Rhodium-Catalyzed anti and syn Enantio- and Diastereoselective Transfer Hydrogenation of α-Amino β-Keto Ester Hydrochlorides through Dynamic Kinetic Resolution

Article abstract of DOI:10.1055/s-0035-1562444

A mild catalytic asymmetric transfer hydrogenation of a series of α-amino β-keto ester hydrochlorides catalyzed by a rhodium(III) complex is reported. The use of the formic acid/triethylamine system as the hydrogen donor source provided the corresponding anti and syn amino alcohols with complete conversions, fair diastereoselectivities (up to 97:3 dr), and high enantioselectivities (ee up to >99%).

Full text of DOI:10.1055/s-0035-1562444

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
Q. Llopis et al.
Paper
Synthesis
Rhodium-Catalyzed anti and syn Enantio- and Diastereoselective
Transfer Hydrogenation of α-Amino β-Keto Ester Hydrochlorides
through Dynamic Kinetic Resolution
Quentin Llopisa
OH
O
Charlène Férarda
Gérard Guillamotb
Phannarath Phansavath*a
Virginie Ratovelomanana-Vidal*a
OMe
NHCOPh
R
1. (R,R)-1 (S/C = 100)
HCO2H/Et3N (5:2)
O
O
9 examples
anti/syn up to 97:3
ee up to >99%
Rh
Cl
NH
1,4-dioxane, 30 °C, 3 h
2. PhCOCl, Et3N
Ar
OMe
NH2·HCl
MeO
TsN
Ph
CH2Cl2, rt, 3 h
100% conversion
OH
O
a PSL Research University, Chimie ParisTech-CNRS, Institut de
Recherche de Chimie Paris, 11 rue Pierre et Marie Curie 75005
Paris, France
b PCAS, 23 rue Bossuet, Z.I. de la vigne aux Loups, 91160
Longjumeau, France
Ph
Ar = Ph, 4-MeC6H4,
3-MeC6H4, 2-MeC6H4,
4-MeOC6H4, 4-ClC6H4,
X
OMe
NHCOPh
X = O, S
(R,R)-1
4-BrC6H4, 4-FC6H4, 2-naphthyl
2-furyl, 2-thienyl
syn/anti up to 88:12
ee up to >99%
phannarath.phansavath@chimie-paristech.fr
virginie.vidal@chimie-paristech.fr
In memory of Professor Jean Normant with profound respect
Received: 13.05.2016
Accepted after revision: 06.06.2016
Published online: 21.07.2016
tion/DKR process7 and their applications in total synthe-
ses,8 we now describe the asymmetric transfer hydrogena-
tion of α-amino β-keto ester hydrochlorides with the Rh(III)
complex (R,R)-1, which contains a TsDPEN ligand and an η5-
cyclopentadiene moiety connected through a carbon tether,
recently developed in our group9 (Table 1). We have previ-
ously shown that (R,R)-1 exhibits an excellent catalytic per-
formance in terms of reactivity and stereoselectivity for the
ATH of ketones, and we were keen to investigate its behav-
ior in the ATH of functionalized ketones, particularly in the
reduction of α-amino β-keto ester hydrochlorides through
DKR.
DOI: 10.1055/s-0035-1562444; Art ID: ss-2016-c0351-op
Abstract A mild catalytic asymmetric transfer hydrogenation of a se-
ries of α-amino β-keto ester hydrochlorides catalyzed by a rhodium(III)
complex is reported. The use of the formic acid/triethylamine system as
the hydrogen donor source provided the corresponding anti and syn
amino alcohols with complete conversions, fair diastereoselectivities
(up to 97:3 dr), and high enantioselectivities (ee up to >99%).
Key words rhodium, asymmetric catalysis, transfer hydrogenation,
amino alcohols, diastereoselectivity, enantioselectivity
Our exploration commenced with the examination of
the reaction parameters by using compound 2a, bearing a
phenyl substituent on the ketone function, as the standard
substrate (Table 1). The reaction, which proceeded readily
in a wide variety of solvents, was initially conducted in ace-
tonitrile at room temperature in the presence of 1 mol% of
the complex (R,R)-1 and a HCO2H/Et3N (5:2) azeotropic
mixture as the hydrogen source. Under these conditions,
the ATH proceeded with full conversion, delivering, after N-
benzoylation, the corresponding anti β-hydroxy α-amido
ester 3a in 65% yield, a 81:19 diastereomeric ratio, and an
80% enantiomeric excess (Table 1, entry 1). Interestingly,
upon increasing the reaction temperature to 30 °C, a higher
yield was obtained (79%) without affecting the stereochem-
ical outcome of the reaction (entry 2). Using these reaction
conditions, we next examined the effect of the solvent on
the DKR (entries 3–15). Of all the solvents explored, metha-
nol and 1,4-dioxane gave the highest yields of 81% and 82%,
respectively (entries 4 and 15).
