Stereoselective nucleophilic addition with a new chiral template and its application to the synthesis of optically active α-arylglycine derivatives

Article abstract of DOI:10.1055/s-2004-815980

Mannich-type reaction of phenols with iminolactone 4, readily prepared from commercially available phenylglycine, proceeded with high stereoselectivity to give α-arylglycine derivatives. The reaction was also applicable to other electron-rich aromatic compounds, arylboronic acids and other nucleophiles. Additionally, several Lewis acid-promoted addition reactions with iminolactone 4 were accomplished efficiently. These adducts could be converted readily to the corresponding optically active α-amino acid derivatives.

Full text of DOI:10.1055/s-2004-815980

PAPER
909
Stereoselective Nucleophilic Addition with a New Chiral Template and Its
Application to the Synthesis of Optically Active a-Arylglycine Derivatives
A
a
N
ew Chiral
h
T
emplate – S
i
ynthes
g
is of
O
ptical
e
ly Active
a
m
-Arylglycine Deriva
i
tives tsu Tohma,a Kentaro Rikimaru,a Atsushi Endo,a Keiko Shimamoto,b Toshiyuki Kan,a Tohru Fukuyama*a
Graduate School of Pharmaceutical Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-0033, Japan
Fax +81(3)58028694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
b
Suntory Institute for Bioorganic Research, Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618, Japan
Received 19 January 2004
As illustrated in Scheme 1, the iminolactone 4 was readily
prepared in a six-step sequence from phenylglycine meth-
yl ester (1), which is commercially available in both enan-
tiomeric forms and relatively inexpensive. After
Abstract: Mannich-type reaction of phenols with iminolactone 4,
readily prepared from commercially available phenylglycine, pro-
ceeded with high stereoselectivity to give a-arylglycine derivatives.
The reaction was also applicable to other electron-rich aromatic
compounds, arylboronic acids and other nucleophiles. Additionally, conversion to the N-Boc-phenylglycine methyl ester,
several Lewis acid-promoted addition reactions with iminolactone
treatment with MeMgBr followed by removal of the Boc
4 were accomplished efficiently. These adducts could be converted
group furnished the alcohol 2. N-Alkylation of 2 with phe-
readily to the corresponding optically active a-amino acid deriva-
nyl bromoacetate and subsequent lactonization afforded
tives.
the desired lactone 3, which, upon treatment with
Key words: Mannich-type reaction, iminolactone, phenols, elec-
Pb(OAc)4 smoothly underwent oxidation to provide the
tron-rich aromatics, arylboronic acids, hydroxyphenylglycines,
highly crystalline iminolactone 4. Because of the two
amino acids, a-arylglycines
geminal methyl groups, the iminolactone 4 is stable
enough to be isolated and is thus amenable to large-scale
preparations. It can also be stored in the air for several
Development of an efficient synthetic method for non-
months.10
proteinogenic a-amino acids has been an important task
owing to the unique bioactivity of these compounds.1 The
a-arylglycines, which constitute an important class of
non-proteinogenic a-amino acids,1,2 are found in numer-
ous natural products, such as amoxicillin and vancomy-
cin. In addition, a-hydroxyarylglycines have been shown
to be highly potent agonists or antagonists for the
glutamate receptors of the central nervous system.3,4 Con-
sequently, the growing need for a convenient synthesis of
a-arylglycines has attracted the interest of synthetic chem-
ists.5,6 However, synthesizing this class of compounds in
optically pure form has proven difficult because the ben-
zylic chiral center is prone to racemization. While the
methodology reported by Williams appears to be quite at-
tractive, it may not be particularly suited for large-scale
preparations of highly functionalized a-arylglycines.7
During the course of our synthetic studies on ecteinascidin
743, we found that an intermolecular Mannich-type reac-
tion of phenol with a cyclic imine proceeded with high
stereoselectivity.8 Inspired by this finding, we launched
an investigation into the scope of such an a-arylglycine
synthesis, using simple cyclic imines with readily remov-
able chiral auxiliaries. After preliminary investigation of
electrophilic glycine equivalents, the lactone 4 was found
to be sufficiently robust and suitable for this purpose.
