Synthesis of diastereo- and enantiomerically pure anti-3-methyl-1,4- pentanediol via lipase catalysed acylation

Article abstract of DOI:10.1016/j.tetasy.2005.01.043

Racemic trans-4,5-dimethylhydrofuran-2(3H)-one was synthesised from 5-methyl-furan-2(3H)-one, (α-angelica lactone). The key reaction in the synthesis was the 1,4-conjugate addition of an organocuprate to 5-methylfuran-2(5H)-one (β-angelica lactone). Different types of organocuprates were tested with the highest anti:syn ratio of 99.4:0.6 being obtained by the use of a Gilman organocuprate reagent. The enantioselective acylation of racemic 3-methyl-pentan-1,4-diol, catalysed by a variety of lipases in organic media, was investigated. The highest enantioselectivity (E >400) was obtained when Novozyme 435 was used as the catalyst at a water activity of a_w ～ 0. Thus, both enantiomers, (3S,4R)- and (3R,4S)-3-methyl- pentan-1,4-diol, were obtained in very high diastereomeric (>99% de) and enantiomeric purities (>99.8% and >97.4% ee, respectively).

Full text of DOI:10.1016/j.tetasy.2005.01.043

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1355–1360
Synthesis of diastereo- and enantiomerically pure
anti-3-methyl-1,4-pentanediol via lipase catalysed acylation
Mona Lindstro¨m,a Erik Hedenstro¨m,a,* Sandrine Bouilly,a
Kelly Veloniab,ꢀ and Ioulia Smonoub
aChemistry, Department of Natural Sciences, Mid Sweden University, SE-851 70 Sundsvall, Sweden
bDepartment of Chemistry, University of Crete, 71409 Heraklion, Crete, Greece
Received 21 December 2004; accepted 31 January 2005
Abstract—Racemic trans-4,5-dimethylhydrofuran-2(3H)-one was synthesised from 5-methyl-furan-2(3H)-one, (a-angelica lactone).
The key reaction in the synthesis was the 1,4-conjugate addition of an organocuprate to 5-methylfuran-2(5H)-one (b-angelica lac-
tone). Different types of organocuprates were tested with the highest anti:syn ratio of 99.4:0.6 being obtained by the use of a Gilman
organocuprate reagent. The enantioselective acylation of racemic 3-methyl-pentan-1,4-diol, catalysed by a variety of lipases in
organic media, was investigated. The highest enantioselectivity (E >400) was obtained when Novozyme 435 was used as the catalyst
at a water activity of aw ꢀ 0. Thus, both enantiomers, (3S,4R)- and (3R,4S)-3-methyl-pentan-1,4-diol, were obtained in very high
diastereomeric (>99% de) and enantiomeric purities (>99.8% and >97.4% ee, respectively).
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Our earlier work7 prompted us to develop a new syn-
thetic approach for the preparation of enantiomerically
pure 3-methyl-pentane-1,4-diol, a potential precursor
for the direct synthesis of threo-isomer of pine sawfly
sex pheromones.
In the northern hemisphere some pine sawfly species are
severe pests on pines.1 The sex pheromones most of the
pine sawfly species employ, are esters of erythro-
(2S,3S,7S)- or threo-(2S,3R,7R)-3,7-dimethyl-2-penta-
decanol (diprionol).2,3 Lately, several structurally similar
sex pheromone precursor alcohols have been identified in
the females of other pine sawfly species.4–6 In fact the
structures identified to date are basically methyl-branched
long-chain 3-methyl-2-alcohols. Our previous long-stand-
ing interest in the synthesis of structurally similar com-
pounds led us to develop a synthetic route as shown in
Scheme 1. Elaboration of D- or L-tartaric acid, after a
few steps leads to cis-4,5-dimethylhydrofuran-2(3H)-
one, a key intermediate in the synthesis of the erythro pine
sawfly sex pheromone. However, the disadvantage of this
method for the preparation of the other diastereomer of
this pheromone, namely the threo compound, is evident
in Scheme 1 in that the synthetic methodology requires
at first the synthesis of the erythro compound, which sub-
sequently leads to the threo compound.7
2. Results and discussion
Our previous experience from the synthetic studies of 3-
methyl-2-pentanols (precursors of pine sawfly sex phero-
mones) and targeting racemic anti-3-methyl-pentane-
1,4-diol led us to select a-angelica lactone 1 as the pre-
cursor. Thus, the commercially available and inexpen-
sive lactone 1 was isomerised to b-angelica lactone 2 in
the presence of triethylamine under reflux conditions
(Scheme 2). After 40 min, the reaction mixture
was cooled and compound 2 obtained in 50% isolated
yield.8
However, gas chromatographic analysis showed that the
thermodynamic equilibrium is achieved after a period of
17 h. Therefore, a better chemical yield of compound 2
can be obtained after prolonged reflux of the reaction
mixture.
