Highly diastereoselective synthesis of arylglycine derivatives via TFA-promoted Friedel-Crafts reactions of phenols with cyclic glyoxylate imines

Article abstract of DOI:10.1016/S0040-4020(03)01142-6

Optically active α-arylglycine derivatives were synthesized by Br?nsted acid (TFA)-promoted Friedel-Crafts reaction of various phenols with chiral cyclic glyoxylate imines (2a-c), followed by deprotection with Pd(OH)₂/C under H₂. The diastereoselectivities of the initially formed F-C reaction products are up to 99%.

Full text of DOI:10.1016/S0040-4020(03)01142-6

Tetrahedron 59 (2003) 7609–7614
Highly diastereoselective synthesis of arylglycine derivatives via
TFA-promoted Friedel–Crafts reactions of phenols with cyclic
glyoxylate imines
*
Yong-Jun Chen, Fei Lei, Li Liu and Dong Wang
*
Laboratory of Chemical Biology, Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080,
People’s Republic of China
Received 20 May 2003; revised 12 June 2003; accepted 14 July 2003
Abstract—Optically active a-arylglycine derivatives were synthesized by Brønsted acid (TFA)-promoted Friedel–Crafts reaction of various
phenols with chiral cyclic glyoxylate imines (2a–c), followed by deprotection with Pd(OH)2/C under H2. The diastereoselectivities of the
initially formed F–C reaction products are up to 99%.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
electrophilic amination of chiral benzylic enolate10 and
some other methods.6a,11 Although many of these methods
offer avenues to access this increasingly important func-
tional array, the subject still constitutes an active area of
research, especially because of a number of unsolved
aspects related to either the functional diversity and the
stereochemistry of the products or the generality of the
reaction. The electrophilic aromatic substitution represented
by Friedel–Crafts (F–C) reaction is one of the most
efficient methods for the formation of carbon–carbon bonds
to aromatic rings.12 However, the use of imines in F–C
reaction as electrophiles, which would lead to new and
interesting arylglycine derivatives, has received only scant
attention.13 On the other hand, chiral cyclic glyoxylate
imines have been shown to be a good chiral template in
some asymmetric synthesis,14 which are able to avoid the
equilibrium between E/Z isomers existing in acyclic alkyl
glyoxylate imines. There is only one example of the use of
chiral cyclic glyoxylate imine in F–C-type reaction,15 but
its preparation suffers from a larger number of synthetic
steps (7 steps). As part of our program to develop a novel
method for the stereoselective synthesis of arylglycine
derivatives,16 we herein describe a highly diastereoselective
synthesis of optically active arylglycines via Brønsted acid
(TFA)-promoted Friedel–Crafts reaction of phenols with
chiral cyclic glyoxylate imines.
There has been considerable interest in the development of
synthetic methods to realize non-proteinogenic a-amino
acids within the synthetic community due to their potential
pharmacological properties and their use as precursors for
novel peptide structures.1 Arylglycines constitute an
important class of non-proteinogenic a-amino acids.
Glycopeptidic antibiotics,2 such as vancomycin,3 are one
of the best-studied and most important natural sources of
arylglycines. Apart from the interesting naturally occurring
arylglycines, there are also a number of synthetic aryl-
glycine derivatives that could serve as a side-chain moiety
of semisynthetic penicillins and cephalosporins.1a In
addition, it was recently discovered that molecules of this
type were found to be potent and selective agonists or
antagonists of metabotropic glutamate receptors.4 On the
other hand, unlike other amino acids, which can be
effectively prepared in enantiomerically pure form,5 the
apparent simplicity of the arylglycine structure is compli-
cated by the ease of racemization at the a-stereocenter,6
rendering these substances challenging synthetic targets to
be obtained in optically pure form.
Recently, a number of reports on the stereoselective
synthesis of arylglycine derivatives have appeared covering
a wide range of reactions1 including: enzymatic resolution
of racemic arylglycine derivatives,7 asymmetric Strecker
reaction,8 C-arylation of electrophilic chiral glycinate9 and
2. Results and discussion
Keywords: arylglycine; F–C reaction; phenol; chiral cyclic glyoxylate
imine; diastereoselective synthesis.
