Kinetic resolution of racemic α-tert-alkyl-α-hydroxy esters by enantiomer-selective carbamoylation

Article abstract of DOI:10.1021/jo201940w

Kinetic resolution of sterically hindered racemic α-tert-alkyl- α-hydroxy esters is performed by enantiomer-selective carbamoylation with the t-Bu-Box-Cu(II) catalyst (Box = bis-(oxazoline)). The reaction with 0.5 equiv of n-C₃H₇NCO is carried out with a substrate-to-catalyst molar ratio of 500-5000 at -20 to 25 °C. The high enantiomer-discrimination ability of the catalyst achieves an excellent stereoselectivity factor (s = k_fast/k_slow) of 261 in the best case. A catalytic cycle for this reaction is proposed (Figure presented).

Full text of DOI:10.1021/jo201940w

Note
pubs.acs.org/joc
Kinetic Resolution of Racemic α-tert-Alkyl-α-hydroxy Esters by
Enantiomer-Selective Carbamoylation
Nobuhito Kurono, Kentaro Ohtsuga, Masanori Wakabayashi, Tadahiro Kondo, Hirohito Ooka,
and Takeshi Ohkuma*
Division of Chemical Process Engineering, Faculty of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
S
* Supporting Information
ABSTRACT: Kinetic resolution of sterically hindered racemic α-tert-
alkyl-α-hydroxy esters is performed by enantiomer-selective
carbamoylation with the t-Bu-Box−Cu(II) catalyst (Box = bis-
(oxazoline)). The reaction with 0.5 equiv of n-C3H7NCO is carried
out with a substrate-to-catalyst molar ratio of 500−5000 at −20 to
25 °C. The high enantiomer-discrimination ability of the catalyst
achieves an excellent stereoselectivity factor (s = kfast/kslow) of 261 in
the best case. A catalytic cycle for this reaction is proposed.
of compounds is required from the scientific and practical
ptically active α-hydroxy esters have been widely used as
Othe intermediates and the chiral auxiliaries for the viewpoints.7
synthesis of biologically useful compounds.1,2 Kinetic
resolution of these racemic alcohols is one of the most
reliable and generally employable methods to obtain the chiral
compounds in an enantiomerically pure form (in principle),
although the chemical yield is 50% at most.2b,3,4 Many useful
asymmetric reactions including enzymatic transformations
have been developed for this purpose. To our knowledge,
however, no efficient procedures applicable to the α-tert-alkyl-
α-hydroxy esters have been reported, primarily because of the
marked steric hindrance around the hydroxy group.5 Figure 1
We recently reported the kinetic resolution of α-hydroxy γ-
lactones with the enantiomer-selective carbamoylation cata-
lyzed by the chiral bis(oxazoline) (Box)−Cu(II) com-
plexes.8−10 The racemic α-hydroxy γ-lactones smoothly reacted
with 0.5 equiv of isocyanates (RNCO) to give the carbamate
and the unreacted substrate in high ee for both compounds.
The reaction was conducted with a substrate-to-catalyst molar
ratio (S/C) of 2000−3000, and the stereoselectivity factor s
11
(kfast/kslow
)
reached 209 in the best case.8 Thus, we expected
that the high catalytic activity and enantioselectivity of the
Box−Cu(II) complex enables efficient kinetic resolution of
bulky α-tert-alkyl-α-hydroxy esters with the enantiomer-
selective carbamoylation.
Racemic methyl 2-hydroxy-3,3-dimethylbutanoate [(±)-1a]
was selected as a substrate to optimize the reaction conditions
(Table 1). When (±)-1a (5.0 mmol, 0.5 M) and 0.5 equiv of n-
C3H7NCO were mixed with [Cu{(S,S)-t-Bu-box}](OTf)2
(TfO− = trifluoromethanesulfonate) [(S,S)-3]8,12 (10 μmol,
S/C = 500) in CH2Cl2 at 25 °C, the conversion reached 50.2%
in 1 h to give the unreacted (R)-1a in 95.1% ee and the
carbamate (S)-2a in 94.4% ee (entry 1). A sufficiently high s
value of 130 was obtained. The enantiomer selectivity was
decreased with the increase of the substrate concentration
(entries 1−3). An increase of reaction temperature during the
carbamoylation under the higher substrate-concentration
conditions due to the heat of the reactions is considered to
be the main reason for the decrease in enantiomer selectivity. It
is noteworthy that the carbamoylation proceeded smoothly at
an S/C of 5000 with maintenance of a high level of
Figure 1. Bioactive molecules with structures derived from α-tert-alkyl-
α-hydroxy esters.
shows examples of bioactive molecules that have structures
derived from chiral α-tert-alkyl-α-hydroxy esters.6 Thus,
development of an efficient resolution method of this class
Received: September 20, 2011
Published: October 29, 2011
© 2011 American Chemical Society
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The Journal of Organic Chemistry
Note
a
Table 1. Carbamoylation of Racemic Methyl 2-Hydroxy-3,3-dimethylbutanoate [(±)-1a] with Chiral Cu(II) Catalyst 3
b
c
d
d
e
f
entry
temp (°C)
[1a]0 (M)
S/C
time (h)
ee1a (%)
ee2a (%)
convn (%)
s
1
25
25
25
25
25
25
0
0.5
0.8
3.4
0.5
0.5
0.5
0.5
0.8
3.4
500
500
1
1
1
1
1
2
1
1
1
1
2
3
3
6
95.1
93.8
92.3
96.6
94.8
94.4
80.5
82.1
95.4
95.8
96.0
92.6
96.4
93.6
94.4
93.9
91.3
93.7
93.3
93.3
96.8
96.7
95.6
93.2
94.8
94.6
96.6
95.7
50.2
50.0
50.3
50.7
50.4
50.3
45.4
45.9
130
112
73
2
3
500
4
1000
2000
5000
500
126
106
104
153
153
170
111
148
121
234
160
5
6
7
8
0
500
g
9
0
500
50.0
h
10
11
12
13
14
0
neat
500
50.7
50.3
49.4
49.9
49.4
0
3.4
3.4
3.4
3.4
1000
2000
500
0
−20
−20
1000
a
b
Unless otherwise stated, reactions were conducted using (±)-1a (1−5 mmol) and 0.5 equiv of n-C3H7NCO in CH2Cl2 containing (S,S)-3. Initial
c
d
e
f
concentration of 1a. Substrate-to-catalyst molar ratio. Determined by chiral GC analysis. Convn = ee1a/(ee1a + ee2a). s = ln[(1 − convn)(1 −
g
h
ee1a)]/ln[(1 − convn)(1 + ee1a)]. Isolated yields of (R)-1a and (S)-2a are 45% and 50%, respectively. Reaction without solvent.
