Stereoselective synthesis and structure of butalactin and lactone II isolated from Streptomyces species

Article abstract of DOI:10.1039/b407820a

The synthesis and stereostructure of butalactin and lactone II isolated from streptomyces species was analyzed. It was observed that butalactin exhibited moderate antibacterial activity against gram positive bacteria. It was also observed that stereoselectivity of the lactones was in the ratio 8:1. The results show that an interesting rearrangement is formed due to intramolecular double esterification of 3-oxymethyl anion.

Full text of DOI:10.1039/b407820a

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A R T I C L E
Stereoselective synthesis and structure of butalactin and lactone II
isolated from Streptomyces species
Toshihiko Ueki and Takamasa Kinoshita*
Department of Chemistry, Graduate School of Science, Osaka City University, Sumiyoshi-ku,
Osaka, 558-8585, Japan
Received 24th May 2004, Accepted 21st July 2004
First published as an Advance Article on the web 23 August 2004
Butalactin (1a) and lactone II (2a) have been synthesized starting from (S)-malic acid and sorbic acid by a straightforward
route. The absolute stereochemistry of 1a and 2a was unambiguously established by this synthesis.
compound 7, []D26 +34.6 (c, 0.9, CHCl3) {ref. 6 []D23 +32.5 (c, 0.9,
CHCl3), 95% ee for (S)-form}. The hydroxyl group of (2S, 3S)-6a
was protected with dihydropyran to give separable diastereomeric
isomers 6b–1 and 6b–2 (6:5) in 90% yield, because THP protection
was, in spite of accompanying by new isomer, more successfully
removed under mild conditions than MOM (methoxymethyl)
protection in the final step. After separation an isomer 6b–1 was
hydrogenolysed with palladium on carbon to yield inseparable
mixture 2,3-cis 8a and 2,3-trans 8b: the ratio was approximately
4:1 by NMR. The mixture arose solely from hydrogenolytic cleav-
age of the benzyl group from 6b–1. It is probably migrated from 8a
to 8b via intramolecular translactonization. The primary hydroxyl
group in 8 was protected with TBDMSCl to afford TBDMS ether 9a
Butalactin (1a) and lactone II (2a), which are highly functional-
ized -butyrolactones including a conjugated epoxy enone, were
isolated from Streptomyces corchorusii1 and Streptomyces sp. Go
40/10,2 respectively. The stereochemistry of epoxide was proposed
to be doubly cis by spectroscopic analysis; however, the relative
and absolute configurations at the four stereogenic centers have
not been determined. There have also been some butyrolactone
autoregulators closely related to 1a, such as A-factor,3a virginiae
butanolides,3b lactone I,2 and so forth, possessing a broad spectrum
of biological activities. It is reported that 1a exhibits moderate anti-
bacterial activity against Gram positive bacteria, and this is the first
example of the 2,3-disubstituted -butyrolactone showing antibiotic
activity. Thus, it is very significant and indispensable to clarify the
stereostructure of 1a and 2a for exploring structure–activity relation-
ships among the autoregulators and 1a. Recently, we achieved the
first synthesis of 2a and reported it as a preliminary communica-
tion.4 Herein the synthesis and the stereochemistry of butalactin 1a
and lactone II 2a will be described in detail. Our synthetic plan is
briefly illustrated in Scheme 1.
Scheme 1
Results and discussion
Synthesis of the lactone part A and the epoxy parts B and C
The requisite lactones 8 and 9 as coupling partners were synthesized
as shown in Schemes 2 and 3. The benzyloxymethyldiester 3 was
obtained by modification of the Seebach alkylation5 of (S)-diethyl
malate. The observed stereoselectivity was 8:1, and the isomers
were separated by chromatography. Reduction of 3 with lithium
aluminium hydride followed by acid hydrolysis gave the triol 4
(74%), which was protected with p-anisaldehyde to afford 5 (81%).
The acetal 5 was transformed by Dess–Martin periodinane and
successive sodium chlorite oxidation followed by acid-catalyzed
deprotection into the -butyrolactone 6a (89%). Smaller coupling
constant (J2,3 = 7.9 Hz) and larger NOE show cis-disposition
as compared with larger coupling constant (J2,3 = 10.2 Hz) and
smaller NOE (Fig. 1). By reductive deoxygenation (via mesylate)
of the hydroxyl group, the lactone 6a was converted to the known
Scheme 2 Reagents, conditions and yields: (i) LDA, ClCH2OCH2Ph,
HMPA, THF, −78 °C to rt, 70%; (ii) (a) LiAlH4, Et2O; (b) HCl, MeOH–H2O,
81%; (iii) ZnCl2, MeOC6H4CHO, Et2O, MS 4A, 81%; (iv) (a) Dess–Martin
periodinane, CH2Cl2; (b) NaClO2, NaH2PO4, t-BuOH–H2O; (c) HCl,
dioxane, 89% (two steps); (v) (a) MsCl, Et3N, CH2Cl2; (b) Zn, NaI, DME,
85 °C, 91%; (vi) DHP, CSA, CH2Cl2, 90%; (vii) H2, Pd–C, EtOH, 100%;
(viii) TBDMSCl, DMF, imidazole, rt, 93%.
T h i s j o u r n a l i s
©
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 7 7 – 2 7 8 5
2 7 7 7

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and 9b (93%, 4:1). The stereochemistries of these compounds were
confirmed by 1H NMR analysis and NOE experiments (Fig. 1). The
signals of H-2 appeared at  4.56 (J = 7.9 Hz) in 9a and  4.46
(J = 9.2 Hz) in 9b, respectively. In 9a, a NOE was observed be-
tween H-2 and H-3, whereas a NOE was not observed in 9b. From
these results, 9a and 9b are presumed to be 2,3-cis and 2,3-trans iso-
mers, respectively. An improved synthesis (shorter step and higher
overall yield) of 6a is also shown in Scheme 3.
Scheme 3 Reagents, conditions and yields: (i) (a) HCl, THF, boil, (b) aq.
KOH, dioxane, 0 °C, (c) p-TsOH, (MeO)2CMe2, acetone, 84%; (ii) BH3–
Me2S, THF, then HCl, 61%.
Scheme 4 Reagents, conditions and yields: (i) ref. 7; (ii)TBDMSOTf, 2,6-
lutidine, CH2Cl2, −78 °C, 76%; (iii) MsCl, CH2Cl2, Et3N, rt, 92%; (iv) TBAF,
THF, rt, 92%; (v) TMSOK, THF, 82%; (vi) DIBAL, Et2O, −78 °C, 54%.
Fig. 1 Selected NOE,  values of H-2 and J2,3 (in Hz) of related com-
pounds.
The epoxy parts (aldehyde B and acid C) were efficiently
synthesized from sorbic acid according to the Sharpless method
(Scheme 4). Selective protection of the hydroxyl group of the known
compound 11a7 [prepared from methyl sorbate and AD-mix-] with
tert-butyldimethylsilyl triflate8 afforded the mono hydroxy TBDMS
ether 11b (76%), which was subjected to mesylation and selective
deprotection of the silyl group with TBAF to yield (4R,5S)-epoxy
ester 12a (64% from 11a). Successful hydrolysis of 12a with
potassium trimethylsilanolate9 afforded (4R,5S)-epoxy acid 13a
(82%) without complication. Reduction of 12a (methyl ester) to 14a
with DIBAL-H resulted in decomposition, however, similar reaction
of 12b (tert-butyl ester) furnished the epoxy aldehyde 14a as a single
product. By a similar oxidation of methyl or tert-butyl sorbate with
AD-mix- and a subsequent series of reactions, the other isomers
(4S,5R)-13b and (4S,5R)-14b were also obtained, respectively.
Synthesis of lactone II
Esterification of 8 (mixture of 8a and 8b, 4:1) with 13a was achieved
by the DCC method to provide separable compounds 15a (67%) and
15b (13%) (Scheme 5). As mentioned on the analysis of 9a and 9b
the stereochemistries of 15a and 15b were confirmed to be 2,3-cis
and 2,3-trans isomers, respectively. On treatment of 15a or 15b with
acetic acid in THF–H2O at 50 °C to remove THPprotection, the final
products 2a and 2b were obtained in satisfactory yield, respectively.
Isomers 2c and 2d were synthesized from 8 and (4S, 5R)-13b in
Scheme 5 Reagents, conditions and yields: (i) DCC, DMAP, CH2Cl2, rt,
24 h, 88%; (ii) AcOH, THF–H2O, 50 °C, 3 h, 63% for 2a, 69% for 2b, 58%
for 2c and 43% for 2d.
1
the same manner. The compounds 2a and 2c have similar H and
13C NMR spectra, as do 2b and 2d. This is most noticeable in the
C2–C3 coupling constants, because they have similar stereochem-
istry on the lactone ring. Of the four compounds, 2a corresponds to
the natural product, because the NMR is the closest match, but more
importantly, because the specific rotations match the most closely
(Fig. 1 and experimental section). From these results, the absolute
configuration of lactone II was determined as 2S,3S,4′R,5′S.
2 7 7 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 7 7 – 2 7 8 5