The following chiral cyclic glyoxylate imines: dihydro-1,4-
oxazin-2-ones 2a–c (Fig. 1) were synthesized via oxidative
rearrangement of oxazolines,17 which were readily prepared
*
Corresponding author. Tel.: þ86-10-62554614; fax: þ86-10-62554449;
e-mail: yjchen@iccas.ac.cn
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01142-6

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Y.-J. Chen et al. / Tetrahedron 59 (2003) 7609–7614
Table 1. Reactions of 1a with 2a–c promoted by TFA
Entry
Phenol
Imine
Product
Yield (%)a
De (%)b
1
2
3
4
1a
1a
1a
1a
(þ)-2a
(þ)-2b
(2)-2c
(þ)-2c
3aa
3ab
73
80
85
83
53
68
99
99
(þ)-3ac
(2)-3ac
Figure 1.
a
Isolated yield.
Determined by H NMR.
b
1
by condensing L-valinol, (1R,2S)-(þ)-cis-1-amino-2-inda-
nol and (1R,2S)-(2)-2-amino-1,2-diphenyl-ethanol or its
enantiomer with ethyl acetimidate respectively according to
Meyers’ method18 (Scheme 1). To the best of our knowl-
edge, these four chiral cyclic glyoxylate imines have never
been used as chiral templates on F–C reaction.
(entries 3 and 4). In the following experiments, we therefore
selected (2)-2c as chiral template.
Subsequently, the effects of Brønsted acids19 as promoter on
the F–C reaction were investigated. As depicted in Table 2,
similar to the case of TFA, a variety of Brønsted acids can
also promote the reaction of 1a with (2)-2c with good
yields (83–85%) and excellent diastereoselectivities (99%)
(entries 1–4). However, BrCH2COOH, CH3CO2H as
promoters in the same reaction conditions could not
promote the reaction. It could be found from the results in
Table 2 that the pKa value of the Brønsted acid is a crucial
factor for promoting the reaction. In contrast to our previous
results,16 which indicated that the Lewis acids used, such as
TiCl4 and Sc(OTf)3, can efficiently promote the F–C
reaction of phenols with N-Tos imino ester and N,O-acetals,
but if TiCl4 or Sc(OTf)3 were employed as promoters in the
reaction of phenols with chiral cyclic glyoxylate imines, no
reaction took place at all.
Scheme 1.
As illustrated in Scheme 2, the F–C reactions were carried
out as shown in the following procedure. To a solution of
phenol and chiral cyclic glyoxylate imine in CH2Cl2 at 08C,
TFA (5 equiv.) was added dropwise by a syringe. After the
reaction mixture was stirred for 3 h at 08C, usual work-up
furnished a residue from which the pure product was
obtained after purification by flash chromatography on silica
gel. Noteworthy is that the reaction can be carried out in the
solvent directly from stock and without protection from air
with the same yield and diastereoselectivity of the reaction.
It should be mentioned that the properties of the organic
solvents play a key role in the F–C reaction. The reaction
proceeded smoothly in dichloromethane and toluene with
good yield and diastereoselectivity while no product was
detected when THF, CH3CN or 1,4-dioxane was used as
solvent.
Table 2. Reactions of 1a with 2c promoted by acids
Entry
Brønsted acid
pKa
Product
Yield (%)a
De (%)b
1
2
3
4
5
6
CF3CF2CF2COOH
CF3COOH
CCl3COOH
HN(SO2CF3)2
BrCH2COOH
CH3CO2H
0.17
0.25
0.64
1.7
2.9
3.75
3ac
3ac
3ac
3ac
NR
NR
85
84
84
83
99
99
99
99
a
Isolated yield.
Determined by H NMR.
b
1
To evaluate the scope and limitation of the reaction, a
variety of substituted phenols were employed as substrates.
Given the results summarized in Table 3, some observations
are worthy of comments. The TFA-promoted F–C reaction
of 2c with substituted phenols occurs mainly at the ortho- or
para-position of phenolic hydroxyl group under the reaction
conditions depending on the substituted pattern. For the
substrates such as 1a–1c in which the 4-position in the
aromatic ring was blocked by a substituent, the addition
took place exclusively at the ortho-position of the phenolic
hydroxyl group with 99% de and moderate to good yields
(entries 1–3). When simple phenol (1d) was used as
substrate, othro- and para-substituted adducts 3dc and 3dcp
were obtained in 38 and 40% yields with identical 99% de,
respectively. The regioisomers 3dc and 3dcp were readily
isolated by flash chromatography (entry 4). Both 2,6-
dimethylphenol 1e and 2,3,6-trimethylphenol 1f afforded
the para-addition products in 80–82 yields and 99% de,
respectively (entries 5 and 6), while 2-methyl phenol 1g
provided a mixture of othro- and para-addition products
that were inseparable (entry 7). It was found that substrate
Scheme 2.
