Rıos-Lombardıa et al.
JOCArticle
(m, 1H), 6.97 (t, J = 8.6 Hz, 2H), 7.09-7.18 (m, 2H), 11.68 (brs,
1H); 13C NMR (CDCl3, 75.5 MHz) δ 20.7, 34.8, 37.8, 41.1, 62.3,
115.3 (d, J = 21 Hz, 2C), 128.7 (d, J = 7 Hz, 2C), 137.9, 161.0 (d,
J = 245 Hz), 171.6, 177.7; MS (ESIþ, m/z) 277 [(M þ Na)þ,
100%]; HRMS (ESIþ) calcd for C13H15FNaO4 [(M þ Na)þ]
277.0847, found 277.0838. [R]20D þ14.2 (c 1.0, EtOH) for >99%
ee. (R)-10c (91% yield): Rf (50% EtOAc/hexane) 0.30; IR
(NaCl) ν 3220, 3023, 2961, 1740, 1711, 1515, 1370, 1241, 1161,
(m, 2H), 2.70-2.89 (m, 2H), 3.31-3.44 (m, 1H), 3.52-3.64 (m,
2H), 3.72 (s, 3H), 3.94(s, 3H), 7.02 (A0B0 system, J = 8.4 Hz, 2H),
7.31 (A0B0 system, J = 8.4 Hz, 2H); 13C NMR (MeOD, 75.5
MHz) δ 39.5, 40.3, 42.8, 52.2, 55.9, 61.0, 115.2 (2C), 129.8 (2C),
136.9, 160.1, 174.8; MS (ESIþ, m/z) 261 [(M þ Na)þ, 100%];
HRMS (ESIþ) calcd for C13H18NaO4 [(M þ Na)þ] 261.1097,
found 261.1100. [R]20D -12.7 (c 1.0, EtOH) for >99% ee.
General Procedure for the Chemical Synthesis of Racemic or
Optically Active Mosher Derivatives. To a solution of racemic or
enantiopure 6a-d (0.04 mmol) in dry CH2Cl2 (400 μL) were
successively added under nitrogen atmosphere DMAP (8 mg,
0.08 mmol) and (S)-(þ)-R-methoxy-R-trifluoromethylphenyl
acetic acid chloride (8 μL, 0.044 mmol). The mixture was stirred
for 2 h at room temperature and after this time the solvent was
evaporated under reduced pressure, obtaining a reaction crude
that was purified by flash chromatography on silica gel (20%
EtOAc/hexane) yielding the corresponding Mosher deriva-
tives as colorless oils (97-99%). R = H (98% yield): Rf (20%
EtOAc/hexane) 0.18; 1H NMR (CDCl3, 600.13 MHz) δ 1.84-
2.01 [6H, m, 2H6 þ 3H9 [isomer (R,R) þ (S,R)] þ 1H10], 2.05-
2.12 (1H, m, 1H10), 2.72-2.79 (1H, m, H5), 3.53 [3H, 2s, 3H13
isomer (R,R) þ (S,R)], 3.77-3.83 (1H, m, 1H7), 3.90-3.95 (1H,
m, 1H7), 3.97-4.07(1H, m, 1H11), 4.17-4.22 (1H, m, 1H11
isomer SR), 4.25-4.31 (1H, m, 1H11 isomer RR), 7.06 (2H,
1
1043, 816 cm-1; H NMR (CDCl3, 300.13 MHz) δ 1.77-2.10
(m, 5H), 2.31 (s, 3H), 2.65 (d, J = 7.2 Hz, 2H), 3.13-3.28 (m,
1H), 3.79-3.88 (m, 1H), 3.94-4.01 (m, 1H), 7.05-7.12 (m, 4H),
9.84 (brs, 1H); 13C NMR (CDCl3, 75.5 MHz) δ 20.7, 20.8, 34.5,
38.0, 41.1, 62.3, 127.1 (2C), 129.2 (2C), 136.3, 139.2, 171.1, 177.7;
MS (ESIþ, m/z) 273 [(M þ Na)þ, 100%]; HRMS (ESIþ) calcd for
C14H18NaO4 [(M þ Na)þ] 273.1103, found 273.1104. [R]20D þ16.5
(c 1.0, EtOH) for >99% ee. (R)-10d (89% yield): Rf (50% EtOAc/
hexane) 0.28; IR (NaCl) ν 2957, 2935, 2836, 1733, 1711, 1611,
1513, 1369, 1249, 1180, 1036, 833 cm-1; 1H NMR (CDCl3, 300.13
MHz) δ 1.75-1.93 (m, 1H), 1.95-2.13 (m, 4H), 2.55-2.68 (m,
2H), 3.12-3.23 (m, 1H), 3.72-3.86 (m, 4H), 3.91-3.99 (m, 1H),
6.81 (A0B0 system, J = 8.7 Hz, 2H), 7.08 (A0B0 system, J = 8.7 Hz,
2H), 9.95 (brs, 1H); 13C NMR (CDCl3, 75.5 MHz) δ 20.7, 34.6,
37.7, 41.3, 55.0, 62.3, 113.9 (2C), 128.1 (2C), 134.2, 158.2, 171.1,
177.6; MS (ESIþ, m/z) 289 [(M þ Na)þ, 100%]; HRMS (ESIþ)
calcd for C14H18NaO5 [(M þ Na)þ] 289.1046, found 289.1048.
