Solid-phase synthesis of enantio-controlled lactic acid oligomers

Article abstract of DOI:10.1016/j.tetasy.2011.08.021

A synthetic method for lactic acid oligomers via solid-phase synthesis under mild reaction conditions with up to 99% yield is presented. The fine control of the chirality on each lactic acid unit of the oligomers was easily achieved by the substitution of (R)-THP-protected lactic acid (R)-2 by (S)-2 without alternating the procedure. The overall synthesis of the trimer and tetramer was completed in one and two days, respectively. Intramolecular cyclizations of enantio-controlled lactic acids were also attempted through the Yamaguchi macrolactonization or the Mitsunobu reaction. However, we were unable to isolate single cyclic oligomers but always obtained a mixture of cyclic oligomers.

Full text of DOI:10.1016/j.tetasy.2011.08.021

Tetrahedron: Asymmetry 22 (2011) 1499–1504
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Solid-phase synthesis of enantio-controlled lactic acid oligomers
a,c
a
a
b
c
d
Seong-Ho Kim , Yong-Kyun Sim , Bum-Tae Kim , Yong Hwan Kim , Yeong-Joon Kim , Seongsoon Park ,
Hyuk Lee
a
a,
⇑
Medicinal Chemistry Research Center, Korea research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-600, Republic of Korea
Department of Chemical Engineering, Kwangwoon University, 447-1 Wolgye-dong, Nowon-gu, Seoul 139-701, Republic of Korea
Department of Chemistry, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Republic of Korea
b
c
d
Department of Chemistry, Center for NanoBio Applied Technology, Institute of Basic Sciences, Sungshin Women’s University, Seoul 136-742, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic method for lactic acid oligomers via solid-phase synthesis under mild reaction conditions
with up to 99% yield is presented. The fine control of the chirality on each lactic acid unit of the oligomers
was easily achieved by the substitution of (R)-THP-protected lactic acid (R)-2 by (S)-2 without alternating
the procedure. The overall synthesis of the trimer and tetramer was completed in one and two days,
respectively. Intramolecular cyclizations of enantio-controlled lactic acids were also attempted through
the Yamaguchi macrolactonization or the Mitsunobu reaction. However, we were unable to isolate single
cyclic oligomers but always obtained a mixture of cyclic oligomers.
Received 9 June 2011
Accepted 24 August 2011
Available online 5 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1
. Introduction
Biodegradable and biocompatible polymers have gained much
catalyzed oligomerization of alkyl lactate has been reported to pro-
duce a mixture of (R)-lactic acid oligomers from a dimer to a hep-
9
tamer. Meanwhile, various cyclic lactic acid oligomers have also
been synthesized through the ring-opening oligomerization of
1
attention in the field of the bio-application of polymers because
biodegradability and biocompatibility of polymers play a key role
in drug delivery and in tissue engineering. Poly-lactic acid is one
of the most promising biodegradable polymers and has been em-
ployed in a variety of bio-applications including drug delivery sys-
tems, sutures, and stents.3 In addition to their biodegradability,
their hydrophilicity makes lactic acid oligomers suitable as a com-
1
0
lactide. These studies have helped facilitate access to lactic acid
oligomers, but the synthetic process to enantio-controlled lactic
acid oligomers including hetero-enantiomeric as well as homo-
enantiomeric oligomers remains limited. Thus, we began to devel-
op a simple and efficient process to synthesize enantio-controlled
lactic acid oligomers.
2
4
ponent of amphiphilic block copolymers in drug delivery systems.
Initially, we attempted to couple acid- and hydroxyl-protected
(R)-lactic acids (R)-1 and (R)-2 in solution to develop a synthetic
process of enantio-controlled lactic acid oligomers (Eq. 1).
Although the esterification between the two different lactic acids
was facile, a significant loss of the product (R,R)-3 occurred during
the multi-step purification. Furthermore, the purification in the
next coupling reaction after the deprotection step was even more
problematic and provided a negligible isolated yield. Thus, an alter-
native strategy was necessary to solve this problem.
Herein, we report a facile solid-phase synthesis of a series of
enantio-controlled lactic acid oligomers. To date, a detailed solid-
phase synthesis for lactic acid oligomers has not been described.
Recently, Riguera coworkers reported a general procedure in a so-
lid-phase synthesis with several hydroxyl carboxylic acids,11 which
seems to be a suitable approach to avoid a multi-step purification
in the synthesis of lactic acid oligomers. The Riguera method
mainly focused on the synthesis of homo-chiral oligomers of lactic
acid. We have developed a synthetic process of enantio-controlled
lactic acid oligomers including hetero-enantiomeric as well as
homo-enantiomeric oligomers.
For example, pluronic/poly-lactic acid block copolymers can form
vesicles to be used as a delivery system of insulin.5
Although racemic or homo-enantiomeric poly-lactic acids have
been used efficiently for the delivery of various drugs and peptides,
enantio-controlled poly-lactic acids are potentially important for
the cellular delivery of drugs because the cell membranes possess
an asymmetric environment. In fact, Piwnica-Worms et al. re-
ported that altering the configuration of each amino acid of a cell
permeable peptide from L to D increases the uptake value by up
6
to 13-fold.
