Practical synthesis of an L-fructose-derived ketone catalyst for asymmetric epoxidation of olefins

Article abstract of DOI:10.1021/jo060335k

An L-fructose-derived ketone catalyst for asymmetric epoxidation of trans- and tri substituted olefins was efficiently prepared from L-sorbose in five steps.

Full text of DOI:10.1021/jo060335k

SCHEME 1
Practical Synthesis of an L-Fructose-Derived
Ketone Catalyst for Asymmetric Epoxidation of
Olefins
Mei-Xin Zhao and Yian Shi*
Department of Chemistry, Colorado State UniVersity,
Fort Collins, Colorado 80523
SCHEME 2. Original Synthesis of L-Fructose (ref 4)
yian@lamar.colostate.edu
ReceiVed February 16, 2006
An L-fructose-derived ketone catalyst for asymmetric epox-
idation of trans- and trisubstituted olefins was efficiently
prepared from L-sorbose in five steps.
Dioxiranes generated in situ from chiral ketones have been
shown to be effective for asymmetric epoxidation of olefins.1
In our earlier studies, we have shown that fructose-derived
ketone 1 (Scheme 1) displayed high enantioselectivity for a wide
range of trans- and trisubstituted olefins.2 Ketone 1 is readily
prepared from very inexpensive D-fructose by ketalization and
oxidation.2,3 The enantiomer of ketone 1 (ketone ent-1) is
synthesized in the same way from L-fructose,2b which can be
prepared from readily available L-sorbose by ketalization,
mesylation, and one-pot acid-base treatment based on the
reported procedure (Scheme 2).4 Ketone ent-1 prepared in this
way shows the same enantioselectivity for epoxidation as ketone
1.2b However, one drawback associated with the synthesis of
ketone ent-1 is that the preparation of L-fructose from L-sorbose
requires a relatively long time, and some steps are sensitive to
reaction conditions.4,5 This consequently hinders the usage of
ketone ent-1 for asymmetric epoxidation. Considering that
ketone ent-1 is potentially useful,6 efforts have been made to
further improve its synthesis. Herein we wish to report our
detailed studies on this subject.
The ketalization of L-sorbose appears to be very sensitive to
reaction conditions such as the amount of SnCl2, temperature,
and reaction time (Schemes 2 and 3). Compound 2 is likely to
be a kinetic product and is easy to isomerize. A prolonged
reaction time leads to a mixture of isomers; thus, the reaction
is usually stopped once the solution becomes clear.4,2b,5 Under
such reaction conditions, we found that the efficiency of the
reaction is affected by the quality and the crystalline state of
the L-sorbose. Presumably, the crystalline state of L-sorbose
influences its solubility, thus affecting the reaction time. We
found that it is beneficial to pulverize the L-sorbose and quench
the reaction before the L-sorbose is completely consumed so
that the reaction time is shortened and isomerization of
compound 2 can be minimized (the remaining L-sorbose can
be readily recovered by filtration and reused). The formed ketal
2 is used directly for mesylation to give mesylate 3 in ca. 40%
yield over two steps after recrystallization (Scheme 3).
In the original procedure (Scheme 2), the one-pot transforma-
tion of mesylate 3 to L-fructose uses acetone as cosolvent and
takes about 3 days. Our efforts were made to improve this
process. After much experimentation, it was found that this
transformation proceeded efficiently when the reaction was
carried out in water without organic solvent. The selective
deprotection of the 4,6-O-isopropylidene group of 3 can be
easily achieved using 4.5% H2SO4 at room temperature for 3 h
to give diol 4 cleanly.7 After the solution became alkaline using
* Corresponding author. Tel: 970-491-7424. Fax: 970-491-1801.
(1) 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. (c) Shi, Y. Acc. Chem. Res. 2004, 37, 488. (d) Yang,
D. Acc. Chem. Res. 2004, 37, 497.
(2) (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.
(3) Tu, Y.; Frohn, M.; Wang, Z.-X.; Shi, Y. Org. Synth. 2003, 80, 1.
(4) Chen, C.-C.; Whistler, R. L. Carbohydr. Res. 1988, 175, 265.
(5) For a stepwise synthesis of L-fructose from L-sorbose, see: Bach,
T.; Hofer, F. J. Org. Chem. 2001, 66, 3427.
(6) For examples using ketone ent-1, see: (a) Morimoto, Y.; Iwai, T.;
Kinoshita, Tetrahedron Lett. 2001, 42, 6307. (b) Morimoto, Y.; Takaishi,
M.; Iwai, T.; Kinoshita, T.; Jacobs, H. Tetrahedron Lett. 2002, 43, 5849.
(c) Altmann, K.-H.; Bold, G.; Caravatti, G.; Denni, D.; Flo¨rsheimer, A.;
Schmidt, A.; Rihs, G.; Wartmann, M. HelV. Chim. Acta 2002, 85, 4086.
(d) Zhang, Q.; Lu, H.; Richard, C.; Curran, D. P. J. Am. Chem. Soc. 2004,
126, 36.
(7) While the reaction rate increased with the concentration of sulfuric
acid, compound 4’s stability decreased. Considering the stability of the
compound and reaction time, 4.5% (w) H2SO4 (using 10 mL of 4.5% H2-
SO4 per gram of substrate) was found to work well. A prolonged reaction
time could also lead to the decomposition of the compound.
10.1021/jo060335k CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/03/2006
J. Org. Chem. 2006, 71, 5377-5379
5377

