The effect of benzyl amine on the efficiency of the base-catalyzed transamination of α-keto esters

Article abstract of DOI:10.1016/j.tet.2012.06.023

This paper describes the effect of benzyl amine on the base-catalyzed transamination of α-keto esters. Among various benzyl amines examined, o-HOC₆H₄CH₂NH₂ was found to be highly effective for the reaction, affording a wide variety of α-amino esters in good yields. The o-OH group of the benzyl amine facilitates the transamination process likely via H-bond. Moderate enantiomeric excess was obtained for α-amino ester when a quinine derived catalyst was used.

Full text of DOI:10.1016/j.tet.2012.06.023

Tetrahedron 68 (2012) 6862e6867
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The effect of benzyl amine on the efficiency of the base-catalyzed transamination
of a-keto esters
,b,
Fazhen Xue a, Xiao Xiao a, Haining Wang a, Yian Shi a
*
a Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190,
China
b Department of Chemistry, Colorado State University, Fort Collins, CO 80523, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 May 2012
Received in revised form 5 June 2012
Accepted 6 June 2012
Available online 15 June 2012
This paper describes the effect of benzyl amine on the base-catalyzed transamination of a-keto esters.
Among various benzyl amines examined, o-HOC6H4CH2NH2 was found to be highly effective for the
reaction, affording a wide variety of -amino esters in good yields. The o-OH group of the benzyl amine
facilitates the transamination process likely via H-bond. Moderate enantiomeric excess was obtained for
-amino ester when a quinine derived catalyst was used.
a
a
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Transamination
Base-catalyzed
Benzyl amine
a
a
-Keto esters
-Amino esters
Enantioselective
1. Introduction
a
-Amino acids and their derivatives are important compounds
in biological systems, drug development, and organic synthesis.1
Great progress has been made in the development of various
efficient methods for the synthesis of
systems, an important process to form
transamination of
-keto acids 1 from pyridoxamine 50-phosphate
catalyzed by transaminase (Scheme 1).3e5 Non-enzymatic
transamination presents an attractive strategy to -amino acid
derivatives and has received intensive studies.6e12 During our
studies, we have shown that a variety of -amino esters can be
a
-amino acids.2 In biological
-amino acids involves
Scheme 1. Biological transamination.
a
a
2
a
a
obtained in high enantioselectivities and reasonable yields with
quinine derived catalyst 7 and o-ClC6H4CH2NH2 as amine source
(Scheme 2).13 However, this transamination system was not
effective for certain substrates, such as phenyl keto ester. In search
for more effective transamination system, various benzyl amines
were examined. It was found that the transamination efficiency
could be significantly enhanced with o-HOC6H4CH2NH2 as amine
source. Herein we wish to report our preliminary studies on this
subject.
Scheme 2. Asymmetric transamination.
2. Results and discussion
Our studies were carried out with phenyl keto ester 8a as sub-
strate and Et3N as catalyst, and substituted benzyl amine as amine
donor. As shown in Table 1, only trace amounts of transamination
products could be detected, when 8a was treated with 20 mol %
Et3N and most of the substituted benzyl amines in CDCl3 at 60 ꢀC for
3 days (Table 1, entries 1e10). However, 65% conversion was
* Corresponding author. Fax: þ1 970 4911801; e-mail address: yian@lamar.
colostate.edu (Y. Shi).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.023

F. Xue et al. / Tetrahedron 68 (2012) 6862e6867
6863
Table 1
Table 2
Effect of benzyl amine on transaminationa
Transamination using o-HOC6H4CH2NH2
a
Entry
11
Yield (%)
Entry
9
Solvent
Conv (%)b
1
2
3
4
5
6
7
8
9a, Ar¼Ph
9b, Ar¼o-ClC6H4
9c, Ar¼o-MeOC6H4
9d, Ar¼o-MeC6H4
9e, Ar¼o-FC6H4
9f, Ar¼m-BrC6H4
9g, Ar¼m-CF3C6H4
9h, Ar¼p-F, o-ClC6H3
9i, Ar¼p-CNC6H4
9j, Ar¼Nap
9k, Ar¼o-HOC6H4
9k
9k
9k
9k
9k
9k
9k
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
ClCH2CH2Cl
THF
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
65
61
51
58
46
65
88
100
1
2
3
4
5
6
11a, X¼H
86
84
84
91
89
85
11b, X¼p-F
11c, X¼p-MeO
11d, X¼p-Me
11e, X¼o-Me
11f, X¼2,5-MeO
9
10
11
12
13
14
15
16
17
18c
7
87
Toluene
EtOAc
CH3CN
MeOH
MeOH
8b
75
a
The reactions were carried out with 8a (0.05 mmol), 9 (0.05 mmol), and Et3N
(0.01 mmol) in solvent (0.50 mL) at 60 ꢀC for 3 d unless otherwise stated.
