4734 J . Org. Chem., Vol. 65, No. 15, 2000
Notes
Thin-layer chromatography was conducted on Baker Si250F silica
gel TLC plates with a fluorescent indicator. Flash column
chromatography was carried out on Silica Gel 60 (230-400
mesh) from E. Merck Co.
Sch em e 2
Gen er a l P r oced u r e for Ar om a tic Su bstitu tion Rea ction
w ith Eth yl Glyoxa la te. To 2 mmol of an aromatic compound
and 0.1 mmol of Yb(OTf)3 in 3 mL of CH2Cl2 at room temperature
was added 2.2 mmol of a freshly distilled ethyl glyoxalate toluene
solution (Fluka). The reaction was stirred or shaken gently and
monitored using TLC. If the starting aromatic compound is not
consumed in 10 h, more ethyl glyoxalate may be added to obtain
a higher yield. The solvent was evaporated, and the crude
product was subjected to chromatographic purification with
hexanes/EtOAc (3:1 to 2:1).
r-Hyd r oxy ester 1 (84%): pale yellow oil; 1H NMR (500
MHz, CDCl3) δ 6.85 (m, 1 H), 6.83 (m, 2 H), 5.23 (s, 1 H), 4.25-
4.17 (m, 2 H), 3.78 (s, 3 H), 3.76 (s, 3 H), 2.16 (s, 1 H), 1.21 (t,
J ) 7.0 Hz, 3 H); 13C NMR (125 MHz) δ 173.8, 153.9, 151.5,
128.2, 115.4, 114.6, 112.6, 70.4, 62.0, 56.4, 56.0, 14.3; HRMS
calcd for C12H16O5 240.0998, found 240.0998.
r-Hyd r oxy ester 2 (80%): clear oil; 1H NMR (500 MHz,
CDCl3) δ 7.09-7.07 (m, 2 H), 6.79 (d, J ) 8 Hz, 1 H), 5.22 (s, 1
H), 4.25-4.16 (m, 2 H), 3.79 (s, 3 H), 3.61 (s, 1 H), 2.27 (s, 3 H),
1.20 (t, J ) 7.0 Hz, 1 H); 13C NMR (125 MHz) δ 174.0, 155.3,
130.4, 130.3, 127.1, 111.3, 70.4, 61.9, 55.8, 20.6. 14.3; HRMS
calcd for C12H16O4 224.1049, found 224.1046.
Ta ble 3. Lip a se-Med ia ted Ster eoselective
Tr a n sester ifica tion
r-Hyd r oxy ester 3 (88%): clear viscous oil; 1H NMR (500
MHz, CDCl3) δ 7.23-7.19 (m, 2 H), 6.79 (d, J ) 8.5 Hz, 1 H),
4.27-4.19 (m, 2 H), 1.28 (s, 9 H), 1.23 (t, J ) 7.0 Hz, 3 H); 13C
NMR (125 MHz) δ 173.6, 152.8, 143.4, 127.1, 126.0, 122.2, 116.9,
72.9, 62.6, 34.3, 31.7, 14.2; HRMS calcd for C14H20O4 252.1362,
found 252.1361.
r-Hyd r oxy ester 4 (90%): clear viscous oil; 1H NMR (500
MHz, CDCl3) δ 7.24 (s, 1 H), 7.11-7.09 (m, 1 H), 6.93-6.90 (m,
2 H), 5.28 (d, J ) 4.0 Hz, 1 H), 4.32-4.17 (m, 2 H), 3.76 (d, J )
4.0 Hz, 1 H), 1.28 (s, 9 H), 1.25 (t, J ) 7.2 Hz, 3 H); 13C NMR
(125 MHz) δ 173.5, 154.8, 154.0, 128.5, 119.7, 117.8, 114.8, 72.5,
62.8, 34.8, 31.4, 14.3; HRMS calcd for C14H20O4 252.1362, found
252.1363.
1
r-Hyd r oxy ester 5 (80%): white solid; mp 108-110 °C; H
NMR (300 MHz, CD3OD) δ 6.73 (d, J ) 3.0 Hz, 1 H), 6.66-6.57
(m, 2 H), 5.36 (s, 1 H), 4.22-4.16 (m, 2 H), 1.20 (t, J ) 7.2 Hz,
3 H); 13C NMR (75 MHz) δ 173.7, 150.0, 148.0, 126.1, 116.1,
115.9, 114.6, 68.7, 61.0, 13.2; HRMS calcd for C10H12O5 212.0685,
found 212.0684.
