Enantioselective synthesis of (R)-propylene carbonate from ethyl (S)-lactate

Article abstract of DOI:10.1055/s-0028-1088015

We report a three-step synthesis of (R)-propylene carbonate from inexpensive, chiral ethyl (S)-lactate. The synthesis involves a borohydride ester reduction and an unusual intramolecular displacement reaction by a carbonate anion. The procedure is simple and reliable, resulting in (R)-propylene carbonate in approximately 60% overall yield with ≥98% ee. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088015

PRACTICAL SYNTHETIC PROCEDURES
1403
Enantioselective Synthesis of (R)-Propylene Carbonate from Ethyl (S)-Lactate
E
nantiosel
o
e
ctive Synth
h
e
sis of
(
R
)-P
n
ropylene CarbonateM. Whitaker, Robert C. Ronald*
Department of Chemistry, Washington State University, Pullman, WA 99164, USA
Fax +1(509)3358867; E-mail: rcr@wsu.edu
Received 17 October 2008; revised 15 December 2008
PSP
No156
Abstract: We report a three-step synthesis of (R)-propylene carbonate from inexpensive, chiral ethyl (S)-lactate. The synthesis involves a
borohydride ester reduction and an unusual intramolecular displacement reaction by a carbonate anion. The procedure is simple and reliable,
resulting in (R)-propylene carbonate in approximately 60% overall yield with ≥98% ee.
Key words: propylene carbonate, cyclic carbonate formation, borohydride reductions, nucleophilic addition, chiral pool
Carbon dioxide is known to readily form carbonate esters
OH
OTs
NaBH4
OTs
TsCl
with primary alcohols6 under basic conditions. Previous
studies have shown that with highly reactive alkyl halides,
the salts of alkyl carbonate esters can undergo nucleo-
philic displacement reactions to form dialkyl carbonates.7
We envisioned that an intramolecular displacement reac-
tion might be achieved from an in situ generated carbon-
ate anion of (S)-2-(tosyloxy)propan-1-ol (4) even though
the nucleophilicity of the carbonate anion might be low,
and that such a displacement would provide the necessary
inversion of stereochemistry at the secondary center with
concomitant formation of the desired cyclic carbonate.
The required (S)-2-(tosyloxy)propan-1-ol (4) could be ob-
tained by hydride reduction of the lactate ester after tosy-
lation of the secondary alcohol (Scheme 1).
EtO
EtO
HO
EtOH, –5 °C
py, 2 °C
4
O
O
84%
2
3
84%
K2CO3, 18-crown-6
CO2 (4.14 bar)
OTs
O
O
O
O
MeCN–THF (1:1)
60 °C
O
O
5
1
82%
Scheme 1
As part of a program for the synthesis of compounds with
anti-HIV/AIDS activities related to Tenofovir1 and analo-
gous compounds, we had need for an efficient synthesis of
(R)-propylene carbonate (1). Propylene carbonate is typi-
cally prepared by reaction of a carbonation reagent, such
as diethyl carbonate with propylene glycol.1a,2 Propylene
carbonate can also be prepared from propylene oxide and
carbon dioxide with an appropriate catalyst.3 While both
optically active propylene glycol and propylene carbonate
in high enantiomeric purity are commercially available,
they are obtained at a cost several times that of optically
active ethyl lactate.
Tosylation of ethyl (S)-lactate in pyridine was accom-
plished using the procedure of Johnston and Slessor.8
(–)-Ethyl (S)-2-O-tosyllactate (3) was obtained in 84%
yield after crystallization in the freezer from a mixture of
pentane–diethyl ether.
