A large-scale synthesis of enantiomerically pure γ-hydroxy-organochalcogenides

Article abstract of DOI:10.1016/j.tetasy.2009.10.009

Enantiomerically pure (R)- and (S)-γ-hydroxy-organochalcogenides are prepared using poly-[R]-3-hydroxybutanoate (PHB) as the starting material.

Full text of DOI:10.1016/j.tetasy.2009.10.009

Tetrahedron: Asymmetry 20 (2009) 2699–2703
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A large-scale synthesis of enantiomerically pure
organochalcogenides
c-hydroxy-
*
Jefferson L. Princival, Morilo S. C. de Oliveira, Alcindo A. Dos Santos , João V. Comasseto
Instituto de Química, Universidade de São Paulo, CP 26077, CEP 05508-000, São Paulo, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiomerically pure (R)- and (S)-c-hydroxy-organochalcogenides are prepared using poly-[R]-
3-hydroxybutanoate (PHB) as the starting material.
Received 23 September 2009
Accepted 7 October 2009
Available online 10 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
In our laboratory, the synthesis of several bioactive chiral com-
pounds using 1c as an optically active precursor was performed2c
and some other syntheses are underway. In view of this fact, a
large-scale preparation of 1c was required. A retrosynthetic analy-
sis of 1c showed that the enantiomerically pure diol 4 should be
the reagent of choice for the preparation of 1c and its sulfur and
selenium analogues (Fig. 2).
Enantiomerically pure
c-hydroxy-organochalcogenides
1
(Fig. 1) have found use in organic synthesis.1,2
The sulfide 1a (R = Ph), has been prepared by the addition of
thiophenol to methyl vinyl ketone (MVK) (100% yield) followed
by baker’s yeast reduction to (S)-1a in 70% yield and 96% ee.1a
In 2007, Tiecco reported an elegant methodology to prepare
enantioenriched 1b, by reacting the commercially available opti-
cally active b-hydroxy-ester with phenyl selenocyanate.3c Re-
cently we have shown the preparation of the tellurides (R)-1c
and (S)-1c (R = nBu) by hydrotelluration of MVK followed by
reduction of the carbonyl group (88% yield) and enzymatic ki-
netic resolution, giving the (R) and (S) enantiomers in 98% and
99% ee, respectively,2a and have demonstrated that these tellu-
rides can be transformed into chiral dianions 2 as shown in
Scheme 1.2
OH
OH
OH
∗
∗
∗
YR
OH
X
1
3
4
X = OTs
Y = S, Se, Te
Figure 2.
Enantiomerically enriched (R)- and (S)-4 have been prepared
by enzymatic kinetic resolution of racemic 4.3 Alternatively, ethyl
acetoacetate was bioreduced to (S)-3-hydroxybutanoate by ba-
ker’s yeast and then reduced with LiAlH4 to (S)-4.4 Poly[R]-3-
hydroxybutanoate (PHB) on reduction with LiAlH4 gave (R)-4.5
This last approach is attractive, since PHB is produced on a
large-scale by bacteria. This phenomenon is known since 1926.6
However, PHB has only recently become available in large-scale
as a green alternative for polymeric materials derived from
petrochemicals.7 Several bacteria are able to store PHB as a food
supply. Nowadays, PHB is industrially produced in high yield (up
to 80–90% of dry biomass) using gram-negative bacteria such as
Alcaligenes eutrophus, recently named Cupriavidus necator8
(responsible for the highest yield production), recombinant Esch-
erichia coli, and Alcaligenes latus.9 PHB produced commercially by
these processes has been applied for many purposes including
biodegradable polymer packaging, pharmacy, medicine, food
industry, and paint industry.10 Although the major production
of PHB (hundreds of tons per year) is destined for large industrial
1a Y = S
OH
1b
Y = Se
∗
1c Y = Te
YR
Figure 1.
Li
O
M
OH
O
nBuLi
MX
Li
∗
Ten-Bu
∗
∗
M
2
1c
1c
(R)- or (S)-
M = Cu, Zn, Ce
Scheme 1. Preparation of reactive organometallics from
c
-hydroxy-butyltelluride.
* Corresponding author. Tel.: +55 11 30911180.
E-mail address: princivalj@yahoo.com.br (A.A. Dos Santos).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.10.009

2700
J. L. Princival et al. / Tetrahedron: Asymmetry 20 (2009) 2699–2703
purposes, its enantiomeric purity (>99% ee) and chemical func-
tionality make it an interesting building block for organic synthe-
sis. For many years, its transformation into the corresponding
enantiomerically pure monomer or diol has found use to gener-
ate a chiral building block in organic synthesis.4,5 In view of this
fact and based on the demonstrated application of hydroxy-
butyltellurides as precursors of dianions,11 we focused our
corresponds to the ee of the acetates 5 derived from 1 as shown
in Scheme 4.