While numerous preparation methods of poly-lactic acid from
7
cyclic lactide dimers have been reported, only a few synthetic pro-
cedures for enantio-controlled lactic acid oligomers have been
established. For examples, Hawker and coworkers designed
elegant synthetic routes to (S)-lactic acid oligomers from a dimer
8
to a 64mer by orthogonal protecting groups. In addition, lipase-
⇑
Corresponding author. Tel.: +82 42 860 7019; fax: +82 42 861 0307.
E-mail address: leeh@krict.re.kr (H. Lee).
0
957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.08.021

1
500
S.-H. Kim et al. / Tetrahedron: Asymmetry 22 (2011) 1499–1504
2
.4. Synthesis of (R)-lactic acid trimer (R,R,R)-10-OH: the second
O
cycle
BnO
(
HO
esterification
OTHP
+
OTHP
BnO
OH
O
O
O
0
O
The coupling of (R)-2 to (R,R)-9 -OH and the deprotection of the
R)-1
(R)-2
(R,R)-3
THP group from the hydroxyl group in the resins were conducted
by following the first cycle procedures to give (R,R,R)-10 -OH. The
cleavage of the (R)-lactic acid trimer from (R,R,R)-10 -OH was then
2 2
performed with trifluoroacetic acid (TFA) in CH Cl . The remaining
resins were removed by filtration, and the filtrate was concen-
trated under reduced pressure to afford the (R)-lactic acid trimer
0
deprotection
of THP group
0
ð1Þ
O
O
esterification
R)-2
BnO
O
BnO
O
OH
O
OTHP
O
(
O
O
(
R,R,R)-10-OH in 99% yield.
(
R,R,R)-5
(R,R)-4
failed to purify
2
1
.5. Synthesis of enantio-controlled lactic acid trimers: (R,R,S)-
0-OH and (R,S,S)-10-OH
2
2
. Results
.1. Synthesis of (R)- and (S)-2-(tetrahydro-2H-pyran-2-
By switching (R)-2 with (S)-2 when the second cycle procedure
0
was carried out with (R,R)-9 -OH, lactic acid trimer, (R,R,S)-10-OH
was obtained in 88% yield. When switching (R)-2 with (S)-2,
respectively, in the first and second cycle procedures, (R,S,S)-10-
OH was obtained in 99% yield.
yloxy)propanoic acid: (R)- and (S)-2
To synthesize each enantiomer of 2, the hydroxyl group of the
R)-lactic acid methyl ester was first protected by dihydropyran.
(
The protection was performed by using 3 equiv of dihydropyran
with 2 mol % of pyridinium p-toluene sulfonate to give (R)-
methyl-2-(tetrahydro-2H-pyran-2-yloxy)propanoate (R)-6 in 66%
yield. After protection, hydrolysis of the ester was carried out un-
der weak basic conditions (LiOH) to provide (R)-2-(tetrahydro-
2.6. Synthesis of (R)-lactic acid tetramer (R,R,R,R)-11-OH: the
third cycle
The (R)-lactic acid tetramer (R,R,R,R)-11-OH, was obtained in
0
95% yield through coupling of (R)-2 to (R,R,R)-10 -OH, the depro-
2H-pyran-2-yloxy)propanoic acid (R)-2 in 50% yield. The other
tection of the THP group from the hydroxyl group on the resins,
enantiomer (S)-2 was similarly synthesized from (S)-lactic acid
and the cleavage of the (R)-lactic acid tetramer from the resins.
methyl ester in 81% yield (Scheme 1).
2
.7. Synthesis of (R,R,R,S)-11-OH
2
.2. Coupling of (R)-2 to Wang resins and deprotection of the
THP group from (R)-7 to give (R)-8
The other enantio-controlled lactic acid tetramer (R,R,R,S)-11-
OH was produced by coupling (S)-2, instead of (R)-2, with
0
The coupling of (R)-2 to Wang resins was accomplished by
diisopropylcarbodiimide (DIC) with 4-dimethylaminopyridine
(R,R,R)-10 -OH during the third cycle. The resulting tetramer was
0
obtained in 99% yield after cleavage from (R,R,R,S)-11 -OH.
(
DMAP) in THF to afford (R)-7. First, 3 equiv of (R)-2 were added
to Wang resins, DIC (3 equiv), and DMAP (0.1 equiv) in THF. After
2.8. Attempt to synthesize the cyclized (R)-lactic acid trimer and
being shaken for 2 h at 40 °C, the resulting resins were washed
tetramer
with THF, acetone, and CH
ing group of (R)-7 was removed by p-TsOH in CH
resulting (R)-8 resins were also washed by the same washing con-
ditions (THF, acetone, and CH Cl ), and used for further expansion
of the lactic acid without determining a yield.
2
Cl
2
, consecutively, and the THP protect-
2
Cl /MeOH. The
2
Two approaches were applied to the synthesis of the cyclized
12
(R)-lactic acid trimer: the Yamaguchi macrolactonization and
1
3
2
2
the Mitsunobu coupling. In the Yamaguchi macrolactonization,
(R,R,R)-10-OH was reacted with 2,4,6-trichlorobenzoyl chloride
for 24 h and then the resulting ester was cyclized in the presence
of DMAP in a diluted concentration (2 mM) for another 24 h (Eq.
