Novel approach to stereoselective synthesis of (E)/(Z)-(N-acyl-oxazolidinone)-eneglycinates

Article abstract of DOI:10.1007/s11164-013-1225-x

(E)-(N-Acyl-oxazolidinone)-eneglycinates were synthesized with high stereoselectivity and in good yield by condensation of aldehydes with glycinates. (Z)-Eneglycinates could be prepared in high purity and moderate yield by transformation of (E)-eneglycinates under mild conditions. The effect on the (E)/(Z)-configuration of eneglycinates of steric hindrance by ?±-substituents on the aldehyde was also examined. The software MMFF94 was used to explain the transformation of the thermodynamic product into the kinetic product and a plausible mechanism is given.

Full text of DOI:10.1007/s11164-013-1225-x

Res Chem Intermed
DOI 10.1007/s11164-013-1225-x
Novel approach to stereoselective synthesis
of (E)/(Z)-(N-acyl-oxazolidinone)-eneglycinates
•
Yanyan Zhang Haopeng Sun Qidong You
•
Received: 19 February 2013 / Accepted: 20 April 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract (E)-(N-Acyl-oxazolidinone)-eneglycinates were synthesized with high
stereoselectivity and in good yield by condensation of aldehydes with glycinates.
(Z)-Eneglycinates could be prepared in high purity and moderate yield by trans-
formation of (E)-eneglycinates under mild conditions. The effect on the (E)/(Z)-
configuration of eneglycinates of steric hindrance by a-substituents on the aldehyde
was also examined. The software MMFF94 was used to explain the transformation
of the thermodynamic product into the kinetic product and a plausible mechanism is
given.
Keywords Eneglycinates Á Stereoselectivity Á Steric hindrance Á Configuration
Introduction
Nitrogen-containing heterocycles, for example pyrazoles, pyrimidines, and pyrroles
[1–6], are important intermediates in the synthesis of a variety of biologically active
natural products and pharmaceutical drugs. (E)/(Z) substituted enamine derivatives
are vital synthons for these azaheterocycles. Diverse approaches have been developed
for construction of (E)/(Z) substituted enamine derivatives. Sabrina Buchini’s group
used commercially available propionaldehyde diethyl acetal to prepare the key
intermediate (E)-3-dimethylamino-2-methylprop-2-enal 1 for synthesis of the target
pyrimidinone [7]; Kah Toh’s group synthesized substituted pyrrole derivatives via
Y. Zhang Á H. Sun
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry,
China Pharmaceutical University, Nanjing 210009, Jiangsu, China
Q. You (&)
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009,
China
e-mail: youqd@cpu.edu.cn; youqidong@gmail.com
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Y. Zhang et al.
preparation of the intermediates (E)/(Z)-N-allyl/propargyl enamine carboxylates 2
[8]; Alessandro Balbi’s group constructed novel pyrazole derivatives via the
intermediates (E)-b-(dimethylamino)vinyl aldehydes 3 [9] (Fig 1). These methods
suffer from such problems as harsh reaction conditions, use of toxic or expensive
reagents, tedious procedures, and low yields. Hence, there is still a demand for
versatile methods for synthesis of the important building blocks (E)/(Z)-substituted
enamine structures from accessible starting materials, with control of the selectivity
of substitution.
Herein we report preparation of new flexible (E)/(Z)-functionalized eneglycinates
(4-7) (Fig. 1) by a new facile route. 4 and 5 were obtained with high (E)/
(Z) selectivity and in high yield. 4 could be converted to 5 under specific conditions.
These new compounds could be used as useful building blocks for a variety of
biologically active natural products and pharmaceutical drugs [1–4].
Our original work focused on construction of the b-lactam ring 14 (Scheme 1)
via the compound (S)-(?)-4-phenyl-2-oxazolidinone 8 [10–18]. However, we did
not obtain any b-lactam, but enamine compounds 4 and 5 were obtained with high
(E)/(Z) selectivity and in high yield (Scheme 2).
