Cu(II)-catalyzed enantioselective 1,3-dipolar cycloaddition of nitrones with α, β-unsaturated acyl phosphonates

Article abstract of DOI:10.1016/j.tet.2017.03.086

A highly enantioselective 1, 3-dipolar cycloaddition of nitrone with α, β-unsaturated acyl phosphonate was developed for the first time by using a chiral indane-bis(oxazoline)-copper(II) complex. The reaction proceeded smoothly under mild conditions to provide isoxazolidines with multi-stereocenters in good yields with high to excellent diastereo- (>20:1 dr) and enantioselectivities (up to 99% ee). The resulting products were readily converted to multi-functional isoxazolidines or γ-amino alcohol compounds.

Full text of DOI:10.1016/j.tet.2017.03.086

Accepted Manuscript
Cu(II)-catalyzed enantioselective 1,3-dipolar cycloaddition of nitrones with α, β-
unsaturated acyl phosphonates
Lei Xie, Hui Bai, Jiaqi Li, Xuan Yu, Zhenhua Zhang, Bin Fu
PII:
S0040-4020(17)30355-1
10.1016/j.tet.2017.03.086
TET 28592
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 February 2017
Revised Date: 27 March 2017
Accepted Date: 31 March 2017
Please cite this article as: Xie L, Bai H, Li J, Yu X, Zhang Z, Fu B, Cu(II)-catalyzed enantioselective
1,3-dipolar cycloaddition of nitrones with α, β-unsaturated acyl phosphonates, Tetrahedron (2017), doi:
10.1016/j.tet.2017.03.086.
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ACCEPTED MANUSCRIPT
Cu(II)-Catalyzed Enantioselective 1,3-Dipolar Cycloaddition of Nitrones with α,
β-Unsaturated Acyl Phosphonates
Lei Xie, Hui Bai, Jiaqi Li, Xuan Yu, Zhenhua Zhang, Bin Fu*
Department of Applied Chemistry, China Agricultural University, Beijing 100193, P. R. China
O
Ph
O
Ph
alkyl
O
N
N
O
1) Cu(OTf)2-L1
Alkyl
P
OEt
OEt
+
CO2Me
R2
2) MeOH, DBU
R2
O
O
up to > 20:1d.r
and >99% ee,
25 examples
N
N
L1 =

ACCEPTED MANUSCRIPT
Cu(II)-Catalyzed Enantioselective 1,3-Dipolar Cycloaddition of Nitrones with α,
β-Unsaturated Acyl Phosphonates
Lei Xie, Hui Bai, Jiaqi Li, Xuan Yu, Zhenhua Zhang, Bin Fu*
Department of Applied Chemistry, China Agricultural University, Beijing 100193, P. R. China
Abstract
A highly enantioselective 1, 3-dipolar cycloaddition of nitrone with α, β-unsaturated acyl phosphonate was
developed for the first time by using a chiral indane-bis(oxazoline)-copper(II) complex. The reaction proceeded
smoothly under mild conditions to provide isoxazolidines with multi-stereocenters in good yields with high to
excellent diastereo- (>20:1 dr) and enantioselectivities (up to 99% ee). The resulting products were readily
converted to multi-functional isoxazolidines or γ-amino alcohol compounds.
Keywords: Dipolar cycloaddition; nitrone; isoxazolidine; α, β-unsaturated acyl phosphonate
1. Introduction
The asymmetric 1, 3-dipolar cycloaddition reactions provide efficient and reliable access to
enantiomerically enriched five-membered heterocyclic systems.1. In particular, the 1, 3-dipolar
cycloaddition of nitrones to electron-deficient alkenes or alkynes afford one powerful method for
the construction of highly substituted isoxazolidine rings.2 which is usually the core framework of
many biologically active compounds and readily converted into β- or γ-amino alcohols and others.
Since the pioneering works of Scheeren3 and Jørgensen4 in 1994, a plenthora of chiral metal
complexes and organocatalysts have been successfully developed for the catalytic asymmetric 1,
3-DC of nitrones. Generally, the dipolarophiles are always limited to N-alkenoyl derivatives of
oxazolidinone,5 thiazolidinethione,6 pyrrolidinone,7 and pyrazolidinone,8 as well as alkylidene
malonate,9 pyridinyl N-oxide,10 α-hydroxy enones,11 and so on.12
On the other hand, α, β-unsaturated acyl phosphonates as a class of useful synthon have been
applied in enantioselective Michael addition and cycloaddition reaction.13 The existing
phosphonates have strong electron-withdrawing nature, coordination ability with metal and easy
transformation to other functional group. However, to the best of our knowledge, α, β-unsaturated
acyl phosphonates as dipolarophiles have never been used in catalytic asymmetric 1,3-DC of
nitrones. In our ongoing research and continuing interest in the development of concise and
efficient catalytic asymmetric methods,14 we recently explored a highly diastereo- and
enantioselective 1,3-dipolar cycloaddition of nitrones with α, β-unsaturated acyl carboxylates
catalyzed by an indane-BOX–Ni(II) complex.15 As a result, we envisioned that the reaction of α,
β-unsaturated acyl phosphonates with nitrones could proceed smoothly to afford optical
isoxazolidine products in good diastereo- and enantioselectivities in the presence of appropriate
Lewis acid catalyst(Scheme 1). We herein report our investigations on this process.
O
O
Ph
O
Ph
R
N
1) Metal-Ligand
2) MeOH, DBU
N
+
R
P
OEt
OEt
Ar
Ar
CO Me
2
1
2
3
Scheme 1
2. Results and discussion
Initially, β-Me substituted unsaturated acyl phosphonate 1a and nitrone 2a as model
1

