A novel quaternary ammonium salts derived from α-amino acids with large steric hindrance group and its application in asymmetric Mannich reaction

Article abstract of DOI:10.1016/j.tet.2020.131484

Quaternary ammonium salts derived from amino acids with large steric hindrance group have been designed and synthesized, which promoted the asymmetric Mannich reaction of glycine imines with N-Boc-aldimines in excellent yields with high enantio- and diast

Full text of DOI:10.1016/j.tet.2020.131484

Tetrahedron 76 (2020) 131484
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel quaternary ammonium salts derived from a-amino acids with
large steric hindrance group and its application in asymmetric
Mannich reaction
,
, *
Zhengtao Tian a, Xiangyu Meng b, Yueyang Luo b, Shaokui Cao a **, Gang Zhao b
a School of Materials Science and Engineering, Zhengzhou University, Zhengzhou, 450001, People’s Republic of China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Center for Excellence in Molecular Synthesis,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Quaternary ammonium salts derived from amino acids with large steric hindrance group have been
designed and synthesized, which promoted the asymmetric Mannich reaction of glycine imines with N-
Boc-aldimines in excellent yields with high enantio- and diastereo-control compared with known cat-
alysts of this type reported by our group.
Received 28 June 2020
Received in revised form
4 August 2020
Accepted 6 August 2020
Available online 19 August 2020
© 2020 Elsevier Ltd. All rights reserved.
Keywords:
Quaternary ammonium salt
Amino acid
Large steric hindrance group
Mannich reaction
1. Introduction
transformed to quaternary ammonium (phosphonium) salts, while
the amine group provided the adjustable hydrogen bonding site.
The chiral ion pair catalysts have been one of the most impor-
tant type of organocatalysts which were extensively applied in
asymmetric synthesis featured by simple operations and mild re-
action conditions [1]. In the past few decades, the development of
chiral ammoniums have attracted intensive attention [2,3], espe-
cially those with H-bonding donors, such as ureas or thioureas. In
2010, Lassaletta and coworkers reported the first thiourea-
containing ammonium salts derived from cinchona alkaloid [4].
Later, Dixon, Zhao and Waser independently reported different
types of (thio)-urea ammonium salts based on different chiral
backbones and their application in a range of asymmetric reactions
(Scheme 1) [5e7].
Amino acids are dominant scaffolds for the synthesis of new
chiral organocatalysts whose catalytic activity could be facilely
regulated by structural modifications. In recent years, our group has
focused on the development of novel bifunctional ion pair catalysts
derived from amino acids (Scheme 2a). The carboxylic acid could be
With these catalysts in hand, varieties of asymmetric reactions have
been successfully realized [7,8].
As we know, Mannich reaction [9] is a typical asymmetric re-
action to form CeC bond, and great progress have been made from
organocatalysts to metal catalysts in the past few decades [10].
Among these transformations, the direct asymmetric Mannich re-
action of glycine imines or
a-amino acid derivatives with N-Boc-
aldimines turned out to be a straightforward method to deliver
a,b-
diamino acid derivatives, which have been found frequently in
natural products, peptides and pharmaceutical compounds [11].
In this text, a series of novel quaternary ammonium salts
derived from amino acids with large steric hindrance group were
synthesized and applied in the asymmetric Mannich reaction of
glycine imines with N-Boc-aldimines. After systematic screening,
these novel quaternary ammonium salts with large steric hin-
drance group proved to be better in both yields and enantiose-
lectivities compared with known catalysts of this type reported by
our group (Scheme 2b).
* Corresponding author.
** Corresponding author.
E-mail addresses: caoshaokui@zzu.edu.cn (S. Cao), zhaog@sioc.ac.cn (G. Zhao).
https://doi.org/10.1016/j.tet.2020.131484
0040-4020/© 2020 Elsevier Ltd. All rights reserved.

2
Z. Tian et al. / Tetrahedron 76 (2020) 131484
Scheme 1. Established (thio)-urea ammonium salts.
Scheme 2. The synthesis of quaternary ammonium salts derived from amino acids.
2. Results and discussion
out to be the best catalyst (Table 3, entry 9), affording the corre-
sponding product 3a in 90% ee with >20 : 1 dr in 24 h. There was no
denying that the additional steric hindrance of catalysts contrib-
uted to enantioselectivities of the products. The relative configu-
ration and absolute configuration of product 3a was confirmed by
comparing the reported 1H NMR spectrum, HPLC spectrum and
optical rotation [10], other products were assigned by analogy.
With the optimized condition in hand, the generality with a
variety of N-Boc protected aldimines and glycine imines were
examined. As shown in Table 4, all the reactions were completed in
24 h. The evaluation of different ester groups on glycine imines
indicated tert-butyl group (Table 4 and 3a) was superior to Ethyl
and Benzyl (Table 4, 3b, 3c), which indicated the large steric hin-
drance group of glycine imines availed to the enantioselectivity of
the product. After the screening of N-Boc-imines with different aryl
substituents, an obvious substituent effect of aryl group was found:
poor diastereoselectivities and enantioselectivities of the products
were obtained for ortho-substituted substrates (Table 4, 3f, 3k, 3n).
As for the meta-substituted or para-substituted N-Boc-imines,
products 3 could be delivered with good diastereoselectivities and
enantioselectivities. In addition, the presence of electronically
withdrawing or neutral substituents basically provided higher
enantioselectivities products than those bearing electron-donating
substituents. Meanwhile, good yields and stereoselectivities of
products 3 were also obtained for heteroaromatic substituted N-
Boc-imines (Table 4, 3r, 3s, 3t). However, poor enantioselectivity of
the product 3u was obtained for cyclohexyl substituted N-Boc-
imine.
Initially, catalysts 4a-4d with different chiral backbones were
evaluated in this reaction (Table 1, entries 1e4). Among these cat-
alysts, 4a derived from L-tert-leucine gave a better result. Later, a
set of H-bonding type catalysts 4e-4g were investigated (Table 1,
entries 5e7). It turned out catalyst 4e with urea as the double H-
donor led to a higher enantioselectivity of the product (Table 1,
entry 5). Then, more urea-ammonium catalysts 4h-4n derived from
L-tert-leucine with different cations were examined (Table 1, en-
tries 8e14) and 4h appeared to be the most suitable catalyst
(Table 1, entry 8), which illustrated the stereoselectivity of product
was greatly dependent on the steric hindrance of catalysts.
In the presence of the optimal catalyst 4h, a variety of solvents
were examined and toluene appeared to be the best media in terms
of enantioselectivities of the products (Table 2, entries 1e9). The
following screening of the bases indicated that Cs2CO3 was the best
one (Table 2, entries 7, 10e14). Lowering the reaction temperature
from room temperature to ꢀ20 ꢁC did not bring an apparent dif-
ference in enantioselectivities of the products, but with a longer
reaction time (Table 2, entries 7, 15e17). Changing the equivalent of
additive of base, there were no obvious changes of experimental
results (Table 2, entries 7, 18e20). However, among these condi-
tions, only moderate enantioselectivities of products could be
obtained.
Considering the steric effect of catalyst 4h owning the tert-butyl
afforded a better result relatively, we wondering that the enantio-
selectivities of the products could be enhanced by increasing the
steric effect of catalyst further. Therefore, a series of novel quater-
nary ammonium salts catalysts with large steric hindrance group
Based on experimental results and previous relevant studies [6],
a possible transition state model was proposed as below (Scheme
3), which indicate that there existed H-bonding interactions be-
tween the carbonyl group of the N-Boc-imine and the urea moiety
were deigned and synthesized based on
D-serine. After systematic
investigation (Table 3, entries 1e10), urea-ammonium 5i turned

Z. Tian et al. / Tetrahedron 76 (2020) 131484
3
Table 1
Optimization of conditions and evaluation of chiral catalysts 4a.
Entry
cat. (10 mol%)
Yield (%)b
drc
ee (%)c
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
82
82
74
85
87
83
96
88
84
86
82
84
86
87
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
36
27
30
7
62
8
26
74
57
73
65
72
67
69
9
10
11
12
13
14
a
Reactions were carried out with 1a (0.12 mmol), 2a (0.10 mmol), catalyst 4 (10 mol%) and additive of base Cs2CO3 (0.5 equiv.) in Toluene (1.0 mL) at room temperature in
24 h.
b
c
Isolated yield.
The dr and ee values were determined by chiral HPLC analysis.
within the catalyst, and the nucleophile glycine Schiff base would
be directed by the quaternary ammonium centre due to the
Coulomb force (electrostatic interaction) between them. Thus, a
more favorable Si-face attack of the nucleophile could be rational
the stereochemical results of the reaction.
4. Experimental
4.1. General information
The 1H NMR spectra were recorded on a Bruker (400 MHz). All
chemical shifts (d) were given in ppm. Data were reported as fol-
lows: chemical shift, integration, multiplicity (s
¼
single,
d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet) and coupling
constants (Hz). 13C NMR spectra and 19F NMR spectra were recor-
ded on a DPX-400 (400 MHz). Flash column chromatography was
performed using H silica gel. For thin-layer chromatography (TLC),
silica gel plates (HSGF 254) were used and compounds were visu-
alized by irradiation with UV light. Analytical high-performance
liquid chromatography (HPLC) was carried out on SHIMADZU
equipment using chiral columns. Melting point was determined on
SGW X-4 melting point and was uncorrected. Optical rotation was
3. Conclusion
In summary, we have developed a novel strategy to obtain
quaternary ammonium salts catalysts with large steric hindrance
group from amino acids, which proved to process superior catalytic
activity to known catalysts of this type in the asymmetric Mannich
reaction of glycine imines with N-Boc-aldimines. It’s no doubt that
these novel catalysts were great complements, which enriched and
developed ion pair catalysts derived from amino acids. A greater
effort towards the application of these catalysts is needed. We
believe these novel catalysts could be used in more asymmetric
reactions due to the excellent catalytic activity.
measured on JASCO P-1010 Polarimeter at
l
¼ 589 nm. IR spectra
were recorded on Perkin-Elmer 983G instrument. Mass spectra
analysis were performed on API 200 LC/MS system (Applied Bio-
systems Co. Ltd.). All simple quaternary ammonium salts catalysts 4

4
Z. Tian et al. / Tetrahedron 76 (2020) 131484
Table 2
Optimization of conditionsa.
Entry
Base
solvent
Temp./ꢁC
t/h
Yield (%)b
drc
ee (%)c
1
2
3
4
5
6
7
8
Cs2CO3 (0.5 equiv.)
