The synthesis of a chiral β-amino acid derivative by the Grignard reaction of an aspartic acid equivalent

Article abstract of DOI:10.3184/030823410X12843925746143

A novel synthetic route to chiral β-amino acid derivative has been developed by a Grignard reaction of 2,4,5-trifluo- rophenyl magnesium bromide with the Weinreb amide derivative of L-aspartic acid. The aspartic equivalent was synthesised from L-aspartic

Full text of DOI:10.3184/030823410X12843925746143

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 517
SEPTEMBER, 517–519
The synthesis of a chiral β-amino acid derivative by the Grignard reaction
of an aspartic acid equivalent
Feng Liu, Wansheng Yu, Wenhua Ou, Xiaojiong Xu, Libo Ruan, Xiaoke Wang, Yiming Li,
Xijiang Peng, Xiaohu Tao, Jun Mao, Jiaomei Wan and Xianhua Pan*
School of Perfume and AromaTechnology, Shanghai Institute ofTechnology, 120 Caobao Rd. Shanghai 200235, P. R. China
A novel synthetic route to chiral β-amino acid derivative has been developed by a Grignard reaction of 2,4,5-trifluo-
rophenyl magnesium bromide with the Weinreb amide derivative of L-aspartic acid. The aspartic equivalent was
synthesised from L-aspartic acid in four steps, and the Grignard reagent was prepared by Br–Mg-exchange reaction.
The target compound was achieved after the Grignard reaction and a subsequent reduction. Tthe stereo structure of
the chiral amine was well preserved from the L-aspartic acid.
Keywords: β-amino acid, aspartic acid, Grignard reaction
Enantiopure β-amino acids and their derivatives have found
extensive application as components of numerous biologically
active natural products as well as being important building
blocks for the synthesis of β-peptides, β-lactam antibiotics and
small molecule pharmaceuticals.1–3 Consequently, developing
new synthetic methods for the construction of β-amino acids
and their derivatives has been important. Research has focused
on facile, practical, and scalable methods for their preparation
involving Arndt–Eistert homologation of the natural α-amino
acid,4 chemical and biological resolution,5 chiral Lewis
acid catalysed Mannich reaction,6 asymmetric hydrogenation
of enamino derivative,7,8 asymmetric Michael addition of a
chiral amine to an unsaturated ester,9 modification of β-amino
acid equivalent.10–16 Given its inherent chiral efficiency and
atom economy, the method that are based on β-amino acid
equivalents potentially appears to be the most versatile.
Here, we report an approach to the enantiopure β-amino
acid derivative, 3-R-Boc-amino-4-(2,4,5-trifluoro-phenyl)
butyric acid methyl ester, a key synthetic intermediate of a
new dipeptidyl peptidase IV (DPP-IV) inhibitor for the treat-
ment of type 2 diabetes mellitus (T2DM), Sitagliptin. In this
approach, the stereochemistry of the chiral amine is retained
from the aspartic acid equivalent, which was synthesised from
L-aspartic acid by a few steps (Scheme 1).
After di-methylation and Boc protection of the amine, the
resultant compound 2 was selectively hydrolysed at the α-
position with aq. LiOH in ethanol. In this process, the pH was
controlled around 10 and the temperature was –10 °C. The
mono acid 3 was condensed with N,O-dimethylhydroxyl-
amine, to give the Weinreb amide, the β-amino acid equivalent
4 in 90% yield. The Grignard reaction was examined using
2,4,5-trifluoro-phenyl magnesium bromide. Since the direct
reaction of Mg and 1-bromo-2,4,5-trifluoro- benzene will
eliminate to yield benzyne and not the anticipated Grignard
reagent, we used a bromine-magnesium-exchange reaction.17
The Br–Mg-exchange of 1-bromo-2,4,5-trifluorobenzene
was performed with i-PrMgBr at –20 °C in 1 h, monitored
by GC at the point of disappearance of the bromobenzene
(Scheme 3).
As the α-BOC-amino Weinreb amide 4 contains an exch-
angeable amino proton, excess Grignard reagent was required
because the deprotonation of the exchangeable amino proton
of 4 was faster than the nucleophilic attack at the Weinreb
amide functional group.18 The pre-deprotonation of the amino
group was implemented by adding 1.0 equiv. of an inexpensive
base i-PrMgBr at –10 °C, whose by-product propane is vola-
tile and easily removed. This was followed by the addition
of 1.1 equiv. of the nucleophile 6 at –20 °C. The α-Boc-
amino ketone ester 7 was obtained in good yield. In this pre-
deprotonation procedure, there was very little waste since only
a small excess of the nucleophile was used. By minimising the
The synthetic work was initiated from L-aspartic acid 1
(Scheme 2), which contains both α- and β-amino acid struc-
tural segment.
Scheme 1 Synthetic strategy of β-amino acid.
Scheme 2
* Correspondent. E-mail:panxh@sit.edu.cn

