Lipase-catalyzed kinetic resolution of (RS)-hydroxy tellurides

Article abstract of DOI:10.1016/j.tetasy.2006.07.024

The enzymatic resolution of racemic mixtures of hydroxy tellurides with a range of lipases has been investigated. Lipase-B from Candida antarctica (CALB) gave the best conversions, providing both enantiomers with high enantiomeric purity. A comparative st

Full text of DOI:10.1016/j.tetasy.2006.07.024

Tetrahedron: Asymmetry 17 (2006) 2252–2259
Lipase-catalyzed kinetic resolution of (RS)-hydroxy tellurides
Alcindo A. Dos Santos,a,* Carlos E. Da Costa,a
Jefferson L. Princivalb and Joao V. Comassetoa
˜
aInstituto de Quı´mica, Universidade de Sa˜o Paulo, C. P. 26077, 05599-070 Sa˜o Paulo SP, Brazil
bDepartamento de Quı´mica Fundamental, Universidade Federal de Pernambuco, 50740-540 Recife PE, Brazil
Received 29 June 2006; accepted 19 July 2006
Available online 22 August 2006
Abstract—The enzymatic resolution of racemic mixtures of hydroxy tellurides with a range of lipases has been investigated. Lipase-B
from Candida antarctica (CALB) gave the best conversions, providing both enantiomers with high enantiomeric purity. A comparative
study of the effect of solvent and substrate on the enzymatic kinetic resolution was performed.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
O
O
M = Li,
1/2CuCNLi.LiCl
M
Li
TeBu
TeBu
Several synthetic methods based on tellurium reagents are
available for the transformation of functional groups and
for the creation of carbon–carbon bonds.1,2 Most of these
processes included in the latter category involve the stereo-
selective synthesis of olefins through the appropriate
manipulation of vinyl tellurides.3 In recent years, these re-
agents have been employed in the total stereoselective syn-
thesis of natural products.4 In contrast, the alkyl tellurides
have been less exploited owing to negative reports concern-
ing their instability in light and air, their toxicity and their
unpleasant odour.5 Recent studies in our laboratory, how-
ever, have shown that such disadvantageous properties do
not always apply.6
ref. 8
ref. 9
2
1
OH
OLi
3
4
Scheme 1. Homoenolates and 1,4-dianions derived from alkyl tellurides.
ural substrates, perform enantioselective hydrolyses and
catalyze the formation of ester and amide bonds.14
Recently, we have reported the enzymatic resolution in
organic media of a range of hydroxy selenides.15 As an
extension of, and a complement to, our previous biocata-
lytic studies of chalcogen-based compounds, we here report
an investigation concerning the enzymatic resolution of
hydroxy tellurides in organic media (Scheme 2). To the best
of our knowledge, enzymatic kinetic resolution has not
previously been used for this purpose.
Functionalized tellurides 1 and 3 have previously been pre-
pared7–9 and used as a source of homoenolates 28 and 1,4-
dianions 49 via a tellurium/lithium exchange reaction
(Scheme 1).1,2,8–11
This peculiar reactivity of the functionalized alkyl tellurides
makes them potential precursors of enantiomerically pure
building blocks for organic synthesis. Among the methods
available for preparing enantiomerically pure reagents, bio-
catalysis,12 particularly involving enzymatic kinetic resolu-
tion,13 is most often employed. In this context, lipases offer
a number of distinct advantages since they tolerate unnat-
2. Results and discussion
2.1. Preparation of hydroxy tellurides 5a–f
Hydroxy tellurides 5a–f were prepared according to pub-
lished procedures as summarized in Figure 1. Sodium phen-
yltellurolate, formed from diphenyl ditelluride and
sodium borohydride,16 gave 5a in 81% isolated yield upon
*
Corresponding author. Tel.: +55 (011)30911180; e-mail: alcindo@
iq.usp.br
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.024

A. A. Dos Santos et al. / Tetrahedron: Asymmetry 17 (2006) 2252–2259
2253
The tellurides described in the present work were light yel-
low oils and were either odourless or presented odours that
were no more unpleasant than many other reagents used in
organic synthesis. The compounds were stable to ambient
light and could be manipulated in air with no appreciable
decomposition. However, prolonged contact with air, espe-
cially when dissolved in hexane or ethyl acetate, should be
avoided. Decomposition of the tellurides in solution can be
minimized by using deoxygenated solvents.
OH
R'
Te
R
n
OAc
lipase
solvents
(S)-5a-f
OH
R'
(RS)-5a-f
Te
+
R
n
OAc
Te
R
R'
n
a, R = Ph, n = 1, R' = CH3
(R)-6a-f
b, R = Ph, n = 1, R' = (CH2)2CH3
c, R = Ph, n = 1, R' = Ph
d, R = CH3, n = 1, R' = Ph
e, R = n-Bu, n = 1, R' = CH3
f, R = n-Bu, n = 2, R' = CH3
2.2. Enzymatic resolution of hydroxy tellurides 5a–f
The enantioselectivity of the enzyme-catalyzed trans-ester-
ification of hydroxy telluride was evaluated in organic
media with (RS)-5a as substrate and vinyl acetate as
acetate donor. Three free lipases, PPL (Porcine pancreatic
lipase), PSL (Pseudomonas sp. lipase) and CRL (Candida
rugosa lipase), and one immobilized lipase, CALB
(Candida antarctica lipase-B), were employed in the assays.