Results and discussion
The synthesis began with N-acylation, which involved reacting (S)-(?)-4-phenyl-2-
oxazolidinone 8 with propanoyl chloride in the presence of triethylamine to afford
N-propanoyl oxazolidinone 9 [19–22] as a white solid in good yield. For the
following nucleophilic addition reaction [23–28], a titanium tetrachloride–tertiary
amine system was found to be the most effective method for generating the enolate
form, which was attacked by the electrophile trimethoxymethane [29–31] to give
the intermediate 10 in high yield (Scheme 2).
Compound 10 was hydrolyzed to give the aldehyde intermediate 15 which was
successfully condensed with glycine methyl ester hydrochloride to give eneglyci-
nates 4 (Scheme 2) in high yield. When 4 was treated with ethyl 3-hydroxybutyrate
in the presence of LiHMDS, the expected nucleophilic addition product 13 was not
Fig. 1 Reported enamine derivatives 1, 2, and 3 and new compounds 4, 5, 6, and 7
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Novel approach to stereoselective synthesis
Scheme 1 Original route for synthesis of b-lactams: (a) CH3CH2COCl, Et3N, toluene, rt *50 °C;
(b) CH(OMe)3, TiCl4, (i-Pr)2NEt, CH2Cl2, 0 °C; (c) TFA ? AcOH ? H2O 1:4:1, 25 °C; (d) glycine
methyl ester hydrochloride, NaHCO3, MgSO4, CH2Cl2, reflux; (e) ethyl 3-hydroxybutyrate, LiHMDS,
THF, rt *-20 °C
Scheme 2 Stereoselective synthesis of (E)/(Z)-eneglycinates: (a) CH3CH2COCl, Et3N, toluene,
rt *50 °C; (b) CH(OMe)3, TiCl4, (i-Pr)2NEt, CH2Cl2, 0 °C; (c)TFA ? AcOH ? H2O 1:4:1, 25 °C;
(d) glycine methyl ester hydrochloride, NaHCO3, MgSO4, CH2Cl2, reflux; (e) ethyl 3-hydroxybutyrate,
LiHMDS, THF, rt *-20 °C
obtained, but a new compound 5 was obtained. It was surprising that 5 was not
detected in the reaction of 15 to give 4, but approximately 60 % of 4 was converted
to 5 by treatment with LiHMDS and ethyl 3-hydroxybutyrate for 4 h and 40 % of 4
remained unreacted. The structures of compounds 4 and 5 were confirmed by ESI
1
MS, H NMR and 13C NMR spectroscopy, HSQC, among other techniques. They
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Y. Zhang et al.
1
have the same formula, C16H16N2O5, but their H and 13C chemical shifts of NH,
C=, and CH= (Table 1) were different, so they are geometric isomers.
As seen from Fig. 2, the (E)/(Z) configuration was determined by 1H–1H COSY.
For stereoisomer 4, no correlations were observed between H(1) and H(3). So, the
methyl group was far from the olefinic hydrogen, and 4 was the (E)-configuration.
For 5, H(2) had no correlation with H(1), but a clear correlation between H(1) and
H(3) was observed, with the coupling constant J = 1,500 MHz. So, the methyl
group was close to the olefinic hydrogen, and 5 was the (Z)-configuration.
The conditions for conversion of 4 to 5 were also studied (Table 2). When
LiHMDS was replaced by NaN(TMS)2, 5 was obtained with high selectivity (Entry
2). However, when the reaction was performed in the absence of ethyl 3-hydroxy-
butyrate, 5 could not be isolated from the reaction mixture (Entries 3 and 4).
Therefore, ethyl 3-hydroxybutyrate was a crucial component for conversion of 4 to
5.
Considering that the size of the substituents at the a-position of the aldehyde may
affect (E)/(Z) selectivity, the methyl group at the a-position of the aldehyde was
replaced by a phenyl group for further research. However, a mixture of 6 and 7 in
1:1 ratio was obtained by the same route (Scheme 3). This means that a bulky
substituent at the a-position of the aldehyde will reduce the (E)/(Z) selectivity of the
C–C double bond.
Proposed mechanism
The software MMFF94 was used to calculate the molecular mechanics and force
fields of these compounds. As shown in Fig. 3, the preferred conformations of
geometric structures of 4 and 5 exist in ‘‘non-planar’’ and ‘‘planar’’ forms (Fig. 3).
