Stereoselective Substitution of Configurationally Labile α-Bromo Arylacetates with Amines and Azlactones by L -Threonine-Mediated Crystallization-Induced Dynamic Resolution

Article abstract of DOI:10.1002/ejoc.201600201

We developed a highly stereoselective C-N and C-C bond-forming reaction by carrying out a crystallization-induced dynamic resolution (CIDR) of α-bromo arylacetates followed by a stereoselective substitution reaction with an amine or azlactone nucleophile. Applications of this synthetic method to the preparation of highly enantioenriched nitrogen-containing six-membered heterocycles and α,β-disubstituted aspartates are also presented.

Full text of DOI:10.1002/ejoc.201600201

DOI: 10.1002/ejoc.201600201
Full Paper
Dynamic Resolution
Stereoselective Substitution of Configurationally Labile
α-Bromo Arylacetates with Amines and Azlactones by
L
-Threonine-Mediated Crystallization-Induced Dynamic
Resolution
Yun Soo Choi,[a] SeHee Park,[a] and Yong Sun Park*[a]
Abstract: We developed a highly stereoselective C–N and C–C lactone nucleophile. Applications of this synthetic method to
bond-forming reaction by carrying out a crystallization-induced the preparation of highly enantioenriched nitrogen-containing
dynamic resolution (CIDR) of α-bromo arylacetates followed by six-membered heterocycles and α,ꢀ-disubstituted aspartates
a stereoselective substitution reaction with an amine or az- are also presented.
Introduction
arylacetates with azlactone as the carbon nucleophile to afford
highly enantioenriched α,ꢀ-disubstituted aspartates.
Several synthetic methods for the crystallization-induced dy-
namic resolution (CIDR) of configurationally labile compounds
have been developed for practical asymmetric synthesis.[1] Re-
cently, some successful chiral-auxiliary-mediated CIDRs of con-
figurationally labile α-halo acid derivatives in nucleophilic sub-
stitution reactions have been reported.[2] We previously re-
ported the N-benzoyl L-threonine isopropyl ester mediated
CIDR of configurationally labile α-bromo phenylacetate 1, in
which the selective crystallization of (αR)-1 was controlled by
the thermodynamics of phase equilibrium. Highly diastereoen-
riched (αR)-1 was obtained as a solid with a diastereomeric ratio
(dr) of >98:2 and then efficiently used in the asymmetric synthe-
sis of α-thio and α-oxy arylacetates.[2f] For the highly stereose-
lective substitution of (αR)-1, the reaction of a sulfur or oxygen
nucleophile should be sufficiently fast relative to the rate of
epimerization at the α-position, as (αR)-1 is configurationally
labile in the presence of a base or polar solvent.
Figure 1. CIDR of α-bromo phenylacetate 1 followed by various nucleophilic
substitution reactions (Nuc = nucleophile).
In continuation of our work on CIDR and the stereoselective
substitution of α-bromo arylacetates with nitrogen and carbon
nucleophiles, we have developed a highly stereoselective C–N
or C–C bond-formation method (Figure 1). Herein, we report
the stereoselective substitution of configurationally labile α-
bromo arylacetates with diverse amines and applications for
the asymmetric synthesis of nitrogen-containing six-membered
heterocyclic compounds such as dihydroquinoxalinones, piper-
azinones, and morpholinones. In addition, we wish to report
the first example of a nucleophilic substitution of α-bromo
Results and Discussion
To apply the CIDR method to the preparation of highly dia-
stereoenriched α-amino-substituted acetates, it is important to
perform the nucleophilic substitution (SN2) reaction under con-
ditions that minimize the epimerization of (αR)-1 upon expo-
sure to base. Thus, we first investigated the substitution reac-
tion of (αR)-1 (>98:2 dr) with benzylamine at various concentra-
tions to establish a relationship between the concentration and
the diastereomeric excess (de) value of product 2.[3] The reac-
tions were monitored for % conversion and % de by NMR analy-
sis of the crude reaction mixture with 2.5 equiv. of benzylamine
in CDCl3 at room temperature for 9 h. Figure 2 (a) clearly shows
the relationship between the concentration and the de value of
2. As the concentration of the reaction mixture increased, the
[a] Department of Chemistry, Konkuk University,
120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea
E-mail: parkyong@konkuk.ac.kr
http://home.konkuk.ac.kr/~parkyong/lab.htm
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600201.
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final de value of 2 decreased. However, at high concentrations ditions, which results in lower dr values. Among the reactions
(above 1.0 ) the de value of 2 was not affected by the concen- with secondary amines, high stereoselectivities were observed
M
tration of 1, and the conversion reached >95 % after 9 h. This by using dibenzylamine, benzylmethylamine, and piperidine to
result indicates that (αR)-1 underwent a fast epimerization proc- afford 8, 9, and 10, respectively, whereas a moderate decrease
ess at high concentrations of benzylamine prior to the substitu- in the stereoselectivity was observed with dibutylamine
tion reaction. Thus, the optimum concentration for the substitu- (Table 1, Entries 7–10). The absolute configurations of α-amino-
tion reaction with amines was determined to be 0.1
shown in Figure 2 (b), the reaction at 0.1 was almost com- age of the chiral auxiliary. The treatment of 8 (96:4 dr) with
plete after 24 h (93 % conversion), and the de value of product LiAlH4 in tetrahydrofuran (THF) furnished 2-(dibenzylamino)-2-
M. As substituted products were determined by the reductive cleav-
M
2 was constant during the reaction.
phenylethanol with an enantiomeric ratio (er) of 96:4 in favor
of the (S) enantiomer.[5]
Table 1. Nucleophilic substitution reactions with amines.
Figure 2. Substitution of (αR)-1 (>98:2 dr) with benzylamine: (a) reactions of
1 at various concentrations with 2.5 equiv. of benzylamine in CDCl3 at room
temp. for 9 h; (b) reaction of 1 (0.1 M) with 2.5 equiv. of benzylamine in CDCl3
at room temp. (de = diastereomeric excess).
Next, the scope of the efficient nucleophilic substitution re-
action with various amine nucleophiles was investigated at the
optimized reaction concentration (0.1
M) as shown in Table 1.
When 1 (>98:2 dr) was treated with benzylamine (2.5 equiv.) in
CHCl3 at room temp. for 24 h, α-amino-substituted product 2
was afforded with 98:2 dr (Table 1, Entry 1).[4] Under the same
conditions, the reactions with primary amines such as pheneth-
ylamine and p-anisidine afforded products 3 and 4 with 95:5
and 96:4 dr, respectively (Table 1, Entries 2 and 3). In contrast,
the reaction with isopropylamine afforded a much lower dr
value of 81:19 with a conversion of 86 % (Table 1, Entry 4).