Cs2CO3 (0.5 equiv.)
Cs2CO3 (0.5 equiv.)
Cs2CO3 (0.5 equiv.)
Cs2CO3 (0.5 equiv.)
Cs2CO3 (0.5 equiv.)
Cs2CO3 (0.5 equiv.)
Cs2CO3 (0.5 equiv.)
Cs2CO3 (0.5 equiv.)
Na2CO3 (0.5 equiv.)
K2CO3 (0.5 equiv.)
K3PO4 (0.5 equiv.)
KF (0.5 equiv.)
Hexane
CH2Cl2
CHCl3
EtOAc
THF
TBME
Toluene
PhF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
24
24
24
24
24
24
24
24
24
24
24
24
24
24
40
48
48
24
24
24
85
84
82
82
86
85
88
84
82
N.R.
36
60
68
90
85
88
87
81
88
91
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
/
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
59
61
60
55
31
69
74
74
71
/
9
PhCF3
10
11
12
13
14
15
16
17
18
19
20
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
9
69
70
72
74
74
74
73
73
72
CsF (0.5 equiv.)
Cs2CO3 (0.5 equiv.)
Cs2CO3 (0.5 equiv.)
Cs2CO3 (0.5 equiv.)
Cs2CO3 (0.5 equiv.)
Cs2CO3 (1.0 equiv.)
Cs2CO3 (2.0 equiv.)
ꢀ10
ꢀ20
rt
rt
rt
a
Reactions were carried out with 1a (0.12 mmol), 2a (0.10 mmol), catalyst 4h (10 mol%) and additive of base in solvent (1.0 mL) at the special temperature.
Isolated yield.
The dr and ee values were determined by chiral HPLC analysis.
b
c
were synthesized according to procedures reported, and catalysts
To a solution of the precursor (1.0 equiv.) in CH2Cl2, adding the
corresponding isocyanate (1.2 equiv.), and the resulting mixture
was stirred at rt for 3 h. Then, the mixture was concentrated under
reduced pressure. The crude mixture was purified by flash column
chromatography to afford the solid product (VEA/VMeOH ¼ 50 : 1e20
: 1). To a solution of the tertiary urea-amino product (1.0 equiv.) in
CH3CN, adding the corresponding bromide (1.2 equiv.), and the
resulting mixture was stirred at room temperature for 12 h. Then,
the mixture was concentrated under reduced pressure. The crude
mixture was purified by flash column chromatography to afford the
desired quaternary ammonium salt catalyst (VEA/VMeOH ¼ 50 : 1e20
: 1).
4a, 4b, 4d, 4e, 4f were synthesized [5]. As for quaternary ammo-
nium salts 5 with large steric hindrance group, the precursors were
synthesized as reported [11]. N-Boc-imines 1 and glycine Schiff
bases 2 were synthesized according to known procedures [12e14].
4.2. Preparation of catalysts 4, 5
All simple quaternary ammonium salts 4c, and 4g-4n were
synthesized according to procedures and reported previously.
Quaternary ammonium salts 5 were synthesized as the scheme
below.

Z. Tian et al. / Tetrahedron 76 (2020) 131484
5
Table 3
Optimization of conditions and evaluation of chiral catalysts 5a.
Entry
cat. (10 mol%)
Yield (%)b
drc
ee (%)c
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
89
84
89
94
89
77
88
83
88
94
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
79
87
79
43
87
76
83
59
90
89
10
5j
a
Reactions were carried out with 1a (0.12 mmol), 2a (0.10 mmol), catalysts 5 (10 mol%) and additive of base Cs2CO3 (0.5 equiv.) in toluene (1.0 mL) at room temperature in
24 h.
b
c
Isolated yield.
The dr and ee values were determined by chiral HPLC analysis.
2
4.2.1. (S)eN-(3,5-bis(trifluoromethyl)benzyl)-2-(3-(3,5-
bis(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-2-phenylethan-1-
aminium bromide (4c)
131.7 (q, JCF ¼ 33.7 Hz), 130.9, 129.2, 128.8, 126.8, 125.3, 122.8 (q,
1JCF ¼ 271.3 Hz), 68.4, 65.9, 53.0, 49.3, 48.1, 36.8, 26.4; 19F NMR
(CDCl3, 376 MHz)
d
ꢀ62.55 (s); IR (Neat): ¼ 3229, 3051, 2967,1661,
n
White solid, m.p.: 106e107 ꢁC; 1H NMR (CDCl3, 400 MHz)
d
9.32
1620,1541,1480,1380,1280,1182,1136, 910, 728 cmꢀ1; HRMS (ESI):
calcd. for [M ꢀ Br]þ (C24H29ON2F6)þ requires 475.2179; found
(s, 1H), 8.16e8.10 (m, 3H), 7.94 (s, 1H), 7.87 (s, 2H), 7.55e7.53 (d,
J ¼ 7.6 Hz, 2H), 7.32 (s, 1H), 7.19e7.15 (m, 2H), 7.08e7.04 (m, 1H),
5.73 (s, 1H), 5.21 (s, 2H), 3.88e3.84 (d, J ¼ 8.8 Hz, 1H), 3.30 (s, 3H),
475.2178; [
a
]D25.0 ¼ þ5.3 (c ¼ 1.0, MeOH).
3.26 (s, 3H), 2.86 (s, 1H); 13C NMR (CDCl3, 100 MHz)
d 154.9, 140.6,
137.8, 132.9 (q, 2JCF ¼ 34.0 Hz), 131.7 (q, 2JCF ¼ 32.7 Hz), 129.4, 129.3,
1
128.8, 126.6, 125.0, 123.1 (q, JCF
¼
272.0 Hz), 122.4 (q,
4.2.3. (S)-2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-N,N,3,3-
tetramethyl-N-(naphthalen-1-ylmethyl)butan-1-aminium bromide
(4h)
1JCF ¼ 271.3 Hz), 117.9, 115.5, 69.4, 66.5, 50.9, 49.9, 30.5; 19F NMR
(CDCl3, 376 MHz)
d
ꢀ63.13 (s), ꢀ63.23 (s); IR (Neat): ¼ 3218, 3051,
n
2955, 1693, 1624, 1574, 1475, 1443, 1388, 1278, 1181, 1134,
White solid, m.p.: 112e113 ꢁC; 1H NMR (CDCl3, 400 MHz)
d 9.50
1045 cmꢀ1; HRMS (ESI): calcd. for [M ꢀ Br]þ (C28H24ON3F12
)
re-
þ
(s, 1H), 8.35e8.30 (d, J ¼ 8.4 Hz, 1H), 8.03 (s, 2H), 7.86e7.50 (m, 5H),
7.44e7.34 (m, 3H), 5.44e5.41 (d, J ¼ 13.2 Hz, 1H), 5.20e5.17 (d,
J ¼ 13.2 Hz, 1H), 4.39e4.25 (m, 2H), 3.92e3.89 (d, J ¼ 13.2 Hz, 1H),
25.0
quires 646.1722; found 646.1720; [
a]
¼ þ23.8 (c ¼ 1.0, MeOH).
D
4.2.2. (S)eN-benzyl-2-(3,5-bis(trifluoromethyl)benzamido)-
N,N,3,3-tetramethylbutan-1-aminium bromide (4g)
3.15 (s, 3H), 3.06 (s, 3H), 1.06 (s, 9H); 13C NMR (CDCl3, 100 MHz)
2
d
155.7, 141.3, 134.0, 133.9, 132.8, 132.2, 131.7 (q, JCF ¼ 33.0 Hz),
White solid, m.p.: 161e162 ꢁC; 1H NMR (CDCl3, 400 MHz)
9.23e9.21 (d, J ¼ 8.8 Hz,1H), 8.75 (s, 2H), 7.91 (s,1H), 7.59e7.57 (d,
129.2, 128.2, 126.6, 125.3, 124.8, 123.3 (q, JCF ¼ 272.0 Hz), 122.6,
1
d
118.0, 115.0, 68.3, 65.3, 53.1, 50.3, 50.1, 36.3, 26.3; 19F NMR (CDCl3,
J ¼ 6.8 Hz, 2H), 7.44e7.38 (m, 3H), 5.25e5.19 (m, 1H), 5.07e5.04 (d,
J ¼ 13.2 Hz, 1H), 4.87e4.84 (d, J ¼ 13.2 Hz, 1H), 4.62e4.58 (t,
J ¼ 9.2 Hz, 1H), 4.08e4.05 (d, J ¼ 13.2 Hz, 1H), 3.18 (s, 3H), 3.09 (s,
376 MHz)
d
ꢀ62.95 (s); IR (Neat): ¼ 3274, 3083, 2966, 1694, 1621,
n
1573, 1475, 1389, 1278, 1221, 1179, 1132, 1057, 880 cmꢀ1; HRMS
(ESI): calcd. for [M ꢀ Br]þ (C28H32ON3F6)þ requires 540.2444; found
3H), 1.05 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d
164.7, 134.9, 133.3,
540.2443; [
a
]D25.0 ¼ ꢀ41.9 (c ¼ 1.0, MeOH).

6
Z. Tian et al. / Tetrahedron 76 (2020) 131484
Table 4
Scope of the Mannich Reaction Catalyzed by quaternary ammonium salt catalyst 5ia.
