Synthesis of (tetrahydrofuran-2-yl)acetates based on a 'cyclization/hydrogenation/enzymatic kinetic resolution' strategy

Article abstract of DOI:10.1016/j.tet.2006.03.077

A variety of (tetrahydrofuran-2-yl)acetates and (pyrrolidin-2-yl)acetates have been prepared by hydrogenation of 2-alkylidenetetrahydrofurans and 2-alkylidenepyrrolidines, which are readily available by cyclization reactions of 1,3-dicarbonyl dianions ('free dianions') or 1,3-bis-silyl enol ethers ('masked dianions') with 1,2-dielectrophiles. The enzymatic kinetic resolution of (tetrahydrofuran-2-yl)acetates with recombinant esterase Est56 proceeded with excellent enantioselectivities (E>100).

Full text of DOI:10.1016/j.tet.2006.03.077

Tetrahedron 62 (2006) 7132–7139
Synthesis of (tetrahydrofuran-2-yl)acetates based on a
‘cyclization/hydrogenation/enzymatic kinetic resolution’ strategy
Esen Bellur,a,b Ilia Freifeld,a Dominique Bottcher,a Uwe T. Bornscheuera,y
¨
and Peter Langerb,c,
*
aInstitut fu€r Chemie und Biochemie, Universita€t Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
bInstitut fu€r Chemie, Universita€t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
cLeibniz-Institut fu€r Katalyse e. V. an der Universita€t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 8 March 2006; revised 20 March 2006; accepted 22 March 2006
Available online 19 May 2006
Abstract—A variety of (tetrahydrofuran-2-yl)acetates and (pyrrolidin-2-yl)acetates have been prepared by hydrogenation of 2-alkylidene-
tetrahydrofurans and 2-alkylidenepyrrolidines, which are readily available by cyclization reactions of 1,3-dicarbonyl dianions (‘free dianions’)
or 1,3-bis-silyl enol ethers (‘masked dianions’) with 1,2-dielectrophiles. The enzymatic kinetic resolution of (tetrahydrofuran-2-yl)acetates
with recombinant esterase Est56 proceeded with excellent enantioselectivities (E>100).
Ó 2006 Elsevier Ltd. All rights reserved.
Me
Me
Me
Me
OH
1. Introduction
O
O
R2
OH
HO
O
O
O
Functionalized tetrahydrofurans occur in a variety of phar-
macologically relevant natural products.1–4,6–8 (Tetrahydro-
furan-2-yl)acetates are present, for example, in the polyether
antibiotics lasalocid A (Fig. 1),2 ferensimycin A, B, and
lysocellin (Fig. 2).3 They also represent versatile synthetic
building blocks and have been used, for example, during
the synthesis of the natural acetogenin solamin isolated
from Annonaceous.4 Many acetogenins exhibit remarkable
cytotoxic, antitumor, antimalarial, immunosuppressive,
pesticidal, and antifeedant activities.1
OH
H
MeOH Et
R1
H
Me Me Et
Ferensimycin A (R1 = Me, R2 = Me)
Ferensimycin B (R1 = Me, R2 = Et)
Lysocellin (R1 = H, R2 = Et)
Figure 2. Ferensimycin A, B, and lysocellin.
tions,5e–f cyclopropanations,5g oxidative carbonylations,5h–j
and codimerizations.5k The hydrogenation5m,6h–i of 2-alkyl-
idenetetrahydrofurans has been applied to the synthesis of
natural products, such as methyl nonactate, which represents
a building block of nonactin.6,7 The spiroketal chalcogran
has been prepared from a bicyclic 2-alkylidenetetrahydro-
furan.8 In recent years, we and others have reported a number
of one-pot syntheses of 2-alkylidenetetrahydrofurans by
cyclization of 1,3-dicarbonyl dianions or 1,3-bis-silyl
enol ethers with 1,2-dielectrophiles,9 and also by other
methods.10c–f 2-Alkylidenetetrahydrofurans have been func-
tionalized by lithiation and subsequent alkylations;10a,b in
addition, the bromination of the exocyclic double bond and
subsequent cross-coupling reactions have been reported.10g,h
Recently, we have reported the synthesis of 6-bromo-3-
oxoalkanoates and functionalized benzofurans by reaction
of 2-alkylidenetetrahydrofurans with boron tribromide
(BBr3).11 In addition, furans and benzofurans have been pre-
pared by sequential ‘[3+2] cyclization/dehydrogenation’12
and ‘[3+2] cyclization/elimination’13 reactions. Herein, we
report a convenient approach to racemic (tetrahydrofuran-
2-yl)acetates14 based on a ‘[3+2] cyclization/hydrogenation’
2-Alkylidenetetrahydrofurans5,6 represent important syn-
thetic building blocks that have been used for the synthesis
of natural products. Numerous synthetic transformations
of 2-alkylidenetetrahydrofurans have been reported, which
include, for example, cycloadditions,5a–d nucleophilic addi-
OH
Me
Me
HO
Et
OH
O
Me
O
O
H
Et H
H
CO2H
Me
Me
Et
Figure 1. Lasalocid A.
Keywords: Cyclizations; Tetrahydrofurans; Pyrrolidines; Enzymatic kinetic
resolution; Hydrogenation.
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412;
e-mail: peter.langer@uni-rostock.de
Fax: +49 383 48680066; e-mail: uwe.bornscheuer@uni-greifswald.de.
y
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.077

E. Bellur et al. / Tetrahedron 62 (2006) 7132–7139
Table 1. Synthesis of (tetrahydrofuran-2-yl)acetates (5a–g)
7133
strategy. In addition, we report the enzymatic kinetic resolu-
Substrate (%)a
5
R1
R2
R3
% (5)a
drb
tion of (tetrahydrofuran-2-yl)acetates. The novel recombi-
nant esterase Est56, extracted from soil samples using the
metagenome approach, and supplied by BRAIN AG (Zwin-
genberg, Germany) has been used for these transforma-
tions.15,16
3a (86)c
3b (79)c
3c (77)d
3d (77)c
3e (72)c
3f (82)c
3g (58)c
a
b
c
d
e
f
OMe
OEt
H
H
H
H
H
H
H
H
H
H
Me
Et
H
97
100
100
83
89
95
—
—
—
—
6:5
6:5
3:2
OiPr
OtBu
OMe
OEt
In the present manuscript, we also report the synthesis of an
ethyl (pyrrolidin-2-yl)acetate by diastereoselective hydroge-
nation of an ethyl (4-methoxypyrrolidin-2-ylidene)acetate.