Scheme 2. Lipase-catalyzed transesterification of the (RS)-hydroxy tellu-
rides 5a–f in organic media.
Telluride
5a, c
Procedure
Ph2Te2 + NaBH4 + oxirane
5b
PhTeCH2TePh + BuLi + aldehyde
RLi + Te0 + oxirane
5d, e
5f
In a typical experiment, lipase was added to a solution of a
racemic mixture of alcohol (RS)-5a and vinyl acetate in
hexane. The mixture was maintained at 30 ꢁC and the
course of conversion was followed by chiral-GC analysis.
The best enantioselectivity was achieved with CALB,
which yielded both (S)-5a and (R)-6a in enantiomeric
excesses (ee) greater than 98% (Table 1, entry 7) within 2 h.
[BuTeLi/H2O] + MVK, carbonyl reduction
Figure 1. General procedure for the preparation of hydroxy tellurides
5a–f.
reaction with propylene oxide, and 5c in 60% isolated yield
upon reaction with styrene oxide.
High stereoselectivity was also obtained with PSL, yielding
(R)-6a in 98% ee (Table 1, entry 3) within 2 h and (S)-5a in
94% ee (Table 1, entry 4) after 24 h. The enantiopreference
of CALB, PSL and PPL was for (R)-5a, whilst that of CRL
was for (S)-5a (Table 1, entries 5 and 6).
Telluride 5b was prepared in 61% yield through tellurium/
lithium exchange reaction between bis-(phenyltellanyl)-
methane and n-butyllithium, followed by the 1,2-addition
of the resulting phenyltellanyl-methyl lithium to butyralde-
hyde.17 Reaction of the appropriate lithium alkyl telluro-
late with styrene oxide or propylene oxide furnished the
hydroxy tellurides 5d and 5e in isolated yields of 60%
and 80%, respectively.
In view of these results, the influence of the solvent on the
resolution of the racemic mixture of the alcohol 5a was
studied using CALB, as the most efficient lipase, and
CRL, since it presented an inverse enantiopreference. The
solvents employed were those commonly used in kinetic
resolution studies. Conversion experiments were performed
at 30 ꢁC, and product yields determined after a 3 h reaction
for CLR and after a 1 h reaction for CALB (Fig. 2).
Telluride 5f was prepared by the conjugate addition of n-
butyltellurol to methylvinyl ketone followed by reduction
of the carbonyl with sodium borohydride. Alternatively,
5f could be obtained in 70% isolated yield by sequential
1,4-addition of n-butyltellurol to methylvinyl ketone and
carbonyl reduction in a one-pot operation.9
It is clear that, whilst the solvent exerted a significant influ-
ence on the level of conversion of substrate, it exhibited no
Table 1. Enzymatic resolutiona of (RS)-1-(phenyltellanyl)-2-propanol 5a using different lipases
Entry
Lipase
PPL
Time (h)
Conversion (%)
ee 5ab (%)
ee 6ac (%)
Absolute configurationd
Ee
1
2
3
4
5
6
7
6
24
6
24
1
32
41
36
49
21
46
50
44
63
56
94
13
93
91
98
96
48
41
98
(R)
(R)
(R)
(R)
(S)
(S)
(R)
40
174
PSL
CRL
3
2
35
>99
3.3
>200
CALB
a The reactions were performed with 0.5 mmol of (RS)-5a and PPL (1 g), PSL (300 mg), CRL (75 mg) or CALB (30 mg) in hexane (10 mL) and vinyl
acetate (2.5 mmol, 0.23 mL).
b Enantiomeric excess (ee) of the recovered alcohol 5a.
c Enantiomeric excess (ee) of the acetate 6a.
d Absolute configuration of the acetate 6a.
e This parameter describes the enantioselectivity of the enzyme.

2254
A. A. Dos Santos et al. / Tetrahedron: Asymmetry 17 (2006) 2252–2259
CALB
CRL
resolved with the usual stereochemical preference for the
Dichloromethane
Vinyl acetate
(R)-configuration in the stereogenic carbinolic centre being
observed. For each substrate, the unreacted (S)-enantio-
mers could be obtained with P90% ee (Table 2, entries 2
and 4), whilst the acetylated products, (R)-6e and (R)-6f,
could be obtained with P96% ee (Table 2, entries 1, 2
and 3). However, the isolated yield was very low (<5%) fol-
lowing the enzymatic resolution of 5f owing to the instabil-
ity of the substrate even in deoxygenated hexane. During
the course of the reaction, a white powder was formed that
was presumed to be a telluroxide. The kinetic resolution of
5f with CALB was thus carried out with dry THF as sol-
vent. Under these conditions, the enzymatic resolution of
5f was achieved with an improved isolated yield (36%)
and with high enantioselectivity (Table 2, entries 5 and
6), even though the enzymatic activity of CALB is lower
in polar solvents. The results obtained with 5a, 5e and 5f
confirmed that hydroxy tellurides bearing a medium-sized
substituent (R0) smaller than an ethyl group (Scheme 2)
can be successfully resolved using CALB.
t-Butylmethyl ether
Diisopropyl ether
Cyclohexane
Hexane
0
10
20
30
40
50
Conversion (%)
Figure 2. Effect of the solvent on the lipase-catalyzed kinetic resolution of
(RS)-1-(phenyltellanyl)-2-propanol 5a at 30 ꢁC.
effect on either the enantioselectivity or enantiopreference
of the enzyme. Thus, in all solvents CALB showed a pref-
erence for (R)-5a, and (R)-6a was obtained in >99% ee. In
contrast, the preference of CRL was for the (S)-5a enantio-
mer, and the enantioselectivity was low (E < 4) in all
solvents.
