Lactic acid oligomers (OLAs) as prodrug moieties

Article abstract of DOI:10.1691/ph.2013.2686

In this paper we propose the use of lactic acid oligomers (OLAs) as prodrug moieties. Two synthetic approaches are presented, on the one hand a non selective oligomerisation of lactic acid and on the other hand a block synthesis to tetramers of lactic acid. Dimers of lactic acid were investigated with respect to their plasma stability and their adsorption to albumine. Ibuprofen was chosen as the first drug for OLAylation. The ester 19 of LA(1)-ibuprofen was evaluated with respect to the degradation to human plasma and the adsorption to albumine. All results indicate that lactic acid oligomers are promising prodrug moieties.

Full text of DOI:10.1691/ph.2013.2686

ORIGINAL ARTICLES
Department of Medicinal Chemistry, University of Vienna, Austria
Lactic acid oligomers (OLAs) as prodrug moieties
J. Kruse, B. Lachmann, R. Lauer, S. Eppacher, C. R. Noe
Received June 21, 2012, accepted July 13, 2012
Prof. Dr. Christian R. Noe, Department of Medicinal Chemistry, University of Vienna, Althanstrasse 14, A-1090 Wien,
Austria
christian.noe@univie.ac.at
Pharmazie 68: 93–99 (2013)
doi: 10.1691/ph.2013.2686
In this paper we propose the use of lactic acid oligomers (OLAs) as prodrug moieties. Two synthetic
approaches are presented, on the one hand a non selective oligomerisation of lactic acid and on the other
hand a block synthesis to tetramers of lactic acid. Dimers of lactic acid were investigated with respect to their
plasma stability and their adsorption to albumine. Ibuprofen was chosen as the first drug for OLAylation.
The ester 19 of LA(1)-ibuprofen was evaluated with respect to the degradation to human plasma and the
adsorption to albumine. All results indicate that lactic acid oligomers are promising prodrug moieties.
1. Introduction
O
O
O
O
A prodrug is by definition a derivative of a pharmacological
agent that must undergo an enzymatic or chemical transforma-
tion in vivo to release the parent drug which can then elicit the
desired pharmacological effect with a decelerated duration of
action (Borchardt et al. 2007; Jarkko 2011; Rautio et al. 2008;
Stella et al. 1985; Zhang et al. 2011, 2005). Prodrugs are a
straightforward way to ‘individualise’ drug properties. Gener-
ally they are designed to change the HLB (hydrophilic-lipophilic
balance) of a drug, to improve resorption and cellular uptake, to
modulate organ specificity, to achieve retarded drug action, to
increase plasma stability, to modify metabolism or to reduce tox-
icity. Typicalprodrugmoietiesaree.g. longlipophilicchainsthat
enhance lipid solubility and are frequently used to achieve slow
release from injected drugs. PEGylation with polyethylglycol is
a further frequently applied prodrug modification. Due to their
amphiphilic character, PEGylated molecules show increased
bioavailability in particular by enhancing plasma solubility.
Although not broadly known, PEG has a polymeric structure,
the conformation of which is largely defined by action of stereo-
electronic effects of the type of the gauche effect. By this effect
the chain adopts a stretched helical conformation also in aqueous
solution, while lipophilic moieties tend to adopt a random com-
pact conformation. The PEG units reach out into the surrounding
space of the drug like an antenna, providing a perfect confor-
mation for hydratisation. At the same time the interactions with
the drug itself are comparatively low. This renders this modifi-
cation particularly suited for bio-molecules, where their role is
not only that of a prodrug, but as a rule rather that of a “next
generation” compound. As a matter of fact PEGylation is more
broadly used to modify the formulation than the drug itself.
Lactic acid is a central metabolite and is therefore physiologi-
cally well accepted. Due to the hydroxyl and acid functionalities
itisabletoformpolyesters. InthecontrasttoPEG, thesepolylac-
tic acids (PLA) are biodegradable and are broadly used as carrier
for pharmaceutical active ingredients in drug delivery systems
(Wischke and Schwendeman 2008). Oligomers of lactic acid
(OLAs) have not yet been extensively studied (for a review see:
Mehta et al. 2005). Several chain lengths have been described
O
O
Drug
Drug
O
O
O
OH
O
O
O
O
O
O
O
O
Fig. 1: Polyethylglycol (PEG) and polylacticacid (PLA) modified drugs
(Zhu et al. 2011). Surprisingly they have not yet been used in
pharmaceutical research and practice in spite of their poten-
tial. LikePEGs, OLAsexhibitconformationalpropertiesdefined
by stereoelectronic effects, and might therefore be particularly
promising candidates for the use as non toxic prodrug moieties.
The preferred conformations of polylactic acid derived from l-
lactic acid (PLLA) are two left handed helices that deviate only
slightly from each other (␣-helix –10/3 and ␤-helix –3/1) (Hoog-
steen et al. 1990). In these systems the drug (often a hydrophobic
compound) is non- covalently encapsulated in a PLA matrix,
leading to slow release of the drug to be used as depot applica-
tion. OLAs prefer also helical conformations (Fig. 1) and might
therefore, due to their “antenna” conformation, be well suited
as prodrug moieties.
In this paper we present the use of oligo-lactic moieties as
prodrug modifications. Both alternative syntheses and stere-
ochemical aspects are considered. Ibuprofen was selected as
‘model drug’ to investigate both methodology of prodrug syn-
thesis and to assess first biological data. Covalent linkage was
achieved by reaction of the lactic acid hydroxy group with the
carboxyl functionality of ibuprofen. Due to the biological char-
acter of lactic acid oligomers it was of particular interest to
investigate to which degree the enzymatic degradation is rele-
vant. Therefore plasma stability of the prodrugs was the first
parameter of interest. Since both enantiomers of lactic acid are
bio-molecules, our work included stereochemical aspects.
Pharmazie 68 (2013)
93

ORIGINAL ARTICLES
O
a)
O
O
O
O
O
O
H O
O
O
O
n
2
1
n=1,3. n=2, 4. n=3, 5. n=4, 6.
n=5, 7. n=6, 8. n=7, 9. n=8 10.
˚
Scheme 1: p-TosOH, toluene, RF, 35days, 4A- mol sieves
Lactic acid oligomers may be synthesized via a non selective
polymerisation of lactic acid derivatives to oligomers of mixed
chain length or by convergent block synthesis to obtain lactic
acid oligomers with a defined chain length.
ratio and 1.5 equivalents of Mukaiyama reagent and 1.5 equiv-
alents of triethylamine yielded the dimer 13 in 60% yield after
MPLC purification and ca. 5–10% racemisation at position 5.
The dimer 13 was on the one hand debenzylated by hydrogena-
tion with H2 Pd/C in 65% yield (Kruse 2001), and on the other
hand the tert-butyl ester was cleaved with TFA in 70% yield
(Kruse 2001). These two building blocks 14 and 15 were again
coupled under Mukaiyama conditions to give the tetramer 16 in a
yieldof10%. Bythisprotocolwepreparedallfourdiastereomers
of 13 (13, 13a-c) (Fig. 2) and 13 of the 16 possible tetramers
2. Investigations and results
2.1. Oligomer synthesis
Polylactic acid is usually obtained by ring opening of the cyclic
lactic acid dimer (lactide) with Sn(II) (Penczek et al. 2000),
Zn(II) (Williams et al. 2003) or Al(III) (Zhong et al. 2002)
lewis acids. We chose an alternative approach (Scheme 1) by
investigating the oligomerisation of (S)-lactic ethylester 2 with
benzyl-S-lactic ethylester 1 as starting unit under acidic condi-
tions (p-TosOH).
By the reaction of 1 with a tenfold excess of 2 we obtained
oligomers with a chain length of n = 1–8 which could be sepa-
rated by medium pressure liquid chromatography (MPLC). In a
second experiment we performed this reaction with enantiomer-
icallypure1andracemiclacticacidethylester. Byapplyingthese
conditions we obtained after MPLC two fractions for the dias-
teriomeric dimers and two fractions for the four diastereomeric
trimers and no reasonable amounts of higher oligomers. The
ratio of dimers was 1.2:1. The main product was identified as
the SS product 3 by co-elution with the dimer 3 obtained by the
oligomerisation described above. The ratio of trimers was inves-
tigated by HPLC yielding a ratio of 1,0 : 1,2 : 1,4 : 2,2. Again
we identified the main product as the SSS product by co-elution
to be compound 4.