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Synthesis of butalactin
The aldol reaction of the lithium enolate of (2S, 3R)-9a with
(4S, 5R)-14b afforded 17a as an inseparable mixture of four
diastereomers (Scheme 6). Although a multitude of isomers is
formed, in the light of the subsequent steps this factor is of minor
significance. Successive treatment of 17a with Dess–Martin
periodinane provided 18a and 18b (75%, 12:1) as a separable
mixture. A NOE was observed between H-3 and H-2′ for the major
isomer, but not for the minor isomer (Fig. 2). From these results, 18a
and 18b are presumed to be 2,3-trans and 2,3-cis isomers, respec-
tively. In stepwise removal of the protecting group in 18a, the THP
group was firstly removed by treatment with acetic acid in THF–
H2O at 40 °C to give 19a (48%) along with 1a (11%). Secondly,
the treatment of 19a with tetrabutylammonium fluoride (TBAF) in
THF at 0 °C yielded surprisingly the unexpected esters 2d, ent-2a
(enantiomer of 2a) and decomposition products (Scheme 6). Simi-
larly, deprotection treatment of 19b with TBAF gave the esters 2c
and ent-2b (enantiomer of 2b). The products were identical with
the samples synthesized according to the procedure mentioned
above, i.e. 2S esters (2c and 2d) and 2R esters (ent-2a and ent-2b)
were prepared from (S)- or (R)-malic acid and 13b, respectively.
A proposed mechanism of the rearrangement (via intramolecular
double esterification) is shown in Scheme 7. The detailed process is
currently under investigation and will be reported in due course.
Concurrent removal of the THP and TBDMS groups in 18a with
acetic acid in THF–H2O at 60 °C gave 1a (-epoxide) in 27% yield
along with cleavage of the epoxide (Scheme 6). It was impossible
to isolate the polar decomposition products. Successive stereo-
selective synthesis of 1a was achieved by the following procedures
(Scheme 8).
The Seebach alkylation of the acetonide 20 [prepared from 6a]
with the epoxy aldehyde 14b and subsequent treatment of the
Dess–Martin oxidation afforded the ketone 21 (68%, 2 steps) as
a single diastereoisomer. The stereochemistry of 21 was deter-
mined to be 2,3-trans configuration by NOE experiment. The final
deprotection of the acetonide group using acetic acid–THF–H2O
at 40 °C furnished 1a in 66% yield. The synthetic 1a was identical
with the natural product by comparing the optical rotation, 1H and
13C NMR spectra with those reported.1 Thus, it has been found that
the absolute configuration of butalactin is assigned to 2R, 3S, 4′S,
5′R. Although another isomer 1b (-epoxide) was, in the same way
(Scheme 6), synthesized from 9a and the aldehyde 14a, this was not
identical with the natural product.
On the contrary, the same deprotection procedure for both 2,3-cis
18b and 2,3-cis 18d resulted in decomposition. Unfortunately, the
cis isomers corresponding to butalactin could not be obtained. How-
ever, while a NOE between H-3 and H-2′ was observed in the 2,3-
trans isomers (18a, 19a, 18c, 19c, 1a, 1b and natural butalactin), no
NOE was observed in the 2,3-cis isomers (18b, 19b, 18d and 19d)
(Fig. 2). Moreover, the optical rotations showed the following
tendency: positive sign for the trans 19a, 19c and butalactin, and
negative sign for the cis 19b and 19d. These results suppose that
2,3-cis derivatives might be non-natural. Judging from the fact that
3-oxymethyl anion of 1a caused intramolecular double migration to
yield 2d and ent-2a, it might be assumed that neither butalactin is
the precursor of lactone II in biogenesis nor lactone II is the artifact
of butalactin in working-up.
Scheme 6 Reagents, conditions and yields: (i) LDA,THF, HMPA, −78 °C;
(ii) Dess–Martin periodinane, CH2Cl2, 75% for 18a and 18b, 57% for 18c
and 18d (two steps); (iii) AcOH, THF, H2O, 40 °C, 14 h, 48% for 19a and
22% for 19b; (iv) Tetrabutylammonium fluoride (TBAF), THF, 0 °C,
(v) AcOH, THF, H2O, 60 °C, 14 h, 27% for 1a and 28% for 1b.
Conclusion
In conclusion, we have achieved the first stereoselective synthesis
of butalactin and lactone II from (S)-malic acid and sorbic acid,
and determined their absolute configurations. The interesting
rearrangement via intramolecular double esterification of 3-
oxymethyl anion, generated from 2,3-trans-3-silyloxymethyl-1′-
ketoalkyl-4-butanolides, was first observed.
Fig. 2 NOE of 18a and 18b.
a JASCO Model DIP-370 polarimeter ([]D-values are in units
of 10−1 ° cm2 g−1). IR spectra were taken on a JASCO A-102
infrared spectrophotometer. 1H and 13C nmr spectra were re-
corded on a JEOL LA-300 (300 MHz) and LA-400 (400 MHz)
in deuteriochloroform solution, unless stated otherwise. Chemi-
cal shifts (in ppm) are given downfield of tetramethylsilane.
Mass spectra were determined on a JEOL AX-500 spectrometer.
Experimental
Melting points were measured with a Yanagimoto MP appara-
tus and are uncorrected. Specific rotations were measured with
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 7 7 – 2 7 8 5
2 7 7 9

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matography (hexane–ethyl acetate, 8:1) to give 3 (7.96 g, 70%) as
a pale yellow oil; []D25 −34.1 (c, 1.28, CHCl3); [Found: (M + H)+,
431.2078. C24H31O7 requires M + H, 431.2070]; max(film)/cm−1
1732, 1456 and 1371; H (300 MHz, CDCl3) 1.16 (3H, t, J 7.0),
1.18 (3H, t, J 7.0), 3.23–3.29 (1H, m), 3.66 (1H, dd, J 7.7 and 9.7),
3.75 (1H, dd, J 6.2 and 9.7), 4.04–4.14 (4H, m), 4.43 (2H, s), 4.54
(1H, d, J 5.3), 4.56 (2H, s), 4.75 (1H, d, J 7.1), 4.80 (1H, d, J 7.1)
and 7.18–7.28 (10H, m); C (75 MHz, CDCl3) 14.00 (q), 14.02 (q),
48.6 (d), 60.9 (t), 61.1 (t), 66.6 (t), 70.1 (t), 73.2 (t), 73.8 (d), 94.6
(t), 127.6 (d), 127.8 (d), 128.3 (d), 137.5 (s), 137.7 (s), 170.1 (s)
and 170.9 (s).
(2S,3R)-3-Benzyloxymethyl-1,2,4-butanetriol 4
To a solution of 3 (1.277 g, 2.97 mmol) in dry ether (20 cm3)
was added LAH (1.0 M in ether, 5.94 cm3, 5.94 mmol), and the
mixture was boiled for 6 h. A small amount of water was slowly
added to decompose excess LAH, and the precipitate was filtered
off through Celite and washed with ethyl acetate. The filtrate was
dried, and concentrated under reduced pressure. The residue was
purified by chromatography (hexane–ethyl acetate, 8:1) to give
(2S,3R)-3-benzyloxymethyl-2-benzyloxy–methoxy-1,4-butanediol
(834 mg, 81%) as a colorless oil; []D25 +13.2 (c, 0.98, CHCl3);
[Found: (M + H)+, 347.1882. C20H27O5 requires M + H, 347.1859];
Scheme 7 Proposed pathway leading to esters.

max(film)/cm−1 3400, 1497, 1456 and 1367; C (75 MHz, CDCl3)
43.3 (d), 61.4 (t), 63.2 (t), 69.4 (t), 70.0 (t), 73.2 (t), 79.6 (d), 95.0
(t), 127.55 (d), 127.62 (d), 127.7 (d), 127.8 (d), 128.3 (d), 128.4 (d),
137.1 (s) and 137.7 (s).
To a solution of the diol (834 mg, 2.41 mmol) in MeOH (3 cm3)
and H2O (1 cm3) was added concentrated HCl (0.5 cm3), and the
mixture was stirred at 55 °C for 2 h. The reaction mixture was
neutralized with solid NaHCO3, filtered, and washed with methanol.
The filtrate was concentrated under reduced pressure. The residue
was purified by chromatography (EtOAc–MeOH, 10:1) to give
the triol 4 (544 mg, 100%) as a colorless viscous oil; []D26 +1.82
(c, 0.94, CHCl3); [Found: (M + H)+, 227.1267. C12H19O4 requires
M + H, 227.1284]; max(film)/cm−1 3234; C (75 MHz, CDCl3) 43.7
(d), 62.1 (t), 64.9 (t), 70.5 (t), 72.5 (d), 73.6 (t), 127.7 (d), 127.9 (d),
128.5 (d) and 137.6 (s).
Scheme 8 Reagents, conditions and yields: (i) (a) H2, Pd–C, EtOAc,
(b) 2,2-dimethoxypropane, CSA, CH2Cl2, 67% (two steps); (ii) (a) LDA,
THF, HMPA, 14b, −78 °C; (b) Dess–Martin periodinane, CH2Cl2, 63% (two
steps); (iii) AcOH, THF, H2O, 40 °C, 66%.
(2S,3S)-3-Benzyloxymethyl-2,4-(4-methoxybenzylidenedioxy)-
butane-1-ol 5
Elemental analyses were performed with a JMS AX-500 elemen-
tal analyzer by the staff at our Instrumental Measurement Center.
Thin-layer chromatography (TLC) was performed with a glass plate
coated Kieselgel 60 GF254 (Merck). Column chromatography was
carried out on silica gel 60 (Merck No. 7734; 63–200 m). Solvents
were dried (drying agent in parenthesis) and distilled prior to use:
THF, diethyl ether and DME (sodium/benzophenone ketyl), DMF
(CaH2), and dichloromethane (P2O5). Organic solutions were dried
over anhydrous Na2SO4. Hexane and ether refer to n-hexane and
diethyl ether, respectively.
To a suspension of 4 (2.3 g, 10.2 mmol) and 4 Å molecular sieve
(3.5 g) in 4-methoxybenzaldehyde (15 cm3) was added a solution
of zinc chloride (2.77 g, 20.4 mmol) in dry ether (20 cm3). After
stirring at room temperature for 17 h, the reaction mixture was
diluted with ethyl acetate and the organic layer was washed with
saturated aqueous NaHCO3 and brine, dried, and concentrated
under reduced pressure. The residue was purified by chromato-
graphy (hexane–ethyl acetate, 2:1) to give the benzylidene acetal 5
(2.85 g, 81%) as a colorless oil; []D25 +4.5 (c, 2.3, CHCl3); [Found:
M+, 344.1598. C20H24O5 requires M, 344.1624]; max(film)/cm−1
3441, 1616, 1518 and 1248; H (300 MHz, CDCl3) 2.22–2.34 (1H,
m), 2.41 (1H, br s, OH), 3.38 (2H, d, J 5.3), 3.65–3.77 (2H, m),
3.79 (3H, s), 3.85–3.91 (2H, m), 4.23 (1H, dd, J 5.0 and 11.4), 4.45
(1H, d, J 11.9), 4.51 (1H, d, J 11.9), 5.46 (1H, s), 6.89 (2H, d, J 8.6),
7.28–7.39 (5H, m) and 7.41 (2H, d, J 8.6), C (75 MHz, CDCl3) 36.1
(d), 55.3 (q), 63.8 (t), 67.8 (t), 68.8 (t), 73.4 (t), 80.1 (d), 101.0 (d),
113.6 (d), 127.4 (d), 127.6 (d), 127.9 (s), 128.5 (d), 130.7 (d), 137.6
(s) and 160.0 (s).
Diethyl (2S,3R)-3-benzyloxymethyl-2-benzyloxymethoxy-
succinate 3
To a solution of lithium diisopropylamide, prepared from di-
isopropylamine (9.05 cm3, 64.6 mmol) in dry THF (100 cm3) and
n-butyllithium (1.6 M in hexane, 36.64 cm3, 59.2 mmol), was
added a solution of diethyl (S)-malate (5.11 g, 26.9 mmol) in dry
THF (5 cm3) at −78 °C under nitrogen, and the mixture was stirred
for 30 min, and then at −20 °C for 1 h. To the cooled (−78 °C)
solution was added benzyl chloromethyl methyl ether (11.1 cm3,
80.7 mmol) in HMPA (23 cm3) over 20 minutes, and the mixture
was stirred at −78 °C for 6 h, then at room temperature for 12 h.
After quenching by addition of a solution of glacial acetic acid
(7.5 cm3) in ether (10 cm3) at 0 °C, the mixture was poured into
water, and extracted with ether. The extract was washed with water,
saturated aqueous NaHCO3 and brine, dried, and concentrated
under reduced pressure. The residue was purified by column chro-
(2S,3S)-3-Benzyloxymethyl-2-hydroxy-4-butanolide 6a
To a solution of 5 (577.5 mg, 1.67 mmol) in dry dichloromethane
(30 cm3) was added Dess–Martin periodinane (4.08 g, 9.62 mmol),
and the mixture was stirred at room temperature for 1 h. After
quenching by addition of saturated aqueous NaHCO3 and aque-
ous sodium thiosulfate, the mixture was extracted with dichloro-
methane. The extract was washed with water and brine, dried, and
concentrated under reduced pressure. The residue was purified
2 7 8 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 7 7 – 2 7 8 5

