Enzymatic resolution of (RS)-β-hydroxy selenides in organic media

Article abstract of DOI:10.1016/j.tetasy.2004.11.007

Kinetic resolutions of a number of β-hydroxy selenides promoted by enzymes were performed using PPL (free Porcine pancreatic lipase), PSL (Amano PS-free Pseudomonas sp. lipase) and CALB (NOVOZYM 435-immobilized Candida Antarctica lipase type B) with (RS)-1-phenylselanyl-propan-2-ol. CALB gave the best results and provided both (R)- and (S)-enantiomers in high enantiomeric purity. A comparative study of the effect of temperature, solvent, enzyme immobilization and the structure of the substrates on the resolution is presented.

Full text of DOI:10.1016/j.tetasy.2004.11.007

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3945–3954
Enzymatic resolution of (RS)-b-hydroxy selenides in organic media
Carlos E. Costa,a,* Giuliano C. Clososki,a Henrique B. Barchesi,a Sandra P. Zanotto,b
M. Grac¸a Nascimentob and Joa˜o V. Comassetoa,*
a
´
Instituto de Quımica, Universidade de Sa˜o Paulo, C.P. 26077, 05599-070, Sa˜o Paulo SP, Brazil
´ ´
Departamento de Quımica, Universidade Federal de Santa Catarina, C.P. 26077, 88040-900, Florianopolis SC, Brazil
b
Received 1 October 2004; accepted 1 November 2004
Abstract—Kinetic resolutions of a number of b-hydroxy selenides promoted by enzymes were performed using PPL (free Porcine
pancreatic lipase), PSL (Amano PS—free Pseudomonas sp. lipase) and CALB (NOVOZYM 435ꢀ—immobilized Candida Antarc-
tica lipase type B) with (RS)-1-phenylselanyl-propan-2-ol. CALB gave the best results and provided both (R)- and (S)-enantiomers
in high enantiomeric purity. A comparative study of the effect of temperature, solvent, enzyme immobilization and the structure of
the substrates on the resolution is presented.
ꢁ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
hydroxy selenides can be used in radical carbon–carbon
bond formation, especially the intramolecular type (radi-
cal cyclizations),6 which is useful for synthesis of organic
molecules.7
Biocatalysis is a powerful synthetic tool to obtain enan-
tiopure building blocks for organic synthesis.1 Selenium
organic compounds have been widely used in useful syn-
thetic transformations2 and enantioselective methodolo-
gies involving this element have been developed.3
However, to our knowledge only one application of bio-
catalysis to prepare enantiopure selenium compounds
has been published to date.4 With the aim of combining
the synthetic potential of the biocatalysis with the
organoselenium chemistry, we initiated a program to ap-
ply biocatalysis in the preparation of enantiopure chiral
selenium organic compounds.5 The selanyl group of b-
Lipases tolerate unnatural substrates and reaction
conditions very well and are ideal candidates to explore
possibilities to prepare enantiopure selenium com-
pounds in transesterification reactions in organic
media. Herein, we report the enzymatic resolution of a
number of b-hydroxy selenides in organic media
(Scheme 1) using free and immobilized lipases in the
presence of vinyl acetate under different experimental
conditions.
OAc
R''
OH
OH
Se
Se
OAc
Se
, Lipase
OH
+
R
+
R''
R
R''
R
solvents (10-25ml)
R'
R'
R'
(S)-1
(R)-2
(RS)-1
a. R = Ph, R' = H, R'' = CH3
O
b. R = Ph, R' = H, R'' = (CH2)2CH3
c. R = Ph, R' = H, R'' = (CH2)5CH3
d. R = Ph, R' = H, R'' = CH(CH3)2
e. R = Ph, R' = H, R'' = Ph
f. R = CH3, R' = H, R'' = Ph
g. R = Ph, R' = SePH, R'' = CH3
h. R = Ph, R' = (CH2)5CH3, R'' = CH3
i. R = Ph, R' = Ph, R'' = CH3
Scheme 1. Lipase-catalyzed transesterification of (RS)-b-hydroxy selenides in organic media.
*
Corresponding authors. Tel.: +55 11 3091 2176; fax: +55 11 3815 5579; e-mail: jvcomass@iq.usp.br
0957-4166/$ - see front matter ꢁ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.007

3946
C. E. Costa et al. / Tetrahedron: Asymmetry 15 (2004) 3945–3954
2. Results and discussion
tivity was achieved for the reaction with CALB, when
both the (S)-1a and (R)-2a were obtained in more than
98% ee at 32ꢂC (Table 1, entries 18 and 19). Control
of the reaction time and temperature, when PSL or
CALB were used as biocatalysts, allowed the isolation
of both (S)-1a and (R)-2a with >99% ee (Table 1, entries
9, 12, 17 and 19).
2.1. Enzymatic resolution
The evaluation of the enzyme enantioselectivity in the
transesterification of b-hydroxy selenides was carried
out with (RS)-1a as the substrate and vinyl acetate as
the acetate donor in organic media. Three lipases, PPL
(free Porcine pancreatic lipase—42units/mg prot), PSL
(Amano PS—free Pseudomonas sp. Lipase—30,000u/g)
and CALB (NOVOZYM 435ꢀ—immobilized Candida
antarctica lipase type B—10,000PLU/g), were chosen
as the enzymes.
The influence of the solvent was also evaluated in the
acylation of (RS)-1a using PSL and CALB in typical
experiments at 32ꢂC in some dry solvents. The conver-
sions were determined measuring the yield of the
products at 24h for PSL and 6h for CALB (Fig. 1). It
was observed that the solvent influenced conversion of
the substrate (enzymatic activity), but no effect in the
enzyme enantioselectivity and enantiopreference, show-
ing the same preference for the (R)-1-phenylselanyl-
Initially, the influence of the temperature was studied
using PPL, PSL and CALB in typical experiments at
5, 10, 20, 32 and 40ꢂC. The conversions were determined
by analyzing the formed products by chiral-GC. Table 1
shows the effects of the temperature on the enzymes in
the resolution of (RS)-1a. The results demonstrated that
the enzymatic activity depends on the temperature em-
ployed. The temperature also had considerable effect
on the enantioselectivity, but no influence in the stereo-
chemical preference for the (R)-1-phenylselanyl-propan-
2-ol enantiomer. It was observed that this enantioprefer-
ence agrees with the KazlauskasÕ rule, an extension of
PrelogÕs rule for hydrolases.8
Hexane
Cyclohexane
t-Butylmethyl
ether
Ethyl ether
Diisopropyl
ether
CALB
PSL-free
Dichloride
methylene
The highest stereoselectivities were obtained using PSL
and CALB at 20–40ꢂC, and the best relation between
enantiomeric excess and conversion was observed at
32ꢂC. In the reaction with PSL both the (S)-1a and
(R)-2a were obtained in more than 92% ee at 32ꢂC
(Table 1, entries 11 and 12), while the best enantioselec-
0
10
20
30
40
50
Conversion / %
Figure 1. Effect of the solvent in the lipase-catalyzed kinetic resolution
of (RS)-1-phenylselanyl-propan-2-ol (1a) at 32ꢂC.