enantioselectivity (s > 100), although superior enantiomer
discrimination was available in the reactions under lower S/C
conditions (entries 4−6). The reaction at 0 °C with an initial
substrate concentration of 0.5 M showed enantioselectivity
higher than that observed at 25 °C (s value, 153 vs 130)
(entries 1 and 7). Interestingly, the higher substrate-
concentration condition of 3.4 M resulted in even better
enantiomer discrimination, although the reason for this result
was not clear (entries 7−9). The carbamoylation without
solvent still afforded very high enantioselectivity (s = 111)
(entry 10). This feature has benefit for application to practical
and green synthesis. The kinetic resolution ([1a]0 = 3.4 M) at 0
°C with an S/C of 1000 or 2000 still exhibited a high level of
enantioselectivity and reactivity (entries 11 and 12). A
remarkably high enantiomer selectivity (s = 234 at S/C =
500, s = 160 at S/C = 1000) was obtained in the reaction at
−20 °C (entries 13 and 14).
The kinetic resolution of a series of α-tert-alkyl-α-hydroxy
esters 1 by using enantiomer-selective carbamoylation with the
Cu(II) catalyst (S,S)-3 (S/C = 500) at 0 °C was examined. The
results are summarized in Table 2. The initial substrate
concentration ([1]0) was set at 2.9−3.4 M, except for the
hardly soluble compounds 1g, 1h, and 1i in CH2Cl2. 2-
Hydroxy-3,3-dimethylbutanoates with a methyl, ethyl, iso-
propyl, or tert-butyl ester moiety, (±)-1a−1d, smoothly reacted
with 0.5 equiv of n-C3H7NCO in 1 h to give the R-enriched
substrates (R)-1a−1d and the corresponding S carbamates (S)-
2a−2d in high ee (entries 1−4). The s values in the range of
153−195 suggest that the size of the ester group (CO2R3) is
not a decisive factor for the enantiomer selection. A high s value
of 182 was obtained in the carbamoylation of the substrate with
an even bulkier α-[dimethyl(phenyl)]methyl group (±)-1e,
although it took a longer period to reach 50% conversion
(entry 5). The α-tert-alkyl structure of the substrates is crucial
to achieve high enantioselectivity. Thus, the s values of the
reactions with the α-isopropyl- and α-(diphenyl)methyl-
substituted hydroxy esters, (±)-1f and -1g, were only 12 and
29, respectively (entries 6 and 7). In contrast, much higher
enantioselectivity (s = 261) was observed in the reaction of the
α-[methyl(diphenyl)]methyl substrate (±)-1h (entry 8). The
kinetic resolution using 50 mmol (13.5 g) of (±)-1h and a 0.6
equiv of n-C3H7NCO was conducted to obtain enantiomeri-
cally pure (R)-1h (entry 9). The R alcohol in >99.9% ee (6.3 g)
was obtained at 53% conversion (see the Experimental
Section). (R)-1h is known to be readily converted to the
enantiomer of an endothelin receptor antagonist BSF302146
(see Figure 1).6a The s value of 21 for the α-[methoxy-
(diphenyl)]methyl substrate (±)-1i was much lower than that
in the reaction of (±)-1h (s = 261), although the bulkiness of
both α-substituents is similar (entries 8 and 10). The β-
methoxy function of 1i may coordinatively interact with the
Cu(II) center of the catalyst 3, resulting in the insufficient
enantiomer discrimination. The α-hydroxy ester with a 1-
methylcyclohexyl group at the α position (±)-1j was also
kinetically resolved with high enantioselectivity (entry 11).
A proposed mechanism for the carbamoylation of α-hydroxy
esters catalyzed by Box−Cu(II) complexes is shown in Scheme
1.8 [Cu(Box)](OTf)2 (A) liberates the counteranion, TfO−, to
become the solvated cationic species [Cu(Box)Sn]2+ (B) in the
reaction mixture. The weakly binding molecules (S) are
replaced by an α-hydroxy ester (HE) to form a chelation
complex C. The species C reacts with RNCO to afford the
carbamate (CAR)−Cu(II) complex D. The mode of
carbamoylation at the stage of C to D is not clear yet. Catalytic
species B and/or C are regenerated with release of the
carbamate. The three cationic species, B, C, and D, could be in
equilibrium. The HE−Cu(II) species C with a rigid five-
membered chelate structure is more stable than the solvated
complex B and the CAR−Cu(II) complex D with a seven-
membered chelate structure, so that this reaction proceeds
without serious product inhibition and achieves a high turnover
number. The carbamoylation is one of the addition reactions
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Note
a
Table 2. Carbamoylation of Racemic α-Hydroxy Esters (±)-1 with Chiral Cu(II) Catalyst 3
b
c
c
d
e
f
entry
1
[1]0 (M)
time (h)
ee1 (%)
ee2 (%)
convn (%)
yield of 1/2 (%)
s
1
1a
1b
1c
1d
1e
1f
3.4
3.2
2.9
2.9
3.4
3.0
1
1
95.4 (R)
96.8 (R)
96.0 (R)
97.2 (R)
97.2 (R)
71.8
95.6 (S)
94.7 (S)
95.3 (S)
95.7 (S)
95.4 (S)
69.1
50.0
50.5
50.2
50.4
50.5
51.0
49.7
49.9
52.8
37.5
49.9
45/50
48/46
42/49
47/45
43/50
45/46
45/43
48/50
47/ −
53/32
50/45
170
153
164
195
182
12
2
3
1
4
1
5
3
6
1
g
7
1g
1h
1h
1i
1.9
2
82.7
83.7
29
8
0.8
0.8
1.7
3.4
12
6
96.6 (R)
>99.9 (R)
51.4
96.9 (S)
89.5 (S)
85.5
261
h
i
9
nd
10
11
3
21
1j
3
94.6 (R)
95.1 (S)
146
a
Unless otherwise stated, reactions were conducted using (±)-1 (1−5 mmol) and 0.5 equiv of n-C3H7NCO at 0 °C in CH2Cl2 containing
b
c
(S,S)-3. S/C = 500. Initial concentration of 1. Determined by chiral GC analysis. Absolute configurations of 1 and 2 are indicated in the
parentheses. Convn = ee1/(ee1 + ee2). Isolated yield. s = ln[(1 − convn)(1 − ee1)]/ln[(1 − convn)(1 + ee1)]. The approximate number is
shown, because 1g is a solid substrate. Reaction using 50 mmol of 1h and 0.6 equiv of n-C3H7NCO. This value is not available, because the ee1
d
e
f
g
h
i
value is almost 1.
but not a substitution reaction. Therefore, there is no leaving
anion that inhibits the catalytic performance of Cu(II) cationic
species.
in high ee. The reaction was carried out with an S/C in the
range of 500−5000 under a high concentration of substrates
(ca. 3 M or without solvent). A remarkably high s value (kfast/
In conclusion, the t-Bu-Box−Cu(II)-catalyzed carbamoylation
precisely discriminates two enantiomers of α-tert-alkyl-α-hydroxy
esters to give the unreacted hydroxy esters and the carbamates
kslow) of 261 is observed in the best case. A series of such
sterically hindered chiral α-hydroxy esters, which are difficult
compounds to prepare by other methods, is obtained through
the enantiomer-selective reaction. The performance of a
multigram-scale reaction demonstrates the facility for scale up
of this process. A plausible catalytic cycle for this reaction is also
described.
