SmI2-promoted imino-Reformatsky reaction for facile synthesis of enantioenriched β-amino acid esters

Article abstract of DOI:10.1007/s11426-010-4180-z

A facile and efficient method for the stereoselective synthesis of β-amino acid esters via SmI₂-promoted imino-Reformatsky reaction is described. Asymmetric addition of tert-butyl bromoacetate to N-tert-butanesulfinyl aldimines afforded β-amino

Full text of DOI:10.1007/s11426-010-4180-z

SCIENCE CHINA
Chemistry
January 2011 Vol.54 No.1: 61–65
doi: 10.1007/s11426-010-4180-z
• ARTICLES •
· SPECIAL TOPIC · The Frontiers of Chemical Biology and Synthesis
SmI2-promoted imino-Reformatsky reaction for facile synthesis of
enantioenriched -amino acid esters
WANG Li, SHEN Chun & XU Ming-Hua*
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Received July 31, 2010; accepted August 31, 2010
A facile and efficient method for the stereoselective synthesis of -amino acid esters via SmI2-promoted imino-Reformatsky
reaction is described. Asymmetric addition of tert-butyl bromoacetate to N-tert-butanesulfinyl aldimines afforded -amino acid
esters in moderate to high yields with excellent diastereoselectivities. The synthetic utilities of the tert-butyl -amino acid es-
ters were expanded by the preparation of -lactams and 3-aminoindan-1-ones derivatives.
-amino acid ester, samarium diiodide, N-tert-butanesulfinyl imine, Reformatsky reaction, -lactam, 3-aminoindan-1-
one, asymmetric synthesis
iliaries for the advantages of good stereodirecting and facile
1 Introduction
removal [15–19]. In contrast to the classical Zn-induced
Reformatsky protocol, the application of other metal salts
such as samarium diiodide by diastereoselective samarium
enolate addition has received little attention in imino-Refor-
matsky reaction [9]. As part of our effort to develop effi-
cient new methods for synthesis of diverse structurally im-
portant molecules, we herein report our findings on the use
of SmI2 for asymmetric Reformatsky reaction of N-tert-
butanesulfinyl imine.
We have previously reported SmI2-induced asymmetric
synthesis of optically pure symmetrical and unsymmetrical
vicinal diamines and -amino alcohols by N-tert-butane-
sulfinyl imine-based reductive homocoupling and cross-
coupling [20–22]. In these studies, a Sm(III)-N-sulfinyl im-
ine chelation model has been proposed to account for the
observed excellent reaction stereoselectivities. With this in
mind, we envisioned that the similar chelation control might
also occur in SmI2-promoted Reformatsky reactions between
-halo esters and N-tert-butanesulfinyl imines, possibly
facilitating the formation of -amino acid ester products
with high diastereoselectivities.
-Amino acid structural units are frequently found in nature
products and pharmacologically important molecules, such
as Cispentacin, (R)--dopa, Moiramide B, Sperabillins, and
Andrimid [1–3]. Furthermore, -amino acid derivatives are
also precursors of many other biologically active com-
pounds, especially -lactams [4–6]. Due to this importance,
the development of the synthetic method to access -amino
acids is of great interest to organic and medicinal chemists.
During the last decade, significant effort has been devoted
to the stereoselective synthesis of these valuable materials
[3, 7]. Of the methods developed, asymmetric addition of
Reformatsky-type reagents to imines is known as an attrac-
tive strategy for optically active -amino acid esters prepa-
ration. In recent years, a number of different chiral auxilia-
ries [8–13] as well as catalysts [14] has been introduced to
provide the products with high stereoselectivities. Among
them, the chiral sulfoxides are found as one of the best aux-
*Corresponding author (email: xumh@mail.shcnc.ac.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2011
chem.scichina.com
www.springerlink.com

