Asymmetric amination of α,α-dialkyl substituted aldehydes catalyzed by a simple chiral primary amino acid and its application to the preparation of a S1P1 agonist

Article abstract of DOI:10.1039/c9ra06210f

The chiral catalytic amination of an α,α-dialkyl substituted aldehyde usually proceeds with low enantioselectivity. We selected naphthyl-l-alanine as the catalyst and observed improved enantioselectivity for the amination. Using this method, racemic α-methyl-α-benzyloxypropanal was aminated to give chiral serine derivatives in 74% ee, which was further increased to >99% ee after recrystallization. Moreover, we also successfully synthesized a chiral phosphonium salt 9 for the preparation of one α-substituted alaninol compound 14 as an S1P₁ agonist in high overall yield.

Full text of DOI:10.1039/c9ra06210f

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PAPER
Asymmetric amination of a,a-dialkyl substituted
aldehydes catalyzed by a simple chiral primary
amino acid and its application to the preparation of
a S1P1 agonist†
Cite this: RSC Adv., 2019, 9, 33497
a
b
a
a
* *
Yifan Tang, Ping Xie and Dali Yin
Qiong Xiao,
The chiral catalytic amination of an a,a-dialkyl substituted aldehyde usually proceeds with low
enantioselectivity. We selected naphthyl-L-alanine as the catalyst and observed improved
enantioselectivity for the amination. Using this method, racemic a-methyl-a-benzyloxypropanal was
aminated to give chiral serine derivatives in 74% ee, which was further increased to >99% ee after
recrystallization. Moreover, we also successfully synthesized a chiral phosphonium salt 9 for the
preparation of one a-substituted alaninol compound 14 as an S1P1 agonist in high overall yield.
Received 9th August 2019
Accepted 24th September 2019
DOI: 10.1039/c9ra06210f
rsc.li/rsc-advances
stereoselectivities were possible utilizing proline derived tetra-
zole catalyst (1b) for the amination of a-alkyl-a-benzyl disub-
stituted aldehydes.19 In addition, no further progress about the
asymmetric amination of a-alkyl-a-alkyl disubstituted alde-
hydes had been reported.
Introduction
a,a-Disubstituted amino alcohols, aldehydes and acids are
important chiral building blocks in organic synthesis. They are
routinely found in a number of peptides,1–5 natural products6,7
and pharmaceuticals.8,9 Due to this importance, their synthesis
has attracted sustained interest from the synthetic community.
Existing methods for the asymmetric approach to scaffolds
include classical Seebach's method,10,11 auxiliary Strecker
synthesis,12 and a variety of asymmetric phase transfer catalysis
reactions.13
Recently, several methods have been reported describing the
asymmetric Michael a-amination of achiral aldehydes via
proline catalysis, resulting in the products being obtained in
good yields and excellent enantioselectivities.14–17 However,
these proline catalysts do not imbue high enantioselectivities in
the amination of branched aldehydes. Wang et al. reported that
3-(1-naphthyl)-L-alanine (1d) successfully promoted the enan-
tioselective a-amination of branched aldehydes with azadi-
carboxylates to give a-alkyl-a-aryl disubstituted aldehydes in up
to 99% ee.18 However, low enantioselectivities only 4–28% ee
were obtained with a-alkyl-a-alkyl disubstituted, potentially
owing to poor stereo-differentiation between the two a-substit-
uents.14 To some extent, the application of this kind of reaction
is limited. In 2005, Barbas et al. reported higher
Results and discussion
Herein, we report the asymmetric Machel a-amination of a-methyl-
a-protected hydroxymethyl aldehydes and their subsequent reduc-
tion and cyclisation to afford oxazolidinones in good ee. We initially
chose 3-(benzyloxy)-2-methylpropanal and dibenzyl azodicarbox-
ylate (DBAD) as a model substrate to determine to optimal reaction
conditions. When L-proline (1a) (30 mol%) was used,14 the reaction
was complete in 48 hours at room temperature and provided the
amino aldehyde in 56% yield, however we obtained poor enantio-
selectivities (32% ee). To improve the enantioselectivity, we screened
a number of catalysts (Fig. 1). For example, tetrazole catalyst (1b)
(15 mol%) in CH3CN provided 42% ee with 68% yield (Table 1, entry
2).17 3-(1-Naphthyl)-L-alanine catalyst (1d) (15 mol%) in CH3CN gave
the amino aldehyde in 70% yield with 46% ee (Table 1, entry 4).18
We then turned our attention to the effects of solvents on
both yield and enantioselectivities (Table 2). Among them,
dioxane, MeOH, MTBE and THF (entries 9, 10, 7 and 8) were all
tolerated and produce the desired oxazolidinones in moderate
aState Key Laboratory of Bioactive Substance and Function of Natural Medicines,
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation,
Department of Medicinal Chemistry, Institute of Materia Medica, Peking Union
Medical College, Chinese Academy of Medical Sciences, Beijing 100050, PR China.
E-mail: yindali@imm.ac.cn
bBeijing Union Pharmaceutical Factory, PR China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra06210f
Fig. 1 Chiral catalysts.
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Table 1 Screening of chiral catalystsa
methyl-a-protected hydroxymethyl substituted aldehydes with
aromatic ring. The results also showed that electron-
withdrawing groups were more successful than electron-
donating groups. Moreover, p-F and p-CF3 substituents both
showed similar enantioselectivities. We then investigated
differing azodicarboxylates and observed that di-p-chlorobenzyl
azodicarboxylate (DCAD) provided the desired products in
excellent yields (90%) and good enantioselectivities (up to ee
74%) while lower enantioselectivities were obtained with diethyl
azadicarboxylate (DEAD) or diisopropyl azadicarboxylate
(DIAD). We also observed good enantioselective control with
catalysts bearing naphthalene rings. This may be due to the p–p
interaction between the aromatic ring of substrate and naph-
thalene ring limiting the conformation of the intermediate,
thus improving the level of stereo-differentiation between the
two a-substituents. Additionally, when the azo reagent con-
tained an aromatic ring this p–p interaction may be further
enhanced, resulting in the observed improvement of
stereoselectivity.
Entry
Catalyst
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
1a
1b
1c
1d
1e
48
12
24
24
24
56
68
45
70
53
32
42
34d
46
44
a
All reactions were carried out with aldehyde (0.75 mmol), DBAD (0.5
mmol), catalyst (15 mol%) in THF solvent (4 mL) at rt under argon,
b
subsequent reduction and cyclisation to the oxazolidinone. Isolated
c
d
yield. Determined by HPLC with a Chiralpak-OD column. With the
opposite enantiomer.
Upon recrystallization from 90% ethanol, the aldehyde 4a-p-
ClBn was obtained in 97% ee (60% yield) and 4h-p-ClBn was
obtained in 97% ee (65% yield), which was subsequently con-
verted to oxazolidinone 5a-p-ClBn in >99% ee and 5h-p-ClBn
was obtained in 98% ee respectively. The absolute conguration
of 5-R was determined to be (R) on CD spectrum. Under ambient
pressure, hydrogenation using 10% Pd/C in methanol/acetic
acid, the benzyloxycarbonyl group was removed. Cleavage of
the hydrazine moiety, 7 was accomplished by treating with
NaNO2 (ref. 14) (Scheme 1). Alcohol 7 was treated with p-TsCl in
pyridine, and the resulting tosylate was successively converted
to iodide 8 with NaI in acetone under a reux condition.20 8 with
triphenylphosphine in DMF provided the desired phosphonium
salt 9 in moderate yield as a stable white solid.20
to good enantioselectivities. Of particular note, THF delivered
the highest enantioselectivity (69% ee) in synthetically useful
yields.