2-Alkylidenepyrrolidines17,18 represent direct precursors
for the stereoselective synthesis of pyrrolidine substruc-
tures18 by reduction18f of the exocyclic double bond. Pyrro-
lidines are present in a variety of alkaloids, such as
hygrine, hygroline or cuskhygrin, and in non-natural prod-
ucts used in the clinic (e.g., the vasodilator buflomedil).18
They are ubiquitous structural motifs in drugs and drug can-
didates displaying antidepressant,19a,b antihypertensive,19a,c
anti-arthritic,19d,e antibacterial,19f–h antithrombotic,19i–k
and analgesic19l,m activities. Recent drug development incor-
porating the pyrrolidine motif has identified candidates with
promising anti-HIV19n,o and antibacterial adjunct19p,q activ-
ities. Numerous applications in the synthesis of natural prod-
ucts have been reported.20 Recently, we have reported21a the
synthesis of 2-alkylidene-4-methoxypyrrolidines by con-
densation of 1,3-bis-silyl enol ethers with 1-azido-2,2-
dimethoxyethane, and cyclization by Staudinger–aza-Wittig
reaction.21b
g
OCH2CH2
86
a
Isolated yields.
b
Diastereomeric ratio, assignment arbitrary.
Known compounds (Ref. 10a,b).
Combined yield (Ref. 12).
c
d
isolated as inseparable 6:5 mixtures of diastereomers. The
hydrogenation of tetrahydro[2,30]bifuranyliden-20-one
3g,10b prepared by cyclization of dilithiated a-acetyl-g-
butyrolactone (1g) with 1-bromo-2-chloroethane, gave the
octahydro[2,30]bifuranyl-20-one 5g as an inseparable 3:2
mixture of diastereomers.
2.2. Synthesis of (tetrahydrofuran-2-yl)acetates based
on cyclizations of masked dianions with 1-chloro-2,2-
dimethoxyethane (method B)
The 4-methoxy-2-alkylidenetetrahydrofurans 4a,b were
prepared, following our recently reported procedure,13 by
TMSOTf catalyzed condensation of 1,3-bis-silyl enol ethers
2a,c (available from 1a,c in two steps) with 1-chloro-2,2-di-
methoxyethane and subsequent DBU-mediated cyclization
(Scheme 2). The hydrogenation of 4a,b afforded the (tetra-
hydrofuran-2-yl)acetates 5a,c by elimination of methanol
and subsequent hydrogenation of the double bond thus
formed (method B). For the synthesis of 5a,c, method A is su-
perior to method B because of the higher yields (method A:
83 and 77%; method B: 61 and 47%) and because less syn-
thetic steps are required (method A: two steps; method B:
five steps).
2. Results and discussion
2.1. Synthesis of (tetrahydrofuran-2-yl)acetates based
on cyclizations of free dianions with 1-bromo-2-chloro-
ethane (method A)
ThePd/Ccatalyzedhydrogenationoftheknown2-alkylidene-
tetrahydrofurans 3a–d, prepared by cyclization of dilithia-
ted methyl, ethyl, iso-propyl and tert-butyl acetoacetate
(1a–d) with 1-bromo-2-chloroethane,10a,b afforded the (tet-
rahydrofuran-2-yl)acetates 5a–d (Scheme 1, Table 1). 3-
Methyl- and 3-ethyl-(tetrahydrofuran-2-yl)acetates 5e and 5f
were prepared by hydrogenation of the known 2-alkylidene-
tetrahydrofurans 3e and 3f, respectively. The latter are again
available by cyclization of 1,3-dicarbonyl dianions 1e,f with
1-bromo-2-chloroethane.10a,b Tetrahydrofurans 5e,f were
OMe
Cl
OMe
OSiMe3
R
Me3SiO
O
i, ii
R
ref. 13
O
MeO
2a,c
4a (R = OMe, 62%)
4b (R = OiPr, 56%)
iii
R2
O
O
O
Cl
O
Br
O
O
R1
R1
R
R
R3 R2
i
R3
O
MeO
O
ref. 10
1a-g
B
3a-g
A
ii
R2
O
O
R
R1
O
O
R3
5a (R = OMe, 98%)
5c (R = OiPr, 83%)
5a-g
Scheme 1. Synthesis of (tetrahydrofuran-2-yl)acetates 5a–g: (i) (1) LDA
(2.3 equiv), THF, 0 ꢀC, 1 h, (2) Br(CH2)2Cl, ꢁ78/20 ꢀC, 14 h, then reflux,
12 h; (ii) H2, Pd/C (0.5 equiv; for 5a: 0.3 equiv), MeOH (or EtOH), 20 ꢀC,
48 h.
Scheme 2. Synthesis of (tetrahydrofuran-2-yl)acetates 5a,c: (i)
ClCH2CH(OMe)2, Me3SiOTf (0.5 equiv), CH2Cl2, ꢁ78/20 ꢀC, 14 h,
then at 20 ꢀC, 2 h; (ii) DBU (2.0 equiv), THF, 20 ꢀC, 6 h; (iii) H2, Pd/C
(0.5 equiv), MeOH, 20 ꢀC, 48 h.

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E. Bellur et al. / Tetrahedron 62 (2006) 7132–7139
2.3. Synthesis of (tetrahydrofuran-2-yl)acetates based
on cyclizations of free dianions with 1,4-dibromobut-2-
ene (method C)
2.5. Synthesis of (pyrrolidin-2-yl)acetates based on [3+2]
cyclizations of 1,3-bis-silyl enol ethers with 1-azido-2,2-
dimethoxyethane
The cyclization of dilithiated ethyl acetoacetate (1b) with
1,4-dibromobut-2-ene afforded, following a known proce-
dure,10a (5-vinyldihydrofuran-2(3H)-ylidene)acetate 6 as
a separable mixture of E/Z isomers (Scheme 3).10h The
hydrogenation of 6 afforded the (5-ethyltetrahydrofuran-2-
yl)acetate 8a by hydrogenation of the vinyl group and the
exocyclic double bond.
The ethyl (4-methoxypyrrolidin-2-ylidene)acetate 10 was
prepared, following our recently reported procedure,21a by
TMSOTf catalyzed condensation of 1,3-bis-silyl enol ether
2b, with 1-azido-2,2-dimethoxyethane and subsequent
cyclization of 9 by Staudinger–aza-Wittig reaction. The
palladium-catalyzed hydrogenation of 10 afforded ethyl
(4-methoxypyrrolidin-2-yl)acetate (11) with 10:1 diastereo-
selectivity (Scheme 5).
