A new class of chiral tetrahydropyran-4-one catalyst for asymmetric epoxidation of alkenes

Article abstract of DOI:10.1016/j.tet.2005.08.112

A new class of chiral α-oxygenated-tetrahydropyran-4-ones for asymmetric epoxidation of alkenes using Oxone is described, affording epoxides with up to 83% ee.

Full text of DOI:10.1016/j.tet.2005.08.112

Tetrahedron 62 (2006) 257–263
A new class of chiral tetrahydropyran-4-one catalyst for
asymmetric epoxidation of alkenes
*
Alan Armstrong and Tomoki Tsuchiya
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
Received 18 May 2005; revised 6 July 2005; accepted 31 August 2005
Available online 28 September 2005
Dedicated to Professor Steven V. Ley on the occasion of his 60th birthday
Abstract—A new class of chiral a-oxygenated-tetrahydropyran-4-ones for asymmetric epoxidation of alkenes using Oxonew is described,
affording epoxides with up to 83% ee.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
axial electronegative a-substituent serves to steer the olefin
to the dioxirane oxygen syn to it.10 Indeed, successful
axially-fluorinated monocyclic cyclohexanones have since
been developed.11 Preparation of 7 would provide some
novel enantiomerically pure ketone catalysts, and also allow
evaluation of whether the bicyclic catalyst framework in our
own catalyst family is necessary for enantioselectivity, or if
the influence of the axial a-substituent is sufficient. Here we
report the results of this study.
Dioxiranes derived from chiral ketone precursors are some
of the most promising catalysts for asymmetric epoxidation
of alkenes.1 In particular, excellent results have been
achieved with trisubstituted and E-alkenes, and encouraging
enantioselectivities are also emerging for other alkene
substitution patterns.2 Our own studies have demonstrated
that catalysts based on the bicyclo[3.2.1]octanone frame-
work can afford high epoxide enantioselectivities.3–6 For
example, the acetate 4 epoxidises E-stilbene with 93% ee at
room temperature.4,5 However, it is currently difficult to
prepare 4 in enantiomerically pure form. We have generally
employed chiral base desymmetrization of the parent
ketones 1 and 3, and while certain desymmetrized products
(for example, the fluoroketone 2)3,6 can be recrystallized to
enantiomeric purity, this is not the case for acetate 4. In
evaluating alternative routes to enantiomerically pure
bicyclo[3.2.1]octanones, we were aware of the diastereo-
selective [4C3]-cycloaddition developed by Hoffmann
(Scheme 1), which affords separable diastereomers 5 and
6.7,8 However, these products have the substituent a- to the
ketone in an equatorial orientation, and our preliminary
attempts to invert this stereocentre were not encouraging.
We reasoned that cleavage of the alkene unit in the two-
carbon bridge should result in ring flipping to place the
a-substituent axial in 7 (Scheme 1).9 Our TS-models for
epoxidation with the bicyclic ketones 2 and 4 have assumed
that the two-carbon bridge prevents attack on the endo-
dioxirane oxygen atom,3,6 but our computational studies of
epoxidation by a-fluorocyclohexanones suggested that the
2. Results and discussion
We first prepared the diastereomerically and enantiomeri-
cally pure ketone 5 according to Hoffmann’s procedure7
(Scheme 1). In order to facilitate handling of later polar
polyol intermediates, ketone reduction and TBS-protection
to give 8 were next effected (Scheme 2). Subsequent
ozonolysis with reductive work up and acetylation of the
resultant primary alcohols afforded 9. The ketone 10 was
now regenerated by TBS-deprotection and TPAP oxi-
dation.12 We were able to effect simultaneous removal of
the a-methylbenzyl auxiliary and ester formation by
reaction of 10 with an acid anhydride in the presence of
FeCl3.13 This method allowed synthesis of a range of
catalysts 11–13, allowing us to probe the effect of the ester
substituent on enantioselectivity. The axial orientation of
1
the ester substituent was demonstrated by analysis of H
NMR coupling constants. For example in 13, one of the H5-
protons (H5ax) has JZ11.6 Hz, indicating a trans–diaxial
relationship with H6. The acetoxymethyl groups are,
therefore, equatorial. JH3–H2 is small (ca. 2 Hz), showing
that the OR substituent at C3 is axial. We found these
ketones to be configurationally stable to the subsequent
Oxone epoxidation conditions. However, heating 13 at
Keywords: Epoxidation; Asymmetric; Ketone; Dioxirane.
*
Corresponding author. Tel.: C44 20 75945876; fax: C44 20 75945804;
e-mail: a.armstrong@imperial.ac.uk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.112

258
A. Armstrong, T. Tsuchiya / Tetrahedron 62 (2006) 257–263
Scheme 1.
the challenging terminal alkenes (entries 2 and 3). The
pivalate ester 12 generally afforded lower enantio-
selectivities than 11 (entries 4–6). However, the benzoate
13 gave better ee values (entries 7–9), albeit with slightly
lower conversions in some cases. This is surprising, since in
our studies of the oxabicyclooctanone series, the acetate 4
generally gave better enantioselectivities than did other
ester derivatives.5 We explored the epoxidation of several
other informative alkene types with 13 (entries 10–14). As
expected, good ee was observed for epoxidation of
phenylstilbene (entry 10), 1-phenylcyclohexene (entry 11)
and for E-methyl cinnamate (entry 12), but conversion was
low in the case of this electron-poor substrate. In line with
our studies on the fluoroketone 2,6 surprisingly low ee
values were observed for silyl enol ethers (entries 13 and
14). We have speculated6 that this is due to the olefinic
hydrogen being less electron deficient in an enol ether than
in a normal alkene, resulting in decreased TS electrostatic
attraction to the electronegative axial substituent a- to the
dioxirane.