ACCEPTED MANUSCRIPT
substrates were used for the condition optimization. The results are illustrated in Table 1 (detailed
results see ST1). The reaction was first carried out in CH2Cl2 at 0oC for 12 hours using a 11mol%
bisoxazoline L1 and 10 mol% metal salt as catalyst,15 in most cases the desired product 3aa was
obtained in moderate yields and ee values. Gratifyingly, the indane-BOX L1-Cu(OTf)2 complex
offered a high yield of product 3aa with excellent diastereo- and enantioselectivity (entry 4, 82%
yield, endo/exo > 20:1, and 96% ee). Subsequently, other bisoxazoline (BOX) ligands were
examined, and L2 also gave rise to almost the same enantioselectivity and reactivity as L1, albeit
other ligands furnished lower yields or ee values (entries 6-8). Moreover, a series of solvents were
screened. Notably, the reaction was completed in CHCl3 within 1 hour, and afforded 3aa in 94%
yield with 98% ee, exhibiting excellent reactivity and enantioselectivity. The next attempt to
increase the temperature to room temperature resulted in a slight decrease in the enantioselectivity
to 95% ee (entry 14). Pleasingly, the catalyst loading could be reduced to 5mol% without any loss
of the stereoselectivity and reactivity (entry 15, detailed screening results see ST1). Therefore, the
optimal reaction condition was identified as following: 5 mol% L1-Cu(OTf)2, CHCl3 as solvent
and 0oC.
Table 1. Optimization of the reaction conditions.a
O
Ph
O
N
O
Ph
N
1) Metal-Ligand
2) MeOH, DBU
Me
P
+
OEt
OEt
1a
Ph
CO2Me
2a
3aa
O
O
O
O
O
O
O
O
N
N
Ph
N
N
Ph
N
N
N
N
Ph
Ph
i-Pr
i-Pr
L1
L4
L3
L2
Entry
1
Metal
Ligand
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
L1
L1
L1
L1
Solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
DCE
Yield(%)b
39
ee (%)c
33
Ni(ClO4)2·6H2O
Mg(ClO4) 2·6H2O
Cu(ClO4) 2·6H2O
Cu(OTf)2
2
51
31
3
71
87
4
82
96
5
Zn(OTf)2
53
56
6
Cu(OTf)2
78
96
7
Cu(OTf)2
77
57
8
Cu(OTf)2
77
35
9
Cu(OTf)2
94
98
10
11
12
13
14 d
15e
Cu(OTf)2
80
95
Cu(OTf)2
AcOEt
Toluene
THF
84
97
Cu(OTf)2
45
96
Cu(OTf)2
74
97
Cu(OTf)2
CHCl3
CHCl3
95
95
Cu(OTf)2
94
98
[a] Unless otherwise noted, reactions were conducted with Ligand–metal (1.1 :1, 10 mol%), 1a (0.3 mmol), and 2a
(0.25 mmol) in solvent (2.0 mL) at 0oC for 1~12h. [b] Isolated yields. [c] Unless otherwise stated, dr > 20:1, as
2

ACCEPTED MANUSCRIPT
determined by 1H NMR spectroscopy and chiral HPLC. [d] at rt. [e] 5 mol% L1-Cu(OTf)2.
With the optimized condition in hand, we next investigated the scope of unsaturated acyl
phosphonates in this reaction, as shown in Table 2. Various β-alkylated unsaturated acyl
phosphonates were evaluated. All the reactions proceeded to completion within 1 hour, giving the
cycloadducts 3 in high yields with excellent enantioselectivities (entries 1-4). Unfortunately, in the
case of β-phenyl substituted unsaturated acyl phosphonate the reaction didn’t occurred, even
prolonging the reaction time to 48h and elevating the reaction temperature to rt (entry 5).
Moreover, other nucleophiles including ethanol, benzyl alcohol, and p-Bromobenzylamine were
examined, more higher reactivity and equal excellent enantioselectivity were exhibited (entries
6-8).
Table 2. The scope of unsaturated acyl phosphonates and nucleophiles.
O
R1
Nu
Ph
O
Ph
N
O
N
1) Cu(OTf)2-L1
2) NuH , DBU
+
R1
P
OEt
OEt
O
2a
3ab-3ai
1
R1
Entry
NuH
Time(h)
Yield (%)b
Ee (%)c
98
1
2
3
4
5
6
7
8
Et
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
1
1
87(3ab)
90(3ac)
82(3ad)
94(3ae)
-(3af)
n-Pr
99
iso-Pr
1
98
n-Hexyl
Ph
1
>99
-
48
1
Me
95(3ag)
92(3ah)
93(3ai)
97
Me
BnOH
1
96
Me
p-BrC6H4NH2
1
95
[a] Unless otherwise noted, reactions were performed with L1–Cu(OTf)2 (1.1 :1, 5 mol%), 1 (0.3 mmol), and 2a
(0.25 mmol) in CHCl3 (2.5 mL) at 0 for the indicated time. [b] Yields of isolated products. [c] The ee value was
determined by chiral HPLC analysis, only one diastereomer was detected by 1H NMR.
Next, the substrate scope was further extended by variation of nitrones, as summarized in
Table 3. A series of different substituted phenyl group 2b-n were first investigated. In most
cases the reaction was completed within 1 h, and afforded the desired products 3ba~na in good to
excellent yields. Moreover excellent diastereo- and enantio- selectivity was observed for almost
all tested substrates (>20:1 dr, 93-98%ee, entries 1~13). However, only 2-methoxyl phenyl
substituted substrate 2la afforded one couple of diastereomers with 16:9 dr value (93% ee for
major isomer, and 71% ee for minor isomer, respectively). Furthermore, other aryl substituted
nitrones including 2-naphthyl and 2-furyl group were also suitable substrates, giving the adducts
in 97% ee values. Even styryl group was also well tolerated in this reaction, leading to 3qa in
good yield with 95% ee value (entry 16). Unfortunately, N-phenyl nitrone with methyl group and
N-methyl nitrone as substrates the reaction didn’t occurred even with an increase of the reaction
temperature to rt for 72 h(entries 17 and 18).
Table 3. The scope of nitrones.a
3

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O
O
R2
O
O
R2
Me
N
N
Me
P
OEt
1) Cu(OTf)2-L1
+
OEt
R1
R1
2) MeOH , DBU
CO2Me
1a
2
3ba-3bq
Entry
1
R1
R2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Time(h) Yield (%)b
dr c
ee (%)d
4-MeC6H4
4-MeOC6H4
4-Cl C6H4
4-Br C6H4
4-CNC6H4
4-NO2 C6H4
3-Me C6H4
3-F C6H4
1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
16:9
98
82(3ba)
87(3ca)
80(3da)
75(3ea)
93(3fa)
96(3ga)
91(3ha)
86(3ia)
75(3ja)
60(3ka)
66(3la)
91(3ma)
80(3na)
95(3oa)
88(3pa)
64(3qa)
-
1
96
2
1
98
3
1
98
4
1
98
5
1
97
6
1
98
7
1
98
8
3-Br C6H4
3-CF3 C6H4
2-MeO C6H4
2-F C6H4
1
96
9
1
96
10
11 d
12
13
14
15
16
17
18
10
1
93% (major isomer)
>20:1
>20:1
>20:1
>20:1
>20:1
-
94
97
97
97
95
-
3,4-di-Br C6H4 Ph
1
2-naphthyl
2-furyl
Ph
Ph
1
1
C6H5-CH=CH- Ph
10
72
72
Ph
Me
Ph
Me
-
-
-
[a] Unless otherwise noted, reactions were performed with L1–Cu(OTf)2 (1.1 :1, 5 mol%), 1a (0.3 mmol), and 2
(0.25 mmol) in CHCl3 (2.5 mL) at 0 for the indicated time. [b] Isolated yields. [c] Only one diastereomer was
detected by 1H NMR except for special statement. [d] The ee value was determined by chiral HPLC analysis.
The absolute configuration of the cycloadduct 3ai was determined to be (3S, 4R, 5S) by
X-ray diffraction analysis, as illustrated in Fig 1.16 The absolute configuration of other
cycloadducts were also assigned by analogy. Based on the observed stereochemistry in this study
we believe that the dipolarophile (unsaturated acyl phosphonate) firstly coordinates to the
Cu(II)-BOX complex through a 1, 4-coordinate pattern and is hence activated, as illustrated in Fig
1. Subsequently nitrone preferentially approaches the dipolarophile from the Re-face of the double
bond due to the steric hindrance between the Si-face indane moiety of ligand and the C-aryl group
of nitrone, leading to the major(3S, 4R, 5S)-configured isoxazolidine product. The detailed
mechanism remains to be further investigated.
4