Scheme 1. Proposed Mechanism for the Cu(II)-Catalyzed
a
Carbamoylation of α-Hydroxy Esters
EXPERIMENTAL SECTION
■
General Remarks. Racemic hydroxy esters 1a−1g and 1j were
prepared via cyanosilylation of the corresponding aldehydes followed
by hydrolysis of the nitrile moiety and esterification with N,N′-
diisopropyl-O-alkylisourea reagents.13 (±)-1h and 1i were prepared in
accordance with the literature.14 (S)-2,2-Isopropylidene-bis(4-tert-
butyl-2-oxazoline) was purchased from a commercial source and
used without further purification. Racemic carbamates 2a−2i were
prepared as described in the literature.15 n-Propyl isocyanate and
anhydrous Cu(OTf)2 were purchased from a commercial source.
Anhydrous THF and CH2Cl2 were purchased from a commercial
source and used without further purification. For preparative column
chromatography and thin layer chromatography, commercially
available silica gel (100−210 mm) and precoated TLC (silica gel,
1.0 mm) were used, respectively. NMR spectra were recorded on two
a
types of spectrometer: 270 MHz for H NMR, 67.8 MHz for 13C
1
HE = α-hydroxy ester, CAR = carbamate, S = solvent or weakly
1
NMR; and 400 MHz for H NMR, 100 MHz for 13C NMR. The
coordinated compounds.
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Note
chemical shifts were reported downfield from TMS (δ = 0 ppm) for
C12H23NO4: C, 58.75, H, 9.45, N, 5.71. Found: C, 58.98, H, 9.67, N,
5.64; HRMS (ESI): m/z calcd 268.1519 [M + Na+], obsd 268.1518;
Chiral GC analysis: column, CP-Chirasil-Dex; carrier gas, helium
(72 kPa); initial column temp, 80 °C (11 min) to 150 °C (8.5 min) at
a rate of 10 °C min−1; tR of (S)-2b: 23.7 min, tR of (R)-2b: 24.2 min;
95% ee.
1H NMR. For 13C NMR, chemical shifts were reported in the scale
relative to the solvent used as an internal reference. High-pressure
liquid chromatography (HPLC) analysis, gas chromatography (GC)
analysis, IR spectra, optical rotations, and melting points (mps) were
measured on standard commercial equipments.
(R)-Isopropyl 2-Hydroxy-3,3-dimethylbutanoate [(R)-1c]. 42%
yield (337 mg, colorless oil); Rf = 0.36 (eluent, n-hexane/ethyl
Typical Procedure for Enantiomer-Selective Carbamoyla-
tion of Racemic Methyl 2-Hydroxy-3,3-dimethylbutanoate
[(±)-1a]. [Cu{(S,S)-t-Bu-box}](OTf)2 [(S,S)-3] was prepared by
the method described in a previous report.8 Freshly distilled (±)-1a
(731 mg, 5.00 mmol) was placed in an oven-dried 20-mL Schlenk flask
equipped with a Teflon-coated magnetic stirring bar, a serum-rubber
cap, and a rubber balloon filled with argon. The 20 mM CH2Cl2
solution of (S,S)-3 (0.50 mL, 10 μmol) was added to this flask through
a syringe filter unit (pore size of 450 nm) to remove turbidity. The
resulting solution was stirred for 10 min at 0 °C. To this solution was
added n-C3H7NCO (0.23 mL, 2.5 mmol), and the reaction mixture
was stirred at 0 °C for 1 h. Methanol (1 mL) was added to the mixture,
and it was concentrated under reduced pressure. The residue was
passed through a silica gel pad eluted with ethyl acetate to remove
metal components, affording a mixture of recovered (R)-1a and the
carbamate (S)-2a. The ee values of 1a and 2a, ee1a and ee2a,
respectively, were determined by GC analysis. The conversion was
estimated by the following equation: convn = ee1a/(ee1a + ee2a).11 The
estimated conversion value agreed well with that determined by GC
analysis using tetralin as an internal standard. The stereoselectivity
factor (s = kfast/kslow) was calculated by the following equation: s =
ln[(1 − convn)(1 − ee1a)]/ln[(1 − convn)(1 + ee1a)].11
acetate = 6:1); [α]22 −24.4 (c 1.04, CHCl3); IR (KBr) 3515, 2981,
D
1721 cm−1; 1H NMR (270 MHz, CDCl3) δ 0.98 (s, 9H), 1.30 (d, 6H,
J = 6.3 Hz), 2.81 (d, 1H, J = 7.4 Hz), 3.75 (d, 1H, J = 7.4 Hz), 5.13
(hept, 1H, J = 6.3 Hz); 13C NMR (67.7 MHz, CDCl3) δ 21.6, 21.7,
25.7, 35.1, 69.0, 78.2, 173.7; HRMS (ESI): m/z calcd 197.1148 [M +
Na+], obsd 197.1151; Chiral GC analysis: column, CP-Chirasil-Dex;
carrier gas, helium (58 kPa); column temp 80 °C (16 min) to 100 °C
at a rate of 10 °C min−1; tR of (S)-1c: 16.9 min, tR of (R)-1c: 17.2 min;
96% ee.
(S)-Isopropyl 3,3-Dimethyl-2-propylaminocarbonyloxybutanoate
[(S)-2c]. 49% yield (587 mg, colorless oil), Rf = 0.17 (eluent,
n-hexane/ethyl acetate = 6:1); [α]23 +8.31 (c 1.08, CHCl3); IR
D
1
(KBr) 3383, 2966, 2876, 1732 cm−1; H NMR (270 MHz, CDCl3) δ
0.93 (t, 3H, J = 7.6 Hz), 1.02 (s, 9H), 1.25 (d, 3H, J = 6.2 Hz),1.28 (d,
3H, J = 6.2 Hz), 1.47−1.57 (m, 2H), 3.15 (q, 2H, J = 6.8 Hz), 4.54 (s,
1H), 4.87 (br s, 1H), 5.09 (hept, 1H, J = 6.2 Hz); 13C NMR (67.8
MHz, CDCl3) δ 11.1, 21.6, 21.7, 23.0, 26.2, 33.6, 42.7, 68.3, 80.0,
155.9, 169.4; Anal. Calcd for C13H25NO4: C, 60.21, H, 9.72, N, 5.40.