[R]20D þ17.0 (c 1.0, EtOH) for >99% ee.
3
2d, JHH = 7.1 Hz, 2H3), 7.19-7.24 (1H, m, H1), 7.27-7.32
(2H, m, 2H2), 7.39-7.45 (3H, m, 2H17 þ H19), 7.48-7.52 (2H,
m, 2H18). R = F (99% yield): Rf (20% EtOAc/hexane) 0.19; 1H
NMR (CDCl3, 600.13 MHz) δ 1.80-1.95 (3H, m, 2H6 þ 1H10),
1.96-1.97 [3H, 2s, 3H9 isomer (R,R) þ (S,R)], 2.04-2.12 (1H, m,
1H10), 2.72-2.79(1H, m, H5), 3.52-3.53 [3H, 2s, 3H13 isomer (R,
R) þ (S,R)], 3.75-3.81 (1H, m, 1H7), 3.89-4.04 (2H, m, 1H7 þ
1H11), 4.17-4.22 (1H, m, 1H11 isomer SR), 4.27-4.32 (1H, m,
1H11 isomer RR), 6.95-7.07 (4H, m, 2H2 þ 2H3), 7.39-7.45 (3H,
m, 2H17 þ H19), 7.47-7.51 (2H, m, 2H18). R = Me (97% yield):
Rf (20% EtOAc/hexane) 0.18; 1H NMR (CDCl3, 600.13 MHz) δ
1.81-1.95 (3H, m, 2H6 þ 1H10), 1.96-1.99 [3H, 2s, 3H9 isomer
(R,R) þ (S,R)], 2.02-2.10 (1H, m, 1H10), 2.31-2.32 [3H, 2s, 3H20
isomer (R,R) þ (S,R)], 2.69-2.76 (1H, m, H5), 3.52-3.54 [3H, 2s,
3H13 isomer (R,R) þ (S,R)], 3.77-3.83 (1H, m, 1H7), 3.89-3.95
(1H, m, 1H7), 3.98-4.07(1H, m, 1H11), 4.17-4.22 (1H, m, 1H11
isomer SR), 4.25-4.30 (1H, m, 1H11 isomer RR), 6.95 (2H, 2d, 3J
HH = 8.1 Hz, 2H2), 7.09 (2H, t, 3J HH = 8.1 Hz, 2H3), 7.39-7.45
(3H, m, 2H17 þ H19), 7.49-7.51 (2H, m, 2H18). R = OMe (99%
yield): Rf (20% EtOAc/hexane) 0.16; 1H NMR (CDCl3, 600.13
MHz) δ 1.78-1.95 (3H, m, 2H6 þ 1H10), 1.96-1.99 [3H, 2s, 3H9
isomer (R,R) þ (S,R)], 2.01-2.10 (1H, m, 1H10), 2.67-2.75 (1H,
m, H5), 3.52 [3H, 2s, 3H13 isomer (R,R) þ (S,R)], 3.76-3.83 (4H,
m, 1H7 þ 3H20), 3.89-3.95 (1H, m, 1H7), 3.98-4.07 (1H, m,
1H11), 4.17-4.22 (1H, m, 1H11 isomer SR), 4.25-4.30 (1H, m,
1H11 isomer RR), 6.83 (2H, t, 3J HH = 8.7 Hz, 2H2), 6.98 (2H, d,
3J HH=8.7 Hz, 2H3), 7.38-7.44 (3H, m, 2H17 þ H19), 7.47-7.53
(2H, m, 2H18).
General Procedure for the Chemical Synthesis of Racemic or
Optically Active Methyl 5-Hydroxy-3-arylpentanoate (11a-d).