Moreover, the reactions of ortho-substituted arylamines such as
o-anisidine and o-ethylaniline afforded lower dr values of the
products with conversions of 87 and 85 %, respectively (Table 1,
Entries 5 and 6). Limited results indicate that steric bulk at the
α- or ortho-position relative to the amino group may affect the
rate of substitution. A control experiment was carried out to
[a] All reactions were carried out with 2.5 equiv. of the amine in CHCl3 (0.1 M)
at room temp. for 24 h. [b] The conversions were determined after 24 h by
1H NMR analysis of the reaction mixture. [c] The dr values were determined
by 1H NMR analysis of the reaction mixture.
Encouraged by the high stereoselectivities of the reactions
of (αR)-1 with various amines (Table 1), we also investigated
the substitution reaction with 1,2-diaminobenzenes for the
asymmetric syntheses of 3-substituted dihydroquinoxalinones
(Scheme 1). When (αR)-1 was treated with three different 1,2-
diaminobenzenes under the same reaction conditions, the sub-
stitution reaction, followed by a spontaneous cyclization step
to remove the chiral auxiliary, afforded dihydroquinoxalinones
12–14 in yields of 79–95 % with er values of 99:1.[4g,4h]
In addition, the CIDR of 1 and the two α-bromo arylacetates
compare the rates of substitution of o-anisidine versus p-anis- 15 and 16 was applied to the asymmetric synthesis of 3-substi-
idine. We found that the reaction rate of o-anisidine is more tuted piperazinones and morpholinones to further demonstrate
than twice as slow than that of p-anisidine. The substitution the synthetic utility of this method (Scheme 2). Under the same
reaction with a sterically hindered nucleophile is also not suffi- optimized conditions, the reactions of (αR)-1, (αR)-15, and (αR)-
ciently fast relative the rate of epimerization of (αR)-1. There- 16 with N,N′-dibenzylethylenediamine afforded 3-aryl-substi-
fore, the epimerization of (αR)-1 is more likely under basic con- tuted 1,4-dibenzylpiperazin-2-ones. The one-pot substitution-
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lactones were selected as suitable carbon nucleophiles, because
they are suitably acidic for enolate formation under weakly ba-
sic conditions and sufficiently nucleophilic for fast substitution,
which is essential to achieve the highly stereoselective substitu-
tion of (αR)-1.[6]
When (αR)-1 was treated with a phenylalanine-derived az-
lactone in the presence of DIEA in N,N-dimethylformamide
(DMF; 0.5
M) at room temp. for 1 h, the substitution reaction
successfully provided the four products 23a–23d, which con-
tain different substituted quaternary carbon centers, in 95 %
yield with 57:16:21:6 dr (Scheme 3). To the best of our knowl-
edge, there is no successful precedent of a direct nucleophilic
substitution reaction between α-substituted α-halo acetates
and alkylated azlactones for the construction of sterically con-
gested C–C bonds.[7] This reaction provides access to an array
of alkylated azlactones that contain adjacent tertiary and qua-
ternary carbon centers. The subsequent ring opening of the
azlactone by treatment with TMSCl in methanol, followed by
the removal of chiral auxiliary with Et3N in methanol, success-
fully afforded dimethyl aspartate derivative 25 with 91:9 dr and
78:22 er. The increase in the dr (91:9) of 25 relative to the ratio
of (23a + 23b)/(23c + 23d) (73:27) is attributed to the rate
difference in the removal of the chiral auxiliary of 24a–24d. The
reactions of 24c and 24d are much slower than those of 24a
and 24b under the basic conditions.[8] The relative configura-
tion of 25 was determined by analogy with the known 1H NMR
spectroscopic data of authentic 25, and the absolute configura-
tion was determined by assuming an inversion of stereochemis-
try at the site of the SN2 substitution reaction of (αR)-1.[9] The
nucleophilic substitution reactions of (αRS)-1 (51:49 dr) with
Scheme 1. Asymmetric synthesis of dihydroquinoxalinones.
cyclization reaction proceeded for 48 h to afford 17–19 in yields
of 78–82 % with er values of 94:6, 86:14, and 88:12, respectively.
Moreover, we were pleased to observe that the substitution
reaction with 2-(benzylamino)ethanol and subsequent sponta-
neous cyclization afforded 4-benzyl-substituted 3-arylmorphol-
inones 20, 21, and 22 in 69–73 % yield with 96:4, 86:14, and
90:10 er, respectively.
Scheme 2. Asymmetric synthesis of piperazinones and morpholinones.
Having successfully developed an asymmetric synthetic
method for the preparation of α-amino arylacetates, we next
focused our attention on a carbon nucleophile that would ena-
ble the stereoselective carbon–carbon bond formation in a re-
action with (αR)-1. Thus, we explored the stereochemical conse-
quences of such a substitution reaction with azlactones that
were derived from N-benzoyl-α-amino carboxylic acids. Az-
Scheme 3. Nucleophilic substitution with an azlactone (DIEA = N,N-diiso-
propylethylamine; TMS = trimethysilyl; Xc = N-benzoyl-L-threonine isopropyl
ester).
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phenylalanine-derived azlactone produced the corresponding concentrations is not sufficiently fast relative to the rate of epi-
products 23a–23d with 36:35:14:15 dr, which indicates that the merization of 1 in DMF. The same reaction of (αR)-1 was then
dynamic kinetic resolution of α-bromo phenylacetate (αRS)-1 is
carried out in the less polar CHCl3 (0.1
23d with a significantly improved dr value of 79:7:12:2 but in a
M
), which afforded 23a–
not functioning in this reaction.[4]
As shown in Scheme 3, the substitution reaction in DMF pro- much lower yield of 12 % (Table 2, Entry 3). To improve the low
duced 23a–23d after 1 h in 95 % yield with 57:16:21:6 dr conversion, the substitution reaction was then carried out in
(Table 2, Entry 1). The comparatively low stereoselectivity may CHCl3 at higher concentrations. The stereoselectivities, however,
be attributed to the epimerization of (αR)-1 that could have
been promoted by the high concentration (0.5 ) of the reac-
tion mixture in a polar solvent. Our initial attempt to improve
the stereoselectivity by lowering the concentration did not im-
prove the dr values of 23 (Table 2, Entry 2). These results indi-
cate that the substitution reaction with the azlactone at both
decreased to 68:9:21:2 dr with a 59 % product yield at a concen-
tration of 0.5 and 62:14:20:4 dr with a 93 % product yield at a
concentration of 2.0 (Table 2, Entries 4 and 5). To our delight,
lowering the reaction temperature to 0 °C increased the stereo-
selectivity to 78:3:18:1 dr in an excellent yield of 92 % (Table 2,
Entry 6), whereas a slightly decreased stereoselectivity was ob-
served when the reaction was performed at –10 °C. This implies
that the substitution reaction with the azlactone in CHCl3
M
M
M
Table 2. Optimization of the substitution conditions.[a]
(2.0 M) at 0 °C is sufficiently fast relative to the rate of epimeriza-
tion of 1 in CHCl3. Therefore, the reaction conditions of Table 2,
Entry 6 were chosen as optimal for the following synthetic stud-
ies with the azlactones.