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by chromatography to afford (2S,3S)-3-benzyloxymethyl-2,4-
(4-methoxybenzylidenedioxy)butanal, (551 mg, 96%) as white
needles; mp 62.5–63 °C; []D25 −16.7 (c, 0.83, CHCl3); [Found: M+,
342.1472. C20H22O5 requires M, 342.1467]; H (300 MHz, CDCl3)
2.35–2.41 (1H, m), 3.70 (1H, dd, J 6.2 and 9.3), 3.79 (3H, s), 3.97
(1H, t, J 9.3), 4.05 (1H, dd, J 2.6 and 11.7), 4.21 (1H, d, J 11.0), 4.41
(1H, d, J 2.6), 4.46 (1H, d, J 11.9), 4.50 (1H, d, J 11.9), 5.52 (1H, s),
6.90 (2H, d, J 8.6), 7.25–7.37 (5H, m), 7.41 (2H, d, J 8.6) and 9.62
(1H, s); C (75 MHz, CDCl3) 37.1 (d), 55.2 (q), 66.9 (t), 68.3 (t),
73.1 (t), 82.4 (d), 101.8 (d), 113.6 (d), 127.5 (d), 127.61 (d), 127.65
(d), 128.3 (d), 130.0 (s), 137.7 (s), 160.2 (s) and 198.8 (d).
To a solution of the aldehyde in t-butanol (20 cm3) and 2-
methyl-2-butene (20 cm3) were added sodium chlorite (NaClO2)
(1.9 g, 16.8 mmol) and sodium dihydrogenphosphate (NaH2PO4)
(1.4 g, 13 mmol) in water (20 cm3). After stirring for 1 h, the
reaction mixture was quenched with water and extracted with
ethyl acetate. The extract was washed with water and brine,
dried, and concentrated under reduced pressure to give (2S,3S)-
3-benzyloxymethyl-2,4-(4-methoxybenzylidenedioxy)butanoic
acid as a white wax. The crude acid was, without further purifi-
cation, hydrolyzed with concentrated hydrochloric acid (0.5 cm3)
in 1,4-dioxane (8 cm3) at room temperature with stirring for 36 h.
The reaction mixture was diluted with water and extracted with
ether. The extract was washed with water and brine, dried and
concentrated under reduced pressure. The residue was purified by
chromatography (hexane–ethyl acetate, 2 : 1) to give 6a (333 mg,
89% from 5) as a pale yellow solid, which was recrystallized
twice from ether-hexane to furnish white microcrystalline; mp
85–86 °C; []D29 +44.1 (c, 0.99, CHCl3); (Found: C, 64.64; H,
6.42%. Calc. for C12H14O4: C, 64.85; H, 6.35%); [Found: M+,
222.0878. C12H14O4 requires M, 222.0892]; max(nujol)/cm−1
3396, 1759, 1456 and 1207; H (300 MHz, CDCl3) 2.95–3.02
(1H, m), 3.16 (1H, br s, OH), 3.63 (1H, d, J 9.9), 3.68 (1H, d, J
9.9), 4.28 (1H, dd, J 5.7 and 9.3), 4.34 (1H, dd, J 2.0 and 9.3),
4.49 (1H, d, J 12.1), 4.52 (1H, d, J 12.1), 4.54 (1H, d, J 7.9) and
7.27–7.37 (5H, m); C (75 MHz, CDCl3) 39.4 (d), 66.8 (t), 68.0
(d), 68.2 (t), 73.4 (t), 127.5 (d), 127.7 (d), 128.4 (d), 137.5 (s)
and 177.3 (s).
To a solution of the mesylate (53.9 mg, 0.18 mmol) in dry DME
(5 cm3) were added sodium iodide (62 mg, 0.41 mmol) and freshly
activated zinc powder (54 mg, 0.83 mmol) [wash several times
with 5% hydrochloric acid, wash in turn with water, methanol,
and ether, and dry],10 and the mixture was stirred at 85 °C for 24 h.
The mixture was filtered, and the filtrate was acidified (pH 2) with
1.0 M hydrochloric acid and stirred for 5 h. The reaction mixture
was diluted with water and extracted with ether. The extract was
washed with aqueous sodium thiosulfate and water, dried, and
concentrated under reduced pressure. The residue was purified by
chromatography (hexane–ethyl acetate, 3:1) to give 7 (33.7 mg,
91%) as a colorless oil; []D26 +34.6 (c, 0.6, CHCl3); lit:6 []D +32.5
(c, 0.9, CHCl3, ee = 95%); [Found: M+, 206.0917. C12H14O3 requires
M, 206.0943]; max(film)/cm−1 2862, 1771, 1367, 1175, 1101, 1024,
743 and 700; H (300 MHz, CDCl3) 2.37 (1H, dd, J 6.2 and 17.6),
2.60 (1H, dd, J 9.0 and 17.6), 2.77–2.90 (1H, m), 3.45 (1H, dd, J 6.7
and 9.2), 3.49 (1H, dd, J 5.9 and 9.2), 4.18 (1H, dd, J 5.5 and 9.2),
4.39 (1H, dd, J 7.5 and 9.2), 4.52 (2H, s) and 7.27–7.39 (5H, m); C
(75 MHz, CDCl3) 31.1 (d), 35.3 (t), 70.3 (t), 70.7 (t), 73.3 (t), 127.6
(d), 127.8 (d), 128.4 (d), 137.5 (s) and 176.8 (s).
(2S,3S)-3-Benzyloxymethyl-2-tetrahydropyranyloxy-4-
butanolide 6b
To a solution of 6a (470 mg, 2.12 mmol) and 3,4-dihydro-2H-
pyran (267 mg, 3.2 mmol) in dry dichloromethane (15 cm3) was
added camphorsulfonic acid (CSA) (5.2 mg), and the mixture
was stirred at room temperature for 18 h. The reaction mixture
was quenched with saturated aqueous NaHCO3 and extracted
with dichloromethane. The extract was washed with saturated
aqueous NaHCO3 and brine, dried, and concentrated under
reduced pressure. The residue was purified by chromatography
(hexane–ethyl acetate, 8:1) to afford 6b–1 (327 mg, 50%) and
6b–2 (266 mg, 41%).
Compound 6b–1. White plates; mp 112–113 °C, []D31 −54.3 (c,
1.11, CHCl3); (Found: C, 66.60; H, 7.32%. Calc. for C17H22O5: C,
66.65; H, 7.24%); [Found: (M + H)+, 307.1546. C17H23O5 requires
M + H, 307.1546]; max(nujol)/cm−1 1790, 1456 and 1375; H
(300 MHz, CDCl3) 1.51–1.83 (6H, m), 2.79–2.85 (1H, m), 3.40
(1H, dd, J 7.3 and 9.5), 3.42–3.48 (1H, m), 3.51 (1H, dd, J 5.0 and
9.5), 4.02 (1H, dd, J 2.8 and 10.8), 4.17 (1H, dd, J 5.9 and 9.3), 4.30
(1H, dd, J 2.4 and 9.3), 4.42 (1H, d, J 11.9), 4.46 (1H, d, J 11.9),
4.58 (1H, d, J 7.5), 4.68 (1H, t, J 2.8) and 7.22–7.27 (5H, m); C
(75 MHz, CDCl3) 19.2 (t), 25.2 (t), 30.1 (t), 39.9 (d), 62.9 (t), 66.5
(t), 68.0 (t), 69.8 (d), 73.5 (t), 98.2 (d), 127.6 (d), 127.7 (d), 128.4
(d), 137.9 (s) and 170.5 (s).
(2R,3S)-3-Benzyloxymethyl-2-hydroxy-4-butanolide: Isomer
of 6a
This compound was obtained from the minor diastereomer of 3 in
the same manner as described above. Colorless oil; H (300 MHz,
CDCl3) 2.71–2.83 (1H, m), 3.05 (1H, d, J 3.4, OH), 3.66 (1H, dd,
J 4.2 and 7.2), 3.68 (1H, dd, J 3.3 and 7.2), 4.12 (1H, dd, J 2.1 and
9.2), 4.39 (1H, dd, J 3.4, and 10.2), 4.43 (1H, dd, J 2.0 and 8.7), 4.55
(2H, s) and 7.30–7.39 (5H, m); C (75 MHz, CDCl3) 44.0 (d), 67.2
(t), 67.4 (d), 68.9 (t), 73.4 (t), 127.7 (d), 127.9 (d), 128.5 (d), 137.5
(s) and 177.4 (s).
Compound 6b–2. Acolorless oil, []D24 +117.5 (c, 0.56, CHCl3);
H (300 MHz, CDCl3) 1.50–1.68 (6H, m), 2.76–2.86 (1H, m), 3.45
(1H, dd, J 7.9 and 9.5), 3.49 (1H, dd, J 5.8 and 9.5), 3.48–3.53 (1H,
m), 4.07 (1H, dd, J 7.4 and 10.8), 4.24 (1H, dd, J 5.9 and 9.5), 4.36
(1H, dd, J 2.5 and 9.5), 4.52 (1H, d, J 12.1), 4.64 (1H, d, J 7.5),
4.74 (1H, t, J 2.8), 4.82 (1H, d, J 12.1) and 7.27–7.35 (5H, m); C
(75 MHz, CDCl3) 18.0 (t), 25.1 (t), 29.7 (t), 38.7 (d), 61.3 (t), 66.4
(t), 67.5 (t), 69.9 (d), 73.5 (t), 97.0 (d), 127.7 (d), 127.8 (d), 128.4
(d), 137.6 (s) and 174.2 (s);
(3S)-3-Benzyloxymethyl-4-butanolide 7
To a solution of 6a (37 mg, 0.17 mmol) in dry dichloromethane
(2 cm3) were added triethylamine (0.12 cm3, 0.83 mmol) and
methanesulfonyl chloride (0.02 cm3, 0.32 mmol) at 0 °C, and the
mixture was stirred at room temperature for 15 h. The mixture
was quenched with water and extracted with dichloromethane.
The extract was washed with water and brine, dried, and con-
centrated under reduced pressure. The residue was purified by
chromatography (hexane/ethyl acetate; 2/1) to afford (2S, 2S)-3-
benzyloxymethyl-2-methanesulfonyl-4-butanolide (50 mg, 100%)
as white plates; mp 102.5–103 °C; []D25 +24.7 (c, 1.4, CHCl3);
(Found: C, 52.02; H, 5.39%. Calc. for C13H16O6S: C, 51.99; H,
5.37%); [Found: M+, 300.0663. C13H16O6S requires M, 300.0668];
(2S,3R)- and (2S,3S)-3-tert-Butyldimethylsiloxymethyl-2-
tetrahydropyranyloxy-4-butanolide, 9a and 9b
A mixture of 6b–1 (100 mg, 0.327 mmol) and 10% palladium on
carbon (30 mg) in 95% ethanol (15 cm3) was stirred under an atmo-
sphere of hydrogen at room temperature for 16 h. The mixture was
filtered, and the filtrate was concentrated under reduced pressure to
give a mixture of alcohol. To a solution of the crude alcohol in dry
DMF (5 cm3) was added imidazole (139 mg, 2.05 mmol) and tert-
butyldimethylsilylchloride (154 mg, 1.03 mmol), and the mixture
was stirred at room temperature for 24 h and diluted with ether.
The organic layer was washed with water and brine, dried, and
concentrated under reduced pressure. The residue was purified by