A possible mechanism was proposed for conversion of 4 to 5 (Scheme 4).
First, ethyl 3-hydroxybutyrate was treated with LiHMDS to form the complex ion
B, and (E)-4 was also attacked by LiHMDS to afford the ‘‘non-planar’’ transition
state A. The hydrogen of the complex ion B then chelated with the carbonyl group
(a) of compound 4 to give C. Intermolecular and intramolecular hydrogen bonding
then led to a conformational change forming the ‘‘planar’’ transition state D,
because of strong steric hindrance between the facial of benzene and the six-
membered ring containing imine double bond. The change in the orientation of the
carbonyl group (b) and the hydrogen bond will have a direct effect on the
Table 1 1H NMR, 13C NMR, and HSQC assignments of compounds 4 and 5 (in CDCl3)
Group
dH (4)
dC (4)
dH (5)
dC (5)
NH
C=
5.10–5.18
3.01
99.55
110.55
138.67
CH=
7.23–7.26
150.80
6.93
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Novel approach to stereoselective synthesis
Fig. 2 1H–1H COSY of compounds 4 and 5
Table 2 Effect of base on product yields
Entry
Reaction conditions
Results (yield)
1
2
3
4
LiHMDS, ethyl 3-hydroxybutyrate, rt *-20 °C.
NaN(TMS)2, ethyl 3-hydroxybutyrate, rt *-20 °C.
LiHMDS, rt *-20 °C.
(Z)-Product (60 %)
(Z)-Product (60 %)
Trace
NaN(TMS)2, rt *-20 °C .
Trace
stereochemical outcome of the reaction. Finally, through post-after the (Z)-
configuration was formed.
The preferred conformation of (Z)-7 and (E)-6 is depicted in Fig. 4 to explain the
effect of the a-phenyl group on stereoselectivity. The energy of the (E) configu-
ration, 6, (85.7 kcal/mol) was higher than that of the (Z) configuration, 7, (75.8 kcal/
mol), and the carbonyl groups of 7 and 6 were also present as the ‘‘planar’’ and
‘‘non-planar’’ forms, respectively. At reflux temperature, however, equilibrium was
achieved. So, the condensation was mainly controlled by thermodynamic factors.
That was why we could not find pure (Z)-7 or (E)-6 in the reaction mixture
(Scheme 3).
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Y. Zhang et al.
Scheme 3 Phenyl-substituted synthetic route: (a) PhCH2COOH, pivaloyl chloride, Et3N, toluene,
110 °C; (b) CH(OMe)3, TiCl4, (i-Pr)2NEt, CH2Cl2, 0 °C; (c) TFA ? AcOH ? H2O 1:4:1, 50 °C;
(d) glycine methyl ester hydrochloride, NaHCO3, MgSO4, CH2Cl2, reflux
Fig. 3 Geometric structures (MMFF94) and conformations of 4 and 5
Experimental
General information
Unless otherwise indicated, chemicals and solvents were purchased from commer-
cial suppliers and were used without further purification. For thin-layer chroma-
tography (TLC), silica gel plates (GF254) were used and compounds were
visualized by irradiation with UV light. 1H NMR and 13C NMR spectra were
measured on a Bruker AV-300 or Bruker AV-500 instrument with TMS as internal
standard. All chemical shifts (d) are given in parts per million. Data are reported as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, or m = multiplet). Melting points were determined with a Melt-Temp
II apparatus and are reported without correction. IR spectra were recorded on a
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Novel approach to stereoselective synthesis
Scheme 4 Possible mechanism for conversion of 4 to 5
Fig. 4 (Color figure online) Geometric structures (MMFF94) of compounds 6 and 7
Nicolet iS10 Avatar FT-IR spectrometer, as KBr disks. High-resolution mass
spectra (HRMS) were recorded on a Waters Q-TOF micro mass spectrometer.
General synthesis of intermediates and target compounds
(S)-4-Phenyl-3-propionyloxazolidin-2-one (9)
(S)-(?)-4-Phenyl-2-oxazolidinone 8 (50 g, 307 mmol), propanoyl chloride (48.2 g,
521 mmol), and toluene (250 mL) were mixed at room temperature and Et3N
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Y. Zhang et al.