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O
N
O
O
Me
O-
O
N
N
HN
Cu
O
Ph
N
+
C
O
P
OEt
Ph
EtO
Re-face favored
Br
Fig.1 The absolute configuration of 3ai and the possible transition model
To show the practicality of the present method, the resulting isoxazolidines could be
further transformed to useful compounds. For example, treatment of 3aa (98%ee) with
LiAlH4 led to the formation of corresponding alcohol, then which was reacted with 2,
4-dichlorobenzoic acid in the presence of DCC/DMAP to afford the corresponding ester 4 in
almost quantitative yield (Scheme 2(a)).17 When 3aa was hydrogenated by Pd/C in AcOEt,
chiral γ-amino alcohol 5 was obtained in good yield without any loss of diastereo- and
enantioselectivity (Scheme 2(b)).18
O
N
O
Ph
Cl
N
1) LiAlH
4
O
O
2) DCC, DMAP,
2,4-Dichlorobenzoic acid
(a)
Cl
Ph
CO Me
2
3aa
4
95% yield and 96% ee
Ph
O
Ph
N
Ph
NH
H , Pd/C, -10
2
OH
Ph
CO Me
2
(b)
MeO C
2
3aa
5
80% yield and 98% ee
Scheme 2. The transformation of isoxazolidine 3aa
3. Conclusion
In summary, we have developed an asymmetric 1, 3-dipolar cycloadditions of nitrones with
unsaturated acyl phosphonate for the first time. Under the catalysis of
indane-bis(oxazoline)-Cu(OTf)2 the reaction can proceed to completion within 1h in most cases,
providing the isoxazolidines in high to excellent diastereo- and enantiosectivities. N-phenyl
substitution in nitrone is important for the reactivity and stereoselectivity of the reaction. The
synthetic application of this methodology was illustrated by the facile transformation of the
cycloadduct into other isoxazolidine derivative and amino alcohol with maintained enantiopurity.
This work well complements our previous report in the chiral Lewis acid-catalyzed asymmetric 1,
3-dipolar cycloaddition of nitrones.15
4. Experimental Section
4.1. General
The 1H and 13C NMR spectra were recorded on a Bruker Avance DPX300 instrument in CDCl3
5

ACCEPTED MANUSCRIPT
solution with TMS as internal standard. Optical rotations were measured on a PerkineElmer 341
LC polarimeter. Infrared spectra were obtained on a Nicolet AVATAR 330 FT-IR spectrometer.
The enantiomeric excesses of (R)- and (S)-enantiomer were determined by HPLC analysis over a
chiral column((Daicel Chiralcel OD-H, AD-H or AS-H; eluted with hexane/isopropyl alcohol; UV
detector). All anhydrous solvents were purified and dried by standard techniques before use. The
β-alkylated unsaturated acyl phosphontes were prepared according to the reported methods in the
literature.19 The C-aryl-N-phenyl nitrones were synthesized according to the literature’s
procedure.17
4.2 General procedure for the asymmetric 1,3-dipolar cycloaddition of unsaturated acyl
phosphonates to nitrones
To a solution of ligand L1 (0.011 mmol) in chloroform (1.0 mL) was added Cu(OTf)2 (0.01
mmol) under nitrogen. The reaction mixture was stirred for 1h at room temperature before
unsaturated acyl phosphonate 1 (0.25 mmol) was added. After stirring for15 min. the resulting
mixture was cooled to 0oC, and then a solution of nitrone 2 (0.2 mmol) in chloroform (1.0 mL)
was added. The reaction proceeded to completion at 0oC (monitored by TLC), alcohol or amine
(0.5 mL) and DBU (100ꢀL) were directly added to the reaction mixture, and stirred for another 1
hour at room temperature. Saturated NH4Cl solution (10 mL) was added and the mixture was
extracted with ethyl acetate (10 mL × 3). The organic layer was combined, and washed (brine),
dried(anhydrous Na2SO4), and concentrated to give the crude product, which was purified by flash
column chromatography on silica gel (eluted with ethyl acetate/petroleum ether (1/20, v/v) to
afford the desired product 3.
(3S, 4R, 5S)-Methyl 5-methyl-2, 3-diphenylisoxazolidine-4-carboxylate (3aa)
Colorless oil, 94% yield. [α]20 =–103.91 (c = 0.66, CH2Cl2); 98% ee, determined by HPLC
D
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm; t (major)
= 4.52 min, t (minor) = 5.90 min]; IR(cm-1): 2953, 2925, 1736, 1598, 1487, 1198, 1030, 755, 697.
1H NMR (300 MHz, CDCl3) δ 7.58 – 7.52 (m, 2H), 7.43 – 7.22 (m, 5H), 7.04 – 6.90 (m, 3H), 5.17
(d, J = 7.0 Hz, 1H), 4.44 (dq, J = 9.1, 6.0 Hz, 1H), 3.70 (d, J = 5.5 Hz, 3H), 3.20 (dd, J = 9.1, 7.1
Hz, 1H), 1.52 (d, J = 6.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.51, 151.37, 141.50, 128.64,
128.57, 127.36, 126.03, 121.19, 113.64, 77.32, 73.26, 65.24, 52.08, 17.12. ESI-HRMS: Calcd for
+
C18H20NO3 ([M+H+]): 298.1438; Found: 298.1439.
(3S, 4R, 5S)-Methyl-5-ethyl-2,3-diphenylisoxazolidine-4-carboxylate (3ab)
Colorless oil, 87% yield. [α]20 = –102.79 (c = 0.90, CH2Cl2); 98% ee, determined by HPLC
D
6