Found: C, 60.13, H, 10.03, N, 5.43; HRMS (ESI): m/z calcd 282.1676
[M + Na+], obsd 282.1673; Chiral GC analysis: column, CP-Chirasil-
Dex; carrier gas, helium (72 kPa); initial column temp, 80 °C (16 min)
to 150 °C (11 min) at a rate of 10 °C min−1; tR of (S)-2c: 30.6 min, tR
of (R)-2c 31.5 min; 95% ee.
(R)-Methyl 2-Hydroxy-3,3-dimethylbutanoate [(R)-1a]. 45% yield
(333 mg, colorless oil); Rf = 0.21 (eluent, n-hexane/ethyl acetate =
8:1); [α]23 −35.5 (c 0.96, CHCl3) (lit.14 [α]22 +40.4 (c 3.22,
D
D
CHCl3), 97% ee (S)); IR (KBr) 3516, 2958, 1733 cm−1; H NMR
(400 MHz, CDCl3) δ 0.97 (s, 9H), 2.74 (d, 1H, J = 8.0 Hz), 3.79
(s, 3H), 3.82 (d, 1H, J = 8.0 Hz); 13C NMR (67.8 MHz, CDCl3) δ
25.7, 35.1, 51.9, 78.4, 174.7; HRMS (ESI): m/z calcd 169.0841, [M +
Na+], obsd 169.0838; Chiral GC analysis: column, CP-Chirasil-Dex
(0.32 mm × 25 m); carrier gas, helium (72 kPa); column temp, 80 °C;
retention time (tR) of (R)-1a: 8.8 min, tR of (S)-1a: 10.2 min; 95% ee.
(S)-Methyl 3,3-Dimethyl-2-propylaminocarbonyloxybutanoate
[(S)-2a]. 50% yield (577 mg, colorless oil); Rf = 0.07 (eluent, n-
(R)-tert-Butyl 2-Hydroxy-3,3-dimethylbutanoate [(R)-1d]. 47%
1
yield (93 mg, colorless oil); Rf = 0.34 (eluent, n-hexane/ethyl acetate
= 10:1); [α]23 −19.7 (c 0.93, CHCl3); IR (KBr) 3510, 2979, 1719,
D
cm−1; 1H NMR (400 MHz, CDCl3) δ 0.97 (s, 9H), 1.50 (s, 9H), 2.86
(d, 1H, J = 8.0 Hz), 3.67 (d, 1H, J = 8.0 Hz); 13C NMR (67.8 MHz,
CDCl3) δ 25.9, 28.0, 35.3, 78.4, 82.4, 173.9; HRMS (ESI): m/z calcd
211.1305 [M + Na+], obsd 211.1308; Chiral GC analysis: column, CP-
Chirasil-Dex; carrier gas, helium (72 kPa); column temp, 100 °C; tR of
(S)-1d: 6.9 min, tR of (R)-1d: 7.2 min; 97% ee.
hexane/ethyl acetate = 8:1); [α]23 +13.8 (c 1.03, CHCl3); IR (KBr)
(S)-tert-Butyl 3,3-Dimethyl-2-propylaminocarbonyloxybutanoate
D
3376, 2964, 2876, 1730 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.93 (t,
3H, J = 6.0 Hz), 1.01 (s, 9H), 1.54 (sext, 2H, J = 6.0 Hz), 3.15 (q, 2H,
J = 6.0 Hz), 4.61 (s, 1H), 4.89 (br s, 1H); 13C NMR (67.8 MHz,
CDCl3) δ 11.0, 22.9, 26.0, 33.5, 42.6, 51.4, 79.8, 155.8, 170.5; Anal.
Calcd for C11H21NO4: C, 57.12, H, 9.15, N, 6.06, Found: C, 56.84, H,
9.12, N, 6.01; HRMS (ESI): m/z calcd 254.1368 [M + Na+], obsd
254.1371; Chiral GC analysis: column, CP-Chirasil-Dex; carrier gas,
helium (72 kPa); initial column temp, 80 °C (11 min) to 140 °C
(8.5 min) at a rate of 10 °C min−1; tR of (S)-2a: 23.8 min, tR of (R)-2a:
24.7 min; 96% ee.
[(S)-2d]. 45% yield (131 mg, colorless oil), Rf = 0.13 (eluent,
n-hexane/ethyl acetate =10:1); [α]23 +7.31 (c 1.31, CHCl3); IR
D
(KBr) 3394, 2967, 2875, 1728, 1712 cm−1
;
1H NMR (400 MHz,
CDCl3) δ 0.92 (t, 3H, J = 7.4 Hz), 1.01 (s, 9H), 1.45−1.63 (m, 11H),
3.15 (q, 2H, J = 6.4 Hz), 4.47 (s, 1H), 4.86 (br s, 1H); 13C NMR
(67.8 MHz, CDCl3) δ 11.1, 23.1, 26.3, 28.0, 33.6, 42.7, 80.2, 81.4,
156.0, 169.1; Anal. Calcd for C14H27NO4: C, 61.51, H, 9.96, N, 5.12,
Found: C, 61.10, H, 10.01, N, 5.10; HRMS (ESI): m/z calcd 296.1832
[M + Na+], obsd 296.1827; Chiral GC analysis: column, CP-Chirasil-
Dex; carrier gas, helium (72 kPa); column temp, 100 °C (10 min) to
150 °C (7 min) at a rate of 10 °C min−1; tR of (S)-2d: 20.8 min, tR of
(R)-2d: 21.3 min; 96% ee.