Br
OMe
N3
O
O
Br
O
OEt
Me3SiO
OSiMe3
OEt
OMe O
O
OMe
OEt
i
N3
O
OEt
i
ref. 10a,h
1b
E-6 (40%)
Z-6 (35%)
ref. 21a
9 (51%)
2b
ii
O
ii
OEt
O
O
H
O
OEt
OEt
8a (85%)
H
N
N
syn/anti = 9:2
iii
Scheme 3. Synthesis of 8a: (i) (1) LDA (2.3 equiv), THF, 0 ꢀC, 1 h, (2)
BrCH2CH]CHCH2Br, ꢁ78/20 ꢀC, 14 h, then at 20 ꢀC, 24 h; (ii) H2,
Pd/C (0.5 equiv), EtOH, 20 ꢀC, 48 h.
MeO
MeO
10 (64%)
11 (100%)
Scheme 5. Synthesis of 11: (i) N3CH2CH(OMe)2, Me3SiOTf (0.5 equiv),
CH2Cl2, ꢁ78/20 ꢀC; (ii) PPh3, THF, 45 ꢀC, 6 h; (iii) H2, Pd/C (0.5 equiv),
EtOH, 20 ꢀC, 24 h.
2.4. Synthesis of (tetrahydrofuran-2-yl)acetates based
on cyclizations of masked dianions with epoxides
(method D)
2.6. Enzymatic kinetic resolution of (tetrahydrofuran-
2-yl)acetates
2-Alkylidenetetrahydrofurans 7a,b were prepared, follow-
ing a known procedure,22a by TiCl4 mediated cyclization
of 1,3-bis-silyl enol ethers 2a,b with 1,2-epoxybutane and
epichlorohydrin, respectively (Scheme 4, Table 2). The hy-
drogenation of 7a afforded the tetrahydrofuran 8a with mod-
erate diastereoselectivity. The hydrogenation of 7b afforded
(5-chloromethyltetrahydrofuran-2-yl)acetate 8b with very
good diastereoselectivity.
To monitor the enantioselectivity in the enzymatic kinetic
resolution of the (tetrahydrofuran-2-yl)acetates, suitable
conditions for gas chromatographic (GC) analysis were
developed (Table 3).
The enzymatic kinetic resolutions of these (tetrahydrofuran-
2-yl)acetates were next studied (Table 4). The analytical
scale enzyme reactions of methyl and ethyl (tetrahydrofu-
ran-2-yl)acetates (5a,b) were carried out with esterases15
(Est56, Est63, Est8) and lipases15 (CAL-B, BCL). For
5a,b, the best resolution results were achieved with the
recombinant esterase Est56.
O
Me3SiO
OSiMe3
R1
R2
O
R2
R1
i
O
ref. 22a
2a,b
7a,b
ii
Enzymatic kinetic resolution of 5a with recombinant ester-
ase Est56 gave (ꢁ)-5a (40%, >99% ee) and the hydrolysis
product (ꢁ)-12 (49%, 87% ee) (Scheme 6, Table 5, entry 4).
The preparative scale reaction of 5a with Est56 was repeated
R2
O
R1
O
8a,b
Scheme 4. Synthesis of 5-alkyl-(tetrahydrofuran-2-yl)acetates 8a,b: (i)
ꢀ
ꢀ
˚
TiCl4 (2 equiv), 4 A MS, CH2Cl2, ꢁ78/20 C, 14 h, then at 20 C, 3 h;
Table 3. GC analysis of (tetrahydrofuran-2-yl)acetates
(ii) H2, Pd/C (0.5 equiv), MeOH (or EtOH), 20 ꢀC, 48 h.
Substrate Temperature (ꢀC)
Retention time (min)a
Substrate (ester)
Product (acid)b,c
18.2 18.8
Table 2. Synthesis of 5-alkyl-(tetrahydrofuran-2-yl)acetates (8a,b)
Substrate (%)a
8
R1
R2
% (8)a
syn/antib
5a
5b
70
70
18.2
18.2
18.8
18.8
29.7 30.5
7a (62)c
7b (66)
a
b
OEt
OMe
Et
CH2Cl
70
100
3:1
>10:1
Chiral column: HydrodexÒ-b-3P, [Heptakis-(2,6-di-O-methyl-3-O-
pentyl)-b-cyclodextrin].
Product of enzyme reactions.
Retention times for methyl ester of hydrolysis products [acid+diazo-
methane/methyl ester].
a
a
b
c
Isolated yields.
Diastereoselectivity (by 1H NMR).
Known compound (Ref. 22a).
b
c

E. Bellur et al. / Tetrahedron 62 (2006) 7132–7139
7135
Table 4. Analytical scale enzymatic kinetic resolution reactions
Enzyme Substrate Conversion Reaction eeS eeP
resolution of (tetrahydrofuran-2-yl)acetates by recombinant
esterase Est56 proceeded with excellent enantioselectivity
affording these compounds in optically pure form.
E-
(%)a,b (%)a,c value
(%)
time (h)
Est56
Est56
Est63
Est8
Est8
CAL-B 5a
CAL-B 5b
5a
5b
5a
5a
5b
59
60
30
18
5
95
95
35
40
49
53
49
48
48
1
1
48
48
>99
88
33
3
<1
—
—
19
23
70
67
75
2
11
—
—
35
33
48
15
9
1
1
1
1
2
2
3. Experimental
3.1. General comments
All solvents were dried by standard methods and all reac-
tions were carried out under an inert atmosphere. For the
1H and 13C NMR spectra the deuterated solvents indicated
were used. The NMR spectra were measured on 300 and
200 MHz instruments. Mass spectral data (MS) were ob-
tained by electron ionization (EI, 70 eV), chemical ioniza-
tion (CI, H2O or DCI, NH3) or electrospray ionization
(ESI). For preparative scale chromatography silica gel
(60–200 mesh) was used. Chiral column used for GC: Hy-
drodexÒ-b-3P, [Heptakis-(2,6-di-O-methyl-3-O-pentyl)-b-
cyclodextrin] (25 m, 0.25 mm).
BCL
BCL
5a
5b
eeS: enantiomeric excess of substrate; eeP: enantiomeric excess of product.
Calculated from gas chromatograms (GC).
a
b
For (ꢁ)-5a.
c
For (ꢁ)-12.
five times and optimized, which finally led to conditions in
which excellent enantioselectivities (E>100) at high conver-
sions and short reaction times were obtained. The resolution
reaction of racemic 5a with Est56 afforded both products
with negative (ꢁ) optical rotation values. Unfortunately,
the absolute configurations of (ꢁ)-5a and (ꢁ)-12 could not
be determined by comparison with literature results: Laxmi
and Iyengar reported23 that the lipase (Candida cylindracea)
mediated enantioselective hydrolysis of 5a afforded (S)-(+)-
5a and (R)-(ꢁ)-12, which were used for the synthesis of the
natural product (R)-(+)-a-lipoic acid. Co-injection (GC) of
(ꢁ)-5a and (ꢁ)-12 proved that the products have different
configurations.