Transition-metal-catalyzed asymmetric transfer hydro-
genation (ATH) is among the most atom-efficient and pow-
erful methods for the synthesis of chiral compounds in en-
antiomerically enriched form.1 In conjunction with a dy-
namic kinetic resolution (DKR) process and by starting from
racemic substrates bearing a labile stereocenter, the reac-
tion permits the installation of two contiguous stereogenic
centers in a single operation.2 In particular, an elegant path
to β-hydroxy α-amino acids, important as building blocks
in natural products and pharmaceuticals,3 relies on the
transition-metal-catalyzed ATH of α-amino β-keto ester de-
rivatives. In this field, only few groups have described the
reduction of these compounds in their N-protected forms
through Ru-catalyzed ATH.4 In this context, we have previ-
ously reported the first example of a Ru-catalyzed ATH of
α-amino β-keto ester hydrochlorides5 by using a tethered
ruthenium complex developed by Wills and co-workers.6
As part of our long-standing program directed toward the
development of efficient catalytic systems for the reduc-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
Q. Llopis et al.
Paper
Synthesis
Table 1 Optimization of the Reaction Conditions for the ATH of 2a
with (R,R)-1a
Whereas the reaction afforded a better diastereomeric
ratio in methanol (82:18 dr versus 74:26 dr for 1,4-diox-
ane), excellent enantioselectivity of 99% ee (versus 90% ee
for methanol) was achieved in 1,4-dioxane. DMF and 2-
methyltetrahydrofuran both gave high enantioselectivities
(98% ee; Table 1, entries 9 and 12), but lower yields and
lower diastereoselectivities (66:34 and 68:32 dr, respec-
tively; entries 9 and 12) were observed in these solvents.
The other solvents investigated (isopropanol, dichloro-
methane, dimethyl carbonate, diethyl carbonate, ethyl ace-
tate, tetrahydrofuran, methyl tert-butyl ether, and diethyl
ether) all gave less satisfactory results than 1,4-dioxane in
terms of yields and asymmetric inductions (entries 3, 5–8,
11, 13 and 14). When the reaction was performed in the ab-
sence of a solvent (in this case, 10 equivalents of the formic
acid/triethylamine (5:2) azeotropic mixture were used), an
enantiomeric excess of only 70% was observed (entry 10)
and the reduced compound was formed in 62% yield along-
side uncharacterized byproducts.
Having established that 1,4-dioxane is the most appro-
priate solvent for the ATH of α-amino β-keto ester hydro-
chloride 2a with catalyst (R,R)-1, we next sought the opti-
mal reaction parameters. The influence of the reaction tem-
perature was first examined. Running the reduction at
room temperature led to a slightly lower yield with no
change in stereoselectivity (Table 1, entry 16). Higher tem-
peratures provided markedly lower diastereoselectivities
(50 and 80 °C; entries 18 and 19), whereas decreasing the
temperature to 10 °C resulted in a better dr of 81:19, albeit
with a significant drop in enantioselectivity (entry 17). The
use of five equivalents instead of three equivalents of the
HCO2H/Et3N (5:2) azeotropic mixture did not notably affect
the outcome of reaction (entry 20). Other hydrogen sources
were then investigated. Sodium formate gave a higher yield,
but at the expense of the diastereoselectivity (entry 21),
whereas ammonium formate produced no conversion (en-
try 22). Changing the catalyst loading to 0.5 mol% of (R,R)-1
did not improve the diastereoselectivity, but the β-hydroxy
ester 3a was obtained in lower yield (entry 23). In light of
these results, having defined conditions to control the ste-
reoselectivity and product distribution, the optimized reac-
tion conditions for the ATH of α-amino β-keto ester hydro-
chloride 2a were set as follows: 1 mol% of the tethered Rh
complex (R,R)-1, 3 equiv of the HCO2H/Et3N (5:2) azeo-
tropic mixture as the hydrogen source, 1,4-dioxane as the
solvent, a reaction temperature of 30 °C, and a reaction
time of three hours.