SCHEME 3. Improved Synthesis of L-Fructose-Derived Ketone Ent-1
9 M NaOH,8 the conversion of compound 4 to triol 6 via epoxide
5 can be efficiently achieved at 90-100 °C in 8 h, which
significantly shortens the reaction time. The 1,2-O-isopropyli-
dene group of triol 6 was then easily removed as before to give
a syrup9 from which L-fructose was obtained by extraction with
hot ethanol several times (Scheme 3). The crude L-fructose was
directly ketalized with dimethoxypropane and H2SO4 in acetone
to give alcohol 7 in 42% overall yield from mesylate 3 (Scheme
3). The oxidation of alcohol 7 with PDC gave ketone ent-1 in
87% yield. The obtained ketone catalyst ent-1 gives comparable
results to 1 for asymmetric epoxidation.
In summary, we have described a practical synthesis of
L-fructose-derived ketone catalyst ent-1. One key improvement
in the current process was the use of water without organic
solvent during the acid-base reaction sequence from mesylate
3 to L-fructose, which greatly reduces the reaction time required
for the process. Multigram quantities of the ketone catalyst have
been readily prepared. The described improvement should be
helpful for those who may wish to use this ketone catalyst.
(10 mL), filtered to remove the unreacted L-sorbose (78.0 g), and
the solid was washed with EtOAc (100 mL). The filtrate was
concentrated to give compound 2 as a syrup.
The above syrup was dissolved in pyridine (966 mL). After
cooling with an ice bath, methanesulfonyl chloride (213.0 mL, 2.75
mol) was added dropwise via an additional funnel over 2 h. After
stirring at 0 °C for an additional 3 h (monitored by TLC), the
reaction mixture was poured into ice-water (6000 mL), stirred for
30 min, and filtered. The filter cake was washed with water several
times and recrystallized from ethanol (ca. 670 mL) to give mesylate
3 as a white crystal (300.8 g, 40% yield over two steps based on
L-sorbose) (50% yield over two steps based on the recovered starting
1
material): mp 120-122 °C; [R]25 ) -28.0 (c, 1.06, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 4.88 (d, J ) 1.8 Hz, 1H), 4.46 (dd,
J ) 3.3, 1.8 Hz, 1H), 4.25 (d, J ) 9.9 Hz, 1H), 4.22 (m, 1H), 4.20
(d, J ) 9.9 Hz, 1H), 4.01 (dd, J ) 13.2, 3.0 Hz, 1H), 3.92 (dd,
J ) 13.2, 3.0 Hz, 1H), 3.16 (s, 3H), 1.55 (s, 3H), 1.47 (s, 3H),
1.42 (s, 3H), 1.38 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 111.5,
109.8, 98.2, 84.2, 73.3, 73.25, 72.1, 60.4, 38.9, 28.3, 26.0, 25.9,
20.1. Anal. Calcd for C13H22O8S: C, 46.14; H, 6.55. Found: C,
46.00; H, 6.39.
Synthesis of Alcohol 7 from Mesylate 3. A suspension of
mesylate 3 (pulverized) (100.0 g, 0.30 mol) in 4.5% (w) H2SO4
(1000 mL) was stirred at room temperature until all the starting
material had been consumed as monitored by TLC (3 h).7 After it
was made alkaline with 9 M NaOH (200 mL, 1.80 mol), the reaction
mixture was heated at 90-100 °C until the reaction was completed
as monitored by TLC (8 h).12 After being acidified to pH ∼1 with
9 M H2SO4 (∼50 mL), the reaction mixture was heated at 70-80
°C for 30 min,9 neutralized (pH 7.0) with 9 M NaOH (∼44 mL),
and concentrated to give a residue. The resulting residue was
extracted by refluxing with ethanol (4 × 500 mL). The ethanol
solution was concentrated to give L-fructose as a yellow syrup.
Experimental Section
Synthesis of Mesylate 3 from L-Sorbose. A solution of dry 1,2-
dimethoxyethane (80 mL) containing SnCl2 (2.0 g, 0.01 mol) was
added to a suspension of L-sorbose (pulverized)10 (400.0 g, 2.22
mol) in 2,2-dimethoxypropane (1200 mL) with vigorous stirring.
The mixture was refluxed gently with stirring under N2 at 70 °C
(bath temperature) for 2.3 h (carefully monitored by GC11 to avoid
isomerization of compound 2 to other isomers). At this point, there
is still a substantial amount of solid (L-sorbose) remaining in the
reaction mixture. The reaction was quenched immediately with Et3N
To a suspension of the above L-fructose syrup13 in acetone (500
mL) was added 2,2-dimethoxypropane (109.0 mL, 0.89 mol). After
cooling to 0 °C, concentrated H2SO4 (4.15 mL, 0.074 mol) was
added dropwise under N2. The resulting reaction mixture was stirred
at 0 °C for 6 h (carefully monitored by GC14). After addition of
concentrated NH4OH (25 mL), the reaction mixture was concen-
(8) Although a higher concentration of base can accelerate the reaction,
the reaction mixture becomes complex. Considering the reaction efficiency
and stability of the product, using 9 M NaOH and refluxing for 8 h worked
well.
(9) The reaction should be carefully monitored by TLC and quenched
as soon as the reaction is finished. Heating the reaction mixture for a long
time causes problems, possibly polymerization of the L-fructose.
(10) Large quantities of L-sorbose were purchased from MP Biomedicals,
LLC (Aurora, OH).
(11) The GC retention time of the main peak is 3.32 min. Conditions:
column, VA-5MS, Varian chromatography systems (VA-122553-20); oven,
from 150 to 250 °C (20 °C/min); carrier, helium, head pressure 25 psi;
detection: FID 250 °C.
(12) The disappearance and appearance of compounds 4-6 can be clearly
detected by TLC. The Rf values of compounds 4, 5, and 6 are 0.57, 0.70,
and 0.30, respectively, using EtOAc as a solvent.
(13) The obtained L-fructose was a sticky syrup. Freezing the syrup with
dry ice led to a solid which was easier to manipulate.
5378 J. Org. Chem., Vol. 71, No. 14, 2006