In our second synthetic approach to obtain oligomers, this time
with a defined chain length, we applied a block synthesis (con-
vergent way) (Scheme 2). We used benzyl lactic acid 11 (Kruse
2001) or ent 11 and lactic acid tertbutylester 12 or ent 12 (Kruse
2001) as monomeric units for the synthesis of the dimers. After
trying DCC/2,4,5-trichlorophenol, DCC, and DCC/HOBt for
the coupling, we finally found 2-chloro-1-methylpyridinium
iodide (Mukaiyama reagent (Mukaiyama 1979, 1975)) to be
most suitable for our purpose. In order to avoid significant
racemisation we applied triethylamine in a sub-stochiometrical
amount. Thereactionofthemonomers 11and12inanequimolar
1
16 (16, 16a-l) (Fig. 3). In the H NMR spectra of the dimers
13 we observed a 0.03 ppm highfield shift for the enantiomeric
pair of SR and RS 13c and 13b corresponding to the benzylic
H-atoms in comparison to the enantiomeric pair of SS/RR 13
and 13a. By measurement of the optical rotation we found the
same optical rotation values for 13 and 13a but with opposite
direction. The same was observed for the pair of enantiomers
of 13b and 13c respectively. Therefore, we can conclude that
13/13a and 13b/13c are enantiomers.
The tetramers were analyzed by HPLC with a Nucleosil column
(MN 250 x 4 Nucleosil 100 7) and a solvent mixture of n-hexane
(99.2%), tertbutylmethylether (0.5%), isopropanol (0.2%) and
methanol (0.1%).
In order to verify the position of racemisation we developed
a capillary zone electrophoresis protocol. In a first experiment
we tried to investigate the dimers 13, 13a-c. But due to their
low solubility in the buffer these substrates were not suitable
for this protocol. Therefore, we used all four diastereomers of
14. In the electropherogram of the samples of 14, 14a-c we
detected a main peak and a smaller peak with longer migration
time which could be verified as the monomer 11 in the sample 14
and 14b and ent 11 for 14a and 14c by co-elution (Fig. 4). This
investigation prove that no racemisation had occured in position
C(5) during deprotection. After optimisation of the capillary
zone electrophoresis protocol we were able to detect all four
dimers of 14 and the two enantiomeric monomers 11 with a
good resolution.
In order to investigate the enantiomeric purity of the dimers 13,
13a-c we directly deprotected the dimers without purification
and analysed the samples of 14 and 14a-c. Therefore, we pre-
pared a mixture of all six detectable products 14, 14a-c, 11 and
ent 11 and mixed this to the deprotected sample 14 obtained
from the dimerisation to 13. In these co-elution experiments we
observed an increase of the peak areas of 14, 14b, 11 and ent
11 but no increase of 14a and 14c. From this experiment we
can conclude that racemisation had occured only at position 5
corresponding to the position of the activated acid.
O
O
a)
O
OtBu
OtBu
O
OH
H O
O
O
O
13
11
12
b)
c)
O
O
O
O
O
OtBu
O
OtBu
O
OH
O
O
OtBu
H O
O
O
O
O
O
O
14
d)
13
13a (ent 13)
15
O
O
O
O
OtBu
O
O
O
OtBu
O
O
O
OtBu
O
O
O
O
O
O
16
13b
13c (ent 13b)
Scheme 2: a) 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent), NEt3;
60%. b) TFA; 70%. c) H2 Pd/c; 70%. d) Mukaiyama reagent, NEt3; 10%
Fig. 2: All four possible diastereoisomers of lactic acid dimers
94
Pharmazie 68 (2013)

ORIGINAL ARTICLES
O
O
O
O
OtBu
OtBu
O
O
O
O
OtBu
O
O
O
O
O
O
O
OtBu
OtBu
O
O
O
O
O
O
O
O
O
O
16
16a (ent 16)
16b
O
O
O
O
O
O
OtBu
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
16c
16d (ent 16c)
16e
O
O
O
O
O
O
OtBu
O
O
O
OtBu
O
O
O
OtBu
O
O
O
O
O
O
O
O
O
O
O
O
16f (ent 16e)
16g
16h (ent 16g)
O
O
O
O
O
O
O
OtBu
O
O
OtBu
O
O
OtBu
O
O
O
O
O
O
O
O
O
O
O
O
O
16i
16j (ent 16i)
16k
O
O
OtBu
O
O
O
O
O
O
16l (ent 16k)
Fig. 3: 13 out of 16 possible diastereoisomers of lactic acid tetramers
chemistry at constant temperature had an influence on the bind-
ing. By increasing the temperature to 37 ◦C the amount bounded
on plasma proteins also increased to approximately 77%. To
investigate the influence of the stereochemistry we also tested
the dimer 14 and found a similar binding with respect to 14b.
14
DD,
14
12
10
8
LD ,
14b
LL,
14a
D,11
L, ent11
DL,
14c
6
mAU
4
2.3. Plasma stability of lactic acid dimers
EOF
2
In order to test the lactic acids oligomers for their suitabil-
ity for the use as prodrugs we examined also their stability
against ubiquitous esterases. All experiments were performed
in pooled blood plasma. After addition of 14b to the plasma
the samples were adjusted to 37 ◦C. The enzymatic reaction
was stopped by addition of methanol after 18, 22 and 40 h. The
lactic acid derivatives were liberated from the proteins by addi-
tion of a PIC-A/methanol mixture. The samples were treated
with p-methoxyphenylacetic acid as internal standard and stored
over night in a refrigerator. The final removal of the plasma
residue was performed by centrifugation at 9500 × g. The super-
natant was directly used for capillary electrophoretic analysis.
To investigate the enzymatic degradation we also executed sam-
ples without plasma as blank to have a comparison in the series
of measurements. In these experiments, we observed almost no
degradation within the first hours and about 5% degradation
after 40 h. The analogous result was obtained with dimer 14.
We analysed the degradation of phenylalanine ethylester under
the conditions mentioned above to have a comparison to our
results. In these experiments, we observed a 50% degradation
and release of phenylalanine after 15 min.
0
-2
4- 10
15
20
25
30
35
40
45
time (min)
Fig. 4: Electropherogram of the four dimers 14 and the monomers 11 and ent 11.
capillary: 77 cm overall length, 70 cm to the detector; buffer: 100 mM
tetraborate, pH 10.3, 10 mM beta-cyclodextrine; separation conditions:
28 kV, 20◦C
2.2. Plasma binding of lactic acid dimers
To investigate whether our oligomers were suitable as carriers in
prodrugs we tested the plasma albumine binding and the plasma
stability. As analytical method we applied the above mentioned
capillary zone electrophoresis protocol.
To analyse albumine binding we used the dimeric acid 14b
with a albumine solution. After incubation of 0.5 h or 6 h at 25
or 37 ◦C we separated the absorbed 14b by ultra filtration. Prior
to the measurement p-methoxyphenylacidic acid was added as
internal standard. The separation of the plasma bound lactic
acid was performed by centrifugation (centrisat-C4 20.000
MWCO-filter with 9500 g in 20 h at 6 ◦C). By this protocol
we could assure that no bound lactic acid was liberated again.
In order to determine the amount of the dimer 14b bound on
the surface of the filter tubes during filtration we performed
this protocol without albumine. This experiment resulted in
recovery values/rates of over 90%.
2.4. Synthesis of lactic acid substituted ibuprofen
In order to work out a method for the attachment of the lactic
acid moiety we synthesised the first OLA prodrug of ibuprofen
with a dimeric lactic acid moiety (OLA(2)). Ibuprofen (17) was
coupled to lactic acid tert-butylester ent 11 in 77% yield apply-
ing Mukaijama conditions (Scheme 3). This coupling product
18 was deprotected to the free acid 19 by treatment with TFA
(35% yield) and again coupled to lactic acid tert-butylester as
mentioned above to give the diester 20 in 11% yield.
As can be seen from the Table, the binding of 14b on albumine
found after centrifugation was approximately 30% of the origi-
nal amount. The corresponding experiment with plasma yielded
a binding of 70%. Neither the incubation times nor the stereo-
Pharmazie 68 (2013)
95

ORIGINAL ARTICLES
Table: Albumin binding of compounds 14
Lactic acid
Medium
Reaction time
Temperature
Filtration
Albumine binding (%)
14b
14b
14b
14b
14b
14b
14
Water
Water
0.5h
0.5h
0.5h
0.5h
0.5h
6.0h
0.5h
6.0h
25 ◦C
25 ◦C
25 ◦C
25 ◦C
37 ◦C
37 ◦C
25 ◦C
25 ◦C
no
yes
yes
yes
yes
yes
no
0
8
Albumine
Plasma
Plasma
Plasma
Water
29
68
76
77
0
14
Plasma
yes
69
O
plasma. We could show that the dimer 14b was bound to plasma
by around 70% and had a high stability towards non selective
esterases. These properties should be favorable with regard to
their use as carrier molecules. An LA(1)-modification 19 of
ibuprofen was synthesised and tested with respect to plasma
stability and plasma binding. The results demonstrate that OLA-
moieties are promising candidates to be used as prodrugs.