Having been successful in the three-step transformation of
α-bromo phenylacetate (αR)-1 into dimethyl aspartate deriva-
tive 25 (Scheme 3), we decided to probe the feasibility of a
procedure that avoids the purification of 23. Thus, the crude
substitution reaction mixture was neutralized by the addition
of a saturated NH4Cl solution, and the resulting mixture was
then subjected to subsequent steps. In addition, we developed
a new one-pot reaction sequence for the ring opening and re-
moval of the chiral auxiliary by employing sodium methoxide.
When the crude reaction mixture, which resulted from (αR)-
1 and phenylalanine-derived azlactone at 0 °C in CHCl3, was
subjected to this optimized one-pot procedure with sodium
methoxide (6.0 equiv.) in MeOH at –15 °C, both dimethyl aspar-
Entry
Reaction conditions
Yield [%]
dr of 23a/23b/23c/23d[b]
1
2
3
4
5
6
DMF (0.5
DMF (0.1
CHCl3 (0.1
CHCl3 (0.5
CHCl3 (2.0
M
), r.t.
), r.t.
), r.t.
), r.t.
), r.t.
95
93
12
59
93
92
57:16:21:6
56:15:21:8
79:7:12:2
68:9:21:2
62:14:20:4
78:3:18:1
M
M
M
M
CHCl3 (2.0 M), 0 °C
[a] All reactions were carried out with azlactone (1.4 equiv.) and DIEA
(2.0 equiv.) for 1 h. [b] The dr values were determined by 1H NMR analysis of
the reaction mixture.
Table 3. Asymmetric syntheses of α,ꢀ-disubstituted aspartates.[a]
Entry
R
Ar
Product
Yield [%]
dr[b]
er[c,d]
1
2
3
4
5
6
7
8
9
Bn
iBu
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-BrC6H4
p-ClC6H4
p-BrC6H4
p-ClC6H4
25
26
27
28
29
30
31
32
33
34
35
65
61
75
74
80
63
61
63
52
62
70
74:26
75:25
76:24
61:39
70:30
76:24
70:30
63:37
63:37
64:36
63:37
95:5
96:4
99:1
92:8
97:3
95:5
98:2
91:9
89:11
93:7
94:6
CH3O2CCH2
p-MeOC6H4CH2
CH3SCH2CH2
Bn
Bn
iBu
iBu
10
11
[a] All the substitution reactions were carried out in CHCl3 (2.0
M
) at 0 °C for 1 h. [b] The dr values were determined by 1H NMR analysis of the final
product. [c] The enantiomeric ratios of major diastereomer are reported. [d] The er values were determined by chiral stationary-phase high-performance liquid
chromatography using a racemic material as the standard.
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column chromatography was performed with silica gel (230–
tate 25 and the corresponding aspartic acid derivative were
produced in a ratio of 2:1. The conversion of the carboxylic acid
into methyl ester 25 was carried out by treating the acid with
HCl in MeOH. From the above reaction of (αR)-1, dimethyl as-
partate 25 was successfully obtained in 65 % overall yield with
74:26 dr and 95:5 er (Table 3, Entry 1).[10]
1
400 mesh). The H and 13C NMR spectroscopic data were recorded
1
with a Bruker (400 MHz for H NMR, 100.6 MHz for 13C NMR) spec-
trometer, and CDCl3 was used as the internal standard. Chemical
shifts (δ) are reported in ppm relative to CDCl3 (CHCl3 at δ =
1
7.26 ppm for H NMR, CDCl3 at δ = 77.07 ppm for 13C NMR). Multi-
plicities are indicated by s (singlet), d (doublet), t (triplet), q (quadru-
plet), and br. (broad). Coupling constants (J) are reported in Hz. HR
mass spectra were measured with a JEOL JMS-700 instrument by
using ESI or FAB.
With a practical procedure in hand, we examined the scope
of this strategy with six different α-amino acid azlactones for
the preparation of highly enantioenriched disubstituted aspar-
tates (Table 3, Entries 2–7). Under the same reaction conditions
as reported in Table 3, Entry 1, this simple procedure with az-
lactones that were derived from leucine, alanine, phenylglycine,
aspartic acid, tyrosine, and methionine successfully provided
highly enantioenriched α,ꢀ-disubstituted aspartates 26–31
with er values that ranged from 92:8 to 99:1 in overall yields of
61–80 %. In contrast, the variation in the aryl group of the α-
bromo arylacetate affected the stereoselectivity of the reaction
with the phenylalanine-derived azlactone. The reactions of
highly diastereoenriched (αR)-15 and (αR)-16 with the phenyla-
lanine-derived azlactone afforded both p-bromo-substituted
(αR)-32 with 63:37 dr and 91:9 er and p-chloro-substituted (αR)-
33 with 63:37 dr and 89:11 er (Table 3, Entries 8 and 9), respec-
tively. In addition, when (αR)-15 and (αR)-16 were treated with
the leucine-derived azlactone, the one-pot process that in-
cludes the substitution and ring-opening reactions along with
the removal of the chiral auxiliary afforded α,ꢀ-disubstituted
aspartates 34 with 64:36 dr and 93:7 er and 35 with 63:37 dr
and 94:6 er (Table 3, Entries 10 and 11). This nucleophilic substi-
tution can be further applied to the asymmetric synthesis of
functionally diverse α,ꢀ-disubstituted aspartate derivatives and
unnatural α-amino acids, which have been known as key build-
ing blocks in the syntheses of biologically active compounds.[11]
General Procedure for the Asymmetric Nucleophilic Substitu-
tion Reactions with Amines: To a solution of
L-threonine-derived
α-bromo ester 1, 15, or 16 (>98:2 dr) in CHCl3 (0.1
M) at room temp.
was added an amine nucleophile (2.5 equiv.). After the resulting
reaction mixture had been stirred at room temp. for 24–72 h, the
solvent was evaporated, and the crude material was purified by
column chromatography to afford an α-amino ester or a heterocy-
cle. The dr values of 2–11 were determined by 1H NMR analysis
using the proton integrations of the two diastereomers, and the er
values of 12–14 and 17–22 were determined by chiral stationary-
phase high-performance liquid chromatography (CSP-HPLC) analy-
sis. The spectroscopic data of 2, 4, 6, 8, 9, 12–14, 17, and 20 are
identical to those of authentic materials, which had been previously
reported.[4]
N-Benzoyl-O-[α-(phenethylamino)phenylacetyl]-L-threonine
Isopropyl Ester (3): Colorless oil (93 % yield). 1H NMR (400 MHz,
CDCl3, major epimer): δ = 7.66–7.09 (m, 15 H), 6.64 (d, J = 9.2 Hz, 1
H), 5.42–5.40 (m, 1 H), 4.89–4.84 (m, 2 H), 4.29 (s, 1 H), 2.76–2.67
(m, 4 H), 2.08 (br., 1 H), 1.22 (d, J = 6.0 Hz, 3 H), 1.18–1.09 (m, 6 H)
ppm. 13C NMR (100 MHz, CDCl3, major epimer): δ = 171.6, 169.2,
167.6, 139.6, 137.9, 133.7, 132.0, 128.7, 128.6, 128.5, 128.2, 127.4,
127.2, 126.3, 71.9, 70.0, 65.6, 55.9, 49.0, 36.4, 21.7, 21.6, 16.8 ppm.