*
Corresponding author. Tel.: +46 60 148729; fax: +46 60 148802;
e-mail: erik.hedenstrom@miun.se
ꢀ Present address: Department of Organic Chemistry, University of
Geneva, CH-1211 Geneva 4, Switzerland.
Our next target was to prepare stereochemically pure
trans-4,5-dimethylhydrofuran-2(3H)-one 3. The high
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.043

1356
M. Lindstro¨m et al. / Tetrahedron: Asymmetry 16 (2005) 1355–1360
O
OH
OH
HOOC
COOH
*
R
R
*
O
*
*
*
H3C
*
H3C
OH
HO
*
*
CH3
CH3
CH3
H3C
threo pine sawfly
sex pheromone
erythro pine sawfly
sex pheromone
D- or L-tartaric acid
cis-3,4-dimethyl-
γ-butyrolactone
Scheme 1. Indirect synthesis of stereoisomerically pure threo pine sawfly sex pheromones through their diastereomer erythro compound.
O
O
O
OH
a
b
c
O
O
OH
O
H3C
CH3
CH3
H3C
H3C
H3C
1
trans-3
rac-4
2
Scheme 2. Synthesis of racemic anti-3-methyl-pentane-1,4-diol, rac-4. Reagents and conditions: (a) Et3N, Dx; (b) CuI, CH3Li, Et2O, ꢁ78 ꢁC;
(c) LiAlH4, Et2O.
anti:syn ratio for compound trans-3 was a crucial struc-
tural demand. For this purpose the 1,4-conjugate addi-
tion of organocuprates to b-angelica lactone 2 was
studied. These results are summarised in Table 1.
afforded an excellent stereoselectivity of an anti:syn ratio
of 99.4:0.6, accompanied by a rather low 44% conver-
sion (entry 5, Table 1). To improve the conversion,
1 equiv of trimethylsilyl chloride (TMSCl) was added
to the previous reaction mixture. It is known that
TMSCl enhances the reaction rate and the product yield
of 1,4-conjugated organocuprate additions.11–13 We also
observed an improvement in the yield, but to our disap-
pointment, the anti:syn ratio was decreased to a 76:24
ratio (entry 6). Finally, an increase in the amount of
the organocuprate used (CH3)2CuLi from 2 to 4 equiv14
led to higher conversion (81%, entry 7, Table 1), accom-
panied by a slight decrease in the anti:syn selection of
97.4:2.6. The observed selectivity and conversion of this
reaction, when taken together, exhibited the best case
among the surveyed organocuprates and was used in
the next step of the synthesis. Trace amounts (2.6%) of
the diastereoisomer cis-3,4-dimethyl-c-butyrolactone
were easily removed by liquid chromatography
(MPLC). Thus, under these experimental conditions,
1.12 g (48% yield) of the racemic lactone trans-3 was
isolated and fully characterised with an excellent
diastereomeric and chemical purity. Reduction of
trans-3 with LiAlH4 afforded the racemic 3-methylpen-
tan-1,4-diol, rac-4, in near quantitative yield.
To achieve a high anti:syn ratio, the reaction of a steri-
cally demanding mixed organocuprate was first
screened. For this purpose, both reagents, CH3(thienyl)-
CuLi and CH3(phenyl)CuLi, were first tested (entries
1 and 2). These organocuprates, under the reaction con-
ditions, did not react with substrate 2. Next, we tried the
cyano organocuprates taking into consideration that
these cuprates,9 at least in some cases, are more reactive
than the corresponding simple organocuprates. It has
been reported previously9 that the cyanide ligand of a
cyano organocuprate causes a build-up of negative
charge in the complex and thus facilitates the alkyl
group transfer. Herein, the reaction of the cyano cuprate
(CH3)2CuCNLi2 with 2 afforded a high anti:syn ratio of
99.1:0.9 (entry 3), however the product yield obtained
was poor. Furthermore, the use of a mixed cyano cup-
rate of the formula CH3(thienyl)CuCNLi2 reverses the
anti:syn ratio to 40:60 (entry 4). This interesting result
was not within the range of this synthesis and thus not
further investigated. To this end, we treated 2 with
2 equiv of a simple Gilman reagent (CH3)2CuLi using
slightly modified standard conditions to the ones used
in the synthesis of the whisky lactone.10 This reaction
Our previous work5,15 and that of others16–18 have dem-
onstrated an efficient lipase catalysed stereoselective
Table 1. Survey of 1,4-conjugate addition of organocuprates to b-angelica lactone 2
Entry
Organocuprate
Equivalentsa
Conversion (%)
anti:syn
1
2
3
4
5
6
7
CH3(thienyl)CuLi
CH3(phenyl)CuLi
(CH3)2CuCNLi2
CH3(thienyl)CuCNLi2
(CH3)2CuLi
2
None
None
ndb
—
—
2
2
99.1:0.9
40:60
2
ndb
2
44
ꢀ100
81
99.4:0.6
75.7:24.3
97.4:2.6
(CH3)2CuLi–TMSCl
(CH3)2CuLi
2:1
4
a Based on compound 2.