As a preliminary study, we first examined the reactions of
4-tert-butyl-phenol (1a) with different dihydro-1,4-oxazin-
2-ones (2a–c) under selected reaction conditions for
screening purpose. Both chiral cyclic glyoxylate imines
(2)-2a and (þ)-2b did not show satisfactory diastereo-
1
selectivities (53% and 68% de determined by H NMR of
the adducts, respectively; Table 1, entries 1 and 2) in the
corresponding adducts 3aa and 3ab. However, when 1a was
allowed to react with (2)-2c or (þ)-2c instead of 2a and 2b,
the des of adducts 3ac and 3ad can be improved to 99%

Y.-J. Chen et al. / Tetrahedron 59 (2003) 7609–7614
7611
Table 3. Reaction of different phenols 1 with 2c promoted by TFA
Yield (%)a De (%)b
Entry
Phenols
Products
1
1a
1b
3ac
3bc
85
41
99 (S)c
Figure 2. X-ray structure of (2)-2c.
2
99 (S)
attack would take place only from the si-face of CvN
double bond to afford the addition product with S
configuration. This is also consistent with an X-ray crystal-
lographic analysis of adduct 3cc (Fig. 3).
3
4
1c
3cc
60
38
40
99 (S)
99 (S)
99 (S)
1d
3dc
3dcp
Figure 3. X-ray structure of 3cc.
The final stage of the study was to remove the chiral
template to form the free amino acid without notable
racemization.21 To this end, the adducts 3dc and 3dcp were
subjected to hydrogenolysis in aqueous methanol using
Pearlman’s catalyst [Pd(OH)2/C] and TFA under 1 atm of
hydrogen gas for 5 h, respectively, and afforded the
corresponding amino acids in good yields (Scheme 3).
The measured optical rotation values of 4d and 4dp were
comparable with reported values of D-p-hydroxyphenyl-
glycines and D-o-hydroxy-phenylglycine (Table 3).22
Furthermore, considering the sign of optical rotation of 4b
and 4c, it was further deduced that the absolute configur-
ation of newly formed chiral center of 3cc is S (Table 4).
5
1e
1f
3ec
3fc
82
99 (S)
99 (S)
6
7
1g
1h
3gc
3hc
75
81
8
99 (S)
a
Isolated yield.
Determined by 1H NMR.
Configuration of newly formed chiral center.
b
c
1h afforded ortho-addition product in 81% yield and 99% de
(entry 8), and no para-adduct was detected from the reaction
mixture. The reason for this unique regioselectivity is not
clear yet. It is worth mentioning that adduct 3 may serve as a
good chiral template for the synthesis of a-alkylated
arylglycine derivatives in light of a recent report20 on the
synthesis of enantiopure a,a-disubstituted amino acids. It
should be mentioned that anisole and N,N-dimethylaniline
are not suitable for this F–C reaction.
Scheme 3.
Table 4. The optical rotation values of 4d and 4dp
Entry
Substrate
Product
Yield (%)a
[a]D
[a]D (ref)
1
2
3dc
3dcp
4d
4dp
85
80
þ152 (S)
þ150 (S)
2158 (R)
2158.4 (R)
X-ray crystallographic analysis of (2)-2c (Fig. 2) provided
a basis for understanding of the stereochemistry of the
reaction when (2)-2c was used as chiral template. Since the
phenyl group at 6-position in dihydro-1,4-oxazin-2-one
takes up an equatorial position, phenyl group at 5-position is
forced to adopt an axial position, shielding re-face of the
CvN double bond from addition. Thus, the nucleophilic
a
Isolated yield.
3. Conclusion
In summary, a novel synthesis of useful optically pure
arlyglycines by means of TFA-promoted diastereoselective

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Y.-J. Chen et al. / Tetrahedron 59 (2003) 7609–7614
Friedel–Crafts reaction of a versatile chiral cyclic
glyoxylate imine 2c with various substituted phenols has
been developed. The method would allow us to synthesize a
variety of highly functionalized optically pure arylglycine
derivatives. Further applications of the F–C reaction
products 3 to synthesize a range of optically pure
a-alkylated arylglycine derivatives are currently under
investigation in our laboratory.