Furthermore, when lowering temperature to 0 ꢀC, we
observed no improvement in enantioselectivity, however the
reaction became notably more sluggish. Increasing catalyst
loading up to 30 mol% did not improve either enantioselectivity
or reaction time.
With these optimized conditions in hand, we probed the
substrate scope of the reaction (Table 3). In general, various
oxazolidinones 5 were obtained in moderate to good yields (54–
89%) and enantioselectivities (24–73% ee). The reactions
showed poor enantioselectivities for a-methyl-a-ethyl and a-
methyl-a-carbethoxy disubstituted aldehydes, but not for a-
Then we applied the chiral phosphonium salt 9 to the
synthesis of biological active compound as S1P1 agonist 14.
These types of compounds possessing a chiral 2-methyl-2-
aminoethanol have shown promise in recent years as the
immunosuppressant.21,22 This compound is an analogue of
SYL930, an immunosuppressant we have been reported
before.23 SYL930 is currently in phase I clinical stage. The
synthesis of 14 started from the aldehyde 11 in only a three step
manipulation.24 Aldehyde 11 was synthesized in good yield from
4-bromobenzaldehyde and dinary pinacol borate ester 10 via
Suzuki reaction with Pd-dimer (dibromobis(tri-tert-butylphos-
phine)dipalladium) as the catalyst.24 The Wittig reaction of 9
with 11 in dry THF at ꢁ78 ꢀC for 3 h furnished the alkenes 12 in
good yield. Subsequently reducing with 10% Pd/C in MeOH for
1 h afforded compound 13 in virtually quantitative yield aer
a ash-ltration. Finally, hydrolysis of the oxazolidinone part
and then acidication with 1 M HCl in Et2O produced the chiral
a-substituted alaninol compound 14.
Table 2 Screening of solventsa
Entry
Solvent
Time
Yieldb (%)
eec (%)
1
2
n-Hexane
Toluene
24
72
72
24
36
36
36
36
24
24
52
49
41
67
47
84
81
76
69
42
48
45
30
54
40
49
69
57
57
57
3
CH2Cl2
4
EtOAc
5
7
CH3OCH2CH2OCH3
MTBE
8
THF
9
Dioxane
10
11
MeOH
Ethylene glycol
Conclusions
a
Reaction conditions: the azodicarboxylate (1 equiv.) was added to the
aldehyde (1.5 equiv.), with catalyst (15 mol%) in THF at rt for the stated
period of time under argon. Reaction without isolation of intermediate.
In this study, we presented an efficient asymmetric amination
of branched racemic aldehydes catalyzed by the commercially
available amino acid (3-(1-naphthyl)-L-alanine). Under the
b
Isolated yield. c Determined by chiral HPLC.
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Table 3 Substrate scopea
Entry
R1
R2
Product
Time (h)
Yieldb (%)
eec (%)
eee (%)
1
2
3
4
5
6
7
8
BnOCH2
BnOCH2
BnOCH2
BnOCH2
Et
Bn
5a-Et
5a-Bn
38
36
48
1
79
81
80
94
54
56
78
67
75
80
89
70
63
79
75
81
71
73
76
89
90
95
77
70
—
78
76
57
69
71d
72
48
54
38
45
56
68
70
57
59
59
52
57
65
62
56
67
74d
73
55
57
—
—
—
97%
>99%
—
—
—
—
—
—
—
—
—
—
—
—
—
p-ClBn
p-ClBn
Bn
p-ClBn
Et
Bn
Et
Bn
p-ClBn
Et
Bn
Bn
p-ClBn
Et
Bn
p-ClBn
Et
Bn
p-ClBn
p-ClBn
Bn
4a-p-ClBn
5a-p-ClBn
5b-Bn
5b-p-ClBn
5c-Et
5c-Bn
5d-Et
5d-Bn
5d-p-ClBn
5e-Et
5e-Bn
5f-Bn
5f-p-ClBn
5g-Et
5g-Bn
5g-p-ClBn
5h-Et
5h-Bn
4h-p-ClBn
5h-p-ClBn
5i-Bn
p-CH3BnOCH2
p-CH3BnOCH2
3,4-DiMeOBnOCH2
3,4-DiMeOBnOCH2
p-FBnOCH2
p-FBnOCH2
p-FBnOCH2
p-ClBnOCH2
p-ClBnOCH2
p-BrBnOCH2
p-BrBnOCH2
p-CNBnOCH2
p-CNBnOCH2
p-CNBnOCH2
p-CF3BnOCH2
p-CF3BnOCH2
p-CF3BnOCH2
p-CF3BnOCH2
p-NO2BnOCH2
THPOCH2
38
36
38
36
37
36
48
39
36
38
48
28
24
48
39
36
48
1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
—
—
—
97%
98%
48
48
48
48
48
Bn
Bn
Bn
Bn
5j-Bn
5k-Bn
5l-Bn
4m-Bn
TrtOCH2
Et
CO2Et
37
24
a
Reaction conditions: the azodicarboxylate (1 equiv.) was added to the aldehyde (1.5 equiv.), with catalyst (15 mol%) in THF at rt for the stated
b
c
period of time under argon. Reaction performed without isolating the intermediate. Isolated yield. Isolated by silica gel column
chromatography. Determined by chiral HPLC. ee determined by chiral HPLC aer recrystallization. Absolute conguration of 5-R to
determined be (R) on CD spectrum.
d
e
optimized conditions, we obtained a-methyl-a-protected had disappeared. NaBH4 (3 eq. in respect to the azodicarbox-
hydroxymethyl substituted aldehydes in high ee. Importantly, ylate) was added in portions at room temperature. The reaction
we developed an efficient catalytic method for synthesizing the mixture was stirred for 1 h, and then it was quenched by adding
Wittig reagent involving a chiral 2-methyl-2-aminoethanol 1 M HCl aq. until the mixture reached pH 7, and it was extracted
structure that could be applied to other syntheses. Further, with CH2Cl2. The combined organic phases were dried over
a new S1P1 agonist 14 has been obtained by this method in high Na2SO4, and the solvent was evaporated under reduced pres-
overall yield.
sure. The resulting crude was puried by ash chromatography
on silica gel eluted with light petroleum ether–ethyl acetate
mixture (4 : 1 v/v) to afford products 5-R as oil or solid.
Experimental
General procedure for the synthesis of 4,4-disubstituted 3-
alkoxycarbonylamino-oxazolidin-2-ones (5-R) by one pot
method
3-Ethyloxycarbonylamino-4-methyl-4-benzyloxy-oxazolidin-2-one
(5a-Et)
1
ꢀ
White solid, yield 79%; mp 50–55 C; H NMR (400 MHz, CDCl3)
Catalyst 1d (15 mol% in respect to the azodicarboxylate) was d 1.24 (m, 6H, 2CH3), 3.27 (d, 1H, J ¼ 8.0 Hz, CH), 3.47 (d, 1H, J ¼
added to a suspension of aldehydes (2, 1.5 eq. in respect to the 12.0 Hz, CH), 4.05 (d, 1H, J ¼ 12.0 Hz, CH), 4.14 (q, 2H, J ¼ 4.0 Hz,
azodicarboxylate) and azodicarboxylate (3) in THF. The mixture CH2), 4.33 (d, 1H, J ¼ 8.0 Hz, CH), 4.51 (s, 2H, CH2), 6.33 (bs, 1H,
stirred at rt under argon until the colour of the azodicarboxylate NH), 7.27–7.38 (m, 5H, Har); 13C NMR (100 MHz, CDCl3) d 14.3, 19.8,
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mmol) in THF (40 mL). The mixture stirred at rt under argon until
the colour of the azodicarboxylate had disappeared and quenched
by the addition H2O, then extracted three times with Et2O (50 ml
ꢂ3). The combined organic layers were dried over Na2SO4, ltered,
and concentrated. The resulting crude was puried by ash chro-
matography on silica gel, eluting with light petroleum ether–ethyl
acetate mixture (4 : 1 v/v) to afford 4a-p-ClBn (1.87 g) as solid in 80%
yield with 71% ee. Recrystallization from 90% ethanol, the aldehyde
4a-p-ClBn (930 mg) was obtained in 97% ee (50% yield). [a]2D0 9.72 (c
0.29, CHCl3). 1H NMR (400 MHz, CDCl3) d 1.34 (s, 3H, CH3), 3.60–
3.77 (m, 2H, CH2), 4.42 (s, 2H, CH2), 5.01–5.15 (m, 4H, 2CH2), 6.70
(s, 1H, NH), 7.16–7.30 (m, 13H, Har), 9.55 (s, 1H, CHO); HRMS calcd
for C27H27N2O6Cl2 [M + H]+ 545.12407, found 545.12390; HPLC
(Daicel Chiralpak AD-H, hexane/isopropanol ¼ 85 : 15, ow rate 1.0
mL minꢁ1, l ¼ 213 nm): tR ¼ 21.62 min (major), tR ¼ 23.77 min
(minor).
