synthesis of both enantiomers of chiral phenylalanine derivatives catalyzed by cinchona alkaloid quaternary ammonium salts as asymmetric phase transfer catalysts

Article abstract of DOI:10.3390/molecules23061421

A practical synthesis of both enantiomers of unnatural phenylalanine derivatives by using two pseudoenantiomeric phase transfer catalysts is described. Through asymmetric α-alkylation of glycine Schiff base with substituted benzyl bromides and 1-(bromomet

Full text of DOI:10.3390/molecules23061421

molecules
Article
Synthesis of Both Enantiomers of Chiral
Phenylalanine Derivatives Catalyzed by
Cinchona Alkaloid Quaternary Ammonium Salts as
Asymmetric Phase Transfer Catalysts
Lei Jin, Shuai Zhao and Xin Chen *
School of Pharmaceutical & Life Sciences, Changzhou University, Changzhou 213164, Jiangsu, China;
15102307@smail.cczu.edu.cn (L.J.); zhaoshuai@cczu.edu.cn (S.Z.)
* Correspondence: xinchen@cczu.edu.cn; Tel.: +86-519-8633-4597; Fax: +86-519-8633-4598
Academic Editor: Raquel P. Herrera
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 24 April 2018; Accepted: 24 May 2018; Published: 12 June 2018
Abstract: A practical synthesis of both enantiomers of unnatural phenylalanine derivatives by using
two pseudoenantiomeric phase transfer catalysts is described. Through asymmetric -alkylation
of glycine Schiff base with substituted benzyl bromides and 1-(bromomethyl)naphthalene
under the catalysis of O-allyl-N-(9-anthracenmethyl) cinchoninium bromide 1f and
O-allyl-N-(9-anthracenylmethyl)cinchonidium bromide (1i), respectively, a series of both (R)- and
(S)-enantiomers of unnatural -amino acid derivatives were obtained in excellent yields and
α
(
)
α
enantioselectivity. The synthetic method is simple and scalable, and the stereochemistry of the
products is fully predictable and controlled: the cinchonine-type phase transfer catalyst 1f resulted
in (R)-α-amino acid derivatives, and the cinchonidine-type phase transfer catalyst 1i afforded
(S)-α-amino acid derivatives.
Keywords: unnatural phenylalanine derivatives; phase transfer catalysts; asymmetric α-alkylation;
glycine Schiff base
1. Introduction
Unnatural
α
-amino acids are important building blocks for synthesis of peptides, pharmaceutical
-phenylalanine derivatives have
molecules and natural products. In particular, unnatural
α
been the subject of numerous investigations for their extensive distribution in biological active
compounds. For example, CPD-15A5, which is a small-molecule negative allosteric modulator
(antagonist) for the β2-adrenergic receptor (β2AR) [1], contains a (S)-3,5-dibromophenylalanine
subunit (Figure 1). Levothyroxine, used for the treatment of hypothyroidism [2–4
], has a
(S)-3,5-diiodophenylalanine backbone. ADEP 4, which shows potent antibacterial activity against
multidrug-resistant pathogens [5,6], has a (S)-3,5-difluorophenylalanine sidechain. In addition,
LY355703, a potent and broad spectrum antitumor agent [
(R)-(3-chloro-5-methoxy)phenylalanine. We are particularly interested in unnatural
derivatives [ ] because they are the key building blocks for synthesizing a series of dipeptides as
allosteric antagonists of the β2-adrenergic receptor (β2AR) [ ] in one of our ongoing research projects.
7,
8], is partially composed of
α
-phenylalanine
9
1
We need both the (R)- and (S)-enantiomers of
α
-phenylalanine derivatives for structure-activity
relationship studies.
Molecules 2018, 23, 1421; doi:10.3390/molecules23061421
www.mdpi.com/journal/molecules

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Figure 1. Chemical structures of some biologically active molecules containing α-phenylalanine subunits.
Although many different methods for the synthesis of
reported in the literature [10 12], these methods have significant drawbacks, such as the use of
very costly catalysts, low yields, and/or poor enantioselectivity for some derivatives. Asymmetric
phase-transfer catalysis has been widely used for the synthesis of chiral -amino acids because
of its operational simplicity, mild reaction conditions, and reduced environmental impact [13 17].
α-phenylalanine derivatives have been
–
α
–
Quaternary cinchona alkaloid catalysts, discovered by O’Donnell et al. [18] and further improved
by Lygo [19] and Corey [20], have been the most useful and practical chiral phase-transfer catalysts
for the synthesis of
asymmetric synthesis of disubstituted
α
-amino acids. On the other hand, only a few examples have been reported for
-phenylalanine derivatives by using quaternary cinchona
α
alkaloid catalysts. Furthermore, some of the reported procedures are not suitable for wide range
of substrates. For example, McAlister et al. prepared a series of substituted 2-nitrophenylalanine
derivatives through asymmetric alkylation of N-(dibenzylidene)glycine tert-butyl ester with substituted
2-nitrobenzyl bromides using a cinchonidine phase transfter catalyst. 5-Methyl-2-nitrobenzyl bromide
gave 5-methyl-2-nitrophenylalanine derivative with 100% ee; however, when the methyl group was
replaced with a trifluoromethyl group, the ee value decreased to 90%, and with a chloro group
replacement, the corresponding product has only 75% ee [21].
Our group recently synthesized some biologically important compounds via asymmetric phase
transfer catalysis [1,22]. We predicted that both enantiomers of the disubstituted α-phenylalanine
derivatives could be obtained by using two pseudoenantiomeric quaternary cinchona alkaloids as the
phase transfer catalysts. Our objective was to develop a straightforward preparative-scale method
for synthesizing the unnatural α-phenylalanine derivatives with high chemical and optical purities
in sufficient quantities to permit rapid preparation of the dipeptides for laboratory bioassays and
animal studies. Herein we report a convenient synthesis of both the (R)- and (S)-enantiomers of
α
-phenylalanine derivatives, including several disubstituted unnatural α-phenylalanine derivatives
which have not been reported in literature, with excellent yield and excellent enantioselectivity through
asymmetric phase-transfer catalysis. The described procedure is simple, mild and scalable, and its
usefulness has been demonstrated with the synthesis of a dipeptide derivative of the β2AR allosteric
antagonist CPD-15A5 by using an enantiomer-enriched 3-chlorophenylalanine derivative.

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2. Results and Discussion
2.1. Condition Screening
Chiral unnatural
α
-phenylalanine derivatives were synthesized through the asymmetric
α
-alkylation reaction of N-(dibenzylidene)glycine tert-butyl ester (
2) [23,24] with substituted benzyl
bromides catalyzed by a phase transfer catalyst. Compounds 1a
–
1h (Figure 2) were chosen
as phase transfer catalysts, and they were obtained from cinchonine according to the reported
procedures [25–30].
Figure 2. Catalysts 1a–1i.
Initially, we selected 3,5-dichlorophenyl bromide (3a) to react with
alkylation conditions similar to our previously described method [22]. Five equivalents of 3a were
reacted with in the presence of 0.1 equivalents of the catalyst and by using 50% aqueous KOH solution
2 to optimize the asymmetric
2
as base and toluene/CHCl3 as solvent. A similar procedure was reported by Nájera et al. for preparing
(S)-tert-butyl N-(diphenylmethylene)phenylalaninate [31]. The alkylation proceeded at room
temperature for 24 h and afforded (R)-tert-butyl N-(diphenylmethylene)-(3,5-dichloro-phenyl)alaninate
(4a). The results are summarized in Table 1. Catalyst 1h gave the best yield (99%) and with moderate
enantioselectivity (81% ee; Table 1, entry 8) for the desired product, but catalyst 1f gave the highest
enantioselectivity (94%) (Table 1, entries 1 to 8). Clearly, catalyst 1f was better than the other
screened catalysts for the asymmetric
the reaction temperature was lowered to
97%) while the enantioselectivity also increased slightly (from 94% to 96%) when the reaction time
was increased to 48 h. When the reaction temperature was lowered to
a little bit (from 96% to 97%), but the yield decreased (from 97% to 95%) even after 72 h (Table 1,
entry 10). After the reaction temperature was further lowered to
60 ◦C, both the ee value and yield
α
-alkylation of
2 with 3a. For achieving better enantioselectivity,
−
20 ◦C, and the yield was slightly improved (from 94% to
◦
−
40 C, the ee values improved
−