4.1.2. (5S)-5-Isopropyl-5,6-dihydro-[1,4]oxazin-2-one
(1)-2a. As a colorless oil (70%). [a]2D0¼þ96 (c 1.0,
CH2Cl2). 1H NMR (CDCl3) d 7.89 (d, J¼2.8 Hz, 1H),
4.46 (dd, J¼4.4, 11.7 Hz, 1H), 4.25 (dd, J¼9.6, 11.6 Hz,
1H), 3.45–3.53 (m, 1H), 1.88–2.00 (m, 1H), 1.06 (t,
J¼6.4 Hz, 6H).
4.1.3. (5R, 6S)-9,9a-Dihydro-4aH-1-oxa-4-aza-fluoren-2-
one (1)-2b. As a pale white solid (87%); mp 85–878,
1
[a]2D0¼þ474 (c 1.0, CH2Cl2). H NMR (CDCl3) d 7.96 (s,
1H), 7.44–7.47 (m, 1H), 7.30–7.35 (m, 3H), 5.39–5.43 (m,
1H), 5.34–5.38 (m, 1H), 3.43 (dd, J¼5.4, 16.9 Hz, 1H),
3.25 (dd, J¼2.6, 16.9 Hz, 1H); 13C NMR (CDCl3) d 152.8,
151.4, 139.1, 138.3, 128.8, 127.8, 125.1, 124.7, 79.5, 62.7,
38.4. IR 3442, 2970, 1730, 1638 cm21. HRMS (FAB) calcd
for [MþHþ] C11H10NO2: 188.0705; found: 188.0708.
4. Experimental
All reactions were performed under a positive atmosphere
of dry nitrogen unless otherwise indicated. Dichloro-
methane (CH2Cl2) was distilled from calcium hydride
(CaH2). The oxazolines were prepared according to a
Ref. 18. Common reagents and materials were purchased
from commercial sources and purified by recrystallization
or distillation. Elemental analyses were performed on a
Carlo Elba 1102 Element Analysis instrument. Melting
points were determined on a Beijing-Tike X-4 apparatus and
were uncorrected. NMR spectra were measured on a Bruker
XL-300 (1H, 300 MHz and 13C, 75 MHz) or Bruker XL-400
(1H, 400 MHz and 13C, 100 MHz). IR spectra were taken as
neat for liquid compounds and as KBr plates on Perkin–
Elmer 500 FT-IR spectrometer. Mass spectra were
measured on Bruker APEX-2 FT-ICRMS spectrometer.
The crystal X-ray structures were measured on Rigaku
R-axis RAPID IP.
4.2. General procedure for the synthesis of 3
4.2.1. (3S,5S,6R)-3-(5-tert-butyl-2-Hydroxy-phenyl)-5,6-
diphenyl-morpho-lin-2-one (1)-3ac. To a mixture of 1a
(18 mg, 0.12 mmol) and 2c (25 mg, 0.1 mmol) in CH2Cl2
(5 mL) was added TFA (40 mL, 0.5 mmol) at 08C. The
reaction mixture was stirred at the same temperature until
(2)-2c was consumed. The reaction was quenched with
saturated aqueous NaHCO3 solution and extracted with
CH2Cl2. The organic phase was washed with brine, dried
over anhydrous Na2SO4, filtered, and evaporated under
reduced pressure. The residue was purified by flash
chromatography on silica gel (ethyl acetate/petroleum
ether¼1:8) to give (þ)-3ac as a pale yellow solid (34 mg,
85%); mp 90–928C. de 99%, [a]2D0¼þ118 (c 1, CH2Cl2). 1H
NMR(CDCl3) d 7.18–7.31 (m, 8H), 6.99–7.01 (m, 4H),
6.86 (d, J¼8.4 Hz, 1H), 5.94 (d, J¼4.0 Hz, 1H), 5.34 (s,
1H), 4.72 (d, J¼3.9 Hz, 1H), 1.29 (s, 9H); 13C NMR
(CDCl3) d 168.4, 154.2, 142.9, 136.0, 134.2, 128.4, 128.2,