4.2.4. (S)-2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-N,N,3,3-
tetramethyl-N-(naphthalen-2-ylmethyl)butan-1-aminium bromide
(4i)
4.2.5. (S)eN-(anthracen-9-ylmethyl)-2-(3-(3,5-
bis(trifluoromethyl)phenyl)ureido)-N,N,3,3-tetramethylbutan-1-
aminium bromide (4j)
White solid, m.p.: 116e117 ꢁC; 1H NMR (CDCl3, 400 MHz)
d
9.42
Light yellow solid, m.p.: 133e134 ꢁC; 1H NMR (CDCl3, 400 MHz)
(s, 1H), 8.01 (s, 2H), 7.98 (s, 1H), 7.77e7.75 (d, J ¼ 12.0 Hz, 3H),
7.57e7.45 (m, 4H), 7.35 (s, 1H), 5.09e5.06 (d, J ¼ 13.2 Hz, 1H),
4.84e4.81 (d, J ¼ 13.2 Hz, 1H), 4.23e4.12 (m, 2H), 3.86e3.82 (d,
J ¼ 13.2 Hz, 1H), 3.21 (s, 3H), 3.12 (s, 3H), 1.06 (s, 9H); 13C NMR
d
9.73 (s, 1H), 8.60e8.58 (d, J ¼ 8.8 Hz, 1H), 8.37 (s, 2H), 8.18 (s, 1H),
7.92e7.72 (m, 3H), 7.51e7.36 (m, 5H), 7.18e7.14 (t, J ¼ 7.2 Hz, 1H),
6.00e5.97 (d, J ¼ 13.2 Hz, 1H), 5.86e5.83 (d, J ¼ 13.2 Hz, 1H),
4.40e4.35 (t, J ¼ 10.0 Hz, 1H), 3.93e3.90 (d, J ¼ 13.2 Hz, 1H), 3.00 (s,
(CDCl3, 100 MHz)
d
155.5, 141.2, 138.8, 138.7, 132.7, 131.6 (q,
3H), 2.89 (s, 3H), 1.13 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 155.9,
2JCF ¼ 33.0 Hz), 129.2, 128.7, 128.3, 128.1, 127.8, 127.3, 123.6, 123.3 (q,
141.4,132.9,132.3,131.6 (q, 2JCF ¼ 34.0 Hz), 129.6,129.2,128.4,128.2,
1JCF ¼ 271.7 Hz), 118.0, 115.1, 69.5, 67.7, 53.0, 50.0, 49.4, 36.3, 26.3;
125.4, 125.3, 124.0, 123.6, 123.3 (q, JCF ¼ 271.7 Hz), 118.0, 116.9,
1
19F NMR (CDCl3, 376 MHz)
d
ꢀ62.94 (s); IR (Neat):
n
¼ 3276, 2966,
115.0, 68.6, 53.4, 51.7, 50.3, 36.4, 31.2, 26.4; 19F NMR (CDCl3,
1696, 1570, 1474, 1389, 1279, 1179, 1132, 1059, 882 cmꢀ1; HRMS
(ESI): calcd. for [M ꢀ Br]þ (C28H32ON3F6)þ requires 540.2444; found
376 MHz)
d
ꢀ62.96 (s); IR (Neat): ¼ 3272, 3054, 2966, 1694, 1624,
n
1569, 1474, 1388, 1278, 1179, 1132, 1057, 733 cmꢀ1; HRMS (ESI):
calcd. for [M ꢀ Br]þ (C32H34ON3F6)þ requires 590.2601; found
540.2442; [
a
]D25.0 ¼ ꢀ40.6 (c ¼ 1.0, MeOH).

Z. Tian et al. / Tetrahedron 76 (2020) 131484
7
Scheme 3. A possible transition state.
25.0
25.0
590.2599; [
a
]
¼ ꢀ48.6 (c ¼ 1.0, MeOH).
(C31H36ON3F6)þ requires 580.2757; found 580.2755; [
(c ¼ 1.0, MeOH).
a]
¼ ꢀ47.1
D
D
4.2.6. (S)eN-(3,5-bis(benzyloxy)benzyl)-2-(3-(3,5-
bis(trifluoromethyl)phenyl)ureido)-N,N,3,3-tetramethylbutan-1-
aminium bromide (4k)
4.2.9. (S)-1-(2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-3,3-
dimethylbutyl)-1-(naphthalen-1-ylmethyl)pyrrolidin-1-ium
bromide (4n)
White solid, m.p.: 106e107 ꢁC; 1H NMR (CDCl3, 400 MHz)
d 9.32
(s, 1H), 8.00 (s, 2H), 7.34e7.23 (m, 12H), 6.66e6,64 (m, 3H),
4.96e4.91 (m, 4H), 4.71e4.67 (d, J ¼ 13.2 Hz, 1H), 4.48e4.45 (d,
J ¼ 13.2 Hz, 1H), 4.11e4.08 (m, 2H), 3.64e3.61 (d, J ¼ 13.2 Hz, 1H),
White solid, m.p.: 122e124 ꢁC; 1H NMR (CDCl3, 400 MHz)
d 9.92
(s, 1H), 8.19e8.14 (m, 3H), 8.00e7.98 (d, J ¼ 9.6 Hz, 1H), 7.71e7.67
(m, 2H), 7.58e7.56 (m, 1H), 7.43e7.35 (m, 3H), 7.13e7.10 (t,
J ¼ 7.6 Hz, 1H), 5.42 (s, 2H), 4.39e4.06 (m, 4H), 3,73e3.69 (d,
J ¼ 13.2 Hz, 1H), 3.27e3.20 (m, 1H), 3.03e2.95 (m, 1H), 2.23e1.95
2.99 (s, 3H), 2.86 (s, 3H), 0.99 (s, 9H); 13C NMR (CDCl3, 100 MHz)
2
d
160.1, 155.4, 141.2, 136.0, 131.6 (q, JCF ¼ 33.3 Hz), 128.6, 128.2,
127.6, 123.3 (q, 1JCF ¼ 271.3 Hz), 122.7, 118.0, 115.0, 112.2, 70.3, 52.8,
(m, 3H), 1.14 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 156.0, 141.5, 134.2,
49.9, 49.2, 36.2, 27.2, 26.6, 26.2; 19F NMR (CDCl3, 376 MHz)
133.6, 133.0, 132.3, 131.8, 131.7 (q, 2JCF ¼ 33.0 Hz), 129.1, 128.0, 126.6,
124.6, 123.3 (q, 1JCF ¼ 271.3 Hz), 123.0, 122.7, 118.0, 115.0, 62.3, 59.9,
57.8, 53.5, 36.4, 31.8, 26.5, 26.3, 20.7; 19F NMR (CDCl3, 376 MHz)
d
ꢀ62.90 (s); IR (Neat): ¼ 3048, 2965, 1694, 1596, 1572, 1474, 1389,
n
1279, 1172, 1133, 1059, 738 cmꢀ1; HRMS (ESI): calcd. for [M ꢀ Br]þ
(C38H42O3N3F6)þ requires 702.3125; found 702.3123;
[
a
]
d
ꢀ62.91 (s); IR (Neat): ¼ 3272, 3050, 2967, 1694, 1571, 1474, 1389,
n
D25.0 ¼ ꢀ32.0 (c ¼ 1.0, MeOH).
1279, 1179, 1132, 1056, 881 cmꢀ1; HRMS (ESI): calcd. for [M ꢀ Br]þ
(C3205H.034ON3F6)þ
requires
¼ ꢀ34.6 (c ¼ 1.0, MeOH).
566.2601;
found
566.2598;
[a
]
4.2.7. (S)-2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-N-(3,5-di-
tert-butylbenzyl)-N,N,3,3-tetramethylbutan-1-aminium bromide
(4l)
D
4.2.10. (R)-N-benzyl-2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-
3-methoxy-N,N-dimethyl-3,3-diphenylpropan-1-aminium bromide
(5a)
White solid, m.p.: 110e111 ꢁC; 1H NMR (CDCl3, 400 MHz)
d 9.37
(s, 1H), 8.00 (s, 2H), 7.49 (s, 2H), 7.32e7.29 (m, 3H), 4.81e4.78 (d,
J ¼ 13.2 Hz, 1H), 4.56e4.53 (d, J ¼ 13.2 Hz, 1H), 4.22e4.16 (m, 2H),
3.68e3.65 (d, J ¼ 13.2 Hz, 1H), 3.20 (s, 3H), 3.04 (s, 3H), 1.24 (s, 18H),
White solid, m.p.: 106e107 ꢁC; 1H NMR (CDCl3, 400 MHz)
d 9.50
(s, 1H), 7.92 (s, 2H), 7.52e7.40 (m, 10H), 7.36e7.28 (m, 6H),
7.24e7.23 (m, 1H), 5.38e5.33 (t, J ¼ 9.2 Hz, 1H), 4.57e4.54 (d,
J ¼ 13.2 Hz, 1H), 4.44e4.40 (d, J ¼ 13.2 Hz, 1H), 3.66e3.63 (d,
J ¼ 13.2 Hz, 1H), 3.53e3.48 (m, 1H), 3.10 (s, 3H), 3.03 (s, 3H), 2.93 (s,
1.02 (s, 9H); 13C NMR (CDCl3,100 MHz)
d 155.5,152.2,141.3,131.6 (q,
2JCF ¼ 32.7 Hz), 127.3, 125.7, 124.9, 123.3 (q, 1JCF ¼ 271.7 Hz), 118.0,
114.9, 70.3, 68.6, 52.8, 50.4, 49.1, 36.2, 34.9, 31.2, 26.3; 19F NMR
(CDCl3, 376 MHz)
d
ꢀ62.96 (s); IR (Neat):
n
¼ 3276, 3086, 2967,
3H); 13C NMR (CDCl3, 100 MHz)
d 155.0, 140.9, 138.1, 136.0, 132.9,
2871, 1697, 1572, 1475, 1389, 1279, 1178, 1135, 882 cmꢀ1; HRMS
131.6 (q, 2JCF ¼ 33.0 Hz), 131.3, 129.4, 129.1, 128.8, 128.4, 128.3 (2C),
(ESI): calcd. for [M ꢀ Br]þ (C32H46ON3F6)þ requires 602.3540; found
128.2, 126.0, 123.3 (q, 1JCF ¼ 271.7 Hz), 118.2, 115.2, 86.5, 70.3, 67.8,
25.0
602.3537; [
a
]
¼ ꢀ31.5 (c ¼ 1.0, MeOH).
53.4, 51.3, 50.7, 49.3; 19F NMR (CDCl3, 376 MHz)
d
ꢀ62.92 (s); IR
D
(Neat):
n
¼ 3267, 3067, 2992, 2831, 1692, 1574, 1475, 1388, 1279,
1179, 1132, 1076, 882, 738 cmꢀ1; HRMS (ESI): calcd. for [M ꢀ Br]þ
4.2.8. (S)-1-(2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-3,3-
dimethylbutyl)-1-(naphthalen-1-ylmethyl)piperidin-1-ium bromide
(4m)
(C3245H.034O2N3F6)þ
requires
¼ þ73.5 (c ¼ 1.0, MeOH).
