, 71.4, 70.6, 70.4, 67.4,
62.9, 62.6, 19.3, 19.1; MS (EI) m/z (relative intensity) 504 (M+,
2), 414 (100); Anal. Calcd for C30H32O7: C, 71.41; H, 6.39.
Found: C, 71.16; H, 6.50.
propanol (75 mg, 1.01 mmol) and p-TsOH (2 mg) was heated
under reflux with a Dean-Stark trap for 12 h. The cooled
reaction mixture was then treated with saturated aqueous
NaHCO3 and extracted with Et2O (3 × 20 mL). The combined
organic extracts were dried over anhydrous MgSO4 and
filtered. The filtrate was concentrated under reduced pressure.
The crude residue was purified by flash column chromatog-
raphy to afford diisobutyl acetal 19 as a syrup (79 mg, 87%):
Dicyclohexylmethyl Ketone 17. To a solution of alcohol
12 (335 mg, 0.65 mmol) in dry CH2Cl2 (10 mL) were added
slowly PDC (293 mg, 0.78 mmol) and powdered 4 Å molecular
sieves (290 mg). The mixture was stirred at room temperature
for 12 h. The mixture was suction filtered through a pad of
silica gel, and the filtrate was concentrated under reduced
pressure. The crude residue was purified by flash column
chromatography to afford dicyclohexylmethyl ketone 17 as a
syrup (308 mg, 92%): Rf 0.41 (hexanes-Et2O, 1:1); [R]23D +4.4
(c 1.0, CHCl3); IR (thin film) 1743, 1729 (CdO) cm-1; 1H NMR
(CDCl3) δ 7.42-7.26 (5H, m), 5.11 (1H, d, J ) 3.0 Hz), 4.99
(1H, d, J ) 11.1 Hz), 4.85 (1H, d, J ) 12.3 Hz), 4.77 (1H, d, J
) 12.3 Hz), 4.17 (1H, d, J ) 15.9 Hz), 4.11 (1H, dd, J ) 10.8,
3.0 Hz), 3.92 (1H, d, J ) 15.9 Hz), 3.28-3.20 (4H, m), 1.79-
1.53 (12H, m), 1.38 (3H, s), 1.25 (3H, s), 1.00-0.90 (10H, m);
13C NMR (CDCl3) δ 201.3, 138.1, 129.1, 128.4, 127.9, 100.9,
100.2, 98.4, 71.6, 70.6, 77.3, 67.8, 66.9, 66.7, 38.7, 38.6, 31.0,
30.9, 30.7, 27.3, 26.7, 26.6, 25.5, 19.1, 19.0; MS (EI) m/z
(relative intensity) 516 (M+, 1), 402 (9), 91 (100); Anal. Calcd
for C30H44O7: C, 69.74; H, 8.58. Found: C, 69.32; H, 8.63.
Dimethyl Acetal 18. A suspension of methyl â-L-ara-
binopyranoside (1.51 g, 9.2 mmol) in methanol (20 mL)
containing 2,2,3,3-tetramethoxybutane (3.27 g, 18.4 mmol),
trimethyl orthoformate (3.2 mL, 36.8 mmol), and 10-camphor-
sulfonic acid (213 mg, 10 mol %) was heated under reflux for
12 h. The cooled reaction mixture was then treated with
powdered NaHCO3 (0.5 g) and filtered, and the filtrate was
concentrated under reduced pressure. The residue was dis-
solved in EtOAc, and the solution was washed with saturated
aqueous NaHCO3 solution. The combined organic extracts
were dried over anhydrous MgSO4 and filtered. The filtrate
was concentrated under reduced pressure. The crude residue
was purified by flash column chromatography to afford di-
methyl acetal 18 as a colorless syrup (1.78 g, 69%): Rf 0.17
(hexanes-EtOAc, 1:1); IR (thin film) 3424 (OH) cm-1; 1H NMR
(CDCl3) δ 4.78 (1H, d, J ) 3.3 Hz), 4.21 (1H, dd, J ) 10.5, 3.3
Hz), 4.11 (1H, dd, J ) 10.5, 3.3 Hz), 3.94 (1H, t, J ) 1.5 Hz),
3.83 (1H, dd, J ) 12.6, 1.2 Hz), 3.76 (1H, dd, J ) 12.8, 1.5
Hz), 3.42 (3H, s), 3.26 (3H, s), 3.24 (3H, s), 1.90 (1H, brs), 1.30
(3H, s), 1.28 (3H, s); 13C NMR (CDCl3) δ 100.6, 98.9, 68.4, 66.1,
65.5, 62.9, 55.6, 48.3, 18.2, 18.1; MS (EI) m/z (relative intensity)
247 (100), 263 ([M - CH3]+, 20); HRMS (EI) calcd for C12H22O7
[M - CH3]+ 263.1125, found 263.1118.