Table 1. Enzymatic resolutiona of (RS)-1-phenylselanyl-propan-2-ol (1a) using different lipases at different temperatures
Entry
Lipase
PPL
Temperature (ꢂC)
Time (h)
Conversion (%)
Ee (S)-1ab (%)
Ee (R)-2ac (%)
Ed
1
2
3
4
5
6
5
10
20
32
32
40
24
24
24
24
98
24
30
39
41
40
49
34
40
57
63
59
81
46
94
90
89
88
84
88
47
33
32
28
28
24
7
PSL
5
10
20
32
32
32
40
24
24
24
24
49
72
24
27
28
31
45
51
52
47
37
39
99
99
>200
>200
>200
161
8
9
45
80
>99
97
10
11
12
13
98
95
92
179
>125
106
>99
85
95
14
15
16
17
18
19
20
CALB
5
10
20
32
32
32
40
6
6
6
2
4
6
5
43
47
48
45
49
50
51
76
88
>99
>99
>99
>99
99
>200
>200
>200
>200
>200
>200
>200
90
80
98
>99
>99
99
98
a The reactions were performed with 0.5mmol of (RS)-1a and 1g of PPL, 100mg of PSL or 15mg of CALB in hexane (25mL for PPL and PSL or
10mL for CALB).
b Enantiomeric excess of the recovered alcohol (S)-1a.
c Enantiomeric excess of the acetate (R)-2a.
d Enantiomeric ratio: this parameter describes the enantioselectivity of the enzyme.

C. E. Costa et al. / Tetrahedron: Asymmetry 15 (2004) 3945–3954
3947
propan-2-ol 1a enantiomer. In all solvents (R)-2a was
obtained in more than 97% ee using PSL and in more
than 99% ee using CALB. The highest enzymatic activ-
ities were observed in nonpolar solvents as hexane
and cyclohexane, while in polar solvents the enzymatic
activity decreased.
PSL immobilized in agar gel and montmorillonite
K10, while using silica or sodium caseinate film as the
support the enzymatic activity decreased. However, the
immobilization of PSL in PEO increased its activity. A
rationalization for this result could be based on the dif-
fusion processes of the reagents and products from the
support to the reaction medium and also due to the
maintenance of the enzyme original structure. Using
PEO, the diffusion was faster than when agar gel was
used.9 In all employed systems (R)-2a was obtained in
more than 92% ee at 35ꢂC. The product (R)-2a was ob-
tained with 92% ee and the unreacted substrate (S)-1a
with >99% ee with 52% of conversion within 24h reac-
tion time, while 45% of conversion and 80% ee for (S)-
1a and 97% ee for (R)-2a were obtained using the free
lipase. The stereochemical preference for the (R)-1-phen-
ylselanyl-propan-2-ol 1a enantiomer leading to the ace-
tate (R)-2a is the same with PSL-free or immobilized,
regardless of the support used.
Enzyme immobilization is a valuable tool for modifying
the kinetic resolution parameters. For instance, PSL
immobilized in agar gel, silica, sodium caseinate film,
poly(ethylene oxide) (PEO) film and montmorillonite
K10. The influence of the support was evaluated by
reacting compound (RS)-1a with the supported en-
zymes, under the same experimental conditions used
for the free enzyme reaction. The results showed the
dependence of the enzymatic activity on the kind of sup-
port employed (Fig. 2). No product was detected using
As discussed above, CALB in hexane at 32ꢂC was found
to be the system of choice to perform the kinetic resolu-
tion of (R,S)-1a. These experiments aimed to investigate
the influence of the R0 0 substituent in the resolution
parameters. In this way, the kinetic resolutions of sele-
nides (R,S)-1b–e (Scheme 1) were performed by mixing
of the substrate (0.5mmol), CALB (300mg) and vinyl
acetate in hexane. Initially, the reaction with (R,S)-1b
was performed at 32ꢂC. However at this temperature
the reaction presented low enzymatic activity (Table 2,
entries 1–3). In view of this fact all reactions were then
performed at 40ꢂC, since at this temperature the enzy-
matic activity of CALB is higher (Table 1, entry 20).
In all cases, the stereochemical preference for the R-
enantiomer was evidenced. The results in Table 2 show
that the reaction time and0 0 the enantioselectivity are
affected by the size of the R group. The presence of a
50
40
30
20
Conversion / %
10
00
PSL - PEO
PSL - Free
PSL - Silica
24
Time / h
18
12
Systems
PSL - Sodium Caseinate
6
Figure 2. Immobilized Pseudomonas sp. lipase (PSL) versus time in
the resolution of (RS)-1-phenylselanyl-propan-2-ol 1a in hexane at
35ꢂC.
Table 2. Enzymatic resolutiona of b-hydroxy selenides with CALB at different temperatures
Entry
Substrate
Temperatures (ꢂC)
Time (days)
Conversion (%)
Ee 1 (%)b
Ee 2 (%)c
Absolut. config.d
Ee
1
2
3
4
5
6
(RS)-1b
32
4
12
16
2
46
56
58
41
58
59
66
99
91
78
71
88
72
70
(S)
(S)
(S)
(S)
(S)
(S)
42
41
41
29
27
28
>99
62
40
40
40
7
98
>99
9
7
8
9
(RS)-1c
(RS)-1d
5
7
9
35
46
59
22
32
42
41
37
33
(S)
(S)
(S)
3
3
3
10
11
12
12
15
20
29
35
45
36
47
69
90
89
86
(S)
(S)
(S)
27
27
29
13
14
15
16
(RS)-1e
(RS)-1f
40
40
20
10
15
20
<1
23
32
36
—
24
32
41
—
79
76
74
—
—
10
10
10
(R)
(R)
(R)
a The reactions were performed with CALB (300mg) in hexane (10mL).
b Enantiomeric excess of the recovered alcohol 1.
c Enantiomeric excess of the acetate 2.
d Absolute configuration of the recovered alcohol 1.
e Enantiomeric ratio: this parameter describes the enantioselectivity of the enzyme.

3948
C. E. Costa et al. / Tetrahedron: Asymmetry 15 (2004) 3945–3954
Table 3. Enzymatic resolutiona of 1g–i with CALB at 32ꢂC
large-sized substitute [compounds (RS)-1b and c] or a
ramification [compound (RS)-1d] had a negative influ-
ence on the kinetic resolution and, in the case of com-
pound (RS)-1e, no acetylated product was detected
(Table 2, entry 13).
Entry
Substrate
Time
(h)
Conv.
(%)
Ee
(%)
Ee
(%)
Eb
1
2
3
(RS)-1g
(RS)-1h
(RS)-1i
25
50
72
50
48
48
99c
93e
92g
>99d
>99f
>99h
>200
>200
>200
These results are in agreement with the literature on the
structural requirements that a secondary alcohol needs
to be successfully resolved with lipases.10 A recent study
using CALB, showed that alcohols bearing a medium-
sized substituent larger than an ethyl group or a
large-sized substituent smaller than a n-propyl group
led to poor enantiomeric ratio (E) values.11 According
to KazlauskasÕs rule,8 our results showed that, for the
b-hydroxy selenides (RS)-1a–e, the phenyl seleno group
behaved as a large substituent. To evaluate the effect
of the size of the seleno group in the resolution of the
b-hydroxy selenides, (RS)-1f was synthesized. This com-
pound has a phenyl group as the R0 group (large-sized)
and a methyl seleno group instead of the phenyl seleno
group (R = Me). The enzymatic resolution of (RS)-1f
presented the stereochemical preference for the S-
enantiomer, differently of the others compounds (Table
2, entries 14–16). According to KazlauskasÕs rule,8 the
methyl seleno group behaved as a medium-sized group,
larger than the ethyl group in the enzymatic resolution
using CALB, leading to poor enantiomeric ratio (E) val-
ues (Table 2, entries 14–16).
a Reactions were performed with 0.5mmol of (RS)-1 and CALB
(15mg) in hexane (10mL).
b Enantiomeric ratio.
c Enantiomeric excess of the recovered alcohol 1g.
d Enantiomeric excess of the acetate 2g.
e Enantiomeric excess of the recovered alcohol after selenoxide
elimination.
f Enantiomeric excess of the acetate after selenoxide elimination.
g Enantiomeric excess of the recovered alcohol after the phenyl seleno
group removal.
h Enantiomeric excess of the acetate after the phenyl seleno group
removal.
into their corresponding alcohols prior to the chiral GC
analysis (Scheme 2).
