A versatile route to functionalized dilactones as monomers for the synthesis of poly(α-hydroxy) acids

Article abstract of DOI:10.1002/ejoc.200300181

A synthetic pathway to functionalized six-membered dilactones structurally analogous to lactide is described. Through the use of orthogonal protecting groups, the synthesis of functionalized dilactones was performed in a straightforward way by cyanuric chloride-mediated cyclization of the corresponding linear α-hydroxy acid dimers. The synthesis of three different dilactones - methylglycolide, benzyloxymethylglycolide, and 2-benzyloxymethyl-5-methylglycolide - by the same procedure demonstrated the versatility of this route. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300181

FULL PAPER
A Versatile Route to Functionalized Dilactones as Monomers for the Synthesis
of Poly(α-hydroxy) Acids
Mark Leemhuis,[a] Jan Hein van Steenis,[a] Michelle J. van Uxem,[a]
Cornelus F. van Nostrum,[a] and Wim E. Hennink*[a]
Keywords: α-Hydroxy acids / Lactide / Lactones / Polymers / Synthetic methods
A synthetic pathway to functionalized six-membered dilac-
tones structurally analogous to lactide is described. Through
the use of orthogonal protecting groups, the synthesis of
functionalized dilactones was performed in a straightforward
different dilactones − methylglycolide, benzyloxymethylgly-
colide, and 2-benzyloxymethyl-5-methylglycolide − by the
same procedure demonstrated the versatility of this route.
way by cyanuric chloride-mediated cyclization of the corres- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ponding linear α-hydroxy acid dimers. The synthesis of three
Germany, 2003)
Introduction
Poly(α-hydroxy) acids such as polylactic acid and poly-
glycolic acid are widely under investigation, particularly for
biomedical and pharmaceutical applications, because of
their good biocompatibility and biodegradability.[1] Deriva-
tives bearing functional groups along the main chain would
be a valuable extension of the present arsenal of biodegrad-
able polymers. In particular, the introduction of hydrophilic
Scheme 1
functional groups would open a considerable range of po- made, and block copolymers of well defined structure also
tential for the design of new poly(α-hydroxy) acids that become available.[7] Scheme 1 shows a simplified represen-
should, for example, display enhanced hydrophilicity and tation of the ring-opening polymerization of lactide/gly-
compatibility with living cells and blood components. Such colide.
polymers can also be used for the formation of supramol-
The two substituents in the dilactone can be identical
ecular structures such as polymeric micelles and hydro- (homodimers) or different (heterodimers). Homodimers are
gels.[2,3] Moreover, it is to be expected that the degradation usually prepared by thermal catalytic depolymerization of
time could be tailored and that non-toxic degradation prod- low molecular weight polycondensate with transition metal
ucts should be formed through proper selection of the complexes as transesterification catalysts (e.g., synthesis of
monomers. Another advantage is that the functional groups lactide and glycolide).[8] A homobislactone was also ob-
can be further derivatized with Ϫ for example Ϫ cytostatic tained by ring-closure mediated by reagents such as HOAt
agents to yield biodegradable polymeric prodrugs.[4]
and HOBt.[9] Heterodimers, however, cannot be prepared
Polylactic acid can be synthesized by a polycondensation easily by this route. Few methods for the synthesis of this
reaction of lactic acid at high temperature. This route, how- kind of unsymmetrical dilactones have been reported,[10Ϫ12]
ever, yields relatively low molecular weight polymers.[5] and, importantly, those that are currently known are not
High molecular weight polylactic acid and polyglycolic very efficient. Drawbacks include limited availability of
acid, as well as their copolymers, can be routinely synthe- starting materials, the need for long oxidation periods, and
sized by ring-opening polymerization of the dilactone of low overall yields.
lactic acid or glycolic acid with stannous 2-ethyl hexanoate
Here we propose a versatile route to substituted gly-
or zinc powder as catalysts.[6] Moreover, the synthesis of colides and lactides starting from α-hydroxy acids. These
poly(α-hydroxy) acids by controlled ring-opening polymer- are converted into linear dimers, which are subsequently cy-
ization allows polymers with a low polydispersity to be clized by a lactonization reaction. Furthermore, to prevent
side reactions during polymerization of the functionalized
[a]
Department of Pharmaceutics, Utrecht Institute for
dilactones, it is essential to introduce protecting groups.
These groups should be inert to the polymerization reaction
conditions. To achieve these structures, mild conditions for
Pharmaceutical Sciences, Utrecht University,
P. O. Box 80082, 3508 TB, Utrecht, The Netherlands
E-mail: W.E.Hennink@pharm.uu.nl
3344
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300181
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A Versatile Route to Functionalized Dilactones
FULL PAPER
ring-closure are required. Several complex macrolides have
been synthesized via 2-pyridinethiol esters, an approach
also known as the CoreyϪNicolaou lactonization.[13Ϫ15]
This method involves the activation both of the hydroxyl
group and of the carboxylic acid. The use of cyanuric chlo-
ride for the synthesis of macrolactones has also been re-
ported.[16] These reports all deal with the synthesis of lac-
tones containing one ester function and 5Ϫ20 (mostly ali-
phatic) carbon atoms in the ring. This tempted us to apply
these methods for the preparation of six-membered dilac-
tones that do not have two or more aliphatic carbon atoms
next to each other.