Rf 0.34 (hexanes-Et2O, 2:1); [R]20 -10.7 (c 0.6, CHCl3); IR
D
1
(thin film) 3434 (OH) cm-1; H NMR (CDCl3) δ 4.74 (1H, d, J
) 3.3 Hz), 4.20 (1H, dd, J ) 10.5, 3.3 Hz), 4.11 (1H, dd, J )
10.5, 3.0 Hz), 3.90 (1H, d, J ) 1.5 Hz), 3.79 (1H, d, J ) 12.6
Hz), 3.73 (1H, dd, J ) 12.6, 1.5 Hz), 3.39 (3H, s), 3.23-3.14
(4H, m), 2.53 (1H, brs), 1.92-1.79 (2H, m), 1.35 (3H, s), 1.30
(3H, s), 0.93-0.87 (12H, m); 13C NMR (CDCl3) δ 100.4, 100.2,
99.0, 68.4, 67.4, 67.1, 65.9, 65.5, 62.8, 55.6, 28.9, 28.9, 20.1,
20.0, 19.9, 19.0, 18.9; MS (FAB) m/z (relative intensity) 385
([M + Na]+, 12), 289 (32), 100 (53), 87 (60), 57 (100); HRMS
(FAB) calcd for C18H34O7 [M + Na]+ 385.2195, found 385.2200.
Diisobutyl Ketone 20. To a solution of alcohol 19 (193 mg,
0.53 mmol) in dry CH2Cl2 (10 mL) were added slowly PCC (171
mg, 0.80 mmol) and powdered 3 Å molecular sieve (200 mg).
The mixture was stirred at room temperature for 12 h. The
mixture was suction filtered through a pad of silica gel, and
the filtrate was concentrated under reduced pressure. The
crude residue was purified by flash column chromatography
to afford diisobutyl ketone 20 as a syrup (180 mg, 94%): Rf
1
0.38 (Et2O-hexane, 2:1); IR (thin film) 1745 (CdO) cm-1; H
NMR (CDCl3) δ 4.88 (1H, d, J ) 10.8 Hz), 4.86 (1H, d, J ) 3.3
Hz), 4.19 (1H, d, J ) 14.7 Hz), 4.11 (1H, dd, J ) 10.8, 3.3 Hz),
3.94 (1H, d, J ) 14.7 Hz), 3.50 (3H, s), 3.27-3.17 (4H, m),
1.87-1.80 (2H, m), 1.35 (3H, s), 1.32 (3H, s), 0.95-0.89 (12H,
m); 13C NMR (CDCl3) δ 200.7, 100.6, 100.0, 98.6, 71.2, 70.3,
67.6, 67.5, 67.0, 56.4, 28.9, 20.0, 19.9, 19.8, 19.7, 18.8, 18.7;
MS (CI) m/z (relative intensity) 360 (M-, 17), 198 (31), 153
(30), 143 (100); HRMS (CI) calcd for C18H32O7 M- 360.2154,
found 360.2146.
Acknowledgment. This research was supported by
the CUHK Direct Grant.
Supporting Information Available: 1H NMR spectral
and HPLC data for the determination of the enantiomeric
excess of the epoxides. 1H and 13C NMR spectral characteriza-
tion data for compounds 4, 7, and 8-20. X-ray data of
compounds 12 and 16. This material is available free of charge
via the Internet at http://pubs.acs.org.
Diisobutyl Acetal 19. A solution of dimethyl acetal 18 (70
mg, 0.25 mmol) in benzene (15 mL) containing 2-methyl-1-
JO050928F
J. Org. Chem, Vol. 70, No. 18, 2005 7289