Efficient stereoselective synthesis of a 1-hydroxymethyl-2-methylglycidol derivative

Article abstract of DOI:10.1016/S0957-4166(01)00149-5

A highly stereoselective synthesis of (2R,3S)-3,4-epoxy-3-methyl-1-(triphenylmethyl)oxybutan-2-ol 3, which is a substructure found in some naturally-occurring bioactive compounds, was achieved starting from commercially available 3-methyl-2-buten-1-ol 4 in three steps, using two applications of the Sharpless asymmetric epoxidation as the key stereochemistry establishing reactions.

Full text of DOI:10.1016/S0957-4166(01)00149-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 943–947
Efficient stereoselective synthesis of a
1-hydroxymethyl-2-methylglycidol derivative
Ippei Uemura,* Ken Yamada, Kayo Sugiura, Hisashi Miyagawa and Tamio Ueno
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
Received 15 March 2001; accepted 23 March 2001
Abstract—A highly stereoselective synthesis of (2R,3S)-3,4-epoxy-3-methyl-1-(triphenylmethyl)oxybutan-2-ol 3, which is a sub-
structure found in some naturally-occurring bioactive compounds, was achieved starting from commercially available 3-methyl-2-
buten-1-ol 4 in three steps, using two applications of the Sharpless asymmetric epoxidation as the key stereochemistry establishing
reactions. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
As a result considerable effort has been expended in
developing a stereoselective synthesis of this key moi-
ety, not only regarding total synthesis, but also for the
structure–activity studies of these biologically active
compounds.6 However, none of the hitherto described
methods are completely satisfactory for convenient and
large-scale preparations. We describe herein the facile
and stereoselective preparation of (2R,3S)-3,4-epoxy-3-
methyl-1-(triphenylmethyl)oxybutan-2-ol 3, which rep-
resents a promising intermediate for the purposes
outlined above.
1-Substituted 2-methylglycidol substructures are found
in some naturally-occurring bioactive compounds and
the stereochemistry of this moiety often affects the
activity of the compound. For example, the substruc-
ture is present in AK-toxins 1,1 which are host-specific
toxins produced by Alternaria alternata Japanese pear
pathotype. Their (8R,9S)-configuration has been shown
to be essential for their phytotoxicity to the toxin-sensi-
tive cultivars of Japanese pear (Fig. 1).2 The same
substructure is also found in Azinomycins 2,3 antitumor
antibiotics which have been isolated from the culture
broth of Streptomyces griseofuscus. In this case, the
glycidol moiety plays a key role in the formation of the
interstrand cross-links in the DNA duplex.4 Structure–
activity relationship studies of 2 have shown that, of the
possible configurations of this moiety, the naturally-
occurring configuration is the most favorable for
activity.5
2. Results and discussion
The construction of asymmetry in the method we
present relies on the Sharpless asymmetric epoxidation
(SAE), which uses a catalytic amount of Ti(OiPr)4/tar-
trate complex (Scheme 1).7 Commercially available 3-
HO
OMe
AcO
N
O
NHAc
O
O
H
N
Ph
O
O
HO
8R
N
H
OTr
9S
R1
O
O
R2
O
O
O
3
CO2H
2 Azinomycin A : R2 = H
Azinomycin B : R2 = CHO
1 AK-toxin I : R1 = CH3
AK-toxin II : R1 = H
Figure 1.
* Corresponding author. Tel.: +81 75 753 6117; fax: +81 75 753 6123; e-mail: uemura@colorado.kais.kyoto-u.ac.jp
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00149-5

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I. Uemura et al. / Tetrahedron: Asymmetry 12 (2001) 943–947
a
b,c
OH
OH
OTr
O
O
4
6
5
> 99% e.e.
HO
HO
d
e
OTr
OTr
O
> 99% d.e.