Figure 1. α-Hydroxy acids used in this study
To demonstrate the versatility of this route we attempted
to synthesize a number of heterodimers based on the com-
binations of three different α-hydroxy acids: glycolic acid,
lactic acid, and benzyloxymethylglycolic acid (Figure 1).
This last compound was prepared from commercially avail-
able O-benzyl protected -serine by diazotization;[18] the
general route is depicted in Scheme 4. The hydroxyl and
acid functionalities of one α-hydroxy acid were first simul-
taneously protected by silylation with TBSCl. The resulting
compound could be converted into the acid chloride by ad-
dition of oxalyl chloride and a catalytic amount of DMF.[19]
These conditions leave the silyl ether unaffected because no
HCl is generated under these reaction conditions. Conden-
sation with an α-hydroxy ester gave the fully protected lin-
ear dimer. It is very important that these protecting groups
are selected on the basis of orthogonality, to provide selec-
tive deprotection.
Results and Discussion
To investigate whether the six-membered ring structure of
the objected dilactones could be synthesized from its linear
precursor through lactonization, lactic acid was used as a
model compound. Its linear dimer was prepared first, by
treatment of lactide (1) with sec-phenethyl alcohol, which
yielded sec-phenethyl O-lactoyllactate (2, Scheme 2), as re-
ported by Nederberg et al.[17] This compound was con-
verted quantitatively into the linear dimer of lactic acid,
lactoyl lactate (3). Cyclization of lactoyl lactate was at-
tempted with two different cyclization reagents: dipyridyl
[13Ϫ15]
disulfide/PPh3
and cyanuric
chloride/Et3N[16]
(Scheme 3). The cyclization reaction with dipyridyl disulf-
ide and with PPh3 in THF was not driven to completion
even after 24 h at reflux, but when cyanuric chloride was
used in acetone in the presence of Et3N the reaction showed
almost complete conversion at room temperature in less
than one hour. This cyclization method was therefore used
for other linear dimers as well.
Scheme 4. i) 2.1 equiv. TBSCl, imidazole, DMF. ii) (COCl)2, cat
DMF, DCM. iii) benzyl (S)-lactate/benzyl glycolate, pyridine, Et2O.
iv) TBAF/HOAc, EtOAc. v) 1 equiv. w/w Pd/C, 1,4-cyclohexadiene,
EtOH. vi) cyanuric chloride, acetone, Et3N
The TBS ether was cleaved selectively in EtOAc contain-
ing TBAF and acetic acid. Several methods to remove the
silyl group were tried (TBAF/THF, camphorsulfonic acid,
HCl/EtOH), but the buffered TBAF solution proved to be
universally applicable. Secondary TBS ethers 11 and 15
were cleaved at elevated temperatures, whereas the primary
TBS ether 5 could be cleaved at room temperature. Sub-
sequently, the benzyl ester had to be removed. When the
mild hydride donor 1,4-cyclohexadiene was used with Pd/C
as a catalyst the benzyl ester could be cleaved selectively,
keeping the benzyl ether intact.[20] This reaction took sev-
eral hours to complete when a fresh batch of Pd/C was
used, contradictory to earlier reports.[20] After both the car-
boxylic acid and the hydroxyl group had been deprotected,
addition of cyanuric chloride yielded the (functionalized)
six-membered dilactone. The optical rotation of the product
lactide 1 showed that the ring-closure occurred with reten-
Scheme 2
Scheme 3
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W. E. Hennink et al.
FULL PAPER
Gemini-300 NMR machine, at 300 MHz (1H) or 75 MHz (13C).
Chemical shifts (δ) are reported in ppm relative to TMS with the
solvent peak as an internal reference. Mass spectra (ES) were re-
corded on a Micromass Quatro Ultima spectrometer. Melting
points were measured on a DSC Q1000 DSC machine.
tion of chirality ([α]2D0 ϭ Ϫ278); this has not been investi-
gated for the heterodimers. The reaction times for the lac-
tonization ranged from one hour (for lactide) to one night
(for 14 and 18). These different reaction times may be due
to steric hindrance, occurring when the transition state
complex between cyanuric chloride and the linear com-
pound is formed. Scheme 5 shows a reaction mechanism
that illustrates this possible steric hindrance and it also
demonstrates that the intermediate has to rotate around the
ester CϪO bond to adapt the right conformation for cycli-
zation. Esters have the tendency to exist almost exclusively
in the s-trans geometry, which is primarily due to dipole
repulsion.[21Ϫ24] Normally the barrier of rotation is quite
low (Յ ca. 10 kcal/mol), but this extra contribution to the
activation free energy makes cyclization difficult. Both fac-
tors explain the need for prolonged reaction times and elev-
ated temperatures to give the desired dilactone.
sec-Phenethyl O-Lactoyllactate (2): DMAP (25.4 g, 0.21 mol) was
dissolved in sec-phenethyl alcohol (250 mL, 2.02 mol) and heated
to 40 °C. -Lactide (30.0 g, 0.21 mol) was added, and the mixture
was stirred for 20 min. After the mixture had cooled to room temp.,
EtOAc (300 mL) was added. Excess DMAP was removed by fil-
tration through a silica filter. The filter was washed with EtOAc.