630.2550;
found
630.2548;
[a
]
D
White solid, m.p.: 122e124 ꢁC; 1H NMR (CDCl3, 400 MHz)
d
10.07 (s, 1H), 8.23e8.18 (m, 3H), 8.03e8.00 (m, 1H), 7.71e7.60 (m,
4.2.11. (R)-2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-3-
methoxy-N,N-dimethyl-N-(naphthalen-1-ylmethyl)-3,3-
diphenylpropan-1-aminium bromide (5b)
3H), 7.40e7.37 (m, 3H), 7.14e7.10 (t, J ¼ 8.0 Hz, 1H), 5.43e5.31 (m,
2H), 4.40e3.97 (m, 6H), 3.45e3.39 (m, 1H), 1.83e1.65 (m, 6H), 1.14
(s, 9H); 13C NMR (CDCl3, 100 MHz)
d
156.1, 141.5, 134.7, 133.7, 133.2,
White solid, m.p.: 117e118 ꢁC; 1H NMR (CDCl3, 400 MHz)
d 9.58
132.3, 131.8, 131.6 (q, 2JCF ¼ 33.0 Hz), 129.1, 128.0, 126.5, 124.6, 123.4
(s, 1H), 8.20e8.18 (d, J ¼ 8.4 Hz, 1H), 7.97 (s, 2H), 7.92e7.84 (m, 2H),
7.60e7.27 (m, 15H), 7.24e7.20 (m, 1H), 5.46e5.42 (t, J ¼ 8.8 Hz, 1H),
5.13e5.10 (d, J ¼ 13.2 Hz, 1H), 4.95e4.92 (d, J ¼ 13.2 Hz, 1H),
3.78e3.70 (m, 2H), 3.10 (s, 3H), 3.04 (s, 3H), 2.92 (s, 3H); 13C NMR
1
(q, JCF ¼ 271.5 Hz), 122.5, 118.0, 115.0, 65.0, 59.4, 58.2, 56.0, 52.6,
36.8, 26.6, 20.5, 20.3, 20.2; 19F NMR (CDCl3, 376 MHz)
d
ꢀ62.92 (s);
IR (Neat):
n
¼ 3267, 3050, 2964, 1694, 1573, 1474, 1389, 1278, 1179,
1132, 1056, 881, 806 cmꢀ1; HRMS (ESI): calcd. for [M ꢀ Br]þ
(CDCl3, 100 MHz) d 155.2, 141.0, 138.4, 136.7, 132.7, 132.4, 131.6 (q,

8
Z. Tian et al. / Tetrahedron 76 (2020) 131484
2JCF ¼ 33.0 Hz), 129.4, 128.9, 128.8, 128.4, 128.3 (2C), 128.2, 126.8,
124.7, 123.3 (q, 1JCF ¼ 270.7 Hz), 123.1, 122.3, 118.1, 115.1, 86.4, 68.5,
4.2.15. (R)-2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-3,3-
bis(3,5-di-tert-butylphenyl)-3-methoxy-N,N-dimethyl- N-
(naphthalen-1-ylmethyl)propan-1-aminium bromide (5f)
White solid, m.p.: 140e141 ꢁC; 1H NMR (CDCl3, 400 MHz)
d 9.45
65.9, 53.4, 51.5, 51.0, 50.1; 19F NMR (CDCl3, 376 MHz)
d
ꢀ62.91 (s);
IR (Neat):
n
¼ 3271, 3049, 2990, 1690, 1574, 1475, 1387, 1278, 1179,
1132, 1076, 941, 880 cmꢀ1; HRMS (ESI): calcd. for [M ꢀ Br]þ
(s, 1H), 8.09e8.07 (d, J ¼ 8.8 Hz, 1H), 8.02 (s, 2H), 7.94e7.86 (m, 2H),
7.69e7.60 (m, 2H), 7.55e7.51 (m, 2H), 7.44e7.35 (m, 7H), 7.27 (s,
1H), 5.58e5.54 (t, J ¼ 8.8 Hz, 1H), 5.04e5.00 (d, J ¼ 13.2 Hz, 1H),
4.71e4.67 (d, J ¼ 13.2 Hz, 1H), 4.31e4.26 (m, 1H), 3.82e3.78 (d,
J ¼ 13.2 Hz, 1H), 3.37 (s, 3H), 2.91 (s, 3H), 2.79 (s, 3H), 1.31 (s, 18H),
(C3285H.036O2N3F6)þ
requires
680.2706;
found
680.2703;
[
a]
¼ þ51.9 (c ¼ 1.0, MeOH).
D
4.2.12. (R)-2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-3,3-
bis(3,5-dimethylphenyl)-3-methoxy-N,N-dimethyl-N-(naphthalen-
1-ylmethyl)propan-1-aminium bromide (5c)
1.25 (s, 18H); 13C NMR (CDCl3, 100 MHz)
d 155.4, 150.6 (2C), 141.0,
136.9,134.0,133.4,132.6,132.5,131.6 (q, 2JCF ¼ 32.7 Hz),129.5,128.4,
126.9, 124.8, 123.3 (q, 1JCF ¼ 271.3 Hz), 122.9, 122.4, 122.1 (2C), 121.8,
121.3, 118.1, 115.0, 87.5, 69.7, 65.2, 54.0, 52.1, 50.1, 50.0, 35.0 (2C),
White solid, m.p.: 135e136 ꢁC; 1H NMR (CDCl3, 400 MHz)
d 9.55
(s, 1H), 8.18e8.16 (d, J ¼ 8.4 Hz, 1H), 7.97e7.85 (m, 4H), 7.69e7.50
(m, 4H), 7.41e7.37 (m, 2H), 7.08 (s, 4H), 6.95 (s, 1H), 6.85 (s, 1H),
5.42e5.37 (t, J ¼ 9.2 Hz, 1H), 5.11e5.08 (d, J ¼ 13.2 Hz, 1H),
4.91e4.87 (d, J ¼ 13.2 Hz, 1H), 3.91e3.85 (m, 1H), 3.68e3.65 (d,
J ¼ 13.2 Hz, 1H), 3.13 (s, 3H), 3.10 (s, 3H), 2.87 (s, 3H), 2.35 (s, 6H),
31.5, 31.4; 19F NMR (CDCl3, 376 MHz)
d
ꢀ62.97 (s); IR (Neat):
n
¼ 3273, 2963, 1696, 1574, 1475, 1388, 1278, 1180, 1136, 880 cmꢀ1
;
HRMS (ESI): calcd. for [M
ꢀ
Br]þ (C54H68O2N3F6)þ requires
25.0
D
904.5210; found 904.5208; [
a
]
¼ þ71.3 (c ¼ 1.0, MeOH).
2.23 (s, 6H); 13C NMR (CDCl3, 100 MHz)
d
155.3, 141.0, 138.9, 138.1,
4.2.16. (R)-2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-3-
methoxy-N,N-dimethyl-N-(naphthalen-1-ylmethyl)-3,3-
di(naphthalen-2-yl)propan-1-aminium bromide (5g)
White solid, m.p.: 162e163 ꢁC; 1H NMR (CDCl3, 400 MHz)
137.5, 137.3, 134.0, 133.5, 132.7, 132.4, 131.7 (q, 2JCF ¼ 33.0 Hz), 129.9,
129.7, 129.4, 128.4, 127.4, 126.8, 126.5, 125.6, 124.7, 123.3 (q,
1JCF ¼ 271.0 Hz), 123.1, 122.3, 118.2, 115.0, 86.6, 68.7, 66.0, 53.6, 51.7,
d
9.56
51.0, 50.2, 21.8, 21.4; 19F NMR (CDCl3, 376 MHz)
d
ꢀ62.99 (s); IR
(s, 1H), 8.14e8.09 (m, 2H), 8.01 (s, 1H), 7.96 (s, 2H), 7.88e7.72 (m,
9H), 7.60e7.36 (m, 10H), 7.28e7.24 (m, 1H), 5.67e5.63 (t, J ¼ 8.4 Hz,
1H), 5.07e5.04 (d, J ¼ 13.2 Hz, 1H), 4.90e4.87 (d, J ¼ 13.2 Hz, 1H),
3.87e3.78 (m, 2H), 3.22 (s, 3H), 3.11 (s, 3H), 2.89 (s, 3H); 13C NMR
(Neat):
n
¼ 3271, 3046, 2983, 1693, 1574, 1474, 1388, 1278, 1180,
1134, 1081, 880, 852 cmꢀ1; HRMS (ESI): calcd. for [M ꢀ Br]þ
(C4225H.044O2N3F6)þ
requires
736.3332;
found
736.3330;
[
a]
¼ þ81.6 (c ¼ 1.0, MeOH).
(CDCl3, 100 MHz) d 155.4, 140.8, 136.4, 134.9, 133.9, 133.5, 132.9,
D
132.8, 132.7, 132.6 (2C), 132.4, 131.7 (q, 2JCF ¼ 33.0 Hz), 129.3, 128.7,
128.6 (2C), 128.4, 128.3, 128.0, 127.6, 127.2, 126.7, 126.6, 126.4, 126.3,
126.0, 125.9, 123.3 (q, 1JCF ¼ 271.3 Hz), 123.0, 122.1, 118.2, 115.2, 86.9,
4.2.13. (R)-3,3-bis(3,5-dimethylphenyl)-3-methoxy-N,N-dimethyl-
2-(3-(naphthalen-1-yl)ureido)-N(naphthalen-1-ylmethyl)propan-
1-aminium bromide (5d)
68.4, 66.2, 54.0, 51.7, 51.1, 49.9; 19F NMR (CDCl3, 376 MHz)
d
ꢀ62.90
(s); IR (Neat):
n
¼ 3266, 3054, 1689, 1574, 1474, 1387, 1278, 1180,
White solid, m.p.: 127e128 ꢁC; 1H NMR (CDCl3, 400 MHz)
d
8.58
1132, 1082, 880, 803 cmꢀ1; HRMS (ESI): calcd. for [M ꢀ Br]þ
(s, 1H), 8.36e8.34 (d, J ¼ 8.0 Hz, 1H), 8.22e8.20 (d, J ¼ 8.4 Hz, 1H),
7.93e7.85 (m, 3H), 7.74e7.71 (m, 2H), 7.61e7.34 (m, 8H), 7.13e7.09
(m, 4H), 6.93 (s, 1H), 6.84 (s, 1H), 5.44e5.39 (t, J ¼ 9.2 Hz, 1H),
5.12e5.09 (d, J ¼ 13.2 Hz, 1H), 4.84e4.80 (d, J ¼ 13.2 Hz, 1H),
4.22e4.14 (m, 1H), 3.59e3.55 (d, J ¼ 13.2 Hz, 1H), 3.21 (s, 3H), 3.12
(s, 3H), 2.75 (s, 3H), 2.34 (s, 6H), 2.23 (s, 6H); 13C NMR (CDCl3,
(C4265H.040O2N3F6)þ
requires
780.3019;
found
780.3018;
[a
]
¼ þ90.5 (c ¼ 1.0, MeOH).