2.3. Determination of the enantiomeric excess of hydroxy
tellurides 5e and 5f
Since the most efficient resolution of (RS)-5a was obtained
with CALB in hexane at 30 ꢁC, this system was employed
in order to study the influence of the substituent groups
R and R0 (Scheme 2) on the kinetic resolution of the race-
mic alcohols. No acetylated products were obtained when
5b, 5c or 5d were substrates (data not shown). These find-
ings are in agreement with the results of a recent study with
CALB in which it was shown that poor enantioselectivities
(E) were obtained with secondary alcohols bearing a
medium-sized substituent smaller than an n-propyl group.18
The ee values of the alcohols 5a, 5e and 5f and of the cor-
responding esters (6a, 6e and 6f) were calculated from the
chiral-GC chromatograms by comparison with racemic
samples. Direct analyses were not, however, possible for
5e and 5f owing to the poorly resolved chiral chromato-
grams obtained. Thus, 5e was transformed into its acetate
6e, and 5f was transformed into its corresponding trifluoro-
acetate 7, prior to chiral-GC analysis (Scheme 3).
According to Kazlauskas’s rule,19 and from a previous
study with CALB,18 the present results indicate that in
(RS)-5a–d, the tellanyl group behaves as a large substitu-
ent. Hence, for a successful resolution by CALB, the
hydroxy tellurides require R0 to be a medium-sized substi-
tuent smaller than an ethyl group, such as, for example, the
methyl group in (RS)-5a. Accordingly, the enzymatic reso-
lution of the hydroxy tellurides (RS)-5e and (RS)-5f was
attempted by mixing the substrate (0.5 mmol), CALB
(30 mg) and vinyl acetate (5 equiv, 2.5 mmol) in deoxygen-
ated hexane and incubating at 30 ꢁC. Under these condi-
tions, the racemic mixture of alcohols 5e and 5f were
O
O
OH
OAc
O
Te
Te
6e
pyridine
5e
O
O
O
F
F
F
F
F
OH
F
O
F
O
F
F
Te
Te
THF
5f
7
Scheme 3. Derivatization reactions to determine the enantiomeric excess
of hydroxy tellurides 5e and 5f.
Table 2. Enzymatic resolutiona of hydroxy tellurides with CALB at 30 ꢁC
Entry
Substrate
Solvent
Time (h)
Conversion (%)
ee (S)-5 (%)b
ee (R)-6 (%)c
Yield (%)d
Ee
1
2
3
4
5
6
(RS-5e)
Hexane
Hexane
Hexane
Hexane
THF
1
2
1
4
8
47
49
45
49
48
50
87
97
80
90
93
99
>99
>99
96
95
99
39
<5
36
>200
120
(RS-5f)
THF
12
98
>200
a The reactions were performed with (RS)-5e (0.5 mmol) or (RS)-5f (0.5 mmol) and CALB (30 mg) in hexane (10 mL) or CALB (50 mg) in THF (10 mL)
and vinyl acetate (2.5 mmol, 0.23 mL).
b Enantiomeric excess (ee) of the recovered alcohol 5e or 5f.
c Enantiomeric excess (ee) of the acetate 6e or 6f.
d Isolated yield of the acetate 6e or 6f.
e This parameter describes the enantioselectivity of the enzyme.

A. A. Dos Santos et al. / Tetrahedron: Asymmetry 17 (2006) 2252–2259
2255
2.4. Determination of the absolute configuration of resolved
compounds
OLi
O
OLi
n-BuLi
OH
5f
CO2
OLi
Te -Bun
Li
O
H+
O
The absolute stereochemistries of the unreacted substrates
5a (>99% ee) and 5e (>98% ee), derived from kinetic reso-
lution with CALB were determined by NMR. The alcohols
were derivatized with the two stereoisomers of a-methoxy-
a-(trifluoromethyl)phenyl acetic acid (MTPA), and the
resulting diastereoisomeric derivatives 8 and 9 presented
different chemical shifts in their 1H NMR spectra. Accord-
ing to Mosher’s model,20 the differences originated from
the anisotropic effect of the aromatic ring in the preferred
conformation. In the case of isomers (S,S)-8 and (S,S)-9,
the methyl group linked to the carbinolic carbon is shielded
by the phenyl group, whereas in isomers (R,S)-8 and (R,S)-
9, the phenyl substituent shields the methylene group (pro-
tons Ha and Hb). Thus, the signal associated with the
methyl group in (R,S)-8 and (R,S)-9 appeared downfield
compared with that of the methyl group in (S,S)-8 and
(S,S)-9. The inverse trend was observed for the respective
methylene group (Fig. 3). Moreover, the same effect in
chemical shifts was found in the 13C and 125Te NMR spec-
tra (Fig. 3). From these considerations, the absolute stereo-
chemistries of alcohols 5a and 5e were determined as (S).
