Synthesis of α-fluoro-β-amino acids via the Reformatsky reaction of chiral N-tert-butylsulfinylimines with ethyl bromofluoroacetate

Article abstract of DOI:10.1016/j.cclet.2011.01.037

Treatment of chiral N-tert-butyl sulfinylimines with ethyl bromofluoroacetate in the presence of activated Zn dust in THF afforded the α-fluoro-β-amino acid derivatives in good yields (70-86%) and moderate diastereoselectivity (66:34-92:8).

Full text of DOI:10.1016/j.cclet.2011.01.037

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 919–922
www.elsevier.com/locate/cclet
Synthesis of a-fluoro-b-amino acids via the Reformatsky reaction of
chiral N-tert-butylsulfinylimines with ethyl bromofluoroacetate
a,b
Zhi Tao Jing a, Yan Gen Huang a, , Feng Ling Qing
*
a College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Received 8 November 2010
Available online 19 May 2011
Abstract
Treatment of chiral N-tert-butyl sulfinylimines with ethyl bromofluoroacetate in the presence of activated Zn dust in THF
afforded the a-fluoro-b-amino acid derivatives in good yields (70–86%) and moderate diastereoselectivity (66:34–92:8).
# 2011 Yan Gen Huang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Fluorinated amino acids; Reformatsky reaction; N-tert-Butyl sulfinylimine
1. Introduction
The (R)- and (S)-isomers of N-tert-butylsulfinylamide reported by Ellman et al. [1,2] are versatile reagents for the
asymmetric synthesis of various classes of substituted amines, amino acids, amino alcohols, and diamines. Staas et al.
reported the diasteroselective synthesis of a,a-difluoro-b-amino acids via the Reformatsky reaction between ethyl
bromodifluoroacetate and N-tert-butylsulfinylimines derived from the Ellman’s N-tert-butylsulfinamide [3]. The
Reformatsky reaction between Davis’ N-sulfinylimines (optically active N-p-toluenesulfinylimines) and ethyl
bromodifluoroacetate was also applied for the asymmetric synthesis of b-substituted a,a-difluoro-b-amino acids [4,5].
Most recently, the asymmetric synthesis of fluorine-containing amino acids mediated by chiral sulfinyl group has been
reviewed [6]. However, the asymmetric Reformatsky reaction between ethyl bromofluoroacetate and chiral
sulfinylimines has not been investigated and the resulting a-fluoro-b-amino acids may have potential medical
applications. In this paper we found that the diastereoselective preparation of a-fluoro-b-amino acids can be readily
achieved by the Reformatsky reaction of Ellman’s N-tert-butyl sulfinylimines with ethyl bromofluoroacetate.
N-tert-Butylsulfinimines 1 were prepared in good yields through Ti(OEt)4 mediated condensation of N-tert-butyl
sulfinylamide with aldehydes and ketones according to the reported procedures [7,8]. The Reformatsky reaction was
performed by the drop wise addition of a solution of 1 (1 equiv) and ethyl bromofluoroacetate (2 equiv) to a suspension
of activated Zn dust in THF at reflux. The addition reaction underwent smoothly and completed within 2 h as
monitored by thin layer chromatography (TLC). Four diastereomers were formed in the diastereoselective
Reformatsky reaction and could be separated from each other in two diastereomer set (I and II) by careful silica gel
* Corresponding author.
E-mail address: hyg@dhu.edu.cn (Y.G. Huang).
1001-8417/$ – see front matter # 2011 Yan Gen Huang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.01.037

920
Z.T. Jing et al. / Chinese Chemical Letters 22 (2011) 919–922
Table 1
The Reformatsky reactions of ethyl bromofluoroacetate with N-tert-butylsulfinimine .
[D$LINE]
a T
O
S
2
1
O
S
1
1
2
R
O
S
R
R
R
F
R
F
BrFCHCO Et
2
CO Et
CO Et
2
2
N
2
N
+
N
R
H
H
Zn, THF, reflux
(S)- 1 a-h
II
I
2 a-h
.
Entry
Substrate
R1
R2
Product
Yieldb (%)
I:IIc
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
H
H
C6H5
2-Br-C6H4
4-Br-C6H4
4-F-C6H4
2a
2b
2c
2d
2e
2f
74
86
80
77
84
70
85
82
77
73:27
92:8
H
80:20
69:31
73:27
66:34
80:20
71:29
64:36d
H
H
4-CH3-C6H4
4-CH3O-C6H4
i-Pr
H
1g
1h
1f
H
2g
2h
2f
Me
H
C6H5
4-CH3O-C6H4
a
1 (1 equiv), ethyl bromofluoroacetate (2 equiv), Zn (2 equiv), THF, reflux, 2 h.
Total yields of isolated products.
The ratios of I and II were determined by 1H NMR and 19F NMR analyses of the crude products.
Toluene was used as solvent.
b
c
d
chromatography except for 2g due to their close polarities. As listed in Table 1, the ratios of the two set of
diastereomers (I and II) were determined by 1H NMR and 19F NMR analyses of the crude products and were in the
range from 66:34 for electron donating group substituted aryl side chains such as p-methoxylphenyl (entries 6 and 9) to
92:8 for sterically hindered aryl side chains such as o-bromophenyl (entry 2). The reactions were efficient to achieve a-
fluoro-b-amino acid derivatives with good yields (70–86%) though the diastereoselectivities (from 66:34 to 92:8) were
not good enough as expected. The diastereomeric ratios were slightly lower than Staas’ results that the reaction of N-
tert-butylsulfinylimines with ethyl bromodifluoroacetate in the presence of zinc dust afforded a,a-difluoro-b-amino
acid derivatives in diastereomeric ratios ranging from 81:19 to 95:5 [3].
Single crystals of 2f were obtained from methanol solution of its diastereomers I. The absolute configuration of the
(SS,S,S)-2f was determined by single crystal X-ray diffraction analysis based on the chiral center of sulfur atom [10]. A
possible mechanism was proposed based on the stereochemical outcome of the addition reactions and previous reports
[3,7–9]. The addition of metal reagent to N-tert-butylsulfinylimines appears to proceed via six-membered chair-like
transition states T1 and T2 (Scheme 1), and T2 is the favored transition state to give the major product because both of
the bulky tert-butyl group and substituent in sulfinylimine could occupy equatorial positions. No diastereoselectivity
[()TD$FIG]
. .
S
O
S
R
R
H
F
BrZnCFHCO2Et
CO2Et
N
H
N
H
Zn
EtOOC
C
O
O
S
H
Br
II
Minor (SS, R)
H
F
T2
N
R = p-CH3OC6H4-
OCH3
. .
S
H
(S)- 1f
O
H
R
S
CO2Et
R
N
BrZnFCHCO2Et
N
H
Zn
EtOOC
C
O
F
Br
H
F
I
Major (SS, S)
T1
Scheme 1. Possible transition states in the Reformatsky reaction.