62
Wang L, et al. Sci China Chem January (2011) Vol.54 No.1
24.1, 27.9, 42.1, 52.5, 55.3, 55.7, 81.1, 110.5, 120.3, 128.1,
2 Experimental
128.6, 128.9, 156.5, 170.7. HRMS-ESI (m/z): [M + H]+
2.1 General information
calcd for C18H30N1O4S1, 356.1883; found, 356.1890.
1
3e H NMR (300 MHz, CDCl3):  1.23 (s, 9H), 1.41 (s,
THF was distilled from sodium/benzophenone. CH2I2 and
tert-butyl bromoacetate were distilled in vacuum. Reactions
were monitored by thin layer chromatography (TLC) on
glass plates coated with silica gel with fluorescent indicator
(Huanghai HSGF254). Flash chromatography was per-
formed on silicagel (Huanghai 300–400) with hexane/
EtOAc as eluent. Mass spectra were recorded on HP-5989
instrument and HRMS were measured on a Finnigan
MA+mass spectrometer. NMR spectra were recorded on a
Varian or a Bruker spectrometer (300 MHz), and chemical
shifts are reported in  (ppm) referenced to an internal TMS
standard 1HNMR and CDCl3 (77.0 ppm) for 13CNMR.
9H), 2.75 (d, 2H, J = 6.3 Hz), 3.80 (s, 3H), 4.63 (d, 1H, J=
2.7 Hz), 4.70–4.75 (m, 1H), 6.81–6.93 (m, 3H), 7.22–7.27
(m, 1H). 13C NMR (75 MHz, CDCl3):  22.6, 28.0, 43.6,
55.2, 55.5, 55.6, 81.7, 112.8, 113.3, 119.6, 129.5, 142.5, 159.7,
170.4. HRMS-ESI (m/z): [M + H]+ calcd for C18H30N1O4S1,
356.1883; found, 356.1890.
1
3f H NMR (300 MHz, CDCl3):  1.21 (s, 9H), 1.40 (s,
9H), 2.73 (m, 2H), 3.80 (s, 3H), 4.56 (d, 1H, J = 2.7 Hz),
4.68–4.73 (m, 1H), 6.86 (d, 2H, J =8.7 Hz), 7.25 (d, 2H, J=
8.7 Hz). 13C NMR (75 MHz, CDCl3):  22.6, 28.0, 43.6,
54.9, 55.2, 55.5, 81.6, 113.8, 128.5, 132.6, 159.1, 170.5.
HRMS-ESI (m/z): [M + H]+ calcd for C18H30N1O4S1,
356.1883; found, 356.1890.
2.2 Starting materials procedure
1
3g H NMR (300 MHz, CDCl3):  1.23 (s, 9H), 1.40 (s,
9H), 2.74 (d, 2H, J = 6.3 Hz), 4.65 (d, 1H, J = 3.9 Hz),
4.66–4.76 (m, 1H), 7.27–7.34 (m, 4H). 13C NMR (75 MHz,
CDCl3):  22.6, 28.0, 29.7, 43.3, 55.0, 55.7, 81.9, 128.7,
133.6, 139.3, 170.2. HRMS-ESI (m/z): [M + H]+ calcd for
C17H27Cl1N1O3S1, 360.1400; found, 360.1395.
Chiral N-tert-butanesulfinyl imines (1a–i) were prepared
from the chiral tert-butanesulfinamide and the correspond-
ing aldehydes by the known method [23, 24].
2.3 General procedure for asymmetric synthesis of -
amino acid esters and characterization
1
3h H NMR (300 MHz, CDCl3):  1.22 (s, 9H), 1.37 (s,
9H), 2.83 (m, 2H, J = 6.0 Hz), 4.74 (d, 1H, J = 4.8 Hz),
4.77–4.83 (m, 1H), 7.27–7.32 (m, 1H), 7.67 (d, 1H, J = 7.2
Hz), 8.55 (d, 1H, J = 4.8 Hz), 8.63 (s, 1H). 13C NMR (75
MHz, CDCl3):  22.6, 27.9, 43.0, 53.6, 55.9, 82.1, 123.4,
135.1, 136.4, 148.9, 149.1, 170.0. HRMS-ESI (m/z): [M +
H]+ calcd for C16H27N2O3S1, 327.1738; found, 327.1737.