10-(S)
Scheme 4. Determination of the absolute configuration of hydroxy
telluride 5f.
hibit lipase activity. Moreover, enzymatic resolution with
CALB of the racemic hydroxy tellurides 5a, 5e and 5f
yielded (R)- and (S)-enantiomers in high enantiomeric pur-
ity. This simple method affords enantiomerically enriched
hydroxy tellurides, which are promising building blocks
in organic synthesis by virtue of their facile Te/M exchange
reaction.1,2,9–11
4. Experimental
4.1. General
CALB (Novozym 435ꢂ; immobilized lipase-B from C. ant-
arctica; 10,000 PLU/g) and PSL (free Pseudomonas sp.
lipase; 30,000 u/g) were kindly donated by Novozyms
Inc. and Amano Pharmaceutical Co., respectively. PPL
(free P. pancreatic lipase; 147 units/mg protein), and
CRL (free C. rugosa lipase; 1440 units/mg protein) were
purchased from Sigma-Aldrich Chemical CO. The solvents
used in the enzymatic resolutions were deoxygenated by
sonication under nitrogen bubbling. NMR spectra were re-
corded on Bruker models AC-200 and DRX-500, and Var-
ian model FT-300, spectrometers with samples dissolved in
CDCl3. The internal references were TMS (1H NMR), the
central peak of the CDCl3 signal (13C NMR) and a capil-
lary of diphenyl ditelluride 1 M (125Te NMR). IR spectra
were recorded on a Bomem MB-100 spectrophotometer,
and optical rotations were determined on a Jasco DIP
370 digital polarimeter. Chiral GC analyses were per-
formed on a Shimadzu GC-17A instrument coupled to a
flame ionization detector (FID) and equipped with Supe-
lcoꢂ BetaDexTM 120 (b-cyclodextrin packing) or Gama-
DexTM 120 (c-cyclodextrin packing) capillary columns
(30 m · 0.25 mm i.d.; 0.25 lm) or with a Varian Chromo-
packTM Chirasil-Dex CB (b-cyclodextrin packing) capillary
column (25 m · 0.25 mm i.d.; 0.25 lm). In each case, the
carrier gas was H2. Mass spectra were recorded by cou-
pling the GC to a Shimadzu model QP 5050A mass
spectrometer.
In order to determine the stereochemistry of 5f, the hydroxy
telluride was converted into the corresponding di-lithium
salt (1,4-dianion) and reacted with carbon dioxide to form
valerolactone 10 (Scheme 4). The absolute stereochemistry
was then determined by comparison of the specific rotation
of 10 with the literature data.21 In this way, the absolute
stereochemistry of alcohol 5f was determined as (S).
3. Conclusions
It has been demonstrated that the presence of a tellanyl
group in the structure of a secondary alcohol does not in-
Me
CH2TeR
(S)
Me
CH2TeR
(S)
MeO
Ph
Ph
MeO
F3C
O
O
View
View
H
H
F3C
(R)
O
(S)
O
Upfield relative to
Downfield relative to
Ha
Hb
Ha
Hb
R
R
Me
C
Me
.
C
Te
Te
MeO
Ph
Ph
OMe
O
O
(S)
(R
)
8 R = Ph
9 R = n-Bu
CF3
CF3
4.2. Synthesis
(R,S)-8 / (R,S)-9
(S,S)-8 / (S,S)-9
δ
δ
δ
δ
δ
δ
Ha(ppm)
Hb(ppm)
=
3.14 / 2.70
3.17 / 2.79
4.2.1. General procedure for the preparation of racemic
mixture of substrates (RS)-5a and (RS)-5c. Diphenyl
ditelluride (2.252 g, 5.5 mmol) was placed in a two-necked
flask and dissolved in dry ethanol (30 mL) under a nitrogen
atmosphere. Sodium borohydride was added slowly at
room temperature until the solution became colour-
less. Following the addition of the appropriate epoxide
=
2.98 / 2.86
1.45 / 1.48
3.06 / 2.91
1.38 / 1.40
H-Me(ppm) =
Te(ppm)
=
440.9 / 204.9
441.9 / 206.3
13.40 / 7.30
20.71 / 20.56
C-Te(ppm)
= 13.35 / 7.23
C-Me(ppm) = 20.86 / 20.70
Figure 3. Mosher’s model for compounds 8 and 9.

2256
A. A. Dos Santos et al. / Tetrahedron: Asymmetry 17 (2006) 2252–2259
(propylene oxide or styrene oxide, 11 mmol), the reaction
mixture was stirred for 2 h at room temperature. Aqueous
Na2CO3 (10%, 20 mL) was added to the mixture and the
whole was extracted with ethyl acetate (3 · 20 mL). The
organic phase was washed with brine, dried with MgSO4
and evaporated to dryness. The residue was purified by
column chromatography over silica gel eluting with
hexane/ethyl acetate (9:1).
4.2.3. General procedure for the preparation of racemic
substrates (RS)-5d and (RS)-5e. n-Methyllithium in
diethyl ether (1.1 mol Lꢀ1, 4.54 mL, 5 mmol) or n-butyl
lithium in hexane (1.4 mol Lꢀ1, 3.57 mL, 5 mmol), as
appropriate, was added to a suspension of elemental tellu-
rium (0.638 g, 5 mmol) in dry THF (25 mL) under nitrogen
and with magnetic stirring. The appropriate epoxide (styr-
ene oxide (0.57 mL, 5 mmol) or propylene oxide [0.70 mL,
10 mmol]) was added and the mixture heated at reflux for
6 h. The reaction mixture was cooled to room temperature,
treated with saturated aqueous NH4Cl (5 mL) solution and
extracted with ethyl acetate (3 · 5 mL). The organic phase
was washed with brine (5 mL), dried over MgSO4 and
evaporated to dryness. The residue was purified by column
chromatography over silica gel eluting with hexane/ethyl
acetate (85:15).
4.2.1.1.