127.9, 127.6, 126.9, 125.9, 124.1, 118.6, 117.2, 81.2, 58.7,
4.1. General procedure for the synthesis of chiral cyclic
glyoxyate imines
4.1.1. (5S,6R)-5,6-Diphenyl-5,6-dihydro-[1,4]oxazin-2-
one (2c). A solution of (5S,6R)-2-methyl-4,5-diphenyl-
4,5-dihydro-oxazoline (1.46 g, 6.16 mmol) in dry dioxane
(60 mL) was added to a suspension of selenium dioxide
(854 mg, 7.7 mmol) in dioxane (60 mL), and the mixture
was heated at reflux for 75 min. The mixture was cooled to
ambient temperature. The mixture was passed through a
short column of silica gel and washed several times with
ethyl acetate and chromatography on silica gel (eluent: ethyl
acetate/light petroleum ether¼1:4) to give (2)-2c as pale
yellow solid (958 mg, 62%); mp: 159–1618C, [a]2D0¼2622
(c 1.0, CH2Cl2). 1H NMR (CDCl3) d 8.29 (s, 1H), 7.18–7.32
(m, 6H), 6.93 (d, J¼7.0 Hz, 2H), 6.70 (d, J¼7.5 Hz, 2H),
5.84 (d, J¼3.7 Hz, 1H), 5.34 (d, J¼3.7 Hz, 1H); 13C NMR
(CDCl3) d 155.7, 153.1, 130.9, 130.3, 129.1, 128.4, 128.1,
127.3, 126.9, 126.0, 80.7, 66.4. IR 3029, 1739, 1630, 1496,
1452 cm21. Anal. calcd for C16H13NO2: C, 76.48, H, 5.21,
N, 5.57%; found: C, 76.84, H, 5.29, N, 5.57%. X-Ray
analysis of 2c: The crystal used for the X-ray study had the
58.2, 34.0, 31.3. IR 3422, 3033, 2961, 1744, 1598 cm21
.
HRMS (FAB) calcd for [M2Hþ] C26H26NO3: 400.1918;
found: 400.1921.
(3R,5R,6S)-(2)-3ac as a pale yellow solid (83%),
[a]2D0¼2122 (c 1.0, CH2Cl2).
4.2.2. 3-(5-tert-Butyl-2-hydroxy-phenyl)-5-isopropyl-
1
morpholin-2-one (3aa). As a pale yellow solid (73%). H
NMR (CDCl3) d 7.28–7.30 (m, 1H), 7.13, 7.20p (s, 1H),
6.86 (d, J¼8.3 Hz, 1H), 4.84, 5.11p (s, 1H), 4.51–4.56 (m,
1H), 4.29–4.36 (m, 1H), 2.94–2.97, 2.99–3.02p (m, 1H),
1.82–1.89 (m, 1H), 1.29–1.31 (m, 9H), 1.00–1.08 (m, 6H),
p two diastereomeric protons, de 53%; 13C NMR (CDCl3) d
168.3, 168.0, 154.5, 153.6, 142.7, 142.6, 127.0, 126.7,
124.6, 121.0, 118.8, 116.9, 71.8, 71.5, 62.4, 58.4, 57.5, 53.0,
34.1, 34.0, 31.5, 31.4, 29.8, 29.3, 18.9, 18.8, 18.6. IR 3293,
2962, 1735, 1612 cm21. HRMS (FAB) cacld for [MþHþ]
C17H26NO3: 292.1907; found: 292.1904.
dimensions
C16H13NO2, M 251.27; orthorhombic; space group, P21
0.29£0.17£0.08 mm3.
Crystal
data:
˚
˚
˚
lattice parameters, a¼5.9439 A, b¼8.4943 A c¼25.5719 A;
V¼1291.11 A Z¼4; Dcalcd¼1.293 g/cm3; F0¼528; number
3
˚
˚
of reflections measured¼2737, l¼0.7107 A. CCDC No:
4.2.3. 3-(5-tert-Butyl-2-hydroxy-phenyl)-4,4a,9,9a-tetra-
hydro-3H-1-oxa-4-aza-fluoren-2-one (3ab). As a pale
white solid (80%). 1H NMR (CDCl3) d 7.26–7.37 (m,
5H), 7.08 (s, 1H), 6.91 (d, J¼8.5 Hz, 1H), 5.12–5.16 (m,
1H), 5.01 (s, 1H), 4.66 (d, J¼5.8 Hz, 1H), 3.34, 3.48p (d,
J¼6 Hz, 2H), 1.30 (s, 9H), ptwo diastereomeric protons, de
212451.