Molecules 2018, 23, 1421
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decreased (Table 1, entry 9). In addition, increasing or decreasing the catalyst’s amount didn’t improve
the enantioselectivity (no better than 96% ee). However, less amount of catalyst (5 mol%) resulted in
lower yield (89%, Table 1, entry 12) whereas 20 mol% of catalyst only increased the yield a little bit
(from 95% to 99%. Table 1, entry 13) with slightly shorter reaction time (60 h). Considering the reaction
efficiency and enantioselectivity, the optimized conditions for asymmetric α-alkylation of 2 with 3a
were determined to be: 1f (10 mol%), toluene/CHCl3, and 50% KOH (5 equivalents) at −40 ◦C.
Table 1. Optimization of the reaction conditions.
Entry a
1
Temp
Time/h
ee c
Yield b
1
2
3
4
5
6
7
8
9
10
11
12d
13e
1a
1b
1c
1d
1e
1f
1g
1h
1f
1f
1f
1f
1f
rt
rt
rt
rt
rt
rt
rt
rt
24
24
24
24
24
24
24
24
48
72
72
72
60
81%
77%
93%
97%
72%
94%
74%
99%
97%
95%
87%
89%
99%
88%
81%
77%
82%
54%
94%
78%
81%
96%
97%
92%
96%
96%
◦
−20 C
◦
−40 C
◦
−60 C
◦
−40 C
◦
−40 C
a
b
Reactions were performed with
2
(0.1 mmol), 3a (0.5 mmol), base (0.5 mmol) and
1
(0.01 mmol) in toluene/CHCl3.
c
Isolated yield.
Enantiomeric excess was determined by HPLC analysis using a chiral column with
d
n-hexane–isopropanol as eluent. Reactions were performed with
1 (0.005 mmol). Reactions were performed with 2 (0.1 mmol), 3a (0.5 mmol), base (0.5 mmol) and 1 (0.02 mmol).
2 (0.1 mmol), 3a (0.5 mmol), base (0.5 mmol) and
e
2.2. Substrate Expansion
With the optimal reaction conditions in hand, we investigated the scope and limitations of the
asymmetric
benzyl bromides 3a-o as well as 1-(bromomethyl)naphthalene (3o) were tested for the alkylation
reaction with , and the results are outlined in Table 2. A variety of substituents, such as halo
(F, Cl, Br and I), electron-withdrawing (nitro and difluoro groups), electron-donating (dimethoxy
group) and -naphthyl groups, were well tolerated under the alkylation conditions, affording
the desired products 4a 4n Eight disubstituted unnatural -phenylalanine derivatives 4a 4h
α-alkylation of glycine Schiff base 2. A variety of disubstituted and monosubstituted
2
α
–
.
α
–
(Table 2, entries 1–8) were obtained with satisfactory yields and enantioselectivity. When the
benzyl bromides containing strong electron-withdrawing groups were used, the corresponding
α
-phenylalanine derivatives were prepared with excellent enantioselectivity. Under the same
alkylation conditions, 1-(bromomethyl)naphthalene was reacted smoothly with , affording
2
(R)-tert-butyl 2-((diphenylmethylene)amino)-3-(1-naphthyl)propanoate (4o) with 85% yield and 97%
ee (Table 2, entry 15).

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Table 2. Asymmetric alkylation of 2 with 3a-o under the catalysis of 1f.
Entry a
R
Product
ee c
Yield b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3,5-Cl2C6H3
3,5-F2C6H3
3,5-Br2C6H3
3-Cl,5-FC6H3
2-Cl,6-FC6H3
3-Cl,4-FC6H3
3-Br,5-FC6H3
3,5-(MeO)2C6H3
3-FC6H4
3-ClC6H4
3-BrC6H4
4-BrC6H4
3-IC6H4
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
95%
95%
95%
93%
68%
86%
83%
85%
77%
76%
98%
95%
82%
99%
81%
97% (R)
94% (R)
93% (R)
97% (R)
98% (R)
97% (R)
96% (R)
96% (R)
95% (R)
96% (R)
95% (R)
95% (R)
96% (R)
95% (R)
96% (R)
4-NO2C6H4
1-naphthyl
a
Reactions were performed with
2 (0.1 mmol), alkylation reagent (0.5 mmol), 50% KOH (0.5 mmol) and 1f
c
(0.01 mmol) in toluene/CHCl3 at
using a chiral column with n-hexane–isopropanol as eluent.
−
40 ◦C. b Isolated yield. Enantiomeric excess was determined by HPLC analysis
After derivatives 4a-o were successfully obtained under the catalysis of cinchonine-type phase
transfer catalyst 1f, we tried to synthesize the enantiomers of 4a-o by using a cinchonidine-type phase
transfer catalyst, O-allyl-N-(9-anthracenemethyl) cinchonidium bromide (1i, Table 3), which is the
pseudoenantiomer of 1f and was prepared according to the same procedure used for 1f. To our
satisfaction, all the enantiomers of 4a
and excellent enantioselectivity (93% to 99% ee) (Table 3) under the identical conditions for 4a
except that catalyst 1f was replaced with 1i. Similar to the results in Table 2, alkylation of with
–
4o were obtained with good to excellent yields (71% to 99%)
–
4o
2
2-chloro-6-fluorobenzyl bromide resulted in the highest enantioselectivity under the catalyst of 1h
(99% ee; Table 3, entry 5).
Table 3. Asymmetric alkylation of 2 with 3a-o under the catalysis of 1i.
Entry a
R
Product
ee c
Yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3,5-Cl2C6H3
3,5-F2C6H3
3,5-Br2C6H3
3-Cl,5-FC6H3
2-Cl,6-FC6H3
3-Cl,4-FC6H3
3-Br,5-FC6H3
3,5-(MeO)2C6H3
3-FC6H4
3-ClC6H4
3-BrC6H4
4-BrC6H4
3-IC6H4
4a’
4b’
4c’
4d’
4e’
4f’
4g’
4h’
4i’
4j’
4k’
4l’
4m’
4n’
4o’
98%
99%
83%
97%
74%
88%
86%
97%
82%
71%
93%
95%
86%
96%
85%
97% (S)
94% (S)
95% (S)
98% (S)
99% (S)
97% (S)
98% (S)
98% (S)
95% (S)
97% (S)
93% (S)
94% (S)
94% (S)
94% (S)
97% (S)
4-NO2C6H4
1-naphthyl
a
Reactions were performed with
2 (0.1 mmol), alkylation reagent (0.5 mmol), 50% KOH (0.5 mmol) and 1h
c
(0.01 mmol) in toluene/CHCl3 at
using a chiral column with n-hexane–isopropanol as eluent.
−
40 ◦C. b Isolated yield. Enantiomeric excess was determined by HPLC analysis