NaBH4 (190 mg, 5.0 mmol) was added to a solution of 4a-p-ClBn
(900 mg, 1.65 mmol) in CH2Cl2/C2H5OH (4 mL). The reaction
mixture was stirred for 1 h, and then it was quenched by adding 1 M
HCl aq. until the mixture reached pH 7, and it was extracted with
CH2Cl2. The combined organic phases were dried over Na2SO4, and
the solvent was evaporated under reduced pressure. The resulting
crude was puried by ash chromatography on silica gel eluted with
light petroleum ether–ethyl acetate mixture (4 : 1 v/v) to afford 5a-p-
ClBn (650 mg) in 94% yield with >99% ee. As oil; [a]2D0 ꢁ12.3 (c 0.13,
CHCl3); 1H NMR (400 MHz, CDCl3) d 1.24 (s, 3H, CH3), 3.26 (d, 1H, J
¼ 8.0 Hz, CH), 3.43 (d, 1H, J ¼ 12.0 Hz, CH), 4.05 (d, 1H, J ¼ 8.0 Hz,
CH), 4.32 (d, 1H, J ¼ 8.0 Hz, CH), 4.49 (s, 2H, CH2), 5.06 (s, 2H, CH2),
6.49 (bs, 1H, NH), 7.24–7.36 (m, 10H, Har);13C NMR (100 MHz,
CDCl3) d 19.8, 61.2, 67.2, 71.4, 71.7, 73.2, 127.8, 128.2, 128.5, 128.7,
128.8, 129.6, 134.0, 134.3, 137.3, 156.0, 156.7; HRMS calcd for
C20H22N2O5Cl [M + H]+ 405.1212, found 405.1204; HPLC (Daicel
Chiralpak OD-H, hexane/isopropanol ¼ 90 : 10, ow rate 1.0
mL minꢁ1, l ¼ 213 nm): tR ¼ 27.77 min (major), tR ¼ 35.0 min
(minor).
Scheme 1 Synthesis of the a-substituted alaninol compound as S1P1
agonist.
29.7, 61.2, 62.5, 71.4, 71.8, 73.2, 127.8, 128.1, 128.7, 137.4, 156.3,
156.7; HRMS calcd for C15H21N2O5 [M + H]+ 309.1445, found
309.1442; HPLC (Daicel Chiralpak OD-H, hexane/isopropanol ¼
90 : 10, ow rate 1.0 mL minꢁ1, l ¼ 254 nm): tR ¼ 16.37 min
(major), tR ¼ 20.63 min (minor), 57% ee.
3-(4-Chloro)benzyloxycarbonylamino-4-methyl-4-(4-methyl)
benzyloxy-oxazolidin-2-one (5b-Bn)
3-Benzyloxycarbonylamino-4-methyl-4-benzyloxy-oxazolidin-2-one
(5a-Bn)
1
Oil, yield 54%; H NMR (400 MHz, CDCl3) d 1.24 (s, 3H, CH3),
2.29 (s, 3H, CH3), 3.24 (d, 1H, J ¼ 12.0 Hz, CH), 3.40 (d, 1H, J ¼
12.0 Hz, CH), 3.99 (d, 1H, J ¼ 8.0 Hz, CH), 4.31 (d, 1H, J ¼ 8.0 Hz,
CH), 4.40–4.48 (m, 2H, CH2), 5.12 (s, 2H, CH2), 6.39 (bs, 1H,
NH), 7.13–7.18 (m, 4H, Har), 7.31–7.37 (m, 5H, Har); 13C NMR
(100 MHz, CDCl3) d 19.8, 21.2, 61.2, 68.0, 71.3, 71.4, 73.0, 73.1,
128.1, 128.2, 128.5, 128.6, 129.2, 129.4, 134.3, 135.4, 138.0,
156.2, 156.7; HRMS calcd for C21H25N2O5 [M + H]+ 385.1758,
found 385.1738; HPLC (Daicel Chiralpak AD-H, hexane/
isopropanol ¼ 90 : 10, ow rate 1.0 mL minꢁ1, l ¼ 254 nm):
tR ¼ 22.42 min (major), tR ¼ 25.10 min (minor), 48% ee.
1
Oil, yield 81%; H NMR (400 MHz, CDCl3) d 1.26 (s, 3H, CH3),
3.27 (d, 1H, J ¼ 12.0 Hz, CH), 3.44 (d, 1H, J ¼ 12.0 Hz, CH), 4.06
(d, 1H, J ¼ 12.0 Hz, CH), 4.32 (d, 1H, J ¼ 12.0 Hz, CH), 4.46 (s,
2H, CH2), 5.14 (s, 2H, CH2), 6.38 (bs, 1H, NH), 7.24–7.35 (m,
10H, Har); 13C NMR (100 MHz, CDCl3) d 19.8, 61.2, 68.1, 71.4,
71.7, 73.2, 127.8, 128.2, 128.3, 128.5, 128.6, 128.7, 135.3, 127.3,
156.1, 156.7; HRMS calcd for C20H23N2O5 [M + H]+ 371.1602,
found 371.1591; HPLC (Daicel Chiralpak OD, hexane/
isopropanol ¼ 90 : 10, ow rate 1.0 mL minꢁ1, l ¼ 254 nm):
tR ¼ 17.15 min (major), tR ¼ 25.28 min (minor) 69% ee.
3-(4-Chloro)benzyloxycarbonylamino-4-methyl-4-(4-methyl)
3-(4-Chloro)benzyloxycarbonylamino-4-methyl-4-benzyloxy-
benzyloxy-oxazolidin-2-one (5b-p-ClBn)
oxazolidin-2-one (5a-p-ClBn)
Oil, yield 56%; 1H NMR (400 MHz, CDCl3) d 1.23 (s, 3H, CH3), 2.30
Catalyst 1d (64 mg, 15 mol% in respect to the azodicarboxylate) was (s, 3H, CH3), 3.24 (d, 1H, J ¼ 12.0 Hz, CH), 3.39 (d, 1H, J ¼ 12.0 Hz,
added to a suspension of 3-(benzyloxy)-2-methylpropanal (1.15 g, CH), 4.04 (d, 1H, J ¼ 8.0 Hz, CH), 4.31 (d, 1H, J ¼ 12.0 Hz, CH), 4.39–
6.46 mmol) and di-p-chlorobenzyl azodicarboxylate (1.58 g, 4.31 4.49 (m, 2H, CH2), 5.08 (s, 2H, CH2), 6.22 (bs, 1H, NH), 7.13–7.16 (m,
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4H, Har), 7.26 (d, 2H, J ¼ 8.0 Hz, Har), 7.32 (d, 2H, J ¼ 8.0 Hz, Har); Har), 7.30 (d, 2H, J ¼ 8.0 Hz, Har), 7.40 (bs, 5H, Har); 13C NMR
13C NMR (100 MHz, CDCl3) d 19.8, 21.2, 61.2, 67.2, 71.2, 71.4, 73.0, (100 MHz, CDCl3) d 19.8, 60.4, 68.1, 71.4, 71.9, 72.5, 115.7,
128.1, 128.8, 129.4, 129.6, 133.9, 134.2, 134.4, 138.1, 156.0, 156.7; 128.2, 128.5, 128.6, 129.4, 129.5, 132.5, 133.2, 135.2, 156.2,
HRMS calcd for C21H24N2O5Cl [M + H]+ 419.1368, found 419.1359; 156.7; HRMS calcd for C20H22N2O5F [M + H]+ 389.1507, found
HPLC (Daicel Chiralpak AD-H, hexane/isopropanol ¼ 90 : 10, ow 389.1502; HPLC (Daicel Chiralpak AD-H, hexane/isopropanol ¼
rate 1.0 mL minꢁ1, l ¼ 254 nm): tR ¼ 23.38 min (major), tR
¼
90 : 10, ow rate 1.0 mL minꢁ1, l ¼ 254 nm): tR ¼ 22.44 min
(major), tR ¼ 24.32 min (minor), 68% ee.
