M. Mujahid et al. / Tetrahedron Letters 55 (2014) 3223–3226
3225
7. (a) Siripragada, M. R.; Chebiyyam, P.; Potlapally, R. K.; Batchu, C. S.;
Mamillapally, R. S. PCT Appl. WO 00/26200.; (b) Potlapally, R. K.; Siripragada,
M. R.; Kotra, N, M.; Sirisilla, R.; Mamillapally, R. S.; Reddy, O. G. US 6559335,
intermediate (S)-4 was obtained by regioselective ring opening of
(S)-epoxide (S)-3a with 4-methoxyphenylmagnesium bromide in
the presence of catalytic amount of CuI in anhydrous THF at
À20 °C. Next, the O-ethylation on substrate (S)-4 was considered
to be important because of the fact that base mediated ethylation
of
a-hydroxy esters generally leads to epimerization at C-2 car-
bon.8b However, in this case, the O-ethylation of protected second-
ary alcohol (S)-4 went smoothly with ethyliodide using sodium
hydride as a base in DMF to produce O-ethylated derivative (S)-5
in 93% yield without any loss in optical purity. Hence, it is note-
worthy to mention here that O-ethylation of protected hydroxyl
derivative (S)-4 provides an attractive alternative to the alkylation
of a-hydroxy ester derivatives to avoid the risk of epimerization at
C-2 carbon. Further, debenzylation of compound (S)-5 followed by
oxidation with sodium chlorite catalyzed by TEMPO and bleach in
an acetonitrile–phosphate buffer (pH 6.8) afforded the acid (S)-7 in
76% yield (two steps). Demethylation of compound (S)-7 was
accomplished using NaSEt in DMF at 130 °C to provide the acid
(S)-8 in 86% yield. Other deprotection conditions such as BBr3
and HI were not favored as they are known to produce unwanted
side products.6b Finally, the acid (S)-8 was esterified using ethanol
under acidic condition to afford EEHP ((S)-1a) in 90% yield. Simi-
larly, IEHP ((S)-1b) was obtained by esterification of the acid (S)-
8 with isopropanol (yield 85%; ee >99%). The structure of (S)-1a
& (S)-1b was confirmed by its IR, 1H NMR, 13C NMR, and mass spec-
troscopic analysis. The enantiomeric excess of compounds (S)-1b
and the intermediate (S)-3a was determined by chiral HPLC
analysis.
In conclusion, we have developed a new and alternative synthe-
sis of important chiral pharmaceutical intermediates EEHP and
IEHP, starting from readily available benzyl glycidyl ether, for the
first time. High enantiopurity (>99%) has been achieved by this
route. We envisage that this simple protocol may find its application
in the chemical and pharmaceutical industry for the large scale pro-
duction of these important intermediates. Further, this strategy is
being exploited for the preparation of other biologically important
and optically active b-hydroxy acid derivatives, in our laboratory.
Spectral data for selected compounds:
(S)-2-(Benzyloxymethyl) oxirane (S)-3a: [a]
25 = +8.1 (c 0.4, EtOH) {lit.10b
[
a
]
23 = +7.8 (c 0.4, EtOH)}; IR (CHCl3, cmÀ1D): mmax 3418, 3020, 2401, 1719,
D
1603,1523,1495,1421,1216, 1094,929,669;lHNMR(200 MHz, CDCl3):dH 2.60–
2.64 (dd, J = 5.1, 2.7 Hz, 1H), 2.78–2.82 (dd, J = 5.3, 4.2 Hz, 1H), 3.15–3.23 (m, 1H),
3.39–3.48 (dd, J = 11.3, 5.8 Hz, 1H), 3.73–3.81 (dd, J = 11.4, 3.0 Hz, 1H), 4.60 (s,
2H), 7.28–7.37 (m, 5H); l3C NMR (50 MHz, CDCl3): dC 137.8 (C), 128.4 (CH, 2
carbons), 127.7 (CH, 3 carbons), 73.3 (CH2), 70.7 (CH2), 50.8 (CH), 44.2 (CH2); MS:
m/z 187 [M+Na]+; ee >99% [chiral HPLC analysis; CHIRALCEL OD-H
(250 Â 4.6 mm) column; eluent: n-hexane/isopropanol = 90:10; flow rate:
0.5 mL/min; detector: 220 nm [(S)-isomer tR = 15.25 min; (R)-isomer
tR = 16.46 min].
(S)-1-(Benzyloxy)-3-(4-methoxyphenyl)propan-2-ol (S)-4: [
CHCl3); IR (CHCl3, cmÀ1):
max 3387, 3019, 2977, 2933, 1612, 1496, 1454, 1370,
1296, 1216, 1104, 929, 757 cmÀ1 1H NMR (200 MHz, CDCl3): dH = 2.76 (d,
a]
25 = +11.3 (c 1.1,
D
m
;
J = 6.5 Hz, 2H), 3.34–3.43 (dd, J = 9.5, 6.8 Hz, 1H), 3.48–3.54 (dd, J = 9.5, 3.5 Hz,
1H), 3.79 (s, 3H), 3.95–4.07 (m, 1H), 4.54 (s, 2H), 6.86 (d, J = 8.6 Hz, 2H), 7.10 (d,
J = 8.6 Hz, 2H), 7.31–7.37 (m, 5H);13CNMR (50 MHz, CDCl3): dC = 158.2(C), 138.0
(C), 138.2 (CH, 2 carbons), 129.8 (C), 128.4 (CH, 2 carbons), 127.7 (CH, 3 carbons),
113.9 (CH, 2 carbons), 73.5 (CH2), 73.3 (CH2), 71.5 (CH), 55.3 (CH3), 38.9 (CH2);
MS: m/z 295 [M+Na]+.