2.3. Determination of the absolute configuration
The absolute stereochemistry of alcohol 1a was deter-
mined by NMR. The unreacted substrate (1a >99%
ee) of the kinetic resolution was derivatized with
the two stereoisomers of a-methoxy-a-trifluoromethyl-
phenylacetyl chloride (MTPA-Cl). The proton NMR
spectra of the resulting diastereoisomeric derivatives
presented different chemical shifts. According to
MosherÕs model,12 the differences were originated by
the anisotropic effect of the aromatic ring in a preferred
Considering these results, we realized that b-hydroxy
selenides need a medium-sized substituent smaller than
the ethyl group in order to be successfully resolved by
CALB, like the methyl group in (RS)-1a. In this way,
the enzymatic resolution of the b-hydroxy selenide0s0
( )-1g–i (which have a methyl group as the R
group) was performed by mixing the substrate
(0.5mmol), CALB (15mg) and vinyl acetate in hexane
at 32ꢂC.
OH
OH
1 eq. n-Bu3SnH
PhSe
PhSe
CCN, Toluene
SePh
Under these conditions, compounds 1g–i were success-
fully resolved. The stereochemical preference for the
R-configuration in the stereogenic carbinyl center was
observed, in accordance with our previous results. The
(S)-enantiomer (unreacted substrate) was obtained with
>92% ee and the product [(R)-enantiomer] with >99% ee
(Table 3). These results demonstrated that (RS)-b-hydr-
oxy selenides bearing a medium-sized substituent smal-
ler than the ethyl group as the R00 group, and an alkyl
or aryl group as R0 group (Scheme 1) can be successfully
resolved by CALB.
1a
1g
OH
OH
PhSe
H2O2
1h
3
OH
OH
PhSe
1 eq. n-Bu3SnH
Ph
CCN, Toluene
Ph
2.2. Determination of the enantiomeric excesses
1l
4i
The enantiomeric excesses (ee) of the alcohols 1a–i and
esters 2a–i were calculated from the chiral-GC chroma-
tograms comparing with the racemic samples. For com-
pounds 1g–i and 2c–i, direct analyses were not possible
in view of the poorly resolved chiral chromatograms.
In this way, alcohol 1g was transformed into the b-hydr-
oxy selenide 1a by reductive deselenenylation, alcohol
1h was transformed into its corresponding allyl alcohol
3, alcohol 1i was transformed into its corresponding
selenium free alcohol 4 and esters 2c–i were transformed
OAc
OH
K2CO3
Se
Se
R
R''
R
R''
H2O/MeOH
R'
R'
2c-i
1c-i
f. R = CH3, R' = H, R'' = Ph
g. R = Ph, R' = SePh, R'' = CH3
h. R = Ph, R' = (CH2)5CH3, R'' = CH3
c. R = Ph, R' = H, R'' = (CH2)5CH3
d. R = Ph, R' = H, R'' = CH(CH3)2
e. R = Ph, R' = H, R'' = Ph
Scheme 2. Transformations to determine the ee.

C. E. Costa et al. / Tetrahedron: Asymmetry 15 (2004) 3945–3954
3949
Me
(S)
(S) Me
CH2SePh
H
3. Conclusions
MeO
Ph
F3C
Ph
MeO
F3C
O
CH2SePh
O
View
View
H
(R)
(S)
O
O
This work demonstrated that the presence of a selenium
group in the structure of a secondary alcohol did not in-
hibit the lipase activity and that enantiopure b-hydroxy
selenide 1a can be obtained by enzymatic resolution
using PSL or CALB in organic medium, providing both
(R)- and (S)-enantiomers in high enantiomeric purity. It
should be also mentioned that the immobilization of
PSL in PEO increased its activity, and decreased the
time of the kinetic resolution. This method represents
a simple enantioselective alternative to afford enantio-
mericaly enriched b-hydroxy selenides, which are impor-
tant building blocks in organic synthesis.
Downfield relative to
Upfield relative to
Ha
Hb
Ha
Hb
Ph
Ph
Me
C
Me
C
.
Se
Se
OMe
MeO
Ph
Ph
O
O
(R)
(S)
CF3
CF3
(RS)
(
SS)
δ
δ
δ
δ
δ
δ
Ha(ppm)
=
3.14
3.17
Hb(ppm)
=
2.93
1.44
3.02
4. Experimental
4.1. General
H-Me(ppm) =
1.35
Se(ppm)
=
269.99
271.12
32.40
19.60
C-Se(ppm)
= 32.20
The NMR spectra were recorded on Bruker AC-200,
Varian FT-300 or Bruker DRX-500 spectrometers using
as solvent CDCl3 and as internal reference TMS
(1H NMR), the central peak of the CDCl3 signal (13C
NMR) and a capillary of diphenyl diselenide 1M
(77Se NMR). Infrared spectra (IR) were recorded on a
Perkin–Elmer 1600 spectrophotometer. The mass spec-
tra were performed on GC–MS Shimadzu GC-17A/
QP5050A. Optical rotations were measured on a Jasco,
DIP 370 Digital polarimeter. The chiral GC analyses
were performed on a Shimadzu GC-17A instrument
equipped with flame ionization detector (FID) and
ALFA DEXTM 120 chiral capillary column (packed a-
cyclodextrin, 30m · 0.25mm · 0.25lm, SUPELCOꢀ),
BETA DEXTM 120 chiral capillary column (packed
b-cyclodextrin, 30m · 0.25mm · 0.25lm, SUPELCO),
GAMA DEXTM 120 chiral capillary column (packed
c-cyclodextrin, 30m · 0.25mm · 0.25lm, SUPELCOꢀ)
or CHIRASIL-DEX CB (packed b-cyclodextrin,
25m · 0.25mm · 0.25lm, CRHOMOPACK-Varianꢀ).
H2 was used as a carrier gas in the analyses. CAL-B
(NOVOZYM 435ꢀ immobilized lipase-B from C.
antarctica) was kindly provided by Novozymes Inc.,
PSL (Pseudomonas sp. lipase free) was kindly provided
by Amano Pharmaceutical Co., PPL (Porcine pancreatic
lipase) was purchased from Sigma–Aldrich Chemical
Co.
C-Me(ppm) = 19.70
Figure 3. MosherÕs model for compound 1a.
conformation. This effect allowed the assignment of the
position of the groups on the carbonyl carbon. In addi-
tion, the 13C NMR and 77Se NMR spectra presented the
same effect in their chemical shifts (Fig. 3). Thus the
absolute stereochemistry of alcohol 1a was determined
as being (S).
The b-hydroxy selenides 1b, 1d, 1f, 1h and 1i were trans-
formed into their corresponding selenium free alcohols
by reductive deselenenylation using n-BuSnH (Scheme
3) or by selenoxide elimination (1h—Scheme 2). The
absolute stereochemistry of these alcohols was deter-
mined by comparison of their optical rotations with
the data published in the literature.13–15 The absolute
stereochemistry of b-hydroxy selenide 1c was deter-
mined by comparison of its optical rotation with the
data published in the literature for the (R)-enantiomer.16
Compound 1g was transformed into b-hydroxy selenide
1a by reductive deselenenylation using n-BuSnH
(Scheme 2) and the absolute stereochemistry was deter-
mined by comparison of its optical rotation with our
data for (S)-1a.