1. (R,R)-1 (1 mol%)
HCO2H/Et3N (5:2) (3 equiv)
OH
O
O
O
[S] = 2 M, solvent, T (°C), 3 h
Ph
OMe
Ph
OMe
NH2·HCl
)-2a
2. PhCOCl, Et3N, CH2Cl2, r.t., 2.5 h
100% conversion
NHCOPh
(
3a
Rh
Cl
MeO
TsN
N
H
Ph
(R,R)-1
Ph
Entry
Solvent
Temp (°C) Yield (%) drb
eec (%)
1
2
MeCN
MeCN
i-PrOH
MeOH
CH2Cl2
DMCd
DECe
r.t.
30
30
30
30
30
30
30
30
30
30
30
30
30
30
r.t.
10
50
80
30
30
30
30
65
79
57
81
43
71
55f
80f
78
62f
61
67
67f
76
82
77
75
80
74
80
89
0
81:19
79:21
80:20
82:18
88:12
75:25
76:24
74:26
66:34
85:15
68:32
68:32
79:21
80:20
74:26
75:25
81:19
68:32
57:43
71:29
46:54
—
80
82
91
90
75
91
85
92
98
70
97
98
82
77
99
99
88
99
98
97
98
—
3
4
5
6
7
8
EtOAc
DMF
9
g
10
11
12
13
14
15
16
17
18
19
20i
21j
22k
23l
–
THF
2-MeTHFh
MTBE
Et2O
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
72
71:29
98
a Reaction conditions: (1) 2a (0.44 mmol), (R,R)-1 (1 mol%), HCO2H/Et3N
(5:2) (3 equiv), 3 h. (2) Crude ATH product (0.44 mmol), BzCl (0.48 mmol),
Et3N (1.32 mmol), CH2Cl2 (2 mL), r.t., 2.5 h.(N-benzoylation was required
for analytical purpose).
b Determined by 1H NMR of the crude ATH product.
c Determined by supercritical fluid chromatography (SFC).
d Dimethyl carbonate.
e Diethyl carbonate.
f Compound 3a was contaminated with byproducts.
g HCO2H/Et3N (5:2) azeotropic mixture (10 equiv) was used as the solvent.
h 2-Methyltetrahydrofuran.
With these optimized reaction conditions in hand, we
further explored the substrate scope and limitations of the
reaction. A variety of aromatic substrates10 were surveyed
(Table 2). The results from these studies indicated that the
current reaction conditions were generally tolerant of sub-
strates containing either electron-donating (Table 2, entries
2, 3, 5, and 9) or electron-withdrawing groups (entries 6–
8). Diastereomeric ratios in these instances varied from
i Five equivalents of the HCO2H/Et3N (5:2) azeotropic mixture were used.
j HCO2Na was used as the hydrogen source.
k HCO2NH4 was used as the hydrogen source.
l The reaction was performed with 0.5 mol% of (R,R)-1.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
Q. Llopis et al.
Paper
Synthesis
63:37 to 74:26 in favor of the anti compound, whereas ex-
cellent enantioinductions were generally achieved (96% to
>99% ee). In the case of an ortho-substituted benzene ring, a
high level of diastereoselection was attained (97:3 dr; entry
4) with no significant erosion in the enantioselectivity (94%
ee; entry 4), although the more sterically hindered position
induced a lower yield of 3d. This result stands in sharp con-
trast with the related Ru-catalyzed asymmetric transfer hy-
drogenation of compound 2d, because we previously re-
ported that the reaction was inefficient in this instance.
Furthermore, ATH of the heteroaromatic substrates 2j and
2k led to a reversal of the diastereoselection. The corre-
sponding reduced furan and thiophene derivatives 3j and
3k were produced in 55% yields with 14:86 dr and 12:88 dr,
respectively, in favor of the syn products, and with excellent
enantioselectivities toward the major isomer in both cases
(99% ee; entries 10 and 11).11,12
Interestingly, higher diastereoselectivities were ob-
served than for the previously reported Ru-promoted ATH,
which gave diastereomeric ratios of 41:59 and 32:68 for
compounds 3j and 3k, respectively. In addition, upon scale-
up (gram scale), a slight improvement in both enantioselec-
tivity and yield (99% ee and 74% yield versus 96% ee and
70% yield; Table 2, entry 3) was observed for α-amino β-hy-
droxy ester 3c, whereas the diastereoselectivity of the reac-
tion remained unchanged.