HRMS: calcd. for C30H35N2O5 [M + 1]+ 503.2546; found 503.2546.
N-Benzoyl-O-[α-(isopropylamino)phenylacetyl]-L-threonine Iso-
propyl Ester (5): Pale yellow oil (86 % yield). 1H NMR (400 MHz,
CDCl3, major epimer): δ = 7.69–7.19 (m, 10 H), 6.73 (d, J = 9.2 Hz, 1
H), 5.50–5.48 (m, 1 H), 5.01–4.94 (m, 2 H), 4.45 (s, 1 H), 2.72–2.69
(m, 1 H), 1.27 (d, J = 6.0 Hz, 3 H), 1.20–1.14 (m, 3 H), 1.06–1.03 (m,
6 H) ppm. 13C NMR (100 MHz, CDCl3, major epimer): δ = 172.3,
169.2, 167.6, 138.3, 133.7, 132.0, 128.8, 128.6, 128.1, 127.4, 127.3,
127.2, 72.0, 70.0, 63.2, 56.0, 46.7, 22.8, 21.7, 21.5, 16.7 ppm. HRMS:
calcd. for C25H33N2O5 [M + 1]+ 441.2389; found 441.2389.
Conclusions
We have developed an efficient synthetic method for the highly
stereoselective formation of carbon–nitrogen and carbon–car-
bon bonds by using the CIDR of α-bromo arylacetates and nu-
cleophilic substitution reactions with amine and azlactone nu-
cleophiles. Evidence for the efficiency of this method was dem-
onstrated by the asymmetric preparation of 3-aryl-substituted
dihydroquinoxalinones, piperazinones, and morpholinones with
high stereoselectivities. Moreover, we reported the first example
of the substitution of α-substituted α-bromo acetates with alk-
ylated azlactone nucleophiles, which can be applied to the
asymmetric synthesis of diverse α,ꢀ-disubstituted aspartates.
This simple protocol, which employs mild reaction conditions
and easily removes the chiral auxiliary, provides an impetus to
further develop the CIDR approach.
N-Benzoyl-O-[α-(o-ethylanilino)phenylacetyl]-L-threonine Iso-
propyl Ester (7): Pale yellow oil (85 % yield). 1H NMR (400 MHz,
CDCl3, major epimer): δ = 7.72–6.34 (m, 15 H), 5.51–5.49 (m, 1 H),
5.09 (s, 1 H), 5.04–4.95 (m, 2 H), 2.62 (q, J = 7.6 Hz, 2 H), 1.30–1.13
(m, 12 H) ppm. 13C NMR (100 MHz, CDCl3, major epimer): δ = 170.9,
169.1, 167.6, 143.3, 137.7, 133.6, 132.0, 129.0, 128.7, 128.4, 128.2,
128.1, 127.2, 127.1, 127.0, 118.2, 110.9, 72.9, 70.2, 60.9, 55.9, 24.1,
21.8, 21.6, 16.5, 13.0 ppm. HRMS: calcd. for C30H35N2O5 [M + 1]+
503.2546; found 503.2546.
N-Benzoyl-O-[α-(1-piperidinyl)phenylacetyl]-L-threonine Iso-
propyl Ester (10): Pale yellow oil (96 % yield). 1H NMR (400 MHz,
CDCl3, major epimer): δ = 7.56–7.22 (m, 11 H), 5.54–5.49 (m, 1 H),
5.00–4.76 (m, 2 H), 3.93 (s, 1 H), 2.35 (br., 4 H), 1.56 (br., 4 H), 1.43
(br., 2 H), 1.26–1.19 (m, 6 H), 1.01 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, major epimer): δ = 170.5, 169.1, 167.8, 135.9,
133.8, 131.9, 128.8, 128.7, 128.6, 128.3, 127.4, 75.4, 71.7, 69.8, 56.0,
52.4, 25.6, 24.2, 21.7, 21.4, 16.8 ppm. HRMS: calcd. for C27H35N2O5
[M + 1]+ 467.2546; found 467.2546.
Experimental Section
General Methods: All reactions were performed in oven-dried
glassware under nitrogen. All chemicals were obtained from com-
mercial sources and used as received. Analytical thin layer chroma-
tography was performed on silica gel plates with QF-254 indicator,
and the developed plates were visualized by using UV light. Flash
N-Benzoyl-O-[α-(dibutylamino)phenylacetyl]-
L-threonine Iso-
propyl Ester (11): Colorless oil (99 % yield). 1H NMR (400 MHz,
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CDCl3, major epimer): δ = 7.80–7.27 (m, 10 H), 6.89 (d, J = 8.8 Hz, 1
H), 5.61–5.59 (m, 1 H), 4.99–4.93 (m, 2 H), 4.52 (s, 1 H), 2.51 (t, J =
7.6 Hz, 4 H), 1.41–1.11 (m, 17 H), 0.81 (t, J = 7.2 Hz, 6 H) ppm. 13C
NMR (100 MHz, CDCl3, major epimer): δ = 171.2, 169.2, 167.7, 137.0,
133.7, 131.9, 128.8, 128.7, 128.6, 128.3, 127.9, 127.2, 71.4, 69.9, 69.4,
1.23 (d, J = 6.0 Hz, 3 H), 1.19 (d, J = 6.0 Hz, 3 H), 1.10 (d, J = 6.4 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 179.4, 169.2, 168.9, 167.4,
161.5, 133.9, 133.5, 133.0, 132.5, 131.9, 130.6, 130.4, 128.7, 128.6,
128.5, 128.3, 128.0, 127.9, 127.3, 127.2, 125.8, 75.2, 72.7, 70.1, 57.8,
55.7, 42.5, 21.7, 21.5, 16.6 ppm. HRMS: calcd. for C38H37N2O7 [M +
56.0, 50.4, 50.3, 29.5, 21.8, 21.6, 20.3, 17.1, 14.0 ppm. HRMS: calcd. 1]+ 633.2601; found 633.2600.
for C30H43N2O5 [M + 1]+ 511.3172; found 511.3173.
