Enantioselective Synthesis of α-Substituted Serine Derivatives via Cu-Catalyzed Oxidative Desymmetrization of 2-Amino-1,3-diols

Article abstract of DOI:10.1021/acs.oprd.8b00407

The enantioselective copper-catalyzed oxidative desymmetrization for the synthesis of chiral α-substituted serine derivatives is reported. The combination of Cu(OTf)₂/(R,R)-PhBOX catalyst system, N-bromosuccinimide, and MeOH enables us to provide chiral α-substituted serines from N-2-methylbenzoyl-protected 2-amino-1,3-diols through a simple procedure at room temperature under an air atmosphere. A variety of α-substituent including aryl and heteroaryl groups were tolerated in this method, and the corresponding chiral serine derivatives were obtained in good to high yields with high enantioselectivities.

Full text of DOI:10.1021/acs.oprd.8b00407

Communication
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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Enantioselective Synthesis of α‑Substituted Serine Derivatives via
Cu-Catalyzed Oxidative Desymmetrization of 2‑Amino-1,3-diols
Kosuke Yamamoto, Shota Ishimaru, Tatsuya Oyama, Satoko Tanigawa, Masami Kuriyama,
and Osamu Onomura*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
S
* Supporting Information
ABSTRACT: The enantioselective copper-catalyzed oxi-
dative desymmetrization for the synthesis of chiral α-
substituted serine derivatives is reported. The combina-
tion of Cu(OTf)2/(R,R)-PhBOX catalyst system, N-
bromosuccinimide, and MeOH enables us to provide
chiral α-substituted serines from N-2-methylbenzoyl-
protected 2-amino-1,3-diols through a simple procedure
at room temperature under an air atmosphere. A variety of
α-substituent including aryl and heteroaryl groups were
tolerated in this method, and the corresponding chiral
serine derivatives were obtained in good to high yields
with high enantioselectivities.
KEYWORDS: oxidation, copper catalyst,
α-substituted serines, desymmetrization
1. INTRODUCTION
Figure 1. Biologically active molecules with α,α-disubstituted amino
acid motifs.
α,α-Disubstituted amino acids are one of the major class of
nonproteinogenic amino acids and have attracted considerable
attention in the field of medicinal and synthetic chemistry,1
and their numerous synthetic methods have been developed.2
this approach has been achieved mostly by using enzymes such
as lipase, esterase, and amidase (Scheme 1c).13 While these
catalytic methods effectively provide chiral α-substituted serine
Among nonproteinogenic amino acids, chiral α-substituted
serine derivatives have been found in many natural products,
such as piperazimycin A,3 altemicidin,4 myriocin,5 and
derivatives, most reactions required cryogenic conditions and/
sphingofungin E,6 which exhibit interesting biological activities
or involved multistep processes for the transformation of the
products to the desired serine scaffolds. Although enzymatic
desymmetrization was commonly performed at room temper-
ature, high substrate specificity of enzymes may limit the
(Figure 1). Thus, many efforts have been made to develop
efficient methods for the preparation of chiral α-serine
derivatives. One of the most common approaches was
expansion of their application to a variety of substrates. Thus,
alkylation of enolizable heterocycles or malonate derivatives
development of more practical and broad substrate-scope
under noncatalytic conditions.7−10 Although noncatalytic
methods for the synthesis of chiral α-substituted serines is still
methods afforded desired serine derivatives with high
highly desired in order to access to the α-substituted serines
enantioselectivities, the chiralities of the products were
possessing various substituents with high efficiency and
dominated by those of the starting natural L-amino acids,
selectivity.
and the use of stoichiometric amount of expensive D-amino
We previously developed the copper-catalyzed enantiose-
acids was required to obtain the opposite enantiomer. In this
lective desymmetrization of meso-1,2-diols using N-bromosuc-
cinimide as an oxidant for the synthesis of α-hydroxy
context, catalytic asymmetric reactions have attracted much
ketones.14 It is noteworthy that this desymmetrization was
attention since both enantiomers of products would be
obtained from achiral compounds by using both enantiomers
performed at room temperature under an air atmosphere. We
of catalytic amount of external chiral sources (Scheme 1). For
envisioned that the oxidative desymmetrization of 2-amino-1,3-
example, the gold-catalyzed aldol reaction11 and phase-transfer
diols would provide a novel synthetic route for α-substituted
catalytic alkylation12 have been developed for the synthesis of
α-substituted serine precursors (Scheme 1a,b). Asymmetric
desymmetrization of prochiral compounds would be one of the
Special Issue: Japanese Society for Process Chemistry
most ideal reactions for the synthesis of enantio-enriched
Received: November 30, 2018
compounds. However, the synthesis of chiral α-serines using
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.8b00407
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Scheme 1. Catalytic Asymmetric Synthesis of α-Substituted
Table 1. Screening of N-Protecting Groups
Serine Derivatives
a
b
entry
substrate
PG
product
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
1aa
1ba
1ca
1da
1ea
1fa
1ga
1ha
1ia
Bz
2aa
2ba
2ca
2da
2ea
2fa
2ga
2ha
2ia
46
51
65
46
64
78
38
n.r.