Table 2 ATH of α-Amino β-Keto Ester Hydrochlorides 2a–k Catalyzed by the Rh Catalyst (R,R)-1a
1. (R,R)-1 (1 mol%), HCO2H/Et3N (5:2) (3 equiv)
1,4-dioxane, 30 °C, 3 h
OH
O
OH
O
O
(
O
or
R
OMe
NHCOPh
R
OMe
NHCOPh
3j,k
R
OMe
2. PhCOCl, Et3N, CH2Cl2, r.t., 3 h
100% conversion
NH2.HCl
)-2a–k
3a–i
Entry ATH productb
Yieldc (%) drd
eee (%)
99
Entry
7
ATH productb
Yieldc (%) drd
eee (%)
>99
OH
O
OH
O
OMe
OMe
NHCOPh
1
82
74:26
75
70:30
NHCOPh
Cl
3g
3a
OH
O
OH
O
OMe
OMe
NHCOPh
2
3
4
5
75
70
41
60
63:37
70:30
97:3
>99
96
8
9
84
72
55
55
75:25
74:26
14:86
12:88
>99
98
NHCOPh
F
3h
3b
3c
3d
OH
O
OH
O
OMe
OMe
NHCOPh
NHCOPh
3i
OH
O
OH
O
O
94
10
11
>99f
99f
OMe
OMe
NHCOPh
NHCOPh
3j
OH
O
OH
O
S
OMe
OMe
NHCOPh
64:36
>99
NHCOPh
O
MeO
3e
3k
OH
OMe
6
68
72:28
>99
NHCOPh
Br
3f
a Reaction conditions: (1) 2a (0.44 mmol), (R,R)-1 (1 mol%), HCO2H/Et3N (5:2) (3 equiv), 3 h. (2) crude ATH product (0.44 mmol), BzCl (0.48 mmol), Et3N (1.32
mmol), CH2Cl2 (2 mL), r.t., 2.5 h. The conversion was determined by 1H NMR of the crude ATH product.
b The relative and absolute configurations of compounds 3a–k were assigned by comparison with reported analytical data or on the basis of the general observed
trends in enantio- and diastereoselectivities.
c Isolated yield.
d The anti/syn ratio was determined by 1H NMR of the crude product after the ATH reaction.
e Determined by HPLC or SFC analysis.
f ee of the syn isomer.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
Q. Llopis et al.
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Synthesis
In summary, we have shown that aromatic α-amino β-
keto ester hydrochlorides undergo ATH induced by the Rh
complex (R,R)-1 with good yields, fair diastereoselection,
and excellent enantioselectivities through a DKR process.
The Rh(III) complex (R,R)-1 containing the TsDPEN ligand
and an η5-arene connected through a carbon tether was ef-
ficiently used in combination with the formic acid/triethyl-
amine (5:2) system as the hydrogen donor source. The reac-
tion generally afforded good yields of the corresponding
anti α-amino β-hydroxy ester derivatives with fair diaste-
reoselectivities and a high level of enantioselectivity (ee up
to >99%). Moreover, we observed an interesting reversal of
diastereoselection for heteroaromatic compounds under
the standard reaction conditions. In these instances, the syn
products were formed with good diastereoselectivities and
excellent enantioselectivities. This transformation serves as
an atom-economical and stereoselective method to prepare
anti and syn α-amino β-hydroxy ester derivatives found in
natural products and bioactive molecules with a high level
of enantioinduction (ee up to >99%).
at 0 °C for 1.5 h and at r.t. for 1 h, then diluted with CH2Cl2. The reac-
tion was quenched with sat. aq NH4Cl, the mixture was extracted
with CH2Cl2, and the combined organic layers were dried (MgSO4).
The crude protected product was purified by flash chromatography.
The enantiomeric excess was determined by SFC or HPLC analysis of
the purified product (on a CHIRALCEL OD-H or CHIRALPAK IA, IC or
AD-H column).
Methyl(2R,3R)-2-(Benzoylamino)-3-hydroxy-3-phenylpropanoate
(3a)13
White solid; yield: 116 mg (82%); Rf = 0.31 (pentane–EtOAc, 6:4);
anti/syn = 74:26; eeanti = 99%.
1H NMR (300 MHz, CDCl3): δ (anti) = 7.76–7.69 (m, 2 H), 7.56–7.50
(m, 1 H), 7.47–7.36 (m, 2 H), 7.29–7.18 (m, 5 H), 6.88 (d, J = 7.0 Hz, 1
H), 5.40 (dd, J = 5.9, 3.4 Hz, 1 H), 5.23 (dd, J = 7.0, 3.4 Hz, 1 H), 4.59 (d,
J = 5.9 Hz, 1 H), 3.79 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ (anti) = 169.9, 168.4, 139.0, 133.0, 132.0,
128.6, 128.2, 128.0, 127.1, 125.8, 75.0, 59.3, 52.5.