4.2. Synthesis
4.2.1. General procedure for the preparation of the
racemic substrates (RS)-1a and (RS)-1e. In a two
necked flask, under nitrogen, diphenyl diselenide
(5mmol) was dissolved in dry ethanol (30mL) and then
sodium borohydride was added slowly at room temper-
ature until the solution became colourless. To the solu-
tion was added the corresponding epoxide (propylene
oxide or styrene oxide—11mmol) and the mixture was
stirred for 2h. A 10% aqueous solution of Na2CO3
(20mL) was added and the reaction mixture was ex-
tracted with ethyl acetate (3 · 20mL). The organic phase
was washed with brine, dried with MgSO4 and evapo-
rated. The residue was purified by silica gel column
OH
OH
n-Bu3SnH
Se
R'
R
R''
R''
CCN, Toluene
R'
1
4
b. R = Ph, R' = H, R'' = (CH2)2CH3
d. R = Ph, R' = H, R'' = CH(CH3)2
f. R = CH3, R' = H, R'' = Ph
b. R = H, R' = (CH2)2CH3
d. R = H, R' = CH(CH3)2
f. R = H, R' = Ph
i. R = Ph, R' = Ph, R'' = CH3
i. R = Ph, R' = CH3
Scheme 3. Transformations for determination of the absolute configu-
ration.

3950
C. E. Costa et al. / Tetrahedron: Asymmetry 15 (2004) 3945–3954
chromatography eluting with hexane–ethyl acetate
(85:15).
4.2.2.2. (RS)-1-(Phenylseleno)-2-octanol, (RS)-1c.
Oil; yield: 0.473g (83%); CAS NR: 52954-45-7; NMR
1H (500MHz): 0.87 (t, 3H, J = 7.1Hz), 1.25–1.31 (m,
8H), 1.51–1.54 (m, 2H), 2.14 (br s, 1 H), 2.87 (dd, 1H,
J = 8.6, 12.7Hz), 3.14 (dd, 1H, J = 3.5, 12.7Hz), 3.63–
3.68 (m, 1H), 7.24–7.27 (m, 3H), 7.51–7.54 (m, 2H);
NMR 13C (125MHz): d 14.0, 22.5, 29.23, 31.7, 36.6,
37.2, 69.8, 127.2, 129.2, 133.0; NMR 77Se (95MHz): d
237.0; IR 691, 736, 1024, 1070, 1478, 1578, 1712, 1799,
1873, 1946, 2855, 2928, 3056, 3070, 3399cmÀ1; MS m/z
(rel int): 286 (68), 172 (96), 158 (71), 129 (23), 91 (78),
77 (70), 69 (96), 55 (100), 51 (48), 45 (42); Anal. Calcd
for C14H22OSe: C, 58.94; H, 7.77. Found: C, 59.31; H,
7.97.
4.2.1.1. (RS)-1-(Phenylseleno)-2-propanol, (RS)-1a.
Oil; yield: 1.913g (89%); CAS NR: 25570-56-3; 1H
NMR (300MHz): d 1.27 (d, 3H, J = 6.2Hz), 2.46 (br
s, 1H), 2.88 (dd, 1H, J = 8.3, 12.7Hz), 3.10 (dd, 1H,
J = 3.9, 12.7Hz), 3.84–3.88 (m, 1H), 7.23–7.28 (m,
3H), 7.50–7.56 (m, 2H); 13C NMR (75MHz): d 22.4,
38.5 (J113CÀ77Se = 64Hz), 66.1, 127.3, 129.3, 129.2,
133.1; NMR 77Se (95MHz):
d 240.8; IR 3390,
3070, 3056, 3016, 2971, 2927, 1578, 1478, 1371, 736,
691cmÀ1; MS m/z (rel int): 216 (60), 215 (4), 172 (47),
158 (57), 157 (50), 91 (100), 77 (72), 78 (89), 59 (68),
51 (63), 45 (53); Anal. Calcd for C9H12OSe: C, 50.24;
H, 5.62. Found: C, 49.86; H, 5.63.
4.2.2.3. (RS)-1-(Phenylseleno)-3-methyl-2-butanol,
(RS)-1d. Oil; yield: 0.379g (78%); CAS NR: 68395-
1
4.2.1.2. (RS)-1-Phenyl-2-(phenylseleno)-ethanol, (RS)-
1e. Oil; yield: 1.800g (65%); CAS NR: 51558-95-3;
98-2; NMR H (500MHz): d 0.89–0.93 (m, 6H), 1.74–
1.80 (m, 1H), 2.89 (dd, 1H, J = 9.5, 12.7Hz), 3.17 (dd,
1H, J = 3.0, 12.7Hz), 3.40–3.44 (m, 1H), 7.23–7.28 (m,
3H), 7.50–7.54 (m, 2H); NMR 13C (125MHz): d 17.7,
18.7, 33.3, 34.9, 74.5, 127.2, 129.2, 129.3, 133.0; NMR
77Se (95MHz): d 240.8; IR 691, 737, 1472, 1578, 1801,
1874, 2874, 2960, 3429; MS m/z (rel int): 244 (57), 183
(4), 172 (71), 157 (72), 91 (74), 77 (76), 69 (100), 51
(60), 45 (44); Anal. Calcd for C11H16OSe: C, 54.32; H,
6.63. Found: C, 54.75; H, 7.05.
1
NMR H (300MHz): d 2.83 (d, 1H, J = 2.8Hz), 3.13
(dd, 1H, J = 9.3, 12.8Hz), 3.29 (dd, 1H J = 3.8,
12.8Hz), 4.73 (dd, 1H, J = 3.8, 9.3Hz), 7.24–7.33 (m,
8H), 7.52–7.55 (m, 2H); NMR 13C (75MHz): d 38.5,
72.3, 125.8, 127.4, 127.9, 128.5, 129.3, 133.1, 133.2,
142.5; NMR 77Se (95MHz): d 251.9; IR 693, 736,
1085, 1437, 1453, 1477, 1578, 2880, 2932, 2983,
3000, 3029, 3058, 3907cmÀ1; MS m/z (rel int): 278
(25), 277 (3), 172 (100), 157 (18), 121 (4), 107 (60),
91 (54), 79 (83), 77 (83); 51 (43), 43 (29); Anal. Calcd
for C14H14OSe: C, 60.66; H, 5.09. Found: C, 60.51; H,
5.34.
4.2.2.4.
(RS)-1-Hexyl-1-(phenylseleno)-2-propanol,
(RS)-1h. Diastereoisomeric mixture; oil; yield: 0514g
(86%); NMR 1H (300MHz): d 0.85–0.93 (m, 6H),
1.18–1.76 (m, 26H), 2.08 (br s, 1H), 2.12 (br s, 1H),
2.97–3.03 (m, 1H), 3.25–3.76 (m, 1H), 3.65–3.76 (m,
1H), 3.80–3.88 (m, 1H), 7.20–7.30 (m, 6H), 7.56–7.60
(m, 4H); NMR 13C (75MHz): d 14.0, 19.8, 20.5, 22.6,
28.1, 28.4, 29.0, 29.1, 31.1, 31.6, 31.7, 31.9, 57.8, 58.0,
68.9, 69.3, 127.5, 127.6, 129.0, 129.1, 129.6, 134.4,
134.9; MS m/z (rel int): 300 (30), 255 (6), 172 (5), 158
(59), 157 (24), 91 (16), 78 (49), 77 (40), 69 (100), 55
(96), 51 (20), 45 (63); Anal. Calcd for C15H24OSe: C,
60.19; H, 8.08. Found: C, 60.34; H, 8.37.