OtBu
OH
OH
a)
O
OtBu
O
O
O
ent11
17
18
b)
O
O
OH
OH
O
c)
O
OtBu
O
OtBu
O
O
O
20
3. Experimental
O
ent11
19
3.1. Reagents and equipment
Scheme 3: a) Mukaiyama reagent, NEt3, 77%, b) TFA, 35%, c)
2-chloro-1-methyl-pyridinium iodide, NEt3, 11%
THF was distilled from Na/benzophenone, toluene from Na, petrol ether
b.p. 50–75 ◦C. TLC: precoated silicagel plates (Merck silica gel 60 F254):
detection by spraying with Mostain solution (400 ml of 10% aq. H2SO4, 20 g
of (NH4)6Mo7O2.H2O, 0.4 g of Ce(SO4)2). Flash chromatography (FC):
silica gel Merck 60 (0.04–0.063 mm). 1H- and 13C-NMR: at 200 MHz and
50 MHz.
2.5. Plasma stability of LA(1)-ibuprofen
In order to test the use of ibuprofen lactic ester 19 as prodrug we
investigated its stability in plasma. Therefore, we treated ibupro-
fen lactic ester 19 with plasma and adjusted the temperature to
37 ◦C. The reaction was stopped by addition of acetonitrile after
1, 2, 4, and 8 h and the corresponding reaction mixture was
stored in the refrigerator. The final separation of the plasma
protein was achieved by centrifugation with 10000 × g. The
supernatant was treated with benzoic acid as internal standard
and analysed by capillary electrophoresis. To confirm that the
degradation was due to the enzymatic activity, we also made a
blank with water instead of plasma. To test the esterase activity
we also investigated the degradation of phenylalanine ethylester
to phenylalanine. By these experiments we could demonstrate
that the degradation of the ibuprofen lactic ester 19 due to non
selective esterases was about 30% after 8 h, while the degra-
dation of phenylalanine ethylester was complete after 2 h. The
control value of the degradation of ibuprofen lactic ester in water
was about 10% after 8 h. According to this experiment we could
show that the liberation of ibuprofen lactic acid ester to ibupro-
fen is suited with respect to the use as prodrug with retarded
duration of action.
Capillary electrophoresis separation: Beckmann P/ACE 5500 with a diode
array detector.
Capillaries: Uncoated fused silica, outside polyamide coated Beckmann
eCAP, 50 ␮m I.D. 375 ␮m O.D. Detection: UV 214 nm, detector on the
cationic side
Separation buffer was prepared by diluting a 0.1 M stock solution of sodium
tetraborate and adjusted with 0.1 M NaOH to the respective pH.
Separation conditions at the measurements of the albumine binding and the
plasma stability:
Capillary: 37 cm, 30 cm to the detector, buffer: 50 mmol sodium tetrabo-
rate + 10 mmol SDS, pH 10.3, temp.: 20 ◦C, voltage 10 kV.
Separation conditions at the measurements of the phenylalanine ethylester
degradation:Capillary:37 cm, 30 cmtothedetector, buffer:50 mmolsodium
tetraborate + 10 mmol SDS, pH 9.8, temp.: 20 ◦C, voltage 10 kV.
3.2. Synthesis of the compounds
3.2.1.
(2S)-2{(2(S)-2(Benzyloxy)-propanoyloxy)propanoicacidethylester (3),
(2S)-2{(2(S)-2-{(2S)-2-(Benzyloxy)-propanoyloxy}propanoyloxy}
propanoicacidethylester (4), (2S)-2{(2(S)-2-{(2S)-2-{(2S)-2-
(Benzyloxy)-propanoyloxy}propanoyloxy}-propanoyloxy}-
propanoicacidethylester (5), (2S)-2{(2(S)-2-{(2S)-2-{(2S)-2-
{(2S)-2-{(Benzyloxy)-propanoyloxy}-propanoyloxy}-propanoyloxy}-
propanoyloxy}-propanoicacidethylester (6), (2S)-2{(2S)-2-{(2S)-2-
{(2S)-2-{(2S)-{(2S)-{(Benzyloxy)-propanoyloxy}-propanoyloxy}-
propanoyloxy}-propanoyloxy}-propanoyloxy}-propanoicaci-
dethylester (7), (2S)-2{(2S)-2-{(2S)-2-{(2S)-2-{(2S)-2-{(2S)-{(2S)-
{(Benzyloxy)-propanoyloxy}-propanoyloxy}-propanoyloxy}-
propanoyloxy}-propanoyloxy}-propanoyloxy}-propanoicacidethy-
lester (8), (2S)-2{(2S)-2-{(2S)-2-{(2S)-2-{(2S)-2-{(2S)-2-{(2S)-{(2S)-
{(Benzyloxy)-propanoyloxy}-propanoyloxy}-propanoyloxy}-
propanoyloxy}-propanoyloxy}-propanoyloxy}-propanoyloxy}-
propanoicacidethylester (9), (2S)-2{(2S)-2-{(2S)-2-{(2S)-2-{(2S)-2-
{(2S)-2-{(2S)-2-{(2S)-{(2S)-{(Benzyloxy)-propanoyloxy}-propanoyl-
oxy}-propanoyloxy}-propanoyloxy}-propanoyloxy}-propanoyloxy}-
propanoyloxy}-propanoyloxy}-propanoicacidethylester (10)
2.6. Plasma binding of (LA(1)) ibuprofen
In the next step we examined the plasma albumine binding.
Therefore we added human plasma to ibuprofen lactic ester 19
for 0.5 and 3 h at 37 ◦C. After filtration of the plasma bound part
the solution was treated with benzoic acid as internal standard
and analysed by capillary electrophoresis. The albumine bound
ester was identified as 75% at 0.5 and 2 h respectively.
2.7. Conclusion
A solution of O-benzyl-S-(-)-lactic acid ethylester (1, 8.33 g, 40 mmol) and
S-lactic acid ethylester (2, 47.3 g, 400 mmol) in 200 ml toluene was treated
with p-TosOH (0.5 g) and heated for 7 days to reflux. The apparatus was
equipped with an Soxhlet extractor filled with 4 Å mol sieve. After 3 days
additionally p-TosOH (0.5 g) was added and after 6 days the mol sieve was
reconditioned. After 7 days the reaction mixture was cooled to RT, treated
In this paper we presented a new type of oligomerisation to
oligolactic acid and a convergent synthesis up to tetramers of
lactic acid. Dimers of lactic acid were investigated with respect
to their binding to plasma albumine and their stability in human
96
Pharmazie 68 (2013)

ORIGINAL ARTICLES
with NaHCO3 (5 g), stirred for 30 min, extracted for three times with water
(t, CH2-CH3); 20.5 (q, H3C-C*); 18.7 (q, (H3C-C*); 16.8 (q, 6 H3C-C*);
14.0 (q, H3C-CH2)
and the water phase reextracted with Et2O. The combined organic phases
were dried with Na2SO4 and evaporated. The crude mixture was purified by
MPLC (petrol ether/Et2O 10:1).
3.2.2. 2-{2-(Benzyloxy)-propanoyloxy}propanoicacid-tert.-butylester
Data of 3: Yellow oil. Rf (petrol ether/Et2O 2:1) 0.43. 1H NMR (200 MHz,
CDCl3): 7.39–7.27 (m, 5 arom. H); 5.15 (q, J = 7.1, C*H); 4.75–4.46 (d,
J = 11.6, OCH2-Ar); 4.20 (q, J = 7.1, CH2-CH3); 4.13 (q, J = 6.9, C-H*);
1.52 (d, J = 7.1, H3C-C*); 1.49 (d, J = 7.0, H3C-C*); 1.29 (t, J = 7.1, CH2-
CH3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 170.4 (s, CO); 137.5 (s,
C(1) of Ph); 128.4 (d, C(2,6) of Ph); 128.0 (d, C(3,5) of Ph); 127.8 (d, C(4)
of Ph); 73.7 (d, MeC*H); 71.9 (t, O-CH2Ph); 68.8 (d, Me-C*H); 61.4 (t,
CH2-CH3); 18.7 (q, H3C-C*), 14.0 (q, H3C-CH2). MS (C15H20O5, 280.32):
280.94.
(general procedure)
A solution of O-benzyllactic acid (2.7 g, 15 mmol), lactic acid-tert.butylester
(2.19 g, 15 mmol) and 2-chlor-1-methylpyridinium iodide (4.6 g 18 mmol)
in 40 ml abs. CH2Cl2 was treated with NEt3 (1.82 g, 18 mmol) and heated
to reflux for 48 h. After cooling to RT the solution was diluted with 100 ml
Et2O, washed for 3 times with 2 N NaOH (50 ml), 3 times with 2 N HCl
(50 ml), and one time with water (30 ml), dried with Na2SO4 and evaporated.
FC (petrol ether/ether 3:1) gave 60% of dimer.