Scheme 2. (a) NaBH4, methanol, K78 8C; (b) TBSOTf, CH2Cl2, 0 8C to rt,
100%; (c) O3, CH2Cl2/MeOH, K78 8C, then NaBH4, 92%; (d) Ac2O,
pyridine, rt, 76%; (e) TBAF, THF, rt, 91%; (f) TPAP, NMO, CH2Cl2, rt,
82%; (g) FeCl3 (3 equiv), acid anhydride (3 equiv), CH2Cl2, 0 8C to rt,
10 min.
reflux in Et3N affords the equatorial C3-epimer, which has
JH3–H2Z10.4 Hz, consistent with the expected trans–diaxial
relationship between these protons in that compound and
further confirming the configuration of 13 itself.
We first tested the acetate 11 under standard Oxonew
epoxidation conditions with three alkenes of differing
substitution pattern (Table 1): E-stilbene 14 (entry 1),
a-methylstyrene 15 (entry 2) and styrene 16 (entry 3).
E-Stilbene was epoxidised with 81% ee, with the (S,S)-
isomer predominating; this sense of enantioselectivity is in
accord with the well established spiro-mode of approach14
on the dioxirane oxygen syn to the axial acetoxy substituent.
The corresponding bicyclic ketone, acetate 4, affords 93%
ee under similar conditions,4,5 so removal of the two-carbon
bridge does result in lowering of enantioselectivity. Never-
theless, the value obtained with monocyclic ketone catalyst
11 is remarkably high, particularly for such a simple
asymmetric environment, and is comparable to the value
obtained (76% ee) for E-stilbene epoxidation using the
fluorotropinone derivative 2.3,6 As with most chiral
dioxiranes, lower enantioselectivities were obtained for
3. Conclusions
In summary, we have developed a new route to enantio-
merically pure tetrahydropyran-4-ones with an axial
a-substituent, providing an alternative to chiral base
chemistry for the synthesis of such compounds. These
novel monocyclic pyranone derivatives have allowed
assessment of the need for the two-carbon bridge in our
previously reported bicyclooctanone catalysts. Loss of the
bicyclic system results in some reduction in epoxide
enantioselectivity, but surprisingly good results are still
obtained (at least for E-alkenes), confirming that an axial
heteroatom can be an effective controller. It should be noted
that these new ketones all appear to be stable to the reaction
conditions, and were employed at the 10 mol% level. In
contrast to the bicyclooctanone catalysts,5 the benzoate
derivative can give better ee values than the acetate. This

A. Armstrong, T. Tsuchiya / Tetrahedron 62 (2006) 257–263
Table 1. Oxonew epoxidation of alkenes 14–20 catalysed by ketones 11–13a
259
Entry
Ketone
Alkene
Conversion (%)b
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
11
11
11
12
12
12
13
13
13
13
13
13
13f
13f
14
15
16
14
15
16
14
15
16
17
18
19
20a
20b
100
100
99
52
83
100
93
79
43
83
78
91
97
43
53
100
9
81 (S,S)c
7 (S)c
19 (S)d
43 (S,S)c
3 (S)c
99
19 (S)d
83 (S,S)c
18 (S)c
31 (S)d
82 (S)c
74 (S,S)d
67 (2R,3S)c
12g
100
100
50
60
100
17
9
10
11
12
13e
14e
—
—
100
27
3g
a Reaction conditions: alkene (1 equiv), ketone (10 mol%), Oxonew (10 equiv of KHSO5), NaHCO3 (15.5 equiv), CH3CN/aq Na2EDTA (0.4 mmol dmK3
solution) (3:2, 25 mL/mmol), 24 h, rt.
b Estimated by integration of the 1H NMR spectrum of the crude reaction mixture.
c Measured by chiral HPLC (Chiracel OD column).
d Measured by chiral GC (ChiraPak G-TA column).
e The product epoxide was treated with 10% HCl in methanol during work up to obtain the a-hydroxyketone.
Catalyst (30 mol%) was used.
f
g Enantiomeric excess of the a-hydroxyketone, measured by chiral HPLC (ChiraPak AD column).
suggests that preparation of a wider range of aromatic ester
derivatives in the ongoing search for improved enantio-
selectivities, particularly for terminal alkenes, is a worth-
while endeavour.
apparatus and are quoted as uncorrected. Optical rotations
were recorded on an Optical-Activity AA-5 Polarimeter,
with a path length of 10 or 5 cm, in chloroform unless stated
otherwise. [a]D values are given in 10K1 degrees cm2 gK1
.
Concentrations (c) are given in grams per 100 mL. Infrared
analyses were recorded as a thin-film (produced from
evaporation of a dichloromethane solution) on NaCl plates
using a Mattson Satellite FTIR spectrometer and absorption
4. Experimental
4.1. General
1
maxima are reported in wavenumber (cmK1). H and 13C
NMR analyses were performed on a Bruker AC250 MHz or
Bruker DRX400 MHz spectrometer in CDCl3. Mass
spectrometry was carried out under CI (ammonia reagent
gas) using a Micromass Autospec-Q spectrometer at the
Imperial College Mass Spectrometry Service.