D
4.2.17. (R)-3-methoxy-N,N-dimethyl-N-(naphthalen-1-ylmethyl)-
3,3-di(naphthalen-2-yl)-2-(3-(4-nitrophenyl)ureido)propan-1-
aminium bromide (5h)
100 MHz)
d
156.6,140.3,138.0,137.9,137.5,134.2,134.0,133.9,133.5,
Yellow solid, m.p.: 155e156 ꢁC; 1H NMR (CDCl3, 400 MHz)
d 9.70
132.7, 132.3, 129.6, 129.4, 129.3, 128.3, 127.9, 127.4, 126.7, 126.2,
126.0, 125.7, 125.5, 124.8, 124.1, 123.4, 123.0, 122.6, 119.1, 86.6, 68.2,
(s, 1H), 8.13e8.11 (d, J ¼ 8.4 Hz, 1H), 8.06 (s, 1H), 7.99e7.97 (m, 3H),
7.91e7.88 (m, 3H), 7.85e7.72 (m, 6H), 7.60e7.40 (m, 11H), 7.31e7.27
(m, 1H), 5.65e5.61 (t, J ¼ 8.0 Hz, 1H), 5.04e5.00 (d, J ¼ 13.2 Hz, 1H),
4.90e4.87 (d, J ¼ 13.2 Hz, 1H), 3.83e3.75 (m, 2H), 3.18 (s, 3H), 3.10
66.1, 53.7, 52.2, 50.9, 49.7, 21.8, 21.5; IR (Neat):
n
¼ 3257, 3047, 2960,
1682, 1598, 1545, 1405, 1343, 1227, 1091, 854, 735 cmꢀ1; HRMS
(ESI): calcd. for [M ꢀ Br]þ (C44H48O2N3)þ requires 650.3741; found
(s, 3H), 2.89 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 155.1, 145.6, 141.8,
25.0
650.3738; [
a
]
¼ 43.1 (c ¼ 1.0, MeOH).
136.1, 134.7, 133.9, 133.5, 132.9 (2C), 132.7, 132.6, 132.5, 129.4, 128.8,
128.7, 128.6, 128.4, 128.3, 128.0, 127.6, 127.4, 127.2, 126.8, 126.7,
126.4, 126.1, 125.9, 124.9, 124.7, 123.0, 122.1, 117.7, 115.2, 86.9, 68.4,
D
4.2.14. (R)-3,3-bis(3,5-bis(trifluoromethyl)phenyl)-2-(3-(3,5-
bis(trifluoromethyl)phenyl)ureido)-3-methoxy-N,N-dimethyl-N-
(naphthalen-1-ylmethyl)propan-1-aminium bromide (5e)
66.2, 53.9, 51.7, 51.2, 50.0; IR (Neat):
n
¼ 3260, 3049, 2830, 1693,
1597,1558,1505,1329,1221,1176,1111,1081, 854 cmꢀ1; HRMS (ESI):
calcd. for [M ꢀ Br]þ (C44H41O4N4)þ requires 689.3122; found
25.0
White solid, m.p.: 128e129 ꢁC; 1H NMR (CDCl3, 400 MHz)
d
9.46
689.3119; [
a
]
¼ þ152.3 (c ¼ 1.0, MeOH).
D
(s, 1H), 8.33e8.30 (d, J ¼ 9.6 Hz, 1H), 8.22e8.20 (d, J ¼ 8.4 Hz, 1H),
7.99e7.81 (m, 10H), 7.61e7.31 (m, 5H), 5.63e5.58 (t, J ¼ 9.2 Hz, 1H),
5.30e5.27 (d, J ¼ 13.2 Hz, 1H), 4.94e4.90 (d, J ¼ 13.2 Hz, 1H),
4.54e4.49 (m, 1H), 3.47e3.44 (d, J ¼ 13.2 Hz, 1H), 3.36 (s, 3H), 3.23
4.2.18. (R)-3-(benzyloxy)-2-(3-(3,5-bis(trifluoromethyl)phenyl)
ureido)-N,N-dimethyl-N-(naphthalen-1-ylmethyl)-3,3-
diphenylpropan-1-aminium bromide (5i)
(s, 3H), 2.87 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d
155.5, 140.1, 139.7,
White solid, m.p.: 100e101 ꢁC; 1H NMR (CDCl3, 400 MHz)
d 9.61
2
134.0, 133.5, 132.8, 132.5, 132.3 (q, JCF ¼ 33.7 Hz), 132.2 (q,
(s, 1H), 8.12e8.10 (d, J ¼ 8.8 Hz, 1H), 7.91e7.86 (m, 4H), 7.54e7.28
(m, 14H), 7.24e7.18 (m, 5H), 7.06e7.05 (m, 2H), 5.50e5.46 (t,
J ¼ 8.8 Hz, 1H), 5.09e5.06 (d, J ¼ 13.2 Hz, 1H), 4.93e4.90 (d,
J ¼ 13.2 Hz, 1H), 4.37e4.34 (d, J ¼ 11.6 Hz, 1H), 3.93e3.90 (d,
J ¼ 11.6 Hz, 1H), 3.80e3.69 (m, 2H), 3.20 (s, 3H), 2.88 (s, 3H); 13C
2JCF ¼ 33.7 Hz), 131.4, 129.6, 128.5, 128.0, 127.8, 127.0, 124.6, 124.3,
1
1
123.2, 123.1 (q, JCF ¼ 271.7 Hz), 122.8, 122.7 (q, JCF ¼ 271.7 Hz),
121.6 (2C), 118.4, 115.9, 85.7, 66.7, 66.1, 54.4, 50.8, 50.1; 19F NMR
(CDCl3, 376 MHz)
d
ꢀ62.71 (s), ꢀ62.92 (s), ꢀ63.20 (s); IR (Neat):
n
¼ 3223, 3050, 1699, 1623, 1574, 1475, 1388, 1279, 1175, 1135,
NMR (CDCl3, 100 MHz) d 155.2, 141.0, 138.6, 137.9, 136.8, 133.9,
904 cmꢀ1; HRMS (ESI): calcd. for [M ꢀ Br]þ (C42H32O2N3F18
)
re-
133.5, 132.6, 132.4, 131.6 (q, 2JCF ¼ 33.0 Hz), 129.3, 128.9 (2C), 128.5,
þ
25.1
quires 952.2202; found 952.2220; [
a
]
¼ þ67.4 (c ¼ 1.0, MeOH).
128.4 (2C), 128.3, 128.0, 127.5, 126.9, 126.8, 124.7, 123.3 (q,
D

Z. Tian et al. / Tetrahedron 76 (2020) 131484
9
1JCF ¼ 271.3 Hz), 123.1, 122.3, 118.1, 115.1, 86.4, 67.8, 66.7, 66.6, 51.4,
PrOH ¼ 97.5/2.5, flow rate 1.0 mL/min, 254 nm, tminor ¼ 9.6 min,
25.1
51.3, 49.6; 19F NMR (CDCl3, 376 MHz)
d
ꢀ62.89 (s); IR (Neat):
tmajor ¼ 18.7 min, 90% ee, dr > 20 : 1; [
a]
¼ ꢀ93.6 (c ¼ 1.0, CHCl3).
D
n
¼ 3273, 3061, 1692, 1575, 1475, 1388, 1278, 1179, 1132, 1066,
880 cmꢀ1; HRMS (ESI): calcd. for [M ꢀ Br]þ (C44H40O2N3F6)þ re-
4.3.2. Ethyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-phenylpropanoate (3b)
Colorless amorphous, 89% yield; 1H NMR (CDCl3, 400 MHz)
25.0
quires 756.3019; found 756.3017; [
a]
¼ þ41.8 (c ¼ 1.0, MeOH).
D
4.2.19. (R)-2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-N,N-
dimethyl-3-(naphthalen-1-ylmethoxy)-N-(naphthalen-1-ylmethyl)-
3,3-diphenylpropan-1-aminium bromide (5j)
d
7.56e7.54 (d, J ¼ 11.2 Hz, 2H), 7.38e7.29 (m, 4H), 7.23e7.12 (m,
7H), 6.42e6.34 (m, 3H), 5.46e5.44 (d, J ¼ 8.0 Hz, 1H), 4.30e4.12 (m,
3H), 1.44 (s, 9H), 1.29e1.25 (t, J ¼ 7.2 Hz, 3H); 13C NMR (CDCl3,
White solid, m.p.: 132e133 ꢁC; 1H NMR (CDCl3, 400 MHz)
d
9.64
100 MHz) d 172.6, 169.9, 155.2, 140.4, 138.8, 135.8, 130.6, 128.9,
(s, 1H), 7.97 (s, 2H), 7.84e7.79 (m, 4H), 7.76e7.73 (m, 2H), 7.67e7.65
(d, J ¼ 7.6 Hz, 2H), 7.56e7.53 (d, J ¼ 10.0 Hz,1H), 7.49e7.28 (m, 15H),
7.22e7.18 (m, 2H), 5.58e5.34 (t, J ¼ 9.2 Hz, 1H), 4.91e4.87 (d,
J ¼ 13.2 Hz, 1H), 4.71e4.86 (d, J ¼ 13.2 Hz, 1H), 4.51e4.83 (d,
J ¼ 13.2 Hz, 1H), 4.28e4.25 (d, J ¼ 13.2 Hz, 1H), 3.68e3.65 (d,
J ¼ 13.2 Hz, 1H), 3.58e3.53 (m, 1H), 2.99 (s, 3H), 2.92 (s, 1H), 2.84 (s,
128.5, 128.0, 127.1 (2C), 126.6, 79.4, 69.7, 61.4, 56.6, 28.4, 14.2; IR
(Neat):
n
¼ 3437, 2978, 1719, 1488, 1367, 1169, 1027, 698 cmꢀ1
;
HRMS (ESI): calcd. for [MþH]þ (C29H32N2O4þHþ)þ requires
473.2362; found 473.2360; HPLC analysis: Chiralpak AD-H, Hexane/
i-PrOH ¼ 98/2, flow rate 1.0 mL/min, 254 nm, tminor ¼ 26.1 min,
tmajor ¼ 28.6 min; tminor ¼ 31.2, tmajor ¼ 39.2, 51% ee; 58% ee, dr ¼ 12
25.0
1H), 2.75 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d
155.1, 141.0, 137.6,
: 1; [
a
]
¼ ꢀ75.3 (c ¼ 1.0, CHCl3).
