Wang et al.
sion to the corresponding epoxide and comparison with
an authentic sample.
approach and the hazards associated with diazomethane,
we would certainly recommend that synthetic chemists
also consider this methodology for the laboratory scale
preparation of R-chloroketones.
Ring-closure of the N-protected â-chlorohydrins is
again well precedented in the literature21 and proceeded
uneventfully. For example, epoxide 10 was formed in 96%
yield and >99% ee upon treatment with potassium tert-
butoxide in a 2-propanol/THF mixed solvent system (eq
10).
Exp er im en ta l Section
Dim eth ylsu lfoxon iu m 2-Oxo-3-(ph en oxy)pr opylide, 4a.
A 100-mL flask was charged with trimethylsulfoxonium
chloride (3.90 g, 30 mmol), tetrahydrofuran (30 mL), and 1.0
M potassium tert-butoxide in THF solution (31.5 mL, 31.5
mmol). The suspension was heated at reflux for 2 h then cooled
to room temperature. Methyl phenoxyacetate (1.66 g, 10 mmol)
was added dropwise over 10 min whereupon the mixture was
stirred overnight at room temperature. After distillation of the
solvent, water (10 mL) was added and the product was
extracted into ethyl acetate (2 × 50 mL). The organic phase
was washed with brine (2 × 10 mL), dried over sodium sulfate,
and concentrated in a vacuum to afford the crude product (2.1
g). Recrystallization from ethyl acetate (10 mL) afforded the
sulfur ylide (1.47 g, 65%) as a white crystalline solid. Anal.
Calcd for C11H14O3S: C, 58.38; H, 6.34. Found: C, 58.50; H,
Although our primary interest was in the large-scale
manufacturing of R-amino epoxides, this chemistry works
quite well on a laboratory scale. As a demonstration of
this, we have carried out the (R)-(BINAP)RuCl2 reduc-
tion/cyclization sequence on a 30-g scale (eq 11). The
1
6.10. H NMR (400 MHz, CDCl3): δ 3.40 (s, 6H), 4.38 (s, 2H),
4.90 (s, 1H), 6.83-6.96 (m, 3H), 7.24 (m, 2H). 13C NMR (100
MHz, CDCl3): δ 41.8, 69.3, 70.3, 114.5, 121.0, 129.4, 158.0,
185.5.
1-Ch lor o-3-p h en oxy-2-p r op a n on e, 5a . A glass tube was
charged with 4a (0.91 g, 4.0 mmol), THF (15 mL), and 4 M
HCl in dioxane solution (1.15 mL, 4.6 mmol). The tube was
sealed with a Teflon stopper and stirred at room temperature
for 10 min then for 2 h in a 70 °C heated block at which time
the mixture was homogeneous. After cooling, the solvent was
removed at reduced pressure. The residue was added to water
(15 mL) and extracted into methyl tert-butyl ether (2 × 10 mL).
Removal of the solvent afforded 5a as a colorless oil (0.72 g,
97%) which crystallized upon standing to a low melting solid.
Anal. Calcd for C9H9ClO2: C, 58.55; H, 4.91. Found: C, 58.57;
H, 5.00. 1H NMR (400 MHz, CDCl3): δ 4.27 (s, 2H), 4.60 (s,
2H), 6.77 (d, J ) 8.0 Hz, 2H), 6.90 (t, J ) 7.4 Hz, 1H), 7.19
(m, 2H). 13C NMR (100 MHz, CDCl3): δ 46.7, 71.3, 114.6, 121.6,
129.6, 157.1, 198.8.
Dim eth ylsu lfoxon iu m (3S)-2-Oxo-3-(ben zyloxyca r bo-
n yla m in o)bu tylid e, 7a . A solution of 1.0 M potassium tert-
butoxide in THF (60 mL, 60 mmol) was added at room
temperature to a suspension of trimethylsulfoxonium chloride
(7.72 g, 60 mmol) in THF (40 mL). The mixture was heated at
reflux for 2 h and was then cooled to 0 °C. A solution of CBZ-
alanine methyl ester (4.74 g, 20 mmol) in THF (10 mL) was
added dropwise at 0 °C and the resultant solution was stirred
for 4 h at 0 °C. The reaction was quenched with water (20
mL). The organic layer was separated and washed with brine
(2 × 20 mL). The solvent was removed at reduced pressure to
afford the crude sulfur ylide (5.76 g, 97%) as an off-white solid.