3.2. General procedure for the reaction of 1,3-bis-silyl
enol ethers with epoxides
To a CH2Cl2 solution (4 mL/mmol) of 1,3-bis-silyl enol ether
2 (1.0 equiv) and the epoxide (1.2 equiv), in the presence
˚
of molecular sieves (4 A), was added TiCl4 (2.0 equiv) at
ꢁ78 ꢀC. The solution was stirred for 4 h at ꢁ78 ꢀC; subse-
quently, the temperature was allowed to rise to 20 ꢀC during
14 h and the solution was stirred for 3 h at 20 ꢀC. The molec-
ular sieves were filtered-off and washed with CH2Cl2. To the
solution was added a saturated aqueous solution of NaHCO3,
the organic layer was separated and the aqueous layer was
repeatedly extracted with CH2Cl2. The combined organic
extracts were dried (Na2SO4), filtered, and the filtrate was
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, n-hexane/EtOAc) to give 7.
The synthesis of 7a has been previously reported.22a
O
OMe
O
(–)-5a
O
Est56
(40%, > 99%ee)
OMe
i
O
O
OH
O
+
5a
(–)-12
(49%, 87%ee)
3.2.1. Methyl (5-chloromethyldihydrofuran-2(3H)-ylidene)
acetate (7b). Starting with 2a (7.814 g, 30 mmol), epichlo-
rohydrin (2.82 mL, 36 mmol) and TiCl4 (6.6 mL,
Scheme 6. Enzymatic kinetic resolution of 5a: (i) (Table 5, entry 4)
recombinant esterase Est56, phosphate buffer (50 mM, pH 7.5), 37 ꢀC,
5 h, the assignment of the absolute configuration is arbitrary.
˚
60 mmol) in CH2Cl2 (250 mL, 4 A molecular sieves), 7b
In conclusion, a variety of (tetrahydrofuran-2-yl)acetates
have been prepared by hydrogenation of 2-alkylidenetetra-
hydrofurans readily available by [3+2] cyclizations of 1,3-
dicarbonyl dianions (‘free dianions’) or 1,3-bis-silyl enol
ethers (‘masked dianions’) with various 1,2-dielectrophiles.
Similarly, (4-methoxypyrrolidin-2-yl)acetate has been
prepared from 2-alkylidenepyrrolidin. Enzymatic kinetic
was isolated after chromatography (silica gel, n-hexane/
EtOAc¼100:1/1:1) as a yellowish oil (3.764 g, 66%). 1H
NMR (CDCl3, 300 MHz): d¼1.97–2.06 (m, 1H, CH2),
2.23–2.32 (m, 1H, CH2), 3.00–3.13 (m, 1H, CH2), 3.25–
3.38 (m, 1H, CH2), 3.64 (d, J¼5.1 Hz, 2H, CH2–Cl), 3.67
(s, 3H, OCH3), 4.62–4.70 (m, 1H, OCH), 5.35 (t,
J¼1.8 Hz, 1H, CH]C). IR (neat, cmꢁ1): ~n¼2987 (w),
2954 (m), 1704 (s), 1642 (s), 1439 (s), 1365 (s), 1295 (m),
1246 (m), 1189 (s), 1121 (s), 1047 (s), 942 (w), 880 (w),
828 (m), 727 (w). MS (EI, 70 eV): m/z (%)¼192 (M+
[37Cl], 5), 190 (M+ [35Cl], 17), 161 (16), 159 (49), 155 (2),
141 (4), 123 (10), 109 (5), 69 (100). HRMS (ESI): Calcd
for C8H11ClO3 [M+]: 192.9885 (37Cl), 190.0391 (35Cl);
found: 192.9883 (37Cl), 190.0387 (35Cl).
Table 5. Preparative scale enzymatic reactions
Entry Est56a 5a
Conversion Time eeS
(h)
eeP
E-
(mL)
(mg) (%)
(%)b,c (%)b,d value
1
2
3
4
5
2
1
2
1.5
2
200 35
216
187
22
5
38
47
>99
>99
>99
71
75
83
87
84
9
11
73
>100
100
4ꢂ20 39
50
50
50
54
54
54
3
3.3. General procedure for the hydrogenation of
2-alkylidenetetrahydrofurans
eeS: enantiomeric excess of substrate; eeP: enantiomeric excess of product.
Crude extract with 50 U/mL (based on a p-nitrophenyl acetate assay).
a
b
For isolated products.
For (ꢁ)-5a.
c
To a H2 concentrated suspension of Pd/C (0.3–0.5 equiv, 10%
Pd on charcoal) in methanol (or ethanol) (5–10 mL/mmol)
d
For (ꢁ)-12.

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E. Bellur et al. / Tetrahedron 62 (2006) 7132–7139
was added 2-alkylidenetetrahydrofuran (3, 6, 7 or 10)
(1.0 equiv). The reaction mixture was concentrated with H2
and stirred under H2 atmosphere at 20 ꢀC for 48 h. Then
the reaction mixture was filtered through Celite, washed
with dichloromethane (4ꢂ15 mL/mmol), and the filtrate
was concentrated in vacuo. The residue was purified by col-
umn chromatography (silica gel, n-hexane/EtOAc) to give
(tetrahydrofuran-2-yl)acetate (5, 8 or 11). Notably, the (tetra-
hydrofuran-2-yl)acetates were not UVactive (neither at short
nor at long wavelength); to detect the products on TLC,
the following solution was used as a dying agent: MnO2
(0.3 g/mL) in ethanol.
(CDCl3, 300 MHz): d¼1.24 (d, J¼6.3 Hz, 6H, 2ꢂCH3),
1.50–1.61 (m, 1H, CH2), 1.85–1.96 (m, 2H, CH2), 2.03–
2.12 (m, 1H, CH2), 2.43 (dd, J¼15.1, 6.3 Hz, 1H, CH2),
2.58 (dd, J¼15.1, 7.0 Hz, 1H, CH2), 3.70–3.79 (m, 1H,
OCH2), 3.84–3.92 (m, 1H, OCH2), 4.24 (quint, J¼6.8 Hz,
1H, OCH), 5.04 (quint, J¼6.3 Hz, 1H, OCH). 13C NMR
(CDCl3, 75 MHz): dC¼21.1 (2C, CH3), 24.9, 30.5, 40.3
(CH2), 66.9 (OCH), 67.4 (OCH2), 74.6 (OCH), 169.9
(O]C–O). IR (neat, cmꢁ1): ~n¼2962 (s), 2934 (s), 2874
(m), 1731 (s), 1649 (w), 1457 (m), 1447 (m), 1408 (w),
1379 (m), 1262 (s), 1232 (m), 1180 (s), 1108 (s), 1070 (s),
1022 (m), 967 (w), 801 (m). MS (EI, 70 eV): m/z
(%)¼172 (M+, 1), 157 (3), 142 (3), 129 (11), 112 (8), 102
(28), 97 (4), 89 (48), 84 (16), 71 (100). HRMS (ESI): Calcd
for C9H16O3 ([M+Na]+): 195.09972; found: 195.09889.