max(nujol)/cm−1 1782, 1456, 1367 and 1178; H (300 MHz, CDCl3)
2.97–3.03 (1H, m), 3.24 (3H, s), 3.64 (1H, dd, J 3.3 and 9.7), 3.64
(1H, dd, J 7.3 and 9.7), 4.39 (1H, dd, J 5.9 and 9.5), 4.45 (1H, dd, J
2.4 and 9.5), 4.52 (2H, s), 5.37 (1H, d, J 8.3) and 7.27–7.36 (5H, m);
C (75 MHz, CDCl3) 38.9 (d), 39.7 (q), 66.0 (t), 68.4 (t), 73.5 (d),
73.6 (t), 127.6 (d), 127.9 (d), 128.5 (d), 137.4 (s) and 170.1 (s).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 7 7 – 2 7 8 5
2 7 8 1

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chromatography (hexane–ethyl acetate, 8:1) to give 9a (85.5 mg,
79%) and 9b (15 mg, 14%).
Methyl (4S,5S,2E)-5-tert-butyldimethylsilyloxy-4-hydroxy-
hexenoate 11b
To a solution of the diol 11a7 (164 mg, 1.03 mmol) in dry dichloro-
methane (15 cm3) were added 2,6-lutidine (0.36 cm3, 3.08 mmol)
and tert-butyldimethylsilyl triflate (TBDMSOTf) (0.23 cm3,
1.03 mmol) at −78 °C. After stirring at −78 °C for 1 h, the reac-
tion mixture was quenched with water and extracted with dichloro-
methane. The organic layer was washed with 0.3 M KHSO4, water,
and brine, dried, and concentrated under reduced pressure. The
residue was purified by chromatography (hexane–ethyl acetate,
10:1) to afford 11b (230.3 mg, 82%) as a colorless oil; []D25 +6.6
(c, 0.90, CHCl3); [Found: (M + H)+, 275.1703. C13H27O4Si requires
M + H, 275.1679]; max(film)/cm−1 3477, 1705 and 1663; H
(300 MHz, CDCl3) 0.02 (3H, s), 0.04 (3H, s), 0.84 (9H, s), 1.16
(3H, d, J 6.2), 2.62 (1H, d, J 5.5), 3.70 (3H, s), 3.71–3.77 (1H, m),
3.99 (1H, ddd, J 1.6, 6.4 and 9.7), 6.09 (1H, dd, J 1.8 and 15.6) and
6.88 (1H, dd, J 4.4 and 15.6); C (75 MHz, CDCl3) −5.1 (q), −4.7
(q), 17.8 (s), 19.6 (q), 25.5 (q), 51.3 (q), 70.8 (d), 74.8 (d), 121.1 (d),
147.6 (d) and 166.6 (s).
Compound 9a. A colorless oil, []D23 −17.8 (c, 0.97, CHCl3);
[Found:(M + H)+,331.1944.C16H31O5SirequiresM + H,331.1941];
H (300 MHz, CDCl3) 0.03 (6H, s), 0.85 (9H, s), 1.51–1.83 (6H, m),
2.69–2.71 (1H, m), 3.48–3.56 (1H, m), 3.75–3.79 (1H, m), 3.77
(1H, dd, J 6.5 and 10.3), 3.78 (1H, dd, J 6.5 and 10.3), 4.25 (1H, dd,
J 5.9 and 9.2), 4.35 (1H, dd, J 2.2 and 9.2), 4.56 (1H, d, J 7.9) and
5.07 (1H, dd, J 2.0 and 4.4); C (75 MHz, CDCl3) −5.6 (q), 18.2 (s),
19.4 (t), 25.2 (t), 25.7 (q), 30.2 (t), 41.3 (d), 59.7 (t), 63.0 (t), 67.7
(t), 69.6 (d), 98.4 (d) and 175.1 (s).
Compound 9b. A colorless oil, [Found: (M + H)+, 331.1969.
C16H31O5Si requires M + H, 331.1941]; max(film)/cm−1 2856, 1790
and 1256; []D25 −117.6 (c, 0.98, CHCl3); H (300 MHz, CDCl3) 0.03
(3H, s), 0.04 (3H, s), 0.86 (9H, s), 1.50–1.79 (6H, m), 2.64–2.68
(1H, m), 3.47–3.54 (1H, m), 3.77–3.84 (1H, m), 3.71 (1H, dd, J
3.3 and 10.4), 3.80 (1H, dd, J 4.8 and 10.4), 4.11 (1H, t, J 9.0),
4.35 (1H, t, J 8.6), 4.46 (1H, d, J 9.2) and 5.11 (1H, t, J 2.0); C
(75 MHz, CDCl3) −5.6 (q), −3.6 (q), 18.1 (s), 19.2 (t), 25.5 (t), 25.7
(q), 30.2 (t), 44.3 (d), 59.8 (t), 62.6 (t), 67.0 (t), 70.5 (d), 98.1 (d)
and 175.8 (s).
Methyl (4S,5S,2E)-5-tert-butyldimethylsilyloxy-4-methanesulf
onyloxyhexenoate 11c
To a solution of the alcohol 11b (652 mg, 2.38 mmol) in dry
dichloromethane (20 cm3) were added triethylamine (1.66 cm3,
11.9 mmol) and methanesulfonyl chloride (0.28 cm3, 3.56 mmol) at
0 °C.After stirring at room temperature for 17 h, the reaction mixture
was quenched with water and extracted with dichloromethane. The
organic layer was washed with brine, dried, and concentrated under
reduced pressure. The residue was purified by chromatography
(hexane–ethyl acetate, 4:1) to afford 11c (806 mg, 96%) as a pale
yellow viscous oil; []D24 −10.4 (c, 1.10, CHCl3); [Found: (M − H)+,
351.1294. C14H27O6SSi requires M − H, 351.1297]; max(film)/cm−1
1728, 1666 and 1364; H (300 MHz, CDCl3) 0.06 (3H, s), 0.07 (3H,
s), 0.86 (9H, s), 1.12 (3H, d, J 4.6), 3.00 (3H, s), 3.74 (3H, s), 4.03
(1H, dt, J 4.0 and 4.6), 4.99 (1H, dt, J 1.3 and 4.0), 6.11 (1H, dd,
J 1.3 and 15.8) and 6.91 (1H, dd, J 4.0 and 15.8); C (75 MHz,
CDCl3) −4.9 (q), −4.8 (q), 17.9 (s), 18.6 (q), 25.7 (q), 38.7 (q), 51.9
(q), 69.2 (d), 82.3 (d), 124.1 (d), 140.7 (d) and 165.7 (s).
(5S,1′R)-2,2-Dimethyl-5-(1′-benzyloxymethylcarboxymethyl)-
1,3-dioxolan-4-one 10
To a solution of the ester 3 (531 mg, 1.23 mmol) in 1,4-dioxane
(10 cm3) was added concentrated hydrochloric acid (0.5 cm3), and
the mixture was stirred at 60 °C for 62 h. The reaction mixture was
diluted with water and extracted with ether. The extract was washed
with brine, dried, and concentrated under reduced pressure to give
a diethyl ester (305.6 mg, 80%) as a pale yellow oil. To a solution
of the diethyl ester (120.9 mg, 0.39 mmol) in 1,4-dioxane (3 cm3)
was added the solution of potassium hydroxide (64 mg, 0.98 mmol)
in water (1 cm3), and the mixture was stirred at room temperature
for 5 h. After removal of 1,4-dioxane under reduced pressure,
the residue was dissolved in water and extracted with ether. The
aqueous layer was acidified (pH 2) with 1.0 M hydrochloric acid
and saturated with solid sodium chloride. The aqueous solution
was successively extracted with ether. The extract was dried, and
concentrated under reduced pressure to give a diacid (91 mg, 92%)
as a colorless oil; []D31 −5.2 (c, 0.96, CHCl3); C (75 MHz, CD3OD)
50.4 (d), 68.2 (t), 69.6 (t), 74.2 (d), 128.7 (d), 128.8 (d), 129.3 (d),
139.4 (s), 174.0 (s) and 176.6 (s).
To a solution of the diacid (40 mg, 0.16 mmol) in 2,2-dimethoxy-
propane (2 cm3) was added a catalytic amount of p-TsOH, and the
mixture was stirred at room temperature for 17 h. The reaction
mixture was quenched with saturated aqueous NaHCO3, and acidi-
fied (pH 4) with aqueous citric acid and extracted with ether. The
extract was washed with water and brine, dried, and concentrated
under reduced pressure to give the acetonide 10 (41.7 mg, 91%)
as a colorless oil; [Found: M+, 294.1077. C15H18O6 requires M,
294.1103]; H (400 MHz, CDCl3) 1.54 (3H, s), 1.57 (3H, s), 3.35
(1H, ddd, J 3.2, 6.3 and 8.6), 3.78 (1H, dd, J 8.7 and 9.5), 3.96 (1H,
dd, J 6.3 and 9.5), 4.57 (1H, d, J 12.1), 4.61 (1H, d, J 12.1), 4.73
(1H, d, J 3.2) and 7.26–7.38 (5H, m); C (100 MHz, CDCl3) 26.0
(q), 26.3 (q), 46.7 (d), 65.8 (t), 71.3 (d), 73.2 (t), 111.2 (s), 127.6 (d),
127.8 (d), 128.4 (d), 137.4 (s), 171.9 (s) and 174.3 (s).
Methyl (4R,5S,2E)-4,5-epoxyhexenoate 12a
To a solution of the mesylate 11c (770 mg, 2.19 mmol) in THF
(20 cm3) were added tetra-n-butylammmonium fluoride (TBAF)
(1.0 M in THF, 4.38 cm3, 4.38 mmol) at 0 °C, and the mixture
was stirred at room temperature for 3 h. The reaction mixture was
quenchedbyadditionofsaturatedaqueousNH4Cl,andextractedwith
ether. The organic layer was washed with brine, dried, and concen-
trated. The residue was purified by chromatography (hexane–ether,
5/1) to afford 12a (285 mg, 92%) as a colorless oil; bp 80–83 °C at
60 mmHg (Kugelrohr); []D31 −66.5 (c, 0.9, CHCl3); max(film)/cm−1
2999, 2955, 1724, 1661, 1437 and 1252; H (300 MHz, CDCl3) 1.30
(3H, d, J 5.3), 3.32 (1H, dq, J 4.4 and 5.4), 3.52 (1H, ddd, J 1.0, 4.4
and 6.6), 3.76 (3H, s), 6.14 (1H, dd, J 1.0 and 15.9) and 6.83 (1H,
dd, J 6.6 and 15.9); C (75 MHz, CDCl3) 25.6 (q), 51.7 (q), 55.2 (d),
55.3 (d), 124.9 (d), 142.1 (d) and 166.0 (s).
(4R,5S,2E)- and (4S,5R,2E)-4,5-Epoxyhexenoic acid, 13a and
13b
To a solution of the ester 12a (15.4 mg, 0.108 mmol) in THF (4 cm3)
was added potassium trimethylsilanolate (Me3SiOK) (17 mg,
0.12 mmol), the mixture was stirred for 3 h. Aqueous citric acid
(0.5 M, 1 cm3) was added, and after a further 1.5 h, the mixture was
washed with water, dried, and concentrated under reduced pressure.
The residue was purified by chromatography (hexane–ether, 1/3) to
give 13a (11.3 mg, 82%) as white microcrystalline; mp 93–93.5 °C
[hygroscopic]. []D21 −70.0 (c, 0.50, CHCl3); [Found: (M − H)+,
127.0390. C6H7O3 requires M − H, 127.0394]; max(nujol)/cm−1
1717, 1456, 1377 and 1285; H (300 MHz, CDCl3) 1.31 (3H, dd, J
1.1 and 5.3), 3.36 (1H, ddq, J 1.1, 4.4 and 5.3), 3.55 (1H, ddd, J 0.9,
Lactone 6a
To a solution of 10 (328 mg, 1.12 mmol) in dry THF (10 cm3) was
added BH3–DMS complex (1.0 M in THF, 0.11 cm3, 1.17 mmol) at
0 °C, and the mixture was stirred at room temperature for 21 h.After
being acidified (pH 1) with 1.0 M hydrochloric acid, the mixture
was stirred for 5 h and diluted with water, and extracted with ether.
The extract was washed with saturated aqueous sodium thiosulfate
and brine, dried, and concentrated under reduced pressure. The resi-
due was purified by chromatography (hexane–ethyl acetate, 3:1) to
give 6a (151.5 mg, 61%) as white needles.
2 7 8 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 7 7 – 2 7 8 5