n.r.
67
64
85
75
77
80
64
4-MeBz
2-MeBz
4-ClBz
2-ClBz
4-NO2Bz
2-NO2Bz
Ts
Cbz
a
Isolated yields after column chromatography. n.r. = no reaction.
Determined by chiral HPLC analysis.
b
the basis of these results, we selected a 2-methylbenzoyl group,
which gave the desired product with the highest enantiose-
lectivity, as an optimal protecting group.
Next, the effects of oxidants and solvents were investigated
as shown in Table 2. The yields of 2ca increased by using the
excess amount of DBDMH, but detrimental effects on
enantioselectivity were observed (Table 2, entries 1−3).
While using 3 equiv of N-bromophthalimide (NBP) as an
oxidant in CH2Cl2 (0.2 M) afforded 2ca with a similar result to
that in entry 1, increasing the amount of NBP improved the
yield and selectivity (entries 4 and 5). Although NBP led to a
better outcome, the resulting phthalimide made it difficult to
isolate 2ca by column chromatography from crude mixtures.
Pleasingly, the use of N-bromosuccinimide (NBS) in place of
NBP eased the purification process since resultant succinimide
was removed by a simple aqueous workup (entries 6 and 7).
More concentrated reaction conditions resulted in a decrease
in both yield and enantioselectivity (entry 8). Several reaction
media were evaluated using 4 equiv of NBS, and the choice of
the reaction media was found to be important to obtain the
desired product 2ca in high yields. For example, this oxidation
reaction did not proceed efficiently in toluene, affording 2ca in
17% yield, but with high enantioselectivity (entry 9). Aprotic
polar solvents, such as THF, acetone, and acetonitrile, also
gave 2ca in low yields (entries 10−12). The effect of a reaction
temperature and a catalyst loading were evaluated using 4
equiv of NBS in CH2Cl2. Although enantioselectivity slightly
increased at 0 °C, the yield of 2ca was significantly dropped
(entry 13).15 Lower catalyst loading resulted in a decrease in
the yield but did not affect the enantioselectivity (entry 14).16
With the optimized conditions in hand, a variety of 2-
methylbenzoyl-protected amino diols were then subjected in
this asymmetric oxidation reaction. The results are summarized
in Scheme 2. We found that the addition of 0.2 equiv of
K2CO3 was effective to improve yield or enantioselectivity for
some substrates. Amino diols with an ethyl (1cb), butyl (1cc),
and isobutyl group (1cd) were tolerated in this reaction,
affording the desired α-alkyl serines (2cb−cd) in good yields
serines under mild reaction conditions via a technically simple
procedure. Herein, we report the copper-catalyzed enantiose-
lective oxidative desymmetrization of a variety of N-2-
methylbenzoyl-protected 2-amino-1,3-diols, which enables us
to prepare α-substituted serine derivatives in high yields and
high enantioselectivities.
2. RESULTS AND DISCUSSION
We commenced this study with the optimization of the N-
protecting group for 2-methyl 2-amino-1,3-diol in the
asymmetric oxidative desymmetrization with copper(II) triflate
and (R,R)-PhBOX as a chiral catalyst. The results are
summarized in Table 1. When N-benzoyl-protected amino
diol (1aa) was treated with 1,3-dibromo-5,5-dimethylhydan-
toin (DBDMH) and MeOH in the presence of the chiral
copper catalyst, the desired α-serine derivative 2aa was
obtained in 46% yield with 67% ee (Table 1, entry 1). While
a 4-methylbenzoyl group gave a similar reaction outcome to
that obtained from a benzoyl group, a 2-methylbenzoyl group
afforded 2ca in a higher yield with 85% ee (entries 2 and 3).