b Not determined.

M. Lindstro¨m et al. / Tetrahedron: Asymmetry 16 (2005) 1355–1360
OH
1357
OH
OAc
a
OH
OAc
OAc
H3C
+
H3C
H3C
CH3
CH3
CH3
rac-4
(3R,4S)-6
(3S,4R)-5
Scheme 3. Lipase catalysed enantioselective acylation of racemic anti-3-methyl-1,4-pentandiol rac-4. Lipase, vinyl acetate, t-BuOMe with controlled aw.
acylation of racemic secondary alcohols structurally
similar to rac-4. Therefore the enantioselective resolu-
tion of rac-4 was tested via an acylation reaction cata-
lysed by lipase (Scheme 3). Vinyl acetate was used as
the acyl donor in this enzymatic acylation reaction.
The screening of a number of promising lipases for high
enantiomeric preference is summarised in Table 2. With-
in a period of 1–40 h, all the lipases used in this study
showed a strong preference for the acetylation of the pri-
mary hydroxyl group of the diol rac-4. The initial test
was performed by the use of Amano PS at different ini-
tial water activities19 aw (entries 1–4). At a higher aw,
entry 1, the reaction was very slow, probably due to
the competing backward20 hydrolysis of the produced
ester. We15 and others21 have shown previously that
small amounts of water in the reaction medium substan-
tially increase the enzyme selectivity for secondary alco-
hols. When the aw was 0.12, entry 2, the reaction rate
increased while the obtained E-value22 was found as
resulting in a high enantioselectivity value of E >400.
This lipase also acylated the primary hydroxyl group
of rac-4 at the highest rate (1.5 h) among the lipases sur-
veyed in this work. At high conversion (c = 80%), entry
9, the reaction afforded the monoacetate enantiomer 6,
in good enantiomeric purity (>97% ee). In this case,
the enantiomeric purity of the remaining substrate 6
was expected to be >99%. It is interesting to note here
that in the presence of small quantities of water, the
Amano PS lipase is shown to preferably catalyse the
hydrolysis of the produced ester instead of acylating
the remaining substrate.20 This competing backwards
reaction decreases the enantiomeric excess of the
remaining substrate, in this case monoacetate 6. To min-
imise this effect, the reaction must be interrupted at con-
versions lower than 60%. This significant observation20
enables us to produce both enantiomers of diol-4 in their
enantiomerically pure forms.
˚
high as 140. Thus, we used dry conditions (4 A molecu-
2.1. Confirmation of the absolute configuration
lar sieves were added to the reaction mixture), entry 3, to
suppress further the undesired hydrolysis of the newly
formed ester and increase the reaction rate. In fact, the
reaction rate was doubled, although, the E-value de-
creased to 55.
To establish the absolute configuration and to confirm
which of the enantiomers, (3R,4S) or (3S,4R), of diol-
4 reacts faster in the lipase catalysed acylation sequence,
diester 3-methyl-pentane-1,4-diylacetate 5 was reduced
with LiAlH4 to the corresponding diol, followed by
monosilylation25 of the primary hydroxyl group to give
Next we investigated the effect of two different immobi-
lisations24 of Amano PS lipase, namely the immobilisa-
tion on tyonite and diationite (entries 4 and 5,
respectively). In these two cases, the reaction rate in-
creased substantially and both gave high enantioselecti-
vity (E >70). Lipase from Pseudomonas fluorescens, entry
6, gave a good E-value of 51 while SP 526, entry 7, gave
a very low E-value of 9. To this end, Novozyme 435,
entry 8, showed an excellent enantiomeric preference,
compound 7 (Scheme 4). The specific rotation of
20
D
½aꢂ ¼ ꢁ5:8 (c 1.88, CHCl3) was identical (within experi-
20
D
mental error) to that of ½aꢂ ¼ þ6 (c 0.11, CHCl3),
which had previously been reported25 for the (3R,4S)-7
enantiomer, with an opposite sign of specific rotation.