4.2.2. General procedure for the preparation of the
racemic substrates (RS)-1b–d, (RS)-1h and i. In a two
necked flask, under nitrogen, the appropriate seleno-
acetal (2mmol)2,17 was dissolved in dry THF (8mL).
n-Butyl lithium (2mmol in hexane) was added slowly
at À78ꢂC and the reaction mixture was stirred for
30min. To the solution was added the corresponding
aldehyde (propynaldehyde, isobutyraldehyde, heptalde-
hyde, acetaldehyde—2mmol) and the mixture was stir-
red for 20min at À78ꢂC and then for 1h at room
temperature. After this period, NH4Cl solution was
added and the reaction mixture was extracted with ethyl
acetate. The organic phase was washed with brine, dried
with MgSO4 and evaporated. The residue was purified
by silica gel column chromatography eluting with hex-
ane–ethyl acetate (85:15).
4.2.2.5. (RS)-1-Phenyl-1-(phenylseleno)-2-propanol,
(RS)-1i. Diastereoisomeric mixture; oil; yield: 0.512g
1
(88%); CAS NR: 623575-61-1; NMR H (200MHz): d
1.15 (d, 3H, J = 5.7Hz), d 1.24 (d, 3H, J = 5.7Hz),
1.95 (br s, 2H), 4.07–4.26 (m, 4H), 7.02–7.37 (m, 20H);
NMR 13C (75MHz): d 20.5, 20.6, 57.3, 60.1, 69.2,
69.6, 127.1, 127.4, 128.3, 128.4, 128.9, 129.0, 135.1,
135.5; MS m/z (rel int): 292 (11), 247 (4), 158 (30), 157
(15), 135 (86), 117 (51), 91 (62), 78 (32), 77 (39), 57
(73), 51 (25), 43 (100).
4.2.2.1. (RS)-1-(Phenyseleno)-2-pentanol, (RS)-1b.
1
Oil; yield: 0.350g (72%); NMR H (300MHz): d 0.89
(t, 3H, J = 7.20Hz), 1.33–1.37 (m, 1H), 1.44–1.54 (m,
3H), 2.18 (br s, 1H), 2.88 (dd, 1H, J = 8.61, 12.73Hz),
3.14 (dd, 1H, J = 3.51, 12.73Hz), 3.66–3.71 (m, 1H),
7.24–7.27 (m, 3H), 7.52–7.53 (m, 2H); NMR 13C
(75MHz): d 14.2, 19.2, 37.5 (J113CÀ77Se = 64Hz), 39.0,
69.91, 127.5, 129.4, 129.7, 133.3; NMR 77Se (95MHz):
d 234.2; IR 691, 737, 1436, 1459, 1474, 1578, 2870,
2928, 2958, 3063, 3401cmÀ1; MS m/z (rel int): 244
(60), 243 (4), 172 (100), 158 (63), 157 (61), 91 (86), 78
(81), 77 (74), 69 (44), 55 (85), 51 (51), 45 (90), 41 (89);
Anal. Calcd for C11H16OSe: C, 54.32; H, 6.63. Found:
C, 54.08; H, 6.85.
4.2.3. General procedure for the preparation of the
racemic substrate (RS)-1f. To a suspension of ele-
mental selenium (5mmol) in dry THF (25mL) under
nitrogen and with magnetic stirring was added n-
butyllithium (in hexane—5mmol). A yellow solution
was formed. To this solution was added styrene oxide
(5mmol). The mixture was then heated at reflux for
24h. After this period, the mixture was cooled to room
temperature, treated with NH4Cl solution and extracted
with ethyl acetate. The organic phase was washed with

C. E. Costa et al. / Tetrahedron: Asymmetry 15 (2004) 3945–3954
3951
brine, dried with MgSO4 and evaporated. The residue
was purified by silica gel column chromatography elut-
ing with hexane–ethyl acetate (85:15).
for C11H14O2Se: C, 51.37; H, 5.49. Found: C, 51.50;
H, 5.54.
4.2.5.2. (RS)-O-Acetyl-1-(phenylseleno)-2-pentanol,
(RS)-2b. Oil; yield: 0.944g (92%); NMR 1H
(500MHz): d 0.89 (t, 3H, J = 7.4Hz), 1.24–1.36 (m,
2H), 1.94 (s, 3H), 3.07 (d, 2H, J = 6.0Hz), 5.01–5.06
(m, 1H), 7.21–7.33 (m, 3H), 7.51–7.54 (m, 2H); NMR
13C (125MHz): 13.8, 18.5, 21.0, 31.6, 35.9, 73.2, 127.1,
129.1, 130.1, 132.8, 170.6; NMR 77Se (95MHz): d
260.3; IR 692, 738, 1237, 1372, 1435, 1459, 1474, 1578,
1739, 2872, 2960, 3057cmÀ1; MS m/z (rel int): 286
(27), 285 (3), 226 (51), 157 (35), 129 (41), 116 (49), 91
(52), 78 (45), 77(51), 69 (80), 51 (44), 43 (100); Anal.
Calcd for C13H18O2Se: C, 54.74; H, 6.36. Found: C,
54.60; H, 6.36.
4.2.3.1.
(RS)-1-Phenyl-2-(metheylseleno)-ethanol,
(RS)-1f. Oil; yield: 0.828g (77%); CAS NR: 56051-
09-3; NMR 1H (200MHz): d 1.95 (s, 3H), 2.79 (dd,
1H, J = 8.8, 12.7Hz), 2.92 (dd, 1H, J = 3.9 12.7Hz),
4.77 (dd, 1H, J = 3.9, 8.8Hz), 7.24–7.39 (m, 5H);
NMR 13C (50MHz): d 4.7, 35.8, 72.1, 125.7, 127.7,
128.4; NMR 77Se (95MHz): d 30.6; MS m/z (rel int):
216 (53), 121(65), 107(94), 91(80), 77(100), 51(66).
4.2.4. General procedure for the preparation of the
racemic substrate, (RS)-1g. In a two necked flask,
under nitrogen, bis(phenylseleno)methane2 (2mmol)
was dissolved in dry THF (8mL), LDA (2mmol) was
slowly added at À78ꢂC and the reaction mixture was
stirred for 30min. To the resulting solution was added
acetaldehyde (2mmol) and the mixture was stirred for
20min at À78ꢂC and 1h at room temperature. After this
period, NH4Cl solution was added and the reaction mix-
ture was extracted with ethyl acetate. The organic phase
was washed with brine, dried with MgSO4 and evapo-
rated. The residue was purified by silica gel column
chromatography eluting with hexane–ethyl acetate (9:1).
4.2.5.3. (RS)-O-Acetyl-1-(phenylseleno)-2-octanol,
(RS)-2c. Oil; yield: 0.965g (82%); CAS NR: 67007-
1
28-7; NMR H (500MHz): d 0.86 (t, 3H, J = 7.2Hz),
1.23–1.29 (m, 8H), 1.62–1.70 (m, 2H), 1.93 (s, 3H),
3.06 (d, 2H, J = 6.0Hz), 4.99–5.04 (m, 1H), 7.21–7.28
(m, 3H), 7.51–7.54 (m, 2H); NMR 13C (125MHz): d
14.0, 21.0, 22.5, 25.2, 29.1, 31.6, 33.8, 73.4, 127.6,
129.9, 132.8, 140.9, 170.6; NMR 77Se (95MHz): d
264,0; IR 691, 736, 1022, 1239, 1579, 1738, 2858, 2959,
2955, 3016, 3058cmÀ1; MS m/z (rel int): 328 (15), 268
(44), 171 (25), 158 (6), 91 (46), 77 (38), 69 (89), 43
(100); Anal. Calcd for C16H24O2Se: C, 58.71; H, 5.39.
Found: C, 59.12; H, 7.67.