Molecules 2018, 23, 1421
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Finally, the absolute configuration of the newly synthesized
α
-amino acid derivatives 4a
–
4o and
4a’
literature. For example, the (S)-configuration of 4l’ was confirmed by comparing its optical rotation
value ([α]2D0 105.4◦, c = 1.09, CHCl3) with the reported result ([α]2D0 110.1◦, c = 1.09, CHCl3) [32].
Gratzer et al. synthesized the same compound through asymmetric -alkylation of glycine Schiff
–4o’ was established by comparison of their optical rotation values with those reported in the
−
−
α
base catalyzed by p-biphenyl-containing pyrrolidinium ammonium bromide in 79% yield and 80%
ee [32]. The (R)-configuration of 4o was established by comparison of its optical rotation value ([α]2D0
331.6◦, c = 1, CH2Cl2) with the reported value ([α]2D0 343.7◦, c = 1.19, CHCl3) [33]. After synthesizing
4o via asymmetric α-alkylation of glycine Schiff base catalyzed by Maruoka catalyst [15], Ooi et al.
cleaved the benzophenone imine and tert-butyl ester with 6 N HCl, protected the amino group with
Boc, and then confirmed the (R)-configuration by comparing the HPLC retention time of the N-Boc
protected amino acid with the literature value [33]. Therefore, (R)-configuration was assigned for
4a–4o, and (S)-configuration for 4a’–4o’.
2.3. Application
The asymmetric α-alkylation of glycine Schiff base with substituted benzyl bromides can be
applied to the synthesis of new derivatives of CPD-15A5 as allosteric antagonists for the β2AR,
such as (2S)-3-(3-chlorophenyl)-2-((2S)-2-(2-cyclohexyl-2-phenylacetamido)-3-phenylpropanamido)-
N-methylpropanamide (13, Scheme 1). (S)-tert-Butyl N-(diphenylmethylene)-(3-chlorophenyl)alaninate
(
4j’
hydrochloride (
affording Fmoc-protected (S)-(3-chloro)phenylalanine (
L-phenylalanine methylamide
)
was hydrolyzed in refluxing hydrochloric acid to give (S)-3-chlorophenylalanine
) in 92% yield, and then the amino group in was protected with Fmoc-Cl,
). In the next step, the Fmoc-protected
with methylamine in the
5
5
6
7
was obtained by condensation of 6
presence of O-benzo-triazol-1-yl-N,N,N0,N0-tetramethyluronium hexafluorophosphate (HBTU) and
hydroxybenzotriazole (HOBt). It should be pointed out that the acidic hydrolysis of 4j’ didn’t racemize
the amino acid, because the ee value of
the resulting L-phenylalanine methylamide
Fmoc-L-4-carbamoylphenylanine ( ) to generate dipeptide 10 in 51% yield. Upon treatment with
7
is 96%. After Fmoc deprotection of
7 (piperidine/DMF),
8
was coupled in the presence of HBTU/HOBt with
9
piperidine in DMF, the Fmoc group in 10 was removed smoothly at room temperature, giving the
corresponding amine 11 in 95% yield. In the final step, 11 was reacted with 2-cyclohexyl-2-phenyl
acetic acid (12) to afford the desired product 13 in 63% yield.

Molecules 2018, 23, 1421
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Scheme 1. Synthetic route to 13.
3. Materials and Methods
3.1. Instruments and Reagents
Melting points were measured on SGW X-4B melting point apparatus (Shenguang, Shanghai,
1
China). H-NMR spectra were recorded on Avance 300 (300 MHz) and 400 (400 MHz) spectrometers
(Bruker, Karlsruhe, Germany). Chemical shifts were reported in ppm from tetramethylsilane with
the solvent resonance resulting from incomplete deuterium incorporation as the internal standard
(CDCl3:
δ
7.26 ppm). 13C-NMR spectra were recorded on Bruker Avance 300 (75 MHz) and
400 (100 MHz) spectrometers with complete proton decoupling. Chemical shifts were reported
in ppm from tetramethylsilane with the solvent resonance as the internal standard. High-resolution
mass spectrometry was performed on a Thermo Orbitrap Elite, instrument (Agilent, Palo Alto, CA,
USA). Optical rotations were measured on an Autopol IV (d = 589 nm, Hg lamp, 50 mm cell) instrument
(Rudolph, NJ, USA). The enantiomeric excess was determined by a 1260 infinity series HPLC (Agilent,
Palo Alto, CA, USA) equipped with Chiralpak OD-H, AD-H and IA columns (4.6 mm
×
250 mm,
Daicel Chiral Technologies, Shanghai, China). Chemicals and solvents were purchased from Linfeng
(Shanghai) and Annaiji (Shanghai) in China, and used as received. Purification of the products was
carried out by flash column chromatography using silica gel (Yantai Jiangyou Company, Shandong,
China, particle size 0.100–0.075 mm).
3.2. General Methods
(R)-tert-Butyl N-(diphenylmethylene)-(3,5-dichlorophenyl)alaninate (4a; R=3,5-Cl2-C6H3): A 10 mL reaction
tube was charged with
2 (30 mg, 0.1 mmol), 3,5-dichlorobenzyl bromide (119 mg, 0.5 mmol,

