Deracemization of 1,2-diol monotosylate derivatives by a combination of enzymatic hydrolysis with the Mitsunobu inversion using polymer-bound triphenylphosphine

Article abstract of DOI:10.1016/j.tetasy.2009.11.005

The deracemization of 1,2-diol monotosylate derivatives is achieved by the sequential combination of enzymatic hydrolysis and Mitsunobu inversion using a polymer-bound triphenylphosphine. After the lipase-catalysed hydrolysis of the racemic 2-acetoxyhexyl tosylate, the subsequent Mitsunobu reaction without separation causes an inversion of the resulting (R)-alcohol to give the (S)-enantiomer of the acetate as a single product. In particular, the reaction using the polymer-bound triphenylphosphine also proceeds smoothly, and the product is easily separated by filtration from the polymer-bound reagent and its by-products. This deracemization process is applicable to the preparation of several optically active 1,2-diol monotosylates.

Full text of DOI:10.1016/j.tetasy.2009.11.005

Tetrahedron: Asymmetry 20 (2009) 2802–2808
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Deracemization of 1,2-diol monotosylate derivatives by a combination
of enzymatic hydrolysis with the Mitsunobu inversion using
polymer-bound triphenylphosphine
*
Yasutaka Shimada, Kazumasa Usuda, Hirokazu Okabe, Tsuguru Suzuki, Kazutsugu Matsumoto
Department of Chemistry, Meisei University, Hodokubo 2-1-1, Hino, Tokyo 191-8506, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The deracemization of 1,2-diol monotosylate derivatives is achieved by the sequential combination of
enzymatic hydrolysis and Mitsunobu inversion using a polymer-bound triphenylphosphine. After the
lipase-catalysed hydrolysis of the racemic 2-acetoxyhexyl tosylate, the subsequent Mitsunobu reaction
without separation causes an inversion of the resulting (R)-alcohol to give the (S)-enantiomer of the ace-
tate as a single product. In particular, the reaction using the polymer-bound triphenylphosphine also pro-
ceeds smoothly, and the product is easily separated by filtration from the polymer-bound reagent and its
by-products. This deracemization process is applicable to the preparation of several optically active 1,2-
diol monotosylates.
Received 10 October 2009
Accepted 6 November 2009
Available online 5 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
group in themselves, we could not select the usual inversion meth-
od, such as mesylation or halogenation followed by substitution. In
Optically active 1,2-diol monotosylates are useful precursors of
chiral non-racemic epoxides,1 amino alcohols,2 alkyl carbinols,3
etc., during the synthesis of natural and biologically active com-
pounds. The hydrolase-mediated kinetic resolutions of the racemic
1,2-diol monotosylate derivatives have been reported as practical
and attractive methods for the preparation of such optically active
compounds.2e,4–6 We have also disclosed the practical preparation
of various optically active 1,2-diol monoarylsulfonates by the en-
zyme-mediated hydrolysis with lipase PS (Burkholderia cepacia)
from Amano Enzyme, Inc. and the methodical study of the sub-
strate specificity.7 However, the maximum theoretical yield of
the kinetic resolution methodology is limited to 50% for each enan-
tiomer, and this inevitable drawback is a bottleneck to the effective
synthesis of the desirable enantiomer. Dynamic kinetic resolution
(DKR), which implies an in situ racemization of the substrate dur-
ing the reaction, is one of the attractive techniques for obtaining a
single enantiomer. Although the DKR reactions of racemic second-
ary alcohols have been developed using enzyme-transition metal
combinations, such as lipase and Ru,8 this method is not always
applicable to all substrates. In addition, DKR is typically restricted
to enzymatic esterification in an organic solvent. For obtaining the
single enantiomers of the 1,2-diol monotosylates via our proce-
dure, we then focused on an alternative approach; that is, the ste-
reospecific inversion of one enantiomer after enzymatic hydrolysis
of the racemates. Since our target compounds have a good leaving
previous papers, deracemization of chiral secondary alcohol deriv-
atives have been carried out by hydrolase-catalysed resolutions
with sequential Mitsunobu esterification.5b,9,10 However, in almost
all cases, the alcohols used are typical substrates for the Mitsunobu
reaction. Furthermore, little attention has been paid to optimiza-
tion of the reaction conditions, and to the improvement of the puri-
fication process due to the troublesome impurities derived from
the Mitsunobu reagent. Herein, we report an effective preparation
of optically active 1,2-diol monotosylate derivatives via deracemi-
zation of the corresponding racemic mixture by the sequential
combination of enzymatic hydrolysis and Mitsunobu esterification
under the optimized reaction conditions. In particular, the reaction
using the polymer-bound triphenylphosphine also proceeded
smoothly, and the product was easily separated by filtration from
the polymer-bound reagent and its by-products.
2. Results and discussion
As the representative target compound, 2-acetoxyhexyl tosylate
1a was selected. The racemic compound ( )-1a was readily synthe-
sized as shown in Scheme 1. After the oxidation of 1-hexene 2
using a catalytic amount of OsO4, the highly selective tosylation
of the resulting diol ( )-3a was carried out using TsCl, Bu2SnO
and Et3N to afford the corresponding ( )-2-hydroxyhexyl tosylate
4a in a high yield (89%) as the only product.11 Successive treatment
of the alcohol with pyridine and acetic anhydride gave compound
( )-1a. Other substrates were prepared as shown in Scheme 2.
Unfortunately, the monotosylations of the diols ( )-3b and 3c via
* Corresponding author. Tel./fax: +81 42 591 7360.
E-mail address: mkazu@chem.meisei-u.ac.jp (K. Matsumoto).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.11.005

Y. Shimada et al. / Tetrahedron: Asymmetry 20 (2009) 2802–2808
2803
OH
( )-3a
PPh3, DEAD
BzOH
THF, 1 h, rt
cat. OsO4, NMO
Acetone-H2O
86%
OH
OBz
HO
TsO
TsO
2
(R)-4a
(S)-9
96%
TsCl, Bu2SnO
OH
Et3N
CH2Cl2
89%
TsO
Scheme 3.
( )-4a
combination with the enzymatic hydrolysis of the acetate 1a, the
use of acetic acid is better, and will afford (S)-1a as the sole prod-
uct. We then examined the Mitsunobu reaction of (R)-2a using ace-
tic acid under the same reaction conditions, but the reaction only
gave a complex mixture. When the Mitsunobu reaction of a steri-
cally hindered alcohol, such as 4a bearing a tosyloxy group, is em-
ployed using acetic acid in an ether solvent, the coupling of the
acetate with the phosphonium adduct between PPh3 and DEAD
preferentially proceeded to afford many undesirable by-products.