ACCEPTED MANUSCRIPT
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm; t (major)
= 4.38 min, t (minor) = 6.45 min]; IR(cm-1): 2925, 2848, 1736, 1597, 1487, 1265, 755, 737, 698.
1H NMR (300 MHz, CDCl3) δ 7.54 – 7.47 (m, 2H), 7.41 – 7.33 (m, 2H), 7.32 – 7.19 (m, 3H), 7.01
– 6.88 (m, 3H), 5.12 (d, J = 6.8 Hz, 1H), 4.29 (td, J = 7.7, 4.8 Hz, 1H), 3.68 (s, 3H), 3.22 (dd, J =
8.6, 6.9 Hz, 1H), 1.93 – 1.75 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
171.06, 151.41, 141.57, 128.76, 128.71, 127.48, 126.17, 121.41, 113.98, 82.54, 73.45, 63.49,
52.18, 25.35, 10.12. ESI-HRMS: Calcd for C19H22NO3 ([M+H+]): 312.1594; Found: 312.1591.
+
(3S, 4R, 5S)-Methyl-2,3-diphenyl-5-propylisoxazolidine-4-carboxylate (3ac)
Colorless oil, 90% yield. [α]20 = –83.22 (c = 0.59, CH2Cl2); 99% ee, determined by HPLC
D
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 95:5, 1.0 mL/min, 254 nm; t (major)
= 4.72 min, t (minor) = 10.15 min]; IR(cm-1): 2930, 2849, 1737, 1598, 1488, 1244, 1197, 1174,
755, 696. 1H NMR (300 MHz, CDCl3) δ 7.54 – 7.47 (m, 2H), 7.40 – 7.33 (m, 2H), 7.33 – 7.27 (m,
1H), 7.26 – 7.20 (m, 2H), 7.01 – 6.86 (m, 3H), 5.11 (d, J = 6.9 Hz, 1H), 4.38 – 4.28 (m, 1H), 3.69
(s, 3H), 3.26 – 3.16 (m, 1H), 1.84 – 1.73 (m, 2H), 1.66 – 1.51 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 171.01, 151.45, 141.59, 128.76, 128.70, 127.48, 126.16, 121.36,
+
113.89, 81.27, 73.38, 63.97, 52.18, 34.39, 19.33, 13.84. ESI-HRMS: Calcd for C20H24NO3
([M+H+]): 326.1751; Found: 326.1748.
(3S, 4R, 5S)-Methyl-5-isopropyl-2, 3-diphenylisoxazolidine-4-carboxylate (3ad)
Colorless oil, 82% yield. [α]20 = –83.33 (c = 0.63, CH2Cl2); 98% ee, determined by HPLC
D
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 0.5 mL/min, 220 nm; t (major)
= 8.14 min, t (minor) = 9.88 min]; IR(cm-1): 2960, 2920, 1738, 1598, 1488, 1260, 1198, 1028, 755,
697. 1H NMR (300 MHz, CDCl3) δ 7.54 – 7.45 (m, 2H), 7.42 – 7.17 (m, 5H), 7.01 – 6.88 (m, 3H),
5.05 (d, J = 6.5 Hz, 1H), 4.27 – 4.11 (m, 1H), 3.67 (s, 3H), 3.28 (dd, J = 8.3, 6.6 Hz, 1H), 2.03 (dq,
J = 13.5, 6.8 Hz, 1H), 1.11 (d, J = 6.7 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 171.78, 151.24, 141.46, 128.73, 128.71, 127.50, 126.14, 121.51, 114.17, 86.37, 74.12,
+
61.72, 52.13, 30.55, 18.61, 18.30. ESI-HRMS: Calcd for C20H24NO3 ([M+H+]): 326.1751; Found:
326.1746.
(3S, 4R, 5S)-Methyl-5-hexyl-2,3-diphenylisoxazolidine-4-carboxylate (3ae)
Colorless oil, 94% yield. [α]20 = –75.90 (c = 0.98, CH2Cl2); 99% ee, determined by HPLC
D
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm; t (major)
7

ACCEPTED MANUSCRIPT
= 4.16 min, t (minor) = 5.77 min]; IR(cm-1): 2930, 2857, 1738, 1598, 1488, 1197, 1171, 754, 725,
697, 674. 1H NMR (300 MHz, DMSO) δ 7.55 – 7.48 (m, 2H), 7.42 –7.34 (m, 2H), 7.33 – 7.20 (m,
4H), 7.00 – 6.89 (m, 3H), 5.11 (d, J = 6.9 Hz, 1H), 4.32 (ddd, J = 8.8, 7.5, 5.0 Hz, 1H), 3.70 (s,
3H), 3.21 (dd, J = 8.9, 6.9 Hz, 1H), 1.87 – 1.73 (m, 2H), 1.69 – 1.30 (m, 8H), 0.90 (t, J = 6.7 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ 171.03, 151.48, 141.60, 128.78, 128.72, 127.49, 126.16,
121.36, 113.87, 81.49, 73.42, 63.96, 52.20, 32.30, 31.51, 29.02, 25.96, 22.40, 13.90. ESI-HRMS:
Calcd for C23H30NO3 ([M+H+]): 368.222; Found: 368.2217.
+
(3S, 4R, 5S)-Ethyl-5-methyl-2, 3-diphenylisoxazolidine-4-carboxylate (3ag)
Colorless oil, 95% yield. [α]20 = –94.59 (c = 1.09, CH2Cl2); 97% ee, determined by HPLC
D
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 0.5 mL/min, 254 nm; t (major)
= 8.66 min, t (minor) = 10.57 min]; IR(cm-1): 2987, 1732, 1598, 1488, 1267, 1186, 1029, 754, 738,
697. 1H NMR (300 MHz, CDCl3) δ 7.58 –7.48 (m, 2H), 7.42 – 7.18 (m, 5H), 7.04 – 6.86 (m, 3H),
5.15 (d, J = 7.0 Hz, 1H), 4.41 (dt, J = 11.8, 6.0 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.23 – 3.09 (m,
1H), 1.50 (d, J = 5.9 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.17,
151.57, 141.72, 128.77, 128.68, 127.46, 126.19, 121.30, 113.81, 77.49, 73.41, 65.49, 61.17, 17.30,
+
13.94. ESI-HRMS: Calcd for C19H22NO3 ([M+H+]): 312.1594; Found: 312.1591.
(3S, 4R, 5S)-Benzyl-5-methyl-2,3-diphenylisoxazolidine-4-carboxylate (3ah)
Colorless oil, 92% yield. [α]20 = –87.5 (c = 0.84, CH2Cl2); 96% ee, determined by HPLC analysis
D
[Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm; t (major) = 5.44
min, t (minor) = 6.88 min]; IR(cm-1): 2918, 1734, 1598, 1454, 1265, 1176, 1029, 754, 738, 696.
1H NMR (300 MHz, CDCl3) δ 7.52 – 7.44 (m, 2H), 7.38 – 7.17 (m, 10H), 7.01 – 6.87 (m, 3H),
5.15 (d, J = 7.0 Hz, 1H), 5.12 (s, 2H), 4.44 (dq, J = 9.0, 6.0 Hz, 1H), 3.22 (dd, J = 9.0, 7.0 Hz, 1H),
1.47 (d, J = 6.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.07, 151.49, 141.56, 135.16, 128.82,
128.71, 128.47, 128.29, 128.00, 127.50, 126.21, 121.39, 113.86, 77.52, 73.51, 66.92, 65.48, 17.32.
+
ESI-HRMS: Calcd for C24H24NO3 ([M+H+]): 374.1751; Found: 374.1746.
(3S, 4R, 5S)-N-(4-bromobenzyl)-5-methyl-2, 3-diphenylisoxazolidine-4-carboxamide (3ai)
White solid, 174-176 oC, 93% yield. [α]2D0 = –76.27 (c = 0.51, CH2Cl2); 95% ee, determined by
HPLC analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 80:20, 1.0 mL/min, 254 nm; t
(minor) = 4.99 min, t (major) = 6.00 min]; IR(cm-1): 3290, 2920, 2336, 1646, 1564, 1487, 1070,
792, 750, 696. 1H NMR (300 MHz, CDCl3) δ 7.44 –7.37 (m, 4H), 7.36 –7.27 (m, 3H), 7.26 –7.17
8