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max(film)/cm−1 1778, 1713, 1651, 1391 and 1362; H (300 MHz,
4.4 and 6.4), 6.15 (1H, d, J 15.6) and 6.94 (1H, ddd, J 0.9, 6.4 and
15.6); C (75 MHz, CDCl3) 13.1 (q), 55.1 (d), 55.5 (d), 124.5 (d),
144.6 (d) and 170.5 (s).
Compound 13b was obtained from 11b (enantiomer of 11a) in
53% yield (four steps) as white microcrystalline; mp 94–95.5 °C;
[]D24 +72.8 (c, 0.5, CHCl3).

CDCl3) 1.30 (3H, d, J 5.5), 1.51–1.80 (6H, m), 2.97–3.05 (1H, m),
3.32 (1H, dq, J 4.4 and 5.5), 3.51 (1H, ddd, J 0.9, 4.4 and 6.6),
3.55–3.59 (1H, m), 3.78–3.85 (1H, m), 4.32 (1H, dd, J 2.9 and 9.9),
4.34–4.44 (2H, m), 4.45 (1H, dd, J 4.5 and 11.5), 4.64 (1H, d, J 7.8),
5.09 (1H, dd, J 2.2 and 3.8), 6.11 (1H, dd, J 0.9 and 15.7) and 6.80
(1H, dd, J 6.6 and 15.7); C (75 MHz, CDCl3) 12.8 (q), 18.9 (t), 24.9
(t), 29.8 (t), 38.5 (d), 54.9 (d), 55.2 (d), 61.2 (t), 62.6 (t), 67.5 (t),
69.1 (d), 98.0 (d), 124.2 (d), 142.8 (d), 164.8 (s) and 174.2 (s).
(4R,5S,2E)- and (4S,5R,2E)-4,5-Epoxyhexenal, 14a and 14b
To a solution of 12b (bp 85–87 °C/60 mmHg (Kugelrohr),
[]D29 −36.8 (c, 1.0, CHCl3) (48.6 mg, 0.26 mmol) in dry ether
(4 cm3) was added DIBAL-H (1.5 M in toluene, 0.39 cm3,
0.58 mmol) at −78 °C for 15 min. After the reaction mixture was
quenched by addition of water, the precipitate was removed by
filtration through Celite. The filtrate was washed with brine, dried,
and concentrated. The residue was purified by chromatography
(hexane–ether, 8:1) to give 14a (16 mg, 54%) as a colorless oil;
bp 70–75 °C/45 mmHg (Kugelrohr); []D26 −82.5 (c, 1.5, CHCl3);
H (300 MHz, CDCl3) 1.32 (3H, d, J 5.5), 3.41 (1H, dq, J 4.4 and
5.5), 3.63 (1H, ddd, J 0.9, 4.4 and 6.4), 6.40 (1H, ddd, J 0.9, 7.7
and 15.8), 6.80 (1H, dd, J 6.4 and 15.8) and 9.60 (1H, d, J 7.7); C
(75 MHz, CDCl3) 13.1 (q), 55.1 (d), 55.7 (d), 135.3 (d), 150.1 (d)
and 192.2 (d).
Compound 15d. A colorless oil, []D25 −121.0 (c, 1.04, CHCl3);
[Found: (M + H)+, 327.1450. C16H23O7 requires M + H, 327.1445];
H (300 MHz, CDCl3) 1.29 (3H, d, J 5.5), 1.55–1.82 (6H, m),
2.90–2.99 (1H, m), 3.34 (1H, dq, J 4.5 and 5.5), 3.54 (1H, dd, J 4.5
and 6.4), 3.78–3.85 (1H, m), 4.07 (1H, t, J 9.1), 4.34 (1H, dd, J 6.3
and 11.7), 4.42 (1H, d, J 9.4), 4.43 (1H, dd, J 3.9 and 11.7), 4.47
(1H, t, J 9.1), 5.16 (1H, br. s), 6.14 (1H, d, J 15.8) and 6.86 (1H, dd,
J 6.4 and 15.8); C (75 MHz, CDCl3) 13.1 (q), 19.0 (t), 25.2 (t), 30.1
(t), 41.7 (d), 55.1 (d), 55.5 (d), 62.1 (t), 62.6 (t), 67.1 (t), 70.8 (d),
98.0 (d), 124.0 (d), 143.4 (d), 165.0 (s) and 174.5 (s).
(2S,3S,4′R,5′S,2′E)-3-(4′,5′-Epoxy-1′-oxohexenyloxymethyl)-2-
hydroxy-4-butanolide 2a: lactone II
Compound 14b was obtained from tert-butylsorbate in 39% yield
(five steps); ]D23 +83.0 (c, 1.7, CHCl3).
A solution of 15a (15.8 mg, 0.048 mmol) in acetic acid (2 cm3),
THF (1 cm3), and water (0.5 cm3) was stirred at 50 °C for 3 h. After
concentration under reduced pressure, the residue was purified by
chromatography (hexane–ethyl acetate, 1:1) to give 2a (7.4 mg,
63%) as white needles; mp 74–75 °C; []D21 +38.8 (c, 0.1, MeOH);
H (300 MHz, DMSO) 1.23 (3H, d, J 5.5), 2.83–2.91 (1H, m), 3.33
(1H, dq, J 4.4 and 5.5), 3.62 (1H, ddd, J 0.8, 4.4 and 7.1), 4.13 (1H,
dd, J 5.4 and 11.0), 4.19 (1H, dd, J 2.0 and 9.3), 4.27 (1H, dd, J
3.9 and 11.0), 4.33 (1H, dd, J 6.2 and 9.3), 4.56 (1H, dd, J 6.0 and
8.0), 6.12 (1H, dd, J 0.8 and 15.7), 6.13 (1H, d, J 5.9, OH) and 6.67
(1H, dd, J 7.1 and 15.7); H (300 MHz, CDCl3) 1.30 (3H, d, J 5.5),
2.95–3.03 (m, 1H), 2.99 (1H, br.s, OH), 3.33 (1H, dq, J 4.6 and 5.5),
3.51 (1H, ddd, J 0.9, 4.4 and 6.6), 4.33 (1H, dd, J 5.5 and 11.7),
4.35–4.43 (2H, m), 4.49 (1H, dd, J 3.8 and 11.7), 4.59 (1H, d, J 8.1),
6.11 (1H, dd, J 0.5 and 15.8) and 6.81 (1H, dd, J 6.4 and 15.8); C
(75 MHz, CDCl3) 13.1 (q), 38.9 (d), 55.2 (d), 55.5 (d), 61.0 (t), 67.6
(t), 67.8 (d), 124.2 (d), 143.5 (d), 165.2 (s) and 176.5 (s).
(2S,3S,4′R,5′S,2′E)- and (2S,3R,4′R,5′S,2′E)-3-(4′,5′-Epoxy-1′-
oxohexenyloxymethyl)-2-tetrahydropyranyloxy-4-butanolide,
15a and 15b
To a solution of the alcohol 8 (mixture of 8a and 8b) (121.5 mg,
0.56 mmol) and the acid 13a (60 mg, 0.47 mmol) in dry dichloro-
methane (10 cm3) were added DMAP (68.7 mg, 0.56 mmol)
and DCC (116.0 mg, 0.56 mmol) at 0 °C, and the mixture was
stirred at room temperature for 24 h. After concentration under
reduced pressure, the residue was purified by chromatography
(hexane–ethyl acetate, 2:1) to give 15a (117.5 mg, 77%) and 15b
(16.8 mg, 11%).
Compound 15a. A colorless oil, []D25 −66.0 (c, 0.89, CHCl3);
[Found: (M + H)+, 327.1448. C16H23O7 requires M + H, 327.1445];
H (300 MHz, CDCl3) 1.30 (3H, d, J 5.3), 1.51–1.81 (6H, m),
2.94–2.96 (1H, m), 3.32 (1H, dq, J 4.4 and 5.3), 3.51 (1H, dd, J 4.4
and 6.4), 3.50–3.55 (1H, m), 3.75–3.78 (1H, m), 4.29–4.40 (3H, m),
4.48 (1H, dd, J 4.4 and 11.6), 4.63 (1H, d, J 7.7), 5.10 (1H, dd, J 2.3
and 4.3), 6.08 (1H, d, J 15.6) and 6.82 (1H, dd, J 6.4 and 15.6); C
(75 MHz, CDCl3) 13.0 (q), 19.1 (t), 25.1 (t), 30.0 (t), 38.8 (d), 55.2
(d), 55.4 (d), 61.3 (t), 62.9 (t), 67.7 (t), 69.3 (d), 98.2 (d), 124.4 (d),
143.1 (d), 165.1 (s) and 174.4 (s).
(2S,3R,4′R,5′S,2′E)-3-(4′,5′-Epoxy-1′-oxohexenyloxymethyl)-
2-hydroxy-4-butanolide 2b
In the same manner as described above, 15b was converted to 2b in
69% yield as a colorless oil; []D21 −78.5 (c, 0.11, MeOH); [Found:
M+, 242.0779. C11H14O6 requires M, 242.0790]; H (300 MHz,
CDCl3) 1.30 (3H, d, J 5.3), 2.83–2.96 (1H, m), 3.35 (1H, dq, J 4.5
and 5.3), 3.55 (1H, ddd, J 0.9, 4.5 and 6.3), 4.00 (1H, br.s, OH), 4.07
(1H, dd, J 9.7 and 9.9), 4.37 (1H, d, J 9.8), 4.36 (1H, dd, J 3.8 and
10.2), 4.45 (1H, dd, J 4.3 and 11.6), 4.47 (1H, dd, J 7.9 and 9.9),
6.15 (1H, dd, J 0.9 and 15.7) and 6.87 (1H, dd, J 6.3 and 15.7); C
(75 MHz, CDCl3) 13.0 (q), 43.1 (d), 55.1 (d), 55.5 (d), 61.9 (t), 66.9
(d), 68.8 (t), 124.0 (d), 143.4 (d), 165.2 (s) and 176.7 (s).
Compound 15b. A colorless oil, []D25 −170.5 (c, 1.10, CHCl3);
[Found: (M + H)+, 327.1459. C16H23O7 requires M + H, 327.1445];