O
OH
O
DMAP, CH2Cl2, N2
attention on the preparation of (R)- and (S)-c-hydroxy-organoch-
alcogenides using this polymer as the starting material, as
YR
YR
O
O
1
(R)-
5
(R)-
, 1h, r.t.
presented herein.
O
Yield (%) e.e. (%)
2. Results and discussion
5a Y = S; R = nBu
5b Y = Se; R = nBu
5c Y = Te; R = nBu
5d Y = S; R = Ph
5e Y = Se; R = Ph
5f Y = Te; R = Ph
86
89
92
87
91
93
> 99.9
> 99.9
> 99.9
> 99.9
> 99.9
> 99.9
The commercially available12 crystalline PHB was reduced with
lithium aluminum hydride in THF in 0.7 mol batches, producing
0.58 mol (84%) of (R)-4 in >99% ee after distillation. The diol 4
was transformed in 56% yield into the monotosylate 3 by reaction
13
with tosyl chloride/pyridine in CHCl3 (Scheme 2).
Scheme 4. Preparation of the enantiomerically pure acetates (R)-5 from (R)-1.
OH OTs
O
O
OH OH
LiAlH4 / THF, N2
TsCl / py
The (S)-
c
-hydroxy-organochalcogenides were prepared by a
O
Mitsunobu reaction17 on the (R)-
c-hydroxy-organochalcogenides
n
CHCl3, -10 ºC
56%
reflux, 5h
84%
4
3
(R)-
(R)-
PHB
prepared above. Treatment of (R)-1a–c with DEAD, triphenylphos-
phine, and acetic acid in THF at 0 °C gave (S)-5a–f in good yields.
Treatment of (S)-5a–f with K2CO3 in methanol at room tempera-
ture led to (S)-1a–f, as shown in Scheme 5.
Scheme 2. Preparation of the monotosylate (R)-3 from PHB.
With (R)-3 in hand, it was transformed into the corresponding
organochalcogenides by reaction with the appropriate metal chal-
cogenolate as shown in Scheme 3.
OH
OH
1) DEAD, Ph3P, AcOH
THF, 0 ºC
2) K2CO3, MeOH, r.t.
YR
YR
1
(R)-
(S)-1
OH OTs
OH
RYM
Overall yield (%) e.e. (%)
YR
THF, N2, r.t., 30 min
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
(S)-1f
Y = S; R = nBu
66
76
74
73
81
78
> 99.9
> 99.9
> 99.9
> 99.9
> 99.9
> 99.9
3
(R)-
1
(R)-
Y = Se; R = nBu
Y = Te; R = nBu
Y = S; R = Ph
Y = Se; R = Ph
Y = Te; R = Ph
Yield (%)
e.e. (%)
> 99.9
> 99.9
> 99.9
> 99.9
> 99.9
> 99.9
1a Y = S; M = Li; R = nBu
1b Y = Se; M = Li; R = nBu
1c Y = Te; M = Li; R = nBu
1d Y = S; M = MgBr; R = Ph
1e Y = Se; M = MgBr; R = Ph
1f Y = Te; M = MgBr; R = Ph
62
79
86
83
89
89
Scheme 5. Preparation of the (S)-hydroxy-organochalcogenides from the (R)-
isomers.
Scheme 3. Preparation of enantiomerically pure
(R)-1 from (R)-3.
c-hydroxy-organochalcogenides
3. Conclusion
In conclusion, the enantiomerically pure (R)- and (S)-hydroxy-
organochalcogenides and the corresponding acetates can be pre-
pared in good yields using the readily available and inexpensive
PHB as the starting material. These chiral building blocks can be
produced on a large-scale preparation as a ‘one-day procedure’
providing chiral functionalized organometallic equivalents.
The tosylate displacement reaction can be conducted using the
unprotected alcohol, due to the poor basic character of the chalco-
genolates. In the case of the nBu chalcogeno derivatives, the lithium
chalcogenolates have been prepared by reaction of nBuLi in hexane
with a THF suspension of the elemental chalcogen, as described re-
cently by us.14 When R was a phenyl group, phenylmagnesium
bromide was reacted with the elemental chalcogen in THF, follow-
ing the literature procedures for the preparation of magnesium sel-
enolates15 and tellurolates.16 The reaction of (R)-3 with the metal
4. Experimental
4.1. General
chalcogenolate was monitored by TLC. After work-up the c-hydro-
xy-organochalcogenides were purified by column chromatography
in hexane/ethyl acetate (8:2) to give 1a–f in the yields as shown in
Scheme 3. The enantiomeric excesses of 1a–f were determined by
chiral gas chromatography. To this end the alcohols 1 were trans-
formed into the corresponding acetates to improve their chromato-
graphic separation. In this way, the ee shown in Scheme 3
Poly[R]-3-hydroxybutanoate was kindly supplied by PHB Indus-
trial S.A. (Serrana, São Paulo, Brazil). nBuLi 15% in hexane was pur-
chased from Chemmetal.