26.35 min (minor), 54% ee.
3-Benzyloxycarbonylamino-4-methyl-4-(3,4-dimethoxy)
benzyloxy-oxazolidin-2-one (5c-Et)
3-(4-Chloro)benzyloxycarbonylamino-4-methyl-4-(4-uoro)
benzyloxy-oxazolidin-2-one (5d-p-ClBn)
Oil, yield 78%; 1H NMR (400 MHz, CDCl3) d 1.20 (m, 6H, 2 CH3), Oil, yield 89%; 1H NMR (400 MHz, CDCl3) d 1.24 (s, 3H, CH3), 3.24
3.21 (d, 1H, J ¼ 8.0 Hz, CH), 3.40 (d, 1H, J ¼ 8.0 Hz, CH), 3.82 (s, (d, 1H, J ¼ 8.0 Hz, CH), 3.43 (d, 1H, J ¼ 12.0 Hz, CH), 4.04 (d, 1H, J ¼
3H, CH3), 3.84 (s, 3H, CH3), 4.01 (d, 1H, J ¼ 8.0 Hz, CH), 4.08– 8.0 Hz, CH), 4.30 (d, 1H, J ¼ 8.0 Hz, CH), 4.40–4.48 (m, 2H, CH2),
4.13 (m, 2H, CH2), 4.28 (d, 1H, J ¼ 8.0 Hz, CH), 4.37–4.44 (m, 2H, 5.07 (s, 2H, CH2), 6.84 (bs, 1H, NH), 7.00 (t, 2H, J ¼ 8.0 Hz, Har),
CH2), 6.45 (bs, 1H, NH), 6.76–6.80 (m, 3H, Har); 13C NMR (100 7.21–7.25 (m, 2H, Har), 7.30 (d, 2H, J ¼ 12.0 Hz, Har); 13C NMR (100
MHz, CDCl3) d 14.3, 14.5, 19.7, 55.8, 55.9, 61.2, 62.4, 71.3, 71.4, MHz, CDCl3) d 19.7, 61.2, 67.3, 71.4, 71.8, 72.5, 115.4, 115.7, 128.8,
72.9, 110.9, 111.0, 120.3, 130.0, 148.9, 149.3, 156.3, 156.9; HRMS 129.0, 129.4, 129.5, 133.1, 133.2, 134.0, 134.2, 156.1, 156.8, 161.3,
calcd for C17H24N2O7Na [M + Na]+ 391.1476, found 391.1471; 163.7; HRMS calcd for C20H21N2O5ClF [M + H]+ 423.1118, found
HPLC (Daicel Chiralpak OD-H, hexane/isopropanol ¼ 90 : 10, 423.1104; HPLC (Daicel Chiralpak AD-H, hexane/isopropanol ¼
ow rate 1.0 mL minꢁ1, l ¼ 254 nm): tR ¼ 21.88 min (major), tR 90 : 10, ow rate 1.0 mL minꢁ1, l ¼ 254 nm): tR ¼ 36.19 min
¼ 27.05 min (minor), 38% ee.
(major), tR ¼ 45.33 min (minor), 70% ee.
3-Benzyloxycarbonylamino-4-methyl-4-(3,4-dimethoxy)
benzyloxy-oxazolidin-2-one (5c-Bn)
3-Ethyloxycarbonylamino-4-methyl-4-(4-chloro)benzyloxy-
oxazolidin-2-one (5e-Et)
1
Oil, yield 67%; 1H NMR (400 MHz, CDCl3) d 1.22 (s, 3H, CH3), 3.22 White solid, yield 78%, mp 80–85 C; H NMR (400 MHz, CDCl3)
(d, 1H, J ¼ 8.0 Hz, CH2), 3.40 (d, 1H, J ¼ 12.0 Hz, CH2), 3.80 (s, 3H, d 1.25 (m, 6H, 2CH3), 3.27 (d, 1H, J ¼ 8.0 Hz, CH), 3.48 (d, 1H, J ¼
CH3), 3.84 (s, 3H, CH3), 4.03 (d, 1H, J ¼ 8.0 Hz, CH), 4.30 (d, 1H, J ¼ 12.0 Hz, CH), 4.06 (d, 1H, J ¼ 8.0 Hz, CH), 4.17 (q, 2H, J ¼ 16 Hz,
8.0 Hz, CH), 4.41 (m, 2H, CH2), 5.11 (s, 2H, CH2), 6.347 (bs, 1H, NH), 8 Hz, CH2), 4.32 (d, 1H, J ¼ 8.0 Hz, CH), 4.47–4.48 (m, 2H, CH2), 6.39
6.79–6.82 (m, 3H, Har), 7.25–7.35 (m, 5H, Har); 13C NMR (100 MHz, (bs, 1H, NH), 6.76–6.80 (m, 4H, Har); 13C NMR (100 MHz, CDCl3)
CDCl3) d 19.7, 55.9, 61.3, 68.0, 71.3, 71.4, 72.9, 111.0, 120.3, 128.2, d 14.3, 19.8, 61.2, 62.6, 71.4, 72.1, 72.5, 128.8, 129.0, 133.9, 135.9,
128.4, 128.6, 129.9, 135.4, 148.9, 149.3, 156.2, 156.9; HRMS calcd for 156.3, 156.7; HRMS calcd for C15H20N2O5Cl [M + H]+ 343.1055,
C22H26N2O7Na [M + H]+ 453.1632, found 453.1638; HPLC (Daicel found 343.1048; HPLC (Daicel Chiralpak OJ-H, hexane/isopropanol
Chiralpak AD-H, hexane/isopropanol ¼ 85 : 15, ow rate 1.0 ¼ 90 : 10, ow rate 1.0 mL minꢁ1, l ¼ 254 nm): tR ¼ 32.27 min
mL minꢁ1, l ¼ 254 nm): tR ¼ 26.31 min (major), tR ¼ 32.42 min (major), tR ¼ 37.97 min (minor), 57% ee.
ꢀ
(minor), 45% ee.