Compared to benzoate, acetate has a strong nucleophilicity to-
wards the phosphonium adduct. According to the report by Hughes
and Reamer,13 the coupling reaction of carboxylates in toluene was
slower than that in ether solvents. We then decided that the Mits-
unobu reaction of 4a should be carried out in toluene under vari-
ous conditions, and these results are summarized in Table 1. As
expected, the reaction with PPh3 (3 equiv), DEAD (3 equiv) and
acetic acid (3 equiv) in toluene for 1 h also proceeded to afford
the corresponding (S)-1a (99% ee) with an inversion of configura-
tion (entry 1). However, the isolated yield was not very high
(62%) due to the presence of the unreacted 4a and some unknown
impurities. Changing the reaction time to 24 h did not improve the
yield. Next, we attempted the reaction with tributylphosphine
(PBu3) (entry 2). In this case, the reaction proceeded slowly, and
after 24-h, the reaction yielded 1a in 61%. Interestingly, the abso-
lute configuration of the obtained 1a was (R) (67% ee). On the other
hand, the 24-h reaction using 1,10-(azodicarbonyl)dipiperidine
(ADDP)14 and PBu3 gave 1a in a good yield (78%), but the stereo-
chemistry was also (R) (97% ee) (entry 3).15 These results indicate
that the attack of the acetate on the phosphonium adduct of PBu3
was faster than that of the sterically hindered alcohol 4a, while the
OAc
Ac2O
Pyridine
TsO
( )-1a
95%
Scheme 1.
the same procedure as the case of 1a gave not only the correspond-
ing ( )-4b and 4c, but also 1-hydroxyalkyl tosylates ( )-5b and 5c
as the minor products, respectively. After some trials, we found
that porcine pancreas lipase (PPL) selectively catalysed the hydro-
lysis of the acetates of 5. Finally, the acetylations and the sequen-
tial enzymatic hydrolyses using PPL gave the compounds ( )-1b
and 1c without any impurities.
We have already succeeded in the hydrolysis of ( )-1a with
lipase PS in 0.1 M phosphate buffer (pH 6.5) containing 10%
i-Pr2O for 24 h at 30 °C with an excellent enantioselectivity to af-
ford the unreacted (S)-1a and the resulting (R)-2-hydroxyhexyl
tosylate 4a (conv. = 0.45, E value12 = 244).7a When the chiral alco-
hol 4a is directly converted into the corresponding carboxylic ester
of opposite configuration by the addition of some reagents, the (S)-
enantiomer can be obtained in a theoretical yield of 100%. Herein,
we first tried to examine the Mitsunobu inversion of the optically
active (R)-4a (99% ee). The reaction of (R)-4a with benzoic acid
(3 equiv) in the presence of diethyl azodicarboxylate (DEAD,
3 equiv) and triphenylphosphine (PPh3, 3 equiv) in THF proceeded
successfully without any group migration to give (S)-benzoate 9
(99% ee) along with an inversion of configuration (Scheme 3).
Although benzoic acid is a typical reagent as the nucleophile, in
1) Ac2O, Py
2) PPL
TsCl, Bu2SnO
OH
Me
OTs
Me
( )-5b
OAc
Me
( )-1b
OH
Me
( )-3b
Et3N
CH2Cl2
90%
buffer–i-Pr2O
+
TsO
HO
TsO
HO
57%
( )-4b
(2 steps)
(12 : 1)
PMBCl, NaH
cat. TBAI
THF, reflux
89%
OH
HO
O
O
2 M HCl aq
THF
O
O
OPMB
OPMB
OH
( )-6
( )-7
( )-3c
93%
1) Ac2O, Py
2) PPL
buffer–i-Pr2O
TsCl, Bu2SnO
Et3N
OH
OH
OAc
+
TsO
OPMB TsO
OPMB
TsO
OPMB
CH2Cl2
92%
73%
( )-4c
( )-5c
( )-1c
(12 : 1)
(2 steps)
OH
OAc
Ac2O
Pyridine
97%
O
TsOH
CH2Cl2, reflux
59%
Cl
TsO
Cl
TsO
Cl
( )-4d
( )-4d
8
Scheme 2.

2804
Y. Shimada et al. / Tetrahedron: Asymmetry 20 (2009) 2802–2808
Table 1
The Mitsunobu reaction of (R)-4a under various conditionsa
phosphine reagent
azodicarbonyl reagent (3 equiv.)
AcOH (3 equiv.)
OH
OAc
TsO
TsO
*
toluene, rt
(R)-4a
1a*
Entry
Phosphine reagentb
Azodicarbonyl reagent
Time (h)
Yield (%)
ee (%)
Abs. configc
1
2
PPh3 (3)
PBu3 (3)
PBu3 (3)
Bu3P = CHCN (CMBP) (3)
PPh3 (4)
DEAD
DEAD
ADDP
1
24
24
24
1
62
61
78
99
67
97
—
99
99
(S)
(R)
(R)
—
(S)
(S)
3
4d
5
No Reaction
100
100
DEAD
DEAD
5
PPh3 (5)
0.25
a
b
c
Unless otherwise noted, the reaction was performed using 30–60 mg of (R)-2a (99% ee), a phosphine reagent, an azodicarbonyl reagent and AcOH in toluene at rt.
A number in parentheses reveals the equivalent of the reagent against the substrate.
Determined by comparing the specific rotation value with the reported value and HPLC analysis of 1a.
Using a phosphorane-type reagent.
d
Table 2
The Mitsunobu reaction of (R)-2a using polymer-supported phosphine reagentsa
acetylation of 4a preferentially occurred with retention of configu-
ration. Unfortunately, the use of a phosphorane-type reagent,
cyanomethylenetributylphosphorane (CMBP),16 did not produce
any esterification products (entry 4). We then focused on the com-
bination of PPh3 and DEAD, and examined the reaction with excess
amounts of reagents in order to improve the conversion. After
some trials, it was found that the amount of PPh3 affected the iso-
lated yield, and the acetyloxylation of (R)-4a using 4 equiv of PPh3
proceeded completely within 1 h to give acetate (S)-1a in a 100%
isolated yield without any racemization (entry 5). Surprisingly,
the reaction using 5 equiv of PPh3 was finished within only
15 min (entry 6).
OH
OAc
, DEAD, AcOH
PPh2
TsO
TsO
*
toluene, rt
(R)-4a
1a*
Entry Based polymer
Time
(h)
Yield (%)
ee (%) Abs.
config.