b
The conversion of 8a into 10 and 11 was determined by 1H NMR of the crude
reaction mixture based on a-keto ester 8a.
c
The reactions were carried out with 8a (0.05 mmol), 9 (0.1 mmol), and Et3N
(0.01 mmol) in MeOH (0.25 mL) at 60 ꢀC for 1 d.
9
11i, X¼H
91
90
89
93
90
10
11
12
13
11j, X¼p-MeO
11k, X¼p-F
11l, X¼o-F
obtained when o-HOC6H4CH2NH2 was used (Table 1, entry 11). The
conversion increased to 88% using MeOH as solvent (Table 1, entry
17). Essentially 100% conversion was obtained at 60 ꢀC for 1 day
with 2 equiv of o-HOC6H4CH2NH2 at higher reaction concentration
(Table 1, entry 18). These results showed that o-HOC6H4CH2NH2
displayed uniquely high reactivity toward the transamination of
phenyl keto ester 8a, which was not effective substrate for other
substituted benzyl amines examined.
11m, X¼m-Cl
14b
95
15b
80
63
As shown in Table 2, the transamination system with o-
HOC6H4CH2NH2 can be extended to a wide variety of keto esters.
In general, the reaction proceeded cleanly in all cases examined.
Remarkably high yields were obtained for various aryl keto esters
(Table 2, entries 1e7), which were challenging substrates in our
previous studies.13 The transamination process was also highly
effective for a variety of alkyl keto esters (Table 2, entries 8e15).
Relatively good yield was also obtained for cyclohexyl keto ester
8p (Table 2, entry 16), which was ineffective with o-
ClC6H4CH2NH2 likely due to the steric hindrance of the cyclohexyl
group.
16b
a
The reactions were carried out with 8 (0.6 mmol), 9k (1.2 mmol), and Et3N
(0.12 mmol) in MeOH (3.0 mL) at 60 ꢀC for 1 d unless otherwise stated.
b
Reacted for 2 d.
To further understand the effect of benzyl amine on the trans-
amination, comparative studies for the transamination of phenyl
keto ester 8a were carried out with o-ClC6H4CH2NH2 (9b), o-
MeOC6H4CH2NH2 (9c), and o-HOC6H4CH2NH2 (9k) (Scheme 3). The
reactions were run with 20 mol % Et3N and 3 equiv of benzyl amine
in CDCl3 at 60 ꢀC and monitored by 1H NMR. Some ketimines were
observed with 9b and 9c, but no such ketimine was detected with
9k. The plots of the conversions of substrate 8a into products 10
and 11a against reaction times clearly show that the trans-
amination with o-HOC6H4CH2NH2 (9k) is much faster than that
with o-ClC6H4CH2NH2 (9b) or o-MeOC6H4CH2NH2 (9c). The hy-
droxyl group of 9k greatly facilitates the transamination likely via
the H-bond (Scheme 4).3e5
pyridoxamine proceeded smoothly, affording a-amino ester 11a in
94% yield after 6 h (Scheme 5). A comparison between 9k and 9l
was carried out for the transamination of phenyl keto ester 8a using
in situ IR by measuring the decrease of the absorbance at
1695 cmꢁ1 (the keto group of 8a) (Scheme 6). The data show that
the transamination of phenyl keto ester 8a with pyridoxamine (9l)
was even faster as compared to o-HOC6H4CH2NH2 (9k), indicating
that the transamination with 9l could be further facilitated by the
pyridine ring. A combination of an ortho hydroxyl group and
a pyridine ring along with other factors makes pyridoxamine and
its derivatives very effective cofactors for the transaminations in
nature.5a
The asymmetric transamination of keto ester 8i with
o-HOC6H4CH2NH2 was also investigated with 10 mol % quinine
In the biological system, pyridoxamine derivatives are involved
in transaminations. Pyridoxamine (9l) also contains an ortho hy-
droxyl group. The transamination of phenyl keto ester 8a with
derived base 7. The reaction proceeded at rt, giving
a-amino ester
11i in 86% yield and 57% ee with the opposite configuration as

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F. Xue et al. / Tetrahedron 68 (2012) 6862e6867
Scheme 7. Asymmetric transamination with o-HOC6H4CH2NH2.