D
136.3, 133.7, 133.6, 133.5, 133.2, 132.5, 132.3, 131.6 (q, 2JCF ¼ 33.0 Hz),
131.3, 129.5, 129.3,129.0, 128.9, 128.6, 128.5,128.4 (2C), 128.3, 126.6,
126.1, 125.8 (2C), 125.3, 124.5, 123.9, 123.3 (q, 1JCF ¼ 271.3 Hz), 122.8,
122.0, 118.2, 115.1, 86.8, 68.3, 66.1, 65.7, 51.3, 49.7; 19F NMR (CDCl3,
4.3.3. Benzyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-phenylpropanoate (3c) [10]
Colorless amorphous, 89% yield; 1H NMR (CDCl3, 400 MHz)
376 MHz)
d
ꢀ62.89 (s); IR (Neat): ¼ 3048, 1689, 1575, 1475, 1388,
n
d
7.56e7.54 (d, J ¼ 7.6 Hz, 2H), 7.39e7.29 (m, 9H), 7.21e7.12 (m, 7H),
6.38e6.36 (m, 3H), 5.50e5.48 (d, J ¼ 8.4 Hz, 1H), 5.19 (s, 2H), 4.27 (s,
1H), 1.44 (s, 9H); 13C NMR (CDCl3, 100 MHz)
172.8, 169.9, 155.2,
1278, 1179, 1131, 804 cmꢀ1; HRMS (ESI): calcd. for [M ꢀ Br]þ
25.0
(C48H42O2N3F6)þ requires 806.3176; found 806.3174; [
(c ¼ 1.0, MeOH).
a
]
¼ ꢀ0.9
D
d
140.3, 138.7, 135.7, 135.6, 130.7, 129.0, 128.9, 128.6, 128.4, 128.3,
128.1, 127.6 (2C), 127.1 (2C), 126.6, 79.5, 69.7, 67.0, 56.6, 28.4; HPLC
analysis: Chiralpak Phenomenex Cellulose-2, Hexane/i-PrOH ¼ 98/
4.3. Quaternary ammonium salt catalyzed the reaction of glycine
imines with N-Boc-aldimines
2, flow rate 1.0 mL/min, 254 nm, tmajorr
¼
15.3 min,
tminor ¼ 40.7 min; tmajor ¼ 23.6, tmajor ¼ 31.9, 0 ee; 25% ee, dr ¼ 5 : 1;
25.0
[a
]
¼ ꢀ38.5 (c ¼ 1.0, CHCl3).
D
4.3.4. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-(3-fluorophenyl)propanoate (3d)
[10]
A mixture of N-Boc-aldimines (0.12 mmol, 1.2 equiv.), Cs2CO3
(0.05 mmol, 0.5 equiv.), catalyst 5i (0.01 mmol, 10 mol%) and
glycine imines (0.10 mmol, 1.0 equiv.) dissolved in toluene (1.0 mL).
The resulting mixture was stirred for 24 h at room temperature
until the reaction finished (monitored by TLC). The resultant solu-
tion was purified through flash column chromatography on silica
gel (VPE/VEA ¼ 8 : 1) to yield pure products 3a-3t. The diastereo-
meric ratio and enantiomeric excess of the product was determined
by HPLC.
Colorless amorphous, 90% yield; 1H NMR (CDCl3, 400 MHz)
d
7.54e7.52 (d, J ¼ 7.2 Hz, 2H), 7.37e7.26 (m, 6H), 7.18e7.17 (m, 1H),
6.94e6.86 (m, 3H), 6.57e6.56 (d, J ¼ 6.8 Hz, 2H), 6.35e6.33 (d,
J ¼ 8.8 Hz,1H), 5.40e5.38 (d, J ¼ 7.6 Hz,1H),1.46 (s, 9H),1.45 (s, 9H);
13C NMR (CDCl3, 100 MHz)
d
172.5, 168.8, 162.8 (d, 1JCF ¼ 245.0 Hz),
155.2, 143.6, 138.7, 136.0, 130.6, 129.7 (d, 3JCF ¼ 8.0 Hz), 128.8, 128.6,
128.3, 128.0, 127.1, 122.2 (d, 4JCF ¼ 2.0 Hz), 113.8 (d, 2JCF ¼ 19.0 Hz),
113.6 (d, JCF ¼ 20.0 Hz), 82.1, 79.5, 69.8, 56.3, 28.4, 27.9; 19F NMR
2
(CDCl3,
376
MHz)
d
ꢀ113.50, ꢀ113.2, ꢀ113.53, ꢀ113.54, ꢀ113.55, ꢀ113.57 (m); HPLC
4.3.1. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-phenylpropanoate (3a) [10]
Colorless amorphous, 87% yield; 1H NMR (CDCl3, 400 MHz)
analysis: Chiralpak AD-H, Hexane/i-PrOH ¼ 98/2, flow rate 1.0 mL/
min, 254 nm, tminor ¼ 11.1 min, tmajor ¼ 17.9 min, 78% ee, dr > 20 : 1;
25.1
[a
]
¼ ꢀ55.6 (c ¼ 1.0, CHCl3).
d
7.56e7.55 (d, J ¼ 7.6 Hz, 2H), 7.38e7.29 (m, 4H), 7.25e7.15 (m, 7H),
D
6.50e6.49 (d, J ¼ 6.4 Hz, 2H), 6.37e6.35 (d, J ¼ 8.8 Hz, 1H),
5.44e5.41 (d, J ¼ 8.4 Hz, 1H), 4.13 (s, 1H), 1.47 (s, 9H), 1.45 (s, 9H);
4.3.5. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-(4-fluorophenyl)propanoate (3e)
[10]
13C NMR (CDCl3, 100 MHz)
d 172.1, 169.1, 155.1, 140.7, 138.9, 136.0,
130.4, 128.8, 128.4, 128.2, 128.1, 127.9, 127.1, 126.9, 126.6, 81.9, 79.2,
56.7, 28.4, 27.9; HPLC analysis: Chiralpak AD-H, Hexane/i-
Colorless amorphous, 94% yield; 1H NMR (CDCl3, 400 MHz)

10
Z. Tian et al. / Tetrahedron 76 (2020) 131484
d
7.56e7.54 (d, J ¼ 8.0 Hz, 2H), 7.38e7.22 (m, 6H), 7.14e7.10 (m, 2H),
[MþH]þ (C31H35BrN2O4þHþ)þ requires 579.1780; found 579.1778;
HPLC analysis: Chiralpak AD-H, Hexane/i-PrOH ¼ 99/1, flow rate
6.93e6.89 (t, J ¼ 8.4 Hz, 2H), 6.56e6.54 (d, J ¼ 6.8 Hz, 2H),
6.36e6.33 (d, J ¼ 8.8 Hz, 1H), 5.39e5.37 (d, J ¼ 8.4 Hz, 1H), 4.09 (s,
1.0 mL/min, 254 nm, tminor ¼ 17.6 min, tmajor ¼ 31.3 min, 77% ee,
25.1
1H), 1.46 (s, 9H), 1.44 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d
172.3,
dr > 20 : 1; [
a]
¼ ꢀ79.2 (c ¼ 1.0, CHCl3).
D
1
168.9, 161.8 (d, JCF ¼ 243.0 Hz), 155.1, 138.7, 136.6, 136.0, 130.6,
3
128.8, 128.6, 128.3, 128.2 (d, JCF ¼ 8.0 Hz), 128.0, 127.1, 114.9 (d,
4.3.10. (2S,3R)-tert-Butyl 3-(4-bromophenyl)-3-((tert-
butoxycarbonyl)amino)-2-((diphenylmethylene)amino)propanoate
(3j) [10]
2JCF ¼ 22.0 Hz), 82.0, 79.5, 70.1, 56.2, 28.4, 27.9; 19F NMR (CDCl3,
376 MHz)
d
ꢀ116.05 (s); HPLC analysis: Chiralpak AD-H, Hexane/i-
PrOH ¼ 98/2, flow rate 1.0 mL/min, 254 nm, tminor ¼ 12.4 min,
Colorless amorphous, 89% yield; 1H NMR (CDCl3, 400 MHz)
25.1
tmajor ¼ 26.7 min, 79% ee, dr > 20 : 1; [
a
]
¼ ꢀ82.8 (c ¼ 1.0, CHCl3).
d
7.56e7.56 (d, J ¼ 7.2 Hz, 2H), 7.40e7.29 (m, 8H), 7.06e7.04 (d,
D
J ¼ 8.0 Hz, 2H), 6.58e6.57 (d, J ¼ 7.2 Hz, 2H), 6.35e6.33 (d,
J ¼ 8.4 Hz, 1H), 5.37e5.35 (d, J ¼ 8.4 Hz, 1H), 4.11 (s, 1H), 1.47 (s, 9H),
4.3.6. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-3-(2-
chlorophenyl)-2-((diphenylmethylene)amino)propanoate (3f)
Colorless amorphous, 92% yield; 1H NMR (CDCl3, 400 MHz)
1.45 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 172.4, 168.8, 155.1, 139.9,
138.7, 135.9, 132.4, 131.2, 130.6, 130.0, 128.8, 128.6, 128.4, 128.3,
128.2, 128.0, 127.1, 120.8, 82.1, 79.5, 69.8, 56.3, 28.4, 27.9; HPLC
analysis: Chiralpak AD-H, Hexane/i-PrOH ¼ 97.5/2.5, flow rate
d
7.57e7.55 (d, J ¼ 7.2 Hz, 2H), 7.44e7.31 (m, 8H), 7.15e7.14 (m, 3H),
6.43e6.39 (m, 2H), 5.82e5.80 (d, J ¼ 8.4 Hz, 1H), 4.32 (s, 1H), 1.48 (s,
9H), 1.46 (s, 9H); 13C NMR (CDCl3, 100 MHz)
172.6, 172.0, 169.0,
d
1.0 mL/min, 254 nm, tminor ¼ 10.6 min, tmajor ¼ 29.2 min, 82% ee,
25.1
155.0, 138.7, 137.9, 137.6, 136.0, 135.8, 133.2, 132.5, 132.4, 130.5,
130.0, 129.4, 129.3, 129.0, 128.7, 128.5, 128.4, 128.3, 128.2, 128.0,
127.9, 126.9, 126.6, 126.4, 81.9, 79.5, 66.8, 54.2, 28.4, 27.9, 27.7; IR
dr > 20 : 1; [
a]
¼ ꢀ42.9 (c ¼ 1.0, CHCl3).