max(film)/cm−1 1790, 1724, 1655 and 1391; H (300 MHz, CDCl3)
1.30 (3H, d, J 5.5), 1.52–1.83 (6H, m), 2.87–2.99 (1H, m), 3.34 (1H,
dq, J 4.4 and 5.5), 3.53 (1H, ddd, J 1.1, 4.4 and 6.2), 3.56–3.58 (1H,
m), 3.77–3.85 (1H, m), 4.08 (1H, t, J 9.3), 4.33 (1H, dd, J 6.4 and
11.7), 4.43 (1H, d, J 9.3), 4.44 (1H, dd, J 4.0 and 11.7), 4.48 (1H,
dd, J 6.3 and 9.3), 5.16 (1H, dd, J 2.3 and 3.5), 6.14 (1H, dd, J 1.1
and 15.8) and 6.86 (1H, dd, J 6.4 and 15.8); C (75 MHz, CDCl3)
13.0 (q), 18.9 (t), 25.1 (t), 30.0 (t), 41.6 (d), 55.0 (d), 55.4 (d), 62.0
(t), 62.5 (t), 67.0 (t), 70.7 (d), 97.9 (d), 124.0 (d), 143.3 (d), 164.9
(s) and 174.5 (s).
(2S,3S,4′S,5′R,2′E)-3-(4′,5′-Epoxy-1′-oxohexenyloxymethyl)-2-
hydroxy-4-butanolide 2c
In the same manner as described above, 15c was converted to 2c in
58% yield as white microcrystalline; mp 94–95 °C; []D20 +121.0
(c, 0.11, MeOH); [Found: M+, 242.0785. C11H14O6 requires M,
242.0790]; H (300 MHz, DMSO) 1.23 (3H, d, J 5.5), 2.82–2.91
(1H, m), 3.33 (1H, dq, J 4.4 and 5.5), 3.61 (1H, dd, J 4.4 and 7.1),
4.15 (1H, dd, J 5.3 and 11.2), 4.20 (1H, dd, J 2.0 and 9.3), 4.25
(1H, dd, J 3.8 and 11.2), 4.34 (1H, dd, J 6.2 and 9.3), 4.56 (1H,
dd, J 5.7 and 7.9), 6.12 (1H, d, J 5.7, OH), 6.13 (1H, d, J 15.6)
and 6.66 (1H, dd, J 7.1 and 15.6); H (300 MHz, CDCl3) 1.31 (3H,
d, J 5.5), 2.95–3.03 (1H, m), 3.18 (1H, br s, OH), 3.33 (1H, dq, J
4.6 and 5.3), 3.51 (1H, ddd, J 0.9, 4.4 and 6.5), 4.34 (1H, dd, J 5.3
and 11.4), 4.34–4.42 (2H, m), 4.46 (1H, dd, J 3.8 and 11.4), 4.60
(1H, d, J 8.0), 6.11 (1H, dd, J 0.9 and 15.7) and 6.80 (1H, dd, J 6.5
(2S,3S,4′S,5′R,2′E)- and (2S,3R,4′S,5′R,2′E)-3-(4′,5′-Epoxy-1′-
oxohexenyloxymethyl)-2-tetrahydropyranyloxy-4-butanolide,
15c and 15d
In the same manner as described above, the reaction of 8 with 13b
gave 15c (128 mg, 54%) and 15d (55.6 mg, 24%).
Compound 15c. A colorless oil, []D26 −4.3 (c, 1.10, CHCl3);
[Found: (M + H)+, 327.1465. C16H23O7 requires M + H, 327.1445];
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 7 7 – 2 7 8 5
2 7 8 3