(R)-Ethyl 2-Hydroxy-3,3-dimethylbutanoate [(R)-1b]. 48% yield
(389 mg, colorless oil); Rf = 0.39 (eluent, n-hexane/ethyl acetate =
6:1); [α]27 −25.3 (c 1.05, CHCl3) (lit.6d [α]25 = −84 (c 1,
(R)-Methyl 2-Hydroxy-3-methyl-3-phenylbutanoate [(R)-1e]. 43%
D
365
CH3OH), >95% ee (R)); IR (KBr) 3513, 2959, 1727 cm−1; 1H NMR
(400 MHz, CDCl3) δ 0.98 (s, 9H), 1.32 (t, 3H, J = 7.2 Hz), 2.78 (d,
1H, J = 7.6 Hz), 3.79 (d, 1H, J = 7.6 Hz), 4.19−4.33 (m, 2H); 13C
NMR (67.8 MHz, CDCl3) δ 14.2, 25.7, 35.2, 61.2, 78.3, 174.3; HRMS
(ESI): m/z calcd 183.0992 [M + Na+], obsd 183.0995; Chiral GC
analysis: column, CP-Chirasil-Dex; carrier gas, helium (72 kPa);
column temp, 80 °C (11 min) to 110 °C at a rate of 10 °C min−1; tR of
(R)-1b: 12.9 min, tR of (S)-1b: 13.3 min; 97% ee.
yield (90.4 mg, colorless oil); Rf = 0.39 (eluent, n-hexane/ethyl acetate
= 4:1); [α]24 −43.2 (c 0.550, CHCl3); IR (KBr) 3507, 2971, 2881,
D
1732 cm−1; 1H NMR (270 MHz, CDCl3) δ 1.42 (s, 3H), 1.46 (s, 3H),
2.70 (d, 1H, J = 7.3 Hz), 3.60 (s, 3H), 4.22 (d, 1H, J = 7.3 Hz), 7.23−
7.37 (m, 5H); 13C NMR (67.8 MHz, CDCl3) δ 24.5, 24.6, 42.3, 51.9,
78.6, 126.3, 126.4, 128.0, 144.8, 173.9; Anal. Calcd for C12H16O3: C,
69.21, H, 7.74, Found: C, 68.93, H, 7.78; HRMS (ESI): m/z calcd
231.0990 [M + Na+], obsd 231.0992; Chiral HPLC analysis: column,
CHIRALPAK AS-H (0.46 cm × 25 cm); eluent, n-hexane/2-propanol
= 90:10; flow, 0.5 mL min−1; column temp, 40 °C; detection, UV 254
nm; tR of (R)-1e: 11.5 min, tR of (S)-1e: 9.3 min; 97% ee.
(S)-Methyl 3,3-Dimethyl-2-propylaminocarbonyloxybutanoate
[(S)-2b]. 46% yield (572 mg, colorless oil); Rf = 0.17 (eluent,
n-hexane/ethyl acetate = 6:1); [α]28 +9.25 (c 1.02, CHCl3); IR
D
1
(KBr) 3377, 2965, 2875, 1731 cm−1; H NMR (400 MHz, CDCl3) δ
(S)-Methyl 3-Methyl-3-phenyl-2-propylaminocarbonyloxybuta-
0.92 (t, 3H, J = 7.4 Hz), 1.02 (s, 9H), 1.28 (t, 3H, J = 7.2 Hz), 1.49−
1.59 (m, 2H), 3.15 (q, 2H, J = 6.6 Hz), 4.15−4.28 (m, 2H), 4.59
(s, 1H), 4.88 (br s, 1H); 13C NMR (67.8 MHz, CDCl3) δ 11.0, 14.0,
23.0, 26.1, 33.5, 42.6, 60.6, 79.9, 155.9, 170.0; Anal. Calcd for
noate [(S)-2e]. 50% yield (150 mg, colorless oil); Rf = 0.25 (eluent,
n-hexane/ethyl acetate = 4:1); [α]24 +40.4 (c 0.93, CHCl3); IR
D
1
(KBr) 3372, 2967, 2876, 1729 cm−1; H NMR (400 MHz, CDCl3) δ
0.88 (t, 3H, J = 7.6 Hz), 1.42 (s, 3H), 1.45−1.50 (m, 5H), 3.09 (q, 2H,
10315
dx.doi.org/10.1021/jo201940w|J. Org. Chem. 2011, 76, 10312−10318

The Journal of Organic Chemistry
Note
J = 6.8 Hz), 3.56 (s, 3H), 4.78 (br s, 1H), 5.09 (s, 1H), 7.21−7.38 (m,
10H); 13C NMR (100 MHz, CDCl3) δ 11.0, 22.9, 24.5, 24.8, 40.5,
42.6, 51.5, 79.5, 126.1, 126.4, 127.9, 144.9, 155.5, 170.1; HRMS (ESI):
m/z calcd 316.1519 [M + Na+], obsd 316.1515; Chiral HPLC
analysis: column, CHIRALPAK AS-H; eluent, n-hexane/2-propanol =
90:10; flow, 0.5 mL min−1; column temp, 40 °C; detection, UV 254
nm; tR of (R)-2e: 8.8 min, tR of (S)-2e: 10.0 min; 95% ee.
column temp, 40 °C; detection, UV 254 nm; tR of (S)-1h: 13.3 min, tR
of (R)-1h: 15.0 min; 97% ee.
(S)-Methyl 3,3-Diphenyl-2-propylaminocarbonyloxybutanoate
[(S)-2h]. 50% yield (893 mg, colorless solid); Rf = 0.21 (eluent,
n-hexane/ethyl acetate =4:1); [α]24 +206 (c 0.99, CHCl3); Mp 99−
D
101 °C; IR (KBr) 3401, 3088, 3061, 3028, 2963, 2878, 1729 cm−1; 1H
NMR (400 MHz, CDCl3) δ 0.79−0.82 (br m, 3H), 0.90 (t, 3H, J = 8.0
Hz), 1.34−1.41 (br m, 2H), 1.46−1.57 (m, 2H), 1.88 (s, 3H), 2.99−
3.02 (br m, 2H), 3.08−3.21 (m, 2H), 3.31 (s, 3H), 4.63 (br s, 1H),
4.86 (br s, 1H), 5.71 (s, 1H), 7.11−7.32 (m, 10H); 13C NMR (67.8
MHz, CDCl3) δ 11.0, 22.9, 23.5, 42.7, 49.1, 51.5, 77.2, 126.3, 126.4,
127.5, 127.7, 127.8, 127.9, 145.1, 145.4, 155.4, 170.0; Anal. Calcd for
C21H25NO4: C, 70.96, H, 7.09, N, 3.94. Found: C, 70.64, H, 7.15, N,
3.91; HRMS (ESI): m/z calcd 378.1676 [M + Na+], obsd 378.1676;
Chiral HPLC analysis: column, CHIRALPAK IA; eluent, n-hexane/2-
propanol = 90:10; flow, 0.5 mL min−1; column temp, 40 °C; detection,
UV 254 nm; tR of (S)-2h: 11.3 min, tR of (R)-2h: 13.8 min; 97% ee.