(RS)-1-(Phenyltellanyl)-propan-2-ol,
(RS)-
5a. Oil; yield 2.13 g (81%); CAS NR. 133617-20-6. 1H
NMR (300 MHz; CDCl3) d 1.30 (3H, d, J = 6.1 Hz), 2.16
(1H, s), 2.96 (1H, dd, J = 12.2, 7.6 Hz), 3.14 (1H, dd,
J = 12.2, 4.5 Hz), 3.89–3.95 (1H, m), 7.17–7.28 (3H, m),
7.72–7.76 (2H, m). 13C NMR (75 MHz; CDCl3) d 21.5
ðJ1
¼ 163 HzÞ, 23.7, 67.4, 111.2, 127.7, 129.2, 138.4.
13C–125Te
125Te NMR (157 MHz, 300 K, CDCl3) d 367.1; IR
(m/cmꢀ1) 3371, 3061, 2968, 2924, 2891, 2873, 1573, 1472,
1451, 1433, 1405, 1320, 1058, 732, 692. MS m/z (rel int.):
264 [M+] (21), 222 (19), 207 (18), 130 (10), 91 (26), 77
(100), 59 (96), 51 (60), 45 (10).
4.2.3.1. (RS)-1-Phenyl-2-(methyltellanyl)-ethanol, (RS)-
5d. Oil; yield 0.791 g (60%). Found: C, 40.71; H, 4.36.
Calcd for C9H12OTe: C, 40.98; H, 4.59. 1H NMR
(200 MHz; CDCl3) d 1.77 (3H, s), 2.98–3.03 (2H, m),
4.78–4.84 (1H, m); 7.27–7.22 (5H, m). 13C NMR
(75 MHz; CDCl3) d 17.3, 73.8, 125.7, 127.8, 128.4, 143.8.
125Te NMR (157 MHz, 300 K, CDCl3) d 25,1. MS m/z
(rel int.) 226 (32), 160 (61), 140 (9), 121 (71), 103 (73), 91
(44), 77 (100), 65 (14), 43 (80).
4.2.1.2. (RS)-1-Phenyl-2-(phenyltellanyl)ethanol, (RS)-
5c. Oil; yield 1.92 g (60%); CAS NR. 55136-89-5. 1H
NMR (300 MHz; CDCl3) d 2.59 (1H, d, J = 3.5 Hz), 3.26
(1H, dd, J = 12.1, 8.1 Hz), 3.32 (1H, dd, J = 12.3,
5.0 Hz), 4.84–4.90 (1H, m), 7.15–7.35 (8H, m), 7.69–7.72
(2H, m). 13C NMR (75 MHz; CDCl3) d 20.6, 73.6, 111.5,
125.6, 127.7, 128.4, 129.2, 138.3, 143.4. IR (m/cmꢀ1) 3407,
3059, 3029, 2989, 2930, 2874, 1574, 1493, 1475, 1452,
1434, 1047, 734, 697. MS m/z (rel int.) 326 (14), 325 [M+]
(3), 220 (16), 205 (15), 121 (18), 103 (33), 91 (50), 77
(100), 51 (58).
4.2.3.2.
(RS)-1-(n-Butyltellanyl)-2-propanol,
(RS)-
5e. Oil; yield 0.794 g (80%); CAS NR. 414902-88-8.
Found: C, 34.33; H, 6.32. Calcd for C7H16OTe: C, 34.49;
H, 6.61. 1H NMR (200 MHz; CDCl3) d 0.92 (3H, t,
J = 7.5 Hz), 1.29 (3H, d, J = 5.7 Hz), 1.32–1.47 (2H, m),
1.72 (2H, quint., J = 7.5 Hz), 2.54–2.91 (4H, m), 3.86
(1H, sext, J = 5.7 Hz), 13C NMR (50 MHz; CDCl3) d
3.16, 13.2, 15.6, 23.5, 24.8, 34.1, 67.4. 125Te NMR
(157 MHz, 300 K, CDCl3) d 118.5; MS m/z (rel int.) 246
(13), 204 (5), 186 (2), 168 (10), 145 (3), 126 (2), 57 (55),
55 (29), 41 (100).
4.2.2. General procedure for the preparation of racemic
mixture of substrate (RS)-5b. Bis-(phenyltellanyl)-meth-
ane22 (0.847 g, 2 mmol) was placed in a two-necked flask
and dissolved in dry THF (8 mL) under a nitrogen atmo-
sphere.
A
solution of n-butyl lithium in hexane
(1.4 mol Lꢀ1, 1.43 mL, 2 mmol) was added slowly at
ꢀ78 ꢁC, and the resulting mixture stirred for 30 min. Butyr-
aldehyde (0.18 mL, 0.144 g, 2 mmol) was added and the
whole solution stirred again for 20 min at ꢀ78 ꢁC and them
for 1 h at room temperature. Following the addition of sat-
urated aqueous NH4Cl solution (2 mL), the reaction mix-
ture was extracted with ethyl acetate (3 · 5 mL), the
organic phase washed with brine (5 mL), dried over MgSO4
and evaporated to dryness. The residue was purified by col-
umn chromatography over silica gel eluting with hexane/
ethyl acetate (9:1).
4.2.4. One-pot procedure for the preparation of (RS)-1-(n-
butyltellanyl)-3-butanol (RS)-5f. Elemental tellurium
(0.638 g, 5 mmol) and THF (10 mL) were added sequen-
tially to a dry two-necked flask under a nitrogen atmo-
sphere.