CH2I2 (0.8 mmol) was added at room temperature to a
Schlenk flask containing samarium powder (0.8 mmol) and
freshly distilled THF (3 mL) under nitrogen. After stirring
for 30 min at rt, the dark green colored mixture was cooled
to 78 °C. Then N-tert-butanesulfinyl imine (0.2 mmol) was
added, followed by tert-butyl bromoacetate (0.4 mmol, dis-
solved in 1 mL THF) being added dropwise over 10 min.
The resulting mixture was stirred at 78 °C for 2 h,
quenched with aqueous NH4Cl, and extracted with ethyl
acetate. The combined organic layers were dried over anhy-
drous Na2SO4, filtered, and concentrated. The residue was
purified by silica gel column chromatography to afford the
corresponding -amino acid esters 3.
1
3i H NMR (300 MHz, CDCl3):  1.22 (s, 9H), 1.37 (s,
9H), 2.97–3.00 (m, 2H), 4.75 (d, 1H, J = 3.9 Hz), 5.53–5.59
(m, 1H), 7.43–7.59 (m, 4H), 7.79 (d, 1H, J = 8.1 Hz), 7.87
(d, 1H, J = 8.4 Hz), 8.18 (d, 1H, J = 8.4 Hz). 13C NMR (75
MHz, CDCl3):  22.6, 27.9, 29.7, 42.8, 52.6, 55.8, 81.6,
123.2, 125.0, 125.2, 125.7, 126.3, 128.5, 129.0, 130.7,
133.9, 136.2, 170.6. HRMS-ESI (m/z): [M + H]+ calcd for
C21H30 N1O3S1, 376.1956; found, 376.1941.
1
3b H NMR (300 MHz, CDCl3):  1.24 (s, 9H), 1.41 (s,
9H), 2.79 (d, 2H, J = 6.3 Hz), 4.63 (d, 1H, J = 3.6 Hz),
4.74–4.80 (m, 1H), 7.28–7.36 (m, 5H). 13C NMR (75 MHz,
CDCl3):  22.6, 28.0, 43.6, 55.6, 81.6, 127.3, 127.8, 128.5,
140.7, 170.4.
2.4 General procedure for synthesis of -lactam 4 and
characterization
Compound 3 (0.3 mmol) was added to a solution of HCl in
dioxane (4 N, 10 mL) and the mixture was stirred at room
temperature for 0.5 h. After removing the solvent in vacuum,
the resulting crude product was dissolved in CH3CN (30 mL),
followed by the addition of NaHCO3 (151 mg, 1.8 mmol)
and MsCl (92 L, 1.2 mmol). The mixture was further
stirred at 60 °C for 8 h, then quenched with H2O (10 mL). The
solution was extracted with ethyl acetate. The combined
organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated. The residue was purified by column
chromatography on silica gel to afford the corresponding
-lactam 4.
1
3c H NMR (300 MHz, CDCl3):  1.21 (s, 9H), 1.39 (s,
9H), 2.43 (s, 3H), 2.73–2.77 (m, 2H), 4.55 (d, 1H, J = 4.5
Hz), 4.50–5.03 (m, 1H), 7.17–7.21 (m, 3H), 7.32–7.35 (m,
1H). 13C NMR (75 MHz, CDCl3):  19.4, 22.6, 27.9, 42.6,
51.5, 55.6, 81.5, 126.1, 126.7, 127.6, 130.6, 135.9, 138.5,
170.5. HRMS-ESI (m/z): [M + H]+ calcd for C18H30N1O3S1,
340.1939; found, 340.1941.
1
3d H NMR (300 MHz, CDCl3):  1.21 (s, 9H), 1.36 (s,
9H), 2.88 (dd, 2H, J=6.3 Hz, J=2.7 Hz ), 3.87 (s, 3H), 4.74
(d, 1H, J = 7.2 Hz), 5.00–5.07 (m, 1H), 6.87–6.95 (m, 2H),
7.26–7.30 (m, 2H). 13C NMR (75 MHz, CDCl3):  22.6,