We therefore conclude that the (3S,4R)-4 enantiomer re-
acts faster to give diacetate (3S,4R)-5, leaving (3R,4S)-4
as the remaining substrate. This result is also in
Table 2. Lipase catalysed acylation of racemic anti-3-methyl-1,4-pentandiol, rac-4f
Entry
Enzyme
aw
0.32
0.12
Time (h)
Conversiona (%)
Eb
Monoacetate eec (%)
Diacetate eec (%)
1
2
3
4
5
6
7
8
9
Amano PS
Amano PS
Amano PS
296
269
120
17
7
42
42
44
44
43
47
42
80
nce
140
55
55
71
ndd
97
ꢀ0
67
76
93
94
Amano PS on tyonite
Amano PS on diationite
Amano PS fluorescens
SP 526
ꢀ0
ꢀ0
ꢀ0
ꢀ0
ꢀ0
ꢀ0
74
72
17
67
74
71
94
92
51
9
217
3.5
72
59
71
66
Novozyme 435
Novozyme 435
>400
nce
>99
80
>97
a Calculated according to the equation c = ees/(ees + eep).23
b Calculated according to the equation E = ln[(1 ꢁ ees)/(1 + ees/eep)]/ln[(1 + ees)/(1 + ees/eep)].22
c Measured by GC on a b-dex 120 chiral column.
d Not determined.
e Not calculated.
f
˚
General procedure: The substrate dissolved in t-BuOMe was stored for 24 h in a vessel containing LiCl satd solution or MgCl satd solution or 4 A
molecular sieves were added into the reaction vessel, depending on the water desired activity. The enzyme was added and the reaction was started by
addition of vinyl acetate.

1358
M. Lindstro¨m et al. / Tetrahedron: Asymmetry 16 (2005) 1355–1360
OAc
OH
OH
b
a
OAc
OH
OTBDPS
H3C
H3C
H3C
CH3
CH3
CH3
(3S,4R)-4
(3S,4R)-5
(3S,4R)-7
Scheme 4. Elaboration of the diacetate (3S,4R)-5 to establish the absolute configuration. Reagents: (a) LiAlH4, Et2O; (b) TBDPSCl, imidazole,
DMF.
O
OH
OH
OH
OH
b
a
O
H3C
H3C
CH3
CH3
H3C CH3
trans-3
rac-4
rac-4
Scheme 5. The synthesis of cis- or trans-4,5-dimethylhydrofuran-2(3H)-one. Reagents: (a) Ag2CO3/Celite; (b) HLADH, NAD+.
agreement with the empirical rules, recently published,
for the stereoselectivity of a lipase towards secondary
alcohols containing two neighbouring stereocentres.26
from Amano Pharmaceutical Co. Ltd. Novozyme 435
and SP 526 were obtained from Novo Nordisk and
Amano PS fluorescens from Biochemica Fluka. Nuclear
magnetic resonance spectra were recorded on a Brucker
DMX 250 spectrometer with CDCl3 as solvent and
TMS as internal reference. Optical rotations were mea-
sured using a Perkin–Elmer 241. Mass spectra were
taken on a Saturn 2000 instrument coupled to a Varian
3800 GC instrument. Preparative liquid chromatogra-
phy (LC) was performed on straight phase silica gel
(Merck 60, 230–400 Mesh) employing a gradient of
eluent.
Furthermore, we investigated an alternative route to ob-
tain both enantiomers of lactone trans-3. Previous work
has shown that of a variety of lactones can be formed
stereoselectively through HLADH (horse liver alcohol
dehydrogenase) catalysed oxidation of diols27,28
(Scheme 5). Thus, the racemic anti-3-methyl-1,4-pentan-
diol rac-4 was enzymatically oxidised by HLADH/
NAD+ in a 100 mM glycine/NaOH buffer at pH 9. After
3 h the conversion reached 44 5% (according to NMR
and GC data) and, after termination of the reaction,
gave the lactone, trans-3, which was analysed on a chiral
GC-column. Unfortunately, both enantiomers were
formed in nearly equal amounts, meaning that this
method was not useful here. However this reaction
proved to be a good alternative route for ring closure
of diol rac-4 to lactone trans-3 when left to completion
compared to the Ag2CO3/Celite method.
4.1. 5-Methyl-2(5H)-furanone (b-angelica lactone), 2
a-Angelica lactone (70 g, 0.714 mol) was added to
0.625 mL triethylamine. The mixture was heated under
reflux and after 40 min the mixture was allowed to reach
room temperature. Upon distillation, 34.7 g (49.5%)
of b-angelica lactone bp 82 ꢁC/10 mmHg was obtained.