1
Poly(ethylene
glycol)b
24
No
reaction
14
—
—
2
3
Silica gelc
24
1
33
99
(R)
(S)
Polystyrened
100
a
The reaction was performed using 30–60 mg of (R)-2a (99% ee), a polymer-
Although the inversion of the stereogenic centre of 4a has been
accomplished as mentioned above, the most significant problem of
this procedure is the difficult removal of any excess PPh3, the oxide
of PPh3 and its by-products by column chromatography for the
purification of 1a. We noticed that the use of an insoluble poly-
mer-supported PPh3 has some advantages for the easy separa-
tion,17,18 although there are only a few examples of inverting the
stereochemistry of secondary alcohols when using the solid-sup-
port PPh3.18d–f We then examined the modified Mitsunobu reaction
of (R)-4a using three kinds of commercially available polymer-sup-
ported reagents (Table 2). The reaction using the polymer-bound
phosphine (5 equiv) was carried out with DEAD (3 equiv) and ace-
tic acid (3 equiv). Unfortunately, the reaction using poly(ethylene
glycol)-supported triphenylphosphine, which is a soluble polymer,
did not proceeded at all (entry 1). On the other hand, the use of 2-
diphenylphosphinoethyl-functionalized silica gel afforded (R)-1a
(33% ee) (entry 2). This result indicated that the esterification oc-
curred with both retention and inversion of configuration. It is
noteworthy that the heterogeneous reaction using polystyryl-
diphenylphosphine (cross-linked with 2% divinylbenzene) for only
1 h was the same as that under the standard homogeneous condi-
tions. As expected, product (S)-1a (100% yield) was easily obtained
without any significant impurities after a simple filtration of the
polymer-bound reagent. Although the reaction using diisopropyl
azodicarboxylate (DIAD) instead of DEAD gave almost the same re-
sult, there were many significant impurities derived from DIAD.
Next, we tried to examine the deracemization of several race-
mic 2-acetoxyalkyl tosylates ( )-1a–d by a two-step procedure
via the combination of the lipase-mediated hydrolysis and a subse-
quent Mitsunobu reaction under the optimized reaction conditions
(Table 3). In the first enzymatic hydrolysis, the conversion should
be over 0.5 in order to keep the ee of the final acetates high;10c
the reaction times were then controlled for 24 h or 48 h depending
on the reactivity of the substrates. For example, the enzyme-med-
bound phosphine reagent (5 equiv), DEAD (3 equiv), and AcOH (3 equiv) in toluene
at rt.
b
For the calculation of the equivalents, we estimated the molecular weight of the
based PEG at ca. 3400 by a TOF-MASS analysis. The loading capacity was ca.
0.51 mmol PPh3/g.
c
The loading capacity was ca. 1.05 mmol PPh2/g.
The loading capacity was ca. 3 mmol PPh3/g resin.
d
iated hydrolysis of ( )-1a for 48 h gave a mixture of (S)-1a (ees,
98%) and (R)-4a (eep, 99%) (entry 1). As expected, in the sequential
Mitsunobu reaction using polystyrene-bound PPh3, only alcohol
(R)-4a was stereospecifically converted to the corresponding ace-
tate, and after filtration of the resin, (S)-1a (eef, 98%) was success-
fully obtained in 91% isolated yield from the racemate as the single
product. This procedure was also applicable to the other substrates
bearing various substituents, such as the methyl 1b, 4-methoxyb-
enzyloxymethyl 1c (–CH2OPMB) and chloromethyl 1d groups (en-
tries 2–4, respectively). In all cases, the enzyme-mediated
hydrolyses proceeded with excellent enantioselectivities, and the
sequential Mitsunobu esterifications gave only the corresponding
acetates with high ees and in good yields. Furthermore, the ees
of the acetates were improved by repeating the lipase-mediated
hydrolyses to afford the enantiomerically pure (S)-1a, -1b, -1c
and (R)-1d in 87%, 79%, 82% and 90% yields, respectively.
Our procedure can give the desired enantiomer of 1,2-diol
monotosylates. The optically active acetate (S)-1a was easily con-
verted to the corresponding alcohol (S)-4a by the addition of DI-
BAL-H at ꢀ78 °C without any racemization (Scheme 4), and,
finally, the Mitsunobu reaction of the product can give the com-
pound (R)-1a with the opposite absolute configuration. In order
to give the final product with a high ee, the E-value of the first
enzymatic process must be excellent and the conversion must be
about 0.5. Although the (R)-enantiomer of the acetates could be
prepared similarly by combination of the enzymatic transesterifi-

Y. Shimada et al. / Tetrahedron: Asymmetry 20 (2009) 2802–2808
2805
Table 3
Combination of enzymatic hydrolysis of ( )-1 and the sequential Mitsunobu reactiona
OAc
R
PPh2
TsO
polystyrene
OAc
OAc
R
lipase PS
buffer–i-Pr2O
30 °C
1* (ees)
DEAD, AcOH
TsO
TsO
toluene
R
OH
1h, rt
1* (eef)
( )-1
TsO
R
4* (eep)
Entry
R
Enzymatic hydrolysis
eep (%)
Mitsunobu reaction
Total yieldd (%)
eef (%)
Time (h)
ees (%)
Conv.b (%)
E valuec
1
2
3
4
a
b
c
Bu
Me
CH2OPMB
CH2Cl
48
24
24
24
98
99
99
99
91
93
95
0.50
0.52
0.52
0.51
>200
113
145
91
85
83
73
98
93
96
95
d
>99
>200
a
b
c
The reaction was performed using 120 mg of the substrates as the starting material.
Calculated using ees/(ees+eep).
Calculated using ln[(1ꢀconv.)(1–ees)]/ln[(1ꢀconv.)(1+ees)].
d
Calculated from the starting ( )-1 (two steps).
4.2. Preparation of the substrates
4.2.1. ( )-2-Acetoxyhexyl tosylate 1a
OAc
OH
DIBAL-H
TsO
TsO
THF, 1.5 h
–78 °C
(S)-1a
(S)-4a
To a solution of 1-hexene 2 (5.03 g, 59.7 mmol) in acetone
(160 mL) and H2O (20 mL) were added 4-methylmorpholine N-
oxide (NMO, 14.4 g, 119 mmol), and a catalytic amount of OsO4,
and the mixture was stirred overnight at room temperature. After
the addition of Na2S2O4, the mixture was filtered through a Celite
pad. The filtrate was diluted with AcOEt, and washed with brine
(ꢁ2) and dried over Na2SO4. After evaporation, the residue was
purified by flash column chromatography on silica gel (AcOEt) to
give ( )-hexan-1,2-diol 3a as a colourless oil (6.06 g, 86%).