According to the same procedure, (5R,6S)-(þ)-2c was
prepared as a pale yellow solid (60%), [a]2D0¼þ628 (c 1.0,
CH2Cl2).

Y.-J. Chen et al. / Tetrahedron 59 (2003) 7609–7614
7613
68%.; 13C NMR (CDCl3) d 168.6, 154.5, 142.9, 139.7,
138.6, 129.3, 129.1, 127.8, 127.7, 127.1, 127.0, 126.9,
125.6, 125.3, 124.6, 124.5, 123.8, 117.3, 116.9, 116.7, 80.5,
60.3, 58.1, 57.8, 56.8, 38.8, 37.8, 34.1, 31.4. IR 3750, 3423,
2959, 2868, 1735, 1616 cm21. HRMS (FAB) calcd for
[MþHþ] C21H24NO3: 338.1750; found: 338.1753.
(82%); mp 193–1958C, de 99%, [a]2D0¼þ96 (c 1.0,
CH2Cl2). 1H NMR (CDCl3) d 7.15–7.27 (m, 8H),
6.93–6.99 (m, 4H), 5.77 (d, J¼3.9 Hz, 1H), 5.10 (s, 1H),
4.74 (d, J¼3.9 Hz, 1H), 2.25 (s, 6H); 13C NMR (CDCCl3)
d 170.3, 152.3, 137.6, 135.1, 129.4, 128.3, 128.1,
127.9, 127.7, 127.1, 126.9, 126.7, 123.8, 83.1, 60.0, 57.6,
16.2. IR 3435, 3033, 2921, 1732, 1632 cm21. HRMS
(FAB) calcd for [MþHþ] C24H24NO3: 374.1750; found:
374.1753.
4.2.4. (3S,5S,6R)-3-(4-Hydroxy-biphenyl-3-yl)-5,6-
diphenyl-morpholin-2-one (3bc). As a pale yellow solid
(41%); mp 107–1098C, de% 99%, [a]2D0¼þ165 (c 0.75,
CH2Cl2). 1H NMR (CDCl3) d 7.58 (d, J¼7.6 Hz, 2H), 7.52
(s, 1H), 7.45 (t, J¼7.4 Hz, 2H), 7.22–7.37 (m, 8H), 6.99–
7.08 (m, 5H), 6.00 (d, J¼4.1 Hz, 1H), 5.49 (s, 1H), 4.80 (d,
J¼4.1 Hz, 1H); 13C NMR (CDCCl3) d 168.0, 156.7, 140.2,
136.1, 134.1, 133.4, 128.8, 128.7, 128.4, 128.2, 128.1,
127.6, 126.8, 126.7, 126.0, 125.9, 119.3, 118.4, 81.3, 58.9,
4.2.9. (3S,5S,6R)-3-(4-Hydroxy-2,3,5-trimethyl-phenyl)-
5,6-dip-henyl-morpholin-2-one (3fc). As a white solid
(80%); mp 176–1788C, de 99%, [a]2D0¼þ158 (c 2.15,
1
CH2Cl2). H NMR (CDCl3) d 7.21–7.30 (m, 6H), 7.04–
7.11 (m, 4H), 6.98 (s, 1H), 5.99 (d, J¼3.9 Hz, 1H), 5.28 (s,
1H), 4.82 (d, J¼3.9 Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.21
(s, 3H); 13C NMR (CDCCl3) d 170.9, 152.4, 137.3, 135.8,
134.2, 129.2, 128.7, 128.4, 128.2, 128.1, 127.2, 124.0,
120.5, 85.2, 59.2, 56.6, 16.4, 16.1, 12.7. IR 3443, 3032,
2925, 1731 cm21. HRMS (FAB) calcd for [MþHþ]
C24H24NO3: 388.1907; found: 388.1905.
58.4. IR 3424, 3032, 2925, 2854, 1742, 1650, 1607cmcm21
;
HR MS (FAB) calcd for [MþHþ] C28H24NO3 422.1751;
found: 422.1750.