(55.8 g, 552 mmol) was added dropwise. The reaction mixture was stirred at 50 °C
for 1 h. When reaction was complete it was quenched with 5 % NaHCO3 then
extracted with EtOAc. The organic phase was washed with water and brine, dried
over Na2SO4, and concentrated under reduced pressure. Isopropyl alcohol (30 mL)
was added into the residue at 0–5 °C and the precipitated solid was isolated by
filtration to give the product as a white powder (55 g), yield 81 %. m.p. 77–79 °C;
[a]2D0 ?70.3 (c, 0.40, CHCl3); 1H NMR (300 MHz, CDCl3) d (ppm): 1.11 (t,
J = 7.3 Hz, 3H), 2.87–3.03 (m, 2H), 4.28 (dd, J = 3.4, 8.8 Hz, 1H), 4.69 (dd,
J = 8.8, 8.8 Hz, 1H), 5.42 (dd, J = 3.4, 8.8 Hz, 1H), 7.26–7.40 (m, 5H); HRMS
(ESI) calcd for C12H14NO3 (M ? H)?: 220.0974, found: 220.0974.
(S)-3-(3,3-Dimethoxy-2-methylpropanoyl)-4-phenyloxazolidin-2-one (10)
TiCl4 (28 g, 15 mmol) and DIPEA (19 g, 15 mmol) were added dropwise at 0 °C to
compound 6 (30 g, 148 mmol) in CH2Cl2 (300 mL). The solution was maintained at
this temperature for 30 min then CH(OMe)3 (18.8 g, 178 mmol) was added. The
mixture was warmed to room temperature and stirred for 3 h. After dilution with
EtOAc, the organic phase was washed with saturated brine, dried, and concentrated
under vacuum. The crude product (40 g, 99 %) was obtained as a white solid and
used directly in the next step without purification. A pure sample was obtained by
crystallization from isopropyl alcohol. m.p. 73–75 °C; [a]2D0 ?42.2 (c, 0.11, CHCl3);
1H NMR (300 MHz CDCl3) d (ppm): 1.16 (d, J = 6.3 Hz, 3H), 3.16 (s, 3H), 3.29
(s, 3H), 4.20–4.26 (dd, J = 4.7, 8.9 Hz, 1H), 4.34–4.42 (m, 2H), 4.68 (dd, J = 8.9,
8.9 Hz, 1H), 5.46 (dd, J = 4.7, 8.9 Hz, 1H), 7.29–7.38 (m, 5H); 13C NMR
(75 MHz, CDCl3) d (ppm): 10.33, 38.27, 49.49, 53.41, 55.59, 67.42, 74.46, 74.89,
75.31, 103.88, 123.78, 126.30, 126.73, 136.47, 151.33, 171.70; IR (KBr): 2972,
2937, 2836, 1652, 1782, 1698, 1041, 946, 760, 703 cm-1; HRMS (ESI) calcd for
C15H19NNaO5 (M ? Na)?: 316.1161, found: 316.1165.
2-Methyl-3-oxo-3-((S)-2-oxo-4-phenyloxazolidin-3-yl)propanal (15)
Compound 10 (5.9 g, 20 mmol) was dissolved in 50 mL of a 4:1:1 mixture of
AcOH, TFA, and H2O at 35 °C and the solution was stirred for 6 h. After dilution
with EtOAc, the organic phase was washed with saturated NaHCO3 and brine, dried
over Na2SO4, and concentrated under vacuum. The crude product was obtained as a
white foam (4.9 g, 98 %) and used without purification in the next step. A pure
sample was obtained by chromatography on silica gel (eluent: hexane–EtOAc 3:1).