Substrates with a 4- or 2-chlorobenzoyl group (1da and 1ea)
were transformed to the desired serine derivatives in moderate
yields with good enantioselectivities (entries 4 and 5). The
substrate having a 4-nitrobenzoyl group (1fa) afforded 2fa in a
higher yield than 1ca, but decreased enantioselectivity was
observed (entry 6). A nitro group at the 2-position of the
benzoyl group showed a negative effect in this reaction,
resulting in a decrease in the yield (entry 7). As for the N-
protecting group, p-toluenesulfonyl (1ha) and benzyloxycar-
bonyl (1ia) groups were not suitable for this transformation,
which did not provide the desired esters (entries 8 and 9). On
B
DOI: 10.1021/acs.oprd.8b00407
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Organic Process Research & Development
Communication
a
a
Table 2. Optimization of Reaction Parameters
Scheme 2. Substrate Scope
b
c
entry
oxidant (equiv)
solvent (M)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
DBDMH (1.5)
DBDMH (1.75)
DBDMH (2.0)
NBP (3.0)
NBP (4.0)
NBS (3.0)
NBS (4.0)
NBS (4.0)
NBS (4.0)
NBS (4.0)
CH2Cl2 (0.25)
CH2Cl2 (0.25)
CH2Cl2 (0.25)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.25)
toluene (0.2)
THF (0.2)
65
69
75
62
83
61
84
71
17
33
44
30
24
85
83
80
85
88
87
86
84
82
86
79
62
90
86
9
10
11
12
13
14
NBS (4.0)
NBS (4.0)
NBS (4.0)
NBS (4.0)
acetone (0.2)
CH3CN (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
d
e
55
a
b
Reactions were carried out on a 0.5 mmol scale. Isolated yields after
c
column chromatography. n.r. = no reaction. Determined by chiral
HPLC analysis. 0 °C, 14 h. Cu(OTf)2 (5 mol %) and (R,R)-PhBOX
(5 mol %), 14 h.
d
e
with high enantioselectivities. The reaction of the substrate
with a cyclohexylmethyl group also smoothly proceeded to
afford the desired product (2ce) in 73% yield with 87% ee.
The absolute configuration of 2ce was unambiguously
determined to be R by X-ray crystallography after the
derivatization to the ester with N-tosyl-L-phenylglycine (see
Supporting Information for details). The serine derivative with
a phenethyl group (2cf) was also obtained in a good yield with
high enantioselectivity. Such α-phenethyl substituted serine
derivatives were utilized for the synthesis of (S)-
(hydroxymethy)glutamic acid, which had been known as one
of the most useful metabotropic glutamate receptor ligands.17
In addition to alkyl groups, an aryl substituent was found to be
a suitable substrate, affording 2cg. Notably, it was difficult to
obtain highly enantio-enriched α-phenyl serine precursors by
the enzymatic desymmetrization process.13e A series of amino
diols bearing benzyl groups were then evaluated. A substrate
with a nonsubstituted benzyl group afforded 2ch in high yield
with high enantioselectivity. Substrates bearing halogen
substituents on the para-position of the benzyl group were
also tolerated in this reaction to afford the corresponding
serines (2ci and 2cj). A p-nitrobenzyl-substituted amino diol
afforded 2ck in 60% yield with 79% ee. Moreover, a pyridine
ring had little effect on the yield and enantioselectivity,
affording 2cl. In order to show the scalability of this reaction,
the present reaction was conducted on a 10 mmol scale using
1ca as a starting material and affording 2ca in 82% yield (2.06
g) with 87% ee (Scheme 3). In addition, compound 2ca was
readily transformed to α-methyl serine hydrochloride (3) in
a
Reactions were carried out on a 0.5 mmol scale. Isolated yields after
purification by column chromatography were reported. The
enantiomeric excess was determined by chiral HPLC analysis. The
reaction was performed in the presence of 0.2 equiv of K2CO3 as an
additive. The reaction was carried out on a 0.2 mmol scale.
b
c
excellent yield by refluxing in aqueous HCl solution (Scheme
4).