View Article Online
(2R,3S,4′S,5′R,2′E)-2-(4′,5′-Epoxyhexen)oyl-2-hydroxy-3-
and 15.7); C (75 MHz, CDCl3) 13.1 (q), 38.9 (d), 55.2 (d), 55.5
(d), 61.1 (t), 67.5 (d), 67.8 (t), 124.3 (d), 143.5 (d), 165.1 (s) and
176.6 (s).
hydroxymethyl-4-butanolide 1a and (2R,3S,4′S,5′R,2′E)-2-
(4′,5′-epoxyhexen)oyl-2-hydroxy-3-tert-butyldimethylsilyloxy-
4-butanolide 19a
(2S,3R,4′S,5′R,2′E)-3-(4′,5′-Epoxy-1′-oxohexenyloxymethyl)-
2-hydroxy-4-butanolide 2d
A solution of 18a (27.5 mg, 0.062 mmol) in acetic acid (2 cm3),
THF (1 cm3), and water (0.5 cm3) was stirred at 40 °C for 14 h.After
concentration under reduced pressure, the residue was purified by
chromatography (hexane–ethyl acetate, 1:1) to give 19a (10.7 mg,
48%) and 1a (1.7 mg, 11%).
In the same manner as described above, 15d was converted to
2d in 43% yield as a colorless oil; []D21 −23.6 (c, 0.19, MeOH);
[Found: M+, 242.0771. C11H14O6 requires M, 242.0790]; H
(300 MHz, CDCl3) 1.30 (3H, d, J 5.5), 2.82–2.95 (1H, m), 3.35
(1H, dq, J 4.5 and 5.5), 3.54 (1H, ddd, J 0.9, 4.5 and 6.2), 4.07
(1H, dd, J 9.4 and 10.2), 4.33 (1H, d, J 10.3), 4.38 (1H, dd, J
6.0 and 11.7), 4.43 (1H, dd, J 5.4 and 11.7), 4.47 (1H, dd, J 8.4
and 10.2), 6.15 (1H, dd, J 0.9 and 15.6) and 6.88 (1H, dd, J 6.2
and 15.6); C (75 MHz, CDCl3) 13.1 (q), 43.2 (d), 55.1 (d), 55.5
(d), 61.8 (t), 66.8 (d), 68.9 (t), 124.0 (d), 143.6 (d), 165.2 (s)
and 176.3 (s).
Compound 19a. A colorless oil, []D24 +55.8 (c, 0.145,
CHCl3); [Found: (M + H)+, 357.1739. C17H29O6Si requires M + H,
357.1733]; H (300 MHz, CDCl3) 0.06 (6H, s), 0.86 (9H, s), 1.29
(3H, d, J 5.3), 2.98–3.02 (1H, m), 3.36 (1H, dq, J 4.4 and 5.3), 3.57
(1H, ddd, J 0.8, 4.4 and 5.3), 3.80 (1H, dd, J 5.1 and 10.2), 3.85
(1H, dd, J 4.4 and 10.2), 4.17 (1H, br s, OH), 4.26 (1H, dd, J 5.0
and 9.0), 4.55 (1H, dd, J 7.4 and 9.0), 6.92 (1H, d, J 15.6) and 7.00
(1H, dd, J 5.5 and 15.6).
(2R,3S,4′S,5′R,2′E)- and (2S,3S,4′S,5′R,2′E)-2-(4′,5′-Epoxy-
hexen)oyl-2-tetrahydro-pyranyloxy-3-tert-butyldimethyl-
silyloxy-4-butanolide, 18a and 18b
Compound 1a (butalactin).Acolorless oil, []D28 +47.2 (c, 0.37,
MeOH); [Found: (M + H)+, 243.0859. C11H15O6 requires M + H,
243.0869]; H (400 MHz, CDCl3) 1.28 (3H, d, J 5.4), 2.90–3.00
(1H, m), 3.37 (1H, dq, J 4.4 and 5.4), 3.57 (1H, ddd, J 1.0, 4.6 and
6.2), 3.87 (2H, br. s), 4.39 (1H, dd, J 4.9 and 9.0), 4.53 (1H, br. s),
4.57 (1H, dd, J 7.8 and 9.0), 6.80 (1H, dd, J 1.0 and 15.4) and 7.07
(1H, dd, J 6.2 and 15.4); C (100 MHz, CDCl3) 13.2 (q), 43.9 (d),
55.5 (d), 56.1 (d), 60.0 (t), 68.9 (t), 81.6 (s), 124.9 (d), 145.8 (d),
173.4 (s) and 192.8 (s).
To a solution of lithium diisopropylamide, prepared from
diisopropylamine (0.17 cm3, 1.18 mmol) in dry THF (10 cm3)
and n-butyllithum (1.6 M in hexane, 0.73 cm3, 1.18 mmol), was
added a solution of the lactone 9a (156 mg, 0.47 mmol) in dry
THF (1 cm3) at −78 °C, and the mixture was stirred for 45 min.
The aldehyde 14b (65 mg, 0.58 mmol) and HMPA (0.05 cm3) in
dry THF (1 cm3) was added over 5 min, and stirred at −78 °C
for 1.5 h. The reaction mixture was quenched by addition of
saturated aqueous NH4Cl (2 cm3) at −78 °C, and extracted with
ethyl acetate. The extract was washed with water and brine,
dried, and concentrated under reduced pressure. The residue was
purified by chromatography (hexane–ethyl acetate, 20 : 1) to give
17a as an oil. A mixture of 17a and Dess–Martin periodinane
(400 mg, 0.95 mmol) in dichloromethane (15 cm3) was stirred
at 0 °C for 1 h. The reaction mixture was quenched by addition
of saturated aqueous NaHCO3 (10 cm3) and saturated aqueous
sodium thiosulfate (10 cm3). After removal of the precipitate, the
filtrate was extracted with dichloromethane. The organic layer
was washed with water and brine, dried, and concentrated under
reduced pressure. The residue was purified by chromatography
(hexane–ethyl acetate, 4/1) to give 18a (143.8 mg, 69%) and 18b
(12.0 mg, 6%).
(2S,3S,4′S,5′R,2′E)-2-(4′,5′-Epoxyhexen)oyl-2-hydroxy-3-
tert-butyldimethylsilyloxy-4-butanolide 19b
In the same manner as described above, 18b was converted to 19b in
12% yield as a single product: a colorless oil; []D23 −2.76 (c, 0.17,
CHCl3); [Found: (M + H)+, 357.1744. C17H29O6Si requires M + H,
357.1733]; H (400 MHz, CDCl3) 0.02 (6H, s), 0.86 (9H, s), 1.30
(3H, d, J 5.4), 2.98–3.03 (1H, m), 3.36 (1H, dq, J 4.5 and 5.4), 3.53
(1H, ddd, J 0.8, 4.5 and 5.8), 3.73 (1H, dd, J 6.1 and 13.9), 3.76 (1H,
dd, J 5.8 and 13.9), 3.95 (1H, br. s, OH), 4.31 (1H, dd, J 9.4 and
10.3), 4.53 (1H, dd, J 8.5 and 10.3), 6.86 (1H, dd, J 0.8 and 15.5)
and 6.94 (1H, dd, J 6.1 and 15.5); C (100 MHz, CDCl3) −5.7 (q),
13.3 (q), 18.1 (s), 25.7 (q), 50.6 (d), 55.5 (d), 55.9 (d), 58.9 (t), 67.6
(t), 82.2 (s), 127.0 (d), 144.0 (d), 174.2 (s) and 193.9 (s).
Rearrangement of 19a and 19b using TBAF
Compound 18a. A colorless oil, []D23 +19.9 (c, 0.93, CHCl3);
[Found: (M + H)+, 441.2325. C22H37O7Si requires M + H,
441.2309]; H (300 MHz, CDCl3) 0.03 (6H, s), 0.86 (9H, s), 1.29
(3H, d, J 5.4), 1.46–1.56 (6H, m), 2.81–2.87 (1H, m), 3.32 (1H,
dq, J 4.4 and 5.4), 3.40 (1H, dd, J 5.8 and 10.3), 3.52 (1H, dd, J
4.4 and 7.2), 3.82 (1H, dd, J 6.4 and 10.3), 3.80–3.91 (2H, m),
4.17 (1H, dd, J 6.0 and 9.2), 4.28 (1H, dd, J 2.8 and 9.2), 5.07
(1H, d, J 5.3), 6.88 (1H, dd, J 7.2 and 15.5) and 7.05 (1H, d, J
15.5); C (75 MHz, CDCl3) −5.6 (q), 13.4 (q), 18.1 (s), 20.6 (t),
24.9 (t), 25.9 (q), 31.3 (t), 45.1 (d), 55.7 (d), 55.8 (d), 59.8 (t),
65.0 (t), 67.5 (t), 85.1 (s), 98.1 (d), 127.9 (d), 142.1 (d), 171.6 (s)
and 192.6 (s).
To a solution of 19a (36 mg, 0.1 mmol) in THF (3 cm3) was added
TBAF (1 M in THF, 0.21 cm3) at 0 °C. After stirring for 45 min, the
reaction mixture was quenched with aqueous NH4Cl and extracted
with ethyl acetate. The extract was washed with water and brine,
dried, and concentrated under reduced pressure. The residue was
purified by chromatography (hexane–ethyl acetate, 1:1) to give
2d (5.8 mg, []D22 −20.5 (c, 0.1, MeOH) and ent-2a (3.0 mg,
1
[]D22 −35.2 (c, 0.1, MeOH). The H NMR spectra of these com-
pounds were in agreement with those of authentic samples 2d and
2a, respectively.
A similar reaction of 19b afforded 2c and ent-2b which were
identical with the authentic samples.
Compound 18b. A colorless oil, []D24 −10.9 (c, 0.75, CHCl3);
[Found: (M + H)+, 441.2315. C22H37O7Si requires M + H,
441.2309]; H (300 MHz, CDCl3) 0.02 (6H, s), 0.85 (9H, s), 1.29
(3H, d, J 5.5), 1.74–1.86 (6H, m), 3.31–3.40 (1H, m), 3.36 (1H, dq,
J 4.6 and 5.4), 3.56 (1H, dd, J 4.5 and 4.8), 3.52–3.59 (1H, m), 3.69
(1H, dd, J 7.4 and 10.4), 3.77 (1H, dd, J 5.4 and 10.4), 3.95–4.04
(1H, m), 4.21 (1H, dd, J 8.8 and 9.7), 4.46 (1H, dd, J 8.2 and 9.7),
4.86 (1H, dd, J 2.6 and 5.0), 6.88 (1H, dd, J 5.4 and 15.5) and 6.99
(1H, d, J 15.5); C (75 MHz, CDCl3) −5.65 (q), −5.63 (q), 13.4 (q),
18.1 (s), 19.9 (t), 25.0 (t), 25.7 (q), 31.2 (t), 47.1 (d), 55.71 (d), 55.73
(d), 59.6 (t), 63.7 (t), 68.4 (t), 87.7 (s), 97.4 (d), 127.7 (d), 143.1 (d),
172.3 (s) and 193.5 (s).
(2R,3S,4′S,5′R,2′E)- and (2S,3S,4′S,5′R,2′E)-2-(4′,5′-Epoxy-
hexen)oyl-2-tetrahydro-pyranyloxy-3-tert-butyldimethyl-
silyloxy-4-butanolide, 18c and 18d
The -epoxy aldehyde isomer 14a and the lactone 9a were treated
as in the synthesis of 18a and 18b to give 18c (275.1 mg, 53%) and
18d (21.2 mg, 4%).
Compound 18c. A colorless oil, []D21 −27.0 (c, 0.93, CHCl3);
[Found:(M + H)+,441.2333.C22H37O7SirequiresM + H,441.2309];
H (300 MHz, CDCl3) 0.06 (6H, s), 0.88 (9H, s), 1.29 (3H, d, J 5.5),
1.50–1.80 (6H, m), 2.76–2.82 (1H, m), 3.29–3.44 (1H, m), 3.58
2 7 8 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 7 7 – 2 7 8 5

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(1H, dd, J 4.4 and 7.1), 3.78–3.91 (2H, m), 3.81 (1H, dd, J 6.4 and
10.1), 3.87 (1H, dd, J 4.7 and 10.1), 4.17 (1H, dd, J 6.1 and 9.2),
4.28 (1H, dd, J 3.0 and 9.2), 5.15 (1H, d, J 6.0), 6.83 (1H, dd, J
7.3 and 15.8) and 7.05 (1H, d, J 15.8); C (75 MHz, CDCl3) −5.59
(q), −5.55 (q), 13.4 (q), 18.1 (s), 20.6 (t), 24.9 (t), 25.7 (q), 31.3 (t),
45.1 (d), 55.69 (d), 55.74 (d), 59.8 (t), 64.9 (t), 67.5 (t), 85.1 (s), 98.1
(d), 127.9 (d), 142.1 (d), 171.6 (s) and 192.6 (s).
solution of the crude diol in dry dichloromethane (15 cm3) was
added 2,2-dimethoxypropane (3 cm3) and camphorsulfonic acid
(10 mg), and the mixture was stirred at room temperature for
3 h. After neutralization with saturated aqueous NaHCO3, the
mixture was extracted with dichloromethane. The organic layer
was washed with water and brine, dried, and concentrated under
reduced pressure. The residue was purified by chromatography
(hexane–ethyl acetate, 2:1) to give 20 (311 mg, 67%) as white
needles; mp 70–72°; []D20 +31.4 (c, 0.10, CHCl3); [Found:
(M + H)+, 173.0821. C8H13O4 requires M + H, 173.0815];
Compound 18d. A colorless oil, [Found: (M + H)+, 441.2322.
C22H37O7Si requires M + H, 441.2309]; H (300 MHz, CDCl3)
0.02 (6H, s), 0.85 (9H, s), 1.29 (3H, d, J 5.5), 1.58–1.86 (6H, m),
3.29–3.41 (1H, m), 3.38–3.43 (1H, m), 3.36 (1H, dq, J 4.4 and 7.0),
3.55 (1H, dd, J 4.4 and 7.0), 3.65 (1H, dd, J 8.0 and 10.2), 3.78
(1H, dd, J 5.3 and 10.2), 3.94–4.01 (1H, m), 4.22 (1H, dd, J 8.8
and 9.7), 4.48 (1H, dd, J 8.2 and 9.7), 4.85 (1H, dd, J 2.7 and 5.5),
6.83 (1H, dd, J 7.1 and 15.6) and 7.05 (1H, d, J 15.6); C (75 MHz,
CDCl3) −5.7 (q), −5.6 (q), 13.4 (q), 18.1 (s), 19.9 (t), 25.0 (t), 25.7
(q), 31.2 (t), 47.1 (d), 55.71 (d), 55.73 (d), 59.6 (t), 63.7 (t), 68.4 (t),
87.7 (s), 97,4 (d), 127.7 (d), 143.1 (d), 172.3 (s) and 193.5 (s).