All solvents and chemicals used were previously purified
according to the usual methods.18 Column chromatography was
carried out with Merck silica gel (230–400 Mesh). Thin layer

J. L. Princival et al. / Tetrahedron: Asymmetry 20 (2009) 2699–2703
2701
chromatography (TLC) was performed on silica gel F-254 on alumi-
num. 1H and 13C NMR spectra were recorded on either a Varian
DPX-300 (1H: 300 MHz; 13C: 75 MHz) or a Bruker AC-200 (1H:
200 MHz; 13C: 50 MHz) spectrometer using tetramethylsilane
and the central peak of CDCl3 at 77 ppm as internal standards.
Chemical shifts (d) are given in ppm, coupling constants (J) in Hz,
and multiplicities are indicated by s (singlet), d (doublet), t (trip-
let), q (quartet), quint (quintuplet), sext (sextuplet), hept (heptet),
m (multiplet), and br (broad). Near infrared spectra were recorded
on a Bomem MB-100 spectrophotometer. Peaks are reported in
cmꢀ1. Low-resolution mass spectra were obtained in a Shimadzu
GCMS-17A/QP5050A instrument equipped with capillary column
(14), 227 (36), 200 (3), 172 (100), 155 (28), 135 (6), 108 (32), 91
(71), 65 (35).
4.2.3. General procedure for the preparation of (R)-3-hydroxy-
organochalcogenides 1a–f
nButyllithium in hexane (1.4 mol Lꢀ1, 7.1 mL, 10 mmol) or
phenylmagnesium bromide in THF (1.0 mol Lꢀ1, 10 mL, 10 mmol)
as appropriate, was added to a suspension of the elemental chalco-
gen (10 mmol) in dry THF (50 mL) under nitrogen and magnetic
stirring. Then (R)-3 (2.44 g, 10 mmol) was added. When the reac-
tion reached completion (monitored by TLC), the mixture was di-
luted with H2O (5 mL), treated with saturated NH4Cl solution
(20 mL), and extracted with ethyl acetate (3 ꢁ 20 mL). The organic
phase was washed with brine (10 mL), dried over MgSO4, and
evaporated. The residue was purified by column chromatography
on silica gel eluting with hexane/ethyl acetate (80:20).
HP-1 (J&W Scientific 25 m ꢁ 0.32 mm ꢁ 1.05
lm). HRMS (high-
resolution mass spectra) were taken with a Micro TOF-MS Bruker
Daltonics ESI. The IUPAC names were obtained using the software
ChemDraw UltraÒ, version 8.0. The enantiomeric excesses of the
organochalcogenides were determined using a Shimadzu GC-17A
gas chromatograph equipped with a chiral capillary column Chira-
4.2.3.1. (R)-1-(nButylthio)-3-butanol (R)-1a. Oil; yield: 1.004 g
(62%); 1H NMR (200 MHz; CDCl3) d 0.92 (3H, t, J = 7.0 Hz), 1.22
(3H, d, J = 6.6 Hz), 1.30–1.46 (2H, m), 1.50–1.62 (2H, m), 1.73
(2H, sext, J = 7.0 Hz), 2.02 (1H, s), 2.53 (2H, t, J = 7.4 Hz), 2.63 (2H,
t, J = 7.4 Hz), 3.95 (1H, sext, J = 6.1 Hz). 13C NMR (50 MHz; CDCl3)
sil-Dex CB b-cyclodextrin (25 m ꢁ 0.25 mm ꢁ 0.25
lm)-Varian.
The carrier gas was hydrogen with a pressure of 100 kPa. Optical
rotations were measured in a Jasco DIP-370 digital polarimeter.
d 12.6, 21.9, 23.4, 28.7, 31.6, 31.7, 38.1, 67.4. IR (film) cmꢀ1
:
4.2. Synthesis of the substrates
3376, 2960, 2929, 2872, 1461, 1374, 1272, 1124, 1053, 946, 746,
664. HRMS (ESI) m/z; calcd for C8H18NaOS [M+Na]+: 185.0976,
4.2.1. Preparation of (R)-butane-1,3-diol by reductive
depolymerization (R)-4
found: 185.0974.); ½a D24
¼ ꢀ8:5 (c 1.0, CHCl3); ee >99.9%.
ꢂ
To a suspension of LiAlH4 (20 g, 0.52 mol) in dry THF (1000 mL)
at 0 °C, PHB was added slowly (60 g, 0.70 mol) under nitrogen and
with magnetic stirring. The resulting mixture was stirred for 2 h at
room temperature and then refluxed for 5 h. The mixture was
cooled to 0 °C and diethyl ether (400 mL), H2O (20 mL), NaOH
(60 mL, 10% w/v solution), and H2O (20 mL) were added in turn.
The residue was filtered through a silica gel pad, which was then
washed with diethyl ether (2 ꢁ 100 mL). The organic phase was
dried over MgSO4 and the solvent was removed under vacuum.