Herein we report a stereoselective Mannich-type reaction
with our new chiral template 49a,b and its conversion to op-
tically active free a-amino acid derivatives.
With the requisite iminolactone 4 in hand, we then exam-
ined the Mannich-type reaction with various nucleophiles
(5a–k).11a,b Under acidic conditions, the additions pro-
ceeded with excellent stereoselectivity and in near quanti-
tative yields to give the corresponding phenylglycine
derivatives (6a–k). The reaction conditions, yields, and
diastereoselectivities are given in Table 1. It is notewor-
thy that highly substituted phenols, such as 5a–g, serve as
excellent substrates in this reaction. In addition, the imi-
nolactone 4 reacts with other electron-rich aromatic ethers
(5h and 5i), an aniline (5j), and an indole (5k). The high
stereoselectivity of the additions can be explained by a
preferential approach of the nucleophiles from the face
opposite to the bulky phenyl group. The stereochemistry
of the adduct was confirmed by X-ray analysis of 7
(Figure 1).12
Scheme 1 Preparation of chiral iminolactone 4. Reagents and con-
ditions: a) Boc2O (1.0 equiv), MeCN, r.t., 88%; b) MeMgBr (3.2 eu-
ivq), THF, 0 °C to r.t., 82%; c) SOCl2 (5.0 equiv), MeOH, r.t., 91%;
d) phenyl bromoacetate (1.1 equiv), propylene oxide (20 equiv),
MeCN, 80 °C, e) toluene, D, 75% (2 steps); f) Pb(OAc)4 (1.4 equiv),
MeCN, r.t., 82%
SYNTHESIS 2004, No. 6, pp 0909–0917
x
x
.
x
x
.2
0
0
4
Advanced online publication: 19.02.2004
DOI: 10.1055/s-2004-815980; Art ID: Z01004SS
© Georg Thieme Verlag Stuttgart · New York

910
S. Tohma et al.
PAPER
Table 1 Mannich-Type Reaction of Various Aromatics 5 with Imi-
nolactone 4
Table 1 Mannich-Type Reaction of Various Aromatics 5 with Imi-
nolactone 4 (continued)
ArH
TFA
(equiv)
Time (h)
Reaction dr (S:R)a Yields
ArH
TFA
(equiv)
Time (h)
Reaction dr (S:R)a Yields
Site
(%)
Site
(%)
5
0.5
X
S (single 93 (6a)b
isomer)
5
0.5
X
S (single 96 (6k)d
isomer)
5k
a Determined by 1H-NMR.
b After recrystallization.
5a: X = H
c The reaction was carried out at –20 °C.
d The reaction was carried out at r.t.
Additionally, the scope and limitations of the Mannich re-
action of the iminolactone 4 are as follows. Among vari-
ous acids (AcOH, PPTS, CSA, and TfOH) and/or Lewis
acids [BF3·OEt2 and Sc(OTf)3], the use of trifluoroacetic
acid gave the most satisfactory yields. Compared to other
solvents, such as THF or toluene, the reaction in dichlor-
omethane or dichloroethane proceeded smoothly. Al-
though, the reaction with phenol (5g) resulted in low
regioselectivity (ca. o:p = 1.1:1) even at –20 °C, in the
case of aniline (5j) an enhancement of the stereo- and re-
gioselectivity was observed at –20 °C to afford predomi-
nantly 6j.
5b: X = H, Y =
OMs
5
0.5
X
X
11:1
12:1
97 (6b)
5c: X = H, Y =
OMOM
2
24
83 (6c)9b
5d: X = Me, Y = H
5e: X = H, Y = Me
5f: X = H, Y = Br
5g: X = Y = H
5
5
Y
X
X
S (single 88 (6d)b
isomer)
Recently, a boronic acid-mediated Mannich reaction has
been reported by Petasis et al.13 The imine 4 was applied
to the Petasis reaction, as shown in Table 2. Treatment of
the iminolactone 4 and the arylboronic acids (8a and 8b)
in the presence of trifluoroacetic acid proceeded smoothly
to give 9a and 9b respectively in high yield. Since numer-
ous arylboronic acids and/or their derivatives can be ob-
tained easily,14 this protocol can be applied to the
synthesis of a wide variety of a-arylglycines. Upon treat-
ment of 9a (Scheme 2) under hydrogenolysis conditions,
deprotection of the benzyl ether proceeded smoothly to
give 6g, which served as the alternative product for the re-
action of phenol (5g) and 4 in Table 1. Since a triflate 10
was readily obtained from 9a, several functional groups
could be incorporated by Pd-mediated cross-coupling
and/or carbonylation with 10.