MS (ESI): m/z = 312 [M + Na]+.
SFC: CHIRALPAK AD-H, scCO2/MeOH (85:15), 3 mL/min, P = 150 bar,
λ = 215 nm; tR [syn] = 7.47 min, tR [syn] = 8.32 min, tR [anti-(R,R)] =
9.72 min (major), tR [anti-(S,S)] = 10.73 min.
Methyl (2R,3R)-2-(Benzoylamino)-3-hydroxy-3-(4-methylphe-
All reactions were performed under argon. Reaction vessels were
oven dried, cooled under vacuum, and flushed with argon before use.
1,4-Dioxane was distilled over calcium hydride. CH2Cl2 was dried over
alumina columns in an Innovative Technologies apparatus. Reagent-
grade hexane and methanol were purchased and used without fur-
ther purification. Reagents were purified according to the methods
described in the literature. Acros Silica Gel 60 (0.0040–0.0063 mm)
was used for flash column chromatography. Analytical TLC was car-
ried out on commercial silica-gel plates (Merck 60 F254), which were
viewed by using UV light (λ = 254 nm) and KMnO4 or p-anisaldehyde
staining solutions. NMR spectra were recorded on a Bruker AVANCE
300 (1H: 300 MHz; 13C: 75 MHz) instrument. Chemical shifts are ex-
pressed in ppm referenced to residual chloroform (7.26 ppm for 1H
and 77.16 for 13C). Supercritical fluid chromatography (SFC) analyses
were performed on a Berger apparatus equipped with Daicel CHIRAL-
nyl)propanoate (3b)13
White solid; yield: 103 mg (75%); Rf = 0.58 (pentane–EtOAc, 1:1);
anti/syn = 63:37, eeanti > 99%.
1H NMR (300 MHz, CDCl3): δ (anti) = 7.74 (d, J = 7.0 Hz, 2 H), 7.55–
7.26 (m, 4 H), 7.17–7.10 (m, 3 H), 6.91 (d, J = 7.2 Hz, 1 H), 5.32 (br s, 1
H), 5.20 (dd, J = 7.2, 3.6 Hz, 1 H), 4.52 (br s, 1 H), 3.75 (s, 3 H), 2.32 (s, 3
H).
13C NMR (75 MHz, CDCl3): δ (anti) = 170.0, 168.5, 137.8, 136.0, 133.1,
132.1, 129.0, 128.6, 127.2, 125.8, 75.1, 59.4, 52.6, 21.1.
MS (ESI): m/z = 336 [M + Na]+.
SFC: CHIRALPAK AD-H, scCO2/MeOH (89:11), 3 mL/min, P = 150 bar,
λ = 215 nm; tR [syn] = 9.07 min, tR [syn] = 20.56 min, tR [anti-(S,S)] =
21.76 min, tR [anti-(R,R)] = 24.06 min (major).
CEL or CHIRALPAK columns coupled with
a dual-wavelength
(215/254 nm) Waters 2489 UV detector. HPLC analyses were per-
formed on a Waters Alliance e2695 system equipped with Daicel CHI-
RALPAK columns and a UV detector operating at 215 nm. Mass spec-
tra (EI, Na) were recorded at ENSCP Chimie ParisTech.
Methyl (2R,3R)-2-(Benzoylamino)-3-hydroxy-3-(3-tolyl)propa-
noate (3c)13
Pale-yellow solid; yield: 102 mg (70%); Rf = 0.44 (pentane–EtOAc,
6:4); anti/syn = 70:30, eeanti = 96%.
1H NMR (300 MHz, CDCl3): δ (anti) = 7.74 (d, J = 6.9 Hz, 2 H), 7.53–
7.35 (m, 3 H), 7.26–7.18 (m, 2 H), 7.10–7.03 (m, 2 H), 6.90 (d, J = 7.5
Hz, 1 H), 5.33 (br s, 1 H), 5.17 (dd, J = 7.5, 3.7 Hz, 1 H), 4.47 (br s, 1 H,),
3.75 (s, 3 H), 2.31 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ (anti) = 170.0, 168.3, 139.0, 137.8, 133.1,
132.0, 128.8, 128.5, 128.1, 127.1, 126.5, 122.9, 74.9, 59.3, 52.4, 21.3.