Normally, esters are reduced using powerful hydride re-
ducing agents such as lithium aluminum hydride, alumi-
num hydride, or diisobutylaluminum hydride,4 but for this
reduction sodium borohydride was selected as a milder,
less expensive alternative. Treatment of 3 in absolute eth-
anol with 2.8 equivalents of sodium borohydride at –5 °C
for 15–30 minutes resulted in complete reduction to 4 in
85% yield after quenching the excess hydride with aque-
ous acetic acid. The facile reduction of the ester in this
case is assisted by the electron-withdrawing effects of the
neighboring tosyloxy group. Compound 4 has only mod-
erate stability at room temperature, but may be stored in
the refrigerator for several weeks.
Our primary considerations in the development of this
synthesis were to obtain the product in good overall yield
and high enantiomeric purity from readily available, inex-
pensive reagents, using reactions easily carried out under
laboratory conditions. We had previous experience in the
use of ethyl (S)-lactate (2) as a chiral pool intermediate in
a synthesis of (R)-methyloxirane4 using an intramolecular
displacement reaction, which led us to develop a similar
strategy for the synthesis of the carbonate ester because of
the known lack of reactivity of most sulfonate esters of
lactate in nucleophilic substitution reactions.5
The crucial cyclization reaction to the carbonate ester re-
quired careful consideration of the relative pKa values of
all the reaction partners in order to avoid undesired cy-
clization to the epoxide. In the presence of carbon dioxide
the alcohol is in equilibrium with the alkyl carbonate 5; an
alkyl carbonate would be expected to have a pKa very sim-
ilar to that of the pKa1 of carbonic acid (carbonic acid has
pKa1 6.3 and pKa2 10.3).9 Therefore, in the presence of po-
tassium carbonate, 4 (pKa ~16 for a primary alcohol)
should not be significantly deprotonated, but the alkyl car-
SYNTHESIS 2009, No. 8, pp 1403–1404
x
x
.
x
x
.2
0
0
9
Advanced online publication: 16.03.2009
DOI: 10.1055/s-0028-1088015; Art ID: M06208SS
© Georg Thieme Verlag Stuttgart · New York

1404
J. M. Whitaker, R. C. Ronald
PRACTICAL SYNTHETIC PROCEDURES
(R)-Propylene Carbonate (1)
bonate 5 should be completely in the form of the anion; a
condition necessary for displacement of the neighboring
tosylate. Thus, when 4 was treated with excess, anhydrous
potassium carbonate in a polar, aprotic solvent under car-
bon dioxide pressure, (R)-propylene carbonate (1) was
produced as the only isolable, neutral product. Optimized
reaction conditions for carbonation of 4 were found using
a 1:1 solvent mixture of tetrahydrofuran–acetonitrile at 60
°C under a carbon dioxide atmosphere at 4.14 bar, with
~10 mol% of 18-crown-6 ether as a phase-transfer catalyst
and finely ground anhydrous potassium carbonate as the
base. These conditions produced propylene carbonate 1
from 4 in 82% yield. The absolute configuration and the
enantiomeric excess of the product were established using
a 30 m Restek Rt-bDEXsm chiral capillary GLPC column
at 120 °C, which showed that synthetic 1 was found to be
a 98:2 mixture in favor of the R-enantiomer.
Crude 4 (20.88 g, 0.0907 mol) was dissolved in THF–MeCN (1:1,
200 mL) in a 1-L Ace Parr pressure vessel. Finely ground anhyd
K2CO3 (31.1 g, 0.225 mol, 2.5 mol equiv) and 18-crown-6 (1.75 g,
0.0065 mol, 0.07 mol equiv) were added. The flask was evacuated
and pressurized with CO2 three times prior to being pressurized to
4.14 mbar, and then placed in oil bath at 60 °C. The reaction was
monitored by TLC (same as solvent as for 4). After 4 d the reaction
had gone to completion. The mixture was filtered to remove solid
material; the solvents were removed using a small fractionating col-
umn. Kugelrohr distillation of the oily residue (65–70 °C/0.33
mbar) gave 1 (7.59 g, 82%) as a colorless oil. GC [30 m Restek
Rt-bDEXsm chiral capillary GLPC column at 120 °C, He flow
23 cm/s]: tR = 12.6 (R), 13.1 (S) min.