Molecules 2018, 23, 1421
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5 equivalent), catalyst 1f (6 mg, 0.01 mmol, 0.1 equivalent) and toluene and CHCl3 (1.5 mL, 2:1 v/v),
and the mixture was cooled to
−
40 ◦C. After the mixture was stirred for 10 min, 50% aq. KOH (28
◦
µL, 0.1 mmol, 5 equivalent) was added, and the whole reaction mixture was stirred at
−
40 C for
72 h before being allowed to warm to ambient temperature. The reaction was quenched by adding
H2O (2 mL), and the resulting mixture was extracted with EtOAc (3 10 mL). The combined extracts
were washed with brine (10 mL) and dried (anhydrous Na2SO4), and the crude product was purified
×
by flash column chromatography (eluting with hexane/EtOAc, 50:1) to afford 4a (43 mg, 95% yield)
as light yellow liquid. 97% ee; [α]2D0 178.8◦ (c = 1.0, CH2Cl2); 1H-NMR (400 MHz, CDCl3):
δ 7.57 (s,
1H), 7.55 (d, J = 1.4 Hz, 1H), 7.40–7.29 (m, 6H), 7.16 (t, J = 1.7 Hz, 1H), 6.95 (d, J = 1.7 Hz, 2H), 6.76
(d, J = 6.1 Hz, 2H), 4.12 (dd, J = 8.9, 4.6 Hz, 1H), 3.19–3.08 (m, 2H), 1.45 (s, 9H); 13C-NMR (100 MHz,
CDCl3):
δ 171.1, 170.2, 141.7, 139.2, 136.1, 134.4, 130.3, 128.7, 128.6, 128.3, 128.3, 128.0, 127.6, 126.4, 81.6,
66.9, 38.9, 28.0; HRMS (ESI, positive): Calcd. for C26H26Cl2NO2 [M + H]+ 454.1335, found: 454.1333.
HPLC analysis: Daicel Chiralcel OD-H, n-hexane/isopropanol = 95:5, flow rate = 0.5 mL/min.
(S)-tert-Butyl N-(diphenylmethylene)-(3,5-dichlorophenyl)alaninate (4a’; R=3,5-Cl2-C6H3): Under the
same reaction conditions for 4a except that catalyst 1f was replaced with 1i, enantiomer 4a’ was
obtained as light yellow liquid. 98% yield; 97% ee; [α]2D9 −183.0◦ (c = 1.0, CH2Cl2).
(R)-tert-Butyl N-(diphenylmethylene)-(3,5-difluorophenyl)alaninate (4b; R=3,5-F2-C6H3): Under the same
reaction conditions for 4a except that 3,5-dichlorophenyl bromide was replaced with 3,5-difluorobenzyl
◦
bromide, 4b was obtained as white solid. M.p. 35–37 C; 98% yield; 94% ee; [α]2D9 150.2◦ (c = 1.0,
CH2Cl2); 1H-NMR (400 MHz, CDCl3):
(d, J = 6.4 Hz, 2H), 6.63–6.59 (m, 3H), 4.13 (dd, J = 8.9, 4.4 Hz, 1H), 3.23–3.10 (m, 2H), 1.44 (s, 9H);
13C-NMR (100 MHz, CDCl3):
170.9, 170.2, 163.9, 163.8, 161.5, 161.3, 142.4, 142.3, 142.2, 139.2, 136.1,
δ 7.58 (s, 1H), 7.56 (d, J = 1.3 Hz, 1H), 7.39–7.25 (m, 6H), 6.78
δ
130.3, 128.7, 128.5, 128.2, 128.0, 127.6, 112.6, 112.6, 112.4, 112.3, 101.9, 101.6, 101.4, 81.5, 67.1, 39.3, 28.0;
HRMS (ESI, positive): calcd. for C26H26F2NO2 [M + H]+ 422.1926, found: 422.1925. HPLC analysis:
Daicel Chiralcel OD-H, n-hexane/isopropanol = 98:2, flow rate = 0.5 mL/min.
(S)-tert-Butyl N-(diphenylmethylene)-(3,5-difluorophenyl)alaninate (4b’; R=3,5-F2-C6H3): Under the same
reaction conditions for 4b except that catalyst 1f was replaced with 1i, enantiomer 4b’ was obtained as
white solid. 99% yield; 94% ee; [α]2D9 −154.6◦ (c = 1.0, CH2Cl2).
(R)-tert-Butyl N-(diphenylmethylene)-(3,5-dibromophenyl)alaninate (4c; R=3,5-Br2-C6H3): Under the same
reaction conditions for 4a except that 3,5-dichlorophenyl bromide was replaced with 3,5-dibromobenzyl
bromide, 4c was obtained as colorless liquid. 95% yield; 93% ee; [α]2D9 174.6◦ (c = 1.0, CH2Cl2);
1H-NMR (400 MHz, CDCl3):
δ
7.56 (s, 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.46 (s, 1H), 7.39–7.25 (m, 6H),
7.15 (d, J = 1.4 Hz, 2H), 6.76 (d, J = 5.3 Hz, 2H), 4.10 (dd, J = 8.8, 4.6 Hz, 1H), 3.18–3.07 (m, 1H), 1.46
(s, 1H); 13C-NMR (100 MHz, CDCl3):
171.1, 170.1, 142.3, 139.2, 136.1, 131.8, 131.6, 130.3, 128.7,
δ
128.6, 128.3, 128.0, 127.6, 122.4, 81.6, 66.9, 38.8, 28.0; HRMS (ESI, positive): Calcd. for C26H26Br2NO2
[M + H]+ 542.0325, 544.0304, found: 542.0326, 544.0306. HPLC analysis: Daicel Chiralcel OD-H,
n-hexane/isopropanol = 95:5, flow rate = 0.5 mL/min.
(S)-tert-Butyl N-(diphenylmethylene)-(3,5-dibromophenyl)alaninate (4c’; R=3,5-Br2-C6H3): Under the same
reaction conditions for 4c except that catalyst 1f was replaced with 1i, enantiomer 4c’ was obtained as
colorless liquid. 83% yield, 95% ee; [α]2D9 −86◦ (c = 1.3, CH2Cl2).
(R)-tert-Butyl N-(diphenylmethylene)-(3-chloro-5-fluorophenyl)alaninate (4d; R=3-Cl-5-F-C6H3): Under
the same reaction conditions for 4a except that 3,5-dichlorophenyl bromide was replaced with
3-
chloro-5-fluorophenyl bromide, 4d was obtained as colorless liquid. 93% yield; 97% ee; [α]2D0
169.0◦ (c = 1.0, CH2Cl2); 1H-NMR (400 MHz, CDCl3):
d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 6.78 (d, J = 5.6 Hz, 2H), 6.71 (d, J = 9.2 Hz, 1H), 4.13 (q, J = 4.4 Hz, 1H),
3.31–3.10 (m, 2H), 1.45 (s, 9H); 13C-NMR (100 MHz, CDCl3):
171.1, 170.3, 163.7, 161.2, 142.3, 142.2,
139.3, 136.3, 134.5, 134.4, 130.5, 128.8, 128.7, 128.4, 128.1, 127.7, 125.9, 125.9, 115.4, 115.2, 114.2, 114.0, 81.7,
δ 7.57 (d, J = 7.2 Hz, 2H), 7.41–7.28 (m, 6H), 6.89
(
δ

Molecules 2018, 23, 1421
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67.1, 39.2, 28.1; HRMS (ESI, positive): Calcd. for C26H25ClFNaNO2 [M + Na]+ 460.1450, found: 460.1450.
HPLC analysis: Daicel Chiralcel OD-H, n-hexane/isopropanol = 95:5, flow rate = 0.5 mL/min.
(S)-tert-Butyl N-(diphenylmethylene)-(3-chloro-5-fluorophenyl)alaninate (4d’; R=3-Cl-5-F-C6H3): Under
the same reaction conditions for 4d except that catalyst 1f was replaced with 1i, enantiomer 4d’ was
obtained as colorless liquid. 97% yield, 98% ee; [α]2D0 −168.2◦ (c = 1.0, CH2Cl2).
(R)-tert-Butyl N-(diphenylmethylene)-(2-chloro-6-fluorophenyl)alaninate (4e; R=2-Cl-6-F-C6H3): Under
the same reaction conditions for 4a except that 3,5-dichlorophenyl bromide was replaced with
2-
chloro-6-fluorophenyl bromide, 4e was obtained as colorless liquid. 68% yield; 98% ee; [α]2D0 274.2◦
(c = 0.9, CH2Cl2); 1H-NMR (300 MHz, CDCl3):
2H), 6.88–6.81 (m, 1H), 6.68 (d, J = 6.9 Hz, 2H), 4.39–4.34 (m, 1H), 3.52–3.45 (m, 1H), 3.36–3.29 (m, 1H),
1.45 (s, 9H); 13C-NMR (75 MHz, CDCl3):
170.8, 170.6, 163.6, 160.3, 139.6, 136.2, 136.1, 136.0, 130.2,
δ 7.60–7.57 (m, 2H), 7.36–7.26 (m, 6H), 7.11–7.01 (m,
δ
129.0, 128.5, 128.2, 128.1, 128.0, 127.8, 125.1, 125.0, 124.7, 124.5, 114.0, 113.7, 81.4, 64.6, 30.1, 28.1; HRMS
(ESI, positive): Calcd. for C26H25ClFNO2Na [M + Na]+ 460.1450, found: 460.1447. HPLC analysis:
Daicel Chiralcel IC, n-hexane/isopropanol = 98:2, flow rate = 0.5 mL/min.
(S)-tert-Butyl N-(diphenylmethylene)-(2-chloro-6-fluorophenyl)alaninate (4e’; R=2-Cl-6-F-C6H3): Under
the same reaction conditions for 4e except that catalyst 1f was replaced with 1i, enantiomer 4e’ was
obtained as colorless liquid. 74% yield, 99% ee; [α]2D0 −231.0◦ (c = 0.8, CH2Cl2).
(R)-tert-Butyl N-(diphenylmethylene)-(3-chloro-4-fluorophenyl)alaninate (4f; R=3-Cl-4-F-C6H3): Under
the same reaction conditions for 4a except that 3,5-dichlorophenyl bromide was replaced with
◦
3-
chloro-4-fluorophenyl bromide, 4f was obtained as colorless liquid. 86% yield; 97% ee; [α]2D0 178.5 (c
= 1.1, CH2Cl2); 1H-NMR (300 MHz, CDCl3):
1H), 6.97 (s, 1H), 6.94 (d, J = 1.2 Hz, 1H), 6.73 (d, J = 6.0 Hz, 1H), 4.10 (q, J = 4.9 Hz, 1H), 3.20–3.07
(m, 2H), 1.45 (s, 9H); 13C-NMR (75 MHz, CDCl3):
170.9, 170.5, 158.5, 155.2, 139.4, 136.3, 135.5, 131.8,
δ 7.59–7.55 (m, 2H), 7.41–7.27 (m, 6H), 7.07 (d, J = 7.2 Hz,
δ
130.5, 129.7, 128.8, 128.6, 128.4, 128.1, 127.7, 120.5, 120.3, 116.2, 116.0, 81.6, 67.5, 38.6, 28.2; HRMS (ESI,
positive): Calcd. for C26H25ClFNO2Na [M + Na]+ 460.1450, found: 460.1445. HPLC analysis: Daicel
Chiralcel OD-H, n-hexane/isopropanol = 95:5, flow rate = 0.5 mL/min.
(S)-tert-Butyl N-(diphenylmethylene)-(3-chloro-4-fluorophenyl)alaninate (4f’; R=3-Cl-4-F-C6H3): Under
the same reaction conditions for 4f except that catalyst 1f was replaced with 1i, enantiomer 4f’ was
obtained as colorless liquid. 88% yield, 97% ee; [α]2D0 −170.0◦ (c = 1.2, CH2Cl2).
(R)-tert-Butyl N-(diphenylmethylene)-(3-bromo-5-fluorophenyl)alaninate (4g; R=3-Br-5-F-C6H3): Under
the same reaction conditions for 4a except that 3,5-dichlorophenyl bromide was replaced with
3-
bromo-5-fluorophenyl bromide, 4g was obtained as colorless liquid. 83% yield; 96% ee; [α]2D0
151.7◦ (c = 1.3, CH2Cl2); 1H-NMR (400 MHz, CDCl3):
(d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 6.75 (d, J = 8.4 Hz, 3H), 4.12 (q, J = 4.4 Hz, 1H), 3.21–3.09 (m, 2H), 1.45
(s, 9H); 13C-NMR (100 MHz, CDCl3):
171.1, 170.3, 163.4, 161.2, 142.7, 142.6, 139.3, 136.3, 130.5, 130.2,
δ 7.57 (d, J = 7.6 Hz, 2H), 7.41–7.29 (m, 6H), 7.05
δ
128.9, 128.8, 128.8, 128.7, 128.4, 128.1, 127.7, 122.1, 122.0, 117.1, 116.8, 116.0, 115.8, 81.7, 67.1, 39.1, 28.1;
HRMS (ESI, positive): Calcd. for C26H26BrFNO2 [M + H]+ 482.1125, found: 482.1119. HPLC analysis:
Daicel Chiralcel OD-H, n-hexane/isopropanol = 95:5, flow rate = 0.5 mL/min.
(S)-tert-Butyl N-(diphenylmethylene)-(3-bromo-5-fluorophenyl)alaninate (4g’; R=3-Br-5-F-C6H3): Under
the same reaction conditions for 4g except that catalyst 1f was replaced with 1i, enantiomer 4g’ was
obtained as colorless liquid. 86% yield, 98% ee; [α]2D0 −154.4◦ (c = 1.3, CH2Cl2).
(R)-tert-Butyl N-(diphenylmethylene)-(3,5-dimethoxyphenyl)alaninate (4h; R=3,5-(MeO)2-C6H3): Under
the same reaction conditions for 4a except that 3,5-dichlorophenyl bromide was replaced with
3,5-dimethoxybenzyl bromide, 4h was obtained as colorless liquid. 85% yield; 96% ee; [α]2D9 160.2◦
(c = 1.0, CH2Cl2); 1H-NMR (400 MHz, CDCl3):
δ
7.60 (s, 1H), 7.58 (d, J = 1.4 Hz, 1H), 7.38–7.26 (m, 6H),
6.65 (d, J = 1.7 Hz, 2H), 6.27 (q, J = 2.2 Hz, 1H), 6.21 (d, J = 2.2 Hz, 2H), 4.12 (dd, J = 9.3, 4.2 Hz, 1H),
3.63 (s, 6H), 3.19–3.08 (m, 2H), 1.46 (s, 9H); 13C-NMR (100 MHz, CDCl3):
170.8, 170.2, 160.4, 140.5,
δ