3
7
,
D-(−)-DET, t-BuOOH, 3 A MS, −25°C, 2 h; (b) (CH3)2S, rt, 1 h; (c) TrCl,
Scheme 1. Reagents and conditions: (a) Ti(OiPr)4,
DMAP, NEt3, rt, overnight; (d) LDA, THF, −50°C to rt, 5 h; (e) Ti(OiPr)4,
,
-(−)-DIPT, t-BuOOH, 3 A MS, −20°C, overnight.
D
methyl-2-buten-1-ol 4 was used as the starting material.
SAE of 4 using -(−)-diethyl tartrate gave epoxyalcohol
lent yield without any racemization at the a-carbon.10
The Horner–Wadsworth–Emmons reaction of 11 with
trimethyl phosphonoacetate was effected by the proto-
col developed by Masamune to yield the ester 12 with
3:1 geometrical selectivity in favor of the (E)-isomer.11
NMR analysis of 12 showed that the configuration at
the a-carbon remained unchanged. Since it was impos-
sible to separate these geometrical isomers, this iso-
meric mixture was used directly in the next reaction.
Desilylation of 12 with tetrabutylammonium fluoride
gave the targeted ester 8 in an isomerically pure form
by flash column chromatography. The specific rotation
of 8 thus obtained was +70.2, which was in fairly good
agreement with the reported value for (4R,5S)-8 of
+68.2.9 Since no racemization at the asymmetric centers
of 3 was observed in this derivatization, its absolute
configuration could be unambiguously assigned as
(2R,3S).
D
5, which was derivatized in situ with trityl chloride to
give the corresponding trityl ether 6 in 70% yield.8
Epoxide cleavage of 6 by LDA gave the secondary
alcohol 7 in 91% yield. The e.e. of 7, as determined by
NMR analysis after derivatization of 7 to the corre-
sponding Mosher ester with (S)-(−)-a-methoxy-a-(tri-
fluoromethyl)phenylacetic acid (MTPA), was >99%
when 6 was purified by recrystallization after chro-
matography on silica gel. Without recrystallization, the
e.e. attained was no more than 83%. The conversion of
7 to the desired epoxyalcohol 3 was effected by the
second SAE using D-tartrate, although the reaction was
somewhat slow and required a prolonged time to reach
completion. The yield was 79% with a d.e. of >99%,
based on NMR analysis, after a single recrystallization
of the crude product. This excellent diastereoselectivity
may be due to the bulk of the trityl group, which is
likely to cause a high degree of steric hindrance in one
of the diastereofaces and would, therefore, favor epoxi-
dation on the other face.
3. Conclusion
We report here the development of an efficient and
highly stereoselective synthesis of (2R,3S)-3,4-epoxy-3-
methyl-1-(triphenylmethyl)oxybutan-2-ol 3, which has
considerable potential for use as a versatile chiral inter-
mediate. The procedure is of great practical value, since
it requires only three steps to obtain 3 from the com-
mercially available material 4, and was applicable up to
a 300 mmol scale without significant loss of yield or e.e.
Compound 3 is now utilized in our ongoing research on
the total synthesis of AK-toxins, as well as their struc-
ture–activity relationship.
Compound 3 was derivatized to the known ester 8 in
order to establish the absolute configuration,9 as fol-
lows (Scheme 2). The secondary hydroxyl group of 3
was protected as tert-butyldiphenylsilyl (TBDPS) ether
using TBDPS chloride and imidazole with a catalytic
amount of 4-(dimethylamino)pyridine. The trityl group
of the resultant TBDPS ether 9 was removed in
aqueous acetic acid to give the corresponding primary
alcohol 10 in 75% yield. Oxidation of 10 using Dess–
Martin periodinane provided the aldehyde 11 in excel-
HO
TBDPSO
TBDPSO
a
c
d
OTr
OR
O
O
O
O
3
9 : R = Tr
10 : R = H
11
b
HO
CO2Me
TBDPSO
CO2Me
e
[α]D26 +70.2 (c 1.19, EtOH)
lit.9 [α]D15 +68.2 (c 1.92, EtOH)
O
O
,
12
8
E : Z = 3 : 1
Scheme 2. Reagents and conditions: (a) TBDPSCl, DMAP, imidazole, DMF, rt, overnight; (b) 90% aq. AcOH, 50°C, 3 h; (c)
Dess–Martin periodinane, CH2Cl2, 1 h; (d) LiCl, DBU, trimethyl phosphonoacetate, CH3CN, 2 h; (e) (n-Bu)4NF, THF, rt, 4 h.