4.2.4.1. (RS)-1,1-Bis(phenylseleno)propan-2-ol, (RS)-
1g. Oil; yield: 0.540g (73%); CAS NR: 77461-31-5;
1
NMR H (200MHz): d 1.38 (d, 3H, J = 6.1Hz), 2.46
(br s, 1H), 3.89–3.99 (m, 1H), 4.49 (d, 1H, J = 3.1Hz),
7.24–7.30 (m, 6H), 7.53–7.62 (m, 4H); NMR 13C
(50MHz): 20.8, 55.3 (J113CÀ77Se = 86.8Hz), 69.2, 128.1,
128.2, 129.2, 129.3, 129.9, 130.3, 134.3, 135.5; NMR
77Se (95MHz): d 355.0, 357.9; MS m/z (rel int): 372
(6), 314 (13), 215 (31), 157 (62), 117 (22), 91 (77), 77
(93), 51 (72), 43 (100).
4.2.5.4. (RS)-O-Acetyl-1-(phenylseleno)-3-methyl-2-
butanol, (RS)-2d. Oil; yield: 0.985g (96%); NMR H
1
(200MHz): d 0.77–0.98 (m, 7H), 1.95 (s, 3H), 3.05–
3.09 (m, 2H), 4.85–4.97 (m, 1H), 7,23–7.32 (m, 3H),
7.50–7.55 (m, 2H); NMR 13C (125MHz): d 17.3, 18.4,
18.7, 20.8, 47.9, 77.4, 127.0, 129.0, 129.1, 132.9, 170.7;
NMR 77Se (95MHz): d 265.4; IR 694, 739, 1021, 1301,
4.2.5. General procedure for the preparation of the
racemic esters. In a two necked flask, under nitrogen,
the b-hydroxy selenide (3.6mmol) was dissolved in dry
pyridine (5mL) and then acetic anhydride (2mL,
21mmol) was slowly added at 0ꢂC. The reaction mixture
was stirred at room temperature and monitored by
TLC. After 4h, 10% aqueous HCl (5mL) was added
and the reaction mixture was extracted with ethyl ace-
tate (10mL). The organic phase was washed with CuSO4
solution (3 · 15mL) and brine, dried with MgSO4 and
evaporated. The residue was purified by silica gel col-
umn chromatography eluting with hexane–ethyl acetate
(9:1).
1474, 1578, 1744, 2874, 2934, 2965, 3032, 3058cmÀ1
;
MS m/z (rel int): 286 (20), 226 (44), 171 (10), 157 (24),
91 (45), 77 (42), 69 (96), 43 (100); Anal. Calcd for
C13H18O2Se: C, 54.74; H, 6.36. Found: C, 54.91; H,
6.31.
4.2.5.5. (RS)-O-Acetyl-1-phenyl-2-(methylseleno) eth-
anol, (RS)-2f. Oil; yield: 0.851g (92%); CAS NR:
1
56268-17-8; NMR H (200MHz): d 1.91 (s, 3H), 2.09
(s, 3H), 2.87 (dd, 1H, J = 6.6, 12.9Hz), 3.00 (dd, 1H,
J = 7.46, 12.9Hz), 5.86–5.93 (m, 1H), 7.26–7.38 (m,
5H); NMR 13C (50MHz): 5.0, 21.1, 30.7, 75.4, 126.7,
128.3, 128.5, 139.6, 170.0; NMR 77Se (95MHz): d
64.3; MS m/z (rel int): 258 (14), 198 (48), 181 (10), 163
(42), 149 (6), 104 (50), 91 (37), 77 (48), 43 (100).
4.2.5.1. (RS)-O-Acetyl-1-(phenylseleno)-2-propanol,
(RS)-2a. Oil; yield: 0.842g (91%); NMR 1H
(300MHz): d 1.33 (d, 3H, J = 6.30Hz), 1.94 (s, 3H),
2.99 (dd, 1H, J = 6.2, 12.8Hz), 3.10 (dd, 1H J = 6.1,
12.8Hz), 5.04–5.10 (m, 1H), 7.21–7.30 (m, 3H), 7.50–
7.54 (m, 2H); NMR 13C (75MHz): d 19.8, 21.1, 33.0,
70.3, 127.1, 129.1, 129.9, 132.8, 170.4; NMR 77Se
(95MHz): d 264,3; IR 691, 738, 1242, 1371, 1438,
4.2.5.6. (RS)-O-Acetyl-1,1-bis(phenylseleno)propan-2-
ol, (RS)-2g. Oil; yield: 1.424g (96%); NMR 1H
(200MHz): d 1.45 (d, 3H, J = 6.6Hz), 1.88 (s, 3H),
4.52 (d, 1H, J = 3.5Hz), 5.14–5.25 (m, 1H), 7.22–7.33
(m, 6H), 7.52–7.55 (m, 4H); NMR 13C (50MHz): d
18.2, 20.8, 48.8, 72.7, 128.1, 128.2, 129.1, 129.2, 130.2,
130.5, 134.2, 134.9, 170.22; NMR 77Se (95MHz): d
374.7, 382.4; MS m/z (rel int): 414 (7), 257 (46), 215
(58), 197 (52), 157 (46), 116 (34), 91 (31), 77 (64), 51
1453, 1478, 1578, 1737, 2932, 2980, 3057, 3071cmÀ1
;
MS m/z (rel int): 257 (1), 215 (1), 198 (12), 181 (4),
157(5), 101 (13), 78 (7), 77 (11), 43 (100); Anal. Calcd

3952
C. E. Costa et al. / Tetrahedron: Asymmetry 15 (2004) 3945–3954
(52), 43 (100); Anal. Calcd for C17H18O2Se2: C, 49.53;
H, 4.40. Found: C, 49.41; H, 4.68.
4.3.5. (R)-O-Acetyl-1-(phenylseleno)-2-octanol, (R)-2c.
Oil; 33% ee; ½aꢀ = +2 (c 2.0, CH2Cl2).
22
D
4.2.5.7. (RS)-O-Acetyl-1-hexyl-1-(phenylseleno)pro-
pan-2-ol, (RS)-2h. Diastereoisomeric mixture; oil;
yield: 1.154g (94%); NMR H (300MHz): d 0.84–0.90
4.3.6. (S)-1-(Phenylseleno)-3-methyl-2-butanol, (S)-1d.
Oil; 69% ee; ½aꢀ = +47 (c 2.0, CH2Cl2).
20
D
1
(m, 6H), 1.24–1.29 (m, 16H), 1.31 (d, 3H, J = 6.3Hz),
1.36 (d, 3H, J = 6.3Hz), 1.50–1.80 (m, 4H), 1.81 (s,
3H), 1.99 (s, 3H), 3.17–3.23 (m, 1H), 3.27–3.34 (m,
1H), 5.01-5-16 (m, 2H), 7.24–7.27 (m, 6H), 7.55–7.59
(m, 4H); NMR 13C (75MHz): d 14.0, 17.2, 17.2, 20.9,
21.1, 22.5, 28.0, 29.0, 31.4, 31.6, 31.7, 50.5, 51.7, 72.6,
73.0, 127.2, 127.4, 128.9, 129.9, 130.0, 134.0, 134.7,
170.4; MS m/z (rel int): 342 (2), 282 (4), 157 (20), 91
(4), 77 (30), 69 (100), 55 (94), 51 (18); Anal. Calcd for
C17H26O2Se: C, 59.82; H, 7.68. Found: C, 60.4; H, 7.82.
4.3.7. (R)-O-Acetyl-1-(phenylseleno)-3-methyl-2-butanol,
(R)-2d. Oil; 86% ee; ½aꢀ = À12 (c 2.0, CH2Cl2).
20
D
4.3.8. (R)-1-Phenyl-2-(methylseleno)-ethanol, (R)-1f.
22
D
Oil; ee = 41%; ½aꢀ = À55 (c 2.0, CH2Cl2).