Concentration in vacuo yielded 2 as an oil. Vacuum distillation
yielded sec-phenethyl-O-lactoyl lactate (30.0 g) as a mixture of dia-
stereoisomers (67%, Bp. (0.6 mbar) ϭ 105Ϫ110 °C). 1H NMR
(CDCl3): δ ϭ 1.40Ϫ1.60 (m, 9 H), 4.34 (q, J ϭ 7 Hz, 1 H), 5.16
(q, J ϭ 7 Hz, 1 H), 5.18 (q, J ϭ 7 Hz, 1 H), 5.87 (q, J ϭ 7 Hz, 1
H), 5.90 (q, J ϭ 7 Hz, 1 H), 7.33 (m, 5 H) ppm. 13C NMR (CDCl3):
δ ϭ 16.6; 16.8; 20.4; 20.4; 21.8; 21.9; 66.6; 69.3; 69.4; 73.6; 73.8;
125.9; 126.0; 128.1; 128.5; 140.6; 169.3; 175.0 ppm. MS (ES): calcu-
lated [M ϩ Na]: 289.1, measured [M ϩ Na]: 289.2.
Lactoyl Lactate (3): Pd/C (250 mg, 10% w/w) was added to a solu-
tion of sec-phenethyl O-lactoyllactate 2 (2.50 g, 9.4 mmol) in EtOH
(40 mL). The mixture was placed under a hydrogen atmosphere
(balloon), and allowed to react overnight at room temp. Pd/C was
removed by filtration through a Hyflo filter. The filter was washed
extensively with EtOH, and the filtrate was concentrated in vacuo.
This yielded 3 (1.56 g, 100%) as a colorless oil. 1H NMR (CDCl3):
δ ϭ 1.47 (d, J ϭ 7 Hz, 3 H), 1.56 (d, J ϭ 7 Hz, 3 H), 4.30 (q, J ϭ
7 Hz, 1 H), 5.21 (q, J ϭ 7 Hz, 1 H) ppm. 13C NMR (CDCl3): δ ϭ
16.7; 20.2; 66.8; 69.2; 175.1 ppm. MS (ES): calculated [M ϩ Na]:
185.1, measured [M ϩ Na]: 185.0.
Scheme 5
L-Lactide (1): Lactoyl lactate 3 (1.56 g, 9.40 mmol) was dissolved
Conclusion
in dry acetone (100 mL). Cyanuric chloride (1.75 g, 9.40 mmol) was
added and the mixture was stirred at room temp. until a clear solu-
tion was obtained. Et3N (2.60 mL, 18.9 mmol) was added, and al-
most immediately a white precipitate appeared. The mixture was
stirred for 1 h. The precipitate was removed by filtration through a
Hyflo filter, the filter was washed extensively with acetone, and the
filtrate was diluted with water (100 mL). The aqueous layer was
extracted with three 80 mL portions of chloroform. The combined
organic layers were dried with MgSO4, filtered, and concentrated
in vacuo. Flash column chromatography with MTBE yielded -
lactide (1.07 g, 80%) as a white solid. (Rf ϭ 0.3). Recrystallization
from toluene gave -lactide as colorless needle-like crystals. M.p.
97 °C. (ref.[25] 95 °C), [α]2D0 ϭ Ϫ278 (c ϭ 1, chloroform).[26] 1H
NMR (CDCl3): δ ϭ 1.61 (d, J ϭ 7 Hz, 6 H), 5.05 (q, J ϭ 7 Hz, 2
H) ppm. 13C NMR (CDCl3): δ ϭ 15.6; 72.4; 167.5 ppm. MS (ES):
calculated [M ϩ I]: 270.95, measured [M ϩ I]: 270.94.
A number of differently substituted dilactones have been
synthesized by the general procedure as described in this
paper. The desired dilactones were obtained relatively easily,
in reasonable overall yields and with good purities. It is
likely that our procedure is not limited to the compounds
synthesized here, but may be applicable to a wide variety of
α-hydroxy acids. Work along these lines is currently in pro-
gress in our laboratory. With this route to hand, a wide
variety of different functionalized dilactones may be synthe-
sized with the goal of preparing a range of different poly(α-
hydroxy) acids with tailored properties.