Wang L, et al. Sci China Chem January (2011) Vol.54 No.1
63
1
4a (35 mg, yield 80% in two steps) Lit. [25]. H NMR
(300 MHz, CDCl3):  2.83–2.88 (dd, 1H, J = 15.0 Hz, J =
0.9 Hz), 3.40–3.46 (m, 1H), 4.71–4.73 (m, 1H), 6.72 (br,
1H), 7.32–7.38 (m, 5H). HPLC: Chiracel OD-H Column
(250 mm); detected at 220 nm; n-hexane/i-propanol =90/10;
flow = 0.7 mL/min; retention times: 13.93 min [(R)-enant-
iomer], 17.09 min [(S)-enantiomer].
3.27–3.36 (m, 1H), 5.70–5.71 (m, 1H), 6.74 (br, 1H), 7.57
(d, 1H, J = 0.9 Hz) 7.67–7.73 (m, 2H). HPLC: Chiracel
AS-H Column (250 mm); detected at 220 nm; n-hexane/
i-propanol = 90/10; flow = 0.7 mL/min; retention times:
11.78 min [(R)-enantiomer], 12.97 min [(S)-enantiomer].
3 Results and discussion
1
4b (40 mg, yield 75% in two steps) Lit. [26]. H NMR
(300 MHz, CDCl3):  2.86–2.91 (dd, 1H, J = 15.0 Hz, J =
2.1 Hz), 3.40–3.48 (m, 1H), 3.82 (s, 3H), 4.70–4.72 (m, 1H),
6.17 (br, 1H), 6.84–6.97 (m, 3H), 7.26–7.33 (m, 1H). HPLC:
Chiracel OD-H Column (250 mm); detected at 220 nm;
n-hexane/i-propanol = 90/10; flow = 0.7 mL/min; retention
times: 14.06 min [(S)-enantiomer], 14.8 min [(R)-enantiomer].
We initiated our study by reacting (R)-N-tert-butanesulfi-
nyl imine 1a with ethyl bromoacetate 2a in the presence of
5 equiv of SmI2 in THF at 78 °C (Table 1, entry 1). Un-
fortunately, only a trace amount of product was observed
possibly due to self-addition of 2a [29–31]. To our delight,
the reaction proceeded smoothly and afforded the expected
-amino acid ester product 3b with excellent diastereoselec-
tivity (93% de) in 66% yield, when tert-butyl bromoacetate
2b was used instead (entry 2). A slightly decreased de value
of 88% was obtained when the reaction temperature was
raised to 40 °C (entry 3). HMPA was found to have no
influence on the reaction diastereoselectivity, but cause de-
leterious effect on yield when the amount was more than 1
equiv (entries 5–7). Decreasing the amount of tert-butyl
bromoacetate or SmI2 resulted in the lower yield of 3b (20%
and 51% respectively, entries 8, 9). Gratifyingly, the reaction
4c (41 mg, yield 76% in two steps) Lit. [25]. []D24
=
97.1 (c 0.55, EtOH). 1H NMR (300 MHz, CDCl3): 
2.81–2.89 (m, 1H), 3.41–3.49 (m, 1H), 4.71 (dd, 1H, J=5.1
Hz, J = 2.4 Hz), 6.43 (br, 1H), 7.28–7.38 (m, 4H). HPLC:
Chiracel OD-H Column (250 mm); detected at 220 nm;
n-hexane/i-propanol = 90/10; flow = 0.7 mL/min; retention
times: 11.8 min [(R)-enantiomer], 13.0 min [(S)-enantiomer].
2.5 General procedure for synthesis of 3-aminoindan-
1-one 6 and characterization
Compound 3 (0.5 mmol) was added to a solution of HCl in
dioxane (4 N, 10 mL) and the mixture was stirred at room
temperature for 0.5 h. After removing the solvent in vacuum,
the resulting crude product was dissolved in (CF3CO)2O (1
mL). The solvent was removed in vacuum after stirring at
room temperature for 0.5 h. The residue was dissolved in
CF3COOH (2 mL) and stirred at room temperature for 3 h.
The solution was poured into sat. aq. NaHCO3, then ex-
tracted with ethyl acetate. The combined organic layers
were dried over anhydrous Na2SO4, filtered, and concen-
trated. The residue was purified by column chromatography
on silica gel to afford the corresponding 3-aminoindan-1-
one 6.
Table 1 Optimization of reaction conditions
SmI2
(equiv)
Entry a)
T (°C)
Time (h) Yield (%) b)
de (%)c)
1 d)
2
5
2
2
2
2
4
4
4
2
2
2
trace
66
66
40
23
60
65
20
51
80
78
78
40
20
78
78
78
78
78
78