5
2.5
>20:1
95 (6e)
98 (6f)
96 (6g)
10
10
4:1
5
3
X:Y = 1:1 >20:1
5h: X = Me,
Y = Z = H
5
3
Z
10:1
96 (6h)
98 (6i)
5i: X = Z = H,
Y = OMe
5
0.5
X
X
>20:1
Further utility of the iminolactone 4 was demonstrated
with several acid promoted nucleophilic additions
(Table 3). Upon treatment of the iminolactone 4 with al-
lylsilane 11a and the ketene silyl acetal 11b in the pres-
ence of TFA, the desired reaction proceeded smoothly to
afford the adducts 12a and 12b in high yield. Addition of
4 with the Grignard reagent 11c was performed in the
presence of BF3·OEt210 to provide 12c (Table 3). These re-
sults demonstrate that the iminolactone 4 can serve as a
useful glycine-cation equivalent.
5
3
S (single 78 (6j)c
isomer)
5j: X = H
Synthesis 2004, No. 6, 909–917 © Thieme Stuttgart · New York

PAPER
A New Chiral Template – Synthesis of Optically Active a-Arylglycine Derivatives
911
BnO
RO
H
H
H
N
H
N
Ph
Ph
a
O
O
O
O
6g: R=H
10: R=Tf
9a
b
Reagents and conditions: a) 5% Pd/C (0.02 eq), H2, EtOH, rt, 99%;
b) Tf2O, Py, CH2Cl2, 0 °C, 92%
Scheme 2 Conversion of 9a to the corresponding triflate 10.
ylidene imine were the appropriate steps to use for this
transformation. A representative reaction with 6a is de-
scribed in Scheme 3. Acidic cleavage of the aminolactone
6a with SOCl2 in benzyl alcohol, followed by conversion
of the phenol to the benzyl ether under Mitsunobu condi-
tions afforded the benzyl ester 14. Oxidative cleavage of
the amino alcohol 14 with H5IO6 provided the aminoester
16 via the benzylidene imine intermediate 15. Finally, si-
multaneous hydrogenolysis of the benzyl ester and the
benzyl ether provided the corresponding amino acid 17a.
Table 3 Addition of Several Nucleophiles 11a–c to Iminolactone 4
H
H
N
N
Ph
R
Ph
(S)
Nu 11a-c
+
O
O
O
O
12a-c
4
Figure 1 ORTEP drawing of adduct 7
Nu
Time (h) Condi-
eq.
dr (S:R)b Yields (%)
tionsa
Table 2 Petasis Reaction of Iminolactone 4 with Arylboronic Acids
8a and 8b
TMS
0.4
5
A
S (single 88 (12a)
isomer)
11a
1.0
5.0
A
B
S (single 75 (12b)
isomer)
OTMS
OMe
11b
MeMgBr
0.5
2.0
S (single 88 (12c)
isomer)
Ar
TFA
Time (h) dr (S:R)a Yields (%)
11c
(equiv)
time (h)
a A: TFA (5.0 equiv), Nu, CH2Cl2, r.t.; B: Nu, BF3·OEt2 (2.0 equiv),
THF, –78 °C.
p-BnOC6H4
8a
5.0
r.t.
1.5
3.5
S (single 94 (9a)
isomer)
b Determined by 1H NMR.
p-MeOC6H4
5.0
r.t.