I. Uemura et al. / Tetrahedron: Asymmetry 12 (2001) 943–947
945
4. Experimental
24.7, 57.9, 62.4, 63.0, 77.2, 127.0, 127.8, 128.7, 143.7;
IR (Nujol) wmax 1490, 1075, 760, 725, 705 cm−1; [h]D25=
−15.2 (c 1.09, CHCl3); Anal. Found: C, 83.56; H, 6.91.
Calcd for C24H24O2: C, 83.69; H, 7.02%.
Melting points were collected on a Yanagimoto MP
apparatus. H and 13C NMR spectra were measured on
1
1
a Bruker AC-300 spectrometer (300 MHz for H; 75
MHz for 13C) and CDCl3 was used as the solvent and
tetramethylsilane as the internal standard. IR spectra
were recorded on a Shimadzu IR-420 or Shimadzu
FTIR-8100AI spectrometer. Optical rotations were
measured on a JASCO DIP-1000 polarimeter. Elemen-
tal analyses were performed at the Microanalytical
Center of Kyoto University.
4.2. (2S)-1-(Triphenylmethyl)oxy-3-methylbut-3-en-2-ol
7
A solution of n-butyllithium in hexanes (1.5 M, 130
mL, 195 mmol) was added dropwise to a stirred solu-
tion of di-iso-propylamine (28.0 mL, 202 mmol) in
tetrahydrofuran (300 mL), keeping the temperature
below −60°C. After stirring for 1 h, a solution of 6
(37.89 g, 110 mmol) in tetrahydrofuran (50 mL) was
added dropwise. Stirring was continued for 1 h at
−60°C, then for 5 h at room temperature. To the
resulting red solution was added water (200 mL) and
the mixture was stirred vigorously for a few minutes.
After evaporating the tetrahydrofuran, the residue was
extracted with diethyl ether (3×200 mL). The combined
organic extract was washed with brine (200 mL), dried
over magnesium sulfate, filtered and concentrated to
give a yellow oil. Flash column chromatography (10%
EtOAc in hexane) provided 7 as a colorless oil (34.59 g,
Reactions requiring anhydrous conditions were carried
out under an inert atmosphere (argon or nitrogen) in
oven-dried glassware. Solvents were dehydrated in
accordance with standard protocols. Reagents were
used as purchased except for an anhydrous
dichloromethane solution of t-butyl hydroperoxide and
a Dess–Martin periodinane, both of which were pre-
pared by the procedures in the literature.7,10 Molecular
sieves (MS) were activated by heating under high vac-
uum prior to use. Column chromatography and flash
column chromatography were performed on silica gel
(Wakogel C-200 and Merck Kieselgel 60, respectively).
1
91%). H NMR l (ppm) 1.60 (s, 3H), 2.43 (d, J=3.5
Hz, 1H), 3.16 (dd, J=7.5, 9.5 Hz, 1H), 3.27 (dd,
J=9.5, 3.7 Hz, 1H), 4.16 (ddd, J=7.5, 3.7, 3.5 Hz, 1H),
4.88 (s, 1H), 5.00 (s, 1H), 7.21–7.33 (m, 9H), 7.43–7.46
(m, 6H); 13C NMR l (ppm) 18.7, 66.6, 74.4, 86.9,
111.9, 127.1, 127.9, 128.7, 143.8, 144.1; IR (film) wmax
3390, 3050, 1490, 1070, 900, 765, 745, 700 cm−1; [h]D26=
+2.1 (c 1.00, CHCl3); Anal. Found: C, 83.55; H, 7.10.
