An improved synthesis of a ketone catalyst for asymmetric epoxidation of olefins

Article abstract of DOI:10.1021/jo0206770

An efficient synthesis of a ketone catalyst for asymmetric epoxidation of olefins from D-glucose in six steps is described.

Full text of DOI:10.1021/jo0206770

SCHEME 1
An Im p r oved Syn th esis of a Keton e
Ca ta lyst for Asym m etr ic Ep oxid a tion of
Olefin s
Lianhe Shu, Yu-Mei Shen, Christopher Burke,
David Goeddel, and Yian Shi*
Department of Chemistry, Colorado State University,
Fort Collins, Colorado 80523
SCHEME 2. Or igin a l Syn th esis of Keton e 2
yian@lamar.colostate.edu
Received October 30, 2002
Abstr a ct: An efficient synthesis of a ketone catalyst for
asymmetric epoxidation of olefins from D-glucose in six steps
is described.
Dioxiranes generated in situ from chiral ketones have
been shown to be highly enantioselective for the asym-
metric epoxidation of olefins.1-3 Previously, we reported
that fructose-derived ketone 1 is an effective epoxidation
catalyst and gives high ee’s for a variety of trans- and
trisubstituted olefins (Scheme 1).4 Recently, we reported
that ketone 2, a nitrogen analogue of 1, provides encour-
agingly high ee’s for the epoxidation of cis-olefins and
* To whom correspondence should be addressed. Phone: 970-491-
7424. Fax: 970-491-1801.
(1) For general leading references on dioxiranes, see: (a) Adam, W.;
Curci, R.; Edwards, J . O. Acc. Chem. Res. 1989, 22, 205. (b) Murray,
R. W. Chem. Rev. 1989, 89, 1187. (c) Curci, R.; Dinoi, A.; Rubino, M.
F. Pure Appl. Chem. 1995, 67, 811. (d) Clennan, E. L. Trends Org.
Chem. 1995, 5, 231.
(2) For reviews on chiral ketone-catalyzed asymmetric epoxidation,
see: (a) Denmark, S. E.; Wu, Z. Synlett 1999, 847. (b) Frohn, M.; Shi,
Y. Synthesis 2000, 1979.
styrenes.5 The drawback of our original synthesis of
ketone 2 is that it requires nine steps and some expensive
reagents (Scheme 2), which makes this ketone catalyst
less convenient. Considering that this ketone catalyst can
potentially be useful, efforts have been made to improve
its synthesis.
The original and improved syntheses of ketone 2 are
outlined in Schemes 2 and 3 respectively. All steps have
been improved except for the preparation of 1-dibenzyl-
amino-1-deoxy-D-fructose (3) via the Amadori rearrange-
ment. For the ketalization of compound 3, it was found
that the reaction gave cleaner products if quenched before
all the starting material was consumed. Compound 4 can
then be obtained in 80-87% yield by a simple filtration
through a short column of silica gel. For the hydrogena-
tion of compound 4, the original procedure is sensitive
to the purity of the starting material, and the hydrogena-
tion product, amino alcohol 5, seems to be unstable. Both
the reaction and the purification of products need to be
carried out carefully. In our subsequent studies, it was
found that the hydrogenation could be facilitated by
addition of acetic acid, and the resulting product could
be used for the next step without further purification.
The initial attempt to directly form the oxazolidinone
(5 to 6) using COCl2-Et3N was unsuccessful.6 In the
(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.; J in, 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) Adam, W.; Fell, R. T.; Saha-Moller, C. R.; Zhao, C.-G.
Tetrahedron: Asymmetry 1998, 9, 397. (l) Armstrong, A.; Hayter, B.
R. Chem. Commun. 1998, 621. (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. (n) Yang, D.; Yip, Y.-C.; Chen, J .; Cheung, K.-K.
J . Am. Chem. Soc. 1998, 120, 7659. (o) Adam, W.; Saha-Moller, C. R.;
Zhao, C.-G. Tetrahedron: Asymmetry 1999, 10, 2749. (p) Carnell, A.