(−)-Methyl 2-Hydroxy-3-methoxy-3,3-diphenylpropanoate
[(−)-1i]. 53% yield (151 mg, colorless solid); Rf = 0.22 (eluent, n-
(−)-tert-Butyl 2-Hydroxy-3-methylbutanoate [(−)-1f]. 45% (94
mg, colorless oil); Rf = 0.53 (eluent, n-hexane/ethyl acetate = 6:1);
[α]25D −4.4 (c 0.31, CHCl3); IR (KBr) 3515, 2964, 2876, 1721 cm−1
;
1H NMR (270 MHz, CDCl3) δ 0.86 (d, 3H, J = 4.5 Hz), 1.02 (d, 3H, J
= 6.9 Hz), 1.49 (s, 3H), 2.01−2.08 (m, 1H), 2.75 (d, 1H, J = 5.9 Hz),
3.92 (dd, 1H, J = 3.3 Hz, 5.9 Hz); 13C NMR (67.8 MHz, CDCl3) δ
15.7, 18.7, 27.9, 32.0, 74.8, 82.0, 174.1; HRMS (ESI): m/z calcd
197.1148 [M + Na+], obsd 197.1152; Chiral GC analysis: column, CP-
Chirasil-Dex; carrier gas, herium (72 kPa); column temp, 100 °C; tR of
major 1f: 6.3 min, tR of minor 1f: 5.8 min; 72% ee.
(+)-tert-Butyl 3-Methyl-2-propylaminocarbonyloxybutanoate
[(+)-2f]. 46% (142 mg, colorless oil); Rf = 0.35 (eluent, n-hexane/
hexane/ethyl acetate =6:1); [α]23 −9.00 (c 1.36, CHCl3); Mp 97−
ethyl acetate = 6:1); [α]26 +1.6 (c 1.28, CHCl3); IR (KBr) 3389,
D
D
100 °C; IR (KBr) 3498, 3059, 3026, 2951, 2833, 1732 cm−1; 1H NMR
(270 MHz, CDCl3) δ 2.95 (d, 1H, J = 8.1 Hz), 3.15 (s, 3H), 3.62 (s,
3H), 5.17 (d, 1H, J = 8.1 Hz), 7.28−7.43 (m, 10 H); 13C NMR (67.8
MHz, CDCl3) δ 52.2 (two signals), 73.7, 84.8, 127.4, 127.56, 127.59,
127.7, 128.4, 128.8, 139.8, 140.5, 172.7, Anal. Calcd for C17H18O4: C,
71.31, H, 6.34. Found: C, 71.36, H, 6.42; HRMS (ESI): m/z calcd
309.1097 [M + Na+], obsd 309.1099; Chiral HPLC analysis: column,
CHIRALPAK IA; eluent, n-hexane/2-propanol = 90:10; flow, 0.5 mL
min−1; column temp, 40 °C; detection, UV 254 nm; tR of minor 1i:
11.4 min, tR of major 1i: 13.0 min; 51% ee.
1
2967, 2876, 1728, 1519 cm−1; H NMR (270 MHz, CDCl3) δ 0.91−
1.00 (m, 9H), 1.47 (s, 9H), 1.51−1.57 (m, 2H), 2.13−2.21 (m, 1H),
3.16 (q, 2H, J = 6.7 Hz), 4.72 (d, 1H, J = 4.3 Hz), 4.86 (br s, 1H); 13
C
NMR (67.8 MHz, CDCl3) δ 11.2, 17.1, 18.7, 23.1, 28.0, 30.2, 42.7,
76.9, 81.5, 156.0, 169.7; HRMS (EI): m/z calcd 260.1862 [M + H+],
obsd 260.1871; Chiral HPLC analysis: column CHIRALPAK AD-H
(0.46 cm × 25 cm), eluent, n-hexane/2-propanol = 97:3, flow, 1.0 mL
min−1, column temp, 40 °C; detection, UV 230 nm; tR of major 2f: 7.5
min, tR of minor 2f: 6.8 min; 69% ee.
(+)-Methyl 2-Hydroxy-3,3-diphenylpropanoate [(+)-1g]. 45%
yield (115 mg, colorless solid); Rf = 0.17 (eluent, n-hexane/ethyl
acetate = 6:1); [α]24D +27.2 (c 0.74, CHCl3); Mp 62−64 °C; IR (KBr)
(+)-Methyl 3-Methoxy-3,3-diphenyl-2-propylaminocarbonyloxy-
propanoate [(+)-2i]. 32% yield (119 mg, colorless wax); Rf = 0.08
(eluent, n-hexane/ethyl acetate = 6:1); [α]24D +90.1 (c 1.10, CHCl3);
1
3487, 3028, 2950, 2923, 1737 cm−1; H NMR (270 MHz, CDCl3) δ
1
IR (KBr) 3370, 3060, 2963, 2876, 2840, 1729 cm−1; H NMR (400
2.77 (d, 1H, J = 6.5 Hz), 3.70 (s, 3H), 4.49 (d, 1H, J = 3.8 Hz), 4.94
(dd, 1H, J = 3.8 Hz, 6.5 Hz), 7.20−7.43 (m, 10H); 13C NMR (67.8
MHz, CDCl3) δ 52.5, 54.2, 73.4, 126.5, 126.7, 127.1, 128.36, 128.38,
128.5, 129.3, 138.9, 141.2, 174.1; Anal. Calcd for C16H16O3: C, 74.98,
H, 6.29. Found: C, 74.93, H, 6.47; HRMS (ESI): m/z calcd 279.0992
[M + Na+], obsd 279.0988; Chiral HPLC analysis: column,
CHIRALCEL OD-H (0.46 cm × 25 cm); eluent, n-hexane/2-
propanol = 90:10; flow, 0.5 mL min−1; column temp, 40 °C; detection,
UV 254 nm; tR of minor 1g: 15.9 min, tR of major 1g: 17.5 min;
83% ee.
MHz, CDCl3) δ 0.75−0.79 (br m, 3H), 0.90 (t, 3H, J = 8.0 Hz),
1.20−1.27 (br m, 2H), 1.47−1.54 (m, 2H), 2.92−2.97 (br m, 2H),
3.08−3.22 (m, 2H), 3.28 (s, 3H), 3.31 (s, 3H), 3.52 (s, 3H), 4.62 (br
s, 1H), 4.78 (br s, 1H), 5.99 (s, 1H), 7.28−7.33 (m, 10H); 13C NMR
(67.8 MHz, CDCl3) δ 11.0, 22.9, 42.8, 51.8, 52.9, 75.6, 83.5, 127.41,
127.47, 127.54, 127.7, 127.9, 128.1, 140.6, 141.2, 155.0, 168.7; HRMS
(ESI): m/z calcd 394.1625 [M + Na+], obsd 394.1627; Chiral HPLC
analysis: column, CHIRALCEL OD-H; eluent, n-hexane/2-propanol =
90:10; flow, 0.5 mL min−1; column temp, 40 °C; detection, UV 254
nm; tR of major 2i: 13.4 min, tR of minor 2i: 16.9 min; 85% ee.