N-Benzoyl-O-{[(αS,4S)-4-benzyl-4,5-dihydro-5-oxo-α,2-diphen-
1,4-Dibenzyl-3-(p-bromophenyl)piperazin-2-one (18): Pale yel-
low oil (79 % yield). 1H NMR (400 MHz, CDCl3): δ = 7.52–7.20 (m, 14
H), 4.61 (d, J = 14.8 Hz, 1 H), 4.52 (d, J = 14.8 Hz, 1 H), 4.09 (s, 1 H),
3.72 (d, J = 13.4 Hz, 1 H), 3.48–3.41 (m, 1 H), 3.14 (d, J = 13.4 Hz, 1
H), 3.12 (m, 1 H), 2.98–2.93 (m, 1 H), 2.50–2.44 (m, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 167.8, 138.6, 137.4, 136.6, 131.6, 130.7,
128.8, 128.7, 128.4, 128.3, 127.6, 127.4, 121.9, 70.6, 58.9, 50.3, 46.7,
45.8 ppm. HRMS: calcd. for C24H24BrN2O [M + 1]+ 435.1072; found
435.1072. HPLC (Chiralcel OD column, 10 % 2-propanol in hexane,
yloxazol-4-yl]acetyl}-L-threonine Isopropyl Ester (23b): Com-
pound 23b was obtained as an inseparable mixture with 23a. 1H
NMR (400 MHz, CDCl3): δ = 7.83–6.97 (m, 20 H), 6.38 (d, J = 9.2 Hz,
1 H), 5.56–5.49 (m, 1 H), 4.81 (d, J = 9.2 Hz, 1 H), 4.71–4.65 (m, 1 H),
4.32 (s, 1 H), 2.89 (d, J = 13.2 Hz, 1 H), 2.70 (d, J = 13.2 Hz, 1 H),
1.25 (d, J = 6.0 Hz, 3 H), 1.09 (d, J = 6.0 Hz, 3 H), 0.88 (d, J = 6.4 Hz,
3 H) ppm.
N-Benzoyl-O-{[(αR,4S)-4-benzyl-4,5-dihydro-5-oxo-α,2-diphen-
yloxazol-4-yl]acetyl}-L
-threonine Isopropyl Ester (23c): 1H NMR
0.5 mL min–1): tR = 27.5 min [(S)-18, major enantiomer] and tR
22.4 min [(R)-18, minor enantiomer]; 86:14 er.
=
(400 MHz, CDCl3): δ = 7.87–7.01 (m, 20 H), 6.96 (d, J = 9.2 Hz, 1 H),
5.54–5.52 (m, 1 H), 4.96 (dd, J = 9.2, 1.6 Hz, 1 H), 4.85–4.82 (m, 1 H),
4.36 (s, 1 H), 3.19 (d, J = 13.2 Hz, 1 H), 2.95 (d, J = 13.2 Hz, 1 H),
1.15 (d, J = 6.0 Hz, 3 H), 1.11 (d, J = 6.0 Hz, 3 H), 0.89 (d, J = 6.4 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.5, 169.1, 168.5, 167.7,
161.3, 133.5, 133.1, 132.7, 132.3, 132.0, 130.4, 130.2, 128.8, 128.7,
128.6, 128.0, 127.8, 127.4, 127.3, 127.2, 125.4, 74.4, 72.9, 70.0, 59.2,
55.7, 42.4, 21.7, 21.3, 16.7 ppm. HRMS: calcd. for C38H37N2O7 [M +
1]+ 633.2601; found 633.2600.
1,4-Dibenzyl-3-(p-chlorophenyl)piperazin-2-one (19): Pale yel-
low oil (82 % yield). 1H NMR (400 MHz, CDCl3): δ = 7.52–7.14 (m, 14
H), 4.61 (d, J = 14.6 Hz, 1 H), 4.52 (d, J = 14.6 Hz, 1 H), 4.11 (s, 1 H),
3.71 (d, J = 13.4 Hz, 1 H), 3.48–3.42 (m, 1 H), 3.15–3.08 (m, 2 H),
2.98–2.93 (m, 1 H), 2.51–2.44 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 167.9, 138.1, 137.4, 136.6, 133.7, 130.4, 128.8, 128.7,
128.6, 128.4, 128.3, 127.7, 127.4, 70.5, 58.9, 50.3, 46.7, 45.8 ppm.
HRMS: calcd. for C24H24ClN2O [M + 1]+ 391.1577; found 391.1577.
HPLC (Chiralcel OD column, 10 % 2-propanol in hexane,
N-Benzoyl-O-{[(αS,4R)-4-benzyl-4,5-dihydro-5-oxo-α,2-diphen-
yloxazol-4-yl]acetyl}-L-threonine Isopropyl Ester (23d): Com-
0.5 mL min–1): tR = 29.1 min [(S)-19, major enantiomer] and tR
24.5 min [(R)-19, minor enantiomer]; 88:12 er.
=
pound 23d was obtained as an inseparable mixture with 23c. 1H
NMR (400 MHz, CDCl3): δ = 7.76–7.03 (m, 20 H), 6.57 (d, J = 9.2 Hz,
1 H), 5.50–5.40 (m, 1 H), 4.82 (dd, J = 9.2, 1.6 Hz, 1 H), 4.75–4.65 (m,
1 H), 4.35 (s, 1 H), 3.20 (d, J = 13.2 Hz, 1 H), 2.95 (d, J = 13.2 Hz, 1
H), 1.15 (d, J = 6.0 Hz, 3 H), 1.11 (d, J = 6.0 Hz, 3 H), 0.89 (d, J =
6.4 Hz, 3 H) ppm.
4-Benzyl-3-(p-bromophenyl)morpholin-2-one (21): Yellow oil
1
(73 % yield). H NMR (400 MHz, CDCl3): δ = 7.55–7.21 (m, 9 H), 4.53
(dt, J = 11.0, 3.1 Hz, 1 H), 4.38–4.34 (m, 1 H), 4.22 (s, 1 H), 3.74 (d,
J = 13.4 Hz, 1 H), 3.17 (d, J = 13.3 Hz, 1 H), 3.02–2.97 (m, 1 H), 2.68–
2.61 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.2, 136.6,
136.5, 131.9, 130.6, 128.8, 128.6, 127.7, 122.5, 69.9, 68.7, 58.9,
46.9 ppm. HRMS: calcd. for C17H17BrNO2 [M + 1]+ 346.0442; found
346.0443. HPLC (Chiralcel AD-H column, 10 % 2-propanol in hexane,
General One-Pot Procedure for the Asymmetric Synthesis of As-
partates 25–35: To a solution of
L-threonine-derived α-bromo ester
1, 15, or 16 (>98:2 dr) in CHCl3 (2.0
M) at 0 °C were added an
0.5 mL min–1): tR = 28.7 min [(S)-21, major enantiomer] and tR
25.1 min [(R)-21, minor enantiomer]; 84:16 er.