α-Amino β-Hydroxy Ester Hydrochlorides 3a–k: General Proce-
dure
A round-bottomed tube fitted with a rubber septum equipped with a
balloon of argon was charged with the appropriate α-amino β-keto
ester hydrochloride 2 (0.44 mmol) and the rhodium complex (R,R)-1
(0.0044 mmol, 1 mol%). The solids were subjected to three vacu-
um/argon cycles before distilled 1,4-dioxane (2 mL) was added, and
another three vacuum/argon cycles were then performed.
HCO2H/Et3N (5:2) azeotropic mixture (110 μL, 1.32 mmol, 3 equiv)
was added, the mixture was stirred at 30 °C for 3 h, and the solvent
was removed under reduced pressure. The conversion and diastereo-
meric excess were determined by 1H NMR analysis of the crude prod-
uct.
MS (ESI): m/z = 336 [M + Na]+.
SFC: CHIRALPAK AD-H, scCO2/MeOH (80:20), 4 mL/min, P = 150 bar,
λ = 215 nm; tR [syn] = 2.37 min, tR [anti-(S,S)] = 4.06 min, tR [syn] =
4.51 min, tR [anti-(R,R)] = 5.63 min (major).
Methyl (2R,3R)-2-(Benzoylamino)-3-hydroxy-3-(2-methylphe-
nyl)propanoate (3d)13
A solution of the crude α-amino β-hydroxy ester hydrochloride (0.44
mmol) in anhyd CH2Cl2 (2 mL) was treated with BzCl (0.48 mmol, 1.1
equiv) and Et3N (1.32 mmol, 3 equiv) at 0 °C. The mixture was stirred
Pale-yellow solid; yield: 54 mg (41%); Rf = 0.63 (pentane–EtOAc, 1:1);
anti/syn = 97:3, eeanti = 94%.
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E
Q. Llopis et al.
Paper
Synthesis
1H NMR (300 MHz, CDCl3): δ (anti) = 7.88–7.76 (m, 2 H), 7.57–7.36
(m, 4 H), 7.23–7.14 (m, 3 H), 7.08 (d, J = 7.5 Hz, 1 H), 5.47 (br s, 1 H),
5.11 (dd, J = 7.5, 3.5 Hz, 1 H), 3.62 (s, 3 H), 3.54 (br s, 1 H), 2.40 (s, 3 H).
Methyl (2R,3R)-2-(Benzoylamino)-3-(4-fluorophenyl)-3-hydroxy-
propanoate (3h)9
White solid; yield: 117 mg (84%); Rf = 0.44 (pentane–EtOAc, 6:4);
anti/syn = 75:25, eeanti > 99%.
13C NMR (75 MHz, CDCl3): δ (anti) = 170.6, 167.8, 137.4, 134.9, 133.5,
1H NMR (300 MHz, CDCl3): δ (anti) = 7.64 (d, J = 7.0 Hz, 2 H), 7.45–
7.11 (m, 5 H), 6.94–6.85 (m, 3 H), 5.24 (d, J = 3.5 Hz, 1 H), 5.07 (dd, J =
7.1, 3.5 Hz, 1 H), 4.71 (br s, 1 H), 3.65 (s, 3 H).
132.2, 130.8, 128.8, 128.1, 127.3, 125.9, 125.9, 71.8, 57.6, 52.4, 19.1.
MS (ESI): m/z = 336 [M + Na]+.
HPLC: CHIRALPAK IA, hexane–i-PrOH (90:10), 1 mL/min, λ = 215 nm;
tR [syn] = 11.83 min, tR [syn] = 12.73 min, tR [anti-(R,R)] = 18.82 min
(major), tR [anti-(S,S)] = 20.90 min.
13C NMR (75 MHz, CDCl3): δ (anti) = 169.8, 168.6, 162.4 (d, 1JCF = 246.2
Hz), 134.9 (d, 4JCF = 3.0 Hz), 132.8, 132.2, 128.7, 127.5, 127.1 (d, 3JCF
8.1 Hz), 115.2 (d, 2JCF = 21.6 Hz), 74.5, 59.4, 52.7.
=
Methyl (2R,3R)-2-(Benzoylamino)-3-hydroxy-3-(4-methoxyphe-
MS (ESI): m/z = 340 [M + Na]+.
nyl)propanoate (3e)9
SFC: CHIRALPAK AD-H, scCO2/MeOH (85:15), 4 mL/min, P = 150 bar,
λ = 215 nm; tR [syn] = 3.14 min, tR [syn] = 4.53 min, tR [anti-(S,S)] =
5.93 min, tR [anti-(R,R)] = 8.23 min (major).
White solid; yield: 83 mg (60%); Rf = 0.35 (pentane–EtOAc, 6:4);
anti/syn = 64:36, eeanti > 99%.