compared to the transamination of 8i with o-ClC6H4CH2NH2.13
While a precise understanding of the enantioselectivity awaits
further study, a plausible transition state model is proposed in
Fig. 1. It appears that the OH group of o-HOC6H4CH2NH2 also alters
the stereodifferentiation process in addition to the reactivity, which
provides an additional controlling factor for the development of
enantioselective transamination.
Scheme 3. Comparison studies between different benzyl amines. The conversions of
8a into 10 and 11a were determined by 1H NMR of the crude reaction mixtures based
on a-keto ester 8a.
Fig. 1. Possible transition states for transamination.
Scheme 4. The effect of the hydroxyl group on transamination.
3. Conclusion
In summary, the transamination of a-keto esters has been in-
vestigated with Et3N as catalyst and various substituted benzyl
amines as amine donors. Studies show that o-HOC6H4CH2NH2 is
highly effective for the transamination process. A wide variety of a-
amino esters can be obtained in high yields. Moderate enantiose-
lectivity was also obtained with a chiral base. It appears that the
hydroxyl group has a large impact on both reactivity and stereo-
selectivity likely via H-bond. Further efforts will be devoted to
better understanding the transamination mechanism as well as
developing effective catalytic asymmetric transamination pro-
Scheme 5.
cesses for a-keto esters and other carbonyl compounds.
4. Experimental section
4.1. General information and materials
All commercially available reagents were used without further
purification. All solvents were freshly distilled under nitrogen from
appropriate drying agents before use. Column chromatography was
performed on silica gel (200e300 mesh). 1H NMR spectra were
recorded on a 400 MHz NMR spectrometer and 13C NMR spectra
were recorded on a 100 MHz NMR spectrometer. IR spectra were
recorded on a FT-IR spectrometer. In situ IR spectra were recorded
on a Mettler Toledo React IRÔ 15 spectrometer fitted with
a DiComp probe. Commercially available reagents were used
without further purification. Compounds 8aep were prepared from
the mono-tert-butyloxalic acid-N-methoxy-N-methylamide by the
addition of appropriate Grignard reagents according to published
procedures.14 o-HOC6H4CH2NH2 (9k) was prepared from 2-
methoxybenzylamine via demethylation using BBr3.15 Pyridox-
amine (9l) was obtained by neutralization of pyridoxamine dihy-
drochloride with aqueous NaOH to pH 9.16
Scheme 6. Comparison studies between 9k and 9l.

F. Xue et al. / Tetrahedron 68 (2012) 6862e6867
6865
4.2. Representative procedure for transamination of
esters
a-keto
7.84e7.76 (m, 1H), 7.59e7.39 (m, 4H), 5.22 (s, 1H), 2.17 (s, 2H), 1.37
(s, 9H); 13C NMR (100 MHz, CDCl3)
173.9, 137.3, 134.3, 131.3, 129.0,
d
128.6, 126.5, 125.9, 125.6, 124.6, 123.8, 81.9, 56.5, 28.1; HRMS (ESI)
A mixture of
a
-keto ester 8a (0.1237 g, 0.60 mmol), o-
calcd for C16H20NO2 (MþH): 258.1489; found: 258.1486.