518 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 3
(S)-methyl 3-(Boc-amino)-4-(methoxy(methyl)amino)-4-oxobuta-
noate (4):22 Isobutylchlorocarbonate (4.08 g, 30 mmol) was added
dropwise at –15 °C to a solution of 3 (7.41 g, 30 mmol) and N-
methylmorpholine (6.5 mL, 60 mmol) in dichloromethane (100 mL).
After stirring for 15 min 3.51 g (36 mmol) of N,O-dimethylhydroxyl-
amine hydrochloride was added. The mixture was stirred for 1 h at
–15 °C, then for 3 h at room temperature; 50 mL of water was added,
the phases were separated, and the organic phase was dried with
Mg2SO4 and concentrated. Flash chromatography with petroleum
ether/ethyl acetate (l:l) resulted in 7.83 g (90%) of 4 as a colourless
oil.21 [α]D20 = –20.5 (c 1.0, CDCl3). IR (cm–1): 3330, 2978, 1740, 1713,
1665, 1501, 1438, 1391, 1367, 1247, 1166, 1049, 1026, 989, 862, 826,
formation of byproducts, purification of the desired ketone
was made easier. This procedure is therefore more economical
to run espercially in large scale production. The ketone 7 was
reduced by Pd/C catalysed hydrogenation in absolute EtOH-
ethereal HCl and the amine was again protected as the Boc
derivative to give the target β-amino acid derivative 8, 3-R-
Boc-amino-4-(2,4,5-trifluoro- phenyl)butyric acid methyl ester
in good yield.19 The stereo configuration of compound 8 was
confirmed after being compared with the reported data.20
In summary, we have developed a novel approach to synthe-
sise the β-amino acid derivative, 3-R-Boc-amino-4-(2,4,5-
trifluoro-phenyl)butyric acid methyl ester, by the Grignard
reaction of aspartic acid equivalent. In this approach the stereo
configuration of the chiral amine is retained from the aspartic
acid equivalent. We hope that this discovery will provide a
practical and efficient method for the preparation of β-amino
acids and their derivatives. Further studies are currently
underway in our laboratory.
1
780, 735. H NMR (400 MHz, DMSO) δ 5.39 (s, 1H), 5.01 (s, 1H),
3.79 (s, 3H), 3.70–3.67 (m, 3H), 3.22 (s, 3H), 2.77 (dd, J = 15.2,
5.7 Hz, 1H), 2.65 (d, J = 6.8 Hz, 1H), 1.38 (s, 9H). ESI-MS m/z
313.1(M + Na)+.
(S)-methyl 3-(Boc-amino)-4-oxo-4-(2,4,5-trifluorophenyl)butanoate
(7):21 A dry three-necked flask equipped with a magnetic stirring bar
and a N2 balloon was charged with 1-bromo-2,4,5-trifluorobenzene
(5; 4.62 g, 22 mmol) in THF (50 mL) and cooled to –20 °C, i-PrMgBr
(22 mL, 22 mmol, 1 M in THF) was added dropwise and the reaction
mixture was stirred at –20 °C for 1 h. At the point GC assay indicated
disappearance of the bromobenzene, then the Grignard reagent 6 was
stored as a THF solution in an inert gas atmosphere. α-BOC-amino
Weinreb amide 4 (5.8 g, 20 mmol) was dissolved in 50 mL of dry
THF, degassed and placed under N2. The solution was cooled to
–20 °C and to the resulting slurry was charged with 20 mL of 1.0 M
i-PrMgBr/THF (20 mmol) dropwise at –15 to –5 °C to afford a clear
solution. After cooling to –20 °C, the Grignard reagent 6 was
exchanged above and added dropwise at f15 °C over 0.5 hour. The
cooling bath was removed, and the mixture was allowed to warm to
room temperature over 30 min. After a 4 h period at room tempera-
ture, the reaction was complete. The mixture was cooled in an ice
bath and 100 mL of 1.0N HCl was added slowly at < 20 °C, followed
by 100 mL of EtOAc. The aqueous layer was cut, and the organic
layer was washed with 100 mL of water and dried over anhydrous
Na2SO4. Evaporation of the solvent afforded a pale yellow oil, after