99%
Scheme 4.
cation of the alcohol with the Mitsunobu reaction, the ees of the fi-
nal products will be low because of the moderate enantioselectiv-
ity of the enzymatic esterification.4a,b
3. Conclusion
Under an argon atmosphere, to Bu2SnO (281 mg, 1.02 mmol)
were added solutions of ( )-3a (6.00 g, 50.8 mmol) in CH2Cl2
(60 mL), TsCl (10.7 g, 56.1 mmol) in CH2Cl2 (40 mL) and Et3N
(7.8 mL, 56.1 mmol). The mixture was stirred overnight at room
temperature, and the reaction was stopped with 2 M HCl at 0 °C.
The products were extracted with CH2Cl2 (ꢁ3), and the organic
layer was washed with H2O, satd NaHCO3 aq and brine, and dried
over Na2SO4. After evaporation under reduced pressure, the resi-
due was purified by flash column chromatography on silica gel
(hexane/AcOEt = 6/1) to give ( )-2-hydroxyhexyl tosylate 4a as a
colourless oil (12.3 g, 89%); IR (neat) 3539, 2955, 2872, 1599,
In conclusion, we have succeeded in the deracemization of 1,2-
diol monotosylate derivatives by the combination of enzyme-
mediated hydrolysis and the modified-Mitsunobu inversion, and
obtained several optically active enantiomers of 1a–d in >70% total
yields. In particular, the separation and isolation of the products
from the by-products, which were derived from the reagents, were
quite easy due to the use of the polymer-supported PPh3. This meth-
od is expected to be a potentially useful tool for organic synthesis.
4. Experimental
4.1. General
1454, 1360, 1177, 1098, 974 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d = 0.88 (t, J = 7.0 Hz, 3H), 1.20–1.36 (m, 3H), 1.36–1.46 (m, 3H),
2.16 (d, J = 4.5 Hz, 1H), 2.46 (s, 3H), 3.80–3.88 (m, 1H), 3.88 (dd,
J1 = 7.0 Hz, J2 = 10.0 Hz, 1H), 4.04 (dd, J1 = 2.5 Hz, J2 = 10.0 Hz, 1H),
7.36 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H); 13C NMR (75 MHz,
CDCl3) d = 13.8, 21.5, 22.4, 27.2, 32.2, 69.2, 73.9, 132.5, 144.9; MS
m/z (rel intensities) 242 (M+, 25), 172(11), 155 (52), 139(10) 107
(20), 91 (100), 87 (42); HRMS m/z 272.1085 (272.1082 calcd for
C13H20O4S, M+).
1H (300 MHz) and 13C (75 MHz) NMR spectra were measured on
a JEOL JNM AL-300 with tetramethylsilane (TMS) as the internal
standard. IR spectra were recorded with Shimadzu IR Prestige-21
spectrometers. Mass spectra were obtained with a JEOL EI/FAB
mate BU25 Instrument by the EI method. Optical rotations were
measured with a Jasco DIP-1000 polarimeter. HPLC data were ob-
tained on Shimadzu LC-10ADVP, SPD-10AVP, and sic 480II data sta-
tion (System Instruments Inc.). E. Merck Kieselgel 60 F254 Art.5715
was used for analytical TLC. Preparative TLC was performed on E.
Merck Kieselgel 60 F254 Art.5744. Column chromatography was
performed with Silica Gel 60 N (63–210 mm, Kanto Chemical Co.
Inc.). All other chemicals were also obtained from commercial
sources. All polymer-bound phosphine reagents were purchased
from Aldrich Chem Co. [poly(ethylene glycol) triphenylphosphine
(No. 532649), 2-diphenylphosphinoethyl-functionalized silica gel
(No. 538019) and polystyryl-diphenylphosphine, cross-linked with
2% divinylbenzene (No. 366445)].
Under an argon atmosphere, acetic anhydride (10.9 mL,
116 mmol) was added to a solution of ( )-4a (10.2 g, 37.5 mol) in
pyridine (20 mL), and the mixture was stirred for 3 h at room tem-
perature. After the mixture was diluted with AcOEt, the organic
layer was washed with 2 M HCl, brine, satd NaHCO3 aqueous solu-
tion and brine, and dried over Na2SO4. After evaporation, the resi-
due was purified by column chromatography on silica gel (hexane/
AcOEt = 4/1) to give ( )-1a as a colourless oil (11.2 g, 95%); IR
(neat) 3460, 2957, 2870, 1730, 1597, 1454, 1362, 1177 cmꢀ1 1H
;
NMR (300 MHz, CDCl3) d = 0.86 (t, J = 7.0 Hz, 3H), 1.13–1.33 (m,
4H), 1.46–1.63 (m, 2H), 1.98 (s, 3H), 2.46 (s, 3H), 4.04 (dd,
J1 = 5.0 Hz, J2 = 10.5 Hz, 1H), 4.10 (dd, J1 = 3.5 Hz, J2 = 10.5 Hz, 1H),

2806
Y. Shimada et al. / Tetrahedron: Asymmetry 20 (2009) 2802–2808
4.90–4.99 (m, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H);
13C NMR (75 MHz, CDCl3) d = 13.7, 20.8, 22.2, 27.0, 30.0, 70.0,
70.9, 127.8, 130.0, 132.7, 145.0, 170.3; MS m/z (rel intensities)
314 (M+, 7.2), 254 (27), 228 (38), 198 (16), 172 (16), 143 (36),
129 (17), 91 (100), 82 (16); HRMS m/z 314.1187 (314.1188 calcd
for C15H22O5S, M+).
7.13–7.22 (m, 2H), 7.29–7.37 (m, 2H), 7.74–7.81 (m, 2H); 13C
NMR (75 MHz, CDCl3) d = 20.8, 21.6, 55.2, 67.0, 68.0, 69.7, 73.0,
113.8, 127.9, 129.3, 129.5, 129.9, 145.0, 159.3, 170.1; MS m/z
(rel intensities) 408 (M+, 7.7), 172 (9.6), 137 (33), 121 (100),
107 (15), 91 (78); HRMS m/z 408.1259 (408.1243 calcd for
C20H24O7S, M+).
4.2.2. ( )-2-Acetoxypropyl tosylate 1b
4.2.4. ( )-2-Acetoxy-3-chloropropyl tosylate 1d
According to the procedure for the preparation of 4a described
above, commercially available ( )-3b was converted to ( )-4b and
5b as a colourless oil (90%; 4b:5b = 12:1).
According to the procedure for the preparation of 1a, the mix-
ture of ( )-4b and 5b was converted to the mixture of ( )-1b and
the acetate of 5b as a colourless oil (93%).