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139.5, 136.3, 130.1, 128.7, 128.2, 127.9, 127.9, 127.7, 107.4, 99.1, 81.3, 67.7, 55.1, 39.8, 28.0; HRMS (ESI,
positive): Calcd. for C28H32NO4 [M + H]+ 446.2326, found: 446.2327. HPLC analysis: Daicel Chiralcel
IA, n-hexane/isopropanol = 95:5, flow rate = 0.5 mL/min.
(S)-tert-Butyl N-(diphenylmethylene)-(3,5-dimethoxyphenyl)alaninate (4h’; R=3,5-(MeO)2-C6H3): Under
the same reaction conditions for 4h except that catalyst 1f was replaced with 1i, enantiomer 4h’ was
obtained as colorless liquid. 98% yield, 98% ee; [α]2D9 −211.4◦ (c = 1.0, CH2Cl2).
(R)-tert-Butyl N-(diphenylmethylene)-(3-fluorophenyl)alaninate (4i; R=3-F-C6H4): Under the same reaction
conditions for 4a except that 3,5-dichlorophenyl bromide was replaced with 3-fluorobenzyl bromide,
4i was obtained as colorless liquid. 77% yield; 95% ee (Lit 90% ee [34]); [α]2D9 169.2◦ (c = 1.1, CH2Cl2);
1H-NMR (400 MHz, CDCl3):
δ
7.57 (d, J = 7.2 Hz, 2H), 7.38–7.24 (m, 6H), 7.14 (dd, J =14.1, 7.8 Hz, 1H),
6.86–6.83 (m, 2H), 6.75 (d, J = 9.9 Hz, 1H), 6.69 (d, J = 6.3 Hz, 2H), 4.12 (dd, J = 9.0, 4.4 Hz, 1H), 3.25–3.13
(m, 2H), 1.44 (s, 9H); 13C-NMR (75 MHz, CDCl3):
170.6, 170.5, 163.8, 161.4, 140.9, 140.8, 139.3, 136.2,
δ
130.2, 129.4, 129.4, 128.7, 128.3, 128.1, 127.9, 127.6, 125.5, 125.5, 116.6, 116.4, 113.1, 112.9, 81.3, 67.5, 39.2,
28.0. HRMS (ESI, positive): Calcd. for C26H26FNNaO2 [M + Na]+ 426.1840, found: 426.1846. HPLC
analysis: Daicel Chiralcel AD-H, n-hexane/isopropanol = 97:3, flow rate = 0.5 mL/min.
(S)-tert-Butyl N-(diphenylmethylene)-(3-fluorophenyl)alaninate (4i’; R=3-F-C6H4): Under the same reaction
conditions for 4i except that catalyst 1f was replaced with 1i, enantiomer 4i’ was obtained as colorless
liquid. 82% yield; 95% ee (Lit 96% ee [35]); [α]2D9 −156.7◦ (c = 0.9, CH2Cl2).
(R)-tert-Butyl N-(diphenylmethylene)-(3-chlorophenyl)alaninate (4j; R=3-Cl-C6H4): Under the same reaction
conditions for 4a except that 3,5-dichlorophenyl bromide was replaced with 3-chlorobenzyl bromide,
4j was obtained as light yellow liquid. 76% yield; 96% ee (Lit 95% ee [30]); [α]2D9 227.4◦ (c = 1.0,
CH2Cl2); 1H-NMR (400 MHz, CDCl3):
δ
7.56 (d, J = 7.2 Hz, 2H), 7.38–7.25 (m, 6H), 7.15–7.09 (m, 2H),
7.02 (s, 1H), 6.97 (d, J = 7.0 Hz, 2H), 6.67 (d, J = 6.3 Hz, 2H), 4.11 (dd, J = 9.0, 4.4 Hz, 1H), 3.22–3.11
(m, 2H), 1.45 (s, 9H); 13C-NMR (100 MHz, CDCl3):
170.7, 170.5, 140.4, 139.3, 136.2, 133.8, 130.2,
δ
129.8, 129.3, 128.7, 128.4, 128.1, 128.1, 128.0, 127.6, 126.3, 81.3, 67.4, 39.1, 28.0; HRMS (ESI, positive):
Calcd. for C26H27ClNO2 [M + H]+ 420.1725, found: 420.1724. HPLC analysis: Daicel Chiralcel OD-H,
n-hexane/isopropanol = 95:5, flow rate = 0.5 mL/min.
(S)-tert-Butyl N-(diphenylmethylene)-(3-chlorophenyl)alaninate (4j’; R=3-Cl-C6H4): Under the same
reaction conditions for 4j except that catalyst 1f was replaced with 1i, enantiomer 4j’ (1.6 g, 92%
yield) was obtained as light yellow oil, and used for synthesis of 13. 97% ee (Lit 91% ee [36], Lit 92%
ee [37,38]); [α]2D9 −223.4◦ (c = 1.0, CH2Cl2); [Lit [α]2D0 −16.3◦ (c = 0.2, CHCl3) [30]].
(R)-tert-Butyl N-(diphenylmethylene)-(3-bromophenyl)alaninate (4k; R=3-Br-C6H4): Under the same
reaction conditions for 4a except that 3,5-dichlorophenyl bromide was replaced with 3-bromobenzyl
bromide, 4k was obtained as colorless liquid. 98% yield, 95% ee (Lit 92% ee [30]); [α]2D9 185.4◦ (c = 1.0,
CH2Cl2); 1H-NMR (400 MHz, CDCl3):
δ
7.56 (d, J = 7.0 Hz, 2H), 7.36–7.30 (m, 7H), 7.18 (s, 1H), 7.07–7.03
(m, 2H), 6.67 (s, 2H), 4.12–4.09 (m, 1H), 3.21–3.10 (m, 2H), 1.45 (s, 9H); 13C-NMR (400 MHz, CDCl3):
δ
170.7, 170.4, 140.7, 139.3, 136.2, 132.7, 130.2, 129.6, 129.2, 128.7, 128.6, 128.4, 128.2, 128.0, 127.5, 122.1, 81.4,
67.4, 39.1, 18.0; HRMS (ESI, positive): Calcd. for C26H26BrNaNO2 [M + Na]+ 486.1039, found: 486.1040.
HPLC analysis: Daicel Chiralcel OD-H, n-hexane/isopropanol = 98:2, flow rate = 0.5 mL/min.
(S)-tert-Butyl N-(diphenylmethylene)-(3-bromophenyl)alaninate (4k’; R=3-Br-C6H4): Under the same
reaction conditions for 4k except that catalyst 1f was replaced with 1i, enantiomer 4k’ was obtained as
colorless liquid. 93% yield, 93% ee; [α]2D9 −188.2◦ (c = 1.0, CH2Cl2).
(R)-tert-Butyl N-(diphenylmethylene)-(4-bromophenyl)alaninate (4l; R=4-Br-C6H4): Under the same reaction
conditions for 4a except that 3,5-dichlorophenyl bromide was replaced with 4-bromobenzyl bromide, 4l
◦
was obtained as colorless liquid. 95% yield; 95% ee; [α]2D9 127.2 (c = 1.0, CH2Cl2); 1H-NMR (400 MHz,
CDCl3):
δ 7.58 (s, 1H), 7.56 (d, J = 1.5 Hz, 2H), 7.40–7.29 (m, 8H), 6.93 (d, J = 8.3 Hz, 2H), 6.67 (d, J = 6.4
Hz, 2H), 4.09 (dd, J = 9.0, 4.4 Hz, 1H), 3.19–3.08 (m, 2H), 1.44 (s, 9H); 13C-NMR (300 MHz CDCl3):
δ