3. CONCLUSION
In conclusion, we have developed a novel synthetic strategy for
the synthesis of chiral α-substituted serine derivatives through
enantioselective oxidative desymmetrization of N-2-methyl-
benzoyl-protected 2-amino-1,3-propanediols by using the
Scheme 3. Gram-Scale Experiment
C
DOI: 10.1021/acs.oprd.8b00407
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Organic Process Research & Development
Communication
Procedure B (for 1cc-cf and 1ch-cl). To a suspension of
diethyl 2-(2-methylbenzamido)malonate (1.47 g, 5.0 mmol)
and cesium carbonate (2.44 g, 7.5 mmol, 1.5 equiv) was added
alkyl bromide or alkyl chloride (5.5 mmol, 1.1 equiv) dropwise
at room temperature. The mixture was stirred for 4 h at 65 °C,
and then H2O was added. The reaction mixture was extracted
with hexane/AcOEt (4:1) and the combined organic layers
were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The resultant crude mixture was dissolved in
dimethoxyethane/MeOH (3:2, 10 mL), and NaBH4 (757 mg,
20 mmol, 4.0 equiv) was added. After stirring for 1 h, the
reaction was quenched by the addition of saturated NH4Cl aq
and the reaction mixture was extracted with AcOEt. The
combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. Recrystallization
(AcOEt/hexane) or column chromatography on silica gel
(hexane/AcOEt as an eluent) afforded the pure compound.
Procedure C (for 1cg). Compound 1cg was prepared
according to the procedure reported by Kang19 using 2-
methylbenzoyl chloride as a N-protecting reagent. To the
solution of 2,2-dimethyl-5-phenyl-1,3-dioxan-5-amine19 (996
mg, 4.8 mmol) in i-PrOH (20 mL, 0.24 M) were added Et3N
(587 mg, 5.8 mmol, 1.2 equiv) and 2-methylbenzoyl chloride
(742 mg, 4.8 mmol, 1.0 equiv) at 0 °C. After stirring for 2 h at
room temperature, all volatiles were removed under reduced
pressure, and the crude product was diluted in AcOEt and then
washed with H2O. The organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure to afford the
N-protected product. The residue was dissolved in AcOH/
H2O (4:1, 30 mL, 0.25 M), and then the mixture was stirred
for 1 h at 60 °C. The reaction mixture was diluted with H2O
and extracted with AcOEt, and the organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure to
afford the crude product. The crude product was purified by
column chromatography on silica gel (hexane/AcOEt = 1:2) to
afford the pure compound.
Scheme 4. Synthesis of α-Methyl Serine Hydrochloride
Cu(OTf)2/(R,R)-PhBOX system. Under the present reaction
conditions, a variety of N-2-methylbenzoyl-protected 2-amino-
1,3-propanediols with an alkyl, benzyl, aryl, and heteroaryl
groups at the 2-position successfully transformed to the
corresponding α-substituted serine derivatives in good to high
yields with high enantioselectivities. Moreover, the reaction did
not require the cryogenic condition and inert atmosphere,
which would be beneficial for the industrial process.18
4. EXPERIMENTAL SECTION
General Methods and Materials. Unless otherwise
noted, all reactions were performed in a test tube equipped
with a magnetic stir bar at room temperature under air. All
chemicals were used as received without further purifications.
All melting points were determined using a Yanako
micromelting point apparatus without correction. Optical
rotations were measured with a JASCO DIP-1000 spectrom-
eter using a 3.5 × 100 mm o.d. cell. Infrared (IR) spectra were
recorded on a SHIMADZU IRAffinity-1 spectrophotometer.
Data were expressed as frequency of absorption (cm−1). H
1
and 13C NMR spectra were recorded on a JEOL JNM-AL400
1
spectrometer (400 MHz for H NMR and 100 MHz for 13C
NMR) or a VARIAN GEMINI 300 spectrometer (300 MHz
1
for H NMR and 75 MHz for 13C NMR). Chemical shift
values are expressed in ppm relative to internal TMS (δ 0.00
ppm) or CDCl3 (δ 7.26 ppm) for 1H NMR and CDCl3 (δ 77.0
ppm) or DMSO-d6 (δ 39.5 ppm) for 13C NMR. Splitting
patterns are indicated as follows: s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; br, broad. Enantiomeric excess was
determined by HPLC using DAICEL CHIRALPAK AD, AS,
AY-H, CHIRALCEL OD-H, and OJ-H columns (4.6 mm id ×
250 mm). HPLC chromatograms were recorded on a C-R8A
CHROMATOPAC with LC-20AT pump, SPD-20A UV
detector (SHIMADZU). High-resolution mass spectra
(HRMS) were recorded on JEOL JMS-700N or JMS-
T100TD by electron impact ionization (EI) mass spectrom-
etry, fast atom bombardment (FAB) mass spectrometry, or
direct analysis in real time (DART) mass spectrometry.