ACCEPTED MANUSCRIPT
(m, 2H), 7.01 – 6.96 (m, 2H), 6.94 – 6.87 (m, 3H), 5.84 (t, J = 5.7 Hz, 1H), 4.97 (d, J = 8.3 Hz,
1H), 4.44 (dq, J = 9.4, 6.0 Hz, 1H), 4.35 (dd, J = 14.9, 6.2 Hz, 1H), 4.20 (dd, J = 14.9, 5.6 Hz, 1H),
2.80 (dd, J = 9.3, 8.4 Hz, 1H), 1.38 (d, J = 6.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 168.42,
152.02, 141.20, 136.61, 131.63, 129.18, 128.87, 128.76, 127.76, 126.12, 121.45, 121.37, 113.89,
77.87, 74.98, 68.18, 42.86, 16.49. ESI-HRMS: Calcd for C24H24BrN2O2 ([M+H+]): 451.1016;
+
Found: 451.1016.
(3S, 4R, 5S)-Methyl-5-methyl-2-phenyl-3-(p-tolyl)isoxazolidine-4-carboxylate (3ba)
Colorless oil, 82% yield. [α]20 = –98.03 (c = 0.92, CH2Cl2); 98% ee, determined by HPLC
D
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm; t (major)
= 5.37 min, t (minor) = 8.97 min]; IR(cm-1): 2952, 2926, 1737, 1598, 1488, 1198, 1177, 1030, 820,
758, 695. 1H NMR (300 MHz, CDCl3) δ 7.44 – 7.37 (m, 2H), 7.27 – 7.15 (m, 4H), 7.01 – 6.97 (m,
3H), 5.09 (d, J = 7.2 Hz, 1H), 4.41 (dq, J = 9.1, 6.0 Hz, 1H), 3.68 (s, 3H), 3.16 (dd, J = 9.1, 7.2 Hz,
1H), 2.35 (s, 3H), 1.50 (d, J = 6.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.70, 151.59, 138.59,
137.18, 129.38, 128.74, 126.12, 121.29, 113.87, 77.40, 73.32, 65.45, 52.15, 20.92, 17.29.
+
ESI-HRMS: Calcd for C19H22NO3 ([M+H+]): 312.1594; Found: 312.1590.
(3S, 4R, 5S)-Methyl-3-(4-methoxyphenyl)-5-methyl-2-phenylisoxazolidine-4-carboxylate
(3ca)
Colorless oil, 87% yield. [α]2D0 = –94.84 (c = 1.15, CH2Cl2); 96% ee, determined by HPLC
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm; t (minor)
= 6.62 min, t (major) = 7.41 min]; IR(cm-1): 2950, 2932, 1736, 1596, 1513, 14888, 1247, 1174,
1031, 834, 758, 696. 1H NMR (300 MHz, CDCl3) δ 7.48 – 7.38 (m, 2H), 7.28 – 7.18 (m, 2H), 7.03
– 6.85 (m, 5H), 5.07 (d, J = 7.2 Hz, 1H), 4.42 (tt, J = 11.9, 5.9 Hz, 1H), 3.79 (s, 3H), 3.68 (s, 3H),
3.15 (dd, J = 8.9, 7.4 Hz, 1H), 1.50 (d, J = 6.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.69,
159.02, 151.57, 133.55, 128.74, 127.41, 121.35, 114.11, 113.95, 77.37, 73.13, 65.44, 55.12, 52.14,
+
17.33. ESI-HRMS: Calcd for C19H22NO4 ([M+H+]): 328.1543; Found: 328.1539.
(3S, 4R, 5S)-Methyl-3-(4-chlorophenyl)-5-methyl-2-phenylisoxazolidine-4-carboxylate (3da)
o
White solid, m.p. 45−46 C, 80% yield. [α]2D0 = –101.26 (c = 0.56, CH2Cl2); 98% ee, determined
by HPLC analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, 254
nm; t (major) = 5.49 min, t (minor) = 7.44 min]; IR(cm-1): 2953, 2927, 1736, 1598, 1489, 1268,
1222, 1090, 1015, 831, 756, 695. 1H NMR (300 MHz, CDCl3) δ 7.51 – 7.42 (m, 2H), 7.37 – 7.30
9

ACCEPTED MANUSCRIPT
(m, 2H), 7.28 – 7.19 (m, 2H), 6.99 – 6.87 (m, 3H), 5.12 (d, J = 6.9 Hz, 1H), 4.41 (dq, J = 9.2, 5.9
Hz, 1H), 3.69 (s, 3H), 3.12 (dd, J = 8.9, 7.1 Hz, 1H), 1.49 (d, J = 6.0 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 170.44, 151.21, 140.22, 133.30, 128.86, 127.63, 121.56, 113.81, 77.45, 72.69, 65.29,
+
52.30, 17.28. ESI-HRMS: Calcd for C18H19NO3 ([M+H+]): 332.1048; Found: 332.1051.
(3S, 4R, 5S)-Methyl-3-(4-bromophenyl)-5-methyl-2-phenylisoxazolidine-4-carboxylate (3ea)
Colorless oil, 75% yield. [α]2D0 = –82.79 (c = 0.61, CH2Cl2); 98% ee, determined by HPLC
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 0.5 mL/min, 254 nm; t (major)
= 11.36 min, t (minor) = 15.99 min]; IR(cm-1): 2921, 2850, 1736, 1597, 1488, 1266, 1199, 1072,
1011, 823, 755, 695. 1H NMR (300 MHz, CDCl3) δ 7.54 – 7.47 (m, 2H), 7.44 – 7.37 (m, 2H), 7.29
– 7.20 (m, 2H), 6.99 – 6.89 (m, 3H), 5.11 (d, J = 7.0 Hz, 1H), 4.47 – 4.35 (m, 1H), 3.70 (s, 3H),
3.11 (dd, J = 9.1, 7.0 Hz, 1H), 1.50 (d, J = 6.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.41,
151.17, 140.72, 131.81, 128.85, 127.95, 121.56, 121.39, 113.78, 77.44, 72.71, 65.23, 52.30, 17.26.
+
ESI-HRMS: Calcd for C18H19BrNO3 ([M+H+]): 376.0543; Found: 376.0540.
(3S, 4R, 5S)-Methyl-3-(4-cyanophenyl)-5-methyl-2-phenylisoxazolidine-4-carboxylate (3fa)
Colorless oil, 93% yield. [α]20 = –88.13 (c = 1.12, CH2Cl2); 98% ee, determined by HPLC
D
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm; t (major)
= 9.81 min, t (minor) = 12.72 min]; IR(cm-1): 2920, 2850, 2228, 1736, 1597, 1488, 1222, 1202,
1021, 840, 760, 696. 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 4H), 7.31 – 7.21 (m, 2H), 7.00 – 6.90
(m, 3H), 5.24 (d, J = 6.7 Hz, 1H), 4.43 (dq, J = 11.9, 5.9 Hz, 1H), 3.72 (s, 3H), 3.11 (dd, J = 9.0,
6.8 Hz, 1H), 1.51 (d, J = 6.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.18, 150.81, 147.18,
132.57, 128.98, 126.99, 121.79, 118.48, 113.67, 111.45, 77.51, 72.56, 65.04, 52.48, 17.22.
+
ESI-HRMS: Calcd for C19H19N2O3 ([M+H+]): 323.139; Found: 323.1385.
(3S, 4R, 5S)-Methyl-5-methyl-3-(4-nitrophenyl)-2-phenylisoxazolidine-4-carboxylate (3ga)
Yellow solid, m.p. 71-72 oC, 96% yield. [α]20 = – 100.49 (c = 1.03, CH2Cl2); 98% ee, determined
D
by HPLC analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, 254
nm; t (major) = 9.91 min, t (minor) = 12.86 min]; IR(cm-1): 2928, 2850, 1736, 1598, 1521, 1488,
1
1347, 1222, 856, 755, 697. H NMR (300 MHz, CDCl3) δ 8.31 – 8.11 (m, 2H), 7.80 – 7.66 (m,
2H), 7.31 – 7.22 (m, 2H), 7.08 – 6.86 (m, 3H), 5.29 (d, J = 6.6 Hz, 1H), 4.45 (dq, J = 11.9, 5.9 Hz,
1H), 3.73 (s, 3H), 3.13 (dd, J = 8.9, 6.8 Hz, 1H), 1.52 (d, J = 5.9 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 170.14, 150.73, 149.15, 147.35, 129.00, 127.15, 123.98, 121.85, 113.69, 77.54, 72.37,
10