The residue was purified by distillation under vacuum
4.2.3.2. (R)-1-(nButylselanyl)-3-butanol (R)-1b. Oil; yield 1.659 g
(79%); H NMR (200 MHz; CDCl3) d 0.92 (3H, t, J = 7.0 Hz), 1.21 (3H,
1
d, J = 6.1 Hz), 1.4 (2H, sext, J = 7.0 Hz), 1.57–1.85 (4H, m), 2.0 (1H,
s), 2.58 (2H, t, J = 7.4 Hz), 2.64 (2H, t, J = 7.4 Hz), 3.91 (1H, sext,
J = 6.1 Hz). 13C NMR (50 MHz; CDCl3) d 13.5, 19.9, 22.9, 23.3, 23.7,
32.5, 39.2, 67.8. IR (film) cmꢀ1: 3369, 2960, 2928, 2871, 1460,
1375, 1256, 1194, 1121, 1050, 939, 842, 737. HRMS (ESI) m/z; calcd
for C8H18NaOSe [M+Na]+: 233.0421, found: 233.0420. ½a 2D3
ꢂ
¼ ꢀ6:2
(c 1.0, CHCl3); ee >99.9%.
(30 mmHg/40 °C). Yield: 52 g (84%); ½a D24
¼ ꢀ30:0 (c 1.0, EtOH) ee
ꢂ
4.2.3.3. (R)-1-(nButyltellanyl)-3-butanol
(R)-1c. Oil;
yield
>99.9%; [lit.19
½
a 2D0
ꢂ
¼ þ30:0 (c 1.0, EtOH) for the (S)-isomer]. CAS
2.236 g (86%); CAS NR. 943643-07-0; 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. IR (film) cmꢀ1 3373, 2959, 2925, 2866,
1458, 1371, 1329, 1157, 1057, 912, 568, 448. MS m/z (rel int.) 260
[M++2] (13), 258 [M+] (13), 256 (7), 255 (3), 254 (2), 215 (3), 186
NR 6290-03-5. 1H NMR (300 MHz; CDCl3) d 1.17 (3H, d, J =
5.2 Hz), 1.6 (2H, q. J = 5.2 Hz), 3.65–3.81 (1H, m), 4.05 (2H, t,
J = 5.2 Hz). 13C NMR (75 MHz; CDCl3) d 23.4, 40.0, 60.6, 67.1. IR
(film) cmꢀ1: 3362, 2967, 2964, 1134, 1088, 1054. MS m/z (rel int.)
91 [M+1] (58), 90 [M+] (10), 85 (1), 73 (16), 72 (22), 67 (1), 61
(3), 57 (20), 55 (32).
(8), 72 (5), 57 (73), 55 (100), 45 (44). ½a D25
¼ ꢀ7:9 (c 1.0, CH2Cl2);
ꢂ
4.2.2. Preparation of (R)-3-hydroxybutyl-4-methylbenzene-
sulfonate (R)-3
ee >99.9%. [lit.2a
99%].
½
a 2D5
ꢂ
¼ þ7:0 (c 1.0, CH2Cl2) for the (S)-isomer, ee
To a solution of diol 4 (20 g, 0.22 mol) in dry CHCl3 (460 mL) un-
der nitrogen atmosphere and magnetic stirring, was added pyri-
dine (54 mL). The resulting solution was cooled to 0 °C and a
solution of tosyl chloride (4 mol Lꢀ1, 58 g, 0.24 mol) in CHCl3 was
slowly added (about 1.5 h) and the mixture was stirred for 3 h.
After that, cold H2O (100 mL) was added and the phases were sep-
arated. The organic phase was washed twice with brine (20 mL)
and CuSO4 saturated solution until the deep blue color disap-
peared. The organic phases were then combined, dried over MgSO4,
filtered, and the solvent was removed under reduced pressure. The
residue was purified by column chromatography over silica gel
4.2.3.4. (R)-1-(Phenylthio)-3-butanol (R)-1d. Oil; yield 1.51 g
(83%); CAS NR. 134641-08-0; 1H NMR (200 MHz; CDCl3) d 1.18
(3H, d, J = 6.6 Hz), 1.69–1.79 (2H, m); 2.25 (1H, s), 2.89–3.12 (2H,
m), 3.9 (1H, sext, J = 6.1 Hz). 13C NMR (50 MHz; CDCl3) d 23.4,
30.0, 38.0, 66.7, 125.8, 128.8, 128.9, 136.3. IR (film) cmꢀ1 3364,
3058, 2966, 2928, 2876, 1457, 1479, 1374, 1274, 1123, 740, 692,
477. HRMS (ESI) m/z; calcd for C10H14NaOS [M+Na]+: 205.0663,
found: 205.0663. ½a D24
ꢂ
¼ ꢀ29:4 (c 1.0, CHCl3) ee >99.9%; [lit.21
½
a 2D0
ꢂ
¼ ꢀ25:9 (c 0.99, CHCl3); ee 91.0%].