All the reactions requiring dry or inert conditions were
conducted in flame-dried glassware under a positive
pressure of nitrogen. Syringes and needles were oven-
dried and allowed to cool in a desiccator over silica gel
before use. Solvents were freshly distilled before use from
sodium/benzophenone (diethyl ether, THF) or CaH2
(CH2Cl2, CH3CN and Et3N). Liquid reagents were distilled
prior to use, while other commercial solids were used as
supplied unless stated in the relevant text. Solutions of butyl
lithium were titrated against diphenylacetic acid before use.
Reaction temperatures were recorded as bath temperatures.
Analytical thin-layer chromatography was performed on
pre-coated Merck silica gel 60 F254 glass-backed plates and
visualised by UV lamp (254 nm) or potassium permanga-
nate or ceric ammonium nitrate or anisaldehyde stains as
appropriate. Flash chromatography was performed silica gel
60 (particle size 40–63 mm) as supplied by Merck. Petrol
ether refers to light petroleum ether, which is the fraction
with bp 40–60 8C.
4.1.1. (K)-(1R,2S,3R,5R)-2-((S)-1-Phenylethoxy)-3-(tert-
butyldimethylsilanyloxy)-8-oxabicyclo[3.2.1]oct-6-ene 8.
To a solution of (K)-(1R,2S,5R)-2-((S)-1-phenylethoxy)-8-
oxabicyclo[3.2.1]oct-6-en-3-one 57 (0.10 g, 0.41 mmol) in
methanol (10 mL) at K78 8C was added sodium boro-
hydride (0.17 g, 0.45 mmol). The mixture was stirred under
a nitrogen atmosphere for 3 h, before water (10 mL) was
added to quench the reaction. The organic layer was
separated and the aqueous layer was extracted with diethyl
ether (3!25 mL). The combined organic layer was dried
over MgSO4 and concentrated under reduced pressure.
Flash column chromatography (diethyl ether) afforded the
alcohol (0.11 g, 100%) as a white solid, mp 107–108 8C;
[a]1D8K51.5 (c 0.78, CHCl3); Rf 0.49 (2:8 petroleum ether/
diethyl ether); nmax/cmK1 3015, 2978, 2952, 2929, 1603,
1451, 1376, 1215, 1086, 1057; dH (250 MHz, CDCl3)
Melting points were obtained using a Kofler hot stage

260
A. Armstrong, T. Tsuchiya / Tetrahedron 62 (2006) 257–263
7.40–7.28 (5H, m, Ph), 6.34 (1H, dd, JZ6.1, 1.2 Hz, H7),
6.28 (1H, dd, JZ6.1, 1.2 Hz, H6), 4.64 (1H, br s, H1), 4.60
(1H, q, JZ6.4 Hz, PhCH), 4.34 (1H, br d, JZ4.3 Hz, H5),
4.21 (1H, m, H3), 3.60 (1H, dd, JZ5.2, 4.6 Hz, H2), 2.67
(1H, d, JZ2.7 Hz, OH), 2.01 (1H, ddd, JZ14.6, 4.9, 4.3 Hz,
H4ax), 1.80 (1H, d, JZ14.6 Hz, H4eq), 1.44 (3H, d, JZ
6.4 Hz, CHCH3); dC (62.5 MHz, CDCl3) 143.1, 136.5,
131.7, 128.6, 128.0, 126.2, 78.8, 78.3, 76.4, 72.4, 65.0, 32.8,
24.3; MS (CI–NH3): m/z (%) 264 (100) [MCNH4]C, 246
(57); calcd for C15H22NO3 [MCNH4]C: 264.1600; found
[MCNH4]C: 264.1610.
CH2O), 3.39 (1H, s, H3), 3.23 (1H, dd, JZ7.6, 3.7 Hz, H2),
3.10 (1H, br s, OH), 3.01–2.92 (1H, m, H6), 1.89 (1H,
apparent q, JZ11.9 Hz, H5ax), 1.51–1.40 (4H, m, CH3,
H5eq), 0.95 (9H, s, SiCCH3), 0.13 (3H, s, SiCH3), 0.10 (3H,
s, SiCH3); dC (62.5 MHz, CDCl3) 143.4, 128.5, 127.9,
127.1, 79.9, 78.8, 73.4, 72.9, 72.9, 65.5, 63.3, 31.7, 25.8,
23.2, 18.0, K4.8; MS (CI–NH3): m/z (%) 310 (97), 414
(100) [MCNH4]C; calcd for C21H36O5Si [MCNH4]C:
414.2676; found [MCNH4]C 414.2679.