A
solution of n-butyl lithium in hexane
(1.4 mol Lꢀ1, 3.5 mL, 5 mmol) was added dropwise with
vigorous stirring to produce a light yellow coloured solu-
tion to which deoxygenated H2O (0.18 mL, 10 mmol) was
added. The mixture was stirred for 5 min, after which
freshly distilled methylvinyl ketone (0.4 mL, 0.35 g,
5 mmol) was added in one portion. The resulting red col-
oured mixture was stirred for 30 min, after which an aque-
ous solution of NaBH4 (1 mol Lꢀ1, 6 mL, 6 mmol) was
added by means of a dropping funnel. When the reaction
had reached completion (monitored by TLC), the mixture
was diluted with H2O (20 mL) and ethyl acetate/hexane
(1:1, 50 mL). The phases were separated, the aqueous
phase washed twice with ethyl acetate/hexane (1:1,
50 mL). The organic phases were then combined, dried
over MgSO4, filtered and the solvent removed under re-
duced pressure. The residue was purified by column chro-
matography over silica gel eluting with hexane/ethyl
acetate (15:1).
4.2.2.1. (RS)-1-(Phenytellanyl)-2-pentanol, (RS)-5b.
Oil; yield 0.355 g (61%). Found: C, 45.62; H, 5.66. Calcd
1
for C11H16OTe: C, 45.27; H, 5.53. H NMR (500 MHz;
CDCl3) d 0.89 (3H, t, J = 7.32 Hz), 1.32–1.37 (1H, m),
1.50–1.61 (2H, m), 2.14 (1H, s), 2.98 (1H, dd, J = 12.26,
7.94 Hz), 3.16 (1H, dd, J = 12.26, 4.03 Hz), 3.69–3.74
(1H, m), 7.17–7.29 (3H, m), 7.73–7.76 (2H, m); 13C
NMR (125 MHz; CDCl3) d 13.9, 19.2, 20.4, 40.1, 70.8,
111.2, 127.8, 129.3, 138.5. MS m/z (rel int.): 292 [M+]
(40), 222 (40), 207 (45), 130 (18), 91 (43), 77 (93), 69 (63),
45 (100), 43 (64).

A. A. Dos Santos et al. / Tetrahedron: Asymmetry 17 (2006) 2252–2259
2257
4.2.4.1. (RS)-1-(n-Butyltellanyl)-3-butanol, (RS)-5f.
4.3. General procedure for the enzymatic resolution
Oil; yield 0.901 g (70%); CAS NR. 861399-10-2; 1H
NMR (200 MHz; CDCl3) d 0.85 (3H, t, J = 6.2 Hz), 1.13
(3H, d, J = 6.3 Hz), 1.31 (2H, sext, J = 7.2 Hz); 1.65 (2H,
quint, J = 7.2 Hz), 1.76–1.85 (2H, m), 2.53–2.69 (4H, m),
3.75 (1H, sext, J = 6 Hz). 13C NMR (50 MHz; CDCl3) d
2.3, 2.7, 13.4, 23.2, 25.0, 34.2, 41.1, 69.1. 125Te NMR
(157 MHz, 300 K, CDCl3) d 251.43. MS m/z (rel int.) 260
[M++2] (13), 258 [M+] (13), 256 (7), 255 (3), 254 (2), 215
(3), 186 (8), 72 (5), 57 (73), 55 (100), 45 (44).
Lipase (0.03–1 g, Tables 1 and 2) and vinyl acetate (5 equiv,
2.5 mmol, 0.23 mL) were added to a solution of the appro-
priate hydroxy telluride (0.5 mmol) dissolved in the appro-
priate solvent (10 mL). The reaction mixture was stirred
and the course of the reaction monitored by chiral GC.
After ca. 50% conversion had been achieved, the enzymes
(free or immobilized) were removed by filtration and the
resulting solution concentrated. The organic residues were
subjected to column chromatography over silica gel in
order to obtain the acetylated product and the unreacted
enantiomer.
4.2.5. General procedure for the preparation of racemic
mixture of esters. Hydroxy telluride (3.6 mmol) was
placed in a two-necked flask and dissolved in dry pyridine
(5 mL) under a nitrogen atmosphere. Acetic anhydride
(2 mL, 21 mmol) was slowly added at 0 ꢁC and the mixture
was stirred at room temperature whilst the reaction was
monitored by TLC. After 4 h, aqueous HCl (10% v/v,
5 mL) was added and the reaction mixture was extracted
with ethyl acetate (10 mL). The organic phase was washed
three times with saturated aqueous CuSO4 solution
(15 mL) and brine (5 mL), dried over MgSO4 and evapo-
rated to dryness. The residue was purified by column chro-
matography over silica gel eluting with hexane/ethyl
acetate (9:1).
28
4.3.1. (S)-1-(Phenyltellanyl)-2-propanol, (S)-5a. Oil; ½aꢁD
¼
þ5 (c 1.0, CH2Cl2); ee >99%.
4.3.2. (R)-O-Acetyl-1-(phenyltellanyl)-2-propanol, (R)-6a.
22
Oil; ½aꢁD ¼ ꢀ6 (c 1.0, CH2Cl2); ee >99%.
23
4.3.3. (S)-1-(Butyltellanyl)-2-propanol, (S)-5e. Oil; ½aꢁD
þ33 (c 1.0, CH2Cl2), ee >99%.
¼
4.3.4.