flash chromatography (silica gel, 3:1 hexane/EtOAc), 6.2 g of BOC-
aminoacetophenone 7 was obtained as a colourless oil in 86% yield.
[α]D20 = –13.1 (c 1.0, CDCl3). IR (cm–1): 3371, 2977, 1710, 1625,
1512, 1427, 1368, 1336, 1291, 1250, 1215, 1163, 1051, 1027, 853,
801. 1H NMR (400 MHz, CDCl3) δ 7.12–6.75 (m, 2H), 5.68 (d,
J = 6.5 Hz, 1H), 5.15 (br, 1H), 3.71 (s, 3H), 3.15–2.97 (m, 1H), 2.88
(d, J = 11.0 Hz, 1H), 1.45 (s, 9H). ESI-MS m/z 384.1 (M + Na)+.
HRMS Calcd for C16H18F3NO5Na (M + Na)+ requires 384.1035, found
313.1043.
Experimental
Melting points were determined with a SGW X-4 micro melting point
apparatus. IR spectra were determined on a Bruker Vertex 70 spectro-
1
photometer. H NMR spectra were recorded using an Avance 400
MHz spectrometer. ESI-MS were recorded on Dionex MSOPlus
Mass Spectrometer. High resolution mass spectra were recorded on
Finnigan MAT XL95 mass spectrometer. GC were determined on Fuli
GC-9790. Optical rotations were obtained on a Perkin-Elmer 241
Autopol polarimeter.
(S)-2-(Boc-amino)-4-methoxy-4-oxobutanoic acid (3):21 To a solu-
tion of L-aspartic acid (26.6 g, 0.2 mol) in 150 mL methanol, thionyl
chloride (25 g, 0.21 mol) was added dropwise at 0 °C. The mixture
was then heated to reflux for 2 h and the cooled solvent was then
removed under vacuum. The white solid residue was suspended on
200 mL of CH2Cl2 and Et3N (45.5 g, 0.45 mol), Boc2O (65.4 g,
0.3 mol) was added at room temperature. The mixture was stirred for
8 hours before water (200 mL) was added. The layers were separated,
the organic layer was washed with sat. NaCl (200 mL), dried over
anhydrous Na2SO4, filtered and concentrated to provide 51.2 g of
crude 2 (98% for two steps). The crude product 2 was dissolved in
200 mL of EtOH at –10 °C, aq. LiOH(2N) was added to the mixture
through the dropping funnel to maintain the pH = 10. The mixture was
stirred until the point that TLC assay indicated complete consumption
of ester starting material. Then the organic solvent was evaporated
under reduced pressure below 40 °C, CH2Cl2 (200 mL) was added to
the aqueous residue and stirred for 5 minutes, the organic layer was
discarder. The aqueous layer was acidified with 1N HCl to pH = 3,
then extracted with CH2Cl2 (2 x150 mL). The combined organic
layers were washed with sat. NaCl (200 mL), dried , filtered and con-
centrated to give the colourless viscous oil 3 (41.2 g, 0.167 mol), 83%
yield. [α]D20 = –18.5 (c 1.0, MeOH). IR (cm–1): 2980, 1717, 1510,
3-R-Boc-amino-4-(2,4,5-trifluoro-phenyl)butyric acid methyl ester
(8): To a solution of 7 (6.2 g, 17.1 mmol) in EtOH (60 mL, absolute).
Ethereal HCl (10 mL) and 1 g of 10% Pd/Cwas added. The mixture
was shaken with H2 (5 atm, 4 h), filtered, and evaporated to give a
light yellow oil. 10% HCl (50 mL) and CH2Cl2 (50 mL) was added to
the residue and stirred for 10 minutes, the organic layer was discarded.
The aqueous layer was neutralised with K2CO3, then extracted with
CH2Cl2 (2 x50 mL). The combined organic layers were washed with
sat. NaCl (50 mL), dried over anhyd. Na2SO4 and filtered. To this
CH2Cl2 solution was added Et3N (3.03 g, 30 mmol), Boc2O (4.36 g,
20 mmol) at room temperature. The mixture was stirred for 8 hours
before water (50 mL) was added, the layers were separated, the
1
1439, 1395, 1369, 1243, 1161, 1048, 1027, 844, 780, 738. H NMR
(400 MHz, CDCl3) δ 10.85 (s, 1H), 5.61 (d, J = 8.3 Hz, 1H), 4.79–
4.57 (m, 1H), 3.76 (s, 3H), 3.05 (d, J = 4.1 Hz, 1H), 2.87 (dd, J = 17.3,
4.5 Hz, 1H), 1.44 (s, 9 H). ESI-MS m/z 248.2(M + 1)+.