Calcd for C24H24O2: C, 83.69; H, 7.02%.
4.1. (2R)-2,3-Epoxy-3-methyl-1-(triphenylmethyl)-
oxybutane 6
,
To a stirred suspension of powdered 3 A MS (13 g) in
dichloromethane (300 mL) was added titanium tetra-
iso-propoxide (4.55 g, 16 mmol) followed by diethyl
-tartrate (4.12 g, 20 mmol) at −25°C as solutions in
D
dichloromethane (5 mL for each reagent). The resulting
mixture was stirred for 1 h, then 3-methyl-2-buten-1-ol
4 (20.0 mL, 200 mmol) was added dropwise. Anhy-
drous t-butyl hydroperoxide in dichloromethane solu-
tion (4.3 M, 50 mL, 215 mmol) was added dropwise,
keeping the temperature below −20°C, and the mixture
stirred for 2 h at this temperature. Dimethyl sulfide (2.0
mL, 27 mmol) was added, the cooling bath was
removed and the reaction mixture was allowed to warm
to room temperature over 1 h. Triethylamine (55 mL,
400 mmol) and 4-(dimethylamino)pyridine (1.34 g, 11
mmol) were sequentially added to the mixture. Trityl
chloride (61.33 g, 220 mmol) was then added portion-
wise, keeping the temperature below 30°C and the
mixture was stirred overnight at room temperature. The
resulting orange suspension was poured onto a mixture
of diethyl ether (1.0 L) and brine (300 mL), which was
then stirred vigorously for 30 min. The two-phase
mixture was filtered through a pad of Celite® to remove
insoluble material; the organic phase of the filtrate was
separated and washed with water (3×300 mL) and brine
(300 mL). The organic phase was dried over magnesium
sulfate, followed by filtration and concentration to give
a brown oil. Column chromatography (5% ethyl acetate
in hexane) and subsequent recrystallization (diethyl
ether–hexane) gave 6 as colorless needles (48.22 g,
70%). Mp 84°C; 1H NMR l (ppm) 1.12 (s, 3H), 1.32 (s,
3H), 3.02 (dd, J=4.9, 5.8 Hz, 1H), 3.13 (dd, J=5.8,
10.3 Hz, 1H), 3.31 (dd, J=4.9, 10.3 Hz, 1H), 7.21–7.33
(m, 9H), 7.44–7.48 (m, 6H); 13C NMR l (ppm) 18.9,
4.3. (2R,3S)-3,4-Epoxy-3-methyl-1-(triphenylmethyl)-
oxybutan-2-ol 3
,
To a stirred suspension of powdered 3 A MS (11 g) in
dichloromethane (250 mL) was added titanium tetra-
iso-propoxide (2.84 g, 10 mmol) followed by di-iso-pro-
pyl
D
-tartrate (2.93 g, 13 mmol) at −20°C as solutions
of dichloromethane (5 mL for each). After 1.5 h, a
solution of 7 (34.45 g, 100 mmol) in dichloromethane
(50 mL) and anhydrous t-butyl hydroperoxide solution
in dichloromethane (4.2 M, 27 mL, 108 mmol) were
added. After 4 h, stirring was stopped and the reaction
vessel was stored at −20°C (refrigerator) overnight.