ACCEPTED MANUSCRIPT
+
65.04, 52.51, 17.24. ESI-HRMS: Calcd for C18H19N2O5 ([M+H+]): 343.1288; Found: 343.1284.
(3S, 4R, 5S)-Methyl-5-methyl-2-phenyl-3-(m-tolyl)isoxazolidine-4-carboxylate (3ha)
Colorless oil, 91% yield. [α]20 = –84.65 (c = 1.14, CH2Cl2); 98% ee, determined by HPLC
D
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 0.5 mL/min, 254 nm; t (major)
= 8.20 min, t (minor) = 10.06 min]; IR(cm-1): 2923, 2851, 1737, 1597, 1488, 1436, 1346, 1221,
1
1176, 1138, 758, 696. H NMR (300 MHz, CDCl3) δ 7.39 – 7.33 (m, 1H), 7.31 – 7.19 (m, 4H),
7.14 – 7.07 (m, 1H), 7.02 – 6.87 (m, 3H), 5.11 (d, J = 7.1 Hz, 1H), 4.41 (dd, J = 9.1, 5.9 Hz, 1H),
3.69 (s, 3H), 3.23 – 3.12 (m, 1H), 2.36 (s, 3H), 1.50 (d, J = 5.9 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 170.68, 151.60, 141.58, 138.46, 128.76, 128.57, 128.26, 126.70, 123.25, 121.28, 113.77,
77.47, 73.45, 65.42, 52.17, 21.30, 17.22. ESI-HRMS: Calcd for C19H22NO3+ ([M+H+]): 312.1594;
Found: 312.1591.
(3S, 4R, 5S)-Methyl-3-(3-fluorophenyl)-5-methyl-2-phenylisoxazolidine-4-carboxylate (3ia)
Colorless oil, 86% yield. [α]20 = –110.16 (c = 0.63, CH2Cl2); 98% ee, determined by HPLC
D
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 0.5 mL/min, 254 nm; t (major)
= 11.02 min, t (minor) = 12.12 min]; IR(cm-1): 2918, 2849, 1737, 1596, 1487, 1451, 1222, 1139,
1030, 789, 760, 695. 1H NMR (300 MHz, CDCl3) δ 7.38 – 7.20 (m, 5H), 7.02 – 6.89 (m, 4H), 5.16
(d, J = 6.8 Hz, 1H), 4.47 – 4.35 (m, 1H), 3.71 (s, 3H), 3.15 (dd, J = 9.1, 6.9 Hz, 1H), 1.50 (d, J =
6.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.46, 163.05 (d, J = 246.4 Hz), 151.18, 144.40 (d, J
= 7.0 Hz), 130.27 (d, J = 8.2 Hz), 128.88, 121.71 (d, J = 2.8 Hz), 121.54, 114.43 (d, J = 21.2 Hz),
113.72, 113.20 (d, J = 22.5 Hz), 77.49, 72.71 (d, J = 1.9 Hz), 65.19, 52.34, 17.23. ESI-HRMS:
+
Calcd for C18H19FNO3 ([M+H+]): 316.1343; Found: 316.1340.
(3S, 4R, 5S)-Methyl-3-(3-bromophenyl)-5-methyl-2-phenylisoxazolidine-4-carboxylate (3ja)
Colorless oil, 75% yield. [α]20 = – 77.49 (c = 1.04, CH2Cl2); 97% ee, determined by HPLC
D
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 0.5 mL/min, 254 nm; t (major)
= 8.88 min, t (minor) = 9.42 min]; IR(cm-1): 2917, 2849, 1736, 1596, 1488, 1260, 1091, 1019, 796,
755, 694. 1H NMR (300 MHz, CDCl3) δ 7.75 – 7.69 (m, 1H), 7.48 – 7.39 (m, 2H), 7.30 – 7.19 (m,
3H), 7.00 – 6.90 (m, 3H), 5.14 (d, J = 6.9 Hz, 1H), 4.40 (dq, J = 9.2, 6.0 Hz, 1H), 3.70 (s, 3H),
3.14 (dd, J = 9.1, 6.9 Hz, 1H), 1.50 (d, J = 6.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.37,
151.16, 144.13, 130.68, 130.31, 129.22, 128.91, 124.83, 122.88, 121.57, 113.70, 77.52, 72.63,
+
65.22, 52.36, 17.22. ESI-HRMS: Calcd for C18H19BrNO3 ([M+H+]): 376.0543; Found: 376.0543.
11