Data of 13: Colorless oil. Rf (petrol ether/Et2O 2:1) 0.40. 1H NMR
(200 MHz, CDCl3): 7.38–7.30 (m, 5 arom. H); 5.00 (q, J = 7.1, C*H);
4.77, 4.46 (d, J = 11.6, OCH2-Ar); 4.12 (q, J = 6.9, C-H*); 1.49 (d, J = 6.9,
H3C-C*); 1.48 (d, J = 7.1, H3C-C*); 1.45 (s, C(CH3)). 13C NMR (50 MHz,
CDCl3): 172.8 (s, CO); 169.5 (s, CO); 137.6 (s, C(1) of Ph); 128.4 (d, C(2,6)
of Ph); 128.0 (d, C(3,5) of Ph); 127.8 (d, C(4) of Ph); 82.1 (s, C(CH3)3);
73.7 (d, MeC*H); 72.0 (t, O-CH2Ph); 69.4 (d, Me-C*H); 27.9 (q, C(CH3)3);
18.8 (q, H3C-C*); 16.9 (q, H3C-C*). Anal. calc. for C17H24O3 (308.38): C
66.21, H 7.84; found: C 66.41, H 7.87. [α]2D5 = −88.9 (CHCl3).
Data of 4: Yellow oil. Rf (petrol ether/Et2O 2:1) 0.34. 1H NMR (200 MHz,
CDCl3): 7.39–7.28 (m, 5 arom. H); 5.20 (q, J = 7.0, C*H); 5.15 (q, J = 7.2,
C*H); 4.74–4.45 (d, J = 11.6, OCH2-Ar); 4.22–4.12 (m, CH2-CH3, C*H);
1.60 (d, J = 7.1, H3C-C*); 1.53–1.50 (m, 2 H3C-C*); 1.26 (t, J = 7.2, CH2-
CH3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 170.1 (s, CO); 169.9
(s, CO); 137.6 (s, C(1) of Ph); 128.4 (d, C(2,6) of Ph); 128.0 (d, C(3,5) of
Ph); 127.8 (d, C(4) of Ph); 73.7 (d, MeC*H); 72.0 (t, O-CH2Ph); 69.2 (d,
MeC*H); 68.6 (d, MeC*H); 61.5 (t, CH2-CH3); 18.7 (q, H3C-C*); 16.9 (q,
H3C-C*); 14.0 (q, H3C-CH2). MS (C18H24O7, 352.39): 351.
Data of 13a: Yellow oil. Rf (petrol ether/Et2O 2:1) 0.40. 1H NMR (200 MHz,
CDCl3): 7.38–7.30 (m, 5 arom. H); 5.00 (q, J = 7.1, C*H); 4.77, 4.46 (d,
J = 11.6, OCH2-Ar); 4.12 (q, J = 6.9, C-H*); 1.49 (d, J = 6.9, H3C-C*); 1.48
(d, J = 7.1, H3C-C*); 1.45 (s, C(CH3)). 13C NMR (50 MHz, CDCl3): 172.8
(s, CO);169.5(s, CO);137.6(s, C(1)ofPh);128.4(d, C(2,6)ofPh);128.0(d,
C(3,5) of Ph); 127.8 (d, C(4) of Ph); 82.1 (s, C(CH3)3); 73.7 (d, MeC*H);
72.0 (t, O-CH2Ph); 69.4 (d, Me-C*H); 27.9 (q, C(CH3)3); 18.8 (q, H3C-
C*); 16.9 (q, H3C-C*). Anal. calc. for C17H24O3 (308.38): C 66.21, H 7.84;
found: C 66.09, H 7.86. [α]2D5 = 89.5 (CHCl3).
Data of 5: Yellow oil. Rf (petrol ether/Et2O 2:1) 0.28. 1H NMR (200 MHz,
CDCl3): 7.37–7.27 (m, 5 arom. H); 5.20 (q, J = 7.0, C*H); 5.23–5.11 (m, 3
C*H); 4.72–4.43 (d, J = 11.6, OCH2-Ar); 4.21–4.111 (m, CH2-CH3, C*H);
1.61–1.44 (m, 4 H3C-C*); 1.26 (t, J = 7.2, CH2-CH3). 13C NMR (50 MHz,
CDCl3): 172.8 (s, CO); 170.1 (s, CO); 169.9 (s, CO); 169.6 (s, CO); 137.5
(s, C(1) of Ph); 128.4 (d, C(2,6) of Ph); 128.1 (d, C(3,5) of Ph); 127.8
(d, C(4) of Ph); 73.7 (d, MeC*H); 72.0 (t, O-CH2Ph); 69.3 (d, MeC*H);
68.9 (d, MeC*H); 68.5 (d, MeC*H); 61.5 (t, CH2-CH3); 18.7 (q, H3C-
C*); 16.7 (q, 3 H3C-C*); 14.0 (q, H3C-CH2). MS (C21H28O9, 424.45):
423.
Data of 13b: Colorless oil. Rf (petrol ether/Et2O 2:1) 0.40. 1H NMR
(200 MHz, CDCl3): 7.39–7.28 (m, 5 arom. H); 5.00 (q, J = 7.1, C*H); 4.70,
4.46 (d, J = 11.6, OCH2-Ar); 4.13 (q, J = 6.8, C-H*); 1.48–1.45 (m, 2 H3C-
C*); 1.46 (s, C(CH3)). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 169.5
(s, CO); 137.6 (s, C(1) of Ph); 128.3 (d, C(2,6) of Ph); 128.0 (d, C(3,5) of
Ph); 127.8 (d, C(4) of Ph); 82.0 (s, C(CH3)3); 73.8 (d, MeC*H); 71.9 (t,
O-CH2Ph); 69.4 (d, Me-C*H); 27.9 (q, C(CH3)3); 18.6 (q, H3C-C*); 16.8
(q, H3C-C*). Anal. calc. for C17H24O3 (308.38): C 66.21, H 7.84; found: C
66.00, H 7.85. [α]2D5 = −31.4◦ (CHCl3).
Data of 6: Yellow oil. Rf (petrol ether/Et2O 2:1) 0.21. 1H NMR (200 MHz,
CDCl3): 7.37–7.27 (m, 5 arom. H); 5.20–5.11 (m, 4 C*H); 4.72–4.43 (d,
J = 11.6, OCH2-Ar); 4.19–4.11 (m, CH2-CH3, C*H); 1.61–1.44 (m, 5 H3C-
C*); 1.25 (t, J = 7.1, CH2-CH3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO);
170.0 (s, CO); 169.9 (s, CO); 169.6 (s, 2 CO); 137.6 (s, C(1) of Ph); 128.4
(d, C(2,6) of Ph); 128.1 (d, C(3,5) of Ph); 127.8 (d, C(4) of Ph); 73.7 (d,
MeC*H); 72.0 (t, O-CH2Ph); 69.3 (d, MeC*H); 68.9 (d, MeC*H); 68.6 (d,
MeC*H); 68.5 (d, MeC*H); 61.5 (t, CH2-CH3); 18.7 (q, 2 H3C-C*); 16.7
(q, 3 H3C-C*); 14.0 (q, H3C-CH2). MS (C24H32O11, 496.51): 495.
Data of 7: Yellow oil. Rf (petrol ether/Et2O 2:1) 0.16. 1H NMR (200 MHz,
CDCl3): 7.37–7.27 (m, 5 arom. H); 5.20–5.13 (m, 4 C*H); 4.72–4.43 (d,
J = 11.6, OCH2-Ar); 4.19–4.11 (m, CH2-CH3, C*H); 1.60–1.47 (m, 6 H3C-
C*); 1.26 (t, J = 7.1, CH2-CH3). 13C NMR (50 MHz, CDCl3): 172.8 (s,
CO); 170.1 (s, CO); 169.9 (s, CO); 196.7 (s, CO); 169.6 (s, 2 CO); 137.6
(s, C(1) of Ph); 128.4 (d, C(2,6) of Ph); 128.1 (d, C(3,5) of Ph); 127.8 (d,
C(4) of Ph); 73.7 (d, MeC*H); 72.0 (t, O-CH2Ph); 69.3 (d, MeC*H); 68.9
(d, MeC*H); 68.6 (d, MeC*H); 68.5 (d, MeC*H); 61.5 (t, CH2-CH3); 18.7
Data of 13c: Yellow oil. Rf (petrol ether/Et2O 2:1) 0.40. 1H NMR (200 MHz,
CDCl3): 7.39–7.28 (m, 5 arom. H); 5.00 (q, J = 7.1, C*H); 4.70, 4.46 (d,
J = 11.6, OCH2-Ar); 4.13 (q, J = 6.8, C-H*); 1.48–1.45 (m, 2 H3C-C*); 1.46
(s, C(CH3)). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 169.5 (s, CO);
137.6 (s, C(1) of Ph); 128.3 (d, C(2,6) of Ph); 128.0 (d, C(3,5) of Ph); 127.8
(d, C(4) of Ph); 82.0 (s, C(CH3)3); 73.8 (d, MeC*H); 71.9 (t, O-CH2Ph);
69.4 (d, Me-C*H); 27.9 (q, C(CH3)3); 18.6 (q, H3C-C*); 16.8 (q, H3C-C*).