3-Benzyloxycarbonylamino-4-methyl-4-(4-chloro)benzyloxy-
3-Ethyloxycarbonylamino-4-methyl-4-(4-triuoro)benzyloxy-
oxazolidin-2-one (5e-Bn)
White solid, yield 63%; mp 75–80 ꢀC; 1H NMR (400 MHz, CDCl3)
oxazolidin-2-one (5d-Et)
White solid, yield 75%; 1H NMR (400 MHz, CDCl3) d 1.21–1.26 (m, d 1.26 (s, 3H, CH3), 3.25 (d, 1H, J ¼ 8.0 Hz, CH), 3.45 (d, 1H, J ¼
6H, 2 CH3), 3.26 (d, 1H, J ¼ 12.0 Hz, CH), 3.46 (d, 1H, J ¼ 8.0 Hz, 8.0 Hz, CH), 4.06 (d, 1H, J ¼ 8.0 Hz, CH), 4.31 (d, 1H, J ¼ 8.0 Hz,
CH), 4.04 (d, 1H, J ¼ 8.0 Hz, CH), 4.13 (m, 2H, CH2), 4.30 (d, 1H, J ¼ CH), 4.41–4.49 (m, 2H, CH2), 5.13 (s, 2H, CH2), 6.60 (bs, 1H,
12.0 Hz, CH), 4.43–4.50 (m, 2H, CH2), 6.61 (bs, 1H, NH), 6.70–7.04 NH), 7.19 (d, 2H, J ¼ 8.0 Hz, Har), 7.29–7.37 (m, 7H, Har); 13C
(m, 2H, Har), 7.22–7.26 (m, 2H, Har); 13C NMR (100 MHz, CDCl3) NMR (100 MHz, CDCl3) d 19.8, 60.4, 61.2, 68.1, 71.4, 71.7, 72.1,
d 14.3, 19.7, 61.2, 62.5, 71.4, 71.9, 72.5, 115.4, 115.6, 129.4, 129.5, 72.5, 127.8, 128.2, 128.5, 128.7, 128.8, 129.0, 133.9, 135.3, 135.9,
133.2, 156.4, 156.8, 161.3, 163.7; HRMS calcd for C15H20N2O5F [M + 156.2, 156.7; HRMS calcd for C20H22N2O5Cl [M + H]+ 405.1212,
H]+ 327.1351, found 327.1341; HPLC (Daicel Chiralpak AS-H, found 405.1201; HPLC (Daicel Chiralpak AD-H, hexane/
hexane/isopropanol ¼ 80 : 20, ow rate 1.0 mL minꢁ1, l ¼ 254 isopropanol ¼ 90 : 10, ow rate 1.0 mL minꢁ1, l ¼ 254 nm):
nm): tR ¼ 51.09 min (major), tR ¼ 76.63 min (minor), 56% ee.
tR ¼ 16.12 min (major), tR ¼ 17.62 min (minor), 59% ee.
3-Benzyloxycarbonylamino-4-methyl-4-(4-uoro)benzyloxy-
oxazolidin-2-one (5d-Bn)
3-Benzyloxycarbonylamino-4-methyl-4-(4-bromo)benzyloxy-
oxazolidin-2-one (5f-Bn)
1
1
ꢀ
Oil, yield 80%; H NMR (400 MHz, CDCl3) d 1.33 (s, 3H, CH3), White solid, yield 79%; mp 80–84 C; H NMR (400 MHz, CDCl3)
3.32 (d, 1H, J ¼ 8.0 Hz, CH), 3.51 (d, 1H, J ¼ 8.0 Hz, CH), 4.12 (d, d 1.33 (s, 3H, CH3), 3.32 (d, 1H, J ¼ 8.0 Hz, CH), 3.52 (d, 1H, J ¼
1H, J ¼ 4.0 Hz, CH), 4.37 (d, 1H, J ¼ 8.0 Hz, CH), 4.51 (s, 2H, 8.0 Hz, CH), 4.12 (d, 1H, J ¼ 8.0 Hz, CH), 4.37 (d, 1H, J ¼ 8.0 Hz,
CH2), 5.21 (s, 2H, CH2), 6.42 (bs, 1H, NH), 7.08 (t, J ¼ 4.0 Hz, 2H, CH), 4.49–4.50 (m, 2H, CH2), 5.20 (s, 2H, CH2), 6.49 (bs, 1H, NH),
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7.19 (d, 2H, J ¼ 4.0 Hz, Har), 7.40 (m, 5H, Har), 7.52 (d, 2H, J ¼ (d, 1H, J ¼ 8.0 Hz, CH), 4.34 (d, 1H, J ¼ 8.0 Hz, CH), 4.51–4.60
8.0 Hz, Har); 13C NMR (100 MHz, CDCl3) d 19.7, 61.2, 68.1, 71.4, 72.2, (m, 2H, CH2), 5.09 (s, 2H, CH2), 6.62 (bs, 1H, NH), 7.25 (d, 2H, J
72.5, 121.9, 128.2, 128.5, 128.7, 129.3, 131.7, 135.4, 136.5, 156.3, ¼ 4.0 Hz, Har), 7.31 (d, 2H, J ¼ 8.0 Hz, Har), 7.37 (d, 2H, J ¼
156.7; HRMS calcd for C20H22N2O5Br [M + H]+ 449.0707, found 8.0 Hz, Har), 7.59 (d, 2H, J ¼ 8.0 Hz, Har); 13C NMR (100 MHz,
449.0710; HPLC (Daicel Chiralpak AD-H, hexane/isopropanol ¼ CDCl3) d 19.7, 61.2, 67.3, 71.4, 72.5, 120.0, 122.7, 125.4, 125.5,
85 : 15, ow rate 1.0 mL minꢁ1, l ¼ 254 nm): tR ¼ 19.46 min 125.6, 125.7, 127.5, 128.9, 133.8, 134.5, 141.4, 156.1, 156.7;
(major), tR ¼ 21.85 min (minor), 59% ee.
HRMS calcd for C21H21N3O5Cl [M + H]+ 430.1164, found
430.1159; HPLC (Daicel Chiralpak AD-H, hexane/isopropanol ¼
85 : 15, ow rate 1.0 mL minꢁ1, l ¼ 254 nm): tR ¼ 50.46 min
(major), tR ¼ 57.77 min (minor), 62% ee.
4-Chlorobenzyl(4-(((4-bromobenzyl)oxy)methyl)-4-methyl-
2-oxooxazolidin-3-yl)carbamate (5f-p-ClBn)
1
Oil, yield 75%; H NMR (400 MHz, CDCl3) d 1.27 (s, 3H, CH3),
3-Ethyloxycarbonylamino-4-methyl-4-(4-triuoro)benzyloxy-
3.27 (d, 1H, J ¼ 10 Hz, CH), 3.45 (d, 1H, J ¼ 10 Hz, CH), 4.08 (d,
1H, J ¼ 8.0 Hz, CH), 4.32 (d, 1H, J ¼ 8.0 Hz, CH), 4.45 (s, 2H,
CH2), 5.11 (s, 2H, CH2), 6.27 (bs, 1H, NH), 7.14 (d, 2H, J ¼ 8.0 Hz,
Har), 7.27 (d, 2H, J ¼ 8.0 Hz, Har), 7.33 (d, 2H, J ¼ 8.0 Hz, Har),
7.47 (d, 2H, J ¼ 8.0 Hz, Har); 13C NMR (100 MHz, CDCl3) d 19.7,
61.2, 68.1, 71.4, 72.2, 72.5, 121.9, 128.2, 128.5, 128.7, 129.3,
131.7, 135.4, 136.5, 156.3, 156.7; HRMS calcd for C20H21N2O5-
ClBr [M + H]+ 483.0317, found 483.0315; HPLC (Daicel Chir-
alpak AD-H, hexane/isopropanol ¼ 85 : 15, ow rate 1.0
mL minꢁ1, l ¼ 254 nm): tR ¼ 22.65 min (major), tR ¼ 27.78 min
(minor), 59% ee.
oxazolidin-2-one (5h-Et)
White solid, yield 76%; 1H NMR (400 MHz, CDCl3) d 1.23 (t, 3H,
J ¼ 8.0 Hz, CH3), 1.29 (s, 3H, CH3), 3.31 (d, 1H, J ¼ 12.0 Hz, CH),
3.52 (d, 1H, J ¼ 12.0 Hz, CH), 4.06 (d, 1H, J ¼ 8.0 Hz, CH), 4.14
(q, 2H, J ¼ 12.0 Hz, 4 Hz, CH2), 4.34 (d, 1H, J ¼ 8.0 Hz, CH), 4.52–
4.62 (m, 2H, CH2), 6.78 (bs, 1H, NH), 7.38 (d, 2H, J ¼ 8.0 Hz,
Har), 7.58 (d, 2H, J ¼ 8.0 Hz, Har); 13C NMR (100 MHz, CDCl3)
d 14.3, 19.6, 61.2, 62.5, 71.3, 72.4, 72.5, 125.5, 127.5, 141.7,
156.4, 156.8; HRMS calcd for C16H20N2O5F3 [M + H]+ 377.1319,
found 377.1315; HPLC (Daicel Chiralpak AD-H, hexane/
isopropanol ¼ 90 : 10, ow rate 1.0 mL minꢁ1, l ¼ 254 nm):
tR ¼ 13.40 min (minor), tR ¼ 15.24 min (major), 56% ee.