(R)-O-Acetyl-1-(butyltellanyl)-2-propanol,
(R)-
23
6e. Oil; yield 0.056 g (39%); ½aꢁD ¼ þ4 (c 1.0, CH2Cl2);
ee = 98%.
22
4.3.5. (S)-1-(Butyltellanyl)-3-butanol, (S)-5f. Oil; ½aꢁD
¼
4.2.5.1.
(RS)-O-Acetyl-1-(phenyltellanyl)-2-propanol,
þ7 (c 1.0, CH2Cl2); ee >99%.
(RS)-6a. Oil; yield 0.925 g (84%). Found: C, 43.10; H,
4.61. Calcd for C11H14O2Te: C, 43.20; H, 4.61. H NMR
1
4.3.6. (R)-O-Acetyl-1-(butyltellanyl)-3-butanol, (R)-6f.
(300 MHz; CDCl3) d 1.34 (3H, d, J = 6.24 Hz), 1.93 (3H,
s), 3.08 (2H, d, J = 6.2 Hz), 5.03–5.13 (1H, m), 7.17–7.28
(3H, m), 7.73–7.76 (2H, m). 13C NMR (75 MHz; CDCl3)
d 14.8, 21.1, 21.2, 71.4, 111.5, 127.8, 128.2, 138.5, 170.3.
125Te NMR (157 MHz, 300 K, CDCl3) d 440.5. IR (m/
cmꢀ1) 3059, 2979, 2932, 2870, 1735, 1574, 1434, 1372,
1241, 733, 692. MS m/z (rel int.) 306 [M+] (5), 249 (2),
222 (1), 207 (5), 101 (36), 77 (26), 43 (100).
22
Oil; yield 0.054 g (36%); ½aꢁD ¼ þ18 (c 1.0, CH2Cl2);
ee = 98%.
4.4. Determination of the enantiomeric excesses
The conditions for chiral GC analyses were—(RS)-5a:
Gama Dex column at 120 ꢁC, 100 min hold, 90 kPa;
tR1 = 84.4 min, tR2 = 85.4 min; (RS)-5e: Gama Dex col-
umn at 65 ꢁC, 150 min hold, 65–98 ꢁC at 0.5 ꢁC minꢀ1
,
4.2.5.2.
(RS)-O-Acetyl-1-(n-butyltellanyl)-2-propanol,
90 kPa; tR1 = 198.4 min, tR2 = 200.2 min; (RS)-6a: Chira-
sil-Dex CB column at 120 ꢁC, 40 min hold, 100 kPa;
tR1 = 35.3 min, tR2 = 39.6 min; (RS)-6e: Chiralsil-Dex
CB column at 80 ꢁC, 120 min hold, 80–110 ꢁC at
2 ꢁC minꢀ1, 125 kPa; tR1 = 102.2 min, tR2 = 125.1 min;
(RS)-6f: Chiralsil-Dex CB column at 60 ꢁC, 3 min hold,
(RS)-6e. Oil; yield 0.875 g (85 %). Found: C, 37.80; H,
1
6.38. Calcd for C9H18O2Te: C, 37.82; H, 6.35. H NMR
(500 MHz; CDCl3) d 0.92 (3H, t, J = 7.4 Hz), 1.35 (3H,
d, J = 6.2 Hz), 1.36–1.42 (2H, m), 1.73 (3H, sext,
J = 7.4 Hz), 2.04 (3H, s), 2.69 (2H, t, J = 7.4 Hz), 2.77
(1H, dd, J = 12.2, 7.2 Hz), 2.83 (1H, dd, J = 12.2,
5.6 Hz), 5.00 (1H, sext, J = 6.2Hz). 13C NMR (125 MHz;
CDCl3) d 3.7, 8.7, 13.4, 20.9, 21.3, 25.0, 34.2, 72.0, 170.4.
125Te NMR (157 MHz, 300 K, CDCl3) d 189.0. MS m/z
(rel int.) 288 (6), 258 (2), 187 (3), 172 (8), 101 (29), 57
(18), 43 (100).
60–190 ꢁC at 5 ꢁC minꢀ1
,
100 kPa; tR1 = 22.0 min,
tR2 = 22.6 min; (RS)-7: Chiralsil-Dex CB column at
80 ꢁC, 90 min hold, 80–140 ꢁC at 1 ꢁC minꢀ1, 120 kPa;
tR1 = 78.6 min, tR2 = 82.0 min; (RS)-10: Chirasil-Dex
CB column at 60 ꢁC, 3 min hold, 60–190 ꢁC at 5 ꢁC minꢀ1
,
100 kPa; tR1 = 10.1 min, tR2 = 10.4 min. E values were
calculated from the enantiomeric excesses of product
(eep) and substrate (ees) according to the Sih, Sharpless
and Fajans equation, namely, E = ln{[1 ꢀ c(1 + eep)]/
ln[1 ꢀ c(1 ꢀ eep)]}, where c = [ees/(ees + eep)].23
4.2.5.3.