HOC6H4CH2NH2 (0.1477 g, 1.20 mmol), and Et3N (0.0121 g,
0.120 mmol) in MeOH (3.0 mL) was stirred at 60 ꢀC for 24 h and
concentrated. The resulting residue was dissolved in THF (6.0 mL),
followed by the addition of aqueous 1 N HCl (6.0 mL). Upon stirring
at rt for 5 h, the mixture was diluted with water (15 mL) then
washed with hexane (3ꢂ10 mL). The organic phase was extracted
with aqueous 1 N HCl (1ꢂ15 mL). The aqueous phases were com-
bined, brought to pH 8.0 with solid NaHCO3, extracted with CH2Cl2
(5ꢂ10 mL), and the organic extracts were dried (MgSO4), filtered,
concentrated, and purified by flash chromatography (silica gel,
4.2.8. tert-Butyl 2-amino-3-cyclohexylpropanoate (11h) (Table 2,
entry 8). Yellow oil; IR (film) 3380, 1729, 1367, 1153 cmꢁ1 1H
;
NMR (400 MHz, CDCl3)
(m, 13H), 1.45 (s, 9H), 0.99e0.81 (m, 2H); 13C NMR (100 MHz,
CDCl3) 176.3, 80.9, 53.0, 43.1, 34.5, 33.9, 33.0, 28.3, 26.7, 26.5,
d
3.36 (dd, J¼8.4, 5.6 Hz, 1H), 1.80e1.06
d
26.4; HRMS (ESI) calcd for C13H26NO2 (MþH): 228.1958; found:
228.1953.
4.2.9. tert-Butyl 2-amino-4-phenylbutanoate (11i) (Table 2, entry
petroleum ether/EtOAc¼5/1 then EtOAc) to give
a-amino ester 11a
9). Yellow oil; IR (film) 3381, 1727, 1368, 1154 cmꢁ1 1H NMR
;
as yellow oil (0.1069 g, 86% yield).
(400 MHz, CDCl3) d 7.32e7.25 (m, 2H), 7.23e7.16 (m, 3H), 3.35 (dd,
J¼7.6, 5.2 Hz, 1H), 2.79e2.64 (m, 2H), 2.08e1.97 (m, 1H), 1.88e1.76
4.2.1. tert-Butyl 2-amino-2-phenylacetate (11a) (Table 2, entry
1). Yellow oil; IR (film) 3377, 1731, 1368, 1152 cmꢁ1 1H NMR
(400 MHz, CDCl3) 7.39e7.25 (m, 5H), 4.48 (s, 1H), 1.88 (s, 2H), 1.39
(s, 9H); 13C NMR (100 MHz, CDCl3)
173.4, 141.2, 128.8, 127.9, 126.9,
(m, 1H), 1.60 (s, 2H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3)
;
d 175.5, 141.8, 128.62, 128.60, 126.1, 81.2, 54.8, 37.0, 32.2, 28.3;
d
HRMS (ESI) calcd for C14H21NNaO2 (MþNa): 258.1465; found:
d
258.1457.
81.7, 59.6, 28.1; HRMS (ESI) calcd for C12H18NO2 (MþH): 208.1332;
found: 208.1327.
4.2.10. tert-Butyl 2-amino-4-(4-methoxyphenyl)butanoate (11j)
(Table 2, entry 10). Yellow oil; IR (film) 3382, 1727, 1513, 1367, 1246,
4.2.2. tert-Butyl 2-amino-2-(4-fluorophenyl)acetate (11b) (Table 2,
entry 2). Yellow oil; IR (film) 3384, 1731, 1509, 1151 cmꢁ1; 1H NMR
1154 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.12 (d, J¼8.0 Hz, 2H), 6.83
(d, J¼8.4, 2H), 3.78 (s, 3H), 3.33 (dd, J¼7.2, 5.2 Hz, 1H), 2.73e2.58
(m, 2H), 2.04e1.92 (m, 1H), 1.87e1.73 (m, 1H), 1.70 (s, 2H), 1.47 (s,
(400 MHz, CDCl3)
d
7.38e7.30 (m, 2H), 7.06e6.98 (m, 2H), 4.47 (s,
173.2,
1H), 2.06 (s, 2H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
9H); 13C NMR (100 MHz, CDCl3)
d 175.5, 158.1, 133.8, 129.5, 114.1,
163.7, 161.3, 136.9, 128.6, 128.5, 115.7, 115.5, 81.9, 58.8, 28.1; Anal.
Calcd for C12H16FNO2: C, 63.98; H, 7.16; N, 6.22; found: C, 63.80; H,
6.80; N, 6.14.