Experimental Section
(tert-Butyldimethylsilanyl) (tert-Butyldimethylsilanyloxy)acetate (4):
Glycolic acid (5.0 g, 65.7 mmol) was dissolved in DMF (60 mL).
Imidazole (13.5 g, 197 mmol) and TBSCl (21.5 g, 138 mmol) were
added successively. The mixture was allowed to react overnight at
room temp. Water was added (100 mL) followed by extraction with
four 80 mL portions of Et2O. The combined organic layers were
washed with 100 mL of water, dried (MgSO4), filtered, and concen-
trated in vacuo to give 4 quantitatively as a white semi-solid
General Information: All reagents and solvents were used without
purification, unless stated otherwise. DMF was dried and stored
˚
over 4 A molecular sieves. Peptide grade dichloromethane was
used. Reagents were purchased from Aldrich unless stated other-
wise. (S)-Benzyl lactate was purchased from Purac Biochem. Reac-
tions were monitored by TLC. Rf values were obtained on silica
coated plastic sheets (Merck silica gel 60 F254) with the indicated
eluent. The compounds were analyzed by use of UV light (254 nm),
I2, or a 5% solution of ammonium molybdate in 2  sulfuric acid
followed by heating. Flash column chromatography was carried out
with Acros silica gel (0.030Ϫ0.075 mm) and the indicated eluent.
Optical rotation was measured on a Jasco P-1010 polarimeter.
1
(20.0 g). H NMR (CDCl3): δ ϭ 0.08 (s, 6 H), 0.26 (s, 6 H), 0.81
Ϫ0.95 (m, 18 H), 4.17 (s, 2 H) ppm. 13C NMR (CDCl3): δ ϭ Ϫ5.5;
Ϫ4.8; Ϫ3.6; 25.5; 25.7; 62.3; 171.9 ppm. MS (ES): calculated [M ϩ
Na]: 327.2, measured [M ϩ Na]: 327.0.
Benzyl 2-[2-(tert-Butyldimethylsilanyloxy)acetoxy]propionate (5):
NMR measurements were performed at 298 K on a Varian Oxalyl chloride (1.7 mL, 19 mmol) was added carefully to an ice-
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Eur. J. Org. Chem. 2003, 3344Ϫ3349

A Versatile Route to Functionalized Dilactones
FULL PAPER
cooled solution of compound 4 (5.0 g, 16.5 mmol) in dichlorometh-
ane (20 mL) containing 10 drops of DMF. The reaction was per-
3-Benzyloxy-2-hydroxypropionic Acid (9): NaNO2 (10.6 g,
153.6 mmol) was added slowly to an ice-cooled solution of O-
formed under a dry nitrogen atmosphere, by use of standard benzyl--serine (20.0 g, 102.4 mmol) in sulfuric acid (0.6 ,
Schlenk techniques. After the vigorous evolution of gas had ceased,
the mixture was allowed to warm to room temp. After 2 hours,
dichloromethane and TBSCl were removed in vacuo. A solution
of Et2O (10 mL), pyridine (10 mL), and (S)-benzyl lactate (12.0 g,
66.5 mmol) was added to the residue, and this mixture was stirred
at room temp. for an additional 1.5 h. The white precipitate was
removed by filtration and the filtrate was concentrated in vacuo.
Flash column chromatography with MTBE/hexane (1:5) yielded
benzyl ester 5 as a colorless oil. Rf ϭ 0.5. Yield: 2.0 g (35% over
500 mL). Instantly a brown gas evolved. The reaction mixture was
heated at reflux overnight, vigorous nitrogen gas evolution being
observed when the reaction had reached reflux temperature. After
cooling to room temperature the aqueous layer was extracted with
four 150 mL portions of chloroform. The combined organic layers
were dried (MgSO4), filtered, and concentrated in vacuo. α-
Hydroxy acid 9 was obtained as a yellow oil in a 70% yield (14.0 g).
No further purification was necessary. 1H NMR (CDCl3): δ ϭ 3.74
(dd, J ϭ 4, J ϭ 15 Hz, 1 H), 3.79 (dd, J ϭ 4, J ϭ 15 Hz, 1 H),
two steps). 1H NMR (CDCl3): δ ϭ 0.08 (s, 6 H), 0.91 (s, 9 H), 1.48 4.36 (t, J ϭ 4 Hz, 1 H), 4.57 (s, 2 H), 7.26Ϫ7.35 (m, 5 H) ppm.
(d, J ϭ 7 Hz, 3 H), 4.32 (s, 2 H), 5.10 (s, 2 H), 5.21 (q, J ϭ 7 Hz,
13C NMR (CDCl3): δ ϭ 70.3; 70.8; 73.5; 127.7; 127.9; 128.9; 137.1;
1 H), 7.30Ϫ7.52 (m, 5 H) ppm. 13C NMR (CDCl3): δ ϭ Ϫ5.6; 176.2 ppm. MS (ES): calculated [M ϩ Na]: 219.1, measured [M ϩ
16.8; 18.3; 25.6; 61.4; 66.9; 68.5; 128.0; 128.3; 128.5; 135.2; 170.2;
171.1 ppm. MS (ES): calculated [M ϩ Na]: 375.2, measured [M ϩ
Na]: 375.2.