4.2.5. (3S,5S,6R)-3-(4-Hydroxy-5-methoxy-phenyl)-5,6-
diphe-nylmorpholin-2-one(3cc). As colorless crystals
(60%); mp 179–1818C, de 99%, [a]2D0¼þ54 (c 0.85,
(CH3)2CO). 1H NMR (CDCl3) d 7.19–7.28 (m, 7H),
6.82–7.00 (m, 6H), 5.92 (d, J¼4.0 Hz, 1H), 5.37 (s, 1H),
4.72 (d, J¼4.1 Hz, 1H), 3.79 (s, 3H); 13C NMR (d6-DMSO)
d 169.6, 152.3, 149.0, 137.9, 136.9, 128.5, 128.4, 128.2,
128.1, 128.0, 127.8, 127.6, 127.4, 126.9, 116.6, 116.3,
114.5, 84.1, 56.8, 56.4, 55.9. IR 3434, 3340, 2963, 2923,
2853, 1735, 1691, 1636 cm21. HRMS (FAB) calcd for
[MþHþ] C23H22NO4: 376.1543; found: 376.1544. X-ray
analysis of 3cc: The crystal used for the X-ray study had the
4.2.10. (3S,5S,6R)-3-(4-Hydroxy-3-methyl-phenyl)- and
(3S,5S,6R)-3-(2-hydroxy-3-methyl-phenyl)-5,6-di-
phenyl-morpholin-2-one (3gc). As a white solid (75%). 1H
NMR (d6-acetone) d 7.30–7.32 (m, 1H), 7.19–7.21 (m,
1H), 7.12–7.17 (m, 6H), 6.98–7.06 (m, 4H), 6.85 (d,
J¼8.3 Hz, 1H), 6.16, 5.84p (d, J¼4.3 Hz, 1H), 5.29, 5.08p
p
(s, 1H), 4.96, 4.81p (d, J¼4.3 Hz, 1H), 2.28 (s, 3H), two
regioisomeric protons (1:2); 13C NMR(d6-acetone): d 169.5,
155.1, 138.3, 136.2, 129.5, 129.4, 127.8, 127.6(2C), 127.3,
126.8, 125.4, 124.4, 114.5, 83.0, 59.6, 56.8, 15.5. IR 3339,
3061, 2480, 1704, 1607cmcm21. HRMS (FAB) calcd for
[MþHþ] C23H20NO3: 358.1437; found: 358.1433.
dimensions
C23H21NO4, M 375.41; Monoclinic; space group, P2(1);
0.33£0.29£0.13 mm3.
Crystal
data:
˚
˚
lattice parameters, a¼9.7520 A, b¼9.6697 A, c¼
10.2717 A; V¼930.52A Z¼2; Dcalcd¼1.340 g/cm3; F0¼
4.2.11. (3S,5S,6R)-3-(2-Hydroxy-4-methyl-phenyl)-5,6-
diphenyl-morpholin-2-one (3hc). As a white solid (81%);
mp 61–638C, de% 99%. 1H NMR (CDCl3) d 7.15–7.25 (m,
6H), 7.07 (d, J¼7.8 Hz, 1H), 6.91–6.97 (m, 4H), 6.75 (s,
1H), 6.70 (d, J¼7.9 Hz, 1H), 5.89 (d, J¼4.2 Hz, 1H), 5.33
(s, 1H), 4.68 (d, J¼4.2 Hz, 1H), 2.30 (s, 3H); 13C NMR
(CDCl3) d 168.5, 157.0, 140.6, 136.4, 134.4, 128.7, 128.5,
128.2, 128.1, 127.7, 127.2, 126.2, 121.2, 118.6, 116.3, 81.3,
3
˚
˚
˚
396; number of reflections measured¼4185, l¼0.7107 A.
CCDC No: 212450.
4.2.6. (3S,5S,6R)-3-(2-Hydroxy-phenyl)-5,6-diphenyl-
morpho-lin-2-one (3dc). White solid (31.8%); mp 158–
1
1608C, de 99%, [a]D20¼þ52.6 (c 1.9, CH2Cl2). H NMR
(CDCl3) d 7.17–7.32 (m, 8H), 6.90–7.00 (m, 6H), 5.92 (d,
J¼4.2 Hz, 1H), 5.38 (s, 1H), 4.72 (d, J¼4.2 Hz, 1H); 13C
NMR (CDCCl3) d 168.2, 157.2, 136.3, 134.2, 130.2, 128.7,
128.4, 128.2, 128.1, 127.6, 127.2, 126.0, 120.3, 119.2,
118.1, 81.3, 58.8, 58.4. IR 3301, 3065, 1742 cm21. HRMS
(FAB) calcd for [MþHþ] C22H20NO3: 346.1437; found:
346.1432.