Acknowledgments
M.M. thanks the CSIR, New Delhi for a research fellowship.
Financial support from the CSIR-India Network projects
(CSC0130, BSC0121 and CSC0108) is gratefully acknowledged.
(S)-1-(3-(Benzyloxy)-2-ethoxypropyl)-4-methoxybenzene (S)-5: [
CHCl3); IR (CHCl3, cmÀ1):
1296, 1216, 1104, 929, 757 cmÀ1
a
]
25 = À3.9 (c 1,
D
m
max 3387, 3019, 2977, 2933, 1612, 1496, 1454, 1370,
;
1H NMR (200 MHz, CDCl3): dH = 1.14 (t,
J = 6.7 Hz, 3H), 2.76–2.81 (m, 2H), 3.42–3.50 (m, 3H), 3.55–3.63 (m, 2H), 3.79 (s,
3H), 4.54(s,2H), 6.79(d, J = 8.6 Hz, 2H), 7.10(d, J = 8.6 Hz, 2H), 7.31–7.36(m, 5H);
13C NMR (50 MHz, CDCl3): dC = 157.3 (C), 137.7 (C), 130.1 (C), 129.7 (CH, 2
carbons), 127.6 (CH, 2 carbons), 127.0 (CH, 2 carbons), 126.8 (CH), 112.9 (CH, 2
carbons), 79.2 (CH), 72.6 (CH2), 70.9 (CH2), 64.8 (CH2), 54.8 (CH3), 36.6(CH2), 14.9
(CH3); MS: m/z 323 [M+Na]+.
Supplementary data
Supplementary data associated with this article can be found, in
(S)-2-Ethoxy-3-(4-methoxyphenyl)propan-1-ol (S)-6: [
a]
25 = +2.8 (c 1.8 CHCl3);
D
IR (CHCl3, cmÀ1):
m
max 3420, 3019, 1635, 1514, 1215, 1113, 928, 770, 669 cmÀ1
;
1H NMR (200 MHz, CDCl3): dH = 1.23 (t, J = 6.9 Hz, 3H), 2.64–2.82 (m, 2H), 3.47–
3.61 (m, 5H), 3.80 (s, 3H), 3.91–3.95 (m, 1H), 6.86 (d, J = 8.5 Hz, 2H), 7.15 (d,
J = 8.5 Hz, 2H); 13C NMR (50 MHz, CDCl3): dC = 157.0 (C), 130.3 (CH, 2 carbons),
130.3 (C), 113.8 (CH, 2 carbons), 81.1 (CH), 65.2 (CH2), 63.2 (CH2), 55.2 (CH3), 36.4
(CH2), 15.5 (CH3); MS: m/z 211 [M+H]+.
References and notes
(S)-2-Ethoxy-3-(4-methoxyphenyl)propanoic acid (S)-7:
CHCl3); IR (CHCl3, cmÀ1):
758 cmÀ1
[
a
]
25 = À15.3 (c 2.7
D
m
max 3412, 3020, 1614, 1425, 1216, 1110, 1031, 928,
;
1H NMR (200 MHz, CDCl3): dH = 1.19 (t, J = 7.0 Hz 3H), 2.90–3.15 (m,
2H), 3.39–3.65 (m, 2H), 3.80 (s, 3H), 4.03–4.16(m,1H), 6.87 (d, J = 8.5 Hz2H), 7.20
(d, J = 8.5 Hz, 2H); 13C NMR (50 MHz, CDCl3): dC = 176.3 (CO), 158.5 (C), 130.4
(CH, 2 carbons), 128.6 (C), 113.7 (CH, 2 carbons), 79.7 (CH), 66.7 (CH2), 55.1 (CH3),
37.8 (CH2), 14.9 (CH3); MS: m/z 247 [M+Na]+.
4. (a) www.lipaglyn.com.; (b) Lohray, B. B.; Lohray, V. B.; Barot, V. K.; Raval, S. K.;
Raval, P. S.; Basu, S. PCT Int. Appl. WO 2003/009841 A1, 2003.
5. Potlapally, R. K.; Siripragada, M. R.; Kotra, N, M.; Sirisilla, R.; Mamillapally, R. S.;
Reddy, O. G. PCT Int. Appl. WO 2002/024625, 2002; Chem. Abstr. 2002, 136,
262990.
Ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (S)-1a: [
a
]
25 = À26.9 (c 0.4,
D
CHCl3), [lit.7c
[
a]
D
25 = À21.3 (c 1.45, CHCl3)]; IR (CHCl3, cmÀ1):
mmax 3386, 3020,
1601, 1557, 1214, 1115, 928; 1H NMR (200 MHz, CDCl3): dH = 1.17 (t, J = 6.9 Hz,
3H), 1.23 (t, J = 6.9 Hz, 3H), 2.90 (d, J = 7.0 Hz, 2H), 3.32–3.44 (m, 1H), 3.53–3.65
(m, 1H), 3.98 (t, J = 6.6 Hz, 1H), 4.15 (dd, J = 14.2, 7.0 Hz, 2H), 5.09 (br s, 1H), 6.77
(d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H); MS: m/z 239 [M+H]+ 261 [M+Na]+.
Isopropyl (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (S)-1b:
[a]
D
25 = À19.4
(c 1.02 CHCl3); IR (CHCl3, cmÀ1):
m
max 3392, 3019, 2400, 1601, 1216, 1116, 928,
757; 1H NMR (200 MHz, CDCl3): dH = 1.14–1.26 (m, 9H), 2.96 (d, J = 6.6 Hz, 2H),