1
m.p. 107–108 °C; [a]2D0 ?78.9 (c, 0.11, CHCl3); H NMR (300 MHz, CDCl3) d
(ppm): 1.34 (dd, J = 3.5, 3.6 Hz, 3H), 4.26–4.35 (m, 1H), 4.64 (q, J = 7.3 Hz, 1H),
4.71–4.78 (m, 1H), 5.44–5.50 (m, 1H), 7.26–7.42 (m, 5H), 9.68 (s, 1H); 13C NMR
(75 MHz, CDCl3) d (ppm): 8.92, 9.29, 50.96, 50.99, 56.69, 56.81, 69.29, 69.39,
124.82, 124.94, 127.74, 127.86, 128.21, 128.25, 137.39, 137.76, 152.81, 167.88,
168.12, 195.26, 195.72; IR (KBr): 3449, 3134, 2944, 2845, 1788, 1739, 1689, 1059,
940, 757, 700 cm-1; HRMS (ESI) calcd for C13H14NO4 (M ? H)?: 248.0923,
found: 248.0925.
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Novel approach to stereoselective synthesis
Preparation of (S,E)-methyl 2-[2-(2-oxo-4-phenyloxazolidine-3-carbonyl)prop-1-
enylamino]acetate (4)
A mixture of aldehyde intermediate 15 (7 g, 28 mmol), NaHCO3 (7.1 g,
85 mmol), MgSO4 (11.9 g, 99 mmol), and glycine methyl ester hydrochloride
(4.2 g, 34 mmol) was dissolved in CH2Cl2 (70 mL). The mixture was heated under
reflux, with stirring, for 3 h. The mixture was then filtered and the filtrate was
concentrated to give the product as a white foam (6.8 g), yield: 97 %. m.p.
124–125 °C; [a]2D0 ?46.9 (c, 0.10, CHCl3); H NMR (300 MHz, CDCl3) d (ppm):
1
1.70 (s, 3H), 3.74 (s, 3H), 3.98 (d, J = 5 Hz, 2H), 4.11 (dd, J = 9.0, 18.0 Hz, 1H),
4.63 (dd, J = 8.6, 17.2 Hz, 1H), 5.19 (dd, J = 9.0, 18.2 Hz, 1H), 5.58 (dd,
J = 9.1, 9.1 Hz, 1H), 7.24 (s, 1H), 7.29–7.33(m, 5H); 13C NMR (75 MHz, CDCl3)
d (ppm): 10.05, 48.89, 52.44, 59.09, 69.64, 99.55, 126.59, 128.57, 129.00, 137.72,
150.80, 155.34, 168.74, 170.20; IR (KBr): 3351, 2961, 2360, 1757, 1620, 1205,
762, 701 cm-1; HRMS (ESI) calcd for C16H19N2O5 (M ? H)?: 319.1294, found:
319.1299.
Preparation of (Z)-methyl 2-[2-(2-oxo-4-phenyloxazolidine-3-carbonyl)prop-1-
enylamino]acetate (5)
A solution of ethyl 3-hydroxybutyrate (30 mg, 0.2 mmol) in THF was added
dropwise to a solution of LiHMDS (1 mol L-1 in THF, 0.2 mL) at -20 °C over a
period of 30 min. A solution of compound 4 (50 mg, 0.2 mmol) in THF (5 mL) was
then added and the mixture was stirred at this temperature for 15 min, then stirred
for 4 h at room temperature, the reaction was quenched by addition of aqueous HCl
(1 M). The reaction mixture was extracted three times with EtOAc. The organic
phase was washed with NaHCO3 solution, phosphate buffer (pH 7), and brine, dried
over Na2SO4, and concentrated under reduced pressure to give the crude product
which was purified by column chromatography (hexane–EtOAc 1:1) to give
colorless oil (18 mg), yield 60 %. [a]2D0 ?70.0 (c, 0.40, CHCl3); 1H NMR
(500 MHz, CDCl3) d (ppm): 1.91 (d, J = 1 Hz, 3H), 3.74 (s, 3H), 4.30 (dd, J = 5.0,
11.5 Hz, 1H), 4.39 (d, J = 6.5 Hz, 1H), 4.55–4.59 (dd, J = 8.0, 12.0 Hz, 1H), 6.21
(dd, J = 5.0, 5.0 Hz, 1H), 6.93 (d, J = 1 Hz, 1H), 7.22–7.40 (m, 5H); 13C NMR
(125 MHz, CDCl3) d (ppm): 12.98, 14.07, 49.66, 52.64, 58.17, 60.28, 62.08,
110.55, 127.44, 127.66, 128.23, 136.71, 138.67, 151.87, 164.44, 167.99; IR (KBr):
3454, 3066, 2954, 2359, 1754, 1701, 1214, 770, 700 cm-1; HRMS (ESI) calcd for
C16H19N2O5 (M ? H)?: 319.1294, found: 319.1306.