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170.6, 170.5, 139.3, 137.4, 136.2, 131.6, 130.2, 128.7, 128.3, 128.1, 128.0, 127.6, 120.0, 81.3, 67.5, 38.9, 28.0;
HRMS (ESI, positive): Calcd. for C26H27BrNO2 [M + H]+ 464.1220, found: 464.1220. HPLC analysis:
Daicel Chiralcel OD-H, n-hexane/isopropanol = 98:2, flow rate = 0.5 mL/min.
(S)-tert-Butyl N-(diphenylmethylene)-(4-bromophenyl)alaninate (4l’; R=4-Br-C6H4): Under the same
reaction conditions for 4l except that catalyst 1f was replaced with 1i, enantiomer 4l’ was obtained a◦s
colorless liquid. 95% yield; 95% ee (Lit 80% ee [32]); [α]2D9
(c = 1.09, CHCl3) [32]].
−
134.4 (c = 1.0, CH2Cl2); [Lit [α]2D7
−
110.1
◦
(R)-tert-Butyl N-(diphenylmethylene)-(3-iodophenyl)alaninate (4m; R=3-I-C6H4): Under the same reaction
conditions for 4a except that 3,5-dichlorophenyl bromide was replaced with 3-iodobenzyl bromide, 4m
was obtained as colorless liquid. 82% yield, 96% ee; [α]2D9 235.6 (c = 1.0, CH2Cl2); 1H-NMR (400 MHz,
◦
CDCl3):
δ 7.56 (d, J = 7.2 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.38–7.25 (m, 7H), 7.05 (d, J = 7.6 Hz, 1H),
6.92 (t, J = 7.7 Hz, 1H), 6.65 (d, J = 5.3 Hz, 2H), 4.09 (dd, J = 4.8, 4.4 Hz, 1H), 3.18–3.07 (m, 2H), 1.45 (s,
9H); 13C-NMR (100 MHz, CDCl3):
δ
170.7, 170.4, 140.8, 139.3, 138.6, 136.2, 135.2, 130.2, 129.8, 129.2,
128.7, 128.3, 128.2, 127.9, 127.6, 94.1, 81.4, 67.4, 39.0, 28.0; HRMS: Calcd. for C26H27INO2 [M + H]+
512.1081, found: 512.1083. HPLC analysis: Daicel Chiralcel OD-H, n-hexane/isopropanol = 95:5, flow
rate = 0.5 mL/min.
+
(S)-tert-Butyl N-(diphenylmethylene)-(3-iodophenyl)alaninate (4m’; R=3-I-C6H4): Under the same reaction
conditions for 4m except that catalyst 1f was replaced with 1i, enantiomer 4m’ was obtained as
colorless liquid. 86% yield; 94% ee (Lit 95% ee [39]); [α]2D9 −191.4◦ (c = 1.0, CH2Cl2).
(R)-tert-Butyl N-(diphenylmethylene)-(4-nitrophenyl)alaninate (4n; R=4-NO2-C6H4): Under the same
reaction conditions for 4a except that 3,5-dichlorophenyl bromide was replaced with 4-nitrobenzyl
bromide, 4n was obtained as light yellow solid. M.p. 129–131 ◦C; 99% yield; 95% ee (Lit 90% ee [30]);
[
α]2D9 184.8◦ (c = 1.0, CH2Cl2); 1H-NMR (400 MHz, CDCl3):
δ 8.06 (dd, J = 7.0, 1.8 Hz, 2H), 7.58 (s, 1H),
7.56 (d, J = 1.5 Hz, 1H), 7.41–7.36 (m, 2H), 7.34–7.29 (m, 4H), 7.26 (d, J = 2.5 Hz, 1H), 7.24 (s, 1H), 6.71
(d, J = 6.8 Hz, 2H), 4.18 (dd, J = 8.1, 5.2 Hz, 1H), 3.35–3.25 (m, 2H), 1.45 (s, 9H); 13C-NMR (100 MHz,
CDCl3):
δ 170.9, 170.0, 146.5, 146.4, 139.0, 135.9, 130.6, 130.4, 128.7, 128.6, 128.3, 128.0, 127.4, 123.2, 81.6,
66.9, 39.3, 28.0; HRMS (ESI, positive): Calcd. for C26H27N2O4 [M + H]+ 431.1965, found: 431.1962.
HPLC analysis: Daicel Chiralcel IA, n-hexane/isopropanol = 94:6, flow rate = 0.5 mL/min.
(S)-tert-Butyl N-(diphenylmethylene)-(4-nitrophenyl)alaninate (4n’; R=4-NO2-C6H4): Under the same
reaction conditions for 4n except that catalyst 1f was replaced with 1i, enantiomer 4n’ was obtained as
light yellow solid. 96% yield; 94% ee (Lit 99% ee [39]); [α]2D9 −165.4◦ (c = 1.0, CH2Cl2).
(R)-tert-Butyl 2-((diphenylmethylene)amino)-3-(1-naphthyl)propanoate (4o; R=α-naphthyl): Under the
same reaction conditions for 4a except that 3,5-dichlorophenyl bromide was replaced with
1-(bromomethyl)naphthalene, 4o was obtained as colorless liquid. 81% yield; 96% ee (Lit 96% ee [40],
Lit 99% ee [33]); [α]2D9 331.6◦ (c = 1.0, CH2Cl2); [Lit [α]2D7 343.7◦ (c = 1.19, CHCl3) [33]]; 1H-NMR (400
MHz, CDCl3):
δ 7.78 (d, J = 8.0 Hz, 1H), 7.72–7.67 (m, 2H), 7.51 (d, J =7.6 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H),
7.33–7.22 (m, 6H), 7.11 (t, J = 7.5 Hz, 1H), 6.95 (t, J = 7.5 Hz, 2H), 6.24 (s, 2H), 4.32 (dd, J = 9.5, 4.0 Hz,
1H), 3.80 (dd, J = 13.7, 4.0 Hz, 1H), 3.50 (dd, J = 13.7, 9.6 Hz, 1H), 1.46 (s, 9H); 13C-NMR (75 MHz,
CDCl3):
δ
171.0, 170.2, 139.3, 135.8, 134.1, 133.6, 132.2, 130.0, 128.6, 128.4, 128.2, 128.2, 127.8, 127.6, 127.2,
+
127.0, 125.6, 125.2, 125.2, 123.6, 81.1, 66.5, 36.6, 28.0; HRMS (ESI, positive): Calcd. for C30H29NNaO2
[M + Na]+ 458.2091, found: 458.2091. HPLC analysis: Daicel Chiralcel AD-H, n-hexane/isopropanol =
97:3, flow rate = 0.5 mL/min.
(S)-tert-Butyl 2-((diphenylmethylene)amino)-3-(1-naphthyl)propanoate (4o’; R=α-naphthyl): Under the same
reaction conditions for 4o except that catalyst 1f was replaced with 1i, enantiomer 4o’ was obtained as
colorless liquid. 85% yield; 97% ee (Lit 98% ee [41]); [α]2D9 −295.3◦ (c = 0.9, CH2Cl2).
(S)-3-Chloro phenylalanine hydrochloride (
5): A mixture of 4j’ (1.2 g, 2.8 mmol) and 6 M HCl (6 mL)
was heated at 100 ◦C for 3 h, and then cooled to ambient temperature, resulting in white precipitates.