58.7, 58.4, 21.2. IR 3272, 3033, 2923, 1741, 1624 cm21
.
HRMS (FAB) calcd for [MþHþ] C23H22NO3: 360.1594;
found: 360.1602.
4.3. General procedure for synthesis of 4
4.3.1. (S)-o-Hydroxy-phenylglycine (4d). TFA (16 mL,
0.21 mmol) was added to a mixture of 3dc (73 mg,
0.21 mmol) and palladium hydroxide (78 mg, 1 equiv. by
mass) in aqueous methanol (20:1 MeOH/H2O,
20 mL mmol21) under a positive atmosphere of hydrogen
(1 atm), the reaction mixture was stirred at ambient
temperature for 24 h, then the solution was filtered and the
solvent removed in vacuo. Trituration of the crude mixture
with ethyl ether, the solid was filtered and dried in vacuo to
give 4d as a white powder (30 mg, 85%); mp 186–1888C,
[a]2D0¼þ152 (c 1.0, 1N HCl). 1HNMR (d6-DMSO) d 7.10–
7.16 (m, 2H), 6.78–6.82 (m, 2H), 4.62 (s, 1H); 13C NMR
(d6-DMSO): d 170.0, 156.3, 129.1, 125.4, 123.2, 119.1,
117.8, 53.9. IR 3417, 3071, 1633, 1462 cm21. HRMS
4.2.7. (3S,5S,6R)-3-(4-Hydroxy-phenyl)-5,6-diphenyl-
morpho-lin-2-one (3dc0). As colorless crystals (40%); mp
213–2158C, de% 99%, [a]2D0¼þ101.1 (c 0.95, acetone). 1H
NMR (d6-acetone) d 7.43 (d, J¼8.6 Hz, 2H), 7.13–7.20(m,
6H), 7.00–7.06(m, 4H), 6.86 (d, J¼8.6 Hz, 2H), 5.85(d,
J¼4.3 Hz, 1H), 5.13 (s, 1H), 4.82(d, J¼4.3 Hz, 1H); 13C
NMR (d6-acetone) d 170.2, 157.9, 139.0, 136.9, 130.2,
129.0, 128.6, 128.4, 128.3, 127.6, 116.1, 83.9, 60.3, 57.6. IR
3361, 3034, 2425, 1705, 1612 cm21. HRMS (FAB) calcd
for [MþHþ] C22H20NO3: 346.1437; found: 346.1432.
4.2.8. (3S,5S,6R)-3-(4-Hydroxy-3,5-dimethyl-phenyl)-
5,6-diphe-nyl-morpholin-2-one (3ec). As a white solid

7614
Y.-J. Chen et al. / Tetrahedron 59 (2003) 7609–7614
(FAB) calcd for [MþHþ] C8H10NO3: 168.0655; found:
Chem. Soc. 1999, 121, 4284–4285. (b) Sigman, M.; Vachal,
P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 1996, 35,
2810–2813. (c) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000,
2, 867–870.
168.0653.
4.3.2. (S)-p-Hydroxyphenylglycine (4dp). As a white
powder (80%); mp 212–2148C, [a]2D0¼þ150 (c 1.0, 1N
HCl). 1H NMR (d6-DMSO) d 7.18 (d, J¼8.2 Hz, 2H), 6.71
(d, J¼8.0 Hz, 2H), 4.14 (s, 1H); 13C NMR (d6-DMSO): d
169.5, 157.6, 129.4, 127.6, 115.5, 57.9. IR 3421, 3030,
1613, 1515 cm21. HRMS (FAB) calcd for [MþHþ]
C8H10NO3: 168.0655; found: 168.0655.
9. Williams, R. M.; Hendrix, J. A. J. Org. Chem. 1990, 55,
3723–3728.
10. (a) Oppolzer, W.; Tamura, O. Tetrahedron Lett. 1990, 31,
991–994. (b) Evans, D. A.; Evrard, D. A.; Rychnovsky, S. D.;
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Acknowledgements
12. (a) Smith, M. B. Organic Synthesis; Mcgraw-Hill: New York,
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We thank the National Natural Science Foundation of
China, Ministry of Science and Technology (No.
2002CCA03100) and The Chinese Academy of Sciences
for financial supports.
13. (a) Johannsen, M. J. Chem. Soc., Chem. Commun. 1999,
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