3.3.1. Methyl (tetrahydrofuran-2-yl)acetate (5a).23
Method A: Starting with 3a (0.500 g, 3.52 mmol) and Pd/C
(10% Pd, 1.123 g, 1.06 mmol) in methanol (20 mL), 5a
was isolated without further purification as a slightly yellow-
ish oil (0.491 g, 97%). Method B: Starting with 4a (0.300 g,
1.74 mmol) and Pd/C (10% Pd, 0.556 g, 0.52 mmol) in
methanol (15 mL), 5a was isolated without further purifica-
tion as a slightly yellowish oil (0.245 g, 98%). GC (chiral
column, 70 ꢀC): retention times (min)¼18.2, 18.8. 1H
NMR (CDCl3, 300 MHz): d¼1.50–1.61 (m, 1H, CH2),
1.87–1.96 (m, 2H, CH2), 2.04–2.15 (m, 1H, CH2), 2.49
(dd, J¼15.2, 5.8 Hz, 1H, CH2), 2.61 (dd, J¼15.2, 7.2 Hz,
1H, CH2), 3.70 (s, 3H, OCH3), 3.72–3.79 (m, 1H, OCH2),
3.85–3.92 (m, 1H, OCH2), 4.26 (quint, J¼7.2 Hz, 1H,
OCH). 13C NMR (CDCl3, 75 MHz): dC¼25.0, 30.6, 39.8
(CH2), 51.1 (OCH3), 67.4 (OCH2), 74.6 (OCH), 171.0
(O]C–O). IR (neat, cmꢁ1): ~n¼2957 (s), 2875 (m), 1741
(s), 1646 (w), 1438 (m), 1417 (w), 1382 (w), 1361 (w),
1322 (w), 1302 (m), 1261 (m), 1201 (m), 1164 (s), 1119
(s), 1100 (m), 1066 (s), 1019 (m), 875 (w), 823 (w), 806
(w). MS (EI, 70 eV): m/z (%)¼143 (M+, 76), 129 (20),
112 (14), 95 (34), 83 (75), 70 (100). HRMS (ESI): Calcd
for C7H12O3 ([M+1]+): 145.08647; found: 145.08567.
3.3.4. tert-Butyl (tetrahydrofuran-2-yl)acetate (5d). Start-
ing with 3d (0.200 g, 1.09 mmol) and Pd/C (10% Pd,
0.580 g, 0.5 mmol) in ethanol (10 mL), 5d was isolated after
chromatography (silica gel, n-hexane/EtOAc¼100:1/
1
10:1) as a colorless oil (0.170 g, 83%). H NMR (CDCl3,
300 MHz): d¼1.45 (s, 9H, OtBu), 1.51–1.61 (m, 1H, CH2),
1.84–1.94 (m, 2H, CH2), 2.01–2.10 (m, 1H, CH2), 2.36
(dd, J¼15.1, 6.7 Hz, 1H, CH2), 2.53 (dd, J¼15.1, 6.7 Hz,
1H, CH2), 3.70–3.78 (m, 1H, OCH2), 3.83–3.91 (m, 1H,
OCH2), 4.20 (quint, J¼6.7 Hz, 1H, OCH). 13C NMR
(CDCl3, 50 MHz): dC¼25.5 (CH2), 28.0 (OtBu), 31.1, 41.8
(CH2), 68.9 (OCH2), 75.4 (OCH), 80.4 (OtBu), 170.6
(O]C–O). IR (neat, cmꢁ1): ~n¼2976 (m), 2946 (w), 2936
(w), 2874 (w), 1730 (s), 1455 (w), 1390 (w), 1368 (m),
1300 (w), 1288 (w), 1257 (m), 1208 (w), 1154 (s), 1102
(w), 1068 (m), 1020 (w). MS (EI, 70 eV): m/z (%)¼186
(M+, 1), 157 (12), 141 (4), 129 (49), 114 (17), 102 (16), 73
(10), 72 (96), 70 (45), 57 (100). MS (DCI, NH3): m/z
(%)¼390 ([2ꢂM+NH4]+, 23), 360 (15), 334 (13), 204
([M+NH4]+, 47), 165 (28), 148 (100). The exact molecular
mass m/z¼186.1256ꢃ2 ppm [M+] for C10H18O3 was con-
firmed by HRMS (EI, 70 eV). Anal. Calcd for C10H18O3
(186.248): C 64.49, H 9.74; found: C 64.52, H 9.75.
3.3.2. Ethyl (tetrahydrofuran-2-yl)acetate (5b). Starting
with 3b (1.000 g, 6.4 mmol) and Pd/C (10% Pd, 3.407 g,
3.2 mmol) in ethanol (25 mL), 5b was isolated without
further purification as a yellowish oil (1.012 g, 100%). GC
(chiral column, 70 ꢀC): retention times (min)¼29.7, 30.5.
1H NMR (CDCl3, 300 MHz): d¼1.15–1.31 (m, 3H, CH3),
1.55–1.69 (m, 1H, CH2), 1.88–1.97 (m, 1H, CH2), 2.05–
2.11 (m, 1H, CH2), 2.28–2.49 (m, 1H, CH2), 2.54–2.79 (m,
2H, CH2), 3.43–3.61 (m, 2H, OCH2), 3.76–3.88 (m, 1H,
OCH), 4.12–4.24 (m, 2H, OCH2). 13C NMR (CDCl3,
75 MHz): dC¼14.2 (CH3), 26.0, 31.5, 39.7 (CH2), 61.4,
64.5 (OCH2), 75 (OCH), 166.7 (O]C–O). IR (neat, cmꢁ1):
~n¼2966 (s), 2875 (w), 1738 (s), 1651 (w), 1446 (m), 1412
(m), 1374 (m), 1304 (m), 1260 (s), 1182 (s), 1164 (s), 1096
(s), 1067 (s), 1030 (s). MS (EI, 70 eV): m/z (%)¼158
(M+, 2), 144 (13), 130 (51), 114 (31), 97 (13), 84 (21), 71
(100).