General Procedure for the Preparation of N-
Protected 1,3-Propanediols. Procedure A (for 1aa-ga
and 1cb). To a stirred solution of 2-amino-2-methyl-1,3-
propanediol (526 mg, 5.0 mmol) and Et3N (506 mg, 5.0
mmol, 1.0 equiv) in i-PrOH (5.0 mL, 1.0 M) was added
benzoyl chloride derivatives (5.0 mmol, 1.0 equiv) at 0 °C.
The reaction mixture was stirred at room temperature until a
TLC indicated that all starting material was consumed. After
the removal of all volatiles under reduced pressure, the residue
was suspended in H2O and extracted with AcOEt. The
combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure to give the crude
product. Recrystallization (AcOEt/hexane) or column chro-
matography on silica gel (hexane/AcOEt as an eluent)
afforded the pure compound.
2-Methyl-N-(1,3-dihydroxy-2-methylpropan-2-yl)-
benzamide (1ca). According to procedure A, 1ca (827 g, 3.7
mmol, 74% yield) was obtained from 2-amino-2-methyl-1,3-
propanediol (526 mg, 5.0 mmol) and 2-methylbenzoyl
chloride (772 mg, 5.0 mmol) as a white solid of mp 98−100
1
°C. IR (ATR): 3329, 3278, 1639, 1533, 1033 cm−1. H NMR
(300 MHz, CDCl3): δ 7.38−7.30 (m, 2H), 7.22 (m, 2H), 6.18
(s, 1H), 3.89−3.70 (m, 6H), 2.45 (s, 3H), 1.32 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 171.6 136.4, 135.7, 131.0, 130.1,
126.7, 125.8, 67.6, 67.5, 59.5, 20.3, 19.7. HRMS (EI), m/z:
[M]+ calcd for C12H17NO3, 223.1208; found, 223.1202.
2-Methyl-N-(1,3-dihydroxy-2-n-butylpropan-2-yl)-
benzamide (1cc). According to procedure B, 1cc (1.18 g, 4.4
mmol, 88% yield) was obtained from N-(2-toluoyl)amino
malonic acid ethyl ester (1.47 g, 5.0 mmol) and n-butyl
bromide (822 mg, 6.0 mmol) as a colorless oil. IR (ATR):
1
3304, 2955, 1636, 1516, 1043 cm−1. H NMR (400 MHz,
CDCl3): δ 7.38−7.30 (m, 2H), 7.24−7.19 (m, 2H), 6.16 (brs,
1H), 3.93 (dd, J = 13.2, 5.4 Hz, 4H), 3.67 (dd, J = 13.2, 8.3
Hz, 2H), 2.45 (s, 3H), 1.70 (m, 2H), 1.39−1.33 (m, 4H), 0.92
(t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 171.6,
136.5, 135.7, 131.1, 130.1, 126.7, 125.8, 66.2, 61.8, 33.3, 25.3,
23.2, 19.7, 14.0. HRMS (FAB), m/z: [M]+ calcd for
C16H23NO4, 265.1678; found, 265.1682.
2-Methyl-N-(1,3-dihydroxy-2-phenylpropan-2-yl)-
benzamide (1cg). According to procedure C, 1cg (1.32 g, 4.2
mmol, 88% yield) was obtained as a colorless oil. IR (ATR):
D
DOI: 10.1021/acs.oprd.8b00407
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
1
3311, 3063, 2926, 1638, 1510, 1061 cm−1. H NMR (300
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.8b00407.
■
MHz, CDCl3): δ 7.51 (d, J = 7.6 Hz, 1H), 7.22−7.43 (m, 8H),
6.77 (brs, 1H), 4.15 (dd, J = 11.7, 5.9 Hz, 2H), 3.99 (dd, J =
11.4, 6.7 Hz, 2H), 3.77 (t, J = 6.7 Hz, 2H), 2.51 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 171.5, 139.1, 136.2, 135.9, 131.3,
130.4, 128.9, 127.9, 126.7, 126.0, 125.9, 67.6, 66.0, 19.9.
HRMS (EI), m/z: [M]+ calcd for C17H19NO3, 285.1365;
found, 285.1367.