Na]: 219.0.
tert-Butyldimethylsilanyl 3-Benzyloxy-2-(tert-butyldimethylsilanyl-
oxy)propionate (10): α-Hydroxy acid 9 (6.20 g, 31.6 mmol) was dis-
solved in DMF (70 mL). Imidazole (6.45 g, 94.8 mmol) was added,
followed by addition of TBSCl (10.3 g, 66.4 mmol). The mixture
was left to react overnight at room temp. Water (100 mL) was ad-
ded, followed by extractive workup with four 80 mL portions of
Et2O. The combined organic layers were washed with an additional
100 mL of water and dried with MgSO4. Filtration and concen-
tration yielded 10 (13.0 g, 97%) as a yellow oil. No further purifi-
Benzyl 2-(2-Hydroxyacetoxy)propionate (6): A solution of com-
pound 5 (7.15 g, 20.3 mmol) in EtOAc (100 mL) was added to a
solution of TBAF (6.4 g, 24.4 mmol) and HOAc (101.5 mmol,
5.8 mL) in EtOAc (100 mL). The reaction mixture was stirred for
3 h at room temp. Water (200 mL) was added, followed by extrac-
tive workup with three 150 mL portions of EtOAc. The combined
organic layers were dried (MgSO4), filtered, and concentrated in
vacuo. Flash column chromatography (EtOAc/hexane, 2:3) yielded
compound 6 (3.65 g) as a colorless oil. Rf ϭ 0.18. Yield: 75%. 20%
of starting material could be recovered. 1H NMR (CDCl3): δ ϭ
1.55 (d, J ϭ 7 Hz, 3 H), 4.2 (d, J ϭ 17 Hz, 1 H), 4.25 (d, J ϭ
17 Hz, 1 H), 5.17 (s, 2 H), 5.22 (q, J ϭ 7 Hz, 1 H), 7.33 (m, 5 H)
ppm. 13C NMR (CDCl3): δ ϭ 16.7; 60.3; 67.1; 69.1; 128.0; 128.3;
128.5; 134.9; 170.1; 172.5 ppm. MS (ES): calculated [M ϩ H]:
239.1, measured [M ϩ H]: 239.0.
1
cation was necessary. H NMR (CDCl3): δ ϭ 0.02 (m, 6 H), 0.21
(m, 6 H), 0.85 (m, 18 H), 3.65 (m, 2 H), 4.29 (t, J ϭ 4 Hz, 1 H),
4.51 (d, J ϭ 17 Hz, 1 H), 4.55 (d, J ϭ 17 Hz, 1 H), 7.24 (m, 5 H)
ppm. 13C NMR (CDCl3): δ ϭ Ϫ5.4; Ϫ4.9; Ϫ4.8; Ϫ3.7; 17.5; 18.3;
25.6; 25.7; 72.6; 73.3; 73.4; 127.4; 127.5; 128.3; 138.0; 171.7 ppm.
MS (ES): calculated [M ϩ Na]: 447.2, measured [M ϩ Na]: 447.3.
1-(Benzyloxycarbonyl)ethyl 3-Benzyloxy-2-(tert-butyldimethylsilan-
yloxy)propionate (11): Oxalyl chloride (0.57 mL, 6.5 mmol) was
carefully added to an ice-cooled solution of compound 10 (2.5 g,
5.9 mmol) in dichloromethane (8 mL) containing DMF (10 drops),
by the same procedure as used for compound 5. After the vigorous
evolution of gas had ceased, the mixture was allowed to warm to
room temp. and left to react overnight. Dichloromethane and
TBSCl were removed in vacuo. A solution of Et2O (8 mL), pyridine
(2 mL), and (S)-benzyl lactate (3.2 g, 17.6 mmol) was added to the
residue, and this mixture was stirred at room temp. for an ad-
ditional 1.5 h. The resulting white precipitate was removed by fil-
tration through a Hyflo/silica filter. The filter was washed exten-
sively with Et2O and the filtrate was concentrated in vacuo. Flash
column chromatography with MTBE/hexane (1:5) yielded benzyl
ester 11 as a colorless oil. Rf ϭ 0.48. Yield: 1.2 g (43%) over two
2-(2-Hydroxyacetoxy)propionic Acid (7): Benzyl ester 6 (3.64 g,
15.3 mmol) was dissolved in EtOH (250 mL). Pd/C (365 mg, 10%
w/w) was added, and the reaction flask was placed under a hydro-
gen atmosphere (balloon). The reaction mixture was stirred vigor-
ously and left to react overnight at room temp. The catalyst was
removed by filtration through a Hyflo filter. The filter was washed
extensively with EtOH and the filtrate was concentrated under re-
duced pressure. This yielded carboxylic acid 7 (2.46 g, 100%) as a
colorless oil. No further purification was needed. 1H NMR
(CDCl3): δ ϭ 1.56 (d, J ϭ 7 Hz, 3 H), 4.24 (d, J ϭ 17 Hz, 1 H),
4.27 (d, J ϭ 17 Hz, 1 H), 5.21 (q, J ϭ 7 Hz, 1 H) ppm. 13C NMR
(CDCl3): δ ϭ 16.7; 60.4; 69.1; 172.8; 173.2 ppm. MS (ES): calcu-
lated [M ϩ Na]: 171.0, measured [M ϩ Na]: 170.7.