2). Alternatively, (R,R,S)-10-OH was cyclized in the presence of
0
2
.3. Extension of (R)-lactic acid from (R)-8 to (R,R)-9 -OH: the
first cycle
3
diethyl azodicarboxylate (DEAD) and PPh in a diluted concentra-
The second lactic acid was coupled to the hydroxyl groups of
R)-8 by following the same procedures of the coupling of (R)-2
to Wang resins. Three equivalents of (R)-2 were added with
R)-8, DIC (3 equiv), and DMAP (0.1 equiv) in THF. After being sha-
ken for 2 h at 40 °C, the resulting resins were washed with THF,
tion (2 mM) (the Mitsunobu coupling) (Eq. 3). When the products
formed in both approaches, they were analyzed by LC/MS-MS spec-
troscopy (data not shown). A mixture of cyclic lactic acid oligo-
mers, sequentially increased lactones started from the cyclic
trimer containing trace amounts of the cyclic dimer was
characterized.
The same approach was also applied to the synthesis of the cy-
clized tetramers of (R,R,R,R)-11-OH and (R,R,R,S)-11-OH. However,
a mixture of cyclic lactic acid oligomers was again obtained.
(
(
acetone, and CH
by p-TsOH in CH
2
Cl
2
, and the THP protection group was eliminated
0
2
Cl
2
/MeOH to afford an (R,R)-9 -OH, which was
used for further expansion of lactic acid without determining a
yield.
OH
LiOH
Wang resins
p-TsOH
O
H O/MeOH
HO
O
O
2
OTHP
OTHP
OTHP
OH
rt, 1 h
DIC/DMAP
THF, 40°C, 2 h
CH Cl /MeOH
2
2
O
O
O
O
4
0 °C, 2 h
(R)-6
(R)-2
(R)-7
(R)-8
Scheme 1. Synthesis of (R)-lactic acid-coupled resins.

S.-H. Kim et al. / Tetrahedron: Asymmetry 22 (2011) 1499–1504
1501
1
) 2,4,6-trichlorobenzoyl
chloride/DIPEA
and provided the most promising results compared to the other
protecting groups in the model solution reactions. Therefore, the
THP group assigned as the hydroxyl protecting group in the cur-
rent solid-phase synthesis, although the preparation of THP-pro-
tected lactic acid from the corresponding lactic acid methyl ester
requires a two-step process and gave a moderate overall yield
(
R,R,R)-10-OH
benzene, rt, 24 h
or
Cyclic lactic acid oligomers
(
R,R,R,R)-11-OH 2) DMAP
benzene, rt, 24 h
ð2Þ
(
33–81%).
For the next coupling reaction of (R)-2 to Wang resins, we inves-
(
R,R,S)-10-OH
DEAD/PPh3
or
Cyclic lactic acid oligomers ð3Þ
0
tigated various activating reagents, such as DIC, DCC (N,N -dicyclo-
toluene, rt, 24 h
(
R,R,R,S)-11-OH
hexylcarbodiimide), CDI (carbonyldiimidazole), and EDCI (1-ethyl-
3
-(3-dimethylaminopropyl)carbodiimide). In the reagents, DIC or
DCC provided the highest yields (data not shown). However, DCC
was discarded in the further experiments because the removal of
dicyclohexylurea, which is formed during the coupling reaction,
was difficult due to its poor solubility in washing solvents (THF,
3
. Discussion
The solid phase synthesis of the lactic acid oligomers was
straightforward and afforded high yields (88–99%) compared to
the synthesis in a solution. The initial conjugation of THP-protected
acetone, and CH
reaction by DIC was easy to wash out. The amount of conjugated
R)-2 to Wang resins by DIC was verified by investigating the
2 2
Cl ), whereas diisopropylurea from the coupling
(R)-lactic acid (R)-2 to Wang resins was conducted by using DIC
(
and the lactic acid-coupled resins were utilized for the next cou-
pling reactions after the THP deprotection. Expansion of the lactic
acid oligomers was achieved by sequential conjugation of (R)-2 to
the lactic acid-coupled resins through the conventional ester cou-
pling and deprotection of the THP groups. This procedure of the
lactic acid expansion successfully generated enantio-controlled
lactic acid oligomers (Schemes 1 and 2).
amount of the detached (R)-2 (>99%) from (R)-7 in acidic
conditions.
(R)-Lactic-acid-coupled resins (R)-8 were generated by the
deprotection of the THP group from (R)-7 and utilized for the next
coupling with (R)-2 to provide the dimeric-lactic-acid-coupled
0
resins (R,R)-9 -OH. The sequential attachments of (R)-2 to
0
(
R,R)-9 -OH by repetitive deprotecting and coupling reactions
The key intermediate in the current process was to properly
protect (R)-2 or (S)-2, which is utilized as a basic unit for increasing
the length of oligomers. Several compounds can be utilized as pro-
tection reagents for the hydroxyl group of lactic acid. Among them,
benzyl or methoxymethyl ether (MOM) protecting reagents for the
hydroxyl group of (R)-lactic acid methyl ester require strong basic
conditions in the protection reaction and could cause epimeriza-
tion of the lactic acid as well as hydrolysis of the ester. Thus, we
discarded these protection reagents in the current investigation.