(R)-Methyl 2-Hydroxy-3,3-pentamethylenebutanoate [(R)-1j]. 50%
yield (92.1 mg, colorless oil); Rf = 0.37 (eluent, n-hexane/ethyl
(−)-Methyl 3,3-Diphenyl-2-propylaminocarbonyloxypropanoate
[(−)-2g]. 43% yield (144 mg, colorless wax); Rf = 0.10 (eluent, n-
hexane/ethyl acetate = 6:1); [α]24 +77.3 (c 1.21, CHCl3); IR (KBr)
D
1
3374, 3066, 3028, 2963, 1730 cm−1; H NMR (400 MHz, CDCl3) δ
acetate = 4:1); [α]23 −27.5 (c 0.48, CHCl3), IR (KBr) 3508, 2927,
D
2856, 1732 cm−1; 1H NMR (400 MHz,CDCl3) δ 0.88 (s, 3H), 1.30−
1.55 (m, 10H), 2.68 (d, 1H, J = 8.0 Hz), 3.79 (s, 3H), 3.96 (d, 1H, J =
8.0 Hz); 13C NMR (67.8 MHz, CDCl3) δ 19.4, 21.59, 21.61, 26.1,
33.7, 34.0, 37.9, 52.0, 77.6, 175.0; HRMS(ESI): m/z calcd for
C10H18O3: 209.1148 [M + Na+], obsd 209.1150; Chiral GC analysis:
column, CP-Chirasil-Dex; carrier gas, helium (80 kPa); column temp,
80 to 130 °C at a rate of 0.5 °C min−1; tR of (R)-1j: 50.9 min, tR of
(S)-1j: 52.0 min; 95% ee.
0.76−0.79 (br m, 3H), 0.86 (t, 3H, J = 7.4 Hz), 1.32 (br m, 2H), 1.47
(sext, 2H, J = 7.4 Hz), 2.96−3.01 (br m, 2H), 3.09 (q, 2H, J = 7.4 Hz),
3.49 (s, 3H), 3.51 (s, 3H), 4.55 (d, 1H, J = 7.4 Hz), 4.63−4.64 (m,
1H), 4.78 (br s, 1H), 5.72 (d, 1H, J = 7.4 Hz), 7.20−7.31 (m, 10H);
13C NMR(100 MHz, CDCl3) δ 11.1, 23.0, 42.8, 52.0, 52.5, 74.6, 126.9,
127.0 (two signals), 128.4, 128.7, 139.5, 139.6, 155.3, 170.7; Anal.
Calcd for C20H23NO4: C, 70.36, H, 6.79, N, 4.10. Found: C, 70.33,
H, 6.88, N, 4.10; HRMS (ESI): m/z calcd 364.1519 [M + Na+],
obsd 364.1515; Chiral HPLC analysis: column, CHIRALCEL OD-H;
eluent, n-hexane/2-propanol = 90:10; flow, 0.5 mL min−1; column
temp, 40 °C; detection, UV 254 nm; tR of minor 2g: 8.8 min, tR of
major 2g: 10.0 min; 84% ee.
(S)-Methyl 3,3-Pentamethylene-2-propylaminocarbonyloxybuta-
noate [(S)-2j]. 45% yield (120 mg, colorless oil); Rf = 0.23 (eluent,
n-hexane/ethyl acetate = 4:1); [α]23 +17.2 (c 0.670, CHCl3), IR
D
1
(KBr) 3386, 3056, 2934, 1719 cm−1; H NMR (400 MHz, CDCl3) δ
(R)-Methyl 2-Hydroxy-3,3-diphenylbutanoate [(R)-1h].6a 48%
yield (650 mg, colorless solid); Rf = 0.35 (eluent, n-hexane/ethyl
0.92 (t, 3H, J = 8.0 Hz), 0.97 (s, 3H), 1.26−1.59 (m, 10H), 3.15 (q,
2H, J = 6.8 Hz), 3.74 (s, 3H), 4.78 (s, 1H), 4.86 (br s, 1H); 13C NMR
(67.8 MHz, CDCl3) δ 11.1, 20.1, 21.3, 21.4, 23.0, 25.9, 34.1, 36.3, 42.7,
51.5, 78.9, 156.0, 170.6; HRMS(ESI): m/z calcd for C14H25NO4:
294.1676 [M + Na+], obsd 294.1674; Chiral GC analysis: column, CP-
Chirasil-Dex; carrier gas, helium (80 kPa); initial column temp, 130
°C; tR of (S)-2j: 98.1 min, tR of (R)-2j: 101.4 min; 95% ee.
Gram-Scale Enantiomer-Selective Carbamoylation of 1h
(Table 2, entry 9). Racemic substrate (±)-1h (13.5 g, 49.9 mmol)
and CH2Cl2 (46 mL) were placed in an oven-dried 200-mL three-
necked flask equipped with a Teflon-coated magnetic stirring bar,
acetate = 4:1); [α]23 −92.3 (c 0.97, CHCl3); Mp 33 °C; IR (KBr)
D
3504, 3088, 3056, 3028, 2950, 1732 cm−1
;
1H NMR (270 MHz,
CDCl3) δ 1.77 (s, 3H), 2.97 (d, 1H, J = 8.1 Hz), 3.45 (s, 3H), 5.00 (d,
1H, J = 8.1 Hz), 7.17−7.36 (m, 10H); 13C NMR (67.8 MHz, CDCl3)
δ 24.3, 51.5, 52.0, 76.2, 126.1, 126.4, 127.81, 127.82, 128.0, 145.0,
146.2, 173.8; Anal. Calcd for C17H18O3: C, 75.53, H, 6.71. Found: C,
75.48, H, 6.83; HRMS (ESI): m/z calcd 293.1148 [M + Na+], obsd
293.1150; Chiral HPLC analysis: column, CHIRALPAK IA (0.46 cm ×
25 cm); eluent, n-hexane/2-propanol = 90:10; flow, 0.5 mL min−1
;
10316
dx.doi.org/10.1021/jo201940w|J. Org. Chem. 2011, 76, 10312−10318

The Journal of Organic Chemistry
Note
a serum-rubber cap, and a rubber balloon filled with argon. A 25 mM
CH2Cl2 solution of (S,S)-3 (4.0 mL, 100 μmol) was added to this flask
through a syringe filter unit. The resulting solution was stirred for 15 min
at 0 °C. To this solution was added n-C3H7NCO (2.60 g, 30.2 mmol,
0.61 equivalents to 1h), and the reaction mixture was stirred for 5.5 h
at 0 °C. Methanol (10 mL) was added to the mixture, which was then
concentrated under reduced pressure to give the crude product (17.1 g)
as a green viscous oil. The crude product was purified by column
chromatography (eluent, n-hexane/ethyl acetate = 8:1 to 2:1) to give
U.S.A. 2006, 103, 3522−3527. (e) Onomura, O.; Mitsuda, M.;
Nguyen, M. T. T.; Demizu, Y. Tetrahedron Lett. 2007, 48, 9080−9084.