=
azlactone nucleophile (1.4 equiv.) and DIEA (2.0 equiv.). After the
resulting mixture had been stirred at 0 °C for 1 h, the reaction
mixture was washed with a saturated solution of NH4Cl and then
concentrated in vacuo. To a solution of the diastereomeric mixture
4-Benzyl-3-(p-chlorophenyl)morpholin-2-one (22): Yellow oil
1
(69 % yield). H NMR (400 MHz, CDCl3): δ = 7.54–7.22 (m, 9 H), 4.54
in methanol (0.3
M) was added sodium methoxide (6.0 equiv.) at
(dt, J = 11.0 Hz, 3.1 Hz, 1 H), 4.39–4.35 (m, 1 H), 4.23 (s, 1 H), 3.74
(d, J = 13.4 Hz, 1 H), 3.17 (d, J = 13.3 Hz, 1 H), 3.02–2.98 (m, 1 H),
2.69–2.62 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.3,
136.6, 136.1, 134.4, 130.2, 129.0, 128.8, 128.6, 127.7, 69.8, 68.7, 58.9,
46.9 ppm. HRMS: calcd. for C17H17ClNO2 [M + 1]+ 302.0948; found
302.0948. HPLC (Chiralcel AD-H column, 10 % 2-propanol in hexane,
–15 °C. After the solution had been stirred at –15 °C for 4 h, the
resulting mixture was dissolved in EtOAc, washed with a saturated
NH4Cl solution, concentrated in vacuo, and then treated with HCl
in methanol. After the mixture had been stirred at room temp. for
48 h, the solvent was evaporated, and the crude material was puri-
fied by column chromatography to afford the dimethyl aspartate as
an inseparable mixture of two diastereomers (75–52 % overall yield
as shown in Table 3) The dr value was determined by 1H NMR analy-
sis using the proton integrations of the two diastereomers, and the
er value was determined by CSP-HPLC analysis. The spectroscopic
data of 25 is identical to that of the authentic material that had
been reported previously.[9]
0.5 mL min–1): tR = 25.2 min [(S)-22, major enantiomer] and tR
22.1 min [(R)-22, minor enantiomer]; 84:16 er.
=
Procedure for the Preparation of 23a–23d: To a solution of L-
threonine-derived α-bromo ester 1 (>98:2 dr) in CHCl3 (2.0
M) at
0 °C were added the phenylalanine-derived azlactone (1.4 equiv.)
and DIEA (2.0 equiv.). After the resulting reaction mixture had been
stirred at 0 °C for 1 h, the solvent was evaporated, and the crude
material was purified by column chromatography to afford 23a–
23d in 95 % yield.
(2R,3R)-N-Benzoyl-2-isobutyl-3-phenyl-L-aspartic Acid Dimethyl
Ester (26): Pale yellow oil (61 % overall yield). 1H NMR (400 MHz,
CDCl3): δ = 7.52–7.22 (m, 10 H), 7.11 (s, 1 H), 4.88 (s, 1 H), 3.87 (s, 3
H), 3.72 (s, 3 H), 3.05 (dd, J = 4.4, 14.0 Hz, 1 H), 2.08 (dd, J = 8.0,
14.4 Hz, 1 H), 1.64–1.57 (m, 1 H), 0.92 (d, J = 6.8 Hz, 3 H), 0.79 (d,
J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.4, 171.6,
166.7, 135.4, 134.2, 131.4, 129.9, 128.5, 128.1, 128.0, 126.7, 66.7, 56.7,
52.9, 52.1, 42.0, 25.0, 23.9, 22.3 ppm. HRMS: calcd. for C23H28NO5
N-Benzoyl-O-{[(αR,4R)-4-benzyl-4,5-dihydro-5-oxo-α,2-diphen-
yloxazol-4-yl]acetyl}-L
-threonine Isopropyl Ester (23a): 1H NMR
(400 MHz, CDCl3): δ = 7.85–6.97 (m, 20 H), 6.35 (d, J = 9.2 Hz, 1 H),
5.41–5.39 (m, 1 H), 5.01–4.98 (m, 1 H), 4.82 (dd, J = 9.2, 2.0 Hz, 1 H),
4.29 (s, 1 H), 2.94 (d, J = 13.2 Hz, 1 H), 2.84 (d, J = 13.2 Hz, 1 H),
Eur. J. Org. Chem. 2016, 2539–2546
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[M + 1]+ 398.1967; found 398.1967. HPLC (Chiralpak AD-H column,
20 % 2-propanol in hexane, 0.5 mL min–1): tR = 47.7 min [(R,R)-26,
major enantiomer] and tR = 18.4 min [(S,S)-26, minor enantiomer];
96:4 er. Diastereomer epi-26 was obtained as an inseparable mixture
with 26. 1H NMR (400 MHz, CDCl3): δ = 7.83–7.22 (m, 11 H), 5.17 (s,
1 H), 3.79 (s, 3 H), 3.59 (s, 3 H), 2.82 (dd, J = 4.4, 13.6 Hz, 1 H), 1.53–
1.44 (m, 2 H), 0.86 (d, J = 6.4 Hz, 3 H), 0.69 (d, J = 6.4 Hz, 3 H) ppm.
(2R,3R)-N-Benzoyl-2-[2-(methylthio)ethyl]-3-phenyl-L-aspartic
Acid Dimethyl Ester (31): Pale yellow oil (61 % overall yield). 1H
NMR (400 MHz, CDCl3): δ = 7.59–7.24 (m, 11 H), 4.69 (s, 1 H), 3.86
(s, 3 H), 3.71 (s, 3 H), 3.30–3.22 (m, 1 H), 2.49–2.39 (m, 2 H), 2.31–
2.23 (m, 1 H), 2.04 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
172.5, 172.0, 166.7, 135.0, 133.6, 131.6, 129.9, 128.6, 128.3, 128.2,
126.8, 66.4, 56.8, 53.2, 52.4, 33.6, 29.2, 15.5 ppm. HRMS: calcd. for
C
22H26NO5S [M + 1]+ 416.1532; found 416.1532. HPLC (Chiralpak
(2R,3R)-N-Benzoyl-2-methyl-3-phenyl-L-aspartic Acid Dimethyl
AD-H column, 20 % 2-propanol in hexane. 0.5 mL min–1): tR
=
Ester (27): Pale yellow oil (75 % overall yield). 1H NMR (400 MHz,
CDCl3): δ = 7.97 (s, 1 H), 7.81–7.32 (m, 10 H), 4.26 (s, 1 H), 3.73 (s, 3
H), 3.72 (s, 3 H), 1.72 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
173.0, 172.9, 167.2, 134.6, 133.2, 131.7, 130.0, 128.6, 128.5, 128.4,
127.0, 62.4, 56.7, 52.8, 52.6, 20.7 ppm. HRMS: calcd. for C20H22NO5
[M + 1]+ 356.1498; found 356.1499. HPLC (Chiralpak AD-H column,
20 % 2-propanol in hexane, 0.5 mL min–1): tR = 21.2 min [(R,R)-27,
major enantiomer] and tR = 18.7 min [(S,S)-27, minor enantiomer];