max(nujol)/cm−1 2980, 1717, 1653, 1393, 1367 and 1155; H
(400 MHz, CDCl3) 1.43 (3H, s), 1.50 (3H, s), 2.44–2.53 (1H, m),
3.72 (1H, dd, J 2.8 and 12.7), 4.17 (1H, dd, J 4.4 and 12.7), 4.41
(1H, dd, J 8.0 and 8.6), 4.46 (1H, d, J 5.8) and 4.49 (1H, dd, J 8.8
and 9.5); C (75 MHz, CDCl3) 20.2 (q), 27.8 (q), 33.2 (d), 56.9 (t),
67.1 (d), 68.6 (t), 98.6 (s) and 175.1 (s).
(2R,3S,4′S,5′R,2′E)-2-(4′,5′-Epoxyhexen)oyl-2-hydroxy-3-
hydroxymethyl-4-butanolide-2,5-acetonide 21
The -epoxy aldehyde 14b and the acetonide 20 were treated
as in the synthesis of 18 to give 21 in 63% yield as a colorless
oil; []D20 +80.8 (c, 0.98, CHCl3); [Found: (M + H)+, 283.1184.
C14H19O6 requires M + H, 283.1182]; max(film)/cm−1 2995,
1774, 1734, 1693, 1628, 1458 and 1202; H (300 MHz, CDCl3)
1.31 (3H, dd, J 0.6 and 5.5), 1.40 (3H, s), 1.48 (3H, s), 3.11 (1H,
m), 3.38 (1H, dq, J 4.9 and 5.5), 3.61 (1H, dd, J 4.4 and 4.9),
3.74 (1H, dd, J 4.7 and 12.5), 4.08 (1H, dd, J 5.0 and 12.5), 4.32
(1H, dd, J 5.9 and 9.0), 4.49 (1H, dd, J 8.0 and 8.8), 6.98 (1H,
dd, J 5.7 and 15.8) and 7.09 (1H, d, J 15.8); C (75 MHz, CDCl3)
12.9 (q), 24.7 (q), 26.5 (q), 33.1 (d), 55.4 (d), 56.0 (d), 57.7 (t),
68.1 (t), 79.8 (s), 100.3 (s), 126.6 (d), 143.6 (d), 171.9 (s) and
193.6 (s).
(2R,3S,4′R,5′S,2′E)-2-(4′,5′-Epoxyhexen)oyl-2-hydroxy-3-
hydroxymethyl-4-butanolide 1b and (2R,3S,4′R,5′S,2′E)-2-
(4′,5′-epoxyhexen)oyl-2-hydroxy-3-tert-butyldimethylsilyloxy-
4-butanolide 19c
To a solution of 18c (51.5 mg, 0.117 mmol) in acetic acid (4 cm3),
THF (2 cm3), and water (1 cm3) was stirred at 60 °C for 4 h, and
concentrated under reduced pressure. The residue was purified by
chromatography (hexane–ethyl acetate, 1/1) to give 1b (8.0 mg,
28%) and 19c (8.5 mg, 20%).
Compound 1b. A colorless oil, []D19 +14.1 (c, 0.66, MeOH);
[Found: (M + H)+, 243.0861. C11H15O6 requires M + H, 243.0869];
H (400 MHz, CDCl3) 1.27 (3H, d, J 5.6), 2.95–3.03 (1H, m), 3.39
(1H, dq, J 4.6 and 5.4), 3.61 (1H, ddd, J 1.0, 4.6 and 5.6), 3.83–3.91
(2H, m), 4.41 (1H, dd, J 5.1 and 9.3), 4.60 (1H, dd, J 7.6 and 9.3),
6.78 (1H, dd, J 1.0 and 15.4) and 7.10 (1H, dd, J 5.6 and 15.4); C
(100 MHz, CDCl3) 13.0 (q), 43.9 (d), 55.5 (d), 56.3 (d), 59.9 (t),
68.9 (t), 81.7 (s), 124.7 (d), 145.6 (d), 173.5 (s) and 193.0 (s).
Butalactin 1a
A solution of 21 (17 mg, 0.06 mmol) in acetic acid (2 cm3), THF
(1 cm3) and water (0.5 cm3) was stirred at 40 °C for 48 h. After
cooling the solvents were evaporated under reduced pressure
to give an oil. The residue was purified by chromatography
(hexane–ethyl acetate, 1 : 2) to afford 1a (9.7 mg, 66%) as a
colorless oil.
Compound 19c. A colorless oil, []D23 +11.5 (c, 0.43, CHCl3);
[Found: (M + H)+, 357.1734. C17H29O6Si requires M + H,
357.1733]; H (300 MHz, CDCl3) 0.06 (6H, s), 0.86 (9H, s), 1.29
(3H, d, J 5.5), 2.99–3.01 (1H, m), 3.35 (1H, dq, J 4.4 and 5.5), 3.58
(1H, dd, J 4.4 and 5.9), 3.81 (1H, dd, J 5.0 and 10.2), 3.86 (1H, dd,
J 4.2 and 10.2), 4.14 (1H, br. s, OH), 4.26 (1H, dd, J 4.8 and 9.0),
4.55 (1H, dd, J 7.3 and 9.0), 6.90 (1H, d, J 15.5) and 7.03 (1H, dd,
J 5.9, 15.5); C (75 MHz, CDCl3) −5.8 (q), 13.1 (q), 18.0 (s), 25.6
(q), 44.4 (d), 55.6 (d), 56.0 (d), 60.4 (t), 69.2 (t), 81.3 (s), 125.7 (d),
144.6 (d), 173.4 (s) and 193.1 (s).
Acknowledgements
T. Ueki thanks Osaka City University for the OCU Grant for
Graduate Course Students.
References
1 S. Chatterjee, E. K. S. Vijayakumar, C. M. M. Franco, U. P. Borde,
J. Blumbach, B. N. Ganguli, H.-W. Fehlhaber and H. Kogler, Tetrahe-
dron Lett., 1991, 32, 141.
(2S,3S,4′R,5′S,2′E)-2-(4′,5′-Epoxyhexen)oyl-2-hydroxy-3-tert-
2 H.-J. Schiewe and A. Zeeck, J. Antibiot., 1999, 52, 635.
3 (a) E. M. Kleiner, S. A. Pilner, V. S. Soifer, V. V. Onoprienko, T. A.
Balasheva, B. V. Rozynov and S. A. Khoklov, Bioorg. Khim., 1976,
2, 1142; K. Mori, Tetrahedron, 1983, 39, 3107; J. M. Crawforth,
J. Fawcett and B. J. Rawlings, J. Chem. Soc., Perkin Trans. I, 1998,
1721; (b) Y. Yamada, K. Sugamura, K. Kondo, M. Yanagimoto and
H. Okada, J. Antibiotics, 1987, 40, 496; K. Mori and N. Chiba, Liebigs
Ann. Chem., 1990, 31.
4 T. Ueki, Y. Morimoto and T. Kinoshita, Chem. Commun., 2001,
1820.
5 (a) D. Seebach, J. Aebi and D. Wasmuth, Org. Synth., 1990, 153, Coll.
Vol. VII; (b) T. Ueki, D. Ichinari, K. Yoshihara, Y. Morimoto and
T. Kinoshita, Tetrahedron Lett., 1998, 39, 667.
butyldimethylsilyloxy-4-butanolide 19d
In the same manner as described above, 18d was converted to 19d in
27% yield as a colorless oil; []D25 −42.3 (c, 0.10, CHCl3); [Found:
(M + H)+, 357.1756. C17H29O6Si requires M + H, 357.1733]; H
(400 MHz, CDCl3) 0.02 (6H, s), 0.86 (9H, s), 1.27 (3H, d, J 5.5),
2.98–3.03 (1H, m), 3.35 (1H, dq, J 4.4 and 5.3), 3.55 (1H, ddd, J
0.8, 4.4 and 5.1), 3.71 (1H, dd, J 6.2 and 10.6), 3.77 (1H, dd, J 5.9
and 10.6), 3.98 (1H, br s, OH), 4.34 (1H, dd, J 9.2 and 10.6), 4.53
(1H, dd, J 8.6 and 10.0), 6.81 (1H, dd, J 0.8 and 15.4) and 6.96 (1H,
ddd, J 1.0, 5.9 and 15.4); C (75 MHz, CDCl3) −5.7 (q), 13.3 (q),
18.0 (s), 25.7 (q), 50.6 (d), 55.5 (d), 55.9 (d), 58.9 (t), 67.6 (t), 82.2
(s), 127.0 (d), 144.0 (d), 172.4 (s) and 193.9 (s).
6 K. Takabe, M. Tanaka, M. Sugimoto, T. Yamada and H. Yoda,
Tetrahedron: Asymmetry, 1992, 3, 1385.
7 D. Xu, G. A. Crispino and K. B. Sharpless, J. Am. Chem. Soc., 1992,
114, 7570.
(2S,3S)-2-Hydroxy-3-hydroxymethyl-4-butanolide-2,5-
8 D. M. Jones, B. Nilsson and M. Szelke, J. Org. Chem., 1993, 58,
2286.
9 E. D. Laganis and B. L. Chenard, Tetrahedron Lett., 1984, 25, 5831.
10 K. Tsuda, E. Ohki and S. Nozoe, J. Org. Chem., 1963, 28, 783.
acetonide 20
The benzyl lactone 6a (596 mg, 2.68 mmol) was treated in ethyl
acetate as in the preparation of 8 to give an oil of the diol. To a
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 7 7 – 2 7 8 5
2 7 8 5