Anal. calc. for C17H24O3 (308.38): C 66.21, H 7.84; found: C 66.25, H 7.76.
[α]2D5 = −32.4◦ (CHCl3).
(q, 2 H3C-C*); 16.7 (q, 4 H3C-C*); 14.0 (q, H3C-CH2). MS (C27H36O13
,
568.58): 523 (M-C2H5O).
3.2.3. 2-{2-(Benzyloxy)-propanoyloxy}propanoic acid (general
Data of 8: Yellow oil. Rf (petrol ether/Et2O 2:1) 0.12. 1H NMR (200 MHz,
CDCl3): 7.37–7.27 (m, 5 arom. H); 5.20–5.13 (m, 5 C*H); 4.72–4.43 (d,
J = 11.6, OCH2-Ar); 4.19–4.11 (m, CH2-CH3, C*H); 1.61–1.47 (m, 7 H3C-
C*); 1.26 (t, J = 7.1, CH2-CH3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO);
170.1 (s, CO); 170.0 (s, CO); 196.7 (s, CO); 169.6 (s, 3 CO); 137.6 (s, C(1)
of Ph); 128.4 (d, C(2,6) of Ph); 128.1 (d, C(3,5) of Ph); 127.8 (d, C(4) of Ph);
73.7 (d, MeC*H); 72.0 (t, O-CH2Ph); 69.3 (d, MeC*H); 69.0 (d, MeC*H);
68.9 (d, MeC*H); 68.5 (d, MeC*H); 61.5 (t, CH2-CH3); 18.7 (q, 2 H3C-C*);
16.8 (q, 5 H3C-C*); 14.0 (q, H3C-CH2). MS (C27H36O13, 640.64.58): 595
(M-C2H5O).
procedure)
A
solution
of
2-[2-(benzyloxy)-propanoyloxy]propanoic
acid-
tert.butylester (0.86 g, 2.8 mmol) in CH2Cl2 (15 ml) was treated
dropwise with a solution of TFA (3.18 ml, 28 mmol) in CH2Cl2 (10 ml),
heated to reflux and stirred for 4 h. The solution was cooled to RT, diluted
with 50 ml Et2O and extracted 3 times with 30 ml of a 5% NaHCO3
solution. The combined aqu. phases were acidified with conc. HCl to pH
1 and extracted three times with Et2O. The combined organic phases were
dried with Na2SO4 and evaporated giving 70% yield.
Data of 9: Yellow oil. Rf (petrol ether/Et2O 2:1) 0.12. 1H NMR (200 MHz,
CDCl3): 7.37–7.30 (m, 5 arom. H); 5.20–5.13 (m, 7 C*H); 4.72–4.43 (d,
J = 11.6, OCH2-Ar); 4.21–4.14 (m, CH2-CH3, C*H); 1.60–1.49 (m, 8 H3C-
C*); 1.25 (t, J = 7.1, CH2-CH3). 13C NMR (50 MHz, CDCl3): 172.9 (s, CO);
172.8 (s, CO); 170.1 (s, CO); 170.0 (s, CO); 169.9 (s, CO); 169.7 (s, CO);
169.6 (s, 2CO); 137.6 (s, C(1) of Ph); 128.4 (d, C(2,6) of Ph); 128.1 (d,
C(3,5) of Ph); 127.8 (d, C(4) of Ph); 73.7 (d, MeC*H); 72.0 (t, O-CH2Ph);
69.5 (d, MeC*H); 69.3 (d, MeC*H); 69.0 (d, MeC*H); 68.9 (d, MeC*H);
68.6 (d, 2 MeC*H); 66.7 (d, MeC*H); 61.5 (t, CH2-CH3); 20.5 (q, H3C-C*);
18.7 (q, (H3C-C*); 16.8 (q, 6 H3C-C*); 14.0 (q, H3C-CH2).
Data of 14: Yellow oil. 1H NMR (200 MHz, CDCl3): 7.35–7.26 (m, 5 arom.
H); 5.20 (q, J = 7.1, C*H); 4.75, 4.47 (d, J = 11.5, OCH2-Ar); 4.14 (q, J = 6.9,
C-H*); 1.58 (d, J = 7.0, H3C-C*); 1.48 (d, J = 6.9, H3C-C*).
Data of 14a: Yellow oil. 1H NMR (200 MHz, CDCl3): 7.37–7.26 (m, 5 arom.
H); 5.20 (q, J = 7.1, C*H); 4.74, 4.47 (d, J = 11.5, OCH2-Ar); 4.13 (q, J = 6.9,
C-H*); 1.57 (d, J = 7.1, H3C-C*); 1.48 (d, J = 6.9, H3C-C*).
Data of 14b: Yellow oil. 1H NMR (200 MHz, CDCl3): 7.38–7.26 (m, 5 arom.
H); 5.18 (q, J = 7.1, C*H); 4.70, 4.46 (d, J = 11.7, OCH2-Ar); 4.15 (q, J = 6.9,
C-H*); 1.57 (d, J = 7.1, H3C-C*); 1.46 (d, J = 6.9, H3C-C*).
Data of 14c: Yellow oil. 1H NMR (200 MHz, CDCl3): 7.37–7.28 (m, 5 arom.
H); 5.18 (q, J = 7.1, C*H); 4.70, 4.46 (d, J = 11.7, OCH2-Ar); 4.15 (q, J = 6.9,
C-H*); 1.57 (d, J = 7.1, H3C-C*); 1.46 (d, J = 6.9, H3C-C*).
Data of 10: Yellow oil. Rf (petrol ether/Et2O 2:1) 0.10. 1H NMR (200 MHz,
CDCl3): 7.35–7.29 (m, 5 arom. H); 5.23–5.13 (m, 8 C*H); 4.73–4.44 (d,
J = 11.6, OCH2-Ar); 4.21–4.14 (m, CH2-CH3, C*H); 1.61–1.51 (m, 9 H3C-
C*); 1.25 (t, J = 7.1, CH2-CH3). 13C NMR (50 MHz, CDCl3): 172.9 (s, CO);
172.8 (s, CO); 172.7 (s, CO); 170.0 (s, CO); 169.9 (s, CO); 169.7 (s, CO);
169.6 (s, 2CO); 169.5 (s, CO); 137.6 (s, C(1) of Ph); 128.4 (d, C(2,6) of
Ph); 128.1 (d, C(3,5) of Ph); 127.8 (d, C(4) of Ph); 73.7 (d, MeC*H); 72.0
(t, O-CH2Ph); 69.3 (d, MeC*H); 69.1 (d, MeC*H); 69.0 (d, MeC*H); 68.9
(d, 2 MeC*H); 68.8 (d, MeC*H); 68.6 (d, MeC*H); 66.7 (d, MeC*H); 61.5
3.2.4. 2-{2-(Hydroxy)-propanoyloxy}propanoicacid-tert.butylester
(general procedure)
A solution of 2-[2-(benzyloxy)-propanoyloxy]propanoic acid-tert.butyl-
ester (0.86 g, 2.8 mmol) in Et2O (20 ml) was treated with 0.2 g Pd/C (10%),
saturated with hydrogen and stirred over night. The excess of hydrogen was
Pharmazie 68 (2013)
97

ORIGINAL ARTICLES
removed with N2 and the solution was filtered over celite, washed with Et2O,
Data of 16d: Colorless oil. 1H NMR (200 MHz, CDCl3): 7.37–7.26 (m,
5 arom. H); 5.23 (q, J = 7.0, C*H); 5.16 (q, J = 7.4, C*H); 4.98 (q, J = 7.0,
C*H); 4.74, 4.44 (AB, J = 11.5, OCH2-Ar); 4.12 (q, J = 6.8, C-H); 1.57–1.43
(m, H3C-C*, C(CH3)3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 169.67
(s, CO); 169.3 (s, CO); 169.2 (s, CO); 137.5 (s, C(1) of Ph); 128.4 (d, C(2,6)
of Ph); 128.0 (d, C(3,5) of Ph); 127.9 (d, C(4) of Ph); 82.2 (s, C(CH3)3);
73.7 (d, MeC*H); 72.0 (t, O-CH2Ph); 69.8 (d, Me-C*H); 69.0 (d, Me-C*H);
68.8 (d, Me-C*H); 27.9 (q, C(CH3)3); 18.5 (q, H3C-C*), 16.9 (q, H3C-C*);
16.7 (q, H3C-C*). [α]2D5 = 18.8 (CHCl3).
dried with Na2SO4, evaporated and separated by FC yielding 65% product.