99:1 er. Diastereomer epi-27 was obtained as an inseparable mixture
with 27. 1H NMR (400 MHz, CDCl3): δ = 7.69–7.30 (m, 10 H), 6.83 (s,
1 H), 4.75 (s, 1 H), 3.69 (s, 3 H), 3.68 (s, 3 H), 1.76 (s, 3 H) ppm.
60.5 min [(R,R)-31, major enantiomer] and tR = 36.0 min [(S,S)-31,
minor enantiomer]; 98:2 er. Diastereomer epi-31 was obtained as an
1
inseparable mixture with 31. H NMR (400 MHz, CDCl3): δ = 7.83–
7.32 (m, 11 H), 5.08 (s, 1 H), 3.78 (s, 3 H), 3.62 (s, 3 H), 3.11–3.06 (m,
1 H), 2.46–2.39 (m, 1 H), 2.21–2.14 (m, 1 H), 2.02–1.96 (s, 4 H) ppm.
(2R,3R)-N-Benzoyl-2-benzyl-3-(p-bromophenyl)-L-aspartic Acid
Dimethyl Ester (32): Colorless oil (63 % overall yield). 1H NMR
(400 MHz, CDCl3): δ = 7.46–7.06 (m, 14 H), 6.77 (s, 1 H), 5.21 (s, 1
H), 4.31 (d, J = 13.6 Hz, 1 H), 3.88 (s, 3 H), 3.79 (s, 3 H), 3.62 (d, J =
13.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.5, 170.9,
167.5, 135.7, 135.2, 133.5, 132.5, 131.6, 131.3, 129.9, 128.6, 128.3,
127.2, 126.6, 122.3, 68.3, 54.9, 53.1, 52.4, 39.1 ppm. HRMS: calcd. for
C26H25BrNO5 [M + 1]+ 510.0916; found 510.0916. HPLC (Chiralpak
(2R,3R)-N-Benzoyl-2,3-diphenyl-L-aspartic Acid Dimethyl Ester
1
(28): Yellow oil (74 % overall yield). H NMR (400 MHz, CDCl3): δ =
8.34 (s, 1 H), 7.91–6.98 (m, 15 H), 4.63 (s, 1 H), 3.79 (s, 3 H), 3.71 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.5, 172.1, 167.0, 135.4,
134.6, 132.7, 131.8, 130.1, 128.8, 128.1, 128.0, 127.7, 127.6, 127.2,
127.0, 68.4, 57.9, 53.3, 52.7 ppm. HRMS: calcd. for C25H24NO5 [M +
1]+ 418.1654; found 418.1654. HPLC (Chiralpak AD-H column, 20 %
2-propanol in hexane, 0.5 mL min–1): tR = 20.7 min [(R,R)-28, major
enantiomer] and tR = 23.8 min [(S,S)-28, minor enantiomer]; 92:8 er.
Diastereomer epi-28 was obtained as an inseparable mixture with
28. 1H NMR (400 MHz, CDCl3): δ = 7.82–7.21 (m, 16 H), 5.15 (s, 1 H),
3.56 (s, 3 H), 3.47 (s, 3 H) ppm.
AD-H column, 20 % 2-propanol in hexane, 0.5 mL min–1): tR
=
51.9 min [(R,R)-32, major enantiomer] and tR = 36.3 min [(S,S)-32,
minor enantiomer]; 91:9 er. Diastereomer epi-32 was obtained as an
1
inseparable mixture with 32. H NMR (400 MHz, CDCl3): δ = 7.70–
6.92 (m, 15 H), 5.38 (s, 1 H), 4.04 (d, J = 13.2 Hz, 1 H), 3.77 (s, 3 H),
3.59 (s, 3 H), 2.84 (d, J = 13.2 Hz, 1 H) ppm.
(2R,3R)-N-Benzoyl-2-benzyl-3-(p-chlorophenyl)-L-aspartic Acid
Dimethyl Ester (33): Pale yellow oil (52 % overall yield). 1H NMR
(400 MHz, CDCl3): δ = 7.46–7.07 (m, 14 H), 6.77 (s, 1 H), 5.22 (s, 1
H), 4.31 (d, J = 13.6 Hz, 1 H), 3.88 (s, 3 H), 3.80 (s, 3 H), 3.63 (d, J =
13.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.5, 171.0,
167.5, 135.7, 135.2, 134.0, 132.9, 132.1, 131.6, 131.2, 129.9, 128.6,
128.3, 127.2, 126.6, 68.4, 54.8, 53.0, 52.4, 39.1 ppm. HRMS: calcd. for
(2R,3R)-N-Benzoyl-2-(methoxycarbonylmethyl)-3-phenyl-L-as-
partic Acid Dimethyl Ester (29): Colorless oil (80 % overall yield).
1H NMR (400 MHz, CDCl3): δ = 7.63–7.24 (m, 11 H), 4.84 (s, 1 H),
4.07 (d, J = 16.8 Hz, 1 H), 3.84 (s, 3 H), 3.72 (s, 3 H), 3.62 (s, 3 H),
3.31 (d, J = 16.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.5,
171.4, 170.9, 167.1, 134.7, 133.1, 131.6, 130.1, 128.6, 128.4, 128.3,
126.9, 63.6, 55.1, 53.3, 52.5, 51.8, 38.1 ppm. HRMS: calcd. for
C22H24NO7 [M + 1]+ 414.1553; found 414.1553. HPLC (Chiralpak AD-
H column, 20 % 2-propanol in hexane, 0.5 mL min–1): tR = 66.5 min
[(R,R)-29, major enantiomer] and tR = 34.0 min [(S,S)-29, minor
enantiomer]; 97:3 er. Diastereomer epi-29 was obtained as an insep-
arable mixture with 29. 1H NMR (400 MHz, CDCl3): δ = 8.13–7.29
(m, 11 H), 5.04 (s, 1 H), 3.77 (s, 3 H), 3.75 (d, J = 16.0 Hz, 1 H), 3.67
(s, 3 H), 3.55 (s, 3 H), 3.06 (d, J = 16.0 Hz, 1 H) ppm.
C
26H25ClNO5 [M + 1]+ 466.1421; found 466.1421. HPLC (Chiralpak
AD-H column, 20 % 2-propanol in hexane, 0.5 mL min–1): tR
=
46.7 min [(R,R)-33, major enantiomer] and tR = 32.8 min [(S,S)-33,
minor enantiomer]; 89:11 er. Diastereomer epi-33 was obtained as
an inseparable mixture with 33. 1H NMR (400 MHz, CDCl3): δ =
7.53–6.92 (m, 15 H), 5.39 (s, 1 H), 4.04 (d, J = 13.2 Hz, 1 H), 3.77 (s,
3 H), 3.60 (s, 3 H), 2.85 (d, J = 13.2 Hz, 1 H) ppm.
(2R,3R)-N-Benzoyl-3-(p-bromophenyl)-2-isobutyl-L-aspartic Acid
Dimethyl Ester (34): Yellow oil (62 % overall yield). 1H NMR
(400 MHz, CDCl3): δ = 7.53–7.12 (m, 10 H), 4.89 (s, 1 H), 3.87 (s, 3
H), 3.72 (s, 3 H), 3.03 (dd, J = 4.8, 14.4 Hz, 1 H), 2.07 (dd, J = 8.0,
14.4 Hz, 1 H), 1.64–1.57 (m, 1 H), 0.92 (d, J = 6.8 Hz, 3 H), 0.79 (d,
J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.2, 171.1,
166.7, 135.1, 133.3, 132.4, 131.6, 131.2, 128.7, 126.7, 122.3, 66.6, 56.0,
53.0, 52.2, 41.9, 25.1, 23.9, 22.3 ppm. HRMS: calcd. for C23H27BrNO5
[M + 1]+ 476.1072; found 476.1072. HPLC (Chiralpak AD-H column,
20 % 2-propanol in hexane, 0.5 mL min–1): tR = 55.9 min [(R,R)-34,
major enantiomer] and tR = 28.2 min [(S,S)-34, minor enantiomer];
93:7 er. Diastereomer epi-34 was obtained as an inseparable mixture
with 34. 1H NMR (400 MHz, CDCl3): δ = 7.81–7.10 (m, 10 H), 5.16 (s,
1 H), 3.80 (s, 3 H), 3.59 (s, 3 H), 2.78 (dd, J = 4.8, 14.0 Hz, 1 H), 1.55–
1.48 (m, 1 H), 1.41 (dd, J = 7.6, 14.0 Hz, 1 H), 0.86 (d, J = 6.4 Hz, 3
H), 0.69 (d, J = 6.4 Hz, 3 H) ppm.