1H NMR (400 MHz, CDCl3): δ 1.30 (d, J ) 16.6 Hz, 3H), 3.34
(s, 3H), 3.36 (s, 3H), 4.16 (m, 1H), 4.61 (S, 1H), 5.08 (s, 2H),
5.81 (d, J ) 7.0 Hz, 1H), 7.28 (m, 5H). 13C NMR (100 MHz,
CDCl3): δ 20.3, 42.0, 42.2, 53.2, 66.7, 68.7, 109.8, 128.2, 128.7,
136.9, 155.9, 188.7.
(3S)-1-Ch lor o-3-(b en zyloxyca r b on yla m in o)-2-b u t a n -
on e, 8a . Crude 7a (6.18 g, 22.0 mmol) was dissolved in THF
(100 mL) and the solution was cooled to 0 °C. Lithium chloride
(1.6 g, 25 mmol) and methanesulfonic acid (1.6 mL, 24 mmol)
were added. The temperature was slowly raised to 70 °C and
stirring was continued at that temperature for 2 h. After
cooling, the reaction was quenched by addition of water (100
mL). The phases were separated and 2:1 heptane/ethyl acetate
(100 mL) was added. To remove DMSO, the organic layer was
washed with saturated NaHCO3 (20 mL), water (2 × 20 mL),
and brine (20 mL) and dried over Na2SO4. Removal of solvent
afforded the crude chloroketone (5.0 g). The enantiomeric
excess was determined to be >99% by supercritical fluid
chromatography (Chiralpak AD-H, 150 × 4.6 mm, 5 µ particle
methanolic solution of â-chlorohydrin obtained from the
hydrogenation was filtered through Celite and treated
with a 10% excess of 1 M sodium hydroxide overnight.
The overall yield of crystalline 11 (>99% ee) for this two-
step sequence was 67%.
Con clu sion
We have demonstrated a straightforward two-step
chain extension of esters to R-chloroketones, which avoids
the use of diazomethane. We have found that even
modestly activated methyl esters will react with dimeth-
ylsulfoxonium methylide to afford the chain-extended
â-keto sulfur ylides in synthetically useful yields. Where
applicable, this is advantageous since methyl esters can
generally be prepared without the intermediacy of a
moisture-sensitive acid chloride. Nevertheless, for unac-
tivated or base-sensitive substrates, the use of the more
reactive aryl esters (such as the 4-nitrophenyl esters) may
be required.
As one application of this methodology, we have
demonstrated a novel and practical route to anti N-
protected R-amino epoxides. It should be noted that the
same chloroketones 8a -c can also be reduced enzymati-
cally22 to the corresponding syn chlorohydrins so that our
route can be used to access both sets of diastereomeric
epoxides. An attractive feature of this chemistry as a
practical route23 to the anti epoxides is that, with the
exception of compound 8b, all of the intermediates are
crystalline solids and hence no chromatographic purifica-
tion is required.
In our opinion, this chemistry represents a useful
advance in the manufacture of R-chloroketones as phar-
maceutical intermediates. Given the simplicity of this
(21) Chen, P.; Cheng, P. T. W.; Spergel, S. H.; Zahler, R.; Wang, X.;
Thottathil, J .; Barrish, J . C.; Polniaszek, R. P. Tetrahedron Lett. 1997,
38, 3175. See also refs 2 and 3.
(22) Patel, R. N.; Banerjee, A.; McNamee, C. G.; Brzozowski, D. B.;
Szarka, L. J . Tetrahedron: Asymmetry 1997, 8, 2547.
(23) Kronenthal, D.; Schwinden, M. D. U.S. Patent 6,399,793, 2002.
1632 J . Org. Chem., Vol. 69, No. 5, 2004