eluting with methylene chloride. Yield: 30 g (56%). ½a D23
¼ ꢀ14:9
ꢂ
(c 1.0, CH2Cl2) ee >99.9%; [lit.20
½
a 2D0
ꢂ
¼ ꢀ14:8 (c 1.0, CH2Cl2). CAS
4.2.3.5. (R)-1-(Phenylsellanyl)-3-butanol (R)-1e. Oil; yield 2.047 g
(89%); 1H NMR (200 MHz; CDCl3) d 1.20 (3H, d, J = 6.1 Hz), 1.75–1.86
(2H, m), 2.07 (1H, s), 2.91–3.04 (2H, m), 3.9 (1H, sext, J = 6.1 Hz),
7.22–7.27 (3H, m), 7.46–7.51 (2H, m). 13C NMR (50 MHz; CDCl3) d
NR 75351-36-9. 1H NMR (200 MHz; CDCl3)
d 1.22 (3H, d,
J = 7.2 Hz), 1.67–1.89 (2H, m), 2.45 (3H, s), 3.91–3.95 (3H, m),
7.27–7.83 (4H, m). 13C NMR (50 MHz; CDCl3) d 9.8, 11.7, 26.0,
52.3, 56.0, 116.0, 118.0, 121.2, 133.0 IR (film) cmꢀ1: 3540, 3416,
2969, 2928, 1354, 1189, 1175, 1096. MS m/z (rel. int.) 245 [M+1]
23.4, 23.9, 39.0, 67.5, 126.7, 129.0, 132.4, 134.9. IR (film) cmꢀ1
:
3366, 3070, 3056, 2967, 2929, 1578, 1477, 1437, 1120, 1072, 1023,

2702
J. L. Princival et al. / Tetrahedron: Asymmetry 20 (2009) 2699–2703
937, 841, 735, 691, 670, 465. HRMS (ESI) m/z; calcd for C10H14NaOSe
691, 608, 475. HRMS (ESI) m/z; calcd for C12H16NaO2S [M+Na]+:
[M+Na]+: 253.0108, found: 253.0103. ½a 2D4
ꢂ
¼ ꢀ40:9 (c 1.0, CHCl3); ee
247.0769, found: 247.0753. ½a D24
¼ ꢀ7:7 (c 1.0, CHCl3); ee >99.9%.
ꢂ
>99.9 %. [lit.3c
½
a 2D2
ꢂ
¼ þ40:6 (c 2.19, CHCl3) for the (S)-isomer].
4.2.4.5. (R)-O-Acetyl-1-(phenylsellanyl)-3-butanol (R)-5e. Oil;
yield 0.500 g (91%); CAS NR. 96004-31-3; 1H NMR (200 MHz;
CDCl3) d 1.21 (3H, d, J = 6.1 Hz), 1.72–1.94 (2H, m), 2.01 (3H,
s), 2.77–2.99 (2H, m), 5.0 (1H, sext, J = 6.1 Hz). 13C NMR
(50 MHz; CDCl3) d 19.7, 21.2, 23.1, 36.4, 70.5, 126.8, 129.0,
132.5, 135.2, 170.5. IR (film) cmꢀ1 3071, 3057, 3016, 2976,
2935, 2874, 1736, 1579, 1478, 1437, 1372, 1242, 1128, 1042,
1023, 950, 737, 691, 608, 464. HRMS (ESI) m/z; calcd for
4.2.3.6. (R)-1-(Phenyltellanyl)-3-butanol (R)-1f. Oil; yield 2.492 g
(89%); 1H NMR (200 MHz; CDCl3) d 1.2 (3H, d, J = 6.2 Hz), 1.65 (1H,
d, J = 4.8 Hz), 1.87–1.98 (2H, m), 2.83–3.00 (2H, m), 3.84 (1H, hept,
J = 6.2 Hz), 7.19–7.27 (3H, m), 7.69–7.74 (2H, m). 13C NMR
(50 MHz; CDCl3) d 4.0, 23.1, 40.7, 69.1, 127.5, 129.1, 138.2, 140.2 IR
(film) cmꢀ1: 3365, 3064, 3051, 2965, 2926, 1574, 1474, 1433, 1373,
1161, 1116, 1062, 1018, 928, 837, 732, 691, 654, 454. HRMS (ESI)
m/z; calcd for C10H14NaOTe [M+Na]+: 303.005, found: 303.007.
C10H20NaO2S [M+Na]+: 295.0213, found: 295.0207. ½a 2D6
¼ þ5:1
ꢂ
½
a 2D4
ꢂ
¼ ꢀ9:9 (c 1.0, CHCl3); ee >99.9%.
(c 1.0, CHCl3); ee >99.9%.