Initially, we examined trimethylsilyl (TMS) chloride and t-
butyldimethylsilyl (TBDMS) chloride as protecting reagents for
the hydroxyl group of lactic acid methyl ester. Although TMS-
and TBDMS-protected lactic acid methyl esters were obtained with
moderate yields (ꢀ70%), both compounds were not suitable for the
further experiments. TMS-protected lactic acid methyl esters pos-
sess high volatility and thus proved difficult to handle. Further-
more, the hydrolysis of TMS- and TBDMS-protected lactic acid
methyl esters resulted in decomposition and produced complex
reaction mixtures. In addition, when the solution-phase coupling
reaction between the TMS- or TBDMS-protected (R)-lactic acid
and (R)-lactic acid benzyl ester (R)-1 was performed, the isolation
of the resulting dimer was unsuccessful during the multiple col-
umn chromatographic purification.
generated lactic acid trimer (R,R,R)-10-OH and tetramer
(
(
R,R,R,R)-11-OH with 99% and 95% yields after the resin cleavages
Table 1).
The fine control of the configuration on each lactic acid unit of
the oligomers was accomplished by the substitution of (R)-2 by (S)-
without altering the above procedure. Through the routes de-
2
scribed in Figure 1, various enantio-controlled lactic acid oligomers
were efficiently synthesized with high yields (88–99%) (Figs. 1 and
2). The overall synthesis of the trimer or tetramer was completed
in one or two days, respectively.
In addition, we attempted to synthesize the intramolecular
cyclization of lactic acid oligomers. We employed the Yamaguchi
macrolactonization and the Mitsunobu coupling to the cyclization
of the trimers (R,R,R)-10-OH and (R,R,S)-10-OH and tetramers
(R,R,R,R)-11-OH and (R,R,R,S)-11-OH. However, we were unable to
isolate single cyclic oligomers but instead obtained a mixture of
cyclic oligomers. Presumably, the additional coupling reaction,
which causes to form a mixture of oligomers, was faster enough
to compete with the cyclization.
4. Conclusion
In contrast, the THP protecting group was quantitatively re-
moved in mild acidic conditions without any decomposition
In conclusion, we have developed a synthetic method for lac-
tic acid oligomers via solid-phased synthesis under mild condi-
O
O
O
O
O
1st Cycle
2nd Cycle
3
rd Cycle
O
OH
O
O
O
O
OH
OH
O
OH
O
O
O
"same conditions"
O
1) (R)-2, DIC/DMAP
THF, 40 °C, 2 h
"same conditions"
O
O
O
O
O
(
R)-8
(R,R)-9'-OH
(R,R,R)-10'-OH
(R,R,R,R)-11'-OH
2) p-TsOH
CH Cl /MeOH
2
2
4
0 °C, 2 h
TFA/CH Cl
2
rt, 1 h
TFA/CH Cl2
2
2
rt, 1 h
O
O
O
HO
O
HO
O
OH
O
OH
O
O
O
O
O
O
(R,R,R)-10-OH
(R,R,R,R)-11-OH
Scheme 2. Synthesis of (R)-lactic acid trimer (R,R,R)-10-OH, and tetramer (R,R,R,R)-11-OH.

1
502
S.-H. Kim et al. / Tetrahedron: Asymmetry 22 (2011) 1499–1504
Table 1
O
O
The yields and optical rotations of oligo-lactic acids generated by the current solid-
phase syntheses
HO
O
HO
O
O
OH
O
OH
O
O
O
O
O
a
Lactic acid oligomers
Yield (%)
[a]
D
(
R,R,S)-10-OH
(R,S,S)-10-OH
(R,R,R)-6-OH
(R,R,S)-6-OH
(R,S,S)-6-OH
(R,R,R,R)-7-OH
(R,R,R,S)-7-OH
>99
88
99
+0.2
+0.1
+0.05
+0.1
+0.1
O
O
HO
O
OH
O
O
95
O
99 (61)c
b
(
R,R,R,S)-11-OH
a
b
c
[
9
>
a
]
D
(c 2.0, CHCl
5% purity. Unknown impurity was contained.
99% purity. The yield decreased after purification by column chromatography.
3
).
Figure 2. Enantio-controlled lactic acid oligomers: (R,R,S)-10-OH, (R,S,S)-10-OH,
and (R,R,R,S)-11-OH.
tions with up to 99% yield. The control of the configuration of
the lactic acid oligomers was easily carried out by switching
the order of linear oligomers without serious side reactions. In
addition, the current method can save significant effort and time
for the synthesis.
3
ester (3.27 g, 31.5 mmol) were dissolved in CHCl (60 mL) at 0 °C.
Into the solution, dihydropyran (3.71 g, 44.1 mmol) was added
dropwise at 0 °C. After addition, the mixture was allowed to warm
to rt. After 1 day, the reaction mixture was extracted with water,
2 4
dried over Na SO , filtered, and concentrated under reduced pres-
sure. Purification by flash column chromatography with hexane/
EtOAc afforded (R)-6 as a colorless oil in a 66% yield (3.92 g). H
5
5
. Experimental
1
NMR (CDCl
and 4.21 (q, J = 6.8 Hz) (1H), d 3.97–3.80 (1H, m), d 3.74 (3H, s), d
.53–3.44 (1H, m), d 1.87–1.38 (9H, m).