To a solution of this diol (0.32 g, 0.82 mmol) in pyridine
(10 mL), acetic anhydride (0.17 mL, 1.80 mmol) was added
at room temperature under nitrogen atmosphere. The
reaction mixture was stirred for 24 h and poured unto
saturated sodium hydrogen carbonate solution (10 mL). The
organic layer was separated and the aqueous layer was
extracted with diethyl ether (3!25 mL). The combined
organic layer was dried over MgSO4 and concentrated under
reduced pressure. The crude product was purified by flash
column chromatography (7:3 petroleum ether/diethyl ether)
giving 9 (0.30 g, 76%) as a white solid, mp 59–60 8C;
[a]2D1K42.9 (c 1.03, CHCl3); Rf 0.38 (4:6 diethyl ether/
petroleum ether); nmax/cmK1 2953, 2927, 2856, 1741, 1617,
1456, 1369, 1248, 1106, 1083, 1037; dH (250 MHz, CDCl3)
7.32–7.20 (5H, m, Ph), 5.10–4.92 (1H, q, JZ6.7 Hz,
PhCH), 4.12–4.08 (2H, m, CH2O), 3.97 (1H, dd, JZ11.3,
6.7 Hz, CHHO), 3.78 (1H, ddd, JZ11.6, 4.6, 2.7 Hz, H4),
3.61 (1H, dd, JZ11.3, 5.8 Hz, CHHO), 3.60–3.51 (1H, m,
H6), 3.41 (1H, br s, H3), 3.34 (1H, apparent t, JZ6.7 Hz,
H2), 2.06 (3H, s, CH3C]O), 1.94 (1H, apparent q, JZ
11.9 Hz, H5ax), 1.75 (3H, s, CH3C]O), 1.54 (1H, dd, JZ
11.9, 4.6 Hz, H5eq), 1.45 (3H, d, JZ6.7 Hz, CH3), 0.96 (9H,
s, SiCCH3), 0.14 (3H, s, SiCH3), 0.10 (3H, s, SiCH3); dC
(62.5 MHz, CDCl3) 170.9, 170.4, 143.6, 128.3, 127.7,
127.1, 78.8, 76.0, 73.9, 72.7, 72.5, 66.6, 64.1, 32.1, 25.8,
23.6, 20.9, 20.6, 18.0, K4.6; MS (CI–NH3): m/z (%) 498
(100) [MCNH4]C; calcd for C25H44NO7Si [MCNH4]C:
498.2887; found [MCNH4]C 498.2887.
A solution of this alcohol (0.10 g, 0.41 mmol) in CH2Cl2
(10 mL) was cooled down to 0 8C under a nitrogen
atmosphere. 2,6-Lutidine (0.10 mL, 0.81 mmol) and tert-
butyldimethylsilyl triflate (0.15 mL, 0.65 mmol) were
added to the solution. The reaction temperature was warmed
back to room temperature. The reaction was monitored with
TLC until complete. The reaction was quenched by the
addition of saturated sodium hydrogen carbonate solution
(10 mL). The organic layer was separated and the aqueous
layer was extracted with diethyl ether (3!25 mL). The
combined organic layer was dried over MgSO4 and
concentrated under reduced pressure. The crude product
was purified by flash column chromatography (8:2
petroleum ether/diethyl ether) to give silyl ether 8 (0.16 g,
100%) as a colourless oil; [a]2D0K20.0 (c 1.00, CHCl3); Rf
0.54 (8:2 petroleum ether/diethyl ether); nmax/cmK1 3018,
2954, 2930, 2986, 2857, 1620, 1601, 1471, 1215, 757; dH
(250 MHz, CDCl3) 7.38–7.27 (5H, m, Ph), 6.18 (1H, dd, JZ
6.1, 1.5 Hz, H7), 6.03 (1H, dd, JZ6.1, 1.5 Hz, H6), 4.61–
4.56 (1H, m, H1), 4.52 (1H, q, JZ6.4 Hz, PhCH), 4.28–4.22
(2H, m, H3 and H5), 3.54 (1H, dd, JZ4.9, 3.7 Hz, H2), 2.02
(1H, ddd, JZ14.3, 4.9, 4.0 Hz, H4ax), 1.60 (1H, dd, JZ14.3,
1.2 Hz, H4eq), 1.41 (3H, d, JZ6.4 Hz, CHCH3), 0.93–0.91
(9H, s, CCH3), 0.05–0.01 (6H, m, SiCH2); dC (62.5 MHz,
CDCl3) 144.6, 134.4, 132.5, 128.5, 127.5, 126.1, 79.5, 78.2,
76.7, 75.4, 66.9, 35.7, 25.8, 24.6, 18.1, K4.8; MS (CI–
NH3): m/z (%) 361 (100) [MCH]C, 257 (75), 122 (48), 378
(18) [MCNH4]C; calcd for C21H33O3Si [MCH]C:
361.2199; found [MCH]C361.2208.
4.1.3. (K)-(2R,3R,6R)-2,6-Bis-acetoxymethyl-3-((S)-1-
phenylethoxy)-tetrahydropyran-4-one 10. To a solution
of 9 (0.35 g, 0.76 mmol) in THF (50 mL), tetrabutyl-
ammonium fluoride (1 M in THF, 0.80 mL, 0.80 mmol)
was added at room temperature under nitrogen atmosphere.