1H, 13C NMR and MS spectral data were similar to pub-
lished data.29,30 IR spectral data were also similar to
published data.31,32
3. Conclusion
4.2. trans-4,5-Dimethylhydrofuran-2(3H)-one, 3
In conclusion, we have developed a new method for the
synthesis of both enantiomers of anti-3-methyl-1,4-pent-
andiol in very high diastereomeric and enantiomeric
purities. These enantiomerically pure building blocks,
after short chemical elaboration, can lead to the direct
synthesis of the pure threo-isomers of the pine sawfly
sex pheromones.
General procedure exemplified with the cuprate
(CH3)2CuLi: A mixture of CuI (2 or 4 equiv) in distilled
dry Et2O (13 vol) was cooled to 0 ꢁC and CH3Li (4 or
8 equiv) was added under argon. After 40 min, the mix-
ture was cooled to ꢁ78 ꢁC and b-angelica lactone
(1 equiv in dry Et2O) was added dropwise. TMSCl
(1 equiv) was then slowly added in some reactions.
The reaction was stirred at ꢁ78 ꢁC for 1–2 days. Satu-
rated ammonium chloride was slowly added and the
reaction temperature left to reach room temperature.
After separation of the organic phase, the water phase
was continuously extracted with Et2O followed by
CH2Cl2 (3 vol · 20). The combined organic phase was
washed with saturated NaCl solution (6 vol · 2), dried
over MgSO4 and the solvent evaporated. After LC,
product 3 was obtained chemically pure in >99% de.
1H, 13C NMR and MS spectral data were similar to pub-
lished data.33,35 Also IR spectral data were identical to
published data.34
4. Experimental
Commercially available chemicals were used without
further purification unless otherwise stated. All dried
˚
solvents were stored over molecular sieves (4 A) under
argon. Et2O was dried by distillation from LiAlH4. Vin-
yl acetate and t-BuOMe were dried with molecular
˚
sieves (3 A) before use. The purity of 5-methylfuran-
2(3H)one (a-Angelica lactone), 1, was determined by
1H NMR before use. Amano PS, Amano PS on diatio-
nite and Amano PS on tyonite-200-P were obtained

M. Lindstro¨m et al. / Tetrahedron: Asymmetry 16 (2005) 1355–1360
1359
4.3. Racemic-3-methyl-1,4-pentanediol, rac-4
phenylsilyl chloride according to a published method25
and the specific rotation of this product {½aꢂ ¼ ꢁ5:8
20
D
(c 1.88, CHCl3)} found to be of the opposite sign
An excess of LiAlH4 was added under argon to dry Et2O
and lactone 3 dissolved in Et2O was added dropwise.
After 0.5 h, the excess of hydride was destroyed by a
small amount of water. LC (10–100% ethyl acetate in
cyclohexane), evaporation of the solvent and bulb to
bulb distillation (75–80 ꢁC/2.8 mbar, lit.36 134 ꢁC/
and of the same amplitude as the literature value
(3R,4S)-configuration
for
a
stereoisomer with
a
20
D
{½aꢂ ¼ þ6 (c 0.11, CHCl3)}.25
The enantiomeric excess (ee) of the mono- and diace-
tates, (3R,4S)-6 and (3S,4R)-5 respectively, were deter-
mined on GC (b-dex 120, b-cyclodextrin capillary
column, premethylated b-CD, 30 m · 0.250 mm, carrier
gas He, pressure 12 psi, 80 ꢁC for 2 min then 1 ꢁC/min
up to 140 ꢁC). Retention time (min) for the enantiomers
of 3-methylpentane-1,4-diyl acetate 5: 45.49; 45.80 and
for 4-hydroxy-3-methylpentyl acetate 6: 44.85; 46.47.
1
20 Torr) gave 1.08 g of diol 4 (yield 89%). H NMR
(250 MHz, CDCl3) d 0.93 (d, 3H, J = 6.8); 1.19 (d, 3H,
J = 6.3); 1.67 (m, 3H); 2.04 (s, 2H, OH); 3.66 (m, 2H);
3.77 (m, 1H). 13C NMR (250 MHz): 16.4, 20.5, 36.1,
38.1, 60.3, 71.7. IR: 3356, 2966, 2931, 1065, 909, 734.
Mass spectrum, m/z (relative intensity): 119 (M+, 2%),
101 (11), 85 (82), 67 (13), 56 (100), 41 (79).