81.2, 55.5, 54.8, 37.2, 31.3, 28.3; HRMS (ESI) calcd for C15H24NO3
(MþH): 266.1751; found: 266.1744.
4.2.11. tert-Butyl 2-amino-4-(4-fluorophenyl)butanoate (11k) (Table
4.2.3. tert-Butyl 2-amino-2-(4-methoxyphenyl)acetate (11c) (Table
2, entry 11). Yellow oil; IR (film) 3383, 1727, 1510, 1155 cmꢁ1 1H
;
2, entry 3). Yellow oil; IR (film) 3383, 1729, 1511, 1249, 1151 cmꢁ1
;
NMR (400 MHz, CDCl3)
d
7.18e7.10 (m, 2H), 6.96 (t, J¼8.4 Hz, 2H),
1H NMR (400 MHz, CDCl3)
4.43 (s, 1H), 3.80 (s, 3H), 1.98 (s, 2H), 1.39 (s, 9H); 13C NMR
(100 MHz, CDCl3) 173.6, 159.3, 133.4, 128.0, 114.2, 81.6, 58.9, 55.4,
d
7.31e7.24 (m, 2H), 6.89e6.84 (m, 2H),
3.31 (dd, J¼7.6, 5.6 Hz, 1H), 2.76e2.61 (m, 2H), 2.05e1.92 (m, 1H),
1.84e1.72 (m, 1H), 1.52 (s, 2H), 1.47 (s, 9H); 13C NMR (100 MHz,
d
CDCl3) d 175.4, 162.8, 160.3, 137.4, 137.3, 130.0, 129.9, 115.4, 115.2,
28.1; HRMS (ESI) calcd for C13H20NO3 (MþH): 238.1438; found:
81.3, 54.7, 37.0, 31.4, 28.3; HRMS (ESI) calcd for C14H21FNO2 (MþH):
238.1434.
254.1551; found: 254.1545.
4.2.4. tert-Butyl 2-amino-2-p-tolylacetate (11d) (Table 2, entry
4.2.12. tert-Butyl 2-amino-4-(2-fluorophenyl)butanoate (11l) (Table
2, entry 12). Yellow oil; IR (film) 3384, 1728, 1492, 1368, 1229,
4). Yellow oil; IR (film) 3384, 1731, 1368, 1152 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
(s, 1H), 2.34 (s, 3H), 1.90 (s, 2H), 1.39 (s, 9H); 13C NMR (100 MHz,
CDCl3) 173.5, 138.2, 137.5, 129.5, 126.7, 81.6, 59.3, 28.1, 21.3; HRMS
d
7.24 (d, J¼8.0 Hz, 2H), 7.14 (d, J¼8.0 Hz, 2H), 4.44
1155 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 7.25e7.12 (m, 2H),
7.09e6.94 (m, 2H), 3.35 (dd, J¼7.6, 5.6 Hz, 1H), 2.84e2.63 (m, 2H),
d
2.07e1.92 (m, 1H), 1.89e1.75 (m, 1H), 1.55 (s, 2H), 1.47 (s, 9H); 13C
(ESI) calcd for C13H20NO2 (MþH): 222.1489; found: 222.1486.
NMR (100 MHz, CDCl3) d 175.3, 162.6, 160.2, 130.9, 130.8, 128.7,
128.5, 127.9, 127.8, 124.2, 124.1, 115.6, 115.3, 81.3, 54.9, 35.5, 28.2,
25.5; HRMS (ESI) calcd for C14H20FNNaO2 (MþNa): 276.1370;
found: 276.1365.
4.2.5. tert-Butyl 2-amino-2-o-tolylacetate (11e) (Table 2, entry
5). Yellow oil; IR (film) 3384, 1731, 1368, 1152 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
1H), 2.44 (s, 3H),1.84 (s, 2H),1.38 (s, 9H); 13C NMR (100 MHz, CDCl3)
173.9, 139.7, 136.1, 130.8, 127.7, 126.6, 125.9, 81.6, 55.9, 28.1, 19.6;
d 7.27e7.22 (m, 1H), 7.20e7.14 (m, 3H), 4.70 (s,
4.2.13. tert-Butyl
(Table 2, entry 13). Yellow oil; IR (film) 3382, 1727, 1368, 1154 cmꢁ1
1H NMR (400 MHz, CDCl3)
2-amino-4-(3-chlorophenyl)butanoate
(11m)
d
;
HRMS (ESI) calcd for C13H20NO2 (MþH): 222.1489; found:
d
7.24e7.12 (m, 3H), 7.08 (d, J¼7.6 Hz,
222.1485.