3-Ethyloxycarbonylamino-4-methyl-4-(4-cyano)benzyloxy-
oxazolidin-2-one (5g-Et)
3-Benzyloxycarbonylamino-4-methyl-4-(4-triuoro)benzyloxy-
Oil, yield 81%; 1H NMR (400 MHz, CDCl3) d 1.22 (m, 6H, 2 CH3),
3.33 (d, 1H, J ¼ 8.0 Hz, CH), 3.55 (d, 1H, J ¼ 8.0 Hz, CH), 4.06 (d,
1H, J ¼ 4.0 Hz, CH), 4.11–4.16 (m, 2H, CH2), 4.34 (d, 1H, J ¼
12.0 Hz, CH), 4.51–4.62 (m, 2H, CH2), 6.892 (bs, 1H, NH), 7.36
(d, 2H, J ¼ 8.0 Hz, Har), 7.58 (d, 2H, J ¼ 8.0 Hz, Har); 13C NMR
(100 MHz, CDCl3) d 14.3, 19.6, 61.2, 62.5, 70.8, 71.3, 72.3, 72.8,
111.4, 118.8, 127.6, 130.3, 132.3, 132.4, 143.1, 156.5, 156.7;
HRMS calcd for C16H20N3O5 [M + H]+ 334.1398, found 334.1416;
HPLC (Daicel Chiralpak AD-H, hexane/isopropanol ¼ 90 : 10,
ow rate 1.0 mL minꢁ1, l ¼ 254 nm): tR ¼ 43.74 min (minor), tR
¼ 48.41 min (major), 57% ee.
oxazolidin-2-one (5h-Bn)
1
Oil, yield 89%; H NMR (400 MHz, CDCl3) d 1.27 (s, 3H, CH3),
3.30 (d, 1H, J ¼ 12.0 Hz, CH), 3.51 (d, 1H, J ¼ 8.0 Hz, CH), 4.05
(d, 1H, J ¼ 8.0 Hz, CH), 4.33 (d, 1H, J ¼ 8.0 Hz, CH), 4.49–4.59
(m, 2H, CH2), 5.12 (s, 2H, CH2), 6.87 (bs, 1H, NH), 7.25–7.38 (m,
7H, Har), 7.58 (d, 2H, J ¼ 4.0 Hz, Har); 13C NMR (100 MHz,
CDCl3) d 19.7, 61.2, 68.1, 71.4, 72.5, 72.6, 125.5, 125.6, 127.4,
128.2, 128.5, 128.6, 135.3, 141.6, 156.3, 156.8; HRMS calcd for
C
21H22N2O5F3 [M + H]+ 439.1475, found 439.1470; HPLC (Daicel
Chiralpak AS-H, hexane/isopropanol ¼ 80 : 20, ow rate 1.0
mL minꢁ1, l ¼ 254 nm): tR ¼ 29.18 min (major), tR ¼ 61.72 min
(minor), 67% ee.
3-Benzyloxycarbonylamino-4-methyl-4-(4-cyano)benzyloxy-
oxazolidin-2-one (5g-Bn)
3-(4-Chloro)benzyloxycarbonylamino-4-methyl-4-(4-triuoro)
benzyloxy-oxazolidin-2-one (5h-p-ClBn)
1
Oil, yield 71%; H NMR (400 MHz, CDCl3) d 1.27 (s, 3H, CH3),
3.31 (d, 1H, J ¼ 8.0 Hz, CH), 3.52 (d, 1H, J ¼ 8.0 Hz, CH), 4.05 (d,
1H, J ¼ 8.0 Hz, CH), 4.33 (d, 1H, J ¼ 8.0 Hz, CH), 4.48–4.58 (m,
2H, CH2), 5.10 (s, 2H, CH2), 7.09 (bs, 1H, NH), 7.25–7.35 (m, 7H,
Har), 7.55 (d, 2H, J ¼ 8.0 Hz, Har); 13C NMR (100 MHz, CDCl3)
d 19.7, 61.2, 68.1, 71.4, 72.3, 72.9, 111.5, 118.7, 127.5, 128.2,
128.5, 128.7, 132.4, 135.3, 143.0, 156.3, 156.7; HRMS calcd for
Catalyst 1d (191 mg, 15 mol% in respect to the azodicarboxylate)
was added to a suspension of 2-methyl-3-((4-(triuoromethyl)
benzyl)oxy)propanal (2.2 g, 8.93 mmol) and di-p-chlorobenzyl
azodicarboxylate (2.17 g, 5.93 mmol) in THF (50 mL). The
mixture stirred at rt under argon until the colour of the azodi-
carboxylate had disappeared and quenched by the addition
H2O, then extracted three times with Et2O (50 mL ꢂ3). The
combined organic layers were dried over Na2SO4, ltered, and
concentrated. The resulting crude was puried by ash chro-
matography on silica gel, eluting with light petroleum ether–
ethyl acetate mixture (4 : 1 v/v) to afford 4h-p-ClBn (3.27 g) as
C
21H22N3O5 [M + H]+ 396.1554, found 396.1573; HPLC (Daicel
Chiralpak AD-H, hexane/isopropanol ¼ 90 : 10, ow rate 1.0
mL minꢁ1, l ¼ 254 nm): tR ¼ 65.86 min (major), tR ¼ 69.48 min
(minor), 65% ee.
3-(4-Chloro)benzyloxycarbonylamino-4-methyl-4-(4-cyano)
benzyloxy-oxazolidin-2-one (5g-p-ClBn)
1
ꢀ
solid in 90% yield with 74% ee. Mp 145–149 C; H NMR (400
MHz, CDCl3) d 1.32 (s, 3H, CH3), 3.71–3.87 (m, 2H, CH2), 4.54 (s,
1
Oil, yield 73%; H NMR (400 MHz, CDCl3) d 1.28 (s, 3H, CH3), 2H, CH2), 5.10–5.20 (m, 4H, 2CH2), 6.71 (s, 1H, NH), 7.22–7.38
3.31 (d, 1H, J ¼ 8.0 Hz, CH), 3.50 (d, 1H, J ¼ 12.0 Hz, CH), 4.08 (m, 10H, Har), 7.62 (d, 2H, J ¼ 4.0 Hz, Har), 9.62 (s, 1H, CHO);
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HRMS calcd for C28H26N2O6Cl2F3 [M + H]+ 613.1115, found
613.1110; HPLC (Daicel Chiralpak AD-H, hexane/isopropanol ¼
85 : 15, ow rate 1.0 mL minꢁ1, l ¼ 254 nm): tR ¼ 18.00 min
(major), tR ¼ 20.29 min (minor).