(2R,3R)-N-Benzoyl-2-(p-methoxybenzyl)-3-phenyl-L-aspartic
Acid Dimethyl Ester (30): Pale yellow oil (63 % overall yield). 1H
NMR (400 MHz, CDCl3): δ = 7.44–7.21 (m, 10 H), 7.02 (d, J = 8.8 Hz,
2 H), 6.77 (s, 1 H), 6.71 (d, J = 8.8 Hz, 2 H), 5.14 (s, 1 H), 4.27 (d, J =
14.0 Hz, 1 H), 3.88 (s, 3 H), 3.78 (s, 3 H), 3.72 (s, 3 H), 3.57 (d, J =
14.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.8, 171.4,
167.4, 158.6, 135.5, 134.4, 131.4, 131.0, 129.9, 128.5, 128.2, 128.0,
127.9, 126.6, 113.7, 68.5, 55.5, 55.1, 52.9, 52.3, 38.2 ppm. HRMS:
calcd. for C27H28NO6 [M + 1]+ 462.1916; found 462.1916. HPLC (Chi-
ralpak AD-H column, 20 % 2-propanol in hexane, 0.5 mL min–1): tR =
83.8 min [(R,R)-30, major enantiomer] and tR = 47.3 min [(S,S)-30,
minor enantiomer]; 95:5 er. Diastereomer epi-30 was obtained as an
1
inseparable mixture with 30. H NMR (400 MHz, CDCl3): δ = 7.73– (2R,3R)-N-Benzoyl-3-(p-chlorophenyl)-2-isobutyl-
L
-aspartic Acid
7.36 (m, 11 H), 6.86 (d, J = 8.8 Hz, 2 H), 6.67 (d, J = 8.8 Hz, 2 H),
5.35 (s, 1 H), 4.01 (d, J = 13.6 Hz, 1 H), 3.75 (s, 3 H), 3.71 (s, 3 H),
3.58 (s, 3 H), 2.85 (d, J = 13.6 Hz, 1 H) ppm.
Dimethyl Ester (35): Yellow oil (70 % overall yield). 1H NMR
(400 MHz, CDCl3): δ = 7.54–7.18 (m, 9 H), 7.10 (s, 1 H), 4.90 (s, 1 H),
3.87 (s, 3 H), 3.72 (s, 3 H), 3.04 (dd, J = 4.4, 14.0 Hz, 1 H), 2.07 (dd,
Eur. J. Org. Chem. 2016, 2539–2546
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of α-bromo phenylacetate (αRS)-1 (50:50 dr), moderate selectivities that
ranged from 71:29 to 81:19 dr were observed in the substitution reac-
tions with amine nucleophiles, which indicates that the dynamic kinetic
resolution of α-bromo phenylacetate (αRS)-1 is not the primary pathway
for the high asymmetric induction. For reviews on dynamic kinetic reso-
lution in the nucleophilic substitution of α-bromo carboxylic acid deriva-
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J = 8.0, 14.0 Hz, 1 H), 1.64–1.57 (m, 1 H), 0.92 (d, J = 6.4 Hz, 3 H),
0.79 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.2,
171.2, 166.7, 135.1, 134.0, 132.7, 131.6, 131.2, 128.7, 128.3, 126.6,
66.7, 55.9, 53.0, 52.2, 41.9, 25.1, 23.9, 22.3 ppm. HRMS: calcd. for
C23H27ClNO5 [M + 1]+ 432.1578; found 432.1578. HPLC (Chiralpak
AD-H column, 20 % 2-propanol in hexane, 0.5 mL min–1): tR
=
49.0 min [(R,R)-35, major enantiomer] and tR = 25.3 min [(S,S)-35,
minor enantiomer]; 94:6 er. Diastereomer epi-35 was obtained as an
1
inseparable mixture with 35. H NMR (400 MHz, CDCl3): δ = 7.82–
7.18 (m, 10 H), 5.17 (s, 1 H), 3.80 (s, 3 H), 3.59 (s, 3 H), 2.79 (dd, J =
5.2 and 14.0 Hz, 1 H), 1.44–1.39 (m, 1 H), 1.42 (dd, J = 7.2 and
13.6 Hz, 1 H), 0.86 (d, J = 6.4 Hz, 3 H), 0.70 (d, J = 6.4 Hz, 3 H) ppm.
Supporting Information (see footnote on the first page of this
article): NMR spectra of all new compounds.
[5] The absolute configuration of 2-(dibenzylamino)-2-phenylethanol was
assigned by comparing the optical rotation value with literature values:
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Acknowledgments
This work was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea (NRF)
and funded by the Ministry of Education (2014R1A1A2057279).
Keywords: Synthetic methods · Kinetic resolution ·
Nucleophilic substitution · Asymmetric synthesis · Chiral
auxiliaries
[7] Reports of the direct substitution of a secondary alkyl halide with an
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24b had reached completion.
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[10] The final dr (74:26) and er (95:5) values of 25 are different from those
ratios obtained from substitution products 23a–23d (78:2:18:2). This dif-
ference is the result of a minor epimerization process that occurred un-
der the reaction conditions with sodium methoxide.
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[3] We have improved the CIDR process of α-bromo phenylacetate 1 by
using an n-hexane/diethyl ether (5:1) mixture at a 0.2
M concentration
of 1 (50:50 dr). After the solvent had been allowed to evaporate at room
temperature over 24 h, (αR)-1 was quantitatively recovered with 90:10
dr. When 1 (90:10 dr) was dissolved in a minimum amount of n-hexane/
diethyl ether (5:1), the recrystallization began within 4–5 h at room tem-
perature. The mixture was allowed to stand at room temperature over-
night and was then filtered to result in approximately 70 % crystalliza-
tion yield with a dr of >98:2. Compared with the previous one-week
crystallization process in n-hexane and ethyl acetate,[2f] the use of the
n-hexane/diethyl ether mixture can shorten the crystallization time to
obtain the same high optical purity of (αR)-1.
[4] A possible alternative to achieve the observed high stereoselectivity is
through a dynamic kinetic resolution. In this pathway, α-bromo acetate
1 undergoes epimerization sufficiently fast relative to the rate of substi-
tution, and under the reaction conditions, one of the two epimers of 1
preferentially undergoes a reaction with the nucleophile. In the reaction
Received: February 22, 2016
Published Online: April 24, 2016
Eur. J. Org. Chem. 2016, 2539–2546
www.eurjoc.org
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