D
4.3.11. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-(o-tolyl)propanoate (3k) [10]
Colorless amorphous, 86% yield; 1H NMR (CDCl3, 400 MHz)
(Neat):
n
¼ 3430, 2972, 1721, 1488, 1361, 1158, 1025, 702 cmꢀ1
;
HRMS (ESI): calcd. for [MþH]þ (C31H35ClN2O4þHþ)þ requires
535.2285; found 535.2282; HPLC analysis: Chiralpak AD-H, Hex-
ane/i-PrOH ¼ 98/2, flow rate 0.7 mL/min, 254 nm, tminor ¼ 8.3 min,
d
7.59e7.57 (d, J ¼ 7.2 Hz, 2H), 7.41e7.27 (m, 5H), 7.21e7.01 (m, 5H),
6.43e6.29 (m, 3H), 5.64e5.62 (d, J ¼ 9.2 Hz,1H), 4.01 (s, 1H), 2.07 (s,
3H), 1.47 (s, 9H), 1.43 (s, 9H); 13C NMR (CDCl3, 100 MHz)
172.2,
tmajor ¼ 28.8 min; tminor ¼ 13.9, tmajor ¼ 20.4, 23% ee; 78% ee, dr ¼ 2 :
d
25.0
1; [
a
]
¼ ꢀ96.3 (c ¼ 1.0, CHCl3).
169.3, 155.1, 138.8, 138.6, 136.0, 134.7, 130.5, 130.2, 129.0, 128.8,
128.7, 128.4, 128.3, 128.1, 128.0, 127.9, 127.2, 127.0, 126.9, 126.4,
126.0, 125.6, 81.8, 79.2, 67.6, 53.7, 31.6, 28.4, 27.9, 27.3; HPLC anal-
ysis: Chiralpak AD-H, Hexane/i-PrOH ¼ 97.5/2.5, flow rate 0.8 mL/
D
4.3.7. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-3-(3-
chlorophenyl)-2-((diphenylmethylene)amino)Propanoate (3g)
Colorless amorphous, 90% yield; 1H NMR (CDCl3, 400 MHz)
min, 254 nm, tminor ¼ 5.9 min, tmajor ¼ 16.1 min; tminor ¼ 8.6 min,
25.0
d
7.55e7.53 (d, J ¼ 11.2 Hz, 2H), 7.38e7.29 (m, 6H), 7.17e7.06 (m,
4H), 6.58e6.57 (d, J ¼ 6.8 Hz, 2H), 6.34e6.32 (d, J ¼ 8.8 Hz, 1H), 4.13
(s, 1H), 1.47 (s, 9H), 1.46 (s, 9H); 13C NMR (CDCl3, 100 MHz)
172.5,
tmajor ¼ 10.0 min, 45% ee; 71% ee, dr ¼ 4 : 1; [
a]
¼ ꢀ60.7 (c ¼ 1.0,
D
CHCl3).
d
168.8, 155.1, 142.9, 138.7, 135.9, 134.1, 132.4, 130.6, 130.0, 129.4,
128.8, 128.6, 128.3, 128.0, 127.1, 124.7, 82.1, 79.6, 69.8, 56.3, 28.4,
4.3.12. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-(m-tolyl)propanoate (3l) [10]
Colorless amorphous, 90% yield; 1H NMR (CDCl3, 400 MHz)
27.9; IR (Neat):
n
¼ 3435, 2977, 1726, 1487, 1364, 1162, 1035,
703 cmꢀ1; HRMS (ESI): calcd. for [MþH]þ (C31H35ClN2O4þHþ)þ
d
7.55e7.53 (d, J ¼ 7.2 Hz, 2H), 7.38e7.23 (m, 6H), 7.11e7.04 (t,
requires 535.2285; found 535.2283; HPLC analysis: Chiralpak AD-
J ¼ 7.6 Hz, 1H), 6.98e6.91 (m, 3H), 6.48e6.46 (d, J ¼ 10.4 Hz, 2H),
6.34e6.32 (d, J ¼ 8.8 Hz, 1H), 5.39e5.37 (d, J ¼ 8.0 Hz, 1H), 4.11 (s,
H, Hexane/i-PrOH
¼
99/1, flow rate 1.0 mL/min, 254 nm,
tminor ¼ 18.1 min, tmajor ¼ 29.5 min, 80% ee, dr > 20 : 1;
1H), 1.46 (s, 9H), 1.44 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 172.0,
25.0
[
a]
¼ ꢀ99.9 (c ¼ 1.0, CHCl3).
169.2, 155.2, 140.5, 139.0, 137.6, 136.1, 130.4, 128.8, 128.4, 128.1,
128.0,127.9, 127.6, 127.5, 123.6, 81.9, 79.2, 70.2, 56.7, 28.4, 28.0, 21.3;
HPLC analysis: Chiralpak AD-H, Hexane/i-PrOH ¼ 97.5/2.5, flow rate
D
4.3.8. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-3-(4-
chlorophenyl)-2-((diphenylmethylene)amino)propanoate (3h) [10]
Colorless amorphous, 90% yield; 1H NMR (CDCl3, 400 MHz)
1.0 mL/min, 254 nm, tminor ¼ 8.5 min, tmajor ¼ 15.3 min, 74% ee,
25.1
dr > 20 : 1; [
a]
¼ ꢀ76.2 (c ¼ 1.0, CHCl3).
D
d
7.55e7.53 (d, J ¼ 7.2 Hz, 2H), 7.38e7.25 (m, 6H), 7.20e7.08 (m, 4H),
6.57e6.55 (d, J ¼ 7.2 Hz, 2H), 6.35e6.33 (d, J ¼ 8.8 Hz, 1H), 4.07 (s,
1H), 1.45 (s, 9H), 1.43 (s, 9H); 13C NMR (CDCl3, 100 MHz)
172.4,
4.3.13. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-(p-tolyl)propanoate (3 m) [10]
Colorless amorphous, 95% yield; 1H NMR (CDCl3, 400 MHz)
d
168.9, 155.1, 139.4, 138.7, 135.9, 132.7, 130.7, 128.8, 128.6, 128.3 (2C),
128.1, 128.0, 127.1, 82.1, 79.5, 69.9, 56.4, 28.4, 27.9; HPLC analysis:
Chiralpak AD-H, Hexane/i-PrOH ¼ 97.5/2.5, flow rate 1.0 mL/min,
d
7.57e7.55 (d, J ¼ 7.2 Hz, 2H), 7.37e7.22 (m, 6H), 7.05e7.02 (m, 4H),
6.53e6.51 (d, J ¼ 6.4 Hz, 2H), 6.34e6.31 (d, J ¼ 8.4 Hz, 1H),
254 nm, tminor ¼ 10.1 min, tmajor ¼ 25.2 min, 85% ee, dr > 20 : 1;
5.39e5.37 (d, J ¼ 8.4 Hz, 1H), 4.11 (s, 1H), 2.27 (s, 3H), 1.46 (s, 9H),
25.1
[
a]
¼ ꢀ57.7 (c ¼ 1.0, CHCl3).
1.44 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 172.0, 169.2, 155.1, 139.0,
D
137.7, 136.4, 128.8, 128.4, 128.2, 128.0, 127.2, 126.5, 81.8, 79.2, 70.2,
56.5, 28.4, 27.9, 21.0; HPLC analysis: Chiralpak AD-H, Hexane/i-
4.3.9. tert-Butyl (2S,3R)-3-(3-bromophenyl)-3-((tert-
butoxycarbonyl)amino)-2-((diphenylmethylene)amino)propanoate
(3i)
PrOH ¼ 97.5/2.5, flow rate 1.0 mL/min, 254 nm, tminor ¼ 10.0 min,
25.0
tmajor ¼ 19.0 min, 80% ee, dr > 20 : 1; [
a]
¼ ꢀ73.6 (c ¼ 1.0, CHCl3).
D
Colorless amorphous, 95% yield; 1H NMR (CDCl3, 400 MHz)
d
7.53e7.52 (d, J ¼ 7.2 Hz, 2H), 7.37e7.26 (m, 8H), 7.10e7.08 (m, 2H),
4.3.14. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-(2-methoxyphenyl)propanoate (3n)
Colorless amorphous, 85% yield; 1H NMR (CDCl3, 400 MHz)
6.56e6.54 (d, J ¼ 6.8 Hz, 2H), 6.33e6.31 (d, J ¼ 8.8 Hz, 1H),
5.38e5.36 (d, J ¼ 8.8 Hz, 1H), 4.11 (s, 1H), 1.46 (s, 9H), 1.45 (s, 9H);
13C NMR (CDCl3, 100 MHz)
d
172.6, 168.8, 155.1, 143.1, 138.7, 135.9,
d
7.52e7.50 (d, J ¼ 7.2 Hz, 2H), 7.34e7.27 (m, 5H), 7.23e7.12 (m, 3H),
130.6, 130.0, 129.9, 129.8, 128.8, 128.7, 128.4, 128.0, 127.1, 125.1,
122.4, 82.2, 79.6, 69.9, 56.3, 28.4, 27.9; IR (Neat):
¼ 3427, 2970,
1714, 1477, 1364, 1161, 1031, 696 cmꢀ1; HRMS (ESI): calcd. for
6.84e6.80 (t, J ¼ 8.0 Hz, 1H), 6.67e6.65 (m, 1H), 6.46e6.44 (d,
J ¼ 6.4 Hz, 2H), 6.23e6.20 (d, J ¼ 8.8 Hz, 1H), 5.70e5.67 (m, 1H),
4.31e4.30 (d, J ¼ 2.8 Hz, 1H), 3.47 (s, 3H), 1.45 (s, 9H), 1.42 (s, 9H);
n

Z. Tian et al. / Tetrahedron 76 (2020) 131484
11
13C NMR (CDCl3, 100 MHz)
130.1, 129.0, 128.8, 128.2, 128.0 (2C), 127.9, 127.8, 127.4, 120.0, 109.8,
d
171.7, 169.7, 155.0, 139.1, 136.3, 130.2,
4.3.19. tert-Butyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-(thiophen-2-yl)propanoate (3s)
[10]
81.4, 79.1, 67.4, 54.8, 52.3, 28.4, 28.0; IR (Neat):
n
¼ 3436, 2970,1714,
1485, 1364, 1315, 1149, 1050, 696 cmꢀ1; HRMS (ESI): calcd. for
[MþH]þ (C32H38N2O5þHþ)þ requires 531.2781; found 531.2779;
HPLC analysis: Chiralpak AD-H, Hexane/i-PrOH ¼ 97.5/2.5, flow rate
Colorless amorphous, 86% yield; 1H NMR (CDCl3, 400 MHz)
7.64e7.62 (d, J ¼ 7.6 Hz, 2H), 7.41e7.31 (m, 6H), 7.11e7.10 (m, 1H),
d
6.87e6.86 (m, 4H), 6.27e6.25 (d, J ¼ 9.2 Hz, 1H), 5.69e5.66 (d,
0.8 mL/min, 254 nm, tmajor ¼ 19.5 min, tminor ¼ 26.9 min, 40% ee,
J ¼ 9.2 Hz, 1H), 4.19 (s, 1H), 1.44 (s, 18H); 13C NMR (CDCl3, 100 MHz)
25.1
dr > 15 : 1; [
a
]
¼ ꢀ84.0 (c ¼ 1.0, CHCl3).
d 172.9, 168.1, 154.9, 144.8, 139.0, 136.2, 130.6, 129.1, 128.7, 128.3,
D
128.0, 127.3, 126.4, 124.6, 124.4, 82.1, 79.4, 70.0, 53.1, 28.4, 27.9;
HPLC analysis: Chiralpak AD-H, Hexane/i-PrOH ¼ 98/2, flow rate
4.3.15. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-(3-methoxyphenyl)propanoate (3o)
[10]
1.0 mL/min, 254 nm, tminor ¼ 10.6 min, tmajor ¼ 26.8 min, 80% ee,
25.1
dr > 20 : 1; [
a
]
¼ ꢀ105.7 (c ¼ 1.0, CHCl3).