Water (100 mL) was poured into the mixture with
vigorous stirring at room temperature. Aqueous sodium
hydroxide (30%, 50 mL) was added to hydrolyze the
tartrate and vigorous stirring was continued for another
30 min. The resultant emulsion was filtered through a
pad of Celite® to give a clear two-phase solution. The
organic phase was diluted with diethyl ether (700 mL),
washed with water (300 mL) and saturated brine (300
mL), dried over magnesium sulfate and filtered. The
filtrate was concentrated to give a colorless oil, which
was purified by recrystallization (diethyl ether–hexane)
to afford 3 as colorless needles (25.19 g, 70%). Mp
1
80°C; H NMR l (ppm) 1.21 (s, 3H), 2.36 (d, J=2.0
Hz, 1H), 2.61 (d, J=4.8 Hz, 1H), 2.96 (d, J=4.8 Hz,
1H), 3.18 (dd, J=5.5, 10.0 Hz, 1H), 3.37 (dd, J=3.7,
10.0 Hz, 1H), 3.75 (ddd, J=2.0, 3.7, 5.5 Hz, 1H),
7.21–7.33 (m, 9H), 7.44–7.47 (m, 6H); 13C NMR l

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I. Uemura et al. / Tetrahedron: Asymmetry 12 (2001) 943–947
(ppm) 18.2, 51.0, 57.3, 64.5, 71.7, 86.8, 127.1, 127.9,
128.6, 143.8; IR (Nujol) wmax 3450, 1094, 1025, 795, 770,
750, 705 cm−1; [h]D26=+1.4 (c 1.29, CHCl3); Anal.
Found: C, 80.15; H, 6.67. Calcd for C24H24O3: C, 79.97;
H, 6.71%.
in dichloromethane (110 mL) over 30 min at room
temperature. After stirring for 30 min, the resultant
cloudy solution was diluted with diethyl ether (200 mL)
and washed with 10% w/v aqueous sodium thiosulfate
solution saturated with sodium bicarbonate (150 mL).
The organic phase was further washed with saturated
brine, dried over anhydrous magnesium sulfate, filtered
and concentrated. The residue was purified by flash
column chromatography to afford 11 as a colorless oil
4.4. (2R,3S)-2-(tert-Butyldiphenylsilyl)oxy-3,4-epoxy-3-
methyl-1-(triphenylmethyl)oxybutane 9
1
tert-Butylchlorodiphenylsilane (26.0 mL, 100 mmol)
was added dropwise to a stirred solution of 3 (30.00 g,
83 mmol), imidazole (17.02 g, 250 mmol), and 4-
(dimethylamino)pyridine (2.44 g, 20 mmol) in N,N-
dimethylformamide (80 mL) at room temperature. The
resultant solution was stirred overnight, and then
poured onto water (600 mL) with vigorous stirring. The
mixture was extracted with diethyl ether (3×250 mL).
The combined organic layer was washed with water
(200 mL) and brine (200 mL), dried over magnesium
sulfate and filtered. The filtrate was concentrated to
give an oily residue, which was then purified by flash
column chromatography and subsequent recrystalliza-
tion (hexane) to give 9 as colorless columns (40.83 g,
(7.11 g, 91%). H NMR l (ppm) 1.12 (s, 9H), 1.34 (s,
3H), 2.29 (d, J=4.8 Hz, 1H), 2.44 (d, J=4.8 Hz, 1H),
3.74 (d, J=1.0 Hz, 1H), 7.36–7.46 (m, 6H), 7.61–7.68
(m, 4H), 9.58 (d, J=1.0 Hz, 1H); 13C NMR l (ppm)
17.3, 19.4, 26.9, 51.6, 56.2, 80.4, 127.8, 127.9, 130.2,
130.2, 132.5, 132.7, 135.8, 200.5; IR (film) wmax 2920,
2850, 1740, 1430, 1115, 705; [h]2D5=+3.3 (c 1.03,
CHCl3); Anal. Found: C, 70.89; H, 7.52. Calcd for
C21H26O3Si: C, 71.15; H, 7.39%.