Dibenzyl 1-(1-ethoxy-2-methyl-1,3-dioxopropan-2-yl)hydrazine-1,2-
dicarboxylate (4m-Bn)
Oil, yield 76%; 1H-NMR (300 MHz, CDCl3): d 1.26 (t, J ¼ 6.0 Hz,
3H, CH3), 1.56 (s, 3H, CH3), 4.18–4.22 (m, 2H, CH2), 5.16 (s, 4H,
2 CH2), 6.60 (brs, 1H, NH), 7.25–7.32 (m, 10H, Har), 9.60 (s, 1H,
CHO); HRMS calcd for C22H25N2O7 [M + H]+ 429.1653, found
429.1656; HPLC (Daicel Chiralpak OD-H, hexane/isopropanol ¼
90 : 10, ow rate 1.0 mL minꢁ1, l ¼ 254 nm): tR ¼ 20.65 min
(major), tR ¼ 22.78 min (minor), 24% ee.
Upon recrystallization from 90% ethanol, the aldehyde 4h-p-
ClBn (2.1 g) was obtained in 98% ee (65% yield). Aer reduction
and cyclization with NaBH4 (380 mg, 10 mmol), 5h-p-ClBn (1.53
g) was obtained in 95% yield with 98% ee. [a]2D0 ꢁ17.84 (c 0.7,
CHCl3); 1H NMR (400 MHz, CDCl3) d 1.34 (s, 3H, CH3), 3.36 (d,
1H, J ¼ 8.0 Hz, CH), 3.56 (d, 1H, J ¼ 8.0 Hz, CH), 4.12 (d, 1H, J ¼
4.0 Hz, CH), 4.38 (d, 1H, J ¼ 4.0 Hz, CH), 4.56–4.46 (m, 2H, CH2),
5.18 (s, 2H, CH2), 6.84 (bs, 1H, NH), 7.38–7.43 (m, 6H, Har), 7.63
(d, 2H, J ¼ 4.0 Hz, Har); 13C NMR (100 MHz, CDCl3) d 19.7, 61.2,
67.3, 71.4, 72.5, 125.4, 122.7, 125.5, 125.6, 127.5, 128.8, 129.6,
133.8, 134.4, 141.4, 156.1, 156.7; HRMS calcd for C21H21N2O5-
ClF3 [M + H]+ 473.1084, found 473.1086; HPLC (Daicel Chir-
alpak AS-H, hexane/isopropanol ¼ 70 : 30, ow rate 1.0
mL minꢁ1, l ¼ 254 nm): tR ¼ 34.57 min (major), tR ¼ 56.49 min
(minor).
(R)-3-Amino-4-(hydroxymethyl)-4-methyloxazolidin-2-one (6)
To a solution of 5h-p-ClBn (670 mg, 1.42 mmol) in 8 ml of
methanol and acetic acid (4 mL). 360 mg of 10% palladium on
charcoal was added. The mixture hydrogenated at ambient
pressure for 12 h and ltered. The ltrate was evaporated to
dryness under reduced pressure. Column chromatography on
silica gel (dichloromethane/methanol, 20 : 1 to 10 : 1) delivered
152 mg (1.03 mmol, 73%) of a colourless solid. Mp 113–115 ꢀC;
[a]2D0 ꢁ3.86 (c 0.9, CH3OH); 1H NMR (400 MHz, CDCl3) d 1.20 (s,
3H, CH3), 3.31 (dd, 1H, J ¼ 12.0 Hz, 1 Hz, CH), 3.55 (bs, 3H, NH2
and OH), 3.76–3.79 (m, 1H, CH), 3.96 (d, 1H, J ¼ 8.0 Hz, CH),
4.40 (d, 1H, J ¼ 8.0 Hz, CH); HRMS calcd for C5H11N2O3 [M + H]+
147.0762, found 147.0764.
3-Benzyloxycarbonylamino-4-methyl-4-(4-nitro)benzyloxy-
oxazolidin-2-one (5i-Bn)
1
Oil, yield 77%; H NMR (400 MHz, CDCl3) d 1.30 (s, 3H, CH3),
3.35 (d, 1H, J ¼ 12.0 Hz, CH), 3.56 (d, 1H, J ¼ 12.0 Hz, CH), 4.10
(d, 1H, J ¼ 4.0 Hz, CH), 4.36 (d, 1H, J ¼ 8.0 Hz, CH), 4.54–4.64
(m, 2H, CH2), 5.13 (s, 2H, CH2), 6.82 (bs, 1H, NH), 7.25–7.35 (m,
5H, Har), 7.41 (d, 2H, J ¼ 8.0 Hz, Har), 8.15 (d, 2H, J ¼ 12.0 Hz,
Har); 13C NMR (100 MHz, CDCl3) d 18.4, 19.8, 29.7, 30.9, 61.2,
68.2, 71.4, 72.1, 73.0, 76.7, 77.1, 77.2, 77.4, 123.8, 127.7, 128.2,
128.6, 128.7, 136.2, 144.8, 147.6, 164.2, 164.6, 207.2; HRMS
calcd for C20H22N3O7 [M + H]+ 416.1452, found 416.1435; HPLC
(Daicel Chiralpak AD-H, hexane/isopropanol ¼ 90 : 10, ow rate
(R)-4-(Hydroxymethyl)-4-methyloxazolidin-2-one (7)
146 mg (1 mmol) of NaNO2 was added dropwise to a solution
of 45.0 mg (0.234 mmol) of 6 in 18 ml of acetic acid and 6 ml of
1 M HCl. The mixture was reuxed for 1 h. The solvent was
evaporated to dryness under reduced pressure. Column
chromatography on silica gel (dichloromethane/methanol,
20 : 1 to 10 : 1) delivered 79 mg (0.6 mmol, 60%) of a white
solid. [a]2D0 ꢁ8.8 (c 0.5, CH3OH); 1H NMR (400 MHz, CDCl3)
d 1.34 (s, 3H, CH3), 3.55 (dd, 1H, J ¼ 12.0 Hz, 4 Hz, CH2), 4.04
(d, 1H, J ¼ 8.0 Hz, CH), 4.33 (d, 1H, J ¼ 8.0 Hz, CH), 5.59 (bs,
1H, NH); 13C NMR (150 MHz, CDCl3) d 22.6, 58.9, 67.5, 72.8,
159.4; HRMS calcd for C5H10NO3 [M + H]+ 132.0654, found
132.0655.
1.0 mL minꢁ1, l ¼ 254 nm): tR ¼ 72.96 min (major), tR
¼
76.57 min (minor), 55% ee.
4-Chlorobenzyl((4R)-4-methyl-2-oxo-4-(((tetrahydro-2H-pyran-
2-yl)oxy)methyl)oxazolidin-3-yl)carbamate (5j-Bn)
1
Oil, yield 70%; H NMR (400 MHz, CDCl3): d 1.26 (s, 3H, CH3),
1.41–1.56 (m, 4H, 2 CH2), 1.60–1.74 (m, 4H, CH2), 3.34–3.84 (m,
4H, CH2), 4.05–4.11 (m, 1H, CH), 4.33–4.38 (m, 1H, CH), 4.43–
4.55 (m, 1H, CH), 5.14 (s, 2H, CH2), 6.93 (bs, 1H, NH), 7.26–7.33 40-(2-Propyloxazol-4-yl)-[1,10-biphenyl]-4-carbaldehyde (11)
(m, 5H, Har); HRMS calcd for C18H24N2O6Na [M + Na]+ 387.1527,
Catalyst Pd-dimer (2.5 mg, 1 mol% in respect to 4-bromo-
found 387.1508; HPLC (Daicel Chiralpak AD-H, hexane/
benzaldehyde) was added to a suspension of 4-bromobenzalde-
isopropanol ¼ 90 : 10, ow rate 1.0 mL minꢁ1, l ¼ 254 nm):
hyde (101 mg, 0.55 mmol), K2CO3 (207 mg, 1.5 mmol) and 10
tR ¼ 26.0 min (major), tR ¼ 34.5 min (minor), 60% ee.