3
, 300 MHz): d 4.82–4.69 (1H, m), d 4.43 (q, J = 7.0 Hz)
.1. General
3
All Chemicals were purchased from Aldrich, Fluka, TCI, and Alfa-
Aesar and used without further purification. All solvents used for
the solid-phase reaction are synthesis grade, and were dried in
5.2.2. Preparation of (R)-2-(tetrahydro-2H-pyran-2-
yloxy)propanoic acid (R)-2
the appropriate manner.14 Wang resins were purchased from TCI
1
(
(
(
100–200 mesh, loading capacity 1.0 mmol/g). H NMR spectra
In a 500 mL round-bottomed flask, (R)-1 (19.7 g, 105 mmol) and
1
3
300 MHz) and C NMR spectra (75 MHz) were recorded in ppm
d) on a Varian Gemini 300 using CDCl as a solvent. Coupling con-
LiOHꢁH
2 2
O (5.27 g, 125 mmol) were dissolved in H O (125 mL) and
MeOH (210 mL), and stirred for 1 h. The reaction mixture was con-
centrated under reduced pressure to remove MeOH, and extracted
3
stants (J) were reported in Hz. IR spectra and LC/MS-MS spectra
were obtained on a Shimadzu IR-435 spectrometer and Thermo
LXQ mass spectrometer (ESI-MS) with Thermo ACCELA LC. For all
solid-phase reactions, yields are referred to the purified materials
and based upon the loading of the starting resin. All solid-phase
reactions were performed by Synthesis 1 (Heidolph).
with CHCl
HCl to pH 6–7, and extracted with CHCl
aqueous layers were acidified with 3 M HCl to pH 4, and extracted
with CHCl /i-PrOH (3:1). The organic layer was dried over Na SO
filtered, and concentrated under reduced pressure to give (R)-2 as a
3
. The combined aqueous layers were acidified with 3 M
3
. Again the combined
3
2
4
,
1
colorless oil (9.08 mg) in a 50% yield. H NMR (CDCl
4.75 (br, 0.33H), 4.64–4.62 (m, 0.67H), 4.46 (q, J = 6.3 Hz 0.33H),
.28 (q, J = 6.3 Hz 0.67H), 4.07–3.97 (m, 0.67H), 3.93–3.84 (m,
0.33H), 3.61–3.50 (m, 1H), 1.95–1.73 (m, 2H), 1.74–1.44 (m, 7H);
3
, 300 MHz): d
5
.2. Synthesis of THP-protected (R)- and (S)-lactic acid
4
5
.2.1. Preparation of (R)-methyl-2-(tetrahydro-2H-pyran-2-
1
3
yloxy)propanoate (R)-6
C NMR (CDCl
3
, 75 MHz): d 178.3, 176.0, 100.2, 98.1, 73.6, 70.1,
In a 100 mL round-bottomed flask, pyridinium p-toluene sulfo-
nate (158 mg, 0.63 mmol, 2 mol %) and (R)-(+)-lactic acid methyl
64.3, 62.7, 30.9, 30.4, 25.4, 25.1, 20.2, 19.2, 18.8, 18.0; IR (NaCl)
mmax 2945, 2873, 1798, 1740, 1454, 1377, 1206, 1129, 1076,
1st Cycle
R)-2
2nd Cycle
3rd Cycle
(
R)-8
(R,R)-9'-OH
(R,R,R)-10-OH
(R,R,R,R)-11-OH
(
(R)-2
(R)-2
1st Cycle
S)-2
2nd Cycle
3rd Cycle
(
(S)-2
(S)-2
(
R,S)-9'-OH
(R,R,S)-10-OH
(R,R,R,S)-11-OH
2nd Cycle
S)-2
(
(
R,S,S)-10-OH
Figure 1. The synthetic routes to diverse enantio-controlled lactic acid oligomers.

S.-H. Kim et al. / Tetrahedron: Asymmetry 22 (2011) 1499–1504
1503
ꢂ1
1
1
034 cm ; HRMS (EI) calcd for C
8
H
14
O
4
: m/z 174.0892, found
5.3.6. Synthesis of (R,R,S)-10-OH
The second cycle with (R,R)-9 -OH and (S)-2, instead of (R)-2,
and resin cleavage from the resulting (R,R,S)-10 -OH provided
0
74.0884.
0
5
.2.3. (S)-2-(Tetrahydro-2H-pyran-2-yloxy)propanoic acid (S)-2
Compound (S)-2 was prepared from (S)-(ꢂ)-lactic acid methyl
(R,R,S)-10-OH as a brownish oil in 88% yield: [
a
]
D
= +0.1 (c 2.0,
1
CHCl
J = 6.9 Hz, 1H), 1.61–1.56(m, 6H), 1.47 (d, J = 7.0 Hz, 3H);
NMR (CDCl , 75 MHz): d 175.1, 169.9, 169.7, 69.4, 69.3, 66.9,
20.1, 16.9, 16.8; IR (NaCl)
3 3
); H NMR (CDCl , 300 MHz): d 5.24–5.16 (m, 2H), 4.41 (q,
13
ester (3.27 g, 31.5 mmol) by following the same procedure of the
preparation of (R)-2 without the isolation of (S)-6 to give a yellow
oil (4.3 g) in 81% yield. H NMR (CDCl
C
3
1
3
, 300 MHz): d 4.76–4.73 (m,
m
max 3450, 2992, 2924, 1746, 1456,
ꢂ1
0
.43H), 4.64–4.62 (m, 0.57H), 4.46 (q, J = 7.1 Hz 0.43H), 4.28 (q,
1377, 1203, 1130, 1097, 1046 cm ; HRMS (EI) calcd for C
H
9 14
O
7
:
J = 6.9 Hz, 0.57H), 4.03–3.97 (m, 0.57H), 3.91–3.84 (m, 0.43H),
m/z 234.0740, found 234.0737.