J .; J ohnstone, 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. (t) Bortolini, O.;
Fogagnolo, M.; Fantin, G.; Maietti, S.; Medici, A. Tetrahedron: Asym-
metry 2001, 12, 1113. (u) Seki, M.; Furutani, T.; Imashiro, R.; Kuroda,
T.; Yamanaka, T.; Harada, N.; Arakawa, H.; Kusama, M.; Hashiyama,
T. Tetrahedron Lett. 2001, 42, 8201. (v) Armstrong, A.; Moss, W. O.;
Reeves, J . R. Tetrahedron: Asymmetry 2001, 12, 2779. (w) Matsumoto,
K.; Tomioka, K. Tetrahedron Lett. 2002, 43, 631. (x) Stearman, C. J .;
Behar, V. Tetrahedron Lett. 2002, 43, 1943. (y) Denmark, S. E.;
Matsuhashi, H. J . Org. Chem. 2002, 67, 3479. (z) Shing, T. K. M.;
Leung, G. Y. C. Tetrahedron 2002, 58, 7545.
(4) (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) Shu, L.; Shi, Y. Tetrahedron 2001,
57, 5213.
(5) (a) Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J . Am. Chem. Soc.
2000, 122, 11551. (b) Tian, H.; She, X.; Xu, J .; Shi, Y. Org. Lett. 2001,
3, 1929. (c) Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J . Org. Chem.
2002, 67, 2435.
10.1021/jo0206770 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/15/2003
J . Org. Chem. 2003, 68, 4963-4965
4963

To a suspension of 1-dibenzylamino-1-deoxy-D-fructose (3)
(26.93 g, 75.0 mmol) and trimethylorthoformate (35.0 mL, 320.0
mmol) in acetone (700 mL) at 0 °C under N2 was added
concentrated hydrochloric acid (9.0 mL, 108.0 mmol). Upon
vigorous stirring at 0 °C for about 1.5 h,10 the reaction mixture
was quenched with NH4OH (12 mL), filtered through a pad of
silica gel with suction to remove NH4Cl, and washed with
additional acetone. The resulting solution was concentrated to
about 50 mL, diluted with hexanes-EtOAc (3:2, 400 mL), and
allowed to stand in the freezer for about 3 h to precipitate most
of the unreacted starting material. The mixture was then filtered
through a second pad of silica gel with suction to remove the
remaining starting material dissolved in the solution, and the
pad was washed with hexanes-EtOAc (3:2, 200 mL). The filtrate
was concentrated and dried under vacuum overnight to give
compound 4 as a pale yellow oil (24.0 g, 80%).5c
SCHEME 3. Im p r oved Syn th esis of Keton e 2
A solution of the above oil (26.0 g, ca. 65.0 mmol) in absolute
ethanol (450 mL) was degassed and purged with N2 three times.
After AcOH (4.3 g, 72.0 mmol) and 10% Pd/C (4.3 g) were added,
the reaction mixture was degassed and filled with H2 three
times. Upon stirring at room temperature under H2 to comple-
tion as judged by TLC (about 4.5 h),11 the reaction mixture was
filtered through a short pad of Celite to remove the catalyst.
The filtrate was then concentrated at room temperature and
dried under vacuum to give compound 5a as a brown solid (17.5
g, crude yield 96%), which was used directly in the next step
without further purification (the product must be dried under
vacuum to remove any remaining EtOH, which will otherwise
consume phosgene in the next step).
To a suspension of the above compound (17.4 g, 62.0 mmol)
and NaHCO3 (30.0 g, 360.0 mmol) in CH2Cl2 (300 mL) was added
dropwise a solution of 20% phosgene in toluene (46.2 mL, 87.0
mmol) at 0 °C under N2 with vigorous stirring over 30 min.12,13
The reaction mixture was stirred at room temperature to
completion as judged by TLC (about 6 h).14 After the flask was
opened to air, MeOH (100 mL) was added dropwise at room
temperature with vigorous stirring over 30 min.15 After an
additional 30 min stirring, the mixture was flushed through a
short column of silica gel and washed with additional methanol
until the brown liquid no longer came off the column (it is
important not to wash with too much methanol in order to
prevent excess salts from passing through the silica gel). The
resulting solution was concentrated and dried under vacuum to
give the crude alcohol 6 as a light brown solid (16.4 g) (the
product must be dried under vacuum to remove any remaining
MeOH, which will otherwise consume PDC in the next step).5c
To a solution of the above alcohol (16.4 g, ca. 62.0 mmol) in
dry CH2Cl2 (300 mL) were added 3 Å MS (unactivated) (56 g),
PDC (35.0 g, 93.0 mmol), and acetic acid (5 drops). Upon stirring
at room temperature to completion as judged by TLC (about 5
original procedure, the oxazolidinone was therefore pre-
pared by a two-step process using expensive 4-methoxy-
phenyl chloroformate (Scheme 2). In our subsequent
studies, it was found the choice of the base is very
important for the formation of the desired oxazolidinone
when COCl2 is used. Among the bases tested, NaHCO3
was found to be the best.7 Treatment of amino alcohol
5a with COCl2-NaHCO3 led to a one-step formation of
oxazolidinone 6 in good yield (Scheme 3).