Data of 15: Yellow oil. 1H NMR (200 MHz, CDCl3): 5.02 (q, J = 7.1, C*H);
4.32 (dq, J = 6.9, C-H*); 2.77 (bs, C-OH); 1.48 (d, J = 7.0, H3C-C*); 1.48 (d,
J = 7.1, H3C-C*); 1.45 (s, C(CH3)). 13C NMR (50 MHz, CDCl3): 172.8 (s,
CO); 169.2 (s, CO); 82.4 (s, C(CH3)3); 69.9 (d, MeC*H); 66.7 (d, Me-C*H);
27.9 (q, C(CH3)3); 20.5 (q, H3C-C*); 16.8 (q, H3C-C*). Anal. calc. for
C10H18O5 (218.25):C55.03, H8.31;found:C54.78, H8.13. [α]2D5 = −40.7
(CHCl3).
Data of 15a: Yellow oil. 1H NMR (200 MHz, CDCl3): 5.02 (q, J = 7.1,
C*H); 4.33 (q, J = 6.9, C-H*); 2.73 (bs, C-OH); 1.49 (d, J = 7.0, H3C-C*);
1.48 (d, J = 7.2, H3C-C*); 1.45 (s, C(CH3)). 13C NMR (50 MHz, CDCl3):
172.8 (s, CO); 169.2 (s, CO); 82.3 (s, C(CH3)3); 69.9 (d, MeC*H); 66.7 (d,
Me-C*H); 27.9 (q, C(CH3)3); 20.5 (q, H3C-C*); 16.8 (q, H3C-C*). Anal.
calc. for C10H18O5 (218.25): C 55.03, H 8.31; found: C 54.81, H 8.36.
[α]2D5 = 39.6 (CHCl3).
Data of 16e: Colorless oil. 1H NMR (200 MHz, CDCl3): 7.37–7.26 (m,
5 arom. H); 5.19 (q, J = 7.1, C*H); 5.16 (q, J = 7.1, C*H); 4.97 (q, J = 7.0,
C*H); 4.69, 4.43 (AB, J = 11.6, OCH2-Ar); 4.13 (q, J = 6.8, C-H); 1.60–1.43
(m, H3C-C*, C(CH3)3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 169.9
(s, CO); 169.5 (s, CO); 169.2 (s, CO); 137.5 (s, C(1) of Ph); 128.4 (d, C(2,6)
of Ph); 128.1 (d, C(3,5) of Ph); 127.8 (d, C(4) of Ph); 82.2 (s, C(CH3)3);
73.6 (d, MeC*H); 72.0 (t, O-CH2Ph); 69.7 (d, Me-C*H); 68.9 (d, Me-C*H);
68.9 (d, Me-C*H); 27.9 (q, C(CH3)3); 18.6 (q, H3C-C*), 16.8 (q, H3C-C*);
16.7 (q, H3C-C*). [α]2D5 = 15.4◦ (CHCl3).
Data of 15b: Yellow oil. 1H NMR (200 MHz, CDCl3): 5.02 (q, J = 7.1,
C*H); 4.37 (dq, J = 6.9, C-H*); 2.75 (bs, C-OH); 1.48 (d, J = 7.0, H3C-C*);
1.45 (s, C(CH3)); 1.44 (d, J = 6.7, H3C-C*);. 13C NMR (50 MHz, CDCl3):
172.8 (s, CO); 169.3 (s, CO); 82.4 (s, C(CH3)3); 70.0 (d, MeC*H); 66.7 (d,
Me-C*H); 27.9 (q, C(CH3)3); 20.1 (q, H3C-C*); 16.8 (q, H3C-C*). Anal.
calc. for C10H18O5 (218.25): C 55.03, H 8.31; found: C 54.86, H 8.37.
[α]2D5 = 30.0 (CHCl3).
Data of 16f: Colorless oil. 1H NMR (200 MHz, CDCl3): 7.37–7.26 (m,
5 arom. H); 5.19 (q, J = 7.1, C*H); 5.16 (q, J = 7.4, C*H); 4.97 (q, J = 7.0,
C*H); 4.69, 4.43 (AB, J = 11.6, OCH2-Ar); 4.13 (q, J = 6.8, C-H); 1.60–1.43
(m, H3C-C*, C(CH3)3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 169.9
(s, CO); 169.2 (s, CO); 169.1 (s, CO); 137.5 (s, C(1) of Ph); 128.4 (d, C(2,6)
of Ph); 128.1 (d, C(3,5) of Ph); 127.8 (d, C(4) of Ph); 82.2 (s, C(CH3)3);
73.6 (d, MeC*H); 71.9 (t, O-CH2Ph); 69.7 (d, Me-C*H); 69.0 (d, Me-C*H);
68.6 (d, Me-C*H); 27.9 (q, C(CH3)3); 18.6 (q, H3C-C*), 16.7 (q, H3C-C*);
16.7 (q, H3C-C*). [α]2D5 = –27.0◦ (CHCl3).
Data of 15c: Yellow oil. 1H NMR (200 MHz, CDCl3): 5.02 (q, J = 7.1, C*H);
4.35 (dq, J = 6.9, C-H*); 2.80 (bs, C-OH); 1.48 (d, J = 7.1, H3C-C*); 1.45
(s, C(CH3)); 1.44 (d, J = 6.7, H3C-C*);. 13C NMR (50 MHz, CDCl3): 172.8
(s, CO); 169.3 (s, CO); 82.4 (s, C(CH3)3); 70.0 (d, MeC*H); 66.7 (d, Me-
C*H); 27.9 (q, C(CH3)3); 20.1 (q, H3C-C*); 16.8 (q, H3C-C*). Anal. calc.
Data of 16g: Colorless oil. 1H NMR (200 MHz, CDCl3): 7.34–7.26 (m,
5 arom. H); 5.20 (q, J = 7.2, C*H); 5.18 (q, J = 7.2, C*H); 4.95 (q, J = 7.1,
C*H); 4.68, 4.44 (AB, J = 11.6, OCH2-Ar); 4.13 (q, J = 6.9, C-H); 1.56–1.43
(m, H3C-C*, C(CH3)3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 169.6
(s, CO); 169.2 (s, CO); 169.1 (s, CO); 137.4 (s, C(1) of Ph); 128.4 (d, C(2,6)
of Ph); 128.0 (d, C(3,5) of Ph); 127.9 (d, C(4) of Ph); 82.3 (s, C(CH3)3);
73.7 (d, MeC*H); 72.0 (t, O-CH2Ph); 70.0 (d, Me-C*H); 69.4 (d, Me-C*H);
68.7 (d, Me-C*H); 27.9 (q, C(CH3)3); 18.6 (q, H3C-C*), 16.9 (q, H3C-C*);
16.7 (q, H3C-C*). [α]2D5 = −18.5◦ (CHCl3).
for C10
H
18O5 (218.25): C 55.03, H 8.31; found: C 54.80, H 8.29. [α]D25
=
−36.7◦ (CHCl3).
3.2.5. 2-{2-{-2{-2(Benzyloxy)propanoyloxy}propanoyloxy}
propanoyloxy}propanoicacid-tert.butylester (general procedure)
A solution of 2-{2-(benzyloxy)-propanoyloxy}propanoic acid (1 equ.),
NEt3 (1.5 equ.) and 2-chlor-1-methylpyridinium iodide (1.5 equ.) in CH2Cl2
(20 ml) under N2 atmosphere was heated for 1 h to reflux and treated
dropwise with a solution of 2-[2-(hydroxy)-propanoyloxy]-propanoicacid-
tert.-butylester (1 equ.) in CH2Cl2 (5 ml) and stirred for 20 h under reflux.
The reaction mixture was cooled to r.t., diluted with Et2O (50 ml), extracted
for 3 times with NaOH (2 N, 25 ml), 3 times with HCl (2 N, 25 ml), one time
with water and dried with Na2SO4 and evaporated. The crude product was
purified by HPLC. Yield ca. 10%.
Data of 16h: Colorless oil. 1H NMR (200 MHz, CDCl3): 7.36–7.26 (m,
5 arom. H); 5.21 (q, J = 7.4, C*H); 5.18 (q, J = 7.4, C*H); 4.95 (q, J = 7.0,
C*H); 4.68, 4.43 (AB, J = 11.6, OCH2-Ar); 4.13 (q, J = 6.8, C-H); 1.56–1.43
(m, H3C-C*, C(CH3)3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 169.6
(s, CO); 169.2 (s, CO); 169.1 (s, CO); 137.4 (s, C(1) of Ph); 128.4 (d, C(2,6)
of Ph); 128.0 (d, C(3,5) of Ph); 127.8 (d, C(4) of Ph); 82.2 (s, C(CH3)3); 73.7
(d, MeC*H); 72.0 (t, O-CH2Ph); 69.9 (d, Me-C*H); 69.3 (d, Me-C*H); 68.7
(d, Me-C*H); 27.8 (q, C(CH3)3); 18.6 (q, H3C-C*), 16.8 (q, 2 H3C-C*).