4.3.9. (S)-O-Acetyl-1-phenyl-2-(methylseleno) ethanol,
22
D
(S)-2f. Oil; 74% ee; ½aꢀ = +12 (c 2.0, CH2Cl2).
4.3.10. (S)-1,1-Bis(phenylseleno)propan-2-ol, (S)-1g.
21
D
Oil; >99% ee; ½aꢀ = À43 (c 2.0, CH2Cl2).
4.2.5.8. (RS)-O-Acetyl-1-phenyl-1-(phenylseleno)pro-
pan-2-ol, (RS)-2i. Diastereoisomeric mixture; oil; yield:
1.103g (92%); NMR 1H (200MHz): d 1.20 (d, 3H,
J = 6.1Hz), 1.30 (d, 3H, J = 6.1Hz), 1.90 (s, 3H), 1.98
(s, 3H), 4.27–4.37 (m, 2H), 5.33–5.49 (m, 2H), 7.11–
7.28 (m, 16H), 7.35–7.43 (m, 4H); NMR 13C
(125MHz): 18.9, 20.9, 21.1, 53.4, 53.7, 72.4, 73.4,
127.3, 127.7, 127.9, 128.2, 128.4, 128.7, 128.9, 129.1,
129.5, 135.0, 135.4, 170.2, 170.4; MS m/z (rel int): 334
(11), 274 (8), 177 (52), 158 (11), 157 (19), 135 (73), 117
(61), 91 (41), 78 (39), 77 (44), 57 (38), 51 (35), 43
(100); Anal. Calcd for C17H18O2Se: C, 61.26; H, 5.44.
Found: C, 61.42; H, 5.56.
4.3.11. (R)-O-Acetyl-1,1-bis(phenylseleno)propan-2-ol,
(R)-2g. Oil; 99% ee; ½aꢀ = +1 (c 2.0, CH2Cl2).
21
D
4.4. Determination of the enantiomeric excesses
Conditions for GC analysis are as follows. (RS)-1a:
GAMA DEXTM, 135ꢂC, 40min hold, tR1 = 24.7min,
tR2 = 25.2min; (RS)-1b: GAMA DEXTM
70min hold, tR1 = 59.5min, tR2 = 61.2min; (RS)-
,
140ꢂC,
1c: GAMA DEXTM, 150ꢂC, 120min hold, tR1 =
106.2min, tR2 = 107.9min; (RS)-1d: GAMA DEXTM
,
135ꢂC, 70min hold, tR1 = 47.1min, tR2 = 48.3min;
(RS)-1f: GAMA DEXTM
125ꢂC, 85min hold,
tR1 = 75.6min, tR2 = 77.6min; (RS)-2a: BETA DEXTM
125ꢂC, 40min hold, tR1 = 38.0min, tR2 = 38.8min;
(RS)-2b: BETA DEXTM
120ꢂC, 60min hold,
,
4.3. General procedure for the enzymatic resolution
,
To a solution of the substrate (0.5mmol) in the appro-
priate solvent (10–25mL) was added the lipase (15mg–
1g—Tables 1–3) and vinyl acetate (5equiv). The reac-
tion mixture was monitored by chiral GC and stirred
until the conversion reached ca. 50%. The enzymes, free
or immobilized, were removed by filtration and the
resulting solution was concentrated. The organic resi-
dues were subjected to silica gel chromatography to
obtain the acetylated product and the unreacted
enantiomer.
,
tR1 = 54.6min, tR2 = 55.1min; (RS)-3: CHIRASIL-
DEX CB, 60ꢂC, 40min hold, 60–120ꢂC, 0.5ꢂC/min,
15min hold, tR1 = 92.0min, tR2 = 95.2min; (RS)-4:
ALFA DEXTM, 50ꢂC, 60min hold, 50–190ꢂC, 1ꢂC/
min, tR1 = 171.8min, tR2 = 173.7min. The E values
were calculated from the enantiomeric excesses (ee) of
products and substrates, according to Sih, Sharpless
and
FajansÕs
equation
{E = ln[1 À c(1 + eep)]/
ln[1 À c(1 À eep)], where c = ees/(ees + eep)}.18
4.3.1. (S)-1-(Phenylseleno)-2-propanol, (S)-1a. Oil;
4.4.1. General procedure for the hydrolysis of the acetates
2c–i. In a flask the acetate of the appropriate b-hydr-
oxy selenide (1mmol) was dissolved in methanol
(5mL) and then H2O (2mL) was added. To the solution
was added K2CO3 (0.2mmol) and the mixture was stir-
red overnight. After this period, the mixture was ex-
tracted with ethyl acetate and the organic phase was
washed with brine, dried and concentrated to give a resi-
due which was purified by flash chromatography on sil-
ica gel.
>99% ee; yield: 0.049g (46%); ½aꢀ22 = +56 (c 2.0, CH2Cl2).
D
4.3.2. (R)-O-Acetyl-1-(phenylseleno)-2-propanol, (R)-
22
D
2a. Oil; >99% ee; yield: 0.054g (42%); ½aꢀ = À7 (c
2.0, CH2Cl2).
4.3.3. (S)-1-(Phenyseleno)-2-pentanol, (S)-1b. Oil;
23
D
>99% ee; yield: 0.036g (30%); ½aꢀ = +41 (c 2.0,
CH2Cl2).
4.3.4. (R)-O-Acetyl-1-(phenylseleno)-2-pentanol, (R)-
4.5. Determination of the absolute configuration
28
D
2b. Oil; 94% ee; yield: 0.050g (35%); ½aꢀ = +1 (c 2.0,
CH2Cl2).
4.5.1. Esterification of (S)-1-(phenylseleno)-2-propanol
(S)-1a with MosherÕs acid cloride. In a two necked
flask, under nitrogen, the alcohol (S)-1a (0.1mmol),
Et3N (1.2mmol) and DMAP (0.1mmol) were dissolved
in dry CH2Cl2 (10mL). The a-methoxy-a-trifluoro-
methyl-phenylacetyl chloride (0.5mmol) was dissolved
4.3.4.1. (S)-1-(Phenylseleno)-2-octanol, (S)-1c. Oil
22
D
70% ee; ½aꢀ = +12 (c 2.0, CHCl3); lit.16 for
19
the (R)-enantiomer: ½aꢀ = À35.5 (c 0.986, CHCl3) 93%
D
ee.

C. E. Costa et al. / Tetrahedron: Asymmetry 15 (2004) 3945–3954
3953
in dry CH2Cl2 (5mL) and added to the solution of the
alcohol (S)-1a. After 15min the solution was washed
with H2O, dried and concentrated to give a residue
which was purified by flash chromatography on silica
gel.
was stirred for 4h, diluted with water and extract with
several portions of ether. The organic phase was washed
with concentrated aqueous Na2CO3 solution and brine,
dried with MgSO4 and evaporated. The residue was
purified by silica gel column chromatography eluting
with hexane–ethyl acetate (9:1).