The reaction was monitored with TLC until complete and
then quenched with water (50 mL). The organic layer was
separated and the aqueous layer was extracted with diethyl
ether (3!25 mL). The combined organic layer was dried
over MgSO4 and concentrated under reduced pressure. The
crude product was purified by flash column chromatography
(2:8 petroleum ether/diethyl ether) giving the alcohol
(0.24 g, 91%) as a white solid, mp 78–79 8C; [a]2D1K26.7
(c 1.05, CHCl3); Rf 0.41 (diethyl ether); nmax/cmK1 3481,
2975, 2931, 2904, 1731, 1377, 1230, 1066, 1028; dH
(250 MHz, CDCl3) 7.35–7.20 (5H, m, Ph), 4.77 (1H, q, JZ
6.4 Hz, PhCH), 4.10 (2H, d, JZ5.5 Hz, CH2O), 3.98 (1H,
dd, JZ11.3, 7.0 Hz, CHHO), 3.83–3.73 (1H, m, H4), 3.69–
3.53 (3H, m, CHHO, H6 and H3), 3.39 (1H, ddd, JZ7.0, 6.4,
5.8 Hz, H2), 2.19 (1H, br s, OH), 2.06 (3H, s, C]OCH3),
1.85 (3H, s, COCH3), 1.81–1.71 (2H, m, H5ax and H5eq),
1.50 (3H, d, JZ6.4 Hz, CHCH3); dC (62.5 MHz, CDCl3)
171.0, 170.5, 143.0, 128.4, 127.8, 126.8, 79.3, 76.1, 73.8,
73.1, 70.6, 66.4, 63.8, 32.2, 23.5, 20.9, 20.8; MS (CI–NH3):
4.1.2. (K)-(2R,3S,4R,6R)-2,6-Bis-acetoxymethyl-3-((S)-
1-phenylethoxy)-4-(tert-butyldimethylsilanyloxy)-tetra-
hydropyran 9. A solution of 8 (154 mg, 0.43 mmol) in 4:1
mixture of CH3OH/CH2Cl2 (5 mL) was cooled down to
K78 8C and treated with a stream of ozone until the colour
of the solution turned into blue. The excess ozone was
removed by passing through a stream of nitrogen until the
colour of the solution became colourless. Sodium boro-
hydride (44 mg, 1.17 mmol) was added to the solution
carefully by potion and stirred at room temperature for 1 h.
The organic layer was separated by adding water (10 mL)
and the aqueous layer was extracted with ethyl acetate (3!
25 mL). The combined organic layer was dried over MgSO4
and concentrated under reduced pressure. The crude product
was purified by flash column chromatography (ethyl
acetate) to yield the diol (156 mg, 92%) as a white solid,
mp 119–120 8C; [a]2D1K63.5 (c 1.02, CHCl3); Rf 0.33 (ethyl
acetate); nmax/cmK1 3426, 2955, 2925, 2889, 2855, 1667,
1463, 1382, 1255, 1083; dH (250 MHz, CDCl3) 7.40–7.24
(5H, m, Ph), 4.99 (1H, q, JZ6.70 Hz, PhCH), 3.89 (1H, br s,
OH), 3.78 (1H, dd, JZ11.6, 4.6 Hz, H4), 3.70–3.40 (4H, m,

A. Armstrong, T. Tsuchiya / Tetrahedron 62 (2006) 257–263
261
m/z (%) 280 (38), 384 (100) [MCNH4]C; calcd for
C19H26O7 [MCNH4]C: 384.2022; found [MCNH4]C
384.2017.
temperature under nitrogen atmosphere, anhydrous FeCl3
(43.1 mg, 0.266 mmol) was added and stirred for 15 min at
0 8C. A solution of 10 (30.1 mg, 0.082 mmol) in CH2Cl2
(2 mL) was then added. The reaction was stirred for 10 min.
The colour of the reaction mixture changed from orange to
very dark green. It was then quenched by addition of
saturated sodium hydrogen carbonate solution (10 mL). The
mixture was stirred for 1 min and then extracted with diethyl
ether (3!25 mL). The combined organic layers were dried
over MgSO4 and the solvent was removed under reduced
pressure. The crude product was purified by flash column
chromatography (diethyl ether) to afford 12 (20.3 mg, 71%)
as colourless oil; [a]2D2K2.10 (c 2.37, CHCl3); Rf 0.33
(diethyl ether); nmax/cmK1 2976, 2936, 2910, 1744, 1370,
1238, 1140, 1049; dH (250 MHz, CDCl3) 4.93 (1H, dd, JZ
1.8, 0.9 Hz, H3), 4.31–4.10 (4H, m, CH2O), 4.06–3.95 (2H,
m, H2 and H6), 2.73 (1H, dd, JZ13.4, 11.6 Hz, H5ax), 2.41
(1H, ddd, JZ13.4, 2.7, 1.2 Hz, H5eq), 2.09 (3H, s,
C]OCH3), 2.06 (3H, s, C]OCH3), 1.24 (9H, s, CCH3);
dC (100 MHz, CDCl3) 201.1, 176.9, 170.6, 170.4, 77.0,
75.3, 74.2, 65.6, 61.7, 41.4, 39.0, 27.0, 20.7, 20.6; MS
(CI–NH3): m/z (%) 362 (100) [MCNH4]C; calcd for
C16H28NO8 [MCNH4]C: 362.1815; found [MCNH4]C:
362.1818.
This alcohol (0.24 g, 0.66 mmol) was dissolved in CH2Cl2
˚
(30 mL) containing 4 A molecular sieves and N-methyl-
morpholine N-oxide (0.16 g, 1.37 mmol). After stirring the
mixture for 10 min at room temperature, tetra-n-propyl-
ammonium perruthenate (12.0 mg, 0.034 mmol) was added.
The reaction was monitored with TLC until complete. The
mixture was diluted with CH2Cl2 and then washed with
sodium sulfite solution (10 mL), brine (30 mL) and finally
saturated copper(II) sulfate solution (3!50 mL). The
aqueous layer was extracted with diethyl ether (3!