S (single 85 (9b)
isomer)
8b
Racemization did not occur during the removal of the
chiral auxiliary. This was confirmed by examining the 1H
NMR spectrum of the MTPA amide of 16. Using a similar
procedure as that for 6a, the adducts 6b and 6c afforded
the hydroxyphenylglycines 17b and 17c, respectively
(Figure 2). Since some hydroxyphenylglycine derivatives
have agonist or antagonist activity for the metabotropic
glutamate receptors (mGlu-Rs),4 we expected 17a–c
would also possess activity.15
a Determined by 1H NMR.
Next, we turned our attention to the removal of the chiral
auxiliary of the adducts and the conversion to the corre-
sponding a-arylglycines. In our preliminary investigation
for removal of the chiral auxiliary, hydrogenation did not
proceed even under high pressure conditions, due to the
bulkiness of the gem-dimethyl group. After numerous at-
tempts, we found that oxidative cleavage of the 1,2-amino
alcohol moiety and subsequent hydrolysis of the benz-
Furthermore, conversion to the amide and ester deriva-
tives of a-arylglycines would be attractive since racemiza-
tion of the a-arylglycine often proceeded under
condensation conditions. Conversion of the ester deriva-
Synthesis 2004, No. 6, 909–917 © Thieme Stuttgart · New York

912
S. Tohma et al.
PAPER
by means of the stereoselective Mannich-type reaction of
the versatile imine 4. The choice of various appropriate
nucleophiles would allow us to synthesize a variety of
amino acids, including the highly functionalized a-aryl-
glycines. Further applications of the chiral template 4 to
the synthesis of optically active amino acids and natural
products are under investigation in our laboratories.
IR spectra were recorded on a JASCO FT/IR-410 spectrophotome-
1
ter. H NMR and 13C NMR spectra were taken on a JEOL JNM-
LA400 spectrometer with tetramethylsilane (TMS) as the internal
standard. Optical rotations were measured on a JASCO DIP-1000
Digital Polarimeter at room temperature, using the sodium D line.
MS and HRMS were measured with a JEOL JMS-GCmate instru-
ment.
Scheme 3 Conversion to a-arylglycine. Reagents and conditions:
a) SOCl2 (3.0 equiv), BnOH, 0 °C to r.t., 92%; b) BnOH, DEAD,
Ph3P, benzene, r.t., 88%; c) H5IO6, MeOH–H2O (4:1), 70 °C, 82%; d)
5% Pd/C (0.1 equiv), H2, EtOH, r.t., 78%.
(S)-tert-Butoxycarbonylaminophenylacetic Acid
To a solution of 117 (23.7 g, 0.142 mmol) in MeCN (200 mL) was
added Boc2O (34.0 g, 0.158 mmol) at r.t. The mixture was stirred
for 30 min and diluted with excess benzene. The solvent was re-
moved under reduced pressure and the resulting yellow solid was
recrystallized from EtOAc–hexane to afford 36.2 g (1.37 mmol,
88%) of Boc-L-phenylglycine methyl ester as a white solid.
tives would be readily carried out by a procedure similar
to that described in Scheme 3. Conversion to the amide
derivative was carried out by aminolysis of the lactone
ring of the Mannich adducts, as shown in Scheme 4, fol-
lowed by conversion to the a-arylglycine amide. After
protection of the aniline group of 6j, treatment with benz-
yl amine in the presence of 2-hydroxypyridine16 caused
the smooth ring opening of 18 to give the corresponding
benzyl amide. Oxidative cleavage of the amino alcohol
with Pb(OAc)4 and subsequent treatment with hydroxyl-
amine provided the amide derivative 19 in enantiomeri-
cally pure form.
1H NMR (CDCl3, 400 MHz): d = 1.43 (9 H, s), 3.72 (3 H, s), 5.32
(1 H, d, J = 8.0 Hz), 7.15–7.55 (5 H, m).
(S)-(2-Hydroxy-2-methyl-1-phenylpropyl)carbamic Acid tert-
Butyl Ester
To a solution of Boc-L-phenylglycine methyl ester (28.0 g, 106
mmol) in THF (400 mL) was added dropwise MeMgBr (0.93 M,
400 mL) in THF (370 mL) solution at 0 °C. The mixture was
warmed to r.t., stirred for 2 h, quenched with sat. aq NH4Cl (40 mL),
and finally filtered through a pad of Celite. The filtrate was concen-
trated under reduced pressure and the resulting yellow solid was re-
crystallized from EtOAc–hexane to afford 23.1 g (86.5 mmol, 82%)
of (S)-N-Boc-b,b-dimethylphenylglycinol as a white solid. The use
of methylmagnesium iodide gave almost the same result.