93
88

5
5
5
5
5
5
5
3
4
6a (92 mg, yield 76% in two steps) Lit. [27]. 1H NMR (300
MHz, CDCl3):  2.67–2.74 (dd, 1H, J=18.6 Hz, J=3.6 Hz),
3.18–3.27 (dd, 1H, J = 18.6 Hz, J = 7.8 Hz), 5.75–5.82 (m,
1H), 7.55–7.60 (m, 1H), 7.69–7.80 (m, 3H), 9.01 (br, 1H).
HPLC: Chiracel AS-H Column (250 mm); detected at 220
nm; n-hexane/i-propanol=90/10; flow=0.7 mL/min; retention
times: 17.2 min [(S)-enantiomer], 23.8 min [(R)-enantiomer].
6b (88 mg, yield 65% in two steps) Lit. [28]. 1H NMR (300
MHz, CDCl3):  2.51–2.59 (dd, 1H, J=19.2 Hz, J=3.6 Hz),
3.22–3.30 (dd, 1H, J = 19.2 Hz, J = 7.8 Hz), 3.82 (s, 3H),
5.63–5.70 (m, 1H), 6.62 (br, 1H), 7.52–7.55 (m, 3H). HPLC:
Chiracel AS-H Column (250 mm); detected at 220 nm;
n-hexane/i-propanol = 90/10; flow = 0.7 mL/min; retention
times: 7.13 min [(R)-enantiomer], 9.01 min [(S)-enantiomer].
6c (108 mg, yield 78% in two steps) Lit. [27]. 1H NMR (300
MHz, CDCl3):  2.59–2.66 (dd, 1H, J=19.2 Hz, J=3.3 Hz),
3
4
5 e)
6 f)
7 g)
8 h)
9

93
92


10 i)
95
a) Unless otherwise noted, 2 equiv of tert-butyl ester 2b was used, and
the concentration of SmI2 was 0.1 M in the reaction system. b) Isolated
yield. c) de was measured as enantiomeric excess for the acetate derivative
of 3b after the removal of the sulfinyl group; determined by HPLC analysis.
d) 2 equiv of 2a was used as additive. e) 2 equiv of HMPA was used as
additive. f) 1 equiv of HMPA was added. g) 0.5 equiv of HMPA was added.
h) 1.2 equiv of ester 2b was used. i) 2b was dissolved in THF and added
over 10 minutes.