JOURNAL OF CHEMICAL RESEARCH 2010 519
3
D. Guenard, R. Guritte-Voegelein and P. Potier, Acct. Chem. Res., 1993, 26,
160.
organic layer was washed with sat. NaCl (50 mL), dried over anhyd.
Na2SO4, filtered and concentrated to provide the crude product, recrys-
tallised from toluene to give a pale yellow solid 8 (4.45 g, 12.8 mmol),
75% for two steps. [α]D20 = +14.2 (c 1.0, MeOH). M.p. 76–78 °C.
{lit.20 [α]D20 = +15.2 (c 1.0, MeOH). M.p. 88–88.5 °C.} IR (cm–1):
3366, 2983, 1733, 1688, 1424, 1335, 1250, 1158, 1029, 838. 1H NMR
(400 MHz, CDCl3) δ 7.17–6.72 (m, 2H), 5.18 (br, 1H), 4.18–4.00 (m,
1H), 3.72 (s, 3H), 2.92–2.85 (m, 2H), 2.58–2.47 (m, 2H), 1.37 (s, 9H).
ESI-MS: 348.1 (M + 1)+.
4
5
G. Guichard, S. Abelem and D. Seebach, Helv. Chim. Acta, 1998, 81, 187.
S.J. Faulconbridge, K.E. Holy, L.G. Sevillano, C.J. Lock, P.D. Tiffin,
N. Tremayne and S. Winter, Tetrahedron Lett., 2000, 41, 2679.
J.L. Vicario, D. Badia and L. Carrillo, Org. Lett., 2001, 3, 773.
S.D. Dreher and N. Ikemoto, Process to chiral β-amino acid derivatives.
WO 2004085661.
B.H. Karl , B. Jaume, D. Spencer, H.Yi, D.A. Joseph III et al. Org. Process
Res. Devel., 2005, 9, 634.
F. Liu, W.-S.Yu, W. Ou, X. Wang, L. Ruan, Y. Li, X. Peng, X. Tao and
X. Pan, J. Chem. Res., 2010, 34, 230.
6
7
8
9
The authors are grateful to the Shanghai Municipal Education
Commission, Research Fundation for Outstanding Young
Teachers in University (Grant No. YYY09021 A06/
4052K090094) and Research Start-up Funds of Shanghai
Institute of Technology (Grant. No. YJ2009-05) for financial
support.
10 C.W. Jefford, J. McNulty, Z.H. Lu and J.B. Wang, Helv.Chim. Acta, 1996,
79, 1203.
11 K. Shimamoto, M. Ishida, H. Shinozaki and Y. Ohfune, J. Org. Chem.,
1991, 56, 4167.
12 E. Juaristi, D. Quintana, M. Balderas and E. GarciaPerez, Tetrahedron:
Asymmetry, 1996, 7, 2233.
13 B.E. Sleebs and A.B. Hughes, J. Org. Chem., 2007, 72, 3340.
14 J.E. Beddow, S.G. Davies, K.B. Ling, P.M. Roberts, A.J. Russell, A.D.
Smith and J.E. Thomson, Org. Biomol.Chem., 2007, 5, 2812.
15 E. Juaristi, E.(ed.), Enantioselective synthesis of β-amino acids. Wiley-
VCH: New York, 1996.
16 J.-A. Ma, Angew. Chem., Int. Ed., 2003, 42, 4290.
17 A. Mohamed, D. Floria and K. Paul, Tetrahedron Lett., 1999, 40, 7449.
18 J. Liu et al. Tetrahedron Lett., 2000, 43, 8223.
19 F.B. Thomas and R. Henry, J. Am. Chem. Soc., 1981, 103, 20, 6157.
20 D. Kim, L.P. Wang and M. Beconi, J. Med. Chem., 2005, 48, 11, 141.
21 K. Ramalingam and R.W. Woodard, J. Org. Chem., 1988, 53, 1900.
22 V.M. Sibrian and D.A. Spivak, J. Org. Chem., 2003, 68, 9604.
Received 8 July 2010; accepted 3 August 2010
Paper 1000238 doi: 10.3184/030823410X12843925746143
Published online: 7 October 2010
References
1
C.N. Drey, Chemistry and biochemistry of the amino acids, Barrett, G. C.
(ed.), Chapman and Hall, New York, 1985, Chap. 3.
2
W.J. Hoekstra, Curr. Med. Chem., 1999, 6, 905.

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