Z.T. Jing et al. / Chinese Chemical Letters 22 (2011) 919–922
921
Table 2
Acidic cleavage of amides to free amino acids.[TD$LINE]
R1 R2
R1 R2
1) 6N HCl
O
S
O
CO2H
2)
CO2Et
H2N
N
H
F
F
2 (I)
3
.
Entry
Substrate (I)
R1
R2
Product
Yield (%)a
1
2
3
5
6
7
8
2a
2b
2c
2d
2e
2f
H
C6H5
2-Br-C6H4
4-Br-C6H4
4-F-C6H4
3a
3b
3c
3d
3e
3f
70
92b
H
H
80
H
87
H
4-CH3-C6H4
4-CH3O-C6H4
C6H5
70
H
70
93b
2h
Me
3h
a
Isolated yields.
b
Isolated yields of a-fluoro-b-amino acids hydrochloride salt.
on the alpha carbon bearing a fluorine atom would be expected due to small steric difference between fluorine and
hydrogen atoms and freely rotation of carbon–carbon single bond in the Reformatsky reagents.
Finally, the protecting groups in the major products (I) of 2a–f, h were removed with 6N HCl at reflux and followed
by treatment with propylene oxide to afford the corresponding free a-fluoro-b-amino acids 3a–f, h in 70–93% yields
(Table 2).
In summary, we have developed a practical method for the asymmetric syntheses of a-fluoro-b-amino acids via
Reformatsky-type addition reaction between N-tert-butylsulfinylimine and ethyl bromofluoroacetate in good yields
(70–86%) and diastereoselectivities (66:34–92:8).
2. Experimental
2.1. General procedure for the Reformatsky reactions between sulfinylimines and ethyl bromofluoroacetate
A round-bottomed flask was flame dried, purged with argon, and charged with freshly activated zinc dust
(4.8 mmol) and dry THF (10 mL). Then a solution of sulfinylimine (2.4 mmol) and ethyl bromofluoroacetate
(4.8 mmol) in THF (6 mL) was added drop wise under reflux. The mixture was allowed to stir at reflux until the color
of zinc was changed from gray to brownish, typically, it takes 2 h, then the reaction mixture was cooled to room
temperature, quenched with saturated aqueous NH4Cl, and diluted with ethyl acetate. The aqueous layer was separated
and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed with brine, dried over
MgSO4, filtered and concentrated. The crude product was purified by flash chromatography to give the desired
product. 2a [isomer I]: white solid; mp 96–98 8C. 1H NMR (400 MHz, CDCl3): d 7.30–7.35 (m, 5 H), 5.28 (dd, 1 H,
J = 48.4, 4.4 Hz), 4.88 (dddd, 1 H, J = 28, 21.6, 6.4, 4.0 Hz), 4.27 (d, 1 H, J = 6.4 Hz), 4.10–4.19 (m, 2 H), 1.22 (s, 9
H), 1.14–1.17 (t, 3 H, J = 7.6 Hz). 19F NMR (376 MHz, CDCl3): d –200.64 (dd, 1 F, J = 48.0, 21.1 Hz).
2.2. General procedure for the cleavage of protecting group to afford free a-fluoro-b-amino acids
A solution of amide (0.3 mmol) in 6 mol/L HCl (10 mL) was refluxed for 4 h with stirring. The aqueous phase was
washed with ether (30 mL) and the aqueous solution was concentrated under reduced pressure to dryness. The
resulting solid was treated with i-PrOH (5 mL) and propylene oxide (2 mmol), and the reaction mixture was stirred for
5 h. Precipitate was collected by filtration and washed with ether to provide free amino acid. 3a: 1H NMR (400 MHz,
D2O): d 7.38–7.42 (m, 5H), 5.34 (dd, 1H, J = 50.8, 2.8 Hz), 4.85 (dd, 1H, J = 28.4, 3.2 Hz). 19F NMR (376 MHz, D2O)
d –197.21 (dd, 1 F, J = 48.5, 27.4 Hz).

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Z.T. Jing et al. / Chinese Chemical Letters 22 (2011) 919–922
Acknowledgments
The Shanghai Pujiang Program (No. 09PJ1400800) and the Fundamental Research Funds for the Central
Universities are greatly acknowledged for funding this work.
References
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