1
3
3
.59–3.49 (m, 1H), 1.88–1.81 (m, 2H), 1.62–1.46 (m, 7H);
C
NMR (CDCl
3
, 75 MHz): d 178.2, 175.8, 100.4, 98.1, 73.7, 70.2,
5.3.7. Synthesis of (R,S,S)-10-OH
By switching (R)-2 with (S)-2 in the first cycle, (R,S)-9 -OH was
obtained from (R)-8. Then the second cycle with (R,S)-9 -OH and
0
6
2
4.5, 62.8, 30.9, 30.5, 25.4, 25.0, 20.3, 19.3, 18.8, 18.0. IR (NaCl)
945, 2874, 1798, 1742, 1454, 1378, 1205, 1129, 1076, 1034 cm
m
max
ꢂ1
0
;
0
HRMS (EI) calcd for C
8
H
14
O
4
: m/z 174.0892, found 174.0880.
(S)-2, and cleavage of resins from the resulting (R,S,S)-10 -OH pro-
vided an (R,S,S)-10-OH as a brownish oil in 99% yield: [
a
]
D
= +0.05
1
(
(
c 2.0, CHCl
q, J = 6.9 Hz, 1H), 1.61–1.54(m, 6H), 1.47 (d, J = 6.9 Hz, 3H);
, 75 MHz): d 175.0, 170.1, 169.9, 69.34, 69.27, 66.9,
9.9, 16.8, 16.7; IR (NaCl) max 3479, 2945, 1749, 1456, 1377,
3 3
); H NMR (CDCl , 300 MHz): d 5.27–5.13 (m, 2H), 4.37
5
5
1
.3. Solid-phase synthesis
13
C
NMR (CDCl
3
.3.1. Coupling with (R)-2 to Wang resins: (R)-7
In a reaction vessel, Wang resins (100–200 mesh) (2.0 g,
.0 mmol/g) and (R)-2 (1.05 g, 6.0 mmol) were dissolved in THF
1
1
2
m
ꢂ1
202, 1130, 1097, 1047 cm ; HRMS (EI) calcd for C
9 14 7
H O : m/z
34.0740, found 234.0747.
(
(
(
20 mL). Into the reaction mixture, 4-dimethylaminopyridine
DMAP) (24 mg, 0.2 mmol) and N,N -diisopropylcarbodiimide
DIC) (758 mg, 6.0 mmol) were added. The reaction mixture was
0
0
5
.3.8. The third cycle to (R,R,R,R)-11 -OH and resin cleavage to
(R,R,R,R)-11-OH
shaken at 40 °C, 800 rpm for 2 h, cannular-filtered, and washed
with THF (3 ꢃ 20 mL), acetone (3 ꢃ 20 mL), and CH Cl
3 ꢃ 20 mL) to give (R)-7, which was used for next reaction without
further purification.
0
Compound (R,R,R,R)-11 -OH was obtained by following the first
cycle except for using (R,R,R)-10 -OH instead of (R)-8. Then resin
cleavage of (R,R,R,R)-11 -OH was performed through the same pro-
cedure in the resin cleavage from (R,R,R)-10 -OH to give (R,R,R,R)-
2
2
0
(
0
0
1
1-OH as a brownish oil in 95% yield. [
a
]
D
= +0.1 (c 2.0, CHCl
, 300 MHz): d 6.70–5.70 (br, 1H), 5.23–5.16 (m,
H), 4.38 (q, J = 6.8 Hz, 1H), 1.61–1.55(m, 9H), 1.50 (d, J = 6.9 Hz,
3
);
5
.3.2. Deprotection of THP group from (R)-7: (R)-8
In a reaction vessel, (R)-7 and p-TsOH (100 mg) were dissolved
in CH Cl /MeOH (97:3) and shaken at 40 °C, 800 rpm for 2 h. The
1
H NMR (CDCl
3
3
3
6
2
2
2
13
H); C NMR (CDCl
9.0, 68.8, 66.7, 20.4, 16.7, 16.7, 16.6; IR (NaCl)
945, 1754, 1455, 1382, 1194, 1131, 1097, 1046 cm ; HRMS (EI)
3
, 75 MHz): d 175.2, 169.7, 169.6, 169.5, 69.1,
reaction mixture was shaken at 40 °C, 800 rpm for 2 h, cannular-
filtered, and washed with THF (3 ꢃ 20 mL), acetone (3 ꢃ 20 mL),
m
max 3489, 2995,
ꢂ1
and CH
2
Cl
2
(3 ꢃ 20 mL). The resulting (R)-lactic acid couple resins,
calcd for C12
18 9
H O : m/z 306.0951, found 306.0920.