To a solution of racemic or optically active compound 10a-d
(0.26 mmol) in MeOH (2.6 mL) was added sodium methoxide
(83 mg, 1.53 mmol). The resulting solution was stirred for 2 h at
room temperature and then ion-exchange resin DOWEX
50WX4 (200-400 mesh) was added until almost saturation of
the organic solution. The mixture was stirred for 1 h, and then
the resin was filtered off and washed with MeOH (2 mL). The
filtrate was dried over anhydrous Na2SO4 and filtered, then the
solvent was carefully evaporated under reduced pressure to
prevent the formation of intramolecular cyclization products,
affording 11a-d as a colorless oil (88-95%). (R)-11a (94%
yield): Rf (50% EtOAc/hexane) 0.26; IR (NaCl) ν 3423, 2953,
1731, 1648, 1446, 1441, 1259, 1158, 1024, 763 cm-1; 1H NMR
(MeOD, 300.13 MHz) δ 1.90-2.14 (m, 2H), 2.71-2.89 (m, 2H),
3.35-3.60 (m, 3H), 3.68 (s, 3H), 7.30-7.51 (m, 5H); 13C NMR
(MeOD, 75.5 MHz) δ 40.1, 40.3, 42.6, 52.2, 60.9, 127.9, 128.8
(2C), 129.8 (2C), 145.1, 174.7; MS (ESIþ, m/z) 231 [(M þ Na)þ,
100%]; HRMS (ESIþ) calcd for C12H16NaO3 [(M þ Na)þ]
231.0992, found 231.0986. [R]20 -5.9 (c 1.0, EtOH) for
D
>99% ee. (R)-11b (95% yield): Rf (50% EtOAc/hexane) 0.28;
IR (NaCl) ν 3451, 3055, 2936, 1733, 1510, 1266, 1244, 1159, 734
1
cm-1; H NMR (MeOD, 300.13 MHz) δ 1.88-2.14 (m, 2H),
2.69-2.89 (m, 2H), 3.37-3.61 (m, 3H), 3.68 (s, 3H), 7.15 (t, J =
9.0 Hz, 2H), 7.36-7.41 (m, 2H); 13C NMR (MeOD, 75.5 MHz)
δ 39.5, 40.1, 42.6, 52.3, 60.7, 116.2 (d, J = 21 Hz, 2C), 130.5 (d,
J = 7 Hz, 2C), 141.0, 163.2 (d, J = 243 Hz), 174.6; MS (ESIþ,
m/z) 249 [(M þ Na)þ, 100%]; HRMS (ESIþ) calcd for C12H15
Acknowledgment. We thank Novo Nordisk Co. for the
generous gift of CAL-B (Novozyme 435) and Amano
Europe for providing us PSL-IM and PSL-SD. This work
ꢀ
was supported by the Spanish Ministerio de Educacion y
Ciencia (Projects CTQ 2007-61126) V.G.-F. thanks the
FNaO3 [(M þ Na)þ] 249.0897, found 249.0894. [R]20 -2.7
D
(c 1.0, EtOH) for >99% ee. (R)-11c (91% yield): Rf (50%
EtOAc/hexane) 0.48; IR (NaCl) ν 3419, 2952, 1730, 1649, 1445,
1441, 1260, 1158, 1025 cm-1; 1H NMR (MeOD, 300.13 MHz)
δ 1.92-2.14 (m, 2H), 2.47 (s, 3H), 2.72-2.90 (m, 2H), 3.34-
ꢀ
Spanish Ministerio de Ciencia e Innovacion (MICINN) for a
personal grant (Ramon y Cajal Program). N.R.-L. thanks
3.45 (m, 1H), 3.52-3.63 (m, 2H), 3.77 (s, 3H), 7.28 (s, 4H); 13
C
ꢀ
Gobierno regional de Asturias (FICYT) for a predoctoral
grant (Severo Ochoa Program)
NMR (MeOD, 75.5 MHz) δ 21.3, 39.9, 40.2, 42.7, 52.2, 60.9,
128.7, 130.4 (2C), 137.5, 141.9, 174.8; MS (ESIþ, m/z) 245 [(M þ
Na)þ, 100%]; HRMS (ESIþ) calcd for C13H18NaO3 [(M þ
Na)þ] 245.1154, found 245.1152. [R]20D -8.9 (c 1.0, EtOH) for
>99% ee. (R)-11d (88% yield): Rf (50% EtOAc/hexane) 0.29;
IR (NaCl) ν 3432, 2951, 1734, 1612, 1514, 1439, 1249, 1179,
Supporting Information Available: HPLC, GC methods,
and full characterization of all novel organic compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
1033, 832 cm-1; H NMR (MeOD, 300.13 MHz) δ 1.90-2.13
J. Org. Chem. Vol. 76, No. 3, 2011 819