1
steps. H NMR (CDCl3): δ ϭ 0.07 (s, 3 H), 0.09 (s, 3 H), 0.89 (s,
9 H), 1.49 (d, J ϭ 7 Hz, 3 H), 3.62 (dd, J ϭ 7, J ϭ 10 Hz, 1 H),
3.76 (dd, J ϭ 7, J ϭ 10 Hz, 1 H), 4.45 (dd, J ϭ 3, J ϭ 7 Hz, 1 H),
4.53 (s, 2 H), 5.12 (s, 2 H), 5.19 (q, J ϭ 7 Hz, 1 H), 7.25Ϫ7.36 (m,
10 H) ppm. 13C NMR (CDCl3): δ ϭ Ϫ5.2; 16.9; 25.6; 67.0; 69.1;
72.4; 72.5; 73.4; 127.5; 128.3; 128.4; 128.6; 170.2 ppm. MS (ES):
calculated [M ϩ Na]: 495.2, measured [M ϩ Na]: 495.1.
3-Methyl-1,4-dioxane-2,5-dione (8): Carboxylic acid
7 (2.40 g,
16.2 mmol) was dissolved in acetone (150 mL). Cyanuric chloride
(2.90 g, 16.2 mmol) was added, and the mixture was stirred at room
temp. until a clear solution was obtained. After addition of Et3N
(4.4 mL, 32 mmol) a pale yellow precipitate appeared. The mixture
was stirred overnight at room temp. The precipitate was removed
by filtration through a Hyflo filter. The yellow filtrate was diluted
1-Benzyloxycarbonylethyl 3-Benzyloxy-2-hydroxypropionate (12): A
with 100 mL of water, and extracted with three 100 mL portions of solution of benzyl ester 11 (500 mg, 1.06 mmol) in EtOAc (10 mL)
chloroform. The combined organic layers were dried with MgSO4,
filtered, and concentrated in vacuo. Flash column chromatography
(EtOAc/hexane, 1:3) yielded compound 8 (1.53 g) as a yellow oil.
was added to a solution of TBAF (290 mg, 1.11 mmol) and acetic
acid (0.3 mL, 5.6 mmol) in EtOAc (10 mL) and the mixture was
heated at reflux. After 1.5 h the reaction mixture was allowed to
cool to room temp., followed by addition of 10 mL of saturated
1
Rf ϭ 0.14, yield: 72%. H NMR (CDCl3): δ ϭ 1.67 (d, J ϭ 7 Hz,
3 H), 4.93 (d, J ϭ 17 Hz, 1 H), 4.99 (d, J ϭ 17 Hz, 1 H), 5.04 (q, NaHCO3 and 15 mL of water. The aqueous layer was extracted
J ϭ 7 Hz, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 16.3; 65.6; 72.0 ppm.
with EtOAc (3 ϫ 20 mL), and the combined organic layers were
MS (ES): calculated [M ϩ I]: 256.931, measured [M ϩ I]: 256.933. dried (MgSO4), filtered, and concentrated under reduced pressure.
Eur. J. Org. Chem. 2003, 3344Ϫ3349
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W. E. Hennink et al.
FULL PAPER
Flash column chromatography with MTBE/hexane (1:1) yielded
benzyl ester 12 (325 mg, 86%) as a pale yellow oil. Rf ϭ 0.28. 10%
of starting material could be recovered. 1H NMR (CDCl3): δ ϭ 1.5
(d, J ϭ 7 Hz, 3 H), 3.72 (dd, J ϭ 5, J ϭ 10 Hz, 1 H), 3.79 (dd,
J ϭ 5, J ϭ 10 Hz, 1 H), 4.40 (m, 1 H), 4.51 (d, J ϭ 12 Hz, 1 H),
4.55 (d, J ϭ 12 Hz, 1 H), 5.14 (s, 2 H), 5.25 (q, J ϭ 7 Hz, 1 H),
7.25Ϫ7.36 (m, 10 H) ppm. 13C NMR (CDCl3): δ ϭ 16.9; 67.1;
69.4; 70.6; 71.3; 73.4; 127.6; 127.7; 128.1; 128.3; 128.4; 128.6; 135.0;
137.6; 169.9; 171.8 ppm. MS (ES): calculated [M ϩ Na]: 381.1,
measured [M ϩ Na]: 381.2.