ACCEPTED MANUSCRIPT
(3S,4R,5S)-Methyl-5-methyl-2-phenyl-3-(3-(trifluoromethyl)phenyl)isoxazolidine-4-carboxyl
ate (3ka)
Colorless oil, 60% yield. [α]20 = –80.97 (c = 0.83, CH2Cl2); 96% ee, determined by HPLC
D
analysis [Daicel Chiralcel AS-H column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm; t (major)
= 6.94 min, t (minor) = 9.98 min]; IR(cm-1): 2919, 2849, 1737, 159, 1489, 1328, 1167, 1125, 1073
1016, 800, 758, 700. 1H NMR (300 MHz, CDCl3) δ 7.82 (s, 1H), 7.77 – 7.70 (m, 1H), 7.60 – 7.45
(m, 2H), 7.31 – 7.21 (m, 2H), 7.01 – 6.91 (m, 3H), 5.24 (d, J = 6.8 Hz, 1H), 4.44 (dq, J = 9.1, 6.0
Hz, 1H), 3.72 (s, 3H), 3.14 (dd, J = 9.1, 6.8 Hz, 1H), 1.51 (d, J = 6.0 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 170.33, 151.11, 142.91, 131.11 (q, J = 32.3 Hz), 129.60, 129.22, 128.93, 124.39 (q, J =
3.7 Hz), 123.88 (dd, J = 544.8, 272.5 Hz), 123.00 (q, J = 3.7 Hz), 121.66, 113.71, 77.52, 72.76,
+
65.22, 52.36, 17.17. ESI-HRMS: Calcd for C19H19F3NO3 ([M+H+]): 366.1312; Found: 366.1309.
(3S, 4R, 5S)-Methyl-3-(2-methoxyphenyl)-5-methyl-2-phenylisoxazolidine-4-carboxylate
(3la)
Colorless oil, 66% yield. [α]2D0 = + 32.18 (c = 1.13, CH2Cl2); 93% ee for major isomer, determined
by HPLC analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 95:5, 1.0 mL/min, 254 nm;
t (major) = 11.50 min, t (minor) = 12.19 min, t (major) = 12.94 min, t (minor) = 18.49 min];
IR(cm-1): 2927, 1739, 1599, 1490, 1437, 1244, 1209, 1048, 753, 694.1H NMR (300 MHz, CDCl3)
δ 7.76 – 7.70 (m, 0.9H), 7.64 – 7.59 (m, 1H), 7.31 – 7.15 (m, 5H), 7.02 – 6.83 (m, 10H), 5.48 (d, J
= 6.1 Hz, 0.9H), 5.30 (d, J = 9.5 Hz, 1H), 4.75 (dq, J = 8.5, 6.1 Hz, 1H), 4.36 (dq, J = 9.2, 6.0 Hz,
0.9H), 3.84 (s, 3H), 3.78 (s, 2.7H), 3.67 (s, 2.7H), 3.39 (dd, J = 9.4, 8.7 Hz, 1H), 3.26 (s, 3H), 3.03
– 2.94 (m, 0.9H), 1.42 (d, J = 6.1 Hz, 5.7H). 13C NMR (75 MHz, CDCl3) δ 171.60, 169.88, 156.13,
155.90, 151.57, 150.31, 129.85, 128.81, 128.71, 128.68, 128.39, 126.55, 126.02, 121.90, 120.97,
120.81, 120.62, 115.84, 113.47, 109.98, 109.74, 78.42, 75.78, 69.38, 65.23, 64.99, 58.77, 55.28,
+
54.97, 51.94, 51.25, 17.87, 16.96. ESI-HRMS: Calcd for C19H22NO4 ([M+H+]): 328.1543; Found:
328.1539.
(3S, 4R, 5S)-Methyl-3-(2-fluorophenyl)-5-methyl-2-phenylisoxazolidine-4-carboxylate (3ma)
Colorless oil, 91% yield. [α]20 = – 88.89 (c = 0.36, CH2Cl2); 93% ee, determined by HPLC
D
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 0.5 mL/min, 254 nm; t (major)
= 9.96 min, t (minor) = 12.50 min]; IR(cm-1): 2919, 2849, 1740, 1598, 1489, 1221, 1175, 1032,
756, 695. 1H NMR (300 MHz, CDCl3) δ 7.78 – 7.69 (m, 1H), 7.33 – 7.22 (m, 3H), 7.21 – 7.14 (m,
12

ACCEPTED MANUSCRIPT
1H), 7.13 – 6.90 (m, 4H), 5.51 (d, J = 6.3 Hz, 1H), 4.42 (dq, J = 9.0, 5.9 Hz, 1H), 3.69 (s, 3H),
3.14 (dd, J = 8.9, 6.4 Hz, 1H), 1.49 (d, J = 6.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.62,
159.75 (d, J = 245.7 Hz), 151.03, 129.07 (d, J = 8.2 Hz), 128.86, 128.59 (d, J = 13.2 Hz), 128.01
(d, J = 3.9 Hz), 124.54 (d, J = 3.4 Hz), 121.48, 115.21 (d, J = 21.3 Hz), 113.69, 78.07, 67.62,
64.52, 52.24, 17.10. ESI-HRMS: Calcd for C18H19FNO3 ([M+H+]): 316.1343; Found: 316.1339.
+
(3S, 4R, 5S)-Methyl-3-(3,4-dibromophenyl)-5-methyl-2-phenylisoxazolidine-4-carboxylate
(3na)
Colorless oil, 80% yield. [α]20 = – 69.17 (c = 1.08, CH2Cl2); 97% ee, determined by HPLC
D
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 0.5 mL/min, 254 nm; t (major)
= 12.91 min, t (minor) = 14.20 min]; IR(cm-1): 2917, 2849, 1736, 1597, 1488, 1260, 1014, 796,
757, 694. 1H NMR (300 MHz, CDCl3) δ 7.87 – 7.80 (m, 1H), 7.66 – 7.57 (m, 1H), 7.38 – 7.21 (m,
3H), 7.01 – 6.89 (m, 3H), 5.11 (d, J = 6.8 Hz, 1H), 4.40 (dq, J = 12.0, 5.9 Hz, 1H), 3.71 (s, 3H),
3.11 (dd, J = 8.9, 7.0 Hz, 1H), 1.50 (d, J = 5.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.21,
150.93, 142.85, 133.90, 131.39, 128.96, 126.43, 125.15, 123.72, 121.74, 113.69, 77.50, 72.03,
+
65.07, 52.44, 17.23. ESI-HRMS: Calcd for C18H18Br2NO3 ([M+H+]): 453.9648; Found:
453.9643.
(3S, 4R, 5S)-Methyl-5-methyl-3-(naphthalen-2-yl)-2-phenylisoxazolidine-4-carboxylate (3oa)
o
White solid, 76-78 C, 95% yield. [α]2D0 = –74.17 (c = 0.76, CH2Cl2); 97% ee, determined by
HPLC analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 0.5 mL/min, 254 nm; t
(major) = 6.37 min, t (minor) = 12.99 min]; IR(cm-1): 2917, 2848, 1736, 1598, 1488, 1260, 1222,
1198, 817, 759, 751, 695. 1H NMR (300 MHz, CDCl3) δ 8.01 (s, 1H), 7.92 – 7.79 (m, 3H), 7.68 –
7.61 (m, 1H), 7.53 – 7.43 (m, 2H), 7.30 – 7.19 (m, 2H), 7.08 – 6.99 (m, 2H), 6.98 – 6.88 (m, 1H),
5.32 (d, J = 7.1 Hz, 1H), 4.47 (dq, J = 11.9, 6.0 Hz, 1H), 3.69 (s, 3H), 3.26 (dd, J = 9.0, 7.3 Hz,
1H), 1.53 (d, J = 5.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.66, 151.61, 138.95, 133.30,
132.87, 128.87, 128.82, 127.90, 127.57, 126.18, 125.90, 124.98, 124.18, 121.45, 113.87, 77.58,
73.72, 65.39, 52.30, 17.33. HPLC analysis (Chiralcel AD-H, n-hexane/i-PrOH = 90:10, 1.0
mL/min, tr (major) = 6.369 min, tr (minor) = 12.991 min, 97%ee). ESI-HRMS: Calcd for
+
C22H22NO3 ([M+H+]): 348.1594; Found: 348.1591.
(3S, 4R, 5S)-Methyl-3-(furan-2-yl)-5-methyl-2-phenylisoxazolidine-4-carboxylate (3pa)
Colorless oil, 88% yield. [α]20 = – 174.53 (c = 1.06, CH2Cl2); 97% ee, determined by HPLC
D
13