50 mL). The combined organic layer was dried over
MgSO4 and concentrated to obtain the crude product. The
product was purified by flash column chromatography (1:1
petroleum ether/diethyl ether), giving 10 (0.20 g, 82%) as
colourless oil; [a]2D1K65.8 (c 1.13, CHCl3); Rf 0.81 (diethyl
ether); nmax/cmK1 2978, 1743, 1455, 1372, 1235, 1048; dH
(250 MHz, CDCl3) 7.31–7.17 (5H, m, Ph), 4.30–4.00 (5H,
m, CH2O, PhCH), 3.86–3.75 (1H, m, H6), 3.63 (1H, td, JZ
6.4, 1.5 Hz, H2), 3.33 (1H, s, H3), 2.90 (1H, dd, JZ13.1,
12.2 Hz, H5ax), 2.26 (1H, d, JZ13.1 Hz, H5eq), 2.02 (3H, s,
CH3C]O), 1.79 (3H, s, CH3C]O), 1.38 (3H, d, JZ6.4 Hz,
CHCH3); dC (62.5 MHz, CDCl3) 205.4, 170.5, 170.3, 141.3,
128.5, 128.1, 126.8, 77.5, 76.7, 76.7, 75.4, 65.7, 62.1, 41.3,
23.8, 20.7, 20.6; MS (CI–NH3): m/z (%) 278 (22), 382 (100)
[MCNH4]C; calcd for C19H24O7 [MCNH4]C: 382.1866;
found [MCNH4]C 382.1852.
4.1.6. (C)-(2R,3S,6R)-2,6-Bis-acetoxymethyl-3-benzoyl-
oxy-tetrahydropyran-4-one 13. To a stirred solution of
benzoic anhydride (92.5 mg, 0.41 mmol) in dry CH2Cl2
(7 mL) at temperature under nitrogen atmosphere,
anhydrous FeCl3 (59.0 mg, 0.36 mmol) was added and
stirred for 15 min at 0 8C. A solution of 10 (49.5 mg,
0.14 mmol) in CH2Cl2 (2 mL) was then added to the
reaction mixture. The reaction was stirred for 10 min. The
colour of the reaction mixture changed from orange to very
dark green. It was then quenched by addition of saturated
sodium hydrogen carbonate solution (10 mL). The mixture
was stirred for 1 min and then extracted with diethyl ether
(3!25 mL). The combined organic layers were dried over
MgSO4 and the solvent was removed under reduced
pressure. The crude product was purified by flash column
chromatography (diethyl ether) to afford 13 (27.8 mg, 56%)
as colourless oil; [a]2D2C6.53 (c 1.07, CHCl3); Rf 0.39
(ether); nmax/cmK1 3068, 3018, 2965, 2879, 1735, 1602,
1263, 1113, 1047; dH (250 MHz, CDCl3) 8.10–8.04 (2H, m,
Ph), 7.67–7.58 (1H, m, Ph), 7.52–7.42 (2H, m, Ph), 5.20
(1H, dd, JZ1.8, 0.9 Hz, H3), 4.42 (1H, dd, JZ11.6, 6.1 Hz,
OCHH), 4.28 (1H, dd, JZ11.6, 6.1 Hz, OCHH), 4.23 (2H,
d, JZ4.9 Hz, OCH2), 4.15–4.01 (2H, m, H2 and H6), 2.86
(1H, dd, JZ13.4, 11.6 Hz, H5ax), 2.46 (1H, dd, JZ13.4,
1.2 Hz, H5eq), 2.10 (3H, s, C]OCH3), 2.05 (3H, s,
C]OCH3); dC (100 MHz, CDCl3) 201.0, 170.6, 170.5,
165.1, 133.9, 130.1, 128.7, 128.5, 77.1, 75.6, 74.9, 65.6,
62.0, 41.6, 20.8, 20.7; MS (CI–NH3): m/z (%) 382 (100)
[MCNH4]C; calcd for C18H24NO8 [MCNH4]C: 382.1503;
found [MCNH4]C: 382.1502.
4.1.4. (K)-(2R,3S,6R)-2,6-Bis-acetoxymethyl-3-acetoxy-
tetrahydropyran-4-one 11. To a stirred solution of acetic
anhydride (0.025 mL, 0.26 mmol) in dry CH2Cl2 (6 mL) at
room temperature under nitrogen atmosphere, anhydrous
FeCl3 (36.0 mg, 0.22 mmol) was added and stirred for
15 min at 0 8C. A solution of 10 (30.0 mg, 0.082 mmol) in
CH2Cl2 (2 mL) was then added then the reaction was stirred
for 10 min. The colour of the reaction mixture changed from
orange to very dark green. It was quenched by addition of
water (10 mL) then extracted with diethyl ether (3!
25 mL). The combined organic layers were dried over
MgSO4 and the solvent was removed under reduced
pressure. The crude product was purified by flash column
chromatography (diethyl ether) to afford 11 (11.1 mg, 45%)
as colourless oil; [a]2D2K3.80 (c 0.79, CHCl3); Rf 0.27
(diethyl ether); nmax/cmK1 2963, 2933, 2899, 1741, 1642,
1434, 1372, 1238, 1045; dH (250 MHz, CDCl3) 5.02 (1H,
dd, JZ2.1, 0.9 Hz, H3), 4.32–4.09 (4H, m, CH2O), 4.09–
3.93 (2H, m, H2 and H6), 2.76 (1H, dd, JZ13.7, 11.6 Hz,
H5ax), 2.45 (1H, ddd, JZ13.7, 2.7, 0.9 Hz, H5eq), 2.16 (3H,
s, C]OCH3), 2.10 (3H, s, C]OCH3), 2.06 (3H, s,
C]OCH3); dC (100 MHz, CDCl3) 200.7 (C, C4), 170.6,
170.4, 169.5 (C, OC]O), 76.8 (CH, C2), 75.4 (CH, C6),
74.1 (CH, C3), 65.6 (CH2, OCH2), 61.7 (CH2, OCH2), 41.6
(CH2, C5), 20.8, 20.7, 20.5 (CH3, CH3); MS (CI–NH3): m/z
(%) 320 (100) [MCNH4]C; calcd for C13H22NO8 [MC
NH4]C: 320.1345; found [MCNH4]C: 320.1346.