1H), 3.31 (dd, J¼7.6, 5.2 Hz, 1H), 2.78e2.60 (m, 2H), 2.06e1.92 (m,
1H), 1.85e1.72 (m, 1H), 1.52 (s, 2H), 1.47 (s, 9H); 13C NMR (100 MHz,
4.2.6. tert-Butyl 2-amino-2-(2,5-dimethoxyphenyl)acetate (11f)
(Table 2, entry 6). Yellow oil; IR (film) 3382, 1729, 1500, 1227,
CDCl3) d 175.4, 143.9, 134.4, 129.9, 128.8, 126.9, 126.4, 81.3, 54.7,
36.6, 31.9, 28.3; HRMS (ESI) calcd for C14H21ClNO2 (MþH):
1154 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
6.84e6.74 (m, 3H), 4.58 (s,
1H), 3.78 (s, 3H), 3.75 (s, 3H), 2.01 (s, 2H), 1.40 (s, 9H); 13C NMR
(100 MHz, CDCl3) 173.6, 153.9, 151.2, 130.9, 114.7, 113.5, 112.0, 81.2,
270.1255; found: 270.1258.
d
4.2.14. tert-Butyl 2-amino-4-(naphthalen-1-yl)butanoate (11n)
56.1, 56.0, 55.7, 28.1; HRMS (ESI) calcd for C14H22NO4 (MþH):
(Table 2, entry 14). Yellow oil; IR (film) 3382, 1726, 1367, 1153 cmꢁ1
;
268.1543; found: 268.1549.
1H NMR (400 MHz, CDCl3)
7.72 (d, J¼7.6 Hz, 1H), 7.57e7.43 (m, 2H), 7.43e7.31 (m, 2H), 3.47
(dd, J¼7.2, 5.6 Hz, 1H), 3.28e3.08 (m, 2H), 2.22e2.08 (m, 1H),
2.05e1.90 (m, 1H), 1.76 (s, 2H), 1.50 (s, 9H); 13C NMR (100 MHz,
d
8.08 (d, J¼8.4, 1H), 7.86 (d, J¼8.4, 1H),
4.2.7. tert-Butyl 2-amino-2-(naphthalen-1-yl)acetate (11g) (Table 2,
entry 7). Yellow oil; IR (film) 3382, 1729, 1368, 1152 cmꢁ1; 1H NMR
(400 MHz, CDCl3)
d
8.20 (d, J¼8.4 Hz, 1H), 7.87 (d, J¼7.6 Hz, 1H),
CDCl3) d 175.5, 138.0, 134.1, 132.1, 129.0, 127.0, 126.3, 126.0, 125.8,

6866
F. Xue et al. / Tetrahedron 68 (2012) 6862e6867
125.7, 123.9, 81.3, 55.3, 36.3, 29.4, 28.3; HRMS (ESI) calcd for
C18H24NO2 (MþH): 286.1802; found: 286.1804.
(0.0509 g, 0.22 mmol) in CH2Cl2 (1.5 mL) were added Et3N
(0.0404 g, 0.40 mmol) and PhCOCl (0.0464 g, 0.33 mmol) suc-
cessively. The reaction mixture was stirred at rt for 30 min and
purified by flash chromatography (silica gel, petroleum ether/
EtOAc¼10/1 to 5/1) to afford N-benzoyl amino ester 12i
(0.0622 g, 83%) as white solid. The sample was subjected to chiral
HPLC (chiralcel OD-H column) to determine the enantiomeric
excess.
4.2.15. tert-Butyl 2-aminohexanoate (11o) (Table 2, entry
15). Yellow oil; IR (film) 3381, 1731, 1368, 1155 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
1.57e1.48 (m, 1H), 1.45 (s, 9H), 1.39e1.22 (m, 4H), 0.89 (t, J¼6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3)
175.8, 81.0, 55.2, 34.9, 28.3, 27.9,
d
3.29 (dd, J¼7.2, 5.6 Hz, 1H), 1.77e1.57 (m, 3H),
d
22.7, 14.1; HRMS (ESI) calcd for C10H21NNaO2 (MþNa): 210.1465;
found: 210.1460.