(S)-4-Phenyl-3-(2-phenylacetyl)oxazolidin-2-one (16)
(S)-(?)-4-Phenyl-2-oxazolidinone 8 (10 g, 61 mmol), phenylacetic acid (16.7 g,
123 mmol), and Et3N (24.8 g, 245 mmol) were dissolved in 130 mL anhydrous
toluene under N2 (g) and warmed to 80 °C. Pivaloyl chloride (14.8 g, 123 mmol) in
toluene (0.2 mL mmol-1, 25 mL) was dropwise over a period of 30 min, then the
solution was heated under reflux, with stirring, for 5 h. When the reaction was
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Y. Zhang et al.
complete it was quenched with 2 mol L-1 HCl solution, and extracted with ethyl
acetate. The extract was washed with brine, dried, and concentrated to give crude
product, which was recrystallization from isopropyl alcohol to give a white powder
(5.8 g, 95 %). [a]2D0 ?82.3 (c, 0.40, CHCl3); 1H NMR (300 MHz, CDCl3) d (ppm):
4.24 (dd, J = 3.9, 8.9 Hz, 3H), 4.28 (s, 2H), 4.66 (dd, J = 8.8, 8.8 Hz, 1H), 5.41
(dd, J = 3.8, 8.7 Hz, 1H), 7.18–7.32 (m, 10H); 13C NMR (75 MHz, CDCl3) d
(ppm): 41.61, 57.73, 69.87, 125.94, 127.14, 128.47, 128.67, 129.10, 129.70, 133.35,
138.84, 153.63, 170.53; IR (KBr): 3409, 3134, 3029, 1765, 1714, 775, 736, 711,
699 cm-1; HRMS (ESI) calcd for C17H15NNaO3 (M ? Na)?: 304.0950, found:
304.0942.
(S)-3-[(S)-3,3-Dimethoxy-2-phenylpropanoyl]-4-phenyloxazolidin-2-one (17)
Compound 16 (16.3 g, 58 mmol), TiCl4 (11.6 g, 61 mmol), and N,N- diisopropyl-
ethylamine (7.5 g, 58 mmol), CH(OMe)3 (7.4 g, 70 mmol) were dissolved in
anhydrous CH2Cl2 (100 mL) as described for compound 10. The product was
recrystallized from isopropyl alcohol to give a white powder (14.7 g, 71 %). [a]D20
?78.5 (c, 0.04, CHCl3); 1H NMR (300 MHz, CDCl3) d (ppm): 3.16 (s, 3H), 3.20 (s,
3H), 4.14 (dd, J = 4.2, 8.8 Hz, 1H), 4.52 (dd, J = 8.8, 8.8 Hz, 1H), 4.93 (d,
J = 8.8 Hz, 1H), 5.32 (dd, J = 4.2, 8.8 Hz, 1H), 5.63 (d, J = 8.8 Hz, 1H),
7.24–7.38 (m, 10H); 13C NMR (300 MHz, CDCl3) d (ppm): 50.68, 51.45, 54.67,
56.78, 68.47, 105.20, 124.78, 126.82, 127.48, 127.56, 127.98, 128.47, 133.26,
137.74, 152.36, 170.05; IR (KBr): 3447, 3128, 3017, 2917, 2836, 2360, 1773, 1703,
753, 763, 715, 700 cm-1; HRMS (ESI) calcd. for C20H21NNaO5 (M ? Na)?:
378.1317, found: 378.1318.