In the original synthesis, the N-Boc group was intro-
duced after the alcohol was protected with TBSCl (Scheme
2). Protection and deprotection add two steps to the
synthesis, and the desilylation of 7 with Et3N‚3HF takes
about 4 days to complete. Efforts were then made to
introduce the Boc group onto the oxazolidinone of ketone
8 directly (Scheme 3), thus avoiding the protection and
deprotection steps. After much experimentation, it has
been found that the Boc group can be added in high yield
by treatment of ketone 8 with (Boc)2O in the presence of
a catalytic amount of DMAP (Scheme 3).
In summary, we report an improved synthesis of a
ketone catalyst for asymmetric epoxidation of olefins. The
ketone can be prepared from D-glucose as starting mate-
rial in six steps without extensive chromatography
purification.
(10) The byproducts formed in this step could significantly retard
the following hydrogenation reaction. Therefore, the reaction needs to
be carefully monitored by TLC and be stopped immediately upon
byproduct appearing on TLC (regardless of whether any impurity is
present, the reaction must not be allowed to stir for longer than 2 h).
TLC was carried out by taking a small amount of the reaction mixture
and quenching it with NH4OH. The Rf of the product is about 0.6 in
hexane-AcOEt 1:1, and the Rf of the byproduct is about 0.5.
(11) EtOAc is used for TLC. The product stays at the baseline. The
starting material and monobenzylamine intermediate can be detected
by UV with Rf values of 0.8 and 0.2, respectively. The reaction time
for the hydrogenation varies with the activity of the Pd catalyst and
stirring. Active catalyst and vigorous stirring usually results in shorter
reaction time and better yield. Also, the reaction goes faster if less
solvent is used.
(12) Phosgene is very toxic and needs to be handled carefully.
(13) Vigorous stirring is required to facilitate the neutralization of
the formed HCl by NaHCO3.
(14) The product Rf is about 0.5 using EtOAc as a solvent, and the
starting material stays at the baseline.
(15) MeOH is used to hydrolyze the unreacted phosgene and the
corresponding chloroformate of compound 6. Methanol should be added
very slowly at the beginning via pipet, and the reaction mixture should
be vigorously stirred to avoid the build-up of HCl, which will catalyze
Exp er im en ta l Section
To a suspension of D-glucose (59.8 g, 332.0 mmol) and Bn2-
NH (64.0 mL, 332.0 mmol) in absolute ethanol (350 mL) was
added HOAc (57.0 mL, 995.7 mmol). Upon refluxing for 3 h,8
the reaction mixture was cooled to 0 °C and filtered with suction.
The resulting filter cake was washed thoroughly with ethanol
to white and dried under vacuum to give 1-dibenzylamino-1-
deoxy-D-fructose (3) as a white solid (98.4 g, 83%).9
(6) Et3N is believed to react with COCl2 to form an ammonium salt
which further decomposes due to the poor reactivity of the primary
amine of 5 with COCl2. For a leading review on amine dealkylations
with acyl chlorides, see: Cooley, J . H.; Evain, E. J . Synthesis 1989, 1.
(7) Other bases such as 2,6-lutidine, Na2CO3, and K2CO3 worked
as well. In the case of Na2CO3 and K2CO3, more phosgene was required
due to the more rapid decomposition of phosgene by these bases.
(8) The reaction mixture became orange and viscous, so it is very
important that stirring continue at all times. Also, to prevent decom-
position, the bath temperature should not exceed 90 °C.
(9) Hodge, J . E.; Fisher, B. E. Methods Carbohydr. Chem. 1963, 2,
99.
the hydrolysis of the dimethyl ketal of compound
undesired diol instead.