Under an argon atmosphere, to a solution of ( )-epichlorohy-
drin 8 (5.13 g, 55.5 mmol) in CH2Cl2 (20 mL) was added a solution
of p-TsOH (10.6 g, 55.5 mmol) in CH2Cl2 (30 mL), and the mixture
was stirred for 2 h at reflux. After the reaction was stopped with
satd NaHCO3 aq, the products were extracted with CH2Cl2 (ꢁ3),
and the organic layer was washed with brine and dried over
Na2SO4. After evaporation under reduced pressure, the residue
was purified by flash column chromatography on silica gel (hex-
ane/AcOEt = 1/1) to give ( )-3-chloro-2-hydroxypropyl tosylate
4d as a colourless oil (8.69 g, 59%).
To a 1-L Erlenmeyer flask containing 500 mg (1.73 mmol; sub.
concn, ca. 10 mM) of the mixture of ( )-1b and the acetate of 5b
were added 17 mL of i-Pr2O and 153 mL of 0.1 M phosphate buffer
(pH 6.5). To the mixture was added 128 mg of Lipase from porcine
pancreas (PPL; Type II, Sigma) (994 u/mg, using olive oil at pH 7.7),
and the solution was incubated for 24 h at 30 °C. After the mixture
was filtered through a Celite pad, the products were extracted with
AcOEt (ꢁ3), washed with brine, and dried over Na2SO4. After evap-
oration, the residue was purified by column chromatography on
silica gel (hexane/AcOEt = 4/1) to give ( )-1b as a colourless oil
(305 mg, 61%); IR (neat) 2992, 2359, 1923, 1732, 1599, 1360,
According to the procedure for the preparation of 1a described
above, ( )-4d was converted to ( )-1d as a colourless oil (97%); IR
(neat) 2959, 2359, 1748, 1597, 1369, 1229, 1177, 997, 816 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d = 2.05 (s, 3H), 2.46 (s, 3H), 3.60 (dd,
J1 = 5.0 Hz, J2 = 11.5 Hz, 1H), 3.66 (dd, J1 = 5.0 Hz, J2 = 11.5 Hz, 1H),
4.23 (d, J = 4.5 Hz, 3H), 5.11 (tdd, J1 = 4.5 Hz, J2 = J3 = 5.0 Hz, 1H),
7.32–7.41 (m, 2H), 7.75–7.84 (m, 2H); 13C NMR (125 MHz, CDCl3)
d = 20.7, 21.7, 41.2, 67.1, 70.0, 128.0, 130.0, 132.4, 145.3, 170.0,
182.7; MS m/z (rel intensities) 306 (M+, 2.9), 185 (6.6), 155 (65),
135 (100), 121 (28); HRMS m/z 306.0327 (306.0329 calcd for
C12H15O5SCl, M+).
1240, 1179, 1098, 953 cmꢀ1 1H NMR (300 MHz, CDCl3) d = 1.22
;
(d, J = 6.5 Hz, 3H), 1.98 (s, 3H), 2.46 (s, 3H), 4.03 (dd, J1 = 5.5 Hz,
J2 = 11.0 Hz, 1H), 4.06 (dd, J1 = 3.5 Hz, J2 = 11.0 Hz, 1H), 5.00–5.07
(m, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d = 16.0, 20.9, 21.6, 67.5, 71.0, 127.9, 128.1,
129.9, 132.7, 145.0, 170.2; MS m/z (rel intensities) 272 (M+, 8.6),
212 (22), 155 (60), 101 (42), 91 (100); HRMS m/z 272.0717
(272.0718 calcd for C12H16O5S, M+).
4.3. Typical procedure for the hydrolysis of acetates 1 with
lipase PS and the sequential Mitsunobu inversion using
polymer-bound triphenylphosphine
4.2.3. ( )-2-Acetoxy-3-(4-methoxy)benzyloxypropyl tosylate 1c
Under an argon atmosphere, to a suspension of NaH (661 mg,
15.1 mmol) in THF (5 mL) were added a solution of ( )-2,2-di-
methyl-4-hydroxymethyl-1,3-dioxolane 6 (1.00 g, 7.57 mmol) in
THF (20 mL), 4-methoxybenzyl chloride (1.6 mL, 11.3 mmol) and
a catalytic amount of TBAI at 0 °C. The mixture was stirred for
1.5 h at reflux and the reaction was stopped with 0.1 M phosphate
buffer (pH 6.5) at 0 °C. The products were extracted with AcOEt
(ꢁ3), and the organic layer was washed with brine and dried over
Na2SO4. After evaporation under reduced pressure, the residue was
purified by flash column chromatography on silica gel (hexane/
AcOEt = 10/1) to give ( )-2,2-dimethyl-4-(4-methoxy)benzyl-
oxymethyl-1,3-dioxolane 7 as a colourless oil (1.71 g, 89%).
To a solution of ( )-7 (1.69 g, 6.69 mmol) in THF (45 mL) was
added a solution of 2 M HCl aq (5 mL) at 0 °C. The mixture was stir-
red overnight at room temperature. After the mixture was satu-
rated with NaCl, the products were extracted with AcOEt (ꢁ5)
and the organic layer was dried over Na2SO4. After evaporation un-
der reduced pressure, the residue was purified by flash column
chromatography on silica gel (hexane/AcOEt = 1/1?AcOEt) to give
( )-3-(4-methoxy)benzyloxypropan-1,2-diol 3c as a colourless oil
(1.32 g, 93%).
To a 200-mL Erlenmeyer flask containing 126 mg (0.401 mmol;
sub. concn, 10 mM) of ( )-1a were added 4 mL of i-Pr2O and 36 mL
of 0.1 M phosphate buffer (pH 6.5). To the mixture was added
30 mg of lipase PS (>23 u/mg, using olive oil), and the solution
was incubated for 48 h at 30 °C. The products were extracted with
AcOEt (ꢁ3), washed with brine and dried over Na2SO4. After evap-
oration, the residue was filtered through a silica pad (SPE Si, Oro-
chem Technology Inc.), and the filtrate was concentrated in
vacuo. The mixture of (S)-1a (98%) and (R)-4a (99%) (118 mg)
was used for the sequential reaction without further purification.
The ees of (S)-1a and (R)-4a were determined by HPLC analysis.
HPLC conditions: column, CHIRALCEL AD-H (Daicel Chemical
Industries, Ltd.); eluent, hexane/2-propanol = 90/10; flow rate,
0.5 mL/min; 254 nm; temperature, 25 °C; retention time, 1a: 18
(S) and 19.5 (R) min, 4a: 32 (R) and 43 (S) min.