3-Oxo-3-((S)-2-oxo-4-phenyloxazolidin-3-yl)-2-phenylpropanal (18)
Compound 17 (5 g, 14 mmol) was dissolved in 50 mL of a 4:1:1 mixture of AcOH,
TFA, and H2O at 50 °C and stirred for 6 h. The reaction mixtures were worked up
as described in the general procedure for compound 15 to give white foam (3.8 g,
87 %). [a]2D0 ?125.9 (c, 0.10, CHCl3); 1H NMR (300 MHz, CDCl3) d (ppm):
4.19–4.27 (m, 1H), 4.60–4.72 (m, 1H), 5.37–5.50 (m, 1H), 5.88 (d, J = 12.2 Hz,
1H), 7.11–7.44 (m, 10H), 9.68–9.69 (d, J = 3.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d (ppm): 57.72, 57.98, 63.08, 63.21, 70.16, 70.35, 125.87, 126.00, 128.70,
128.75, 128.83, 128.86, 129.07, 129.14, 129.28, 129.47, 129.57, 130.23, 130.49,
138.25, 138.36, 153.41, 153.65, 167.28, 167.52, 193.67, 194.38; IR (KBr): 3427,
3064, 3033, 2922, 2849, 1778, 1705, 762, 700 cm-1; HRMS (ESI) calcd for
C18H16NO4 (M ? H)?: 310.1079, found: 310.1081.
(S,E)-Methyl 2-((3-oxo-3-(2-oxo-4-phenyloxazolidin-3-yl)-2-phenylprop-1-en-1-
yl)amino)acetate and (S,Z)-methyl 2-((3-oxo-3-(2-oxo-4-phenyloxazolidin-3-yl)-2-
phenylprop-1-en-1-yl)amino)-acetate (6 and 7)
Aldehyde intermediate 18 (3.8 g, 12 mmol), NaHCO3 (3.1 g, 37 mmol), MgSO4
(5.2 g, 43 mmol), and methyl ester hydrochloride (1.8 g, 15 mmol) were dissolved
123

Novel approach to stereoselective synthesis
in CH2Cl2 (80 mL) at room temperature. The mixture was heated under reflux for
3 h. After filtration, the filtrate was concentrated under reduced pressure and
purified by column chromatography on silica gel (eluent: hexane–EtOAc 2:1) to
furnish a yellow oil (3.3 g, 71 %). [a]2D0 ?40.0 (c, 0.10, CHCl3); 1H NMR
(500 MHz, CDCl3) d (ppm): 3.73 (d, J = 0.5 Hz, 6H), 3.91–3.93 (m, 4H),
4.05–4.15 (m, 3H), 4.48–4.51 (dd, J = 9.0, 9.0 Hz, 1H), 4.58–4.61 (dd, J = 9.0,
9.0 Hz, 1H), 5.25–5.28 (dd, J = 8.0, 16.5 Hz, 2H), 5.31(s, 1H), 5.51–5.54 (dd,
J = 9.0, 18.0 Hz, 1H), 6.77 (s, 1H), 6.79 (s, 1H), 7.05–7.30 (m, 20H); 13C NMR
(75 MHz, CDCl3) d (ppm): 48.94, 49.57, 52.53, 52.53, 58.89, 58.99, 69.44, 69.54,
104.90, 107.04, 125.85, 126.90, 127.11, 127.29, 128.24, 128.66, 128.75, 128.85,
129.00, 129.03, 129.13, 129.41, 130.38, 133.95, 137.76, 137.79, 138.88, 149.74,
155.36, 168.07, 168.91, 169.27, 169.81; IR (KBr): 3392, 3143, 2360, 2342, 1773,
1648, 763, 699 cm-1; HRMS (ESI) calcd. for C21H21N2O5 (M ? H)?: 381.1450,
found: 318.1457.
Conclusions
Herein we have reported a convenient and stereoselective method for synthesis of
new building blocks (E) or (Z)-(N-acyl-oxazolidinone)-eneglycinates. According to
MMFF94, the carbonyl groups of eneglycinates have a ‘‘planar’’ or ‘‘non-planar’’
configuration in the presence of ethyl 3-hydroxybutyrate, which results in stable
thermodynamic or kinetic controlled products.
When the (E) and (Z) configurations were achieved at equilibrium ratio in the
reaction mixture, the ‘‘steady-state’’ was not affected by the amount of the base and
glycinates. Transformation of the thermodynamic product to the kinetic product was
investigated, and a mechanism was proposed by use of molecular mechanics. All the
intermediates were purified after simple crystallization with excellent yields, and the
reactions could be performed safely on a large scale.
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