D
Colorless amorphous, 92% yield; 1H NMR (CDCl3, 400 MHz)
4.3.20. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-(thiophen-3-yl)propanoate (3t)
Colorless amorphous, 96% yield; 1H NMR (CDCl3, 400 MHz)
d
7.56e7.54 (d, J ¼ 7.2 Hz, 2H), 7.38e7.24 (m, 6H), 7.14e7.10 (t,
J ¼ 8.0 Hz, 1H), 6.75e6.70 (m, 2H), 6.66 (s, 1H), 6.52e6.51 (d,
J ¼ 6.8 Hz, 2H), 6.34e6.32 (d, J ¼ 8.4 Hz, 1H), 5.39e5.37 (d,
J ¼ 8.8 Hz, 1H), 4.13 (d, J ¼ 2.0 Hz, 1H), 3.64 (s, 3H), 1.46 (s, 9H), 1.44
d
7.57e7.56 (d, J ¼ 7.2 Hz, 2H), 7.38e7.29 (m, 6H), 7.17e7.15 (m, 1H),
(s, 9H); 13C NMR (CDCl3, 100 MHz)
d 172.0, 169.1, 159.5, 155.2, 142.3,
7.02 (s, 1H), 6.85e6.84 (d, J ¼ 4.8 Hz, 1H), 6.74e6.73 (d, J ¼ 6.8 Hz,
2H), 5.49e5.47 (d, J ¼ 8.8 Hz, 1H), 4.16 (s, 1H), 1.44 (s, 18H); 13C NMR
138.9,136.0,130.5,129.1,128.8,128.5,128.2,128.0,127.2,118.9,113.1,
111.7, 81.9, 79.3, 70.1, 56.7, 55.1, 28.4, 27.9; HPLC analysis: Chiralpak
AD-H, Hexane/i-PrOH ¼ 97/3, flow rate 0.8 mL/min, 254 nm,
(CDCl3, 100 MHz)
d 172.2, 169.0, 155.1, 142.3, 139.0, 136.2, 130.5,
130.1, 128.8, 128.6, 128.4, 128.3, 128.0, 127.3, 126.5, 125.4, 121.1, 81.9,
79.3, 69.6, 53.3, 28.4, 27.9; IR (Neat):
n
¼ 3438, 2972, 1717, 1486,
tminor ¼ 11.1 min, tmajor ¼ 21.3 min, 90% ee, dr > 20 : 1;
1364, 1315, 1161, 1050, 703 cmꢀ1; HRMS (ESI): calcd. for [MþH]þ
(C29H34N2O4S þ Hþ)þ requires 507.2239; found 507.2238; HPLC
analysis: Chiralpak AD-H, Hexane/i-PrOH ¼ 97.5/2.5, flow rate
25.1
[
a
]
¼ ꢀ92.9 (c ¼ 1.0, CHCl3).
D
4.3.16. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-(4-methoxyphenyl)propanoate (3p)
[10]
1.0 mL/min, 254 nm, tminor ¼ 12.9 min, tmajor ¼ 30.6 min, 88% ee,
25.1
dr > 20 : 1; [
a
]
¼ ꢀ68.6 (c ¼ 1.0, CHCl3).
D
Colorless amorphous, 91% yield; 1H NMR (CDCl3, 400 MHz)
7.56e7.55 (d, J ¼ 7.2 Hz, 2H), 7.37e7.23 (m, 6H), 7.08e7.06 (d,
4.3.21. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-3-
cyclohexyl-2-((diphenylmethylene)amino)propanoate (3u)
Colorless amorphous, 60% yield; 1H NMR (CDCl3, 400 MHz)
d
J ¼ 8.4 Hz, 2H), 6.76e6.73 (d, J ¼ 8.8 Hz, 2H), 6.55e6.54 (d,
J ¼ 6.8 Hz, 2H), 6.32e6.30 (d, J ¼ 8.8 Hz, 1H), 5.36e5.34 (d,
J ¼ 8.4 Hz, 1H), 4.08 (s, 1H), 3.74 (s, 3H), 1.45 (s, 9H), 1.43 (s, 9H); 13C
d
7.66e7.64 (d, J ¼ 7.6 Hz, 2H), 7.43e7.39 (m, 4H), 7.36e7.33 (m, 2H),
7.14e7.13 (m, 2H), 5.66e5.64 (d, J ¼ 10.0 Hz, 1H), 4.66e4.65 (d,
J ¼ 2.4 Hz, 1H), 3.95e3.90 (m, 1H), 1.84e1.73 (m, 6H), 1.44 (s, 9H),
NMR (CDCl3, 100 MHz)
d 172.0, 169.2, 158.5, 155.1, 138.9, 136.1,
133.0, 130.5, 128.8, 128.4, 128.2, 128.0, 127.7, 127.2, 113.5, 81.8, 79.2,
70.2, 56.2, 55.3, 28.4, 27.9; HPLC analysis: Chiralpak AD-H, Hexane/
1.41 (s, 9H), 1.30e1.19 (m, 5H); 13C NMR (CDCl3, 100 MHz)
d 171.6,
170.5, 155.7, 139.2, 136.6, 130.5, 128.9, 128.8, 128.4, 128.0, 127.4, 81.4,
78.6, 77.3, 77.0, 76.7, 65.8, 57.7, 40.6, 29.5, 29.3, 28.4, 27.8, 26.2, 26.1,
i-PrOH ¼ 97.5/2.5, flow rate 1.0 mL/min, 254 nm, tminor ¼ 16.0 min,
25.1
tmajor ¼ 57.2 min, 87% ee, dr > 20 : 1; [
a]
¼ ꢀ65.6 (c ¼ 1.0, CHCl3).
D
26.0; IR (Neat):
n
¼ 3448, 2929, 2855, 2360, 1737, 1721, 1493, 1367,
1172, 1024, 801, 705 cmꢀ1; HRMS (ESI): calcd. for [MþH]þ
(C31H42N2O4þHþ)þ requires 507.3145; found 507.3142; HPLC
analysis: Chiralpak IC, Hexane/i-PrOH ¼ 98/2, flow rate 0.7 mL/min,
4.3.17. tert-Butyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-(naphthalen-1-yl)propanoate (3q)
[10]
214 nm, tminor ¼ 9.7 min, tmajor ¼ 14.0 min, 11% ee, dr > 20 : 1;
Colorless amorphous, 90% yield; 1H NMR (CDCl3, 400 MHz)
7.81e7.71 (m, 3H), 7.53e7.51 (d, J ¼ 7.2 Hz, 2H), 7.44e7.27 (m, 7H),
25.1
[a
]
¼ ꢀ15.6 (c ¼ 1.0, CHCl3).
D
d
7.04e7.00 (t, J ¼ 7.6 Hz, 1H), 6.81e6.77 (t, J ¼ 7.6 Hz, 2H), 6.55e6.53
Declaration of competing interest
(d, J ¼ 8.4 Hz,1H), 6.26e6.24 (d, J ¼ 8.4 Hz,1H), 5.93 (m, 2H), 4.29 (s,
1H), 1.54 (s, 9H), 1.47 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 172.2,
We (Authors) herein declare no competing financial interest or
personal relationships that could have appeared to influence the
work reported in this paper.
169.4,155.1, 138.8,135.8, 135.4,133.7,130.4,133.0,128.7,127.9,127.7,
126.4, 126.1, 123.5, 122.1, 82.0, 79.4, 67.9, 53.6, 28.4, 27.0; HPLC
analysis: Chiralpak AD-H, Hexane/i-PrOH ¼ 98/2, flow rate 0.5 mL/
min, 254 nm, tminor ¼ 12.9 min, tmajor ¼ 34.2 min; tminor ¼ 22.1 min,
Acknowledgment
25.0
tmajor ¼ 28.9 min, 70% ee; 83% ee, dr ¼ 4 : 1; [
a]
¼ ꢀ56.8 (c ¼ 1.0,
D
CHCl3).
Financial support from Chinese Academy of Sciences (XDB
20020100) and the National Natural Science Foundation of China
(Nos. 21871282) is gratefully acknowledged.
4.3.18. tert-Butyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-
((diphenylmethylene)amino)-3-(furan-2-yl)propanoate (3r) [10]
Colorless amorphous, 88% yield; 1H NMR (CDCl3, 400 MHz)
Appendix A. Supplementary data
d
7.56e7.54 (d, J ¼ 8.0 Hz, 2H), 7.37e7.27 (m, 6H), 7.22 (s, 1H),
6.89e6.87 (d, J ¼ 6.4 Hz, 2H), 6.22 (m, 1H), 6.12e6.09 (m, 2H),
5.49e5.47 (d, J ¼ 9.2 Hz, 1H), 4.34 (s, 1H), 1.45 (s, 9H), 1.44 (s, 9H);
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131484.
13C NMR (CDCl3, 100 MHz)
d 172.6, 168.7, 155.1, 153.8, 141.5, 139.2,
136.2, 130.5, 128.9, 128.7, 128.3, 127.9, 127.4, 110.3, 106.3, 82.0, 79.5,
67.8, 51.8, 28.4, 27.9; HPLC analysis: Chiralpak AD-H, Hexane/i-
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