[α]2D5 = 22.2◦ (CHCl3).
Data of 16: Colorless oil. 1H NMR (200 MHz, CDCl3): 7.36–7.26 (m, 5
arom. H); 5.18 (q, 2H, J = 7.1, C*H); 4.97 (q, J = 7.0, C*H); 4.74, 4.45
(AB, J = 11.6, OCH2-Ar); 4.11 (q, J = 6.9, C-H); 1.60–1.42 (m, H3C-C*,
C(CH3)3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 169.9 (s, CO); 169.5
(s, CO); 137.5 (s, C(1) of Ph); 128.4 (d, C(2,6) of Ph); 128.0 (d, C(3,5) of
Ph); 127.8 (d, C(4) of Ph); 82.2 (s, C(CH3)3); 73.7 (d, MeC*H); 72.0 (t,
O-CH2Ph); 69.7 (d, Me-C*H); 68.9 (d, Me-C*H); 68.5 (d, Me-C*H); 27.9
(q, C(CH3)3); 18.7 (q, H3C-C*), 16.7 (q, H3C-C*). [α]2D5 = –95.6 (CHCl3).
Data of 16i: Colorless oil. 1H NMR (200 MHz, CDCl3): 7.37–7.26 (m,
5 arom. H); 5.21 (q, J = 7.1, C*H); 5.19 (q, J = 7.4, C*H); 4.94 (q, J = 7.1,
C*H); 4.75, 4.46 (AB, J = 11.5, OCH2-Ar); 4.12 (q, J = 6.9, C-H); 1.59–1.43
(m, H3C-C*, C(CH3)3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 169.7
(s, CO); 169.4 (s, CO); 169.1 (s, CO); 137.6 (s, C(1) of Ph); 128.4 (d, C(2,6)
of Ph); 128.0 (d, C(3,5) of Ph); 127.8 (d, C(4) of Ph); 82.3 (s, C(CH3)3);
73.7 (d, MeC*H); 72.0 (t, O-CH2Ph); 70.0 (d, Me-C*H); 69.1 (d, Me-C*H);
68.5 (d, Me-C*H); 27.8 (q, C(CH3)3); 18.7 (q, H3C-C*), 16.8 (q, H3C-C*).
[α]2D5 = –60.7◦ (CHCl3).
Data of 16a: Colorless oil. 1H NMR (200 MHz, CDCl3): 7.36–7.26 (m,
5 arom. H); 5.18 (q, 2H, J = 7.0, C*H); 4.97 (q, J = 7.1, C*H); 4.74, 4.45
(AB, J = 11.5, OCH2-Ar); 4.11 (q, J = 6.9, C-H); 1.60–1.43 (m, H3C-C*,
C(CH3)3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 169.9 (s, CO); 169.5
(s, CO);169.2(s, CO);137.6(s, C(1)ofPh);128.4(d, C(2,6)ofPh);128.1(d,
C(3,5) of Ph); 127.8 (d, C(4) of Ph); 82.2 (s, C(CH3)3); 73.7 (d, MeC*H);
72.0 (t, O-CH2Ph); 69.8 (d, Me-C*H); 68.9 (d, Me-C*H); 68.6 (d, Me-
C*H); 27.9 (q, C(CH3)3); 18.7 (q, H3C-C*), 16.8 (q, H3C-C*). [α]2D5 = 96.9
(CHCl3).
Data of 16j: Colorless oil. 1H NMR (200 MHz, CDCl3): 7.36–7.26 (m,
5 arom. H); 5.21 (q, J = 7.1, C*H); 5.19 (q, J = 7.4, C*H); 4.94 (q,
J = 7.1, C*H); 4.75, 4.46 (AB, J = 11.5, OCH2-Ar); 4.132 (q, J = 6.9, C-
H); 1.60–1.43 (m, H3C-C*, C(CH3)3). 13C NMR (50 MHz, CDCl3): 172.8
(s, CO); 169.7 (s, CO); 169.4 (s, CO); 169.0 (s, CO); 137.5 (s, C(1) of Ph);
128.4 (d, C(2,6) of Ph); 128.0 (d, C(3,5) of Ph); 127.8 (d, C(4) of Ph); 82.3
(s, C(CH3)3); 73.7 (d, MeC*H); 72.0 (t, O-CH2Ph); 70.0 (d, Me-C*H); 69.1
(d, Me-C*H); 68.5 (d, Me-C*H); 27.9 (q, C(CH3)3); 18.7 (q, H3C-C*), 16.8
(q, H3C-C*). [α]2D5 = 62.9 (CHCl3).
Data of 16b: Colorless oil. 1H NMR (200 MHz, CDCl3): 7.37–7.26 (m,
5 arom. H); 5.21 (q, J = 7.4, C*H); 5.18 (q, J = 7.4, C*H); 4.98 (q, J = 7.1,
C*H); 4.69, 4.44 (AB, J = 11.6, OCH2-Ar); 4.13 (q, J = 6.9, C-H); 1.56–1.42
(m, H3C-C*, C(CH3)3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 169.6
(s, CO); 169.2 (s, CO); 169.1 (s, CO); 137.5 (s, C(1) of Ph); 128.4 (d, C(2,6)
of Ph); 128.0 (d, C(3,5) of Ph); 127.8 (d, C(4) of Ph); 82.2 (s, C(CH3)3);
73.8 (d, MeC*H); 72.0 (t, O-CH2Ph); 69.7 (d, Me-C*H); 69.0 (d, Me-C*H);
68.8 (d, Me-C*H); 27.9 (q, C(CH3)3); 18.5 (q, H3C-C*), 16.8 (q, H3C-C*);
16.7 (q, H3C-C*). [α]2D5 = 63.9 (CHCl3).
Data of 16k: Colorless oil. 1H NMR (200 MHz, CDCl3): 7.35–7.26 (m,
5 arom. H); 5.23 (q, J = 7.0, C*H); 5.16 (q, J = 7.4, C*H); 4.95 (q, J = 6.9,
C*H); 4.69, 4.43 (AB, J = 11.6, OCH2-Ar); 4.13 (q, J = 6.8, C-H); 1.58–1.43
(m, H3C-C*, C(CH3)3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 169.6
(s, CO); 169.3 (s, CO); 169.0 (s, CO); 137.4 (s, C(1) of Ph); 128.3 (d, C(2,6)
of Ph); 128.0 (d, C(3,5) of Ph); 127.8 (d, C(4) of Ph); 82.2 (s, C(CH3)3);
73.6 (d, MeC*H); 71.9 (t, O-CH2Ph); 69.9 (d, Me-C*H); 69.0 (d, Me-C*H);
68.5 (d, Me-C*H); 27.8 (q, C(CH3)3); 18.6 (q, H3C-C*), 16.7 (q, H3C-C*).
[α]2D5 = –22.2 (CHCl3).
Data of 16c: Colorless oil. 1H NMR (200 MHz, CDCl3): 7.376–7.26 (m,
5 arom. H); 5.22 (q, J = 7.0, C*H); 5.15 (q, J = 7.0, C*H); 4.98 (q, J = 7.1,
C*H); 4.74, 4.44 (AB, J = 11.6, OCH2-Ar); 4.12 (q, J = 6.9, C-H); 1.56–1.42
(m, H3C-C*, C(CH3)3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 169.7
(s, CO); 169.3 (s, CO); 169.2 (s, CO); 137.5 (s, C(1) of Ph); 128.4 (d, C(2,6)
of Ph); 128.0 (d, C(3,5) of Ph); 127.9 (d, C(4) of Ph); 82.2 (s, C(CH3)3); 73.7
(d, MeC*H); 72.0 (t, O-CH2Ph); 69.8 (d, Me-C*H); 69.0 (d, Me-C*H); 68.8
(d, Me-C*H); 27.9 (q, C(CH3)3); 18.7 (q, H3C-C*), 16.8 (q, 2 H3C-C*).
[α]2D5 = 18.4◦ (CHCl3).
Data of 16l: Colorless oil. 1H NMR (200 MHz, CDCl3): 7.36–7.26 (m,
5 arom. H); 5.23 (q, J = 7.4, C*H); 5.16 (q, J = 7.4, C*H); 4.95 (q, J = 7.1,
C*H); 4.69, 4.43 (AB, J = 11.7, OCH2-Ar); 4.13 (q, J = 6.8, C-H); 1.58–1.43
(m, H3C-C*, C(CH3)3). 13C NMR (50 MHz, CDCl3): 172.8 (s, CO); 169.6
(s, CO); 169.3 (s, CO); 169.0 (s, CO); 137.4 (s, C(1) of Ph); 128.3 (d, C(2,6)
of Ph); 128.0 (d, C(3,5) of Ph); 127.8 (d, C(4) of Ph); 82.2 (s, C(CH3)3);
98
Pharmazie 68 (2013)

ORIGINAL ARTICLES
73.5 (d, MeC*H); 71.9 (t, O-CH2Ph); 69.9 (d, Me-C*H); 69.0 (d, Me-C*H);
44,6 (d, C(2ꢀꢀ); 30.1 (d, CH2CH(CH3)2); 27.9 (q, C(CH3)3); 22.4
(q, CH2(CH(CH3)2)); 18.6 (d, C(3ꢀꢀ)); 16.8 (q, C(3ꢀ)), 16.7 (q, C(3)).