Compounds 1aa−ba, 1da−ga, and 1cb were prepared
according to a procedure A. Compound 1ha was prepared
according to the modified procedure A using p-toluenesulfonyl
chloride. Compound 1ia was synthesized according to the
reported method.20 Compounds 1cd−cf and 1ch−cl were
prepared according to procedure B. See the Supporting
Information for details.
General Procedure for the Synthesis of α-Substituted
Serine Derivatives. A reaction vessel was charged with
Cu(OTf)2 (18.1 mg, 0.05 mmol, 10 mol %) and (R,R)-PhBOX
(16.7 mg, 0.05 mmol, 10 mol %), and then CH2Cl2 (2.5 mL,
0.2 M) and MeOH (48.1 mg, 1.5 mmol, 3.0 equiv) were
added. The resulting solution was stirred for 10 min at room
temperature, and then amino diol 1 (0.5 mmol) was added.
After the solution was stirred for 5 min at the same
temperature, N-bromosuccinimide (356 mg, 2.0 mmol, 4.0
equiv) was added to the reaction vessel, and the resulting
mixture was stirred for additional 4 h. To the reaction mixture
was added saturated Na2S2O3 aq, and the mixture was
extracted with CH2Cl2. The combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced
pressure to afford a crude product. Purification by silica gel
column chromatography afforded the desired serine deriva-
tives.
N-(2-Methylbenzoyl)-α-methylserine Methyl Ester (2ca).
Colorless oil, 106 mg, 84% yield, 86% ee, [α]1D9 = −2.01 (c
1.00, CHCl31). IR (ATR): 3329, 2951, 1734, 1638, 1522, 1128,
1053 cm−1. H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 7.3
Hz, 1H), 7.35−7.32 (m, 1H), 7.26−7.20 (m, 2H), 6.61 (brs,
1H), 4.18 (dd, J = 11.5, 6.6 Hz, 1H), 3.92 (dd, J = 11.5, 6.6
Hz, 1H), 3.83 (s, 3H), 3.59 (t, J = 6.6 Hz, 1H), 2.47 (s, 3H),
1.64 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 173.6, 170.5,
136.1, 135.8, 131.1, 130.2, 126.9, 125.8, 66.8, 62.4, 53.0, 20.4,
19.7. HPLC HIRALPAK AY-H column, hexane/i-PrOH = 7:1,
wavelength 254 nm, flow rate 1.0 mL/min, tR = 13.9 min
(major), 16.6 min (minor). HRMS (EI) m/z: [M]+ calcd for
C13H17NO4, 251.1158; found, 251.1162.
S
Experimental procedure, ORTEP drawing of S1, crystal
data, 1H and 13C NMR spectrum for all compounds, and
HPLC chromatograms of the products (PDF)
Crystallographic data of compound S1 (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: onomura@nagasaki-u.ac.jp. Tel: (+81)-95-819-2429.
ORCID
Kosuke Yamamoto: 0000-0002-8189-7141
Masami Kuriyama: 0000-0002-4871-6273
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by MEXT Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysts” (No. 26105746) and JSPS
Grant-in-Aid for Scientific Research (C) (No. 16K08167).
ABBREVIATIONS
■
DBDMH, 1,3-dibromo-5,5-dimethylhydantoin; NBS, N-bro-
mosuccinimide; NBP, N-bromophthalimide; TLC, thin layer
chromatography
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Gram-Scale Experiment. A reaction vessel was charged
with Cu(OTf)2 (362 mg, 1.0 mmol, 10 mol %) and (R,R)-
PhBOX (334 mg, 1.0 mmol, 10 mol %), and then CH2Cl2 (50
mL, 0.2 M) and MeOH (961 mg, 30 mmol, 3.0 equiv) were
added. The resulting solution was stirred for 10 min at 26 °C,
and then 1ca (2.23 g, 10 mmol) was added. After the solution
was stirred for 5 min at the same temperature, N-
bromosuccinimide (7.12 g, 40 mmol, 4.0 equiv) was added
to the reaction vessel, and the resulting mixture was stirred for
an additional 13.5 h. To the reaction mixture was added
saturated Na2S2O3 aq, and the mixture was extracted with
CH2Cl2. The combined organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure to afford a
crude product. Purification by silica gel column chromatog-
raphy afforded the desired serine derivatives 2ca (2.06 g, 82%
yield, 87% ee).
́
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