OMe
OR1
1H NMR (CDCl3, 400 MHz): d = 1.06 (6 H, s), 4.51 (1 H, s), 1.57
R2O
O
(9 H, s), 5.50 (1 H, s), 7.26–7.35 (5 H, m).
Me
17b: R1=Ms
R2=H
H
H
(S)-1-Amino-2-methyl-1-phenylpropan-2-ol (2)18
NH2
NH2
17c: R1=H
MeO
To a solution of of (S)-N-Boc-b,b-dimethylphenylglycinol (40.1 g,
0.150 mol) in MeOH (80.3 mL) was added dropwise SOCl2 at 0 °C.
The mixture was stirred for 1 h at r.t., diluted with excess CH2Cl2
and NH3 gas was bubbled for 1 h. The mixture was filtered through
a pad of Celite and the filtrate was concentrated under reduced pres-
sure to afford 22.5 g (0.136 mol, 91%) of 2 as a brown solid.
R2=Ms
17a
O
OH CO2H
CO2H
Figure 2 a-Hydroxyphenylglycines
1H NMR (CDCl3, 400 MHz): d = 1.05 (3 H, s) 1.14 (3 H, s), 3.83 (1
H, s), 7.26–7.33 (5 H, m).
(S)-6,6-Dimethyl-5-phenylmorpholin-2-one (3)
To a solution of 2 (10.6 g, 64.0 mmol) in MeCN (60 mL) and pro-
pylene oxide (70 mL, 1.28 mol) was added phenyl bromoacetate
(15.1 g, 70.4 mmol) at r.t. and the mixture was heated to 80 °C. The
mixture was stirred for 4 h at 80 °C, cooled to r.t. and concentrated
under reduced pressure. The resulting crude product was used in the
next reaction without purification. A solution of this compound in
toluene (1.0 L) was heated at reflux for 15 h. The solution was
cooled to r.t., and the solvent was removed under reduced pressure.
The resulting crude product was recrystallized from EtOH–hexane
(3:1, 40 mL) to afford 5.90 g of 3. The filtrate was passed through a
short pad of silica gel, then the resulting product was again recrys-
Scheme 4 Conversion to a-arylglycine amide. Reagents and condi-
tions: a) BzCl, Et3N, CH2Cl2, 0 °C; b) BnNH2, 2-hydroxypyridine (5.0
equiv), toluene, 80 °C, 87% (2 steps); c) Pb(OAc)4, MeCN, r.t.;
HCl·H2NOH (5.2 equiv), NaOAc (7.1 equiv), EtOH, r.t., 95% (2
steps).
In conclusion, we have developed an efficient synthetic
method for the optically active a-amino acid derivatives tallized from EtOH (5 mL) to afford 1.59 g (48.0 mmol, 75%) of 3
as white crystals; mp 152–153 °C; [a]D25 +103 (c = 2.5, CHCl3).
Synthesis 2004, No. 6, 909–917 © Thieme Stuttgart · New York

PAPER
A New Chiral Template – Synthesis of Optically Active a-Arylglycine Derivatives
913
IR (film): 3307, 2984, 1710, 1484, 1374, 1333, 1277, 1161, 867,
769 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.33 (3 H, s), 1.35 (3 H, s), 3.85
(1 H, s), 3.93 (2 H, s), 7.34–7.39 (5 H, m).
13C NMR (CDCl3, 100 MHz): d = 21.6, 26.5, 49.0, 65.9, 85.5, 128.0,
128.2, 128.3, 138.2, 168.4.
1H NMR (CDCl3, 400 MHz): d = 1.39 (6 H, s), 3.23 (3 H, s), 4.16
(1 H, s), 5.09 (1 H, s), 6.03 (1 H, s), 6.05 (1 H, s), 6.09 (1 H, s), 7.32–
7.37 (5 H, m).