1
r-Hyd r oxy ester 6 (68%): brown viscous oil; H NMR (400
MHz, CD3OD) δ 6.96 (d, J ) 10.0 Hz, 1 H), 6.21-6.18 (m, 2 H),
5.18 (s, 1 H), 4.31-4.12 (m, 2 H), 3.29 (q, J ) 7.6 Hz, 4 H), 1.24
(t, J ) 6.4 Hz, 3 H), 1.12 (t, J ) 7.2 Hz, 6 H); 13C NMR (75
MHz) δ 174.0, 156.5, 149.7, 129.9, 111.0, 104.3, 100.3, 72.6, 62.4,
44.6, 14.3, 14.2, 12.8.
r-Hyd r oxy ester 7 (81%): clear viscous oil; 1H NMR (300
MHz, CD3OD) δ 7.14 (s, 1 H), 6.96-6.90 (m, 2 H), 6.83-6.80
(m, 1 H), 5.27 (s, 1 H), 4.32-4.20 (m, 2 H), 3.83 (s, 1 H), 1.25 (t,
J ) 7.2 Hz, 3 H); 13C NMR (75 MHz) δ 172.9, 158.1, 155.7, 151.1,
123.93, 123.86, 118.7, 118.6, 116.7, 116.5, 115.6, 115.3, 115.1,
71.9, 63.2, 14.2; HRMS calcd for C10H11FO4 214.0641, found
214.0644.
The absolute configurations of ester (S)-4e and alcohol
(R)-4 was determined by complete hydrolysis to (+)- and
(-)-2-hydroxy-2-(2-hydroxy-4-tert-butylphenyl)ethanoic
acids, which are known enantiomerically pure com-
pounds.5 The absolute configurations of the other com-
pounds were assigned via polarimetric measurements
and further confirmed by 1H NMR experiments using
chiral shifting reagents.
In conclusion, an efficient route to enantiomerically
pure hydroxylated aromatic compounds has been devel-
oped using Yb(OTf)3-catalyzed aromatic substitution
reactions followed by lipase-mediated stereoselective
transesterification. This process provides a clean, effec-
tive, and low-cost method for the preparation of a variety
of aromatic R-hydroxy acid derivatives which are an
important class of building blocks in organic synthesis.
1
r-Hyd r oxy ester 8 (82%): pale yellow viscous oil; H NMR
(500 MHz, CDCl3) δ 8.4 (s, 1 H), 8.29 (m, 1 H), 7.78 (m, 1 H).
7.50 (m, 2 H), 7.38 (d, J ) 8.5 Hz, 1 H), 7.25 (d, J ) 8.5 Hz, 1
H), 5.47 (s, 1 H), 4.29-4.22 (m, 2 H), 4.19-4.13 (m, 1 H), 1.20
(t, J ) 7.0 Hz, 3 H); 13C NMR (125 MHz) δ 173, 151.8, 134.7,
127.6, 127.1, 126.0, 125.8, 122.5, 120.0, 114.8, 73.7, 63.0, 14.2;
HRMS calcd for C14H14O4 246.0892, found 246.0890.
1
r-Hyd r oxy ester 9 (86%); purple viscous oil; H NMR (500
MHz, CDCl3) δ 8.48 (s, 1 H), 8.28 (d, J ) 7.5 Hz, 1 H), 8.18 (d,
J ) 7.5 Hz, 1 H), 7.60 (t, J ) 7.0 Hz, 1 H), 7.53 (t, J ) 7.0 Hz,
1 H), 7.36 (s, 1 H), 5.43 (s, 1 H), 4.31 (s, 1 H), 4.30-4.24 (m, 1
H), 4.22-4.16 (m, 1 H), 1.22 (t, J ) 7.5 Hz, 3 H); 13C NMR (125
MHz) δ 172.9, 150.9, 131.5, 128.1, 126.8, 126.4, 125.6, 124.3,
122.9, 114.9, 73.1, 63.3, 14.2; C14H20ClO4 280.0502, found
280.0500.
Exp er im en ta l Section
Gen er a l Meth od s. All reagents and solvents were purchased
from commercial sources and used directly without purification
or treatment unless specified otherwise. 1H and 13C NMR spectra
were recorded on a 300, or 400, or 500 MHz NMR spectrometer.
r-Hyd r oxy ester 10 (83%): clear oil; 1H NMR (500 MHz,
CDCl3) δ 6.13 (s, 1 H), 5.06 (d, J ) 7.0 Hz, 1 H), 4.33-4.22 (m,
2 H), 3.29 (d, J ) 7.0 Hz, 1 H), 2.17 (s, 3 H), 1.90 (s, 3 H), 1.27
(t, J ) 7.0 Hz, 3 H); 13C NMR (125 MHz) δ 172.0, 148.5, 148.0,