4.7. Methyl (4R,5S)-4-(tert-butyldiphenylsilyl)oxy-5,6-
epoxy-5-methylhex-2-enoate 12
Trimethyl phosphonoacetate (1.62 mL, 10 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (1.42 mL, 9.5 mmol)
were added successively at room temperature to a
stirred suspension of lithium chloride (0.40 g, 9.5 mmol)
in acetonitrile (30 mL). After stirring for 30 min, a
solution of 11 (2.60 g, 7.3 mmol) in acetonitrile (4 mL)
was added dropwise to the resultant clear solution and
the mixture was stirred for a further 2 h. The reaction
mixture was poured onto saturated aqueous ammo-
nium chloride solution (30 mL) and the bulk of the
acetonitrile was removed by evaporation. The residue
was extracted with diethyl ether (3×30 mL). The com-
bined extract was washed with saturated aqueous
sodium bicarbonate solution (50 mL) and brine (50
mL), dried over magnesium sulfate and filtered. The
filtrate was concentrated and the residue was purified
by flash column chromatography to give 12 (2.57 g,
85%) as a colorless oil. The isomeric ratio of the
product was determined to be 2(E):2(Z)=3:1 by 1H
1
82%). Mp 101°C; H NMR l (ppm) 1.06 (s, 9H), 1.17
(s, 3H), 2.20 (s, 2H), 3.19 (dd, J=9.7, 4.5 Hz, 1H), 3.25
(dd, J=9.7, 5.5 Hz, 1H), 3.51 (dd, J=5.5, 4.5 Hz, 1H),
7.20–7.44 (m, 21H), 7.64–7.67 (m, 4H); 13C NMR l
(ppm) 16.6, 19.4, 27.0, 53.5, 56.9, 65.8, 75.8, 86.8,
126.9, 127.5, 127.7, 128.8, 129.6, 129.8, 133.6, 133.8,
135.9, 136.1, 143.9; IR (KBr) wmax 2855, 1490, 1450,
1100, 705; [h]2D5=−28.9 (c 1.59, CHCl3); Anal. Found:
C, 80.19; H, 7.30. Calcd for C40H42O3Si: C, 80.23; H,
7.07%.
4.5. (2R,3S)-2-(tert-Butyldiphenylsilyl)oxy-3,4-epoxy-3-
methylbutan-1-ol 10
Compound 9 (18.00 g, 30 mmol) was dissolved in acetic
acid (200 mL) at 50°C with stirring. Water (22 mL) was
added to the solution, and the resultant cloudy mixture
became clear after stirring at the same temperature for
3 h. Concentration of the solution gave an oily residue
containing the powdery solid of triphenylmethylalcohol
(TrOH). After this mixture was diluted with 10%
diethyl ether in hexane, the TrOH was filtered off.
Flash column chromatography (16% ethyl acetate in
hexane) of the concentrated filtrate afforded 10 as a
1
NMR analysis. H NMR l (ppm) (2E)-isomer: 1.10 (s,
9H), 1.30 (s, 3H), 1.86 (d, J=4.7, 1H), 2.21 (d, J=4.7
Hz, 1H), 3.75 (s, 3H), 3.86 (dd, J=4.4, 1.7 Hz, 1H),
6.16 (dd, J=15.7, 1.7 Hz, 1H), 6.99 (dd, J=15.7, 4.4
Hz, 1H), 7.3–7.5 (m, 6H), 7.6–7.7 (m, 4H); (2Z)-isomer:
1.07 (s, 9H), 1.34 (s, 3H), 2.44 (d, J=5.1 Hz, 1H), 2.58
(d, J=5.1 Hz, 1H), 3.48 (s, 3H), 5.39 (d, J=9.0 Hz,
1H), 5.61 (d, J=11.7, 1H), 6.07 (dd, J=11.7, 9.0 Hz,
1H), 7.3–7.5 (m, 6H), 7.6–7.7 (m, 4H); IR (film) wmax
2920, 2850, 1725, 1430, 1270, 1115, 1080, 820, 700;