13C NMR (CDCl3, 100 MHz): d = 22.0, 26.6, 37.6, 56.6, 60.9, 76.7,
87.6, 102.8, 112.4, 116.6, 128.4, 128.5, 132.7, 133.6, 136.4, 137.7,
145.0, 169.8.
HRMS (FAB): m/z calcd for C20H21NO8S, 435.0988; found,
435.0985.
HRMS (FAB): m/z calcd for C12H15NO3, 205.1103; found,
205.1093.
(3S,5S)-3-(4-Hydroxy-3-methylphenyl)-6,6-dimethyl-5-phenyl-
morpholin-2-one (6d)
In a manner similar to that used in the preparation of 6a, 5d (211
mg, 1.95 mmol) gave 534 mg of 6d (88%) as white crystals
mp 138–139 °C; [a]D22 +52.2 (c = 2.7, CHCl3).
(S)-6,6-Dimethyl-5-phenyl-5,6-dihydro[1,4]oxazin-2-one (4)
To a solution of 3 (7.21 g, 35.0 mmol) in MeCN (70 mL) was added
Pb(OAc)4 (purity ca. 95%, 23.0 g, 53.0 mmol) at 0 °C. The mixture
was warmed to r.t., stirred for 2 h, quenched with pinacol (2.05 g,
18.0 mmol), diluted with excess EtOAc and then filtered through a
pad of Celite. The filtrate was partitioned between EtOAc and sat.
aq NaHCO3. The organic layer was washed with brine and dried
over anhyd MgSO4. The solvent was removed under reduced pres-
sure. The resulting crude product was recrystallized from EtOH to
afford 5.38 g (26.1 mmol, 75%) of 4. The mother liquor was con-
centrated under reduced pressure to a minimum volume, and the re-
sulting oil was purified by silica gel chromatography (20% EtOAc–
hexane) to afford 0.51 g (2.54 mmol, 7%) of 4 as white crystals;
mp 84–85 °C; [a]D22 +74.7 (c = 2.7, CHCl3).
IR (film): 3343, 2984, 1714, 1610, 1511, 1456, 1321, 1267, 1115,
985, 820, 757 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.38 (3 H, s), 1.40 (3 H, s), 2.24
(3 H, s), 4.16 (1 H, s), 4.97 (1 H, s), 6.75 (2 H, d, J = 9.6 Hz), 7.06
(2 H, d, J = 8.0 Hz), 7.11 (1 H, s), 7.26–7.38 (5 H, m).
13C NMR (CDCl3, 100 MHz): d = 20.7, 22.3, 27.0, 57.9, 60.8, 87.1,
117.2, 122.7, 128.2, 128.2, 128.4, 128.4, 129.2, 130.4, 137.5, 153.1,
170.3.
HRMS (FAB): m/z calcd for C19H21NO3, 311.1521; found,
311.1522.
IR (film): 2984, 1732, 1636, 1454, 1374, 1312, 1177, 1119, 984,
900, 756 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.14 (3 H, s), 1.46 (1 H, s), 4.78
(1 H, d, J = 2.0 Hz), 7.22–7.34 (5 H, m), 8.13 (1 H, d, J = 2.8 Hz).
13C NMR (CDCl3, 100 MHz): d = 21.4, 27.2, 68.7, 83.6, 128.2,
128.3, 128.5, 136.4, 153.3, 154.5.
(3S,5S)-3-(2-Hydroxy-5-methylphenyl)-6,6-dimethyl-5-phenyl-
morpholin-2-one (6e)
In a manner similar to that used in the preparation of 6a, 5e (181 mg,
1.67 mmol) gave 495 mg of 6e (95%) as white crystals; mp 175–
176 °C; [a]D24 +72.7 (c = 5.0, CHCl3).
HRMS (FAB): m/z calcd for C12H13NO2, 203.0946; found,
203.0950.
IR (film): 3310, 2985, 1718, 1611, 1511, 1469, 1387, 1372, 1260,
1118, 1057, 987, 817, 756 cm–1.