trated to a solid which was then dissolved in CH2Cl2 (400 mL).
The resulting solution was washed with water (2 × 200 mL), brine
(200 mL), dried over Na2SO4, filtered, concentrated, and purified
by silica gel chromatography (ethyl acetate: hexane, 1:5 to 1:3,
v/v) to give alcohol 7 as a white solid (32.5 g, 42% yield from
mesylate 3): mp 115-116 °C; [R]25D ) +142.4 (c, 1.05, CHCl3);
acetic acid (10 drops). After stirring at room temperature under N2
overnight, the reaction mixture was filtered through a pad of silica
gel and washed (ethyl ether:hexane, 1:1, v/v, 500 mL) until no
product came out. The filtrate was concentrated and recrystallized
from hot hexane (40-45 mL) to give ketone ent-1 as a white crystal
(9.0 g, 87%): mp 99-100 °C; [R]25 ) + 120.0 (c 1.0, CHCl3);
D
1
1
IR (NaCl, film): 3458 cm-1; H NMR (300 MHz, CDCl3) δ 4.21
IR (NaCl, film): 1743 cm-1; H NMR (300 MHz, CDCl3) δ 4.73
(ddd, J ) 5.7, 2.7, 0.6 Hz, 1H), 4.19 (d, J ) 9.0 Hz, 1H), 4.14 (dd,
J ) 6.9, 5.7 Hz, 1H), 4.13 (dd, J ) 13.2, 2.7 Hz, 1H), 4.02 (d,
J ) 13.2 Hz, 1H), 3.99 (d, J ) 9.0 Hz, 1H), 3,67 (dd, J ) 8.1, 6.9
Hz, 1H), 2.01(d, J ) 8.1 Hz, 1H), 1.54 (s, 3H), 1.52 (s, 3H), 1.45
(s, 3H), 1.38 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 111.9, 109.4,
104.6, 76.8, 73.5, 72.3, 70.4, 60.8, 28.2, 26.6, 26.5, 26.2. Anal.
Calcd for C12H20O6: C, 55.37; H, 7.74. Found: C, 55.55; H, 7.60.
Synthesis of Ketone Ent-1. To a solution of alcohol 7 (10.4 g,
0.04 mol) in CH2Cl2 (100 mL) was added PDC (22.57 g, 0.06 mol),
followed by freshly powdered 3 Å molecular sieves (37.6 g) and
(d, J ) 5.4 Hz, 1H), 4.60 (d, J ) 9.6 Hz, 1H), 4.55 (dd, J ) 5.4,
2.4 Hz, 1H), 4.39 (dd, J ) 13.5, 2.4 Hz, 1H), 4.12 (d, J ) 13.5
Hz, 1H), 3.99 (d, J ) 9.6 Hz, 1H), 1.55 (s, 3H), 1.46 (s, 3H), 1.40
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 196.9, 113.9, 110.7, 104.2,
78.1, 76.0, 70.1, 60.2, 27.4, 26.8, 26.3, 26.2. Anal. Calcd for
C12H18O6: C, 55.81; H, 7.02. Found: C, 56.09; H, 7.27.
Acknowledgment. We are grateful for the generous financial
support from the General Medical Sciences of the National
Institutes of Health (GM59705-07).
(14) Alcohol 7 is the kinetic product of the reaction. Controlling the
reaction time is important to minimize its isomerization to the thermody-
namic product. The GC retention time of the main peak is 4.42 min.
Conditions: column, VA-5MS, Varian chromatography systems (VA-
122553-20); oven, 170 °C; carrier, helium, head pressure 25 psi; detection,
FID 250 °C.
Supporting Information Available: The NMR spectral data
for compounds 3, 7, and ent-1. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO060335K
J. Org. Chem, Vol. 71, No. 14, 2006 5379