Acknowledgements
4.2.16. tert-Butyl 2-amino-2-cyclohexylacetate (11p) (Table 2, entry
We gratefully acknowledge the National Basic Research Program
of China (973 program, 2010CB833300) and the Chinese Academy
of Sciences for the financial support.
16). Yellow oil; IR (film) 3383, 1727, 1367, 1153 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
d
3.15 (d, J¼4.8 Hz, 1H), 1.84e1.52 (m, 8H), 1.47 (s,
9H), 1.34e1.02 (m, 5H); 13C NMR (100 MHz, CDCl3)
d
175.0, 81.0,
60.3, 42.5, 29.9, 28.3, 28.0, 26.51, 26.49, 26.4; HRMS (ESI) calcd for
C12H24NO2 (MþH): 214.1802; found: 214.1797.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.06.023.
4.3. Procedure for transamination of phenyl keto ester 8a
with pyridoxamine (9l)
A mixture of 8a (0.0618 g, 0.30 mmol), pyridoxamine (9l)
(0.0605 g, 0.36 mmol), and Et3N (0.0061 g, 0.06 mmol) in MeOH
(1.5 mL) was stirred at 60 ꢀC for 6 h and concentrated. The resulting
residue was dissolved in THF (3.0 mL), followed by the addition of
aqueous 1 N HCl (3.0 mL). Upon stirring at rt for 5 h, the mixture
was diluted with water (8 mL) then washed with hexane
(3ꢂ10 mL). The organic phase was extracted with aqueous 1 N HCl
(1ꢂ10 mL). The aqueous phases were combined, brought to pH 8.0
with solid NaHCO3, extracted with CH2Cl2 (5ꢂ10 mL), and the or-
ganic extracts were dried (MgSO4), filtered, concentrated, and pu-
rified by flash chromatography (silica gel, petroleum ether/
References and notes
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4.4. General procedure for comparison experiment between
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A mixture of phenyl keto ester 8a (0.0412 g, 0.20 mmol),
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(9l) (0.0336 g, 0.20 mmol), and Et3N (0.0040 g, 0.04 mmol) in MeOH
(2.0 mL) at 50 ꢀC was monitored by in situ IR every 1 min.
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4.5. The procedure for asymmetric transamination of
ester (Scheme 7)
a-keto
4.5.1. Asymmetric transamination of
Schlenk tube charged with molecular sieves 4 A (0.030 g),
a-keto ester 8i. A well-dried
ꢀ
a-keto
ester 8i (0.0702 g, 0.30 mmol), o-OHC6H4CH2NH2 (0.0739 g,
0.60 mmol), and catalyst 7 (0.0110 g, 0.030 mmol) was evacuated
and refilled with N2. The process was repeated three times. Dry
benzene (3.0 mL) was added. Upon stirring at 25 ꢀC for 48 h, the
reaction mixture was concentrated. The resulting residue was
treated with THF (3.0 mL), followed by the addition of aqueous 1 N
HCl (3.0 mL). Upon stirring at rt for 5 h, the mixture was diluted
with water (10 mL) then washed with hexane (3ꢂ10 mL). The or-
ganic phase was extracted with aqueous 1 N HCl. The aqueous
phases were combined, brought to pH 8.0 with solid NaHCO3,
extracted with CH2Cl2 (5ꢂ10 mL), and the organic extracts were
dried (MgSO4), filtered, concentrated, and purified by flash chro-
matography (silica gel, petroleum ether/EtOAc¼5/1 then EtOAc/
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CH3OH¼10/1) to give
a
-amino ester 11i (0.0607 g, 86% yield); ½a D20
ꢃ
þ13.1 (c 0.89, CHCl3) (57% ee).
4.5.2. Preparation of N-benzoyl derivative of amino ester for the
determination of the enantiomeric excess. To a solution of 11i

F. Xue et al. / Tetrahedron 68 (2012) 6862e6867
6867
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