Molecules 2018, 23, 1421
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5
(525 mg, 92% yield) was obtained by suction filtration as white solid, and was used for the next step
without further purification. M.p. 264–266 ◦C; 1H-NMR (300 MHz, DMSO-d6):
δ 3.18 (d, J = 6.2 Hz,
2H), 4.17 (s, 1H), 7.26–7.39 (m, 4H), 8.62 (s, 3H), 13.88 (s, 1H); 13C-NMR (75 MHz, DMSO-d6):
δ
35.1, 52.9, 127.2, 128.5, 129.5, 130.4, 133.1, 137.7, 170.2; HRMS (ESI, positive): calcd. for C9H11ClNO2
[M + H]+ 200.0473, found: 200.0474.
(9H-Fluoren-9-yl)methyl (S)-(3-chloro)phenylalanine (6): To an ice-cold solution of 5 (525 mg, 2.6 mmol),
dioxane (3 mL) and 10% Na2CO3 aqueous solution (6 mL) was added dropwise a solution of Fmoc-Cl
(673 mg, 2.6 mmol) in dioxane (3 mL). The mixture was stirred at 0 ◦C for 4 h, and then warmed to
ambient temperature with the stirring continued for an additional 18 h. The reaction was quenched by
adding 2 M HCl (5 mL) and H2O (40 mL). The resulting mixture was extracted with EtOAc (2 × 60 mL),
and the combined extracts were washed with brine (2
×
30 mL) and dried. The crude product was
(644 mg, 59%
2.88 (q, J = 7.7 Hz, 1H),
3.17 (s, 1H), 4.09–4.17 (m, 3H), 4.25 (q, J = 4.8 Hz, 1H), 7.20–7.39 (m, 9H), 7.61 (d, J = 7.4 Hz, 2H), 7.87
d, J = 7.5 Hz, 2H); 13C-NMR (75 MHz, DMSO-d6):
36.5, 46.6, 55.9, 65.6, 120.2, 125.2, 125.4, 126.3,
purified by flash column chromatography (eluting with hexane/EtOAc, 20:1) to give
6
◦
1
yield) as white solid. M.p. 123–125 C; H-NMR (300 MHz, DMSO-d6):
δ
(
δ
127.1, 127.7, 128.0, 129.2, 129.9, 132.7, 140.6, 140.7, 141.2, 143.8, 143.9, 155.9, 173.9; HRMS (ESI, positive):
calcd. for C24H20ClNO4Na [M + Na]+ 444.0973, found: 444.0967.
(9H-Fluoren-9-yl)methyl(S)-(3-(3-chlorophenyl)-1-(methylamino)-1-oxopropan-2-yl)carbamate (
hydrochloride (202 mg, 3 mmol) and N,N-diisopropylethylamine (DIEA, 388 mg, 3 mmol) was added
successively to an ice-cold stirred solution of the substituted (624 mg, 1.5 mmol), HOBt (405 mg, 3 mmol)
7): Methyl-amine
6
and HBTU (1.1 g, 3 mmol) in DMF (6 mL) at 0 ◦C. The reaction mixture was stirred for 30 min at the
same temperature, and then allowed to warm to ambient temperature while the stirring continued
for an additional 12 h. The solvents and volatiles were removed under reduced pressure, and the
residue was dissolved in EtOAc (150 mL) and then washed with saturated NaHCO3 solution (50 mL)
and brine (2
×
50 mL) and finally dried (anhydrous Na2SO4). After the solvent was concentrated,
the crude product was crysta◦llized from EtOAc to give
7
(504 mg, 77% yield) as white solid. M.p.
2.57 (d, J = 4.5 Hz,
◦
179–181 C; 96% ee; [α]2D1
−
0.6 (c = 0.7, CH2Cl2); 1H-NMR (300 MHz, DMSO-d6):
δ
3H), 2.76–2.98 (m, 4H), 3.16 (s, 1H), 4.46 (d, J = 5.0 Hz, 1H), 7.14–7.29 (m, 5H), 7.38 (d, J = 1.7 Hz, 2H),
7.76 (d, J = 8.2 Hz, 2H), 7.91 (d, J = 4.3 Hz, 2H), 8.12 (d, J = 7.8 Hz, 1H); 13C-NMR (75 MHz, DMSO-d6):
δ
26.0, 37.6, 47.0, 56.6, 66.1, 120.6, 125.7, 125.8, 126.8, 127.5, 128.1, 128.4, 129.6, 130.3, 133.1, 141.0, 141.1,
141.4, 144.2, 144.2, 156.3, 172.1; HRMS (ESI, positive): calcd. for C25H24ClN2O3 [M + H]+ 435.1470,
found: 435.1470. HPLC analysis: Daicel Chiralcel OD-H, n-hexane/isopropanol = 85:15, flow rate =
1.0 mL/min.
(S)-2-Amino-3-chloro-N-methylpropanamides (8): To a stirred solution of 7 (480 mg, 1.1 mmol) in DMF
(4 mL) was added piperidine (2 mL) at room temperature. The reaction mixture was stirred at
ambient temperature and under nitrogen atmosphere for 2 h. The solvent and volatiles were removed
under reduced pressure, and the residue was purified by flash column chromatography (eluting
with DCM/MeOH, 20:1) to afford
DMSO-d6): 7.91 (d, J = 4.5 Hz, 1H), 7.32–7.23 (m, 3H), 7.16 (m, 1H), 3.42 (dd, J = 8.1, 5.2 Hz, 1H),
2.92 (dd, J = 13.4, 5.1 Hz, 1H), 2.77 (s, 2H), 2.65 (dd, J = 13.4, 5.1 Hz, 1H), 2.58 (d, J = 4.7 Hz, 3H);
8
(210 mg, 90% yield) as light yellow liquid; 1H-NMR (300 MHz,
δ
13C-NMR (75 MHz, DMSO-d6):
δ 174.3, 141.4, 132.9, 130.0, 129.3, 128.2, 126.3, 56.1, 40.5, 25.6; HRMS
(ESI, positive): calcd. for C10H14ClN2O [M + H]+ 213.0789, found: 213.0789.
(9H-Fluoren-9-yl)methyl((S)-1-(((S)-3-(3-chlorophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-3
-(4-carbamoylphenyl)-1-oxopropan-2-yl)carbamate (10): HOBt (126 mg, 0.9 mmol) and HBTU (354 mg,
0.9 mmol) were added to a stirred solution of
9 (0.52 mmol) in DMF (6 mL) at rt. After the mixture was
cooled to 0 ◦C,
8
(165 mg, 0.8 mmol) and DIEA (1 mmol) were introduced. After the whole reaction
mixture was stirred at rt for 12 h, the solvents and volatiles were removed under reduced pressure.
The solid residue was crystallized from dichloromethane to give 10 (350 mg, 51% yield) as white solid.