4.2.4. General procedure for the preparation of (R)-O-acetyl-1-
(butylchalcogenyl)-3-butanol 5a–f
4.2.4.6. (R)-O-Acetyl-1-(phenyltellanyl)-3-butanol, (R)-5f. Oil;
yield 0.600 g (93%); 1H NMR (200 MHz; CDCl3) d 1.20 (3H, d,
J = 6.1 Hz), 1.94–2.12 (2H, m), 2.00 (2H, s), 2.73–2.95 (2H, m), 4.9
(1H, sext., J = 6.1 Hz), 7.16–7.32 (3H, m), 7.68–7.73 (2H, m). 13C
NMR (50 MHz; CDCl3) d 2.7, 19.4, 21.2, 38.1, 72.0, 127.6, 129.1,
138.2, 140.4, 170.5. IR (film) cmꢀ1: 3065, 2975, 2934, 1735, 1574,
1474, 1433, 1372, 1243, 1126, 1022, 949, 733, 693, 608, 454. HRMS
(ESI) m/z; calcd for C12H16NaO2Te [M+Na]+: 345.0110, found:
To the appropriate alcohol (R)-4a–f (2 mmol) dissolved in dry
CH2Cl2 (10 mL) under a nitrogen atmosphere were added DMAP
(0.1 mmol) and acetic anhydride (0.2 mL, 2.1 mmol). The mixture
was stirred at room temperature for 1 h. After that, aqueous HCl
(10% v/v, 1 mL) was added and the reaction mixture was extracted
with ethyl acetate (3 mL). The organic phase was separated, dried
over MgSO4, and evaporated. The residue was purified by column
chromatography over silica gel eluting with hexane/ethyl acetate
(9:1).
345.0106. ½a 2D4
¼ þ16:6 (c 1.0 CHCl3); ee >99.9%.
ꢂ
4.2.5. General procedure for the preparation of (S)-O-acetyl-1-
(butylchalcogenyl)-3-butanol and (S)-O-acetyl-1-(phenylchalc-
ogenyl)-3-butanol 5a–f by Mitsunobu reaction
4.2.4.1. (R)-O-Acetyl-1-(nbutylthio)-3-butanol (R)-5a. Oil; yield
0.350 g (86%); 1H NMR (200 MHz; CDCl3) d 0.91 (3H, t, J = 7.0 Hz),
1.20 (3H, d, J = 6.1 Hz), 1.29–1.60 (4H, m); 1.71–1.94 (2H, m),
2.04 (3H, s), 2.47–2.54 (4H, m), 5.0 (1H, sext, J = 6.1 Hz). 13C NMR
(50 MHz; CDCl3) d 13.6, 19.8, 21.2, 21.9, 27.8, 31.6, 31.7, 35.9,
69.9, 170.6. IR (film) cmꢀ1 2958, 2931, 2872, 1738, 1461, 1373,
1244, 1050, 1025, 953. HRMS (ESI) m/z; calcd for C10H20NaO2S
To a stirred solution of the alcohol (R)-1a–f (10 mmol)and triphen-
ylphosphine (2.80 g, 12 mmol) in dry THF (30 mL) at 0 °C was slowly
added DEAD (1.25 g, 12 mmol). After 5 min. acetic acid (14 mmol)
was subsequently added dropwise. When the reaction had reached
completion (monitored by TLC), the reaction mixture was concen-
trated in vacuum, the residue dissolved in a mixture of diethyl
ether/pentane (50:50), and passed through a silica gel pad. The filtrate
was concentrated and the residue was purified by column chromatog-
raphy on silica gel using hexane/ethyl acetate (90:10) as eluant.
[M+Na]+: 227.1082, found: 227.1082. ½a 1D9
¼ þ3:5 (c 1.0, CHCl3);
ꢂ
ee >99.9%.
4.2.4.2. (R)-O-Acetyl-1-(nbutylselanyl)-3-butanol (R)-5b. Oil; yield
0.450 g 89(%); 1H NMR (200 MHz; CDCl3) d 0.91 (3H, t, J = 7.0 Hz),
1.20 (3H, d, J = 6.1 Hz), 1.40 (2H, sext, J = 7.0 Hz), 1.64 (2H, quint.,
J = 7.0 Hz), 1.74–1.98 (2H, m), 2.04 3H, s), 2.48–2.59 (4H, m), 5.0
(1H, sext, J = 6.1 Hz) . 13C NMR (50 MHz; CDCl3) d 13.5, 18.8, 19.6,
21.2, 22.9, 23.7, 32.5, 36.9, 70.6, 170.5. IR (film) cmꢀ1 2959, 2930,
1738, 1460, 1372, 1242, 1030, 951. HRMS (ESI) m/z; calcd for
4.2.5.1. (S)-O-Acetyl-1-(nbutylthio)-3-butanol (S)-5a. Oil; yield:
0.70 g (73%); ½a 2D2
¼ ꢀ3:5 (c 1.0, CHCl3); ee >99.9%.