171.1 ppm. MS (ES): calculated [M ϩ Na]: 481.2, measured [M ϩ
Na]: 481.1.
Benzyloxycarbonylmethyl 3-Benzyloxy-2-hydroxypropionate (16): A
solution of benzyl ester 15 (1.6 g, 3.5 mmol) in EtOAc (15 mL) was
added to a solution of TBAF (985 mg, 3.7 mmol) in EtOAc
(15 mL) containing acetic acid (1.1 mL, 18.5 mmol). The mixture
was heated at reflux. After 2.5 h the mixture was cooled to room
temp. followed by addition of 10 mL of saturated NaHCO3 and
40 mL of water. The aqueous layer was extracted with EtOAc (3 ϫ
50 mL); the combined organic layers were dried (MgSO4), filtered,
and concentrated under reduced pressure. Flash column chroma-
tography with MTBE/hexane (1:1) yielded benzyl ester 16 (746 mg,
62%) as a pale yellow oil. Rf ϭ 0.15. 35% of starting material could
be recovered. 1H NMR (CDCl3): δ ϭ 3.78 (d, J ϭ 3.5 Hz, 2 H),
4.16 (s, 1 H), 4.55Ϫ4.78 (m, 4 H), 5.17 (s, 2 H), 7.25Ϫ7.36 (m, 10
H) ppm. 13C NMR (CDCl3): δ ϭ 61.2; 67.2; 70.7; 71.0; 73.4; 127.6;
127.7; 128.3; 128.4; 128.5; 128.6; 137.5; 167.0; 171.9 ppm. MS (ES):
calculated [M ϩ Na]: 367.1, measured [M ϩ Na]: 367.1.
2-(3-Benzyloxy-2-hydroxypropoxy)propionic Acid (13): Pd/C (10%,
1.5 g, 1:1 w/w) was added to a solution of benzyl ester 12 (1.5 g,
4.2 mmol) in EtOH (50 mL). Five equivalents of 1,4-cyclohexadi-
ene (1.7 g, 2 mL) were added and the mixture was stirred vigorously
at room temp. under a nitrogen atmosphere. After 4 h the catalyst
was removed by filtration through a Hyflo filter. The filter was
washed extensively with EtOH, and the filtrate was concentrated
under reduced pressure to yield compound 13 (985 mg, 90%) as a
1
pale yellow oil. H NMR (CDCl3): δ ϭ 1.55 (d, J ϭ 7 Hz, 3 H),
3.80Ϫ3.85 (m, 2 H), 4.42 (t, J ϭ 3.5 Hz, 1 H), 4.59 (s, 2 H), 5.30
(q, J ϭ 7 Hz, 1 H), 7.25Ϫ7.36 (m, 5 H) ppm. 13C NMR (CDCl3):
δ ϭ 16.7; 17.7; 58.1; 69.4; 70.5; 71.3; 73.4; 127.7; 128.3; 137.4;
171.8 ppm. MS (ES): calculated [M ϩ Na]: 291.1, measured [M ϩ
Na]: 291.0.
2-(3-Benzyloxy-2-hydroxypropoxy)acetic Acid (17): Pd/C (10%,
740 mg) was added to a solution of benzyl ester 16 (740 mg,
1.61 mmol) in EtOH (15 mL). 1,4-Cyclohexadiene (0.76 mL,
8.06 mmol) was added and the mixture was stirred vigorously at
room temp. After 1.5 h the catalyst was removed by filtration
through a Hyflo filter. The filter was washed extensively with
EtOH, and the filtrate was concentrated in vacuo to yield car-
3-Benzyloxymethyl-6-methyl-1,4-dioxane-2,5-dione (14): Cyanuric
chloride (700 mg; 3.8 mmol) was added to a solution of compound
13 (984 mg, 3.7 mmol) in dry acetone (40 mL). After a clear solu-
tion was obtained, Et3N (1.6 mL, 7.6 mmol) was added. A white
precipitate instantly appeared. The mixture was heated at 40 °C for
1 hour, and was subsequently stirred at room temp. overnight. The
precipitate was removed by filtration through a Hyflo filter, the
filter was washed extensively with acetone, and the filtrate was di-
luted with water (50 mL). The aqueous layer was extracted with
three 40 mL portions of chloroform. The combined organic layers
were dried with MgSO4, filtered, and concentrated in vacuo. Flash
column chromatography with EtOAc/hexane (1:2) yielded com-
pound 14 (550 mg, 60%) as a white solid. (Rf ϭ 0.35) Recrystalliza-
tion from toluene gave 14 as white, needle-like crystals. M.p. 88 °C.
1H NMR (CDCl3): δ ϭ 1.56 (d, J ϭ 7 Hz, 3 H), 3.90 (d, J ϭ 3 Hz,
2 H), 4.59 (s, 2 H), 5.11 (m, 2 H), 7.25Ϫ7.36 (m, 5 H) ppm. 13C
NMR (CDCl3): δ ϭ 17.5; 68.5; 73.1; 73.9; 127.6; 127.9; 128.3 ppm.