Molecules 2018, 23, 1421
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◦
M.p. 238–240 C; 1H-NMR (300 MHz, DMSO-d6):
δ
2.57 (d, J = 4.3 Hz, 3H), 2.68–2.88 (m, 2H), 2.95–3.01
(m, 2H), 4.00–4.31 (m, 4H), 4.44–4.51 (m, 1H), 7.16–7.42 (m, 12H), 7.60 (t, J = 7.57 Hz, 3H), 7.78–7.93 (m,
6H), 8.24 (d, J = 8.2 Hz, 1H); 13C-NMR (75 MHz, DMSO-d6):
δ
25.6, 37.4, 37.7, 46.6, 53.9, 56.0, 65.8,
120.2, 125.3, 125.4, 126.5, 127.2, 127.4, 127.7, 128.1, 129.1, 130.0, 132.4, 132.8, 140.3, 140.8, 141.6, 143.8,
143.9, 155.8, 167.9, 171.0, 171.3; HRMS (ESI, positive): calcd. for C35H33ClN4O3Na [M + Na]+ 647.2032,
found: 647.2035.
4-((S)-2-Amino-3-(((S)-3-(3-chlorophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-3-oxopropyl)benzamide
(11): Piperidine (2 mL) was added to a stirred solution of 10 (330 mg, 0.5 mmol) dissolved in DMF
(4 mL), and the mixture was stirred at rt for 2 h. After the completion of the reaction, the solvent and
volatiles were removed under reduced pressure, and the solid residue was crystallized from EtOAc to
give 11 as light yellow solid (200 mg, 95% yield). M.p. 237–239 ◦C; 1H-NMR (300 MHz, DMSO-d6): δ
2.54 (t, J = 10.5 Hz, 3H), 2.79–3.39 (m, 3H), 4.46 (s, 1H), 7.12–7.31 (m, 6H), 7.77 (d, J = 7.8 Hz, 2H), 7.99
(t, J = 9.1 Hz, 2H), 8.20 (d, J = 5.8 Hz, 1H); 13C-NMR (75 MHz, DMSO-d6):
δ 25.6, 37.6, 53.3, 56.2, 126.4,
127.4, 128.1, 129.1, 129.2, 129.9, 132.2, 132.7, 140.4, 142.2, 167.8, 171.0, 174.0; HRMS (ESI, positive): calcd.
for C20H23ClN4O3Na [M + Na]+ 245.1351, found: 245.1350.
(2S)-3-(3-Chlorophenyl)-2-((2S)-2-(2-cyclohexyl-2-phenylacetamido)-3-phenylpropan-amido)-N-methyl
-propanamide (13): HOBt (114 mg, 0.8 mmol) and HBTU (320 mg, 0.8 mmol) were added to a stirred
◦
solution of 12 (0.8 mmol) in DMF (4 mL) at rt. After the mixture was cooled to 0 C, 11 (170 mg,
0.4 mmol) was added, followed by addition of DIEA (1.2 mmol). The reaction mixture was stirred at
ambient temperature for 12 h, the solvent and volatiles were evaporated under reduced pressure,
and then the solid residue was crystallized from EtOAc to generate 13 (160 mg, 63% yield) as white
◦
1
solid. M.p. 243–245 C; H-NMR (300 MHz, DMSO-d6):
δ 0.56–0.64 (m, 3H), 0.81–0.93 (m, 6H),
1.06–1.59 (m, 3H), 2.55 (d, J = 4.5 Hz, 3H), 2.68–3.06 (m, 3H), 3.19 (d, J = 10.8 Hz, 1H), 4.39–4.44 (m, 2H),
6.96 (d, J = 8.4 Hz, 1H), 7.18–7.33 (m, 7H), 7.52 (d, J = 8.1 Hz, 1H), 7.77–7.94 (m, 3H), 8.21–8.25 (m, 3H);
13C-NMR (75 MHz, DMSO-d6):
δ 24.9, 25.2, 25.9, 26.0, 30.8, 37.7, 39.1, 42.7, 54.1, 57.3, 121.8, 126.8, 127.5,
128.6, 128.7, 129.3, 129.7, 130.6, 132.2, 132.5, 132.6, 140.8, 141.3, 141.7, 168.1, 171.1, 171.2, 173.0; HRMS
(ESI, positive): calcd. for C34H40ClN4O4 [M + H]+ 603.2733, found: 603.2730.
The 1H and 13C-NMR spectra of the compounds are available in supplementary materials.
4. Conclusions
In summary, we have developed a practical method for synthesizing both enantiomers of
unnatural
ester ( ) with substituted benzyl bromides and 1-(bromomethyl)naphthalene under the catalysis of
O-allyl-N-(9-anthracenmethyl) cinchodium bromide (1f) and O-allyl-N-(9-anthracenmethyl) bromide
1i), respectively. A series of both (R)- and (S)-enantiomers of unnatural -amino acid derivatives were
α-amino acid derivatives by asymmetric α-alkylation of N-(dibenzylidene)glycine tert-butyl
2
(
α
obtained in good to excellent yields and with excellent enantioselectivity, and the procedure is simple,
mild and scalable. Furthermore, the stereochemistry of the products is fully predictable and controlled:
the cinchonine-type phase transfer catalyst 1f resulted in all (R)-
cinchonidine-type phase transfer catalyst 1i afforded the (S)- -amino acid derivatives. Both resulting
-phenylalanine derivatives have been used for synthesizing new
α-amino acid derivatives, whereas the
α
enantiomers of the substituted
α
allosteric antagonists for β2AR.
Supplementary Materials: The supplementary materials containing NMR spectra and HPLC chromatograms
can be accessed online.
Author Contributions: X.C. conceived and designed the experiments; L.J. and S.Z. carried out the synthesis and
characterization of all compounds; All authors discussed the contents of the manuscript.
Acknowledgments: We gratefully acknowledge the financial support from the National Science Foundation of
China (21602018, 21272029) and Changzhou Science and Technology Program (CJ20160056).
Conflicts of Interest: The authors declare no conflict of interest.

Molecules 2018, 23, 1421
14 of 16
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Sample Availability: Samples of the compounds 4a–4o, 4a’–4o’ and 5–13 are available from the authors.
©
2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).