3.3.5. Methyl (3-methyltetrahydrofuran-2-yl)acetate
(5e). Starting with 3e (0.350 g, 2.24 mmol) and Pd/C (10%
Pd, 1.192 g, 1.12 mmol) in methanol (15 mL), 5e was
isolated after chromatography (silica gel, n-hexane/
EtOAc¼100:1/10:1) as a colorless oil (0.316 g, 89%, an
inseparable 6:5 mixture of diastereomers). 1H NMR
(CDCl3, 200 MHz, for both diastereomers): d¼0.92 (d,
J¼7.0 Hz, 3H, CH3), 1.05 (d, J¼6.5 Hz, 3H, CH3), 1.48–
1.67 (m, 2H, CH2), 1.79–1.96 (m, 1H, CH), 2.01–2.19 (m,
2H, CH2), 2.28–2.39 (m, 1H, CH), 2.42–2.61 (m, 4H,
2ꢂCH2), 3.70 (s, 6H, 2ꢂOCH3), 3.71–3.98 (m, 5H,
2ꢂOCH2, OCH), 4.19–4.29 (m, 1H, OCH). 13C NMR
(CDCl3, 50 MHz): Major diastereomer: dC¼16.8 (CH3),
34.3 (CH2), 39.0 (CH), 39.2 (CH2), 51.6 (OCH3), 67.0
(OCH2), 81.7 (OCH), 171.9 (O]C–O). Minor diastereo-
mer: dC¼14.2, 33.5, 35.3, 36.0, 51.6, 66.4, 77.6, 172.1. IR
(neat, cmꢁ1): ~n¼2961 (s), 2876 (m), 1741 (s), 1455 (m),
1438 (m), 1381 (w), 1325 (w), 1303 (w), 1282 (m), 1257
(w), 1198 (m), 1169 (s), 1128 (w), 1107 (w), 1087 (m),
1043 (w), 1016 (m). MS (EI, 70 eV): m/z (%)¼158 (M+,
3), 143 (2), 130 (30), 127 (6), 98 (17), 85 (100), 72 (21).
The exact molecular mass m/z¼158.0943ꢃ2 ppm [M+] for
C8H14O3 was confirmed by HRMS (EI, 70 eV).
3.3.3. iso-Propyl (tetrahydrofuran-2-yl)acetate (5c).
Method A: Starting with 3c (0.150 g, 0.88 mmol) and Pd/C
(10% Pd, 0.469 g, 0.44 mmol) in ethanol (10 mL), 5c was
isolated without further purification as a slightly yellowish
oil (0.152 g, 100%). Method B: Starting with 4b (0.250 g,
1.25 mmol) and Pd/C (0.664 g, 10% Pd, 0.62 mmol) in
methanol (15 mL), 5c was isolated without further purifica-
1
tion as a slightly yellowish oil (0.179 g, 83%). H NMR

E. Bellur et al. / Tetrahedron 62 (2006) 7132–7139
7137
3.3.6. Ethyl (3-ethyltetrahydrofuran-2-yl)acetate (5f).
Starting with 3f (0.280 g, 1.52 mmol) and Pd/C (10% Pd,
0.809 g, 0.76 mmol) in ethanol (15 mL), 5f was isolated after
chromatography (silica gel, n-hexane/EtOAc¼100:1/
10:1) as slightly yellowish oil (0.268 g, 95%, inseparable
6:5 mixture of diastereomers). 1H NMR (CDCl3, 300 MHz,
for both diastereomers): d¼0.94 (dt, J¼7.2, 4.8 Hz, 6H, 2ꢂ
CH3), 1.27 (t, J¼7.2 Hz, 6H, 2ꢂOCH2CH3), 1.32–1.48 (m,
1H, CH), 1.50–1.66 (m, 4H, 2ꢂCH2), 1.70–1.82 (m, 1H,
CH), 2 00–2.22 (m, 4H, 2ꢂCH2), 2.36–2.43 (m, 2H, CH2),
2.45–2.56 (m, 2H, CH2), 3.73 (q, J¼7.8 Hz, 1H, OCH),
3.80 (t, J¼6.0 Hz, 2H, OCH2), 3.84–3.97 (m, 2H, OCH2),
4.17 (q, J¼7.2 Hz, 4H, 2ꢂOCH2CH3), 4.37 (q, J¼6.6 Hz,
1H, OCH). 13C NMR (CDCl3, 50 MHz): Major diastereo-
mer: dC¼12.6, 14.1 (CH3), 25.5, 32.0, 40.1 (CH2), 46.2
(CH), 60.4 (OCH2CH3), 67.1 (OCH2), 80.3 (OCH), 171.8
(O]C–O). Minor diastereomer: dC¼12.8, 14.1, 21.9, 30.5,
36.2, 43.3, 60.4, 66.6, 77.4, 171.5. IR (neat, cmꢁ1):
~n¼2965 (s), 2934 (m), 2876 (m), 1738 (s), 1459 (w), 1377
(w), 1309 (m), 1261 (m), 1172 (s), 1141 (w), 1082 (m),
1036 (s). MS (EI, 70 eV): m/z (%)¼186 (M+, 1), 158 (44),
143 (22), 130 (5), 116 (10), 110 (13), 99 (100), 84 (16), 70
(31). The exact molecular mass m/z¼186.1256ꢃ2 ppm
[M+] for C10H18O3 was confirmed by HRMS (EI, 70 eV).
J¼6.6 Hz, 1H, OCH), 4.15 (q, J¼7.2 Hz, 2H, OCH2), 4.24
(quint, J¼6.6 Hz, 1H, OCH). 13C NMR (CDCl3, 50 MHz):
Major diastereomer: dC¼9.8, 13.8 (CH3), 28.5, 30.0, 30.7,
40.9 (CH2), 59.9 (OCH2), 74.9, 80.6 (CH), 170.9 (O]C–O).
Minor diastereomer: dC¼9.8, 13.8, 28.3, 30.9, 31.5, 40.6,
59.9, 74.5, 79.9, 170.8. IR (neat, cmꢁ1): ~n¼2969 (s), 2936
(m), 2877 (m), 1737 (s), 1462 (m), 1376 (m), 1299 (m),
1252 (m), 1193 (s), 1165 (s), 1079 (s), 1036 (s), 957 (w).
MS (EI, 70 eV): m/z (%)¼186 (M+, 4), 171 (4), 157 (64),
141 (6), 130 (78), 126 (5), 114 (27), 110 (100), 99 (78), 83
(54), 70 (76). MS (DCI, NH3): m/z (%)¼204 ([M+NH4]+,
100), 192 (43), 187 (M+, 7), 151 (43), 134 (35), 108 (10).
HRMS (ESI): Calcd for C10H18O3 ([M+1]+): 187.13342;
found: 187.13281. Anal. Calcd for C10H18O3 (186.248): C
64.49, H 9.74; found: C 64.46, H 9.78.