(157 mg, 0.5 mmol) in toluene : EtOH : H2O ¼ 1 : 1 : 1 (v/v/v). The
mixture was reuxed for 4 h. Then the solvent was removed under
Benzyl(4-ethyl-4-methyl-2-oxooxazolidin-3-yl)carbamate (5l-Bn)
vacuum. The crude material was extracted with Et2O and washed
Oil, yield 78%; 1H-NMR (600 MHz, CDCl3): d 0.86–0.96 (m, 3H, CH3), with brine. The organic phase was dried (Na2SO4) and the solvent
1.24–1.33 (s, 3H, CH3), 1.55–1.70 (m, 2H, CH2), 4.06 (d, J ¼ 6.0 Hz, was evaporated under reduced pressure. The crude product was
1H, CH), 4.20 (d, J ¼ 6.0 Hz, 1H, CH), 5.19 (s, 2H, CH2), 6.53 (bs, 1H, chromatographed (silica gel, light petroleum ether/ethyl acetate
NH), 7.26–7.38 (m, 5H, Har); 13C NMR (150 MHz, CDCl3) d 7.7, 22.1, ¼ 20 : 1) to afford the aldehyde (116 mg, 80%) as a white solid.
29.8, 53.4, 61.8, 68.2, 72.1, 128.3, 128.5, 128.6, 135.3, 156.0, 156.3; Mp 100 ꢀC; 1H NMR (400 MHz, CDCl3) d 1.04 (t, 3H, J ¼ 8.0 Hz,
HRMS calcd for C14H18N2O4Na [M + Na]+ 301.1159, found 301.1154; CH3), 1.84–1.89 (m, 2H, CH2), 2.83 (m, 2H, CH2), 7.69 (m, 2H,
HPLC (Daicel Chiralpak AD-H, hexane/isopropanol ¼ 90 : 10, ow Har), 7.78–7.85 (m, 4H, Har), 7.89 (s, 1H, Har), 7.95–8.01 (m, 4H,
rate 1.0 mL minꢁ1, l ¼ 254 nm): tR ¼ 21.53 min (major), tR
¼
Har), 10.06 (s, 1H, CHO); HRMS calcd for C19H18NO2 [M + H]+
292.1332, found 292.1335.
23.23 min (minor), 37% ee.
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(R,E)-4-Methyl-4-(2-(4'-(2-propyloxazol-4-yl)-[1,10-biphenyl]-
4-yl)vinyl)oxazolidin-2-one (12)
CH3), 1.34 (s, 3H, CH3), 1.81–1.92 (m, 2H, CH2), 2.68–2.72 (m,
2H, CH2), 2.83–2.86 (m, 2H, CH2), 3.52–3.57 (m, 2H, CH2), 3.62–
3.65 (m, 2H, CH2), 7.31 (d, 2H, J ¼ 8.0 Hz, Har), 7.58 (d, 2H, J ¼
8.0 Hz, Har), 7.65 (d, 2H, J ¼ 8.0 Hz, Har), 7.77 (d, 2H, J ¼ 8.0 Hz,
Har), 8.23 (s, 1H, Har); 13C NMR (100 MHz, CDCl3) d 14.0, 20.4,
21.6, 30.2, 30.8, 38.7, 58.8, 66.3, 127.2, 128.2, 128.3, 130.0, 136.0,
139.9, 140.7, 141.9, 142.1, 167.8; HRMS calcd for C23H29N2O2 [M
+ H]+ 365.2224, found 365.2212.
To a suspension of the phosphonium salt (235 mg, 0.48 mmol)
in THF was added n-butyllithium (2.5 M in hexane, 0.37 mL,
0.937 mmol) at ꢁ78 ꢀC and then the solution was stirred for
30 min at the same temperature. Aer the addition of benzal-
dehyde (70 mg, 0.24 mmol) at ꢁ78 ꢀC, the reaction mixture was
warmed to ambient temperature and stirred for 3 h. Aer
quenching with saturated aq. NH4Cl, the resulting biphasic
mixture was extracted with AcOEt. The combined organic layer
was washed with water and brine, dried over Na2SO4, ltered,
and evaporated. Purication by silica gel column chromatog-
raphy (hexane : AcOEt ¼ 4 : 1 to 1 : 1) provided 12 (131 mg,
73%) as a white solid. Mp 235 ꢀC; [a]D20 ꢁ17.8 (c 0.1, CH3OH); 1H
NMR (400 MHz, CDCl3) d 1.03 (t, 3H, J ¼ 8.0 Hz, CH3), 1.81–1.90
(m, 2H, CH2), 2.82 (t, 2H, J ¼ 8.0 Hz, CH2), 4.17–4.21 (m, 1H,
CH), 4.58–4.65 (m, 2H, CH2), 5.12 (s, 1H, NH), 6.16–6.22 (m, 1H,
CH), 6.66 (d, 1H, J ¼ 16.0 Hz, CH), 7.46 (d, 2H, J ¼ 8.0 Hz, Har),
7.59–7.65 (m, 4H, Har), 7.80 (d, 2H, J ¼ 8.0 Hz, Har), 7.87 (s, 1H,
Har); 13C NMR (100 MHz, CDCl3) d 13.7, 20.7, 30.2, 56.2, 70.2,
125.9, 126.3, 127.2, 127.3, 130.6, 133.2, 133.7, 134.3, 139.6,
140.1, 140.9, 158.9, 165.5; HRMS calcd for C24H25N2O3 [M + H]+
389.1860, found 389.1882.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This work was nancially supported by the Drug Innovation
Major Project (No. 2018ZX09711001-005-012), National Key R&D
Program of China (No. 2018YFC1706403) and CAMS Innovation
Fund for Medical Sciences (No. 2016-I2M-2-002).
Notes and references
¨
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(R)-4-Methyl-4-(2-(40-(2-propyloxazol-4-yl)-[1,10-biphenyl]-4-yl)ethyl)
oxazolidin-2-one (13)
To a solution of 12 (120 mg, 0.32 mmol) in methanol was added
10% Pd/C (30 mg), and then the suspension was stirred for 2 h
under a hydrogen atmosphere at ambient temperature. The
reaction mixture was ltered and evaporated in vacuo, providing
the product 13 (112 mg, 92%) as a white solid. Mp 185 ꢀC;
[a]2D0 14.4 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.04 (t, 3H,
J ¼ 8.0 Hz, CH3), 1.44 (s, 3H, CH3), 1.84–1.89 (m, 2H, CH2), 1.93–
1.97 (m, 2H, CH2), 2.70–2.74 (m, 2H, CH2), 2.75–2.86 (m, 2H,
CH2), 4.10 (d, 1H, J ¼ 8.0 Hz, CH), 4.22 (d, 1H, J ¼ 8.0 Hz, CH),
5.42 (bs, 1H, NH), 7.25 (d, 1H, J ¼ 8.0 Hz, CH), 7.55 (d, 1H, J ¼
8.0 Hz, CH), 7.61 (d, 2H, J ¼ 8.0 Hz, Har), 7.79 (m, 2H, J ¼ 8.0 Hz,
Har), 7.86 (s, 1H, Har); 13C NMR (100 MHz, CDCl3) d 13.7, 20.6,
26.0, 30.0, 30.1, 42.2, 57.6, 75.6, 125.9, 127.2, 127.3, 128.7, 129.8,
133.2, 138.8, 139.8, 139.9, 140.3, 158.7, 165.6; HRMS calcd for
C
24H27N2O3 [M + H]+ 391.2016, found 391.2011.
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¨
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1
33504 | RSC Adv., 2019, 9, 33497–33505
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Paper
RSC Advances
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RSC Adv., 2019, 9, 33497–33505 | 33505