Mannich-Type Reaction with Phenols, Aromatic Ethers,
Aniline and Other Nucleophiles
1H NMR (CDCl3, 400 MHz): d = 1.41 (3 H, s), 1.42 (3 H, s), 2.26
(3 H, s), 4.25 (1 H, s), 5.26 (1 H, s), 6.79 (1 H, d, J = 7.6 Hz), 6.97
(1 H, s), 7.01 (1 H, d, J = 8.8 Hz).
13C NMR (CDCl3, 100 MHz): d = 15.9, 22.1, 26.7, 60.6, 60.8, 86.9,
115.3, 124.8, 125.6, 128.3, 128.3, 129.9, 130.8, 138.2, 154.0, 170.7.
(3S,5S)-3-(5-Hydroxy-2,4-dimethoxy-3-methylphenyl)-6,6-di-
methyl-5-phenylmorpholin-2-one (6a); Typical Procedure
To a mixture of 5a (510 mg, 3.02 mmol) and 4 (650 mg, 3.2 mmol)
in CH2Cl2 (6 mL) was added TFA (0.23 mL, 15.0 mmol) at 0 °C.
The reaction mixture was stirred at the same temperature for 30 min,
poured into sat. aq NaHCO3 solution, and extracted with EtOAc.
The extracts were washed with brine, dried over anhyd MgSO4, fil-
tered, and evaporated under reduced pressure. The resulting crude
product was recrystallized from EtOAc–hexane to afford 1.04 g
(2.80mmol, 93%) of 6a as a white crystal; mp 183–183 °C (de-
comp); [a]D25 +62.7 (c = 1.3, CHCl3).
HRMS (FAB): m/z calcd for C19H21NO3, 311.1521; found,
311.1505.
(3S,5S)-3-(5-Bromo-2-hydroxyphenyl)-6,6-dimethyl-5-phenyl-
morpholin-2-one (6f)
In a manner similar to that used in the preparation of 6a, 5f (192 mg,
1.11 mmol) gave 408 mg of 6f (98%) as white crystals; mp 174–
175 °C (decomp); [a]D25 +80.6 (c = 4.3, CHCl3).
IR (film): 3567, 2967, 1711, 1454, 1409, 1305, 1115, 1033, 989,
833, 735 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.26 (6 H, s), 2.14 (3 H, s), 3.76
(3 H, s), 3.78 (3 H, s), 4.19 (1 H, s), 5.28 (1 H, s), 6.44 (1 H, s), 7.29–
7.39 (5 H, m).
13C NMR (CDCl3, 100 MHz) 9.3, 22.2, 26.8, 56.1, 57.9, 60.9, 61.0,
86.7, 106.2, 120.2, 121.6, 128.3, 128.4, 138.4, 141.2, 146.5, 151.1,
169.6.
IR (film): 3304, 2986, 1712, 1600, 1495, 1386, 1370, 1303, 1271,
1187, 1116, 988, 817, 758 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.39 (3 H, s), 1.45 (3 H, s), 4.19
(1 H, s), 5.23 (1 H, s), 6.63 (1 H, d, J = 8.8 Hz), 7.21 (1 H, d, J = 8.8
Hz), 7.22 (1 H, s), 7.30–7.38 (5 H, m).
13C NMR (CDCl3, 100 MHz): d = 22.2, 26.9, 57.3, 60.9, 87.5, 112.0,
119.3, 124.9, 128.0, 128.5, 128.6, 130.3, 132.4, 137.0, 154.6, 170.1.
HRMS (FAB): m/z calcd for C21H26NO5 (M + H)+, 372.1806; found,
372.1808.
HRMS (FAB): m/z calcd for C18H18BrNO3 375.0470, found
375.0470.
(3S,5S)-3-[7-Hydroxy-6-(methylsulfonyl)oxy-1,3-benzodioxol-
4-yl]-6,6-dimethyl-5-phenylmorpholin-2-one (6b)
(3S,5S)-3-(4-Hydroxyphenyl)-6,6-dimethyl-5-phenylmorpho-
lin-2-one (6g)
In a manner similar to that used in the preparation of 6a, 5b (205
In a manner similar to that used in the preparation 6a, 5g (91.0 mg,
0.967 mmol) gave 276 mg of 6g (96%, 1:1 mixture of regioisomers)
as a white foam. The Mannich adduct gave inseparable regioiso-
mers (reaction at the ortho- or para- position of the phenol). A sin-
gle regioisomer (para-adduct) 6g was obtained using the procedure
22
mg, 0.883 mmol) gave 373 mg (97%) of 6b as a white foam; [a]D
+43.6 (c = 3.2, CHCl3).