(R)-8 were used for the next coupling reaction without further
purification.
5
.3.9. Synthesis of (R,R,R,S)-11-OH
0
The third cycle with (R,R,R)-10 -OH and (S)-2, and the following
0
5
.3.3. The first cycle: from (R)-8 to (R,R)-9 -OH
0
resin cleavage of (R,R,R,S)-11 -OH provided (R,R,R,S)-11-OH as a
brownish oil in 99% yield. [
3
1
In a reaction vessel, (R)-lactic acid conjugated resins (R)-8 pro-
1
a
]
D
= +0.1 (c 2.0, CHCl
3 3
); H NMR (CDCl ,
duced from the above procedures and (R)-2 (1.05 g, 6.0 mmol)
were dissolved in THF (20 mL), and then DMAP (24 mg, 0.20 mmol)
and DIC (758 mg, 6.00 mmol) were added. The reaction mixture
was shaken at 40 °C, 800 rpm for 2 h, cannular-filtered, and
00 MHz): d 5.23–5.13 (m, 3H), 4.70 (br, 1H), 4.43–4.38 (m, 1H),
.71–1.55(m, 9H), 1.51–1.45 (m, 3H); C NMR (CDCl , 75 MHz):
3
13
d 175.0, 170.0, 169.9, 169.7, 69.42, 69.37, 69.31, 66.9, 20.0, 16.83,
1
1
3
6.78, 16.72; IR (NaCl)
198, 1130, 1097, 1046 cm ; HRMS (EI) calcd for C12
m
max 3481, 2994, 2945, 1750, 1455, 1380,
washed with THF (3 ꢃ 20 mL), acetone (3 ꢃ 20 mL), and CH
3 ꢃ 20 mL). The THP deprotection was performed through the
same procedure as in the deprotection of the THP group from
R)-7.
2
Cl
2
ꢂ1
18 9
H O : m/z
(
06.0951, found 306.0934.
(
5
.4. Attempt to synthesize cyclic (R)-lactic acid oligomers
0
0
5
.3.4. The second cycle: from (R,R)-9 -OH to (R,R,R)-10 -OH
5.4.1. Intramolecular cyclization of (R,R,R)-10-OH through
Yamaguchi macrolactonization
0
(
R,R,R)-10 -OH was obtained by following the first cycle except
0
for using (R,R)-9 -OH instead of (R)-8.
In an 1 L round bottomed flask, (R,R,R)-10-OH (217 mg,
0
.927 mmol), DIPEA (240 mg, 1.86 mmol), and 2,4,6-trichloroben-
0
5
.3.5. Resin cleavage from (R,R,R)-10 -OH: (R,R,R)-10-OH
zoyl chloride (314 mg, 1.40 mmol) were dissolved in benzene
(40 mL). The reaction mixture was stirred at rt for 24 h. Next,
DMAP (341 mg, 2.79 mmol) dissolved in benzene (400 mL) was
added dropwise into the reaction mixture at rt. After another
24 h, the reaction mixture was evaporated and dissolved in ethyl
acetate (EtOAc). The organic layer was washed with 2 M NaOH
(aq) and 1 M HCl (aq), respectively. The combined organic layers
were dried over MgSO , filtered, and concentrated under reduced
pressure. Purification by column chromatography with hexane/
EtOAc (9:1) provided a mixture of cyclic lactic acid oligomers as
a white solid (82 mg). H NMR (CDCl , 300 MHz): d 5.23–5.15 (m,
0
In a reaction vessel, (R,R,R)-10 -OH was dissolved in trifluoro-
acetic acid/CH Cl (1:1) (20 mL). The reaction mixture was shaken
at rt. After 1 h, the reaction mixture was filtered and concentrated
2
2
under reduced pressure to afford (R,R,R)-10-OH as a yellowish oil
1
in a >99% yield. [
3
a]
D
= +0.2 (c 2.0, CHCl
00 MHz): d 6.50–5.50 (br, 1H), 5.21–5.15 (m, 2H), 4.38 (q,
J = 6.9 Hz, 1H), 1.61–1.55(m, 6H), 1.49 (dd, J = 6.9 Hz, J = 2.4 Hz,
3
); H NMR (CDCl
3
,
4
1
3
3
6
1
C
H); C NMR (CDCl
3
, 75 MHz): d 175.1, 169.8, 169.6, 69.19,
max 3486, 2994, 1753,
9.16, 66.9, 20.3, 16.7, 16.6; IR (NaCl)
m
ꢂ1
1
445, 1381, 1196, 1131, 1098, 1047 cm ; HRMS (EI) calcd for
3
H
9 14
O
7
: m/z 234.0740, found 234.0754.
1H), 1.57–1.48 (m, 3H).

1
504
S.-H. Kim et al. / Tetrahedron: Asymmetry 22 (2011) 1499–1504
5
.4.2. Yamaguchi macrolactonization of (R,R,R,R)-11-OH
References
The Yamaguchi macrolactonization of (R,R,R,R)-11-OH (224 mg,
.731 mmol) was conducted under the same conditions of (R,R,R)-
0-OH. However, a mixture of cyclic lactic acid oligomers was
1.