1H NMR (300 MHz, CDCl3): δ (anti) = 7.73 (d, J = 7.3 Hz, 2 H), 7.56–
7.38 (m, 3 H), 7.19 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 7.3 Hz, 1 H), 6.85 (d,
J = 8.8 Hz, 2 H), 5.30 (s, 1 H), 5.19 (dd, J = 7.3, 3.7 Hz, 1 H), 4.48 (br s, 1
H), 3.78 (s, 3 H), 3.77 (s, 3 H),
13C NMR (75 MHz, CDCl3): δ (anti) = 169.9, 168.7, 136.6, 133.6,
133.13, 133.1, 133.06, 132.2, 128.7, 128.1, 128.0, 127.7, 127.2, 126.2,
126.1, 125.0, 123.7, 75.4, 59.5, 52.7.
Methyl (2R,3R)-2-(Benzoylamino)-3-hydroxy-3-(2-naphthyl)pro-
panoate (3i)13
White solid; yield: 107 mg (72%); Rf = 0.35 (pentane–EtOAc, 6:4);
anti/syn = 74:26, eeanti = 98%.
1H NMR (300 MHz, CDCl3): δ (anti) = 7.87–7.66 (m, 6 H), 7.55–7.34
(m, 6 H), 6.93 (d, J = 7.1 Hz, 1 H), 5.56 (br s, 1 H), 5.33 (dd, J = 7.1, 3.4
Hz, 1 H), 4.69 (d, J = 5.3 Hz, 1 H), 3.78 (s, 3 H).
MS (ESI): m/z = 352 [M + Na]+.
13C NMR (75 MHz, CDCl3): δ (anti) = 169.9, 168.7, 136.6, 133.6,
133.13, 133.1, 133.06, 132.2, 128.7, 128.1, 128.0, 127.7, 127.2, 126.2,
126.1, 125.0, 123.7, 75.4, 59.5, 52.7.
SFC: CHIRALPAK IA, scCO2/MeOH (85:15), 4 mL/min, P = 150 bar, λ =
215 nm; tR [syn] = 7.01 min, tR [syn] = 8.83 min, tR [anti-(S,S)] = 9.66
min, tR [anti-(R,R)] = 13.03 min (major).
MS (ESI): m/z = 372 [M + Na]+.
Methyl (2R,3R)-2-(Benzoylamino)-3-(4-bromophenyl)-3-hydroxy-
SFC: CHIRALPAK IA, scCO2/MeOH (80:20), 4 mL/min, P = 150 bar, λ =
215 nm; tR [syn] = 3.49 min, tR [syn] = 4.95 min, tR [anti-(S,S)] = 5.41
min, tR [anti-(R,R)] = 6.15 min (major).
propanoate (3f)9
White solid; yield: 114 mg (68%); Rf = 0.44 (pentane–EtOAc, 6:4);
anti/syn = 74:26, eeanti > 99%.
1H NMR (300 MHz, CDCl3): δ (anti) = 7.74 (d, J = 7.7 Hz, 2 H), 7.54–
7.24 (m, 5 H), 7.13 (d, J = 7.7 Hz, 2 H), 6.93 (d, J = 7.2 Hz, 1 H), 5.33 (br
s, 1 H), 5.17 (dd, J = 7.0, 3.4 Hz, 1 H), 4.86 (s, 1 H), 3.78 (s, 3 H).
Methyl (2S,3S)-2-(Benzoylamino)-3-(2-furyl)-3-hydroxypropa-
noate (3j)9
Orange solid; yield: 71 mg (55%); Rf = 0.23 (pentane–EtOAc, 6:4);
anti/syn = 14:86, eesyn > 99%, eeanti = 96%.
13C NMR (75 MHz, CDCl3): δ (anti) = 169.6, 168.5, 138.3, 132.7, 132.2,
1H NMR (300 MHz, CDCl3): δ (syn) = 7.76–7.72 (m, 2 H), 7.51–7.31 (m,
4 H), 7.15 (d, J = 8.8 Hz, 1 H), 6.32–6.27 (m, 1 H), 6.25 (dd, J = 3.3, 1.8
Hz, 1 H), 5.35–5.33 (m, 1 H), 5.17 (dd, J = 8.8, 3.2 Hz, 1 H), 4.07 (br s, 1
H), 3.74 (s, 3 H).
131.3, 128.6, 127.6, 127.1, 121.9, 74.5, 59.3, 52.7.
MS (ESI): m/z = 402 [M + Na]+.