(RS)-O-Acetyl-1-(n-butyltellanyl)-3-butanol,
(RS)-6f. Oil; yield 0.993 g (92%). Found: C, 40.02; H,
1
6.53. Calcd for C10H20O2Te: C, 40.05; H, 6.72. H NMR
(300 MHz; CDCl3) d 0.92 (3H, t, J = 7.5 Hz), 1.23 (3H,
d, J = 6.3 Hz), 1.38 (2H, sext, J = 7.5 Hz), 1.72 (2H, quint,
J = 7.5 Hz), 2.04 (3H, s), 1.87–2.11 (2H, m), 2.49–2.67 (4H,
m). 13C NMR (125 MHz; CDCl3) d ꢀ3.6, 2.8, 13.4, 19.5,
21.3, 25.0, 34.2, 38.8, 72.2, 170.6. 125Te NMR (157 MHz,
300 K, CDCl3) d 270.15.
4.4.1. General procedure for the hydrolysis of acetates
6. The appropriate acetoxy telluride (1 mmol) was dis-
solved in methanol (5 mL), and H2O (2 mL) and K2CO3
(0.2 mmol) added. The mixture was stirred overnight and
then extracted with ethyl acetate (2 · 5 mL). The organic

2258
A. A. Dos Santos et al. / Tetrahedron: Asymmetry 17 (2006) 2252–2259
phase was washed with brine (2 mL), dried and then con-
centrated to yield a residue that was purified by flash chro-
matography over silica gel.
4.5.2. Procedure for the preparation of valerolactone 10.
A
,
solution of n-butyl lithium in hexane (1.4 mol Lꢀ1
1.57 mL, 2.2 mmol) was added dropwise with continuous
stirring to hydroxy telluride 5e (0.25 g, 1 mmol) dissolved
in THF (5 mL) while maintaining at ꢀ70 ꢁC in a round-
bottomed flask. The reaction mixture was stirred for
20 min at ꢀ70 ꢁC and then saturated with dry CO2,
warmed to room temperature and stirred for 1 h. Aqueous
HCl (50% v/v, 5 mL) was added, the mixture extracted
with diethyl ether (3 · 5 mL), the organic phase washed
with brine (5 mL), dried with MgSO4 and the solvent re-
moved by distillation. The residue was purified by column
chromatography over silica gel eluting with hexane:diethyl
ether (9:1).
4.5. Determination of the absolute configuration
4.5.1. Esterification of (S)-1-(phenyltellanyl)-2-propanol (S)-
5a and (S)-1-(n-butyltellanyl)-2-propanol (S)-5e with
Mosher’s acid. The appropriate alcohol (S)-5a or (S)-5e
(0.1 mmol), Et3N (1.2 mmol) and DMAP (0.1 mmol) were
dissolved in dry CH2Cl2 (10 mL) under a nitrogen atmo-
sphere, and a-methoxy-a-trifluoromethyl-phenyl acetyl
chloride (0.5 mmol) dissolved in dry CH2Cl2 (5 mL) added.
After 15 min reaction time, the solution was washed with
H2O (3 · 2 mL), dried and concentrated to yield a residue,
which was purified by flash chromatography on silica gel.
Derivatives were, however, unstable on silica gel and were
purified by rapid and simple filtration over silica gel, ini-
tially with hexane and then with ethyl acetate.
23
4.5.2.1. Valerolactone. Oil; ½aꢁD ¼ þ30 (c 1.0; CHCl3);
ee = 98%; lit.21 (S)-enantiomer: [a]D = ꢀ26.7 (c 1.0,
CHCl3) ee 74%; CAS NR. 58917-25-2; 1H NMR
(300 MHz; CDCl3) d 1.43 (3H, d, J = 6.3 Hz), 1.78–1.91
(1H, m), 2.54–2.59 (2H, m), 4.6–4.71 (1H, m). 13C NMR
(75 MHz; CDCl3) d 21.0, 29.1, 29.8, 77.4, 177.6. IR (m/
cmꢀ1) 2998, 1777, 1432, 1130. MS m/z (rel int.): 41 (47),
43 (34), 56 (100), 85 (45), 100 (8).
4.5.1.1. (1S,2R)-1-Methyl-2-(phenyltellanyl)ethyl 3,3,3-
trifluoro-2-methoxy-2-phenylpropionate
(1S,2R)-8. Oil;
1
yield 0.025 g (52%); H NMR (500 MHz; CDCl3) d 1.45
(3H, d, J = 6.23 Hz), 2.98 (1H, dd, J = 12.32, 7.32 Hz),
3.14 (1H, dd, J = 12.32, 5.84 Hz), 3.56 (3H, s), 5.30–5.36
(1H, m), 7.27–7.64 (10H, m). 13C NMR (125 MHz; CDCl3)
d 13.35, 20.86, 55.50, 74.80, 111.38, 127.34, 128.41, 129.39,
129.60, 130.02, 138.50, 165.84. 125Te NMR (157 MHz,
300 K, CDCl3) d 440.9.
Acknowledgements
The authors wish to thank FAPESP, CAPES and CNPq
for financial support. Amano Pharmaceutical CO. and
Novozymes Inc. are acknowledged for their generous gifts
of lipases.
4.5.1.2. (1S,2S)-1-Methyl-2-(phenyltellanyl)ethyl 3,3,3-
trifluoro-2-methoxy-2-phenylpropionate
(1S,2S)-8. Oil;
1
yield 0.024 g (50%); H NMR (500 MHz; CDCl3) d 1.38
(3H, d, J = 6.21 Hz), 3.06 (1H, dd, J = 12.35, 7.05 Hz),
3.17 (1H, dd, J = 12.35, 6.25 Hz), 3.56 (3H, s), 5.29–5.34
(1H, m), 7.26–7.59 (10H, m). 13C NMR (125 MHz; CDCl3)
d 13.39, 20.72, 55.63, 74.92, 111.32, 127.71, 128.41, 129.43,
129.60, 130.03, 138.55, 165.94. 125Te NMR (157 MHz,
300 K, CDCl3), d 441.9.
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