ꢂ
4.2.5.2. (S)-O-Acetyl-1-(nbutylselanyl)-3-butanol (S)-5b. Oil; yield:
1.0 g (81%); ½a 2D5
¼ þ10:3 (c 1.0, CHCl3); ee >99.9%.
ꢂ
C10H20NaO2S [M+Na]+: 275.0526, found: 275.0517. ½a 2D4
¼ þ10:1 (c
ꢂ
4.2.5.3. (S)-O-Acetyl-1-(nbutyltellanyl)-3-butanol (S)-5c. Oil; yield:
1.0, CHCl3); ee >99.9%.
1.20 g (80%); ½a 2D2
¼ ꢀ19:3 (c 1.0, CHCl3); ee >99.9 %.
ꢂ
4.2.4.3. (R)-O-Acetyl-1-(nbutyltellanyl)-3-butanol (R)-5c. Oil; yield
0.993 g (92%); CAS NR. 915040-57-2; 1H 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 (75 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. IR (film) cmꢀ1 1157, 1057, 912, 568, 448.3059,
2979, 2932, 2870, 1735, 1574, 1458, 1371, 1329, 735. MS m/z (rel
int.) 302 (M+, 7%); 300 (M 7%); 298 (4%); 186 (2%); 185 (3%); 184
4.2.5.4. (S)-O-Acetyl-1-(phenylthio)-3-butanol (S)-5d. Oil; yield:
1.83 g (82%); ½a 2D3
¼ þ7:7 (c 1.0, CHCl3); ee >99.9 %.
ꢂ
4.2.5.5. (S)-O-Acetyl-1-(phenylsellanyl)-3-butanol (S)-5e. Oil;
yield: 2.36 g (87%); ½a D24
¼ ꢀ5:2 (c 1.0, CHCl3); ee >99.9 %.
ꢂ
4.2.5.6. (S)-O-Acetyl-1-(Phenyltellanyl)-3-butanol (S)-5f. Oil;
yield: 2.73 g (85%); ½a D23
¼ ꢀ16:6 (c 1.0, CHCl3); ee >99.9 %.
ꢂ
(2%); 183 (3%); 115 (45%); 55 (100%). ½a D25
¼ þ19:5 (c 1.0, CHCl3); ee
ꢂ
>99.9%.
4.2.6. General procedure for the preparation of (S)-3-hydroxy-
organochalcogenides (1a–f)
4.2.4.4. (R)-O-Acetyl-1-(phenylthio)-3-butanol (R)-5d. Oil; yield
0.390 g (87%); CAS NR. 110920-29-1; 1H NMR (200 MHz; CDCl3) d
1.23 (3H, d, J = 6.6 Hz), 1.71–1.95 (2H, m), 2.03 (3H, s), 2.80–3.02
(2H, m), 5.0 (1H, sext. J = 6.6 Hz), 7.17–7.35 (5H, m). 13C NMR
(50 MHz; CDCl3) d 19.8, 21.2, 29.5, 35.4, 69.7, 126.0, 128.8, 129.1,
136.0, 170.5. IR (film) cmꢀ1 3074, 3058, 3019, 2976, 2934, 2873,
1736, 1584, 1480, 1439, 1372, 1244, 1129, 1053, 1025, 953, 739,
To a suspension of K2CO3 (0.138 g, 1 mmol) in dry MeOH (1 mL)
under a nitrogen atmosphere was slowly added the appropriate
acetate (S)-5a–f. The resulting mixture was stirred for 40 min at
room temperature and filtered. The residue was purified by col-
umn chromatography on silica gel eluting with hexane/ethyl ace-
tate (80:20).

J. L. Princival et al. / Tetrahedron: Asymmetry 20 (2009) 2699–2703
2703
4.2.6.1. (S)-1-(nButylthio)-3-butanol (S)-1a. Oil; yield: 0.146 g
Tetrahedron 2009, 65, 8447; (e) Ferrarini, R. S.; Comasseto, J. V.; Dos Santos, A.
A. Tetrahedron: Asymmetry, 2009, 20, 2043.
3. (a) Eguchi, T.; Mochida, K. Biotech. Lett. 1993, 15, 955; (b) Izquierdo, I.; Plaza, M.
T.; Rodriguez, M.; Tamayo, J. A.; Martos, A. Tetrahedron: Asymmetry 2001, 12,
293; (c) Tiecco, M.; Testaferri, L.; Temperini, A.; Terlizzi, R.; Bagnoli, L.; Marini,
F.; Santi, C. Org. Biomol. Chem. 2007, 5, 3510.
(90%); ½a 2D3
¼ þ8:5 (c 1.0, CHCl3); ee >99.9%.
ꢂ
4.2.6.2. (S)-1-(nButylselanyl)-3-butanol (S)-1b. Oil; yield: 0.197 g
(94%); ½a 2D5
¼ þ6:3 (c 1.0, CHCl3); ee >99.9%.