SFC: CHIRALPAK AD-H, scCO2/MeOH (80:20), 4 mL/min, P = 150 bar,
λ = 215 nm; tR [syn] = 3.56 min, tR [syn] = 5.93 min, tR [anti-(S,S)] =
9.56 min, tR [anti-(R,R)] = 12.38 min (major).
13C NMR (75 MHz, CDCl3): δ (syn) = 170.5, 167.8, 152.6, 142.4, 133.6,
131.7, 128.4, 127.1, 110.2, 107.2, 68.2, 56.4, 52.7.
Methyl (2R,3R)-2-(Benzoylamino)-3-(4-chlorophenyl)-3-hydroxy-
MS (ESI): m/z = 312 [M + Na]+.
propanoate (3g)9
SFC (er measurement for the anti compound): CHIRALPAK IC, sc-
CO2/MeOH (90:10), 4 mL/min, P = 150 bar, λ = 215 nm; tR [syn × 2] =
4.28 min, tR [anti] = 6.39 min, tR [anti] = 7.46 min.
White solid; yield: 109 mg (75%); Rf = 0.36 (pentane–EtOAc, 6:4);
anti/syn = 70:30, eeanti > 99%.
1H NMR (300 MHz, CDCl3): δ (anti) = 7.75–7.66 (m, 2 H), 7.46–7.16
(m, 7 H), 6.89 (d, J = 7.2 Hz, 1 H), 5.35 (br s, 1 H), 5.18 (dd, J = 7.2, 3.4
Hz, 1 H), 4.81 (br s, 1 H), 3.78 (s, 3 H).
SFC (er measurement for the syn compound): CHIRALCEL OD-H, sc-
CO2/MeOH (95:5), 2 mL/min, P = 150 bar, λ = 215 nm; tR [syn-(S,S)] =
11.30 min (major), tR [anti × 2] = 12.25 min, tR [syn-(R,R)] = 15.04 min.
13C NMR (75 MHz, CDCl3): δ (anti) = 169.7, 168.6, 137.7, 133.7, 132.8,
132.4, 128.7, 128.4, 127.3, 127.1, 74.5, 59.4, 52.7.
MS (ESI): m/z = 356 [M + Na]+.
Methyl (2S,3S)-2-(Benzoylamino)-3-hydroxy-3-(2-thienyl)propa-
noate (3k)9
Orange solid; yield: 73 mg (55%); Rf = 0.23 (pentane–EtOAc, 6:4);
anti/syn = 12:88, eesyn = 99%, eeanti = 96%.
1H NMR (300 MHz, CDCl3): δ (syn) = 7.78–7.74 (m, 2 H,), 7.48–7.34
(m, 4 H), 7.24 (d, J = 8.8 Hz, 1 H), 7.18 (d, J = 8.9 Hz, 1 H), 6.99–6.88 (m,
1 H), 5.63 (br s, 1 H), 5.28–5.25 (m, 1 H), 5.13 (dd, J = 8.8, 3.2 Hz, 1 H),
3.74 (s, 3 H).
SFC: CHIRALPAK AD-H, scCO2/MeOH (85:15), 4 mL/min, P = 150 bar,
λ = 215 nm; tR [syn] = 4.60 min, tR [syn] = 7.71 min, tR [anti-(S,S)] =
11.82 min, tR [anti-(R,R)] = 14.97 min (major).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
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Synthesis
13C NMR (75 MHz, CDCl3): δ (syn) = 170.5, 167.8, 152.6, 142.4, 133.6,
131.7, 128.4, 127.1, 110.2, 107.2, 68.2, 56.4, 52.7.
MS (ESI): m/z = 312 [M + Na]+.
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(c) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
SFC: CHIRALPAK AD-H, scCO2/MeOH (80:20), 4 mL/min, P = 150 bar,
λ = 215 nm; tR [syn-(S,S)] = 2.98 min (major), tR [syn-(R,R)] = 3.83 min,
tR [anti] = 5.26 min, tR [anti] = 5.85 min.
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Acknowledgment
Q.L. is grateful to PCAS for a grant (2014-2017). We are grateful to Dr.
M.-N. Rager for carrying additional NMR experiments.
(5) Echeverria, P.-G.; Férard, C.; Phansavath, P.; Ratovelomanana-
Vidal, V. Catal. Commun. 2015, 62, 95.
Supporting Information
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Chem. Soc. 2005, 127, 7318. (b) Morris, D. J.; Hayes, A. M.; Wills,
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J.; Wills, M. Org. Lett. 2009, 11, 847.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562444.
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characteristic of a trans-substituted oxazolidinone.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G