MS (ES): calculated [M ϩ I]: 376.9886, measured [M ϩ I]:
376.9904.
1
boxylic acid 17 (380 mg, 93%) as a yellow oil. H NMR (CDCl3):
δ ϭ 3.8 (s, 2 H), 4.4 (t, J ϭ 3.5 Hz, 1 H), 4.6 (d, J ϭ 3 Hz, 2 H),
4.7 (s, 2 H), 7.3 (m, 5 H) ppm. 13C NMR (CDCl3): δ ϭ 60.9; 70.5;
70.9; 73.4; 128.7; 127.7; 127.8; 128.3; 137.2; 170.7; 171.8 ppm. MS
(ES): calculated [M ϩ H]: 255.1, measured [M ϩ H]: 255.0.
3-Benzyloxymethyl[1,4]dioxane-2,5-dione (18): Cyanuric chloride
(572 mg, 3.1 mmol) was added to a solution of compound 17
(765 mg, 3.0 mmol) in dry acetone (35 mL). When a clear solution
was obtained, Et3N (0.85 mL, 6.2 mmol) was added. A yellow pre-
cipitate instantly appeared. The mixture was heated at 40 °C for 1
hour, and was subsequently stirred at room temp. overnight. The
precipitate was removed by filtration through a Hyflo filter, the
filter was washed extensively with acetone, and the filtrate was di-
luted with water (50 mL). The aqueous layer was extracted with
three 40 mL portions of chloroform. The combined organic layers
were dried with MgSO4, filtered, and concentrated in vacuo. Flash
column chromatography with EtOAc/hexane (1:2) as an eluent
yielded compound 18 (90 mg, 13%) as an off-white solid. (Rf ϭ
0.25). Recrystallization from toluene gave 18 as white, needle-like
1-(Benzyloxycarbonyl)ethyl 2-tert-Butyldimethylsilanyloxypropion-
ate (15): Oxalyl chloride (0.45 mL, 5.2 mmol) was added carefully
to an ice-cooled solution of compound 10 (2.0 g, 4.7 mmol) in di-
chloromethane (8 mL) containing 10 drops of DMF by the same
procedure as used for compound 5. After the vigorous evolution
of gas had ceased, the mixture was allowed to warm to room temp.
and left to react for 2.5 h. Dichloromethane and TBSCl were re-
moved in vacuo. A solution of Et2O (8 mL), pyridine (2 mL), and
benzyl glycolate (2.35 g, 14.2 mmol) was added to the residue, and
this mixture was stirred overnight at room temp. The resulting pre-
cipitate was removed by filtration through a Hyflo/silica filter. The
filter was washed extensively with Et2O and the filtrate was concen-
trated in vacuo. Flash column chromatography with MTBE/hexane
(1:5) yielded benzyl ester 15 as a colorless oil. Rf ϭ 0.45. Yield:
1
crystals. M.p. 51 °C. H NMR (CDCl3): δ ϭ 3.9 (dd, J ϭ 2.5, J ϭ
8 Hz, 1 H), 4.1 (dd, J ϭ 2.5, J ϭ 8 Hz, 1 H), 4.5 (s, 2 H), 4.8 (d,
J ϭ 17 Hz, 1 H), 5.0 (d, J ϭ 17 Hz, 1 H), 5.1 (t, J ϭ 2.5 Hz, 1 H),
7.3 (m, 5 H) ppm. 13C NMR (CDCl3): δ ϭ 65.3; 70.6; 73.7; 76.3;
127.6; 128.2; 128.5; 136.2; 163.6; 164.5 ppm. MS (ES): calculated
[M ϩ I]: 362.9730, measured [M ϩ I]: 362.9723.
Acknowledgments
T. F. J. Veldhuis is gratefully acknowledged for the synthesis of sec-
phenethyl lactoyl lactate. M. W. H. Pinkse is gratefully acknowl-
1
1.7 g (78%) over two steps. H NMR (CDCl3): δ ϭ 0.08 (m, 6 H),
0.9 (m, 9 H), 3.7 (m, 2 H), 4.5 (m, 1 H), 4.6 (d, J ϭ 3 Hz, 2 H), edged for assistance with Mass Spectrometric analysis. These in-
4.6 (d, J ϭ 12 Hz, 1 H), 4.7 (d, J ϭ 12 Hz, 1 H), 5.2 (s, 2 H), 7.3
vestigations were sponsored by the Netherlands Research Council
(m, 10 H) ppm. 13C NMR (CDCl3): δ ϭ Ϫ5.1; 25.7; 60.9; 67.1; for Chemical Sciences with financial aid from the Netherlands
72.3; 72.4; 73.5; 127.6; 127.6; 128.3; 128.4; 128.5; 128.6; 138.0; Technology Foundation. (CW/STW 790.35.622).
3348
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3344Ϫ3349

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