4.5.1.1. (1S,2R)-1-Methyl-2-(phenylseleno)ethyl 3,3,3-
trifluoro-2-methoxy-2-phenylpropionate. Oil;
yield:
4.5.3.1. (S)-3-Nonen-2-ol 3 from (1R,2S)-1-hexyl-1-
(phenylseleno)-2-propanol and (1S,2S)-1-hexyl-1-(phenyl-
seleno)-2-propanol. Oil; yield: 0.027g (95%); CAS NR:
173144-01-9; NMR 1H (200MHz): d 0.89 (t, 3H,
J = 4.50Hz), 1.25–1.39 (m, 8H), 1.97–2.04 (m, 3H),
4.22–4.31 (m, 1H), 5.50 (dd, 1H, J = 4.35, 10.45Hz),
5.67 (dt, 1H, J = 4.40, 10.45Hz); E.M., m/z (% rel.):
0.029g (67%); NMR 1H (500MHz): d 1.44 (d, 3H,
J = 6.29Hz), 2.93 (dd, 1H, J = 6.76, 12.82Hz), 3.14
(dd, 1H, J = 6.30, 12.82Hz), 3.55 (s, 3H), 5.25–5.31
(m, 1H), 7.23–7.55 (m, 10H); NMR 13C (125MHz,
CDCl3), d (ppm): 19.7, 32.2, 55.5, 73.1, 165.9; RMN
77Se (95MHz, CDCl3), d (ppm): 269.8; E.M., m/z (%
rel.): 431 (19), 275 (43), 217 (11), 198 (68), 189 (100),
157 (64), 105(49), 91 (37), 77 (78), 69 (17), 51 (32).
142 (1), 124 (25), 84 (23), 71 (100), 68 (72), 58 (30), 54
21
D
(55), 43 (12); 92% ee; ½aꢀ = À8 (c 1.5, CHCl3); lit.15
19
for the (R)-enantiomer: ½aꢀ = +10.68 (c 1.03, CHCl3)
D
4.5.1.2. (1S,2S)-1-Methyl-2-(phenylseleno)ethyl 3,3,3-
97% ee.
trifluoro-2-methoxy-2-phenylpropionate. Oil;
yield:
0.030g (69%); NMR 1H (500MHz): d 1.35 (d, 3H,
J = 6.26Hz), 3.02 (dd, 1H, J = 6.07, 12.88Hz), 3.17
(dd, 1H, J = 6.99, 12.88Hz), 3.58 (s, 3H), 5.24–5.30
(m, 1H), 7.25–7.57 (m, 10H); NMR 13C (125MHz): d
20.0, 32.8, 56.1, 73.5, 166.4; NMR 77Se (95MHz): d
271.0; E.M., m/z (% rel.): 431 (13), 275 (36), 217 (11),
198 (65), 189 (100), 157 (68), 105 (54), 91 (42), 77 (88),
69 (20), 51 (39).
Acknowledgements
We thank FAPESP and CNPq for support. Amano
Pharmaceutical Co. and Novozymes Inc. are acknowl-
edged for their generous gifts of lipases.
References
4.5.2. General procedure for the reductive deselenenyl-
ation. In a two necked flask, under nitrogen, a catalytic
amount of CCN [1,10-azobis(cyclohexanecarbonitrile)]
and the b-hydroxy selenide (0.2mmol) were dissolved
in dry toluene (3mL). To the solution was added triphen-
yltin hydride (0.2mmol) and the mixture was stirred
under reflux for 4h. After this period, the system was
cooled to room temperature, hexane was added and
the mixture was extracted with acetonitrile. The aceto-
nitrile phase was evaporated and the residue was puri-
fied by silica gel column chromatography eluting with
hexane–ethyl acetate (9:1).
1. (a) Davis, B. G.; Boyer, V. Nat. Prod. Rep. 2001, 18, 618–
640; (b) Roberts, S. M. Biocatalysis for fine chemical
synthesis; Oxford University Press: Oxford, 1999.
2. Organoselenium Chemistry; Back, T., Ed.; Oxford Univer-
sity Press: Oxford, 1999.
3. Tiecco, M. Topics in Current Chemistry: Organoselenium
Chemistry: Modern Developments in Organic Synthesis.
In Electrophilic Selenium, Selenocyclizations; Wirth, T.,
Ed.; Springer-Verlag: Heidelberg, 2000.
4. Ferraboschi, P.; Grisenti, P.; Santaniello, E. Synlett 1990,
545.
5. (a) Comasseto, J. V.; Omori, A. T.; Porto, A. L. M.;
Andrade, L. H. Tetrahedron Lett. 2004, 45, 473–476; (b)
Andrade, L. H.; Omori, A. T.; Porto, A. L. M.; Comass-
eto, J. V. J. Mol. Catal. B: Enzym. 2004, 29, 47–54; (c)
Comasseto, J. V.; Andrade, L. H.; Omori, A. T.; Assis, L.
F.; Porto, A. L. M. J. Mol. Catal. B: Enzym. 2004, 29, 55–
61.
4.5.2.1. (R)-Pentan-2-ol (4b) from (S)-1b. Ee >99%;
19
½aꢀ = À12 (c 1.0, CHCl3); lit.13 for the (S)-enantiomer:
D
[a]D = + 10.25 (CHCl3) 79% ee.
6. Tiecco, M.; Testaferri, L.; Bagnoli, L.; Purgatorio, V.;
Temperini, A.; Marini, F.; Santi, C. Tetrahedron: Asym-
metry 2004, 15, 405–412.
7. Besev, M.; Engman, L. Org. Lett. 2002, 4, 3023–3025.
8. Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.;
Cuccia, A. J. Org. Chem. 1991, 56, 2656–2665.
9. Queiroz, N.; Nascimento, M. G. Tetrahedron Lett. 2002,
43, 5225–5227.
10. Faber, K. Biotransformation in Organic Chemistry, 4th ed.;
Springer-Verlag: Berlin, 2000.
11. Rotticci, D.; Hæffner, F.; Orrenius, C.; Norin, T.; Hult, K.
J. Mol. Catal. B: Enzym. 1998, 5, 267–272.
4.5.2.2. (R)-3-Methyl-2-butanol (4d) from (S)-
20
D
1d. Ee = 69%; ½aꢀ = À2 (c 2.0, CHCl3); lit.13 for the
(R)-enantiomer: [a]D = À2.74 (CHCl3) 86% ee.
4.5.2.3. (S)-1-Phenylethanol 4f from (R)-1f.
20
D
Ee = 41%; ½aꢀ = À24 (c 2.0, CHCl3); lit.14 for the
25
(S)-enantiomer: ½aꢀ = À55.1 (c 1.63, CHCl3) >99% ee.
D
4.5.2.4. (S)-1-Phenyl-2-propanol (4i) from [(1R,2S)-1-
phenyl-1-(phenylseleno)-2-propanol and (1S,2S)-1-phenyl-
21
D
1-(phenylseleno)-2-propanol]. Oil; 92% ee; ½aꢀ
25
=
12. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95(2),
512.
13. Keinan, E.; Hafeli, E. K.; Seth, K. K.; Lamed, R. J. Am.
Chem. Soc. 1986, 108, 162–169.
+37 (c 2.0, CHCl3); lit.14 for the (S)-enantiomer:
½aꢀ = +41.7 (c 1.19, CHCl3) >99% ee.
D
4.5.3. Selenoxide elimination. In a flask, the b-hydroxy
selenide (RS)-1h (0.2mmol) was dissolved in THF
(5mL) and hydrogen peroxide (30% sol.—0.6mmol)
was slowly added at room temperature. The mixture
14. Nakamura, K.; Matsuda, T. J. Org. Chem. 1998, 63, 8957–
8964.
15. Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.;
Kozawa, M.; Murata, K.; Katayama, E.; Yokozawa, T.;

3954
C. E. Costa et al. / Tetrahedron: Asymmetry 15 (2004) 3945–3954
Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1998, 120,
13529–13530.
16. Toshimitso, A.; Nakano, K.; Mukai, T.; Tamao, K. J.
Am. Chem. Soc. 1996, 118, 2756–2757.
17. Clarembeau, M.; Cravador, A.; Dumont, W.; Hevesi, L.;
Krief, L.; Lucchetti, J.; Ende, D. V. Tetrahedron 1985, 41,
4793–4812.
18. Sir, C. J.; Wu, S. H. Topics Stereochem. 1989, 19, 63.