(f) Shiina, I.; Nakata, K.; Ono, K.; Sugimoto, M.; Sekiguchi, A.
Chem.Eur. J. 2010, 16, 167−172.
(4) For kinetic resolution of α-hydroxy esters and their analogues by
enzymatic methods, see: (a) Kallwass, H. K. W.; Yee, C.; Blythe, T.
A.; McNabb, T. J.; Rogers, E. E.; Shames, S. L. Bioorg. Med. Chem.
1994, 2, 557−566. (b) Adam, W.; Fell, R. T.; Hoch, U.; Saha-Moller,
̈
C. R.; Schreier, P. Tetrahedron: Asymmetry 1995, 6, 1047−1050.
(R)-1h in >99.9% ee (6.27 g, 47% yield); [α]23 −98.2 (c 1.13,
D
(c) Adam, W.; Lazarus, M.; Schmerder, A.; Humpf, H.-U.; Saha-
CHCl3).
Moller, C. R.; Schreier, P. Eur. J. Org. Chem. 1998, 2013−2018.
̈
Determination of the Absolute Configuration of Products. The
absolute configurations of (R)-1c and -1d were determined by
comparing their chiral GC behaviors with those of the authentic
samples prepared from commercially available (S)-2-hydroxy-3,3-
dimethylbutanoic acid by esterification according to the method
described in the literature.13c
(d) Groger, H. Adv. Synth. Catal. 2001, 343, 547−558. (e) Campbell,
̈
R. F.; Fitzpatrick, K.; Inghardt, T.; Karlsson, O.; Nilsson, K.; Reilly,
J. E.; Yet, L. Tetrahedron Lett. 2003, 44, 5477−5481. (f) Huang, S.-H.;
Tsai, S.-W. J. Mol. Catal. B: Enzym. 2004, 28, 65−69. (g) Lee, Y. S.;
Hong, J. H.; Jeon, N. Y.; Won, K.; Kim, B. T. Org. Process Res. Dev.
2004, 8, 948−951. (h) Itoh, T.; Matsushita, Y.; Abe, Y.; Han, S.; Wada,
S.; Hayase, S.; Kawatsura, M.; Takai, S.; Morimoto, M.; Hirose, Y.
Chem.Eur. J. 2006, 12, 9228−9237.
The absolute configurations of (R)-1e, -1h, and -1j were estimated
1
by H NMR analysis after conversion to the (R)- and (S)-2-methoxy-
2-phenyl-2-(trifluoromethyl)acetic acid (MTPA) esters.16 The values
(5) For example, horseradish peroxidase effectively catalyzed
enantiomer-selective reduction of methyl 2-hydroperoxybutanoate to
the hydroxy ester. However, no conversion was observed in the
reaction of methyl 2-hydroperoxy-3,3-dimethylbutanoate. See ref 4b
for details.
of Δδ (δR−δS) are listed below.
(6) See for example: (a) Jansen, R.; Knopp, M.; Amberg, W.;
Bernard, H.; Koser, S.; Muller, S.; Munster, I.; Pfeiffer, T.; Riechers, H.
̈
̈
Org. Process Res. Dev. 2001, 5, 16−22. (b) Murakami, N.; Tamura, S.;
Koyama, K.; Sugimoto, M.; Maekawa, R.; Kobayashi, M. Bioorg. Med.
Chem. Lett. 2004, 14, 2597−2601. (c) Morrissette, M. M.; Stauffer, K.
J.; Williams, P. D.; Lyle, T. A.; Vacca, J. P.; Krueger, J. A.; Lewis, S. D.;
Lucas, B. J.; Wong, B. K.; White, R. B.; Miller-Stein, C.; Lyle, E. A.;
Wallace, A. A.; Leonard, Y. M.; Welsh, D. C.; Lynch, J. J.; McMasters,
D. R. Bioorg. Med. Chem. Lett. 2004, 14, 4161−4164. (d) Nelson,
T. D.; LeBlond, C. R.; Frantz, D. E.; Matty, L.; Mitten, J. V.; Weaver,
D. G.; Moore, J. C.; Kim, J. M.; Boid, R.; Kim, P.; Gbewonyo, K.;
Brower, M.; Sturr, M.; McLaughlin, K.; McMasters, D. R.; Kress,
M. H.; McNamara, J. M.; Dolling, U. H. J. Org. Chem. 2004, 69, 3620−
3627.
(7) Asymmetric hydrogenation of α-tert-alkyl-α-keto esters is a direct
method to obtain the optically active α-hydroxy esters; however, the
bulkiness of these substrates makes it difficult to achieve high
reactivity. To our knowledge, only one example of highly
enantioselective hydrogenation of 3,3-dimethyl-2-oxobutanoate cata-
lyzed by a Ru(II) complex has been reported (S/C = 37, 150 bar of
H2, 50 °C, 24 h; 97.5% yield, >98% ee); see: Sirges, W.; Dreisbach, C.
U.S. Patent 2002/0035271 A1, 2002; Chem. Abstr. 2002, 136, 37900.
(8) Kurono, N.; Kondo, T.; Wakabayashi, M.; Ooka, H.; Inoue, T.;
Tachikawa, H.; Ohkuma, T. Chem. Asian J. 2008, 3, 1289−1297.
(9) For the asymmetric carbamoylation of meso-diols catalyzed by a
Ph-Box−Cu(II) complex with an S/C of 10 at −40 °C to give the
chiral products in up to 93% ee, see: Matsumoto, K.; Mitsuda, M.;
Ushijima, N.; Demizu, Y.; Onomura, O.; Mastumura, Y. Tetrahedron
Lett. 2006, 47, 8453−8456.
(10) For recent reviews on Box−metal-catalyzed asymmetric
reactions, see: (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J.
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ASSOCIATED CONTENT
* Supporting Information
NMR spectra of compounds 1 and 2. This material is available
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S
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ohkuma@eng.hokudai.ac.jp.
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ACKNOWLEDGMENTS
This work was supported by Grants-in-Aid from the Japan
Society for the Promotion of Science (JSPS) (No. 21350048).
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REFERENCES
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Note
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