68.5 (d, Me-C*H); 27.9 (q, C(CH3)3); 18.7 (q, H3C-C*), 16.7 (q, H3C-C*).
[α]2D5 = 22.5◦ (CHCl3).
References
3.2.6. ( )-Ibuprofen-d-lactic acid-tert-butylester (18)
Borchardt R, Hageman M, Maag H, Oliyai R, Stella V, Tilley J (2007)
Prodrugs: Challenges and Rewards. Springer, New York.
Hoogsteen W, Postema AR, Pennings AJ, Ten Brinke G, Zugenmaier P
(1990) Crystal structure, conformation and morphology of solution-spun
poly(L-lactide) fibers. Macromolecules 23: 634–642.
Jarkko R (2011) Prodrugs and Targeted Delivery. Wiley-VCH, Weinheim.
Kruse J (2001) NMDA-Rezeptor-Antagonisten: Prodrugstrukturen und
SPECT-Liganden. Diss. Univ. Frankfurt.
Mehta R, Kumar V, Bhunia H, Upadhyay SN (2005) Synthesis of poly(lactic
acid): A review. J Macromol Sci Polym Rev C45: 325–349.
MukaiyamaT(1979)Newsyntheticmethods. 29. Newsyntheseswithonium
salts of azaarenes. Angew Chem 91: 798–812.
Mukaiyama T, Usui M, Shimada E, Saigo K (1975) Convenient method for
the synthesis of carboxylic esters. Chem Lett 1045–1048.
Penczek S, Duda A, Kowalski A, Libiszowski J, Majerska K, Biela T (2000)
On the mechanism of polymerization of cyclic esters induced by Tin(II)
octoate. Macromol Symp 157: 61–70.
Rautio J, Kumpulainen H, Heimbach T, Oliyai R, Oh D, Jaervinen T,
Savolainen J (2008) Prodrugs: design and clinical applications. Nat Rev
Drug Discov 7: 255–270.
A solution of ibuprofen (3 g, 15 mmol), d-lactic acid-tert.-butylester (2.2 g,
15 mmol) and 2-chlor-1-methylpyridinium iodide (4.6 g, 18 mmol) in
CH2Cl2 (40 ml) was treated dropwise with a solution of NEt3 (1.8 g) in
CH2Cl2 (10 ml) and heated to reflux for 24 h. The solution was cooled to
r.t., diluted with ether (50 ml) and extracted for 3 times with 2 N NaOH
(30 ml), 3 times with 2 N HCl (30 ml) and one time with water (30 ml). The
organic phase was dried with Na2SO4 and evaporated. The crude product
was purified by FC (petrolether/ethyl acetate = 19:1) to give 18 (76.8%).
1H NMR (200 MHz, CDCl3): 7.26–7.07 (m, 4 arom. H); 4.91 (1 H); 3.76
(1 H); 2.43 (2 H); 1.84 (1 H); 1.53 (3 H); 1.44 (6 H); 1.37 (5 H); 1.34
(3H), 0.90 (6 H). 13C NMR (50 MHz, CDCl3): 129.3 (d, C(3ꢀꢀ,5ꢀꢀ) of Aryl);
127.3 (d, C(2ꢀꢀ,6ꢀꢀ of Aryl); 81.8 (s, C(CH3)3); 69.3 (d, C(2)); 45.0 (t,
CH2CH(CH3)2);44,7(d, C(2ꢀ);29,7(d, CH2CH(CH3)2);27.9(q, C(CH3)3);
22.4 (q, CH2(CH(CH3)2)); 18.7 (q, C(3ꢀ)), 16.8 (q, C(3)).
3.2.7. ( )-Ibuprofen-d-lactic acid (19)
A solution of 18 (1.67 g, 5 mmol) in CH2Cl2 (30 mL) was treated dropwise
with TFA (5,7 g, 50 mmol) in CH2Cl2 (20 ml) and heated to reflux for 4 h.
The solution was cooled to r.t. and diluted with 50 ml ether and extracted
for 3 times with NaHCO3 (5% aqu. 20 ml). The combined aqu. phases were
adjusted with conc. HCl to pH 1 and extracted for 3 times with ether (50 ml).
The combined org. phases were dried with Na2SO4 and evaporated to give
19 (35.2% yield).
Stella VJ, Charman WN, Naringrekar VN (1985) Prodrugs. Do they have
advantages in clinical practice? Drugs 29: 455–473.
Williams CK, Breyfogle LE, Choi SK, Nam W, Young VG Jr., Hillmyer
MA, Tolman WB (2003) A highly active zinc catalyst for the controlled
polymerization of lactide. J Am Chem Soc 125: 11350–11359.
Wischke C, Schwendeman SP (2008) Principles of encapsulating hydropho-
bic drugs in PLA/PLGA microparticles. Int J Pharm 364: 298–327.
Zhang L, Fu J-Y, Xia Z-X, Wu P, Zhang X-F (2011) Synthesis and character-
ization of a well-defined amphiphilic block copolymer and its paclitaxel
prodrug from methoxy poly(ethylene glycol) and oligomer of glycolic
acid. J Appl Polym Sci 122: 758–766.
Zhang X, Li Y, Chen X, Wang X, Xu X, Liang Q, Hu J, Jing X (2005) Synthe-
sis and characterization of the paclitaxel/MPEG-PLA block copolymer
conjugate. Biomaterials 26: 2121–2128.
Zhong Z, Dijkstra PJ, Feijen J (2002) [(salen)Al]-mediated, controlled
and stereoselective ring-opening polymerization of lactide in solution
and without solvent: synthesis of highly isotactic polylactide stereo-
copolymers from racemic D,L-lactide. Angew Chem Int Ed 41: 4510–
4513.
1H NMR (200 MHz, CDCl3): 7.26–7.07 (m, 4 arom. H); 5.08 (1 H); 3.79
(1 H); 2.44 (2 H); 1.85 (1 H); 1.53 (6 H); 1.34 (3H), 0.90 (6 H). 13C NMR
(50 MHz, CDCl3): 174.8 (s, CO); 129.3 (d, C(3ꢀꢀ,5ꢀꢀ) of Aryl); 127.3 (d,
C(2ꢀꢀ,6ꢀꢀ of Aryl); 68.5 (d, C(2)); 45.1 (t, CH2(CH(CH3)2)); 44,7 (d, C(2ꢀ);
30.1 (d, CH2CH(CH3)2); 22.3 (q, CH2CH(CH3)2); 18.3 (q, C(3ꢀ)), 16.6 (q,
C(3)).
3.2.8. (2R)-2-{(2R)-2-(( )-Ibuprofen)-propanoyloxy}propanoic
acid-tert.butylester (20)
A solution of 19 (460 mg, 1.65 mmol), d-lactic acid-tert.-butylester (245 mg,
1.65 mmol) and 2-chlor-1-methylpyridinium iodide (510 mg, 1.89 mmol) in
CH2Cl2 (20 ml) was treated dropwise with a solution of NEt3 (280 mg) in
CH2Cl2 (5 ml) and heated to reflux for 24 h. The solution was cooled to
r.t., diluted with ether (20 ml) and extracted for 3 times with 2N NaOH
(10 ml), 3 times with 2N HCl (10 ml) and one time with water (30 ml). The
organic phase was dried with Na2SO4 and evaporated. The crude product
was purified by FC (petrolether/ethyl acetate = 20:1) to give 20 (11%).
1H NMR (300 MHz, CDCl3): 7.26–7.07 (m, 4 arom. H); 4.93 (2 H); 3.72
(1 H); 2.35 (2 H); 1.77 (1 H); 1.38 (18 H); 0.83 (6 H). 13C NMR (50 MHz,
CDCl3): 129.3 (d, C(3ꢀꢀꢀ,5ꢀꢀꢀ) of Aryl); 127.3 (d, C(2ꢀꢀꢀ,6ꢀꢀꢀ of Aryl); 82.0
(s, C(CH3)3); 69.6 (d, C(2)); 68.5 (d, C(2ꢀ); 45.0 (t, CH2CH(CH3)2);
Zhu H, Xu X-P, Cui W, Zhang Y-Q, Mo H-P, Shen Y-M (2011) Synthesis
and characterization of well-defined lactic acid-PEG cooligomers and its
tricarbonyl rhenium conjugates. J Polym Sci, Part A: Polym Chem 49:
1745–1752.
Pharmazie 68 (2013)
99