3.3.9. Methyl (5-chloromethyltetrahydrofuran-2-yl)ace-
tate (8b). Starting with 7b (0.500 g, 2.62 mmol) and Pd/C
(10% Pd, 1.396 g, 1.31 mmol) in methanol (30 mL), 8b
was isolated without further purification as a slightly yellow-
ish oil (0.505 g, 100%, inseparable 10:1 [syn/anti] mixture
of diastereomers). 1H NMR (CDCl3, 300 MHz): Major dia-
stereomer: d¼1.56–1.73 (m, 1H, CH2), 1.84–1.89 (m, 1H,
CH2), 2.04–2.10 (m, 2H, CH2), 2.52 (dd, J¼15.3, 2.7 Hz,
1H, CH2), 2.67 (dd, J¼15.3, 3.0 Hz, 1H, CH2), 3.45–3.63
(m, 2H, CH2–Cl), 3.70 (s, 3H, OCH3), 4.19 (m, 1H, OCH),
4.34 (m, 1H, OCH). 13C NMR (CDCl3, 75 MHz): Major dia-
stereomer: dC¼27.8, 29.8, 39.4 (CH2), 46.0 (CH2–Cl), 51.0
(OCH3), 75.1, 77.5 (OCH), 170.1 (O]C–O). IR (neat, cmꢁ1):
~n¼2955 (m), 2927 (w), 2879 (w), 1739 (s), 1649 (w), 1439
(m), 1390 (w), 1377 (w), 1352 (w), 1320 (w), 1298 (w),
1278 (w), 1260 (w), 1201 (m), 1177 (m), 1093 (m), 1065
(m), 1012 (w), 901 (w), 883 (w), 796 (w), 746 (w). MS
(EI, 70 eV): m/z (%)¼192 (M+, 1), 163 (1), 161 (5), 157
(17), 143 (100), 132 (4), 127 (1), 125 (5), 121 (19), 119
(60), 116 (36), 110 (71), 103 (2), 101 (21), 85 (6), 83 (65),
77 (5), 75 (11), 72 (8), 70 (19). HRMS (ESI): Calcd for
C8H13ClO3 [M+]: 193.0440 (37Cl), 191.0469 (35Cl); found:
193.0440 (37Cl), 191.0466 (35Cl).
3.3.7. Octahydro-[2,30]bifuranyl-20-one (5g). Starting with
3g (0.300 g, 1.95 mmol) and Pd/C (10% Pd, 0.500 g,
0.47 mmol) in ethanol (10 mL), 5g was isolated after chro-
matography (silica gel, n-hexane/EtOAc¼50:1/1:1) as
a colorless oil (0.261 g, 86%, an inseparable 3:2 mixture of
1
diastereomers). H NMR (CDCl3, 300 MHz, for both dia-
stereomers): d¼1.66–1.77 (m, 1H, CH2), 1.84–2.07 (m, 6H,
3ꢂCH2), 2.11–2.46 (m, 5H, 3ꢂCH2), 2.64–7.72 (m, 1H,
CH of minor diastereomer), 2.82–2.89 (m, 1H, CH of major
diastereomer), 3.72–3.82 (m, 2H, OCH2), 3.84–3.92 (m, 2H,
OCH2), 4.13–4.20 (m, 2H, OCH2), 4.21–4.29 (m, 2H,
OCH2), 4.34–4.43 (m, 2H, 2ꢂOCH). 13C NMR (CDCl3,
50 MHz): Major diastereomer: dC¼25.8, 26.1, 28.0 (CH2),
42.7 (CH), 67.0, 68.7 (OCH2), 78.8 (OCH), 177.1 (O]C–O).
Minor diastereomer: dC¼23.9, 25.8, 29.9, 44.0, 66.9, 68.4,
77.4, 177.5. IR (neat, cmꢁ1): ~n¼2078 (m), 2915 (w), 2876
(m), 1768 (s), 1455 (w), 1380 (m), 1218 (m), 1167 (s),
1133 (w), 1070 (m), 1026 (s), 956 (w). MS (EI, 70 eV): m/z
(%)¼155 (M+, 27), 141 (7), 128 (19), 112 (9), 97 (5), 86
(24), 72 (77), 70 (53), 57 (48), 55 (43), 41 (100). Anal. Calcd
for C8H12O3 (156.181): C 61.52, H 7.74; found: C 61.46,
H 7.94.
3.3.10. Ethyl (4-methoxypyrrolidin-2-yl)acetate (11).
Starting with 1021a (0.200 g, 1.08 mmol) and Pd/C
(0.345 g, 10% Pd, 0.32 mmol) in ethanol (10 mL), 11 was
isolated without further purification as a yellowish oil
(0.202 g, 100%, inseparable 10:1 mixture of diastereomers).
1H NMR (CDCl3, 300 MHz): Major diastereomer: d¼1.26
(dt, J¼7.2, 1.8 Hz, 3H, CH3), 1.94 (dt, J¼10.6, 3.4 Hz,
1H, CH2), 1.92–1.98 (m, 1H, CH2), 2.87 (dd, J¼17.3,
7.4 Hz, 1H, CH2), 3.22 (dd, J¼17.3, 7.2 Hz, 1H, CH2),
3.33 (s, 3H, OCH3), 3.40 (dd, J¼12.5, 4.9 Hz, 1H, CH2–
NH), 3.54 (d, J¼12.5 Hz, 1H, CH2–NH), 3.71 (q,
J¼7.04 Hz, 1H, CH–NH), 4.07–4.11 (m, 1H, OCH), 4.18
(dq, J¼7.2, 1.8 Hz, 2H, OCH2), 8.00 (br s, 1H, NH). 13C
NMR (CDCl3, 75 MHz): Major diastereomer: dC¼13.9
(CH3), 35.8, 37.0 (CH2), 49.1 (CH2–NH), 54.4 (CH–NH),
56.7 (OCH3), 60.9 (OCH2), 78.4 (OCH), 170.2 (O]C–O).
IR (neat, cmꢁ1): ~n¼3419 (m), 2982 (s), 2937 (s), 2831
(m), 2747 (m), 1732 (s), 1640 (w), 1445 (w), 1403 (m),
1381 (m), 1347 (w), 1324 (m), 1259 (m), 1202 (s), 1106
(s), 1068 (m), 1028 (m). MS (EI, 70 eV): m/z (%)¼187
(M+, 2), 159 (5), 156 (7), 142 (4), 128 (54), 111 (7), 100
(86), 96 (39), 84 (25), 69 (100). HRMS (ESI): Calcd for
C9H17NO3 ([M+1]+): 188.12867; found: 188.12782.