IR (neat): 1790 cm–1 (s, C=O).
1H NMR (300 MHz, CDCl3): d = 4.88 (m, 1 H), 4.57 (dd, J = 7.8,
8.4 Hz, 1 H), 4.04 (dd, J = 7.2, 8.4 Hz, 1 H), 1.50 (d, J = 6.3 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 154.9, 73.5, 70.5, 19.2.
1H NMR spectra were recorded at 300 MHz in CDCl3 and are re-
ported in ppm on the δ scale downfield from TMS (d = 0.00). 13C
NMR spectra were recorded at 75 MHz and are reported in ppm on
the d scale relative to CDCl3 (d = 77.00). IR spectra were recorded
on a FTIR spectrometer as a neat film on NaCl discs. Chiral GC
data were obtained under the following conditions: 30 m Restek
Rt-βDEXsm chiral capillary GLPC column at 120 °C, He flow 23
cm/s. Melting points were obtained on Thomas-Hoover Unimelt ap-
paratus and are uncorrected. Reagents were used as received from
commercial sources unless otherwise specified. All products are
known, see 3,8 4,10 and 1.3a
Acknowledgment
We thank Microbiológica Química e Farmacêutica, Rio de Janeiro,
RJ, Brazil, and the Sclavo Research Fund (WSU) for financial sup-
port.
References
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(–)-Ethyl (S)-2-O-Tosyllactate (3)
Prepared following the method of Johnston and Slessor.8 Recrystal-
lization (pentane–Et2O) gave 3 (81.9 g, 84%).
Mp 31.5–32 °C (Lit.8 31 °C).
IR (neat): 1749 cm–1 (s, C=O).
1H NMR (300 MHz, CDCl3): d = 7.82 (d, J = 8.4 Hz, 2 H), 7.35 (d,
J = 8.4 Hz, 2 H), 4.93 (q, J = 7.2 Hz, 1 H), 4.12 (q, J = 7.2 Hz, 2 H),
2.45 (s, 3 H), 1.51 (d, J = 7.2 Hz, 3 H), 1.21 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 169.0, 145.0, 133.3, 129.7, 129.0,
74.1, 61.8, 21.6, 18.4, 13.9.
(S)-2-(Tosyloxy)propan-1-ol (4)
To a soln of 2 (15.02 g, 0.055 mol) in abs EtOH (150 mL) at –5 °C
was added NaBH4 (5.87 g, 0.155 mol, 2.8 mol equiv) dissolved in
an ice/H2O mixture (40 mL). The reaction progress was monitored
by TLC (MeOH–EtOH–CH2Cl2–hexanes, 10:10:25:55) and upon
completion the mixture was brought to pH 4 by dropwise addition
of AcOH. The mixture was partitioned between H2O and EtOAc
and the combined organic extracts were dried (MgSO4) and concen-
trated to give 4 (10.712 g, 84%) as a pale yellow oil that was not pu-
rified further.
(7) (a) Cella, J. A.; Bacon, S. W. J. Org. Chem. 1984, 49, 1122.
(b) Lissel, M.; Dehmlow, E. V. Chem. Ber. 1981, 114, 3348.
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(9) The Chemist’s Companion; Gordon, G.; Ford, R., Eds.;
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IR (neat): 3300–3600 cm–1 (br, O–H).
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1H NMR (300 MHz, CDCl3): d = 7.81 (d, J = 8.4 Hz, 2 H), 7.35 (d,
J = 8.4 Hz, 2 H), 4.67 (m, 1 H), 3.62 (m, 2 H), 3.12 (br s, OH), 2.45
(s, 3 H), 1.20 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 144.7, 133.6, 129.7, 127.6, 65.3,
21.6, 16.9.
Synthesis 2009, No. 8, 1403–1404 © Thieme Stuttgart · New York