[h]2D4=−7.3 (c 1.09, CHCl3); Anal. Found: C, 70.18; H,
7.47. Calcd for C24H30O4Si: C, 70.21; H, 7.36%.
1
colorless oil (7.85 g, 73%). H NMR l (ppm) 1.09 (s,
9H), 1.36 (s, 3H), 1.83 (t, J=6.4 Hz, 1H), 2.15 (d,
J=4.8 Hz, 1H), 2.31 (d, J=4.8 Hz, 1H), 3.36 (t, J=4.9
Hz, 1H), 3.71 (m, 2H), 7.36–7.45 (m, 6H), 7.65–7.70 (m,
4H); 13C NMR l (ppm) 16.5, 19.4, 27.0, 53.8, 57.2,
64.4, 76.2, 127.7, 127.9, 130.1, 133.1, 133.4, 135.7,
136.0; IR (film) wmax 3420, 2920, 2850, 1430, 1115, 1080,
700 cm−1; [h]D25=−5.6 (c 1.02, CHCl3); Anal. Found: C,
70.68; H, 7.99. Calcd for C21H28O3Si: C, 70.74; H,
7.92%.
4.8. Methyl (2E,4R,5S)-5,6-epoxy-4-hydroxy-5-methyl-
hex-2-enoate 8
To a stirred solution of 11 (2.47 g, 6.0 mmol) in
tetrahydrofuran was added dropwise a solution of tet-
rabutylammonium fluoride in tetrahydrofuran (1 M,
9.0 mL, 9 mmol). After stirring for 4 h at room
temperature, the reaction mixture was poured onto
saturated aqueous ammonium chloride solution (30
4.6. (2S,3S)-2-(tert-Butyldiphenylsilyl)oxy-3,4-epoxy-3-
methylbutanal 11
Dess–Martin periodinane (10.57 g, 25 mmol) was added
portionwise to a stirred solution of 10 (7.85 g, 22 mmol)

I. Uemura et al. / Tetrahedron: Asymmetry 12 (2001) 943–947
1982, 23, 4469–4472.
947
mL). The bulk of the tetrahydrofuran was removed by
evaporation. The aqueous residue was extracted with
three portions of ethyl acetate (30 mL). The combined
extract was washed with water (50 mL) and brine (50
mL), dried over magnesium sulfate, filtered and concen-
trated. Purification of the residual oil by flash column
chromatography afforded isomerically pure 8 (0.71 g,
2. Kuroda, H.; Miyashita, M.; Irie, H.; Ueno, T. Chem.
Pharm. Bull. 1994, 42, 1328–1330.
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1
69%). H NMR l (ppm) 1.41 (s, 3H), 2.63 (d, J=4.6
Hz, 1H), 2.88 (d, J=4.6 Hz, 1H), 3.76 (s, 3H), 4.32 (dd,
J=5.0, 1.6 Hz, 1H), 6.18 (dd, J=15.6, 1.6 Hz, 1H),
6.93 (dd, J=15.6, 5.0 Hz, 1H); 13C NMR l (ppm) 18.0,
49.9, 51.7, 58.4, 71.4, 122.3, 144.7, 166.6; IR (KBr) wmax
3400, 1713, 1125, 990, 928, 866, 818 cm−1; [h]D26=+70.2
(c 1.19, EtOH), lit.9 +68.2 (EtOH at 15°C), (4S,5S)-iso-
mer: +61.9 (c 1.34, EtOH at 15°C); Anal. Found: C,
56.06; H, 6.92. Calcd for C8H12O4: C, 55.81; H, 7.02%.
6. Bryant, H. J.; Dardonville, C. Y.; Hodgkinson, T. J.;
Hursthouse, M. B.; Abdul Marik, K. M.; Shipman, M. J.
Chem. Soc., Perkin Trans. 1 1998, 1249–1255 and refer-
ences cited therein.
7. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
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This research was supported in part by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Science, Sports and Culture of Japan (No. 10460048).
The authors thank Dr. Masahiko Seki of Tanabe
Seiyaku Co. for critical reading of the manuscript and
helpful suggestions.
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P.; Masamune, S.; Roush, W. R.; Sasaki, T. Tetrahedron
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