4.4. Enantioselective acylation of racemic trans-3-
methyl-1,4-pentanediol, 4. General procedure
4.5. (3S,4R)-3-Methylpentane-1,4-diyl diacetate,
(3S,4R)-5
To control the water activity, the substrate was dis-
solved in t-BuOMe and stored for 24 h in a vessel
containing a saturated solution of LiCl. Pure solvent
(t-BuOMe) and vinyl acetate were stored in the same
way but in separate vessels. This procedure gives an ini-
tial water activity of 0.11–0.12. To achieve an initial
water activity of 0.32 a saturated solution of MgCl2
was used and dry conditions (aw ꢀ 0) obtained by add-
99.8% ee (GC, b-dex 120). 1H NMR (250 MHz, CDCl3)
d 0.86 (d, 3H, J = 6.8 Hz); 1.10 (d, 3H, J = 6.4 Hz); 1.34
(m, 1H); 1.71 (m, 2H); 1.97 (S, 3H); 1.98 (s, 3H); 4.05
(m, 2H); 4.73 (m, 1H). 13C NMR (250 MHz): d 14.6,
16.2, 20.8, 21.1, 31.0, 34.3, 62.4, 73.8, 170.4, 170.9. IR:
2961, 2932, 1740, 1371, 1244, 1042. Mass spectrum, m/e
(relative intensity): 202 (M+, 1%), 143 (9), 115 (6), 99
(14), 83 (35), 72 (17), 56 (20), 43 (100). Anal. Calcd
for C10H18O4: C, 59.4; H, 9.0. Found: C, 59.4; H, 9.1.
˚
ing 4 A molecular sieves to the reaction mixture under
argon.
4.6. (3R,4S)-4-Hydroxy-3-methylpentyl acetate,
(3R,4S)-6
Substrate 4 (70 mg, 0.59 mmol), the enzyme (Table 2)
and t-BuOMe (1 mL) were added to the reaction bottle.
The reaction was started under magnetic stirring by
addition of vinyl acetate (0.31 g, 3.7 mmol). The bottle
was kept closed with a septum during the reaction. Stir-
ring was kept at 500 rpm. The conversion was followed
on GC and the reaction was stopped at ꢀ40% conver-
sion. The reaction was filtered through a Pasteur pipette
containing cotton wool and absorbed on 3–4 g silica gel
followed by LC (10–100% ethyl acetate in cyclohexane).
The mono- and diesters (3R,4S)-6 and (3S,4R)-5, respec-
tively, were obtained chemically pure (>99%) and com-
pletely separated from each other according to GC.
97.4% ee (GC, b-dex 120). 1H NMR (250 MHz, CDCl3)
d 0.92 (d, 3H, J = 6.7 Hz); 1.16 (d, 3H, J = 6.3 Hz); 1.45
(m, 1H); 1.61 (m, 1H); 1.86 (m, 1H); 1.97 (s, 1H, OH);
2.05 (s, 3H); 3.66 (m, 1H); 4.12 (m, 2H). 13C NMR
(250 MHz): d 14.8, 19.7, 21.0, 31.2, 37.0, 63.0, 71.4,
171.3. IR: 3422, 2970, 2932, 1740, 1457, 1368, 1248,
1098, 1051. Mass spectrum, m/e (relative intensity):
161 (M+, 6%), 143 (1), 115 (6), 101 (69), 83 (92), 61
(16), 56 (68), 43 (100). Anal. Calcd for C8H16O3: C,
60.0; H, 10.1. Found: C, 57.2; H, 9.9.
4.7. (3S,4R)-3-Methyl-1,4-pentanediol
The conversion of diol rac-4 to the mono- and diace-
tates, 6 and 5 respectively, were measured on GC (VA-
1, fused silica capillary column 30 m · 0.25 mm,
df = 0.25 lm, carrier gas He, pressure 13 psi, 70 ꢁC for
4 min then 8 ꢁC/min up to 300 ꢁC). Retention time
(min) for 3-methylpentane-1,4-diol rac-4: 9.45, 3-meth-
ylpentane-1,4-diyl acetate: 12.37, 4-hydroxy-3-methyl-
pentyl acetate: 14.78. The actual conversions were
calculated from the ee values obtained (Table 2).
Reduction (as above for lactone 3) of the diacetate
(3S,4R)-5 (from entry 8 Table 2) gave the title com-
pound nearly quantitatively and with >99.8% ee
25
(GC, b-dex 120). ½aꢂ ¼ ꢁ15:2 ꢃ 0:7 (c 0.67, CHCl3).