Under an argon atmosphere, to polymer-supported PPh3 (poly-
styryl-diphenylphosphine, cross-linked with 2% divinylbenzene;
391 mg, ca. 1.17 mmol, ca. 3 mmol PPh3/g resin) were added a
solution of (S)-1a and (R)-4a (118 mg) in toluene (9 mL), AcOH
(35.5 ll, 0.602 mmol) and DEAD (0.27 mL, 0.60 mmol, 40% toluene
solution), and the suspension was stirred for 1 h at rt. After the
mixture was filtered, the filtrate was diluted with AcOEt, washed
with satd NaHCO3 aq, and brine and dried over Na2SO4. After
evaporation under reduced pressure, the residue was purified by
flash column chromatography on silica gel (hexane/AcOEt = 4/1)
to give (S)-1a (98% ee) as a colourless oil (115 mg, 91% from
( )-1a).
The reactions of the other substrates were carried out by the
same procedure. The results are shown in the text. All the spectral
data (1H and 13C NMR, IR and MS) were in full agreement with
those of the racemates.
According to the procedure for the preparation of 4a, ( )-3c was
converted to the mixture of ( )-4c and 5c as a colourless oil (92%,
4c:5c = 12:1).
According to the procedure for the preparation of 1b, the mix-
ture of ( )-4c and 5c was converted to ( )-1c as a colourless oil
(73%, two steps); IR (neat) 2934, 2359, 1744, 1512, 1364, 1246,
1177, 1096, 816 cmꢀ1 1H NMR (300 MHz, CDCl3) d = 2.00 (s, 3H),
;
2.03 (d, J = 5.5 Hz, 2H), 2.44 (s, 3H), 3.81 (s, 3H), 4.199 (dd,
J1 = 5.5 Hz, J2 = 10.5 Hz, 1H), 4.21 (dd, J1 = 4.0 Hz, J2 = 10.5 Hz, 1H),
5.08 (ddt, J1 = 4.0 Hz, J2 = J3 = 5.5 Hz, 1H), 6.83–6.90 (m, 2H),

Y. Shimada et al. / Tetrahedron: Asymmetry 20 (2009) 2802–2808
2807
4.4. Typicalprocedureforthepreparationofthe enantiomerically
pure acetates (S)-1 with lipase PS
4.6.4. Acetate (R)-1d
>99% ee, ½a 2D8
¼ ꢀ5:4 (c 0.99, CHCl3). HPLC conditions: column,
ꢂ
CHIRALCEL AD-H (Daicel Chemical Industries, Ltd); eluent: hexane/
2-propanol = 95/5; flow rate, 0.5 mL/min; 254 nm; temperature,
25 °C; retention time, 47 (R) and 44 (S) min (1d), 119 (S) and 145
(R) min (4d).
To 200-mL Erlenmeyer flask containing 113 mg (0.358 mmol;
sub. concn, 10 mM) of (S)-1a (98% ee) were added 4 mL of i-Pr2O
and 36 mL of 0.1 M phosphate buffer (pH 6.5). To the mixture
was added 31 mg of lipase PS, and the solution was incubated for
24 h at 30 °C. The products were extracted with AcOEt (ꢁ3),
washed with brine and dried over Na2SO4. After evaporation under
reduced pressure, the residue was purified by flash column chro-
matography on silica gel (hexane/AcOEt = 9/1) to give (S)-1a
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scien-
tific Research (No. 21550051) from the Ministry of Education, Cul-
ture, Sports and Science and Technology, Japan. We thank Material
Science Research Center (Meisei university) for NMR analysis.
(>99% ee) as a colourless oil (98.0 mg, 87%); ½a D23
¼ ꢀ16:3 (c 1.26,
ꢂ
CHCl3). The absolute configuration of 1a was confirmed by compar-
ing the specific rotation value with the reported one: ½a D25
¼ ꢀ13:3
ꢂ
(c 0.96, CHCl3), 80% ee.7a
References
The reactions of the other substrates were carried out by the
same procedure.
1. (a) Zhu, X.-M.; He, L.-L.; Yang, G.-L.; Lei, M.; Chen, S.-S.; Yang, J.-S. Synlett 2006,
3510–3512; (b) Guaragna, A.; De Nisco, M.; Pedatella, S.; Palumbo, G.
Tetrahedron: Asymmetry 2006, 17, 2839–2841; (c) Wang, C.; Kunts, D. A.;
Hamlet, T.; Sim, L.; Rose, D. R.; Pinto, B. M. Bioorg. Med. Chem. 2006, 14, 8332–
8340; (d) Ghosh, A. K.; Gong, G. Org. Lett. 2007, 9, 1437–1440; (e)
Chattopadhyay, A.; Vichare, P.; Dhotare, B. Tetrahedron Lett. 2007, 48, 2871–
2873; (f) Martynow, J. G.; Jozwik, J.; Szelejewski, W.; Achmatowicz, O.; Kutner,
A.; Wisniewski, K.; Winiarski, J.; Zegrocka-Stendel, O.; Golebiewski, P. Eur. J.
Org. Chem. 2007, 689–703; (g) Bedore, M. W.; Chang, S.-K.; Paquette, L. A. Org.
Lett. 2007, 9, 513–516; (h) Zhen, A.-B.; Gao, J.; Wu, Y. J. Org. Chem. 2008, 73,
7310–7316; (i) Carreno, M. C.; Hernandez-Torres, G.; Urbano, A.; Colobert, F.
Eur. J. Org. Chem. 2008, 2035–2038.
2. For recent examples, see: (a) El Ashry, E. S. H.; Abdel-Rahman, A.; Rashed, N.;
Awad, L. F.; Rasheed, H. A. Nucleosides Nucleotides Nucleic Acids 2006, 25, 299–
305; (b) Ikura, M.; Nakatani, S.; Yamamoto, S.; Habashita, H.; Sugiura, T.;
Takahashi, K.; Ogawa, K.; Ohno, H.; Nakai, H.; Toda, M. Bioorg. Med. Chem. 2006,
14, 4241–4252; (c) Koo, B.; McDonald, F. E. Org. Lett. 2007, 9, 1737–1740; (d)
Paolucci, C.; Rosini, G. Tetrahedron: Asymmetry 2007, 18, 2923–2946; (e) Kamal,
A.; Ramesh Khanna, G. B.; Krishnaji, T. Helv. Chim. Acta 2008, 90, 1723–1730.