6 to give the
4964 J . Org. Chem., Vol. 68, No. 12, 2003

h),16 the reaction mixture was filtered through a short column
of silica gel and washed with EtOAc-hexane (3:1).17 The filtrate
was concentrated, dried under vacuum,18 and recrystallized
using hexane-CH2Cl2 (3:1) to afford ketone 8 as a white solid
(6.0 g, 38% overall yield from compound 4):5c IR (film) 3378, 3319,
1759, 1731 cm-1; 1H NMR (300 MHz, CDCl3) 5.48 (brs, 1H), 4.82
(d, J ) 5.4 Hz, 1H), 4.64-4.53 (m, 2H), 4.32 (d, J ) 10.7 Hz,
1H), 4.23 (d, J ) 13.5 Hz, 1H), 3.38 (dd, J ) 10.7, 0.6 Hz, 1H),
1.46 (s, 3H), 1.42 (s, 3H); 13C NMR (75 MHz, CDCl3) 195.1, 155.9,
111.1, 102.8, 77.6, 75.6, 61.2, 45.4, 27.3, 26.2.
To a solution of the above ketone 8 (2.56 g, 10.5 mmol) and
(Boc)2O (2.75 g, 12.6 mmol) in freshly distilled THF (32 mL) was
added DMAP (0.013 g, 0.11 mmol). Upon stirring under N2 at
room temperature to completion as judged by TLC (about 15-
20 min),19,20 the reaction mixture was immediately quenched
with oxalic acid (0.01 g, 0.11 mmol), immediately flushed
through a prepacked column of silica gel, and washed with
hexanes-EtOAc (dried over K2CO3) (1:1, 42 mL). The solution
was concentrated, and the residue began to crystallize. Hot
hexanes-ether (3:1, 27 mL) was added to the solid, and the
resulting suspension was stirred for 10 min (without further
heating). The suspension was then filtered with suction and
washed with cold hexanes-ether (3:1, 20 mL). Ketone 2 was
obtained as a white solid21 (3.02 g, 84% yield):5c IR (film) 3446
(hydrate), 1823, 1756, 1731 cm-1 1H NMR (300 MHz, CDCl3)
;
4.79 (d, J ) 5.6 Hz, 1H), 4.61 (dd, J ) 5.6, 1.8 Hz, 1H), 4.56 (d,
J ) 11.6 Hz, 1H), 4.51 (dd, J ) 13.6, 1.8 Hz, 1H), 4.23 (d, J )
13.6 Hz, 1H), 3.71 (d, J ) 11.6 Hz, 1H), 1.53 (s, 9H), 1.45 (s,
3H), 1.41 (s, 3H); 13C NMR (75 MHz, CDCl3) 194.7, 148.8, 148.4,
111.3, 98.9, 85.0, 77.4, 75.5, 61.3, 48.5, 28.1, 27.3, 26.1.
Ack n ow led gm en t. We are grateful for the generous
financial support from the General Medical Sciences of
the National Institutes of Health (GM59705-04), the
Camille and Henry Dreyfus Foundation, the Alfred P.
Sloan Foundation, DuPont, Eli Lilly, and GlaxoSmith-
Kline.
(16) The product in this step is a mixture of the ketone and its
hydrate. In EtOAc, the Rf of the ketone is about 0.8, but the hydrate
only appears slightly above the starting material at around 0.5. The
two can be differentiated by color with p-anisaldehyde stain. The
hydrate has a reddish tint, while the starting material appears darker.
(17) Excess wash should be avoided to reduce impurities which will
affect the following recrystallization.
J O0206770
(18) The hydrate can be converted to the ketone by extensive drying
under high vacuum line.
(19) The reaction time and the amount of (Boc)2O used are critical
factors. Too little time leads to a messy mixture of the starting material
and product, while too much time results in product decomposition,
since ketone 2 seems to be unstable in this reaction mixture. Longer
reaction time and excess (Boc)2O will make the reaction less clean.
(20) The product is a mixture of the ketone and its hydrate. The Rf
of the ketone is about 0.6 in hexanes-EtOAc (1: 1). TLC shows that
the reaction mixture also contains a small amount of impurity [Rf about
0.8 in hexanes-EtOAc (1:1)]. The impurity is removed during the
subsequent treatment with hexanes-ether (3:1).
(21) To simplify the NMR spectrum, the hydrate can be converted
to the ketone by heating the compound under vacuum.
J . Org. Chem, Vol. 68, No. 12, 2003 4965