D
4.8. (3R,4S)-3-Methyl-1,4-pentanediol
Reduction (as above for lactone 3) of the mono acetate
(3R,4S)-6 (from entry 9 Table 2) gave the title com-
pound nearly quantitatively and with >97.4% ee
The absolute configuration of the faster reacting enan-
tiomer of rac-4 was determined on the product, 3-meth-
ylpentane-1,4-diyl acetate, obtained from an enzymatic
reaction using Novozyme 435 according to the general
procedure at 33% conversion. The obtained diacetate
was reduced (as above for lactone 3) to the correspond-
ing diol, which was purified by LC (10–100% ethyl
acetate in cyclohexane) and distilled bulb to bulb.
The pure diol was then mono silylated with tert-butyldi-
25
(GC, b-dex 120). ½aꢂ þ 16:2 ꢃ 0:5 (c 1.19, CHCl3).
D
4.9. General methods for the formation of trans-4,5-
dimethylhydrofuran-2(3H)-one
Method 1: Following a known procedure used for other
lactones,28 the anti diol 4 (21 mg, 0.18 mmol) was
added to a solution of NAD+ (240 mg, 0,36 mmol) in

1360
M. Lindstro¨m et al. / Tetrahedron: Asymmetry 16 (2005) 1355–1360
6. Tai, A.; Syouno, E.; Tanaka, K.; Fujita, M.; Sugimura, T.;
Higashiura, Y.; Kakizaki, M.; Hara, H.; Naito, T. Bull.
Chem. Soc. Jpn. 2002, 75, 111–121.
7. Karlsson, S.; Hedenstro¨m, E. Acta Chem. Scand. 1999, 53,
620–630, and references cited therein.
8. Ho¨rnfeldt, A.-B. Ark. Kemi 1968, 28, 571–586.
9. Lipshutz, B. H. Synthesis 1987, 325–341.
10. Tsuboi, S.; Sakamoto, J.-i.; Yamashita, H.; Sakai, T.;
Utaka, M. J. Org. Chem. 1998, 63, 1102–1108.
11. Beak, P. Org. Lett. 2002, 4, 2657–2660.
12. Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 6015–
6018.
a glycine/NaOH buffer at pH 9. The reaction was started
by the addition of HLADH (Horse liver alcohol dehy-
drogenase, 3 mg). The pH was periodically checked
and adjusted by the addition of 15% NaOH. After 2–
3 h, the reaction had reached 40–45% conversion and
was then stopped by the addition of an excess of brine
followed by heating to 40 ꢁC. After continuous extrac-
tion of the water phase with diethyl ether, the produced
lactone was obtained in high yield.
Method 2:37 Formation of Ag2CO3–Celite: Celite (6.0 g)
and silver(I)nitrate (6.0 g) in water (40 mL) was stirred
and Na2CO3Æ10H20 (6.0 g) in water (60 mL) added
dropwise over a period of 0.5 h. The reaction vessel
was kept in the dark during this time. The solid was
washed with water to give the Ag2CO3–Celite, which
was then dried in vacuum for 4 h. Diol 4 (9.9 mg,
0.08 mmol) and Ag2CO3–Celite (0.96 g, 1.5 mmol
Ag2CO3) in CHCl3 (3.4 mL) were heated under reflux
for 5 h, after which filtration and evaporation of the sol-
vent gave the trans-lactone in low yield.38
13. Matsuzawa, S.; Horiguchi, I.; Nakamura, E.; Kuwajima,
I. Tetrahedron 1989, 45, 349–362.
´
14. Herradon, B.; Fenude, E.; Bao, R.; Valverde, S. J. Org.
Chem. 1996, 61, 1143–1147.
15. Lundh, M.; Smitt, O.; Hedenstro¨m, E. Tetrahedron:
Asymmetry 1996, 7, 3277–3284.
16. Theil, F.; Weidner, J.; Ballschuh, S.; Kunath, A.; Schick,
H. J. Org. Chem. 1994, 59, 388–393.
17. Ziegler, T.; Bien, F.; Jurisch, C. Tetrahedron: Asymmetry
1998, 9, 765–780.
18. Kazlauskas, R. J.; Bornscheuer, U. T. In Biotransforma-
tions with Lipases; Rehm, H.-J., Reed, G., Eds.; Biotech-
nology: Biotransformations I; VCH, 1998; 8a; pp 38–191,
and references cited therein.
19. Valivety, R. H.; Halling, P. J.; Macrae, A. R. Biochim.
Biophys. Acta 1992, 1118, 218–222.
20. Lundh, M.; Nordin, O.; Hedenstrom, E.; Ho¨gberg, H.-E.
Tetrahedron: Asymmetry 1995, 6, 2237–2244.
21. Orrenius, C.; Norin, T.; Hult, K.; Carrea, G. Tetrahedron:
Asymmetry 1995, 6, 3023–3030.