ꢂ
4. Mori, K.; Watanabe, H. Tetrahedron 1984, 40, 299.
5. (a) Seebach, D.; Züger, M. Helv. Chim. Acta 1982, 65, 495; (b) Zarbin, P. H. G.;
Oliveira, A. R. M.; Delay, C. E. Tetrahedron Lett. 2003, 44, 6849.
6. Lemoigne, M. Bull. Soc. Chem. Biol. 1926, 8, 770–782.
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Biochem. Eng. Biotechnol. 2001, 71, 263–291; (b) Khanna, S.; Srivastava, A. K.
Process Biochem. 2005, 40, 607.
8. Vandamme, P.; Coenye, T. Int. J. Syst. Evol. Microbiol. 2004, 54, 2285–2289.
9. Valappil, S. P.; Misra, S. K.; Boccaccini, A. R.; Keshavarz, T.; Bucke, C.; Roy, I. J.
Biotechnol. 2007, 132, 251–258.
4.2.6.3. (S)-1-(nButyltellanyl)-3-butanol (S)-1c. Oil; yield: 0.239 g
(92%); ½a 2D4
¼ þ7:7 (c 1.0, CH2Cl2); ee >99.9%.
ꢂ
4.2.6.4. (S)-1-(Phenylthio)-3-butanol (S)-1d. Oil; yield: 0.161 g
(82%); ½a 2D4
ꢂ
¼ þ30:1 (c 1.0, CHCl3); ee >99.9%; [lit.21
½
a 2D0
ꢂ
¼ ꢀ25:9
(c 0.99, CHCl3) ee 91.0% for the (R)-isomer].
10. Anderson, A. J.; Dawes, E. A. Microbiol. Rev. 1990, 54, 450.
11. (a) Princival, J. L.; Barros, S. M. G.; Comasseto, J. V.; Dos Santos, A. A. Tetrahedron
Lett. 2005, 46, 4423; (b) Bassora, B. K.; Da Costa, C. E.; Gariani, R. A.; Comasseto,
J. V.; Dos Santos, A. A. Tetrahedron Lett. 2007, 48, 1485; (c) Comasseto, J. V.; Dos
Santos, A. A. Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 939; (d) Princival,
J. L.; Dos Santos, A. A.; Comasseto, J. V. Tetrahedron Lett. 2009, 50, 6368.
12. www.biocycle.com.br
13. Kabalka, G. W.; Varm, M.; Varma, R. S. J. Org. Chem. 1986, 51, 2386.
14. Comasseto, J. V.; Gariani, R. A.; Princival, J. L.; Dos Santos, A. A.; Zinn, F. K. J.
Organomet. Chem. 2008, 693, 2929.
4.2.6.5. (S)-1-(Phenylselanyl)-3-butanol (S)-1e. Oil; yield: 0.269 g
(93%); ½a 2D5
ꢂ
¼ þ42:7 (c 1.0, CHCl3); ee >99.9%. [lit.3c
½
a 2D3
ꢂ
¼ þ40:6 (c
2.19, CHCl3)].
4.2.6.6. (S)-1-(Phenyltellanyl)-3-butanol (S)-1f. Oil; yield 0.257 g
(92%); ½a 2D4
¼ þ9:8 (c 1.0, CH2Cl2); ee >99.9%.
ꢂ
15. Forter, D. G. Org. Synth., Collect. 1955, 3, 771.
Acknowledgments
16. Kemmitt, T.; Levanson, W. Organometallics 1989, 8, 1303.
17. For a recent review on the Mitsunobu reaction see: Swamy, K. C.; Kumar, N. N.;
Balaraman, E.; Kumar, K. V. P. Chem. Rev. 2009, 109, 2551.
18. Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of Laboratory
Chemicals, 2nd ed.; Pergamon Press: London, 1980.
The authors thank FAPESP, CNPq, and CAPES for the support.
PHB Industrial S/A is acknowledged for the donation of PHB.
19. (a) Huang, P.; Lan, H.; Zheng, X.; Ruan, Y. J. Org. Chem. 2004, 69, 3964; (b)
Gerlach, Von H.; Oertle, K.; Thalmann, A. Helv. Chim. Acta 1976, 59, 755; (c)
Murakam, S.; Harada, T.; Tai, A. Bull. Chem. Soc. Jpn. 1980, 53, 1356; (d)
Hungerbühler, Von E.; Seebach, D.; Wasmuth, D. Helv. Chim. Acta 1981, 64,
1467.
20. (a) O’Neill, J. A.; Lindell, S. D.; Simpson, T. J.; Willis, C. L. Tetrahedron: Asymmetry
1994, 5, 117; (b) Louwrier, S.; Ostendorf, M.; Bomm, A.; Hiemstra, H.;
Speckamp, W. N. Tetrahedron 1996, 52, 2603.
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