2.
3.
Uhrich, K. E.; Cannizzaro, S. M.; Langer, R. S.; Shakesheff, K. M. Chem. Rev. 1999,
9, 3181–3198.
0
1
9
(a) Winzenburg, G.; Schmidt, C.; Fuchs, S.; Kissel, T. Adv. Drug Deliv. Rev. 2004,
56, 1453–1466; (b) Gunatillake, P. A.; Adhikari, R. Eur. Cell. Mater. 2003, 5, 1–16.
Auras, R. A.; Lim, L.-T.; Selke, S. E. M.; Tsuji, H. Poly(lactic acid): Synthesis,
Structures, Properties, Processing, and Applications; John Wiley & Sons: Hoboken,
New Jersey, 2010.
again obtained as a white solid (82 mg). And the same spectros-
1
copy data of (R,R,R)-10-OH were obtained from H NMR and LC/
MS-MS.
4.
Letchford, K.; Burt, H. Eur. J. Pharm. Biopharm. 2007, 65, 259–269.
5
.4.3. Intramolecular cyclization of (R,R,S)-10-OH through
Mitsunobu reaction
In 1 L round bottomed flask, (R,R,S)-10-OH (230 mg,
.982 mmol) and PPh (336 mg, 1.28 mmol) were dissolved in tol-
5. Xiong, X. Y.; Li, Y. P.; Li, Z. L.; Zhou, C. L.; Tam, K. C.; Liu, Z. Y.; Xie, G. X. J. Control.
Release 2007, 120, 11–17.
6.
Gammon, S. T.; Villalobos, V. M.; Prior, J. L.; Sharma, V.; Pixnica-Worms, D.
a
Bioconjugate Chem. 2003, 14, 368–376.
0
3
7. (a) Odelius, K.; Finne, A.; Albertsson, A. C. J. Polym. Sci., Part A: Polym. Chem.
006, 44, 596–605; (b) Dobrzynski, P.; Kasperczyk, J. J. Polym. Sci. Part. A: Polym.
2
uene (500 mL). Next, DEAD (223 mg, 1.28 mmol) was added drop-
wise at 0 °C for 15 min. Then the reaction mixture was stirred at rt
for 24 h, evaporated under reduced pressure, and dissolved in
EtOAc. The organic layer was washed with 1 M NaOH (aq) and
Chem. 2006, 44, 3184–3201; (c) Takasu, A.; Narukawa, Y.; Hirabayashi, T. J.
Polym. Sci., Part A: Polym. Chem. 2006, 44, 5247–5253; (d) Hodgson, L. M.;
White, A. J. P.; Williams, C. K. J. Polym. Sci., Part A: Polym. Chem. 2006, 44, 6646–
6
7
651; (e) Basacuteko, M.; Kubisa, P. J. Polym. Sci., Part A: Polym. Chem. 2006, 44,
071–7081; (f) Jalabert, M.; Fraschini, C.; Prud’homme, R. E. J. Polym. Sci., Part A:
3
4
M HCl (aq), dried over MgSO , filtered, and concentrated under
Polym. Chem. 2007, 45, 1944–1955; (g) Shang, X.; Liu, X.; Cui, D. J. Polym. Sci.,
Part A: Polym. Chem. 2007, 45, 5662–5672.
reduced pressure. The residue was purified by column chromatog-
raphy to provide trace amounts of a mixture of cyclic lactic acid
oligomers.
8
.
.
(a) Takizawa, K.; Nulwala, H.; Hu, J.; Yoshinaga, K.; Hawker, C. J. J. Polym. Sci.,
Part A: Polym. Chem. 2008, 46, 5977–5990; (b) Zhu, H.; Xu, X.; Cui, W.; Zhang,
Y.; Mo, H.; Shen, Y.-M. J. Polym. Sci., Part A: Polym. Chem. 2011, 49, 1745–1752.
Ohara, H.; Onogi, A.; Yamamoto, M.; Kobayashi, S. Biomacromolecules 2010, 11,
9
2
008–2015.
5
.4.4. Intramolecular Mitsunobu reaction of (R,R,R,S)-11-OH
The intramolecular Mitsunobu reaction of (R,R,R,S)-11-OH
1
1
0. Chisholm, M. H.; Gallucci, J. C.; Yin, H. Dalton Trans. 2007, 4811–4821.
1. (a) Kuisle, O.; Quiñoá, E.; Riguera, R. J. Org. Chem. 1999, 64, 8063–8075; (b)
Kuisle, O.; Quiñoá, E.; Riguera, R. Tetrahedron Lett. 1999, 40, 1203–1206.
(
186 mg, 0.607 mmol) was conducted under the same conditions
of (R,R,S)-10-OH. However, trace amounts of a mixture of cyclic
lactic acid oligomers were again obtained.
12. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
979, 52, 1989–1993.
1
1
3. Mitsunobu, O.; Yamada, Y. Bull. Chem. Soc. Jpn. 1967, 40, 2380–2382.
4. Perrin, D.; Armaregeo, W. L. F. Purification of laboratory Chemicals; Pergamon
Press: Oxford, 1988.
1
Acknowledgments
The authors acknowledge the Korea Research Institute of Chem-
ical Technology.