The enantiomeric excess (ee) of the trans-4,5-dimeth-
ylhydrofuran-2(3H)-one was detected on GC (HP-
Chiral, b-cyclodextrin-containing capillary column,
20% premethylated, 30 m · 0.250 mm, carrier gas He,
pressure 15 psi, oven temp 140ꢁ). Retention time (min)
for the enantiomers of trans-4,5-dimethylhydrofuran-
2(3H)-one: 13.6 (4S,5R); 15.0 (4R,5S).
22. Faber, K. Biotransformations in Organic Chemistry; A
Textbook, 4th ed.; Springer: Berlin, 2000; pp 40–45.
23. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G. G.; Sih, C. J. J.
Am. Chem. Soc. 1982, 104, 7294–7299.
Acknowledgements
24. Bovara, R.; Carrea, G.; Ferrara, L.; Riva, S. Tetrahedron:
Asymmetry 1991, 2, 931–938.
25. Mutou, T.; Kondo, T.; Ojika, M.; Yamada, K. J. Org.
Chem. 1996, 61, 6340–6345.
26. Schulz, T.; Schmid, R. D.; Pleiss, J. J. Mol. Model. 2001,
7, 265–270.
27. Irwin, A. J.; Jones, J. B. J. Am. Chem. Soc. 1977, 99, 556–
561.
28. Ng, G. S. Y.; Yuan, L. C.; Jakovac, I. J.; Jones, J. B.
Tetrahedron 1984, 40, 1235–1243.
29. Tiecco, M.; Testaferri, L.; Tingoli, M.; Bartoli, D.
Tetrahedron 1990, 46, 7139–7150.
We gratefully thank Amano Pharmaceutical Co., Ltd
for the gift of different Amano PS lipases and Novo
Nordisk A/S for the gift of Novozyme 435. Further we
would like to thank NUTEK and Vinnova for financial
support. The research group in Crete acknowledge the
financial support from General Secretariat of Research
and Technology (PENED 2002). D. Bougioukou is
also acknowledged for repeating HLADH-catalysed
reactions.
´
30. Asensio, G.; Miranda, M. A.; Sabater, M. J.; Perez-Prieto,
J.; Simon-Fuentes, A.; Mello, R. J. Org. Chem. 2000, 65,
References
´
964–968.
31. Chen, S.-Y.; Joullie, M. M. J. Org. Chem. 1984, 49, 2168–
2174.
32. Tsuboi, S.; Sakamoto, J.-i.; Kawano, T.; Utaka, M.;
Takeda, A. J. Org. Chem. 1991, 56, 7177–7179.
33. Reissig, H.-U.; Angert, H.; Kunz, T.; Janowitz, A.;
Handke, G.; Bruce-Adjei, E. J. Org. Chem. 1993, 58,
6280–6285.
34. Hackmann, C.; Scha¨fer, H. J. Tetrahedron 1993, 49, 4559–
4574.
35. Berrada, S.; Desert, S.; Metzner, P. Tetrahedron 1988, 44,
3575–3586.
36. Nenitzescu, C. D.; Cioranescu, E.; Cantuniari, I. P. Chem.
Ber. 1937, 70, 277–281.
37. Paquette, L. A. In Enzyclopedia of Reagents for Organic
Synthesis; John Wiley & Sons, 1995; Vol. 6, pp 4448–4452.
38. Fetizon, M.; Golfier, M.; Louis, J. M. Tetrahedron 1975,
31, 171–176.
´
1. Smith, D. R. Systematics, Life History, and Distribution
of Sawflies. In Sawfly Life History Adaptations to Woody
Plants; Wagner, M. R., Raffa, K. F., Eds.; Academic: San
Diego, 1993; pp 3–32.
2. Anderbrant, O. Pheromone biology of sawflies. In Sawfly
Life History Adaptations to Woody Plants; Wagner, M. R.,
Raffa, K. F., Eds.; Academic: San Diego, 1993; pp 119–
154.
3. Anderbrant, O. Sawflies and Seed Wasps. In Pheromones
of Non-Lepidoperan Insects Associated with Agricultural
Plants; Hardie, J., Minks, A. K., Eds.; CABI Publishing:
Wallingford, 1999; pp 199–226.
4. Hedenstro¨m, E.; Andersson, F. J. Chem. Ecol. 2002, 28,
1237–1254, and references cited therein.
5. Hedenstro¨m, E.; Edlund, H.; Lund, S.; Abersten, M.;
Persson, D. J. Chem. Soc., Perkin Trans. 1 2002, 1810–
1817, and references cited therein.