64
Wang L, et al. Sci China Chem January (2011) Vol.54 No.1
A plausible reaction mechanism for the observed stereo-
selective addition process is presented in Scheme 2. Upon
treatment with SmI2, the tert-butyl bromoacetate (2b) is
reduced to generate samarium enolate [30, 31], which then
undergoes intermolecular addition to the C=N bond of the
N-tert-butanesulfinyl imine. Because of the coordination of
the sulfinyl moiety in the imine intermediate to the enolate
samarium, the Zimmerman-Traxler type six-membered
transition state 5 favors approach of the enolate from the
Si-face of N-sulfinyl imine 1 [20, 21, 33]. Therefore, the
addition reaction takes place with high stereospecificity to
give (S)-product.
afforded 3b in improved yield (80%) at 78 °C when
tert-butyl bromoacetate 2b was added to the reaction mix-
ture over 10 minutes as a solution of THF (entry 10).
With the optimized conditions in hand, the scope of this
reaction with various aryl-substituted aldimines was ex-
plored (Table 2). In all cases, the desired -amino acid es-
ters with high des (95%–97%) were obtained in moderate to
good yields. Substitution groups on the aromatic ring did
not seem to affect the reaction rate as well as diastereose-
lectivity significantly. Moreover, the phenyl substitution
could be extended to other aromatics, such as pyridyl and
naphthyl.
To highlight the synthetic utility, rapid construction of a
series of -lactams and 3-aminoindan-1-ones was perfor-
med. Both of these compounds are valuable intermediates
and exhibit interesting biological activities [34, 35]. With
the obtained -amino acid esters, the sulfinyl group and
tert-butyl ester can be easily cleaved by acidic hydrolysis in
one step to give free -amino acids in high yields, which
then undergo further lactamization [32] or Friedel-Crafts
acylation [36] conveniently to furnish the corresponding
-lactams (4) and 3-aminoindan-1-ones (6) without loss of
enantioselectivity (Scheme 3).
To determine the absolute configuration of the products,
compound 3g was chosen to convert into the known
-lactam for further optical rotation study. As illustrated in
Scheme 1, removal of the sulfinyl group and tert-butyl ester
under acidic conditions, followed by cyclization using the
literature procedure [32], afforded the corresponding
-lactam 4c in good yield. The chirl HPLC analysis of 4c
clearly revealed its excellent enantiomeric excess (95% ee),
and the major enantiomer is speculated to has S configura-
tion by comparison to literature optical rotation value [25].
Table 2 Asymmetric synthesis of -amino acid esters
Entry a)
Ar
Product
3b
Yield (%) b)
de (%) c)
95
1
Ph
80
74
92
77
77
90
65
82
2
2-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-ClC6H4
3c
97
3
4 d)
3d
97
3e
95
5
3f
97
Scheme 2 Proposed reaction mechanism.
6
3g
95
7
3-pyridyl
3h
95
8
1-naphthyl
3i
95
a) Reactions were carried out on a 0.2 mmol scale under N2 with 2 equiv
of ester 2b and 4 equiv of SmI2 at 78 °C. b) Isolated yield. c) de was
measured as enantiomeric excess for the acetate derivative of 3 after their
removal of the sulfinyl group; determined by HPLC analysis. d) de was
measured as enantiomeric excess for its -lactam derivative; determined by
HPLC analysis.
Scheme 3 Access to -lactams and 3-aminoindan-1-ones.
Scheme 1 Determination of the absolute configuration.

Wang L, et al. Sci China Chem January (2011) Vol.54 No.1
65
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4 Conclusions
In summary, a facile and efficient method for the asymmet-
ric synthesis of -amino acid esters via SmI2-promoted
imino-Reformatsky reaction using N-tert-butanesulfinyl
imine is described. A series of highly enantiomerically en-
riched -amino acid esters has been easily accessed in good
yields. Moreover, conversion the resulting -amino acid esters
into -lactams and 3-aminoindan-1-ones were accomplished
with ease by taking advantage on the facile sulfinyl removal
and ester hydrolysis. Further extension of this methodology
is now under investigation in our laboratory.
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Financial support from the National Natural Science Foundation of China
(20721003), the Chinese Academy of Sciences, the State Key Laboratory of
Drug Research, SIMM and National Science & Technology Major Project
(2009ZX09301-001 & 2008ZX09401-004) is acknowledged.
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