3. For recent examples, see: (a) Masutani, K.; Minowa, T.; Hagiwara, Y.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 2006, 79, 1106–1117; (b) Miranda, P. O.;
Ramirez, M. A.; Martin, V. S.; Padron, J. I. Org. Lett. 2006, 8, 1633–1636; (c)
Sharma, G. V. M.; Reddy, J. J.; Reddy, K. L. Tetrahedron Lett. 2006, 47, 6531–
6535; (d) Chen, C.-L.; Sparks, S. M.; Martin, S. F. J. Am. Chem. Soc. 2006, 128,
13696–13697; (e) Mohapatra, D. K.; Ramesh, D. K.; Giardello, M. A.; Chorghade,
M. S.; Gurjar, M. K.; Grubbs, R. H. Tetrahedron Lett. 2007, 48, 2621–2625; (f)
Fernandez, C.; Gandara, Z.; Gomez, G.; Covelo, B.; Fall, Y. Tetrahedron Lett. 2007,
48, 2939–2942; (g) Suhara, Y.; Oka, S.; Kittaka, A.; Takayama, H.; Waku, K.;
Sugiura, T. Bioorg. Med. Chem. 2007, 15, 854–867; (h) Sinha, S. C.; Chen, Z.;
Huang, Z.-Z.; Nakamura-Ogiso, E.; Pietraszkiewicz, H.; Edelstein, M.; Valeriote,
F. J. Med. Chem. 2008, 51, 7045–7048.
4. For enzymatic hydrolysis of acyl derivatives of 1,2-diol monotosylates in an
aqueous media, see: (a) Hamaguchi, S.; Ohashi, T.; Watanabe, K. Agric. Biol.
Chem. 1986, 50, 375–380; (b) Hamaguchi, S.; Ohashi, T.; Watanabe, K. Agric.
Biol. Chem. 1986, 50, 1629–1632; (c) Hamaguchi, S.; Katayama, K.; Ohashi, T.;
Watanabe, K. JP 62158250, 1987.; (d) Hamaguchi, S.; Kobayashi, M.; Katayama,
K.; Ohashi, T.; Watanabe, K. JP 62209049, 1987.; (e) Kobayashi, M.; Hamaguchi,
S.; Katayama, K.; Ohashi, T.; Watanabe, K. JP 62212382, 1987.; (f) Pederson, R.
L.; Liu, K. K.-C.; Rutan, J. F.; Chen, L.; Wong, C.-H. J. Org. Chem. 1990, 55, 4897–
4901; (g) Chen, C.-S.; Liu, Y.-C.; Marsella, M. J. Chem. Soc., Perkin Trans. 1 1990,
2559–2561.
5. For enzymatic esterification of 1,2-diol monotosylates in an organic solvent,
see: (a) Chen, C.-S.; Liu, Y.-C. Tetrahedron Lett. 1989, 30, 7165–7168; (b)
Chênevert, R.; Gagnon, R. J. Org. Chem. 1993, 58, 1054–1057; (c) Neagu, C.; Hase,
T. Tetrahedron Lett. 1993, 34, 1629–1630; (d) Boaz, N. W.; Zimmerman, R. L.
Teatrahedron: Asymmetry 1994, 5, 153–156; (e) Boaz, N. W.; Falling, S. N.;
Moore, M. K. Synlett 2005, 1615–1617. For enzymatic hydrolysis in an organic
solvent, see: Ref. 5c For enzymatic alcoholysis in an organic solvent, see: Refs.
5a,4g..
4.5. Transformation of (S)-1a to (S)-4a
Under an argon atmosphere, to a solution of (S)-1a (>99% ee,
179 mg, 0.568 mmol) in THF (4 mL) were added DIBAL-H (2.3 mL,
1.0 M toluene solution) at ꢀ78 °C. After the mixture was stirred
for 1.5 h, the reaction was stopped with 0.1 M phosphate buffer
(pH 6.5). The products were extracted with CH2Cl2 (ꢁ3), and the
organic layer was washed with brine and dried over Na2SO4. After
evaporation under reduced pressure, the residue was purified by
flash column chromatography on silica gel (hexane/AcOEt = 6/1)
to give (S)-4a (>99% ee) as a colourless oil (155 mg, 99%);
½
a 2D7
ꢂ
¼ þ8:5 (c 1.08, CHCl3).
4.6. Data for the compounds
4.6.1. Benzoate (S)-9
99% ee, ½a 2D5
¼ þ11:6 (c 1.01, CHCl3). The absolute configuration
ꢂ
of 9 was confirmed by comparing the specific rotation value with
an authentic sample prepared from (R)-4a with DCC, DMAP and
benzoic acid: ½a D22
¼ ꢀ14:1 (c 1.00, CHCl3), 99% ee, (R)-form. HPLC
ꢂ
conditions: column, CHIRALCEL AD-H (Daicel Chemical Industries,
Ltd); eluent: hexane/2-propanol = 95/5; flow rate, 0.5 mL/min;
254 nm; temperature, 25 °C; retention time, 35 (S) and 48 (R) min.
IR (neat); 2955, 2932, 2860, 1719, 1362, 1177, 914 and 733 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d = 0.87 (t, J = 6.5 Hz, 3H), 1.18–1.41 (m,
4H), 1.59–1.85 (m, 2H), 2.36 (s, 3H), 4.19 (dd, J1 = 5.0 Hz,
J2 = 11.0 Hz, 1H), 4.24 (dd, J1 = 3.5 Hz, J2 = 11.0 Hz, 1H), 5.15–5.24
(m, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.38–7.47 (m, 2H), 7.54–7.62 (m,
2H), 7.71–7.78 (m, 2H), 7.90–7.97 (m, 2H); 13C NMR (75 MHz, CDCl3)
d = 13.8, 21.6, 22.4, 27.1, 30.0, 70.1, 71.5, 127.9, 128.3, 129.7, 129.8,
133.1, 144.8, 165.7, 181.9; MS m/z (rel intensities) 376 (M+, 1.2%),
254 (3.2), 155 (15), 105 (100), 91 (33), 78 (43); HRMS m/z
376.1345 (376.1344 calcd for C20H24O5S, M+).
4.6.2. Acetate (S)-1b
>99% ee, ½a 2D9
¼ ꢀ13:5 (c 1.35, CHCl3). HPLC conditions: column,
ꢂ
6. For enantioselective decomposition of 1,2-diol monotosylates by
microorganisms, see: Saito, Y.; Nakamura, T. JP 10057096, 1998.
CHIRALCEL AD-H (Daicel Chemical Industries, Ltd); eluent: hexane/
2-propanol = 98/2; flow rate, 0.5 mL/min; 254 nm; temperature,
25 °C; retention time, 63 (S) and 59 (R) min (1b): eluent: hexane/
2-propanol = 95/5, 82 (R) and 100 (S) min (4b).
7. (a) Shimada, Y.; Sato, H.; Minowa, S.; Matsumoto, K. Synlett 2008, 367–370; (b)
Shimada, Y.; Sato, H.; Mochizuki, S.; Matsumoto, K. Synlett 2008, 2981–2984.