ACCEPTED MANUSCRIPT
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm; t (major)
= 10.91 min, t (minor) = 12.69 min]; IR(cm-1): 2921, 2850, 1738, 1597, 1487, 1207, 1139, 1014,
796, 753, 737, 695. 1H NMR (300 MHz, CDCl3) δ 7.45 – 7.39 (m, 1H), 7.32 – 7.23 (m, 2H), 7.13
– 7.05 (m, 2H), 7.00 – 6.91 (m, 1H), 6.43 – 6.31 (m, 2H), 5.25 (d, J = 6.3 Hz, 1H), 4.39 (dq, J =
8.8, 6.0 Hz, 1H), 3.67 (s, 3H), 3.43 (dd, J = 8.8, 6.3 Hz, 1H), 1.55 (d, J = 6.0 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 170.45, 153.00, 150.77, 142.59, 128.80, 121.82, 114.30, 110.29, 107.06, 77.39,
67.29, 60.79, 52.32, 17.32. ESI-HRMS: Calcd for C16H18NO4 ([M+H+]): 288.123; Found:
+
288.1227.
(3R, 4R, 5S)-Methyl-5-methyl-2-phenyl-3-((E)-styryl)isoxazolidine-4-carboxylate (3qa)
Colorless oil, 64% yield. [α]20 = –131.78 (c = 0.65, CH2Cl2); 95% ee, determined by HPLC
D
analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 90:10, 0.5 mL/min, 254 nm; t (major)
= 14.43 min, t (minor) = 21.18 min]; IR(cm-1): 2917, 2846, 1736, 1597, 1488, 1266, 1219, 968,
738, 694. 1H NMR (300 MHz, CDCl3) δ 7.46 – 7.38 (m, 2H), 7.37 – 7.23 (m, 5H), 7.10 – 7.02 (m,
2H), 7.00 – 6.91 (m, 1H), 6.82 – 6.73 (m, 1H), 6.49 – 6.35 (m, 1H), 4.70 (t, J = 6.9 Hz, 1H), 4.36
(dq, J = 12.1, 5.9 Hz, 1H), 3.70 (s, 3H), 3.14 – 2.99 (m, 1H), 1.51 (d, J = 5.9 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 170.48, 151.43, 136.19, 131.15, 128.79, 128.60, 128.44, 127.70, 126.45,
+
121.55, 114.16, 76.79, 72.22, 62.48, 52.20, 17.28. ESI-HRMS: Calcd for C20H22NO3 ([M+H+]):
324.1594; Found: 324.1595.
((3S,4S,5S)-5-methyl-2, 3-diphenylisoxazolidin-4-yl)methyl 2,4-dichlorobenzoate (4)
To a suspension of lithium aluminum hydride(60 mg, 0.3 mmol) in THF(2 mL)was added the
cycloadduct 3aa (60 mg, 0.2 mmol) at 0 oC, then the mixture was stirred at rt for 1 h. The reaction
was quenched with water and the mixture was extracted with EtOAc (3 ×15 mL). The combined
extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude
product which was used directly in the next step. To a solution of the crude reduction product in
CH2Cl2 (2 mL) was added 1, 3-dicyclohexylcarbodiimide (49 mg, 0.24 mmol),
4-(dimethylamino)pyridine (12.2 mg, 0.1 mmol), and 2,4-dichlorobenzoic acid (27 mg, 0.3mmol).
The mixture was allowed to stir at rt for 2 h. The solution was washed with hydrochloric acid (5
mL × 2, 0.5 M) and saturated aqueous NaHCO3 (5mL × 2). The combined organic layer was dried
(Na2SO4), concentrated, and purified by column chromatography (ethyl acetate/petroleum ether,
o
1/10, v/v) to obtain the product 4 as a white solid. m.p. 74-76 C, 95% yield. [α]2D0 = –53.04 (c =
14

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1.24, CH2Cl2); 96% ee, determined by HPLC analysis [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 90:10, 1.0 mL/min, 254 nm; t (major) = 5.33 min, t (minor) = 7.51 min];
IR(cm-1): 2917, 28497, 17347, 1586, 1487, 1281, 1242, 1101, 1049, 753, 698. 1H NMR (300 MHz,
CDCl3) δ 7.58 –7.50 (m, 2H), 7.43 – 7.26 (m, 5H), 7.26 – 7.18 (m, 2H), 7.17 – 7.11 (m, 1H), 7.01
– 6.86 (m, 3H), 4.61 (d, J = 7.2 Hz, 1H), 4.45 (d, J = 4.9 Hz, 2H), 4.25 (dq, J = 8.9, 6.0 Hz, 1H),
2.72 – 2.59 (m, 1H), 1.49 (d, J = 6.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 164.03, 151.82,
141.79, 138.32, 134.77, 132.21, 130.77, 128.68, 127.38, 127.06, 126.77, 126.15, 121.11, 113.63,
+
76.37, 73.67, 62.63, 60.27, 16.94. ESI-HRMS: Calcd for C24H22Cl2NO3 ([M+H+]): 442.0971;
Found: 442.0969.
(2R, 3S)-Methyl-3-hydroxy-2-((S)-phenyl(phenylamino)methyl)butanoate (5)
To a stirred solution of 3aa (90 mg, 0.3 mmol) in AcOEt (3 mL) was added Pd/C (10 wt%, 55 mg)
at room temperature. After several times of purging with H2, the reaction mixture was stirred at
o
–10 C for overnight under H2 atmosphere (1atm). After 3aa was consumed completely
(monitored by TLC), the reaction mixture was filtered and concentrated. The residue was purified
by column chromatography (ethyl acetate/petroleum ether, 1/5, v/v) to obtain the pure product 5 as
a white solid. m.p. 123−124 oC, 80% yield. [α]20 = –52.74 (c = 0.62, CH2Cl2); 98% ee, determined
D
by HPLC analysis [Daicel Chiralcel AD-H column, n-hexane/i-PrOH = 80:20, 1.0 mL/min, 254
nm; t (minor) = 8.22 min, t (major) = 17.71 min]; IR(cm-1): 3393, 2951, 1712, 1604, 1516, 1497,
1
1307, 1175, 748, 690. H NMR (300 MHz, CDCl3) δ 7.22 – 7.09 (m, 5H), 7.07 – 6.99 (m, 2H),
6.71 – 6.56 (m, 3H), 4.80 (d, J = 9.1 Hz, 1H), 4.31 – 4.15 (m, 3H) , 3.33 (s, 3H), 2.82 (t, J = 8.7
Hz, 1H), 1.16 (d, J = 6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.72, 145.90, 140.11, 129.02,
128.37, 127.58, 126.70, 119.37, 115.61, 69.01, 60.99, 59.32, 51.36, 21.61. ESI-HRMS: Calcd. for
+
C18H22NO3 ([M+H+]): 300.1594; Found: 300.1592.
Acknowledgement
This work was supported by the National Natural Science Foundation of China (No. 21172255)
and the Ministry of Science and Technology of China (No. 2015BAK45B01).
Supplementary data
Supplementary data associated with this article can be found in the online version, at
References and notes
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