4.2. Epoxidation procedure
To a solution of ketone and alkene (0.1 mmol) in
acetonitrile (1.5 mL) was added aqueous Na2EDTA
solution (1.0 mL of a 0.4 mM aqueous solution). Oxonew
(307 mg, 1.0 mmol KHSO5) and NaHCO3 (130 mg,
1.55 mmol) were added in portions simultaneously over
4.1.5. (K)-(2R,3S,6R)-2,6-Bis-acetoxymethyl-3-(2,2-
dimethylpropionyloxy)-tetrahydropyran-4-one 12. To a
stirred solution of 2,2-dimethylpropionic anhydride
(0.05 mL, 0.246 mmol) in dry CH2Cl2 (7 mL) at room

262
A. Armstrong, T. Tsuchiya / Tetrahedron 62 (2006) 257–263
60 min. The reaction was stirred vigorously at room
temperature until completion (monitored by TLC) and for
24 h, then diluted with water (10 mL) and the reaction
mixture extracted into petrol ether or diethyl ether as
appropriate (3!25 mL). The combined organic extracts
were dried over Na2SO4, filtered and evaporated to dryness
under reduced pressure. Flash column chromatography on
silica, previously washed with 2% Et3N in petroleum ether,
eluting with appropriate proportion of petroleum ether and
diethyl ether afforded the relevant epoxide. Epoxide data as
described previously.6
Acknowledgements
We are grateful to Bristol-Myers Squibb, Pfizer, and Merck
Sharpe and Dohme for unrestricted support of our research
programmes.
References and notes
1. Reviews: Frohn, M.; Shi, Y. Synthesis 2000, 1979–2000.
Armstrong, A. Angew. Chem., Int. Ed. 2004, 43, 1460–1462.
Shi, Y. Acc. Chem. Res. 2004, 37, 488–496. Yang, D. Acc.
Chem. Res. 2004, 37, 497–505. Recent examples: Shing,
T. K. M.; Leung, G. Y. C.; Yeung, K. W. Tetrahedron Lett.
2003, 44, 9225–9228. Shing, T. K. M.; Leung, Y. C.; Yeung,
K. W. Tetrahedron 2003, 59, 2159–2168. Shing, T. K. M.;
Leung, G. Y. C. Tetrahedron 2002, 58, 7545–7552. Bez, G.;
Zhao, C. G. Tetrahedron Lett. 2003, 44, 7403–7406. Stearman,
C. J.; Behar, V. Tetrahedron Lett. 2002, 43, 1943–1946.
Matsumoto, K.; Tomioka, K. Tetrahedron Lett. 2002, 43,
631–633. Klein, S.; Roberts, S. M. J. Chem. Soc., Perkin
Trans. 1 2002, 2686–2691. Denmark, S. E.; Matsuhashi, H.
J. Org. Chem. 2002, 67, 3479–3486. Bortolini, O.; Fantin, G.;
Fogagnolo, M.; Forlani, R.; Maietti, S.; Pedrini, P. J. Org.
Chem. 2002, 67, 5802–5806.
4.3. Determination of epoxide enantiomeric purity in
Table 1
Entries 1, 4 and 7: chiral HPLC on Chiracel OD (Diacel
Chemical Industries Ltd, catalogue number: 14025), 20%
iPrOH/hexane, 1.0 mL/min, at 30 8C in oven, detecting at
254 nm, as detailed by Shi.15 Absolute configuration
determined by comparison to Shi’s results.
Entries 2, 5 and 8: chiral HPLC on Chiracel OD (Diacel
Chemical Industries Ltd, catalogue number: 14025), 5%
iPrOH/hexane, 0.8 mL/min, at 30 8C in oven, detecting at
254 nm, as detailed by Shi.15 Absolute configuration
determined by comparison to Shi’s results.
2. Tian, H. Q.; She, X. G.; Shu, L. H.; Yu, H. W.; Shi, Y. J. Am.
Chem. Soc. 2000, 122, 11551–11552. Tian, H. Q.; She, X. G.;
Xu, J. X.; Shi, Y. Org. Lett. 2001, 3, 1929–1931. Tian, H. Q.;
She, X. G.; Yu, H. W.; Shu, L. H.; Shi, Y. J. Org. Chem. 2002,
67, 2435–2446. Shu, L. H.; Wang, P. Z.; Gan, Y. H.; Shi, Y.
Org. Lett. 2003, 5, 293–296. Shu, L. H.; Shi, Y. Tetrahedron
Lett. 2004, 45, 8115–8117. Hickey, M.; Goeddel, D.; Crane,
Z.; Shi, Y. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5794–5798.