3.3.8. Ethyl (5-ethyltetrahydrofuran-2-yl)acetate (8a).
Method C: Starting with 6 (0.500 g, 2.74 mmol) and Pd/C
(10% Pd, 1.460 g, 1.37 mmol) in ethanol (30 mL), 8a was
isolated after chromatography (silica gel, n-hexane/
EtOAc¼100:1/3:1) as a colorless oil (0.435 g, 85%, an in-
separable 9:2 [syn/anti] mixture of diastereomers). Method
D: Starting with 7a (0.16 g, 0.87 mmol) and Pd/C (10% Pd,
0.469 g, 0.44 mmol) in ethanol (30 mL), 8awas isolated after
chromatography (silica gel, n-hexane/EtOAc¼100:1/3:1)
as a colorless oil (0.11 g, 70%, an inseparable 3:1 [syn/anti]
1
mixture of diastereomers). H NMR (CDCl3, 300 MHz):
d¼0.91 (t, J¼7.2 Hz, 3H, CH3), 1.26 (t, J¼7.2 Hz, 3H,
CH3), 1.42–1.52 (m, 2H, CH2), 1.53–1.65 (m, 2H, CH2),
1.91–2.11 (m, 2H, CH2), 2.44 (dd, J¼15.0, 6.6 Hz, 1H,
CH2), 2.63 (dd, J¼15.0, 6.6 Hz, 1H, CH2), 3.79 (quint,

7138
E. Bellur et al. / Tetrahedron 62 (2006) 7132–7139
3.4. General procedure for the enzymatic kinetic
resolution of (tetrahydrofuran-2-yl)acetates
by using diazomethane, 70 ꢀC): retention time (min)¼18.7,
86.3% ee. Rotation (CDCl3): [a]2D0 ꢁ6.9. 1H NMR (CDCl3,
300 MHz): d¼1.52–1.64 (m, 1H, CH2), 1.89–2.00 (m, 2H,
CH2), 2.08–2.18 (m, 1H, CH2), 2.58 (d, J¼0.9 Hz, 1H,
CH2), 2.60 (d, J¼2.1 Hz, 1H, CH2), 3.77–3.84 (m, 1H,
OCH2), 3.90–3.97 (m, 1H, OCH2), 4.26 (quint, J¼6.9 Hz,
1H, OCH), 9.93 (br s, 1H, OH). 13C NMR (CDCl3,
75 MHz): dC¼25.5, 31.2, 40.0 (CH2), 68.2 (OCH2), 75.0
(OCH), 174.7 (O]C–OH). IR (neat, cmꢁ1): ~n¼3404 (br),
2926 (m), 2861 (w), 1722 (s), 1433 (w), 1276 (w), 1261
(w), 1255 (w), 1252 (w), 1201 (w), 1171 (w), 1099 (w),
1058 (m). MS (EI, 70 eV): m/z (%)¼130 (M+, 14), 83 (1),
72 (1), 55 (3), 44 (100), 28 (97). MS (EI, 70 eV): m/z
(%)¼130 (M+, 14), 83 (1), 72 (1), 55 (3), 44 (100), 28 (97).
3.4.1. Analytical scale. For small-scale reactions, (tetra-
hydrofuran-2yl)acetate (5a,b) (0.025–0.035 mmol) and re-
combinant esterase Est56 solution (100 ml) were dissolved
in phosphate buffer (ad 1000 mL, 50 mM, pH 7.5) and tolu-
ene (10% v/v). The mixture was shaken in a thermoshaker at
37 ꢀC and 1400 rpm. After certain time intervals, to the
sample (100 mL) taken, distilled water (100 mL) was added.
The sample was acidified by HCl (aq, 1 N) addition, and
extracted with diethylether (3ꢂ200 mL). The combined
organic extracts were dried (Na2SO4) and from this solution,
enantiomeric excess and conversions were determined by
GC analysis. For 5a,b, first substrate (ester) was extracted
at neutral to basic pH, and then after acidification, the free
acid, which was produced during the enzymatic hydrolysis,
was extracted separately.
3.4.6. Co-injection of (L)-5a and (L)-12. GC (chiral col-
umn, after conversion of the acid to the methyl ester by using
diazomethane, 70 ꢀC): retention times (min)¼18.8 and 19.4.
3.4.2. Preparative scale. The substrate (5a) (0.25–
0.35 mmol) was added to a solution of recombinant esterase
Est56 (crude extract with 50 U/mL, based on a p-nitrophenyl
acetate assay, 1.0 mL) in phosphate buffer (50 mM, pH 7.5,
9 mL) and the mixture was stirred at 37 ꢀC until 50% conver-
sion (determined by GC analysis) was reached. Method 1: To
the reaction mixturewas added HCl (aq, 10%, 10 mL) and the
resulting acidic mixture was extracted with dichloromethane
(4ꢂ20 mL). The combined organic extracts were dried
(Na2SO4), filtered, and the filtrate was concentrated in vacuo.
The residue was purified by column chromatography (silica
gel, n-hexane/EtOAc) to give the enantiomerically pure ester
and hydrolysis product (acid), respectively. Method 2: To
the reaction mixture were added water (10 mL) and aq
Na2CO3 solution (concd, 1 mL), and the resulting basic mix-
ture was extracted with dichloromethane (or diethylether)
(4ꢂ20 mL). The combined organic extracts were dried
(Na2SO4), filtered, and the filtrate was concentrated in vacuo
to give the enantiomerically pure ester without further purifi-
cation. The aqueous layer was acidified by HCl addition (aq,
10%) and extracted with dichloromethane (4ꢂ20 mL). The
combined organic extracts were dried (Na2SO4), filtered,
and the filtrate was concentrated in vacuo to give the enantio-
merically pure hydrolysis product (acid) without further puri-
fication. In some cases, the residues were purified by column
chromatography (silica gel, n-hexane/EtOAc) for better
rotation values. Purity and structure of compounds were
confirmed by 1H NMR. For reaction details see Table 5.
Acknowledgements
Financial support from the DAAD (scholarship for E.B.), the
BASF AG, the state of Mecklenburg-Vorpommern (Landes-
forschungsschwerpunkt ‘Neue Wirkstoffe und Screeningver-
€
fahren’), the Deutsche Bundesstiftung Umwelt (Osnabruck,
Germany, grant no AZ13071), and from the Deutsche For-
schungsgemeinschaft is gratefully acknowledged. We thank
the BRAIN AG (Zwingenberg, Germany) and Amano Phar-
maceuticals (Nagoya, Japan) for the provision of enzymes.
References and notes
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(Method 2) Starting with racemic 5a (50 mg, 0.35 mmol)
and Est56 (1.5 mL), (ꢁ)-5a (20 mg, 40%) and (ꢁ)-12
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3.4.4. Methyl (tetrahydrofuran-2-yl)acetate [(L)-5a].23
GC (chiral column, 70 ꢀC): retention time (min)¼18.6,
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12].23 GC (chiral column, after conversion to the methyl ester

E. Bellur et al. / Tetrahedron 62 (2006) 7132–7139
7139
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