8. For recent examples, see: (a) Bogár, K.; Martin-Matute, B.; Bäckvall, J.-E.
Beilstein J. Org. Chem. 2007, 3, 50; (b) Strubing, D.; Krumlinde, P.; Piera, J.;
Bäckvall, J.-E. Adv. Synth. Catal. 2007, 349, 1577–1581; (c) Parvulescu, A. N.;
Jacobs, P. A.; De Vos, D. E. Adv. Synth. Catal. 2008, 350, 113–121; (d) Kim, M.-J.;
Choi, Y. K.; Kim, S.; Kim, D.; Han, K.; Ko, S.-B.; Park, J. Org. Lett. 2008, 10, 1295–
1298; (e) Han, K.; Park, J.; Kim, M.-J. J. Org. Chem. 2008, 73, 4302–4304; (f) Ahn,
Y.; Ko, S.-B.; Kim, M.-J.; Park, J. Coord. Chem. Rev. 2008, 252, 647–658; (g) Haak,
R. M.; Berthiol, F.; Jerphagnon, T.; Gayet, A. J. A.; Tarabiono, C.; Postema, C. P.;
Ritleng, V.; Pfeffer, M.; Janssen, D. B.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G.
J. Am. Chem. Soc. 2008, 130, 13508–13509.
4.6.3. Acetate (S)-1c
>99% ee, ½a 2D7
¼ þ4:6 (c 1.46, CHCl3). HPLC conditions: column,
ꢂ
CHIRALCEL AD-H (Daicel Chemical Industries, Ltd); eluent: hexane/
2-propanol = 90/10; flow rate, 0.5 mL/min; 254 nm; temperature,
25 °C; retention time, 56 (S) and 68 (R) min (1c), 93 (R) and 107
(S) min (4c).
9. Mitsunobu, O. Synthesis 1981, 1–28.

2808
Y. Shimada et al. / Tetrahedron: Asymmetry 20 (2009) 2802–2808
10. (a) Danda, H.; Furukawa, Y.; Umemura, T. Synlett 1991, 441–442; (b) Takano,
S.; Suzuki, M.; Ogasawara, K. Tetrahedron: Asymmetry 1993, 4, 1043–1046; (c)
Vänttinen, E.; Kanerva, L. T. Tetrahedron: Asymmetry 1995, 6, 1779–1786; (d)
Steinreiber, A.; Edeger, K.; Mayer, S. F.; Faber, K. Tetrahedron: Asymmetry 2001,
12, 2067–2071; (e) Steinreiber, A.; Stadler, A.; Mayer, S. F.; Faber, K.; Kappe, C.
O. Tetrahedron Lett. 2001, 42, 6283–6286; (f) Compostella, F.; Franchini, L.;
Giovenzana, G. B.; Panza, L.; Prosperi, D.; Ronchetti, F. Tetrahedron: Asymmetry
2002, 13, 867–872; (g) Liu, H. L.; Anthonsen, T. Chirality 2002, 14, 25–27; (h)
Wallner, A.; Mang, H.; Glueck, S. M.; Steinreiber, A.; Mayer, S. F.; Faber, K.
Tetrahedron: Asymmetry 2003, 14, 2427–2432; (i) Guanti, G.; Banfi, L.; Basso, A.;
Bevilacqua, E.; Bondanza, L.; Riva, R. Tetrahedron: Asymmetry 2004, 15, 2889–
2892; (j) Bouzemi, N.; Aribi-Zouioueche, L.; Fiaud, J.-C. Tetrahedron: Asymmetry
2006, 17, 797–800; (k) Felluga, F.; Forzato, C.; Ghelfi, F.; Nitti, P.; Pitacco, G.;
Pagnoni, U. M.; Roncaglia, F. Tetrahedron: Asymmetry 2007, 18, 527–536; (l) Ou,
L.; Xu, Y.; Ludwig, D.; Pan, J.; Xu, J.-H. Org. Process Res. Dev. 2008, 12, 192–195.
11. Martinelli, M. J.; Vaidyanathan, R.; Pawlak, J. M.; Nayyar, N. K.; Dhokte, U. P.;
Doecke, C. W.; Zollars, L. M. H.; Moher, E. D.; Khau, V. V.; Kosmrlj, B. J. Am.
Chem. Soc. 2002, 124, 3578.
13. Hughes, D. L.; Reamer, R. A. J. Org. Chem. 1996, 61, 2967–2971.
14. Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34, 1639–1642.
15. The reaction of 2a with ADDP and PPh3 did not proceed at all.
16. Tsunoda, T.; Ozaki, F.; Shirakata, N.; Tamaoka, Y.; Yamamoto, H.; Ito, S.
Tetrahedron Lett. 1996, 37, 2463–2466.
17. For recent examples of organic reaction using polymer-bound PPh3, see: (a)
Pedatella, S.; Guaragna, A.; D’Alonzo, D.; De Nisco, M.; Palumbo, G. Synthesis
2006, 305–308; (b) Wang, Y.; Sarris, K.; Sauer, D. R.; Djuric, S. W. Tetrahedron
Lett. 2006, 47, 4823–4826; (c) Pothukanuri, S.; Winssinger, N. Org. Lett. 2007, 9,
2223–2225; (d) Liu, H.-L.; Jinag, H.-F. Tetrahedron 2008, 64, 2120–2125; (e)
Ayesa, S.; Samuelsson, B.; Classon, B. Synlett 2008, 97–99; (f) Liu, H.-L.; Jiang,
H.-F.; Xu, L.; Zhan, H.-Y. Tetrahedron Lett. 2007, 48, 8371–8375.
18. For examples of Mitsunobu reaction using polymer-bound PPh3, see: (a)
Alexandratos, S. D.; Miller, D. H. J. Macromolecules 1996, 29, 8025–8029; (b)
Wentworth, P., Jr.;Vandersteen, A. M.; Janda, K. D. Chem. Commun. 1997, 759–760;
(c) Tunoori, A. R.; Dutta, D.; Georg, G. I. Tetrahedron Lett. 1998, 39, 8751–8754; (d)
Barrett, A. G. M.; Roberts, R. S.; Schröder, J. Org. Lett. 2000, 2, 2999–3001;(e) White,
J. M.; Tunoori, A. R.; Dutta, D.; Georg, G. I. Comb. Chem. High Throughput Screening
2000, 3, 103–106; (f) Charette, A. B.; Janes, M. K.;Boezio, A. A. J. Org. Chem. 2001, 66,
2178–2180; (g) Valeur, E.; Roche, D. Tetrahedron Lett. 2008, 49, 4182–4185.
12. Chen, C.-S.; Fujimoto, Y.; Grdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104,
7294–7299.