Entries 3, 6 and 9: chiral GC on Chiraldex G-TA (Advanced
Separation Technologies Ltd, catalogue number: 71020),
helium head pressure 13 psi, at 75 8C in oven, injection
temperature 200 8C, detection by FID at 250 8C, as detailed
by Shi.15 Absolute configuration determined by comparison
to Shi’s results.
Entry 10: chiral HPLC on Chiracel OD (Diacel Chemical
Industries Ltd, catalogue number: 14025), 20% iPrOH/
hexane, 1.0 mL/min, at 30 8C in oven, detecting at 254 nm,
as detailed by Shi.15 Absolute configuration determined by
comparison to Shi’s results.
3. Armstrong, A.; Hayter, B. R. Chem. Commun. 1998, 621–622.
4. Armstrong, A.; Hayter, B. R.; Moss, W. O.; Reeves, J. R.;
Wailes, J. S. Tetrahedron: Asymmetry 2000, 11, 2057–2061.
5. Armstrong, A.; Moss, W. O.; Reeves, J. R. Tetrahedron:
Asymmetry 2001, 12, 2779–2781.
Entry 11: chiral GC on Chiraldex G-TA (Advanced
Separation Technologies Ltd, catalogue number: 71020),
helium head pressure 13 psi, at 65 8C in oven, injection
temperature 200 8C, detection by FID at 250 8C, retention
times 140.22 min (major enantiomer), 154.55 min (minor
enantiomer), as detailed by Shi.15 Absolute configuration
determined by comparison to Shi’s results.
6. Armstrong, A.; Ahmed, G.; Dominguez-Fernandez, B.;
Hayter, B. R.; Wailes, J. S. J. Org. Chem. 2002, 67,
8610–8617.
7. Stark, C. B. W.; Pierau, S.; Wartchow, R.; Hoffmann, H. M. R.
Chem. Eur. J. 2000, 6, 684–691.
8. Misske, A. M.; Hoffmann, H. M. R. Chem. Eur. J. 2000, 6,
3313–3320.
9. For use of this concept to influence ring-opening metathesis of
oxabicyclo[3.2.1]octenes, see: Wright, D. L.; Usher, L. C.;
Estrella-Jimenez, M. Org. Lett. 2001, 3, 4275–4277.
10. Armstrong, A.; Washington, I.; Houk, K. N. J. Am. Chem. Soc.
2000, 122, 6297–6298.
Entry 12: chiral HPLC on Chiracel OD (Diacel Chemical
Industries Ltd, catalogue number: 14025), 5% iPrOH/
hexane, 1.0 mL/min, at 30 8C in oven, detecting at
254 nm, retention times 11.85 min (major enantiomer),
17.64 min (minor enantiomer). Absolute configuration of
product determined by comparison of sign of optical
rotation to the literature value ([a]2D2K72.3 (c 0.83,
CHCl3)); lit.16 ([a]D22K111.8 (c 1.17, CHCl3)) at 92% ee.
11. Solladie-Cavallo, A.; Jierry, L.; Bouerat, L.; Taillasson, P.
Tetrahedron:
Asymmetry
2001,
12,
883–891.
Solladie-Cavallo, A.; Jierry, L.; Bouerat, L.; Schmitt, M.
Tetrahedron 2002, 58, 4195–4199. Solladie-Cavallo, A.;
Jierry, L.; Klein, A. C. R. Chim. 2003, 6, 603–606.
Solladie-Cavallo, A.; Lupattelli, P.; Jierry, L.; Bovicelli, P.;
Angeli, F.; Antonioletti, R.; Klein, A. Tetrahedron Lett. 2003,
44, 6523–6526. Solladie-Cavallo, A.; Jerry, L.; Klein, A.;
Schmitt, M.; Welter, R. Tetrahedron: Asymmetry 2004, 15,
3891–3898. Solladie-Cavallo, A.; Jierry, L.; Lupattelli, P.;
Entries 13 and 14: chiral HPLC on Chiracel AD (Diacel
Chemical Industries Ltd, catalogue number: 19025), 5%
iPrOH/hexane, 1.0 mL/min, at 30 8C in oven, detecting at
254 nm, retention times 27.25 min (major enantiomer),
39.19 min (minor enantiomer).

A. Armstrong, T. Tsuchiya / Tetrahedron 62 (2006) 257–263
263
Bovicelli, P.; Antonioletti, R. Tetrahedron 2004, 60,
11375–11381. Solladie-Cavallo, A.; Jierry, L.; Norouzi-Arasi,
H.; Tahmassebi, D. J. Fluorine Chem. 2004, 125, 1371–1377.
Solladie-Cavallo, A.; Bouerat, L. Org. Lett. 2000, 2,
3531–3534. Solladie-Cavallo, A.; Bouerat, L.; Jierry, L. Eur.
J. Org. Chem. 2001, 4557–4560.
13. Padron, J. I.; Vazquez, J. T. Tetrahedron: Asymmetry 1995, 6,
857–858. Kula, J. Synth. Commun. 1986, 16, 833–836.
14. Houk, K. N.; Liu, J.; DeMello, N. C.; Condroski, K. R. J. Am.
Chem. Soc. 1997, 119, 10147–10152.
15. Tu, Y.; Wang, Z. X.; Shi, Y. J. Am. Chem. Soc. 1996, 118,
9806–9807.
12. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639–666.
16. Nemoto, T.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc.
2001, 123, 9474–9475.