IR (film): 3721, 2938, 1719, 1459, 1367, 1172, 1117, 1047, 964,
812 cm–1.
Synthesis 2004, No. 6, 909–917 © Thieme Stuttgart · New York

914
S. Tohma et al.
PAPER
shown in Scheme 2. The para-adduct 6g was isolated white crys-
tals; mp 181–182 °C (decomp). [a]D24 +74.6 (c = 0.7, CHCl3).
(3S,5S)-3-(1H-Indol-3-yl)-6,6-dimethyl-5-phenylmorpholin-2-
one (6k)
In a manner similar to that used in the preparation of 6a, 5k (88 mg,
0.751 mmol) gave 231 mg of 6k (96%) as a pale red solid; mp 169–
170 °C (decomp); [a]D23 +31.8 (c = 1.0, CHCl3).
IR (film): 3343, 1713, 1612, 1515, 1455, 1373, 1231, 1116, 986,
832 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.38 (3 H, s), 1.40 (3 H, s), 4.15
(1 H, s), 5.00 (1 H, s), 6.82 (2 H, d, J = 22 Hz), 7.36 (2 H, d, J = 22
Hz), 7.23–7.52 (5 H, m).
13C NMR (CDCl3, 100 MHz): d = 22.2, 26.8, 60.7, 60.8, 87.0, 115.9,
128.4, 128.4, 128.5, 131.0, 138.2, 155.8, 170.6.
IR (film): 3339, 2985, 1717, 1456, 1373, 1290, 1187, 1117, 1052,
982, 835 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.41 (3 H, s), 1.44 (3 H, s), 4.20
(1 H, s), 5.29 (1 H, s), 7.11–7.37 (9 H, m), 7.64 (1 H, d, J = 10.0 Hz).
13C NMR (CDCl3, 100 MHz): d = 22.1, 26.8, 54.5, 61.2, 86.7, 111.8,
113.9, 118.1, 120.0, 122.4, 123.0, 125.6, 128.2, 128.3, 128.3, 128.5,
136.4, 138.4, 170.5.
HRMS (FAB): m/z calcd for C18H19NO3, 297.1365; found,
297.1356.
(3S,5S)-3-(2,4-Dimethoxy-3-methylphenyl)-6,6-dimethyl-5-
phenylmorpholin-2-one (6h)
HRMS (FAB): m/z calcd for C20H20N2O2, 320.1525; found,
320.1520.
In a manner similar to that used in the preparation of 6a, treatment
of 5h (152 mg, 0.999 mmol) gave 341 mg of 6h (96%) as white
crystals; mp 140–141 °C; [a]D24 +35.9 (c = 3.7, CHCl3).
(3S,5S)-3-(4-Benzyloxyphenyl)-6,6-dimethyl-5-phenylmorpho-
lin-2-one (9a); Petasis Boronic Mannich Reaction; Typical
Procedure13
IR (film): 3339, 2989, 2836, 1733, 1600, 1487, 1465, 1370, 1288,
To a mixture of 8a (502 mg, 2.20 mmol) and 4(492 mg 2.42 mmol)
in CH2CH2 (10 mL) was added TFA (0.85 mL, 11.0 mmol) at r.t.
The reaction mixture was stirred at the same temperature for 30 min,
poured into sat. NaHCO3 solution, and extracted with EtOAc. The
extracts were washed with brine, dried over anhyd MgSO4, filtered,
and evaporated under reduced pressure. Purification by silica gel
chromatography (EtOAc→30% EtOAc–hexane) afforded 749 mg
1267, 1108, 991, 800, 758 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.55 (6 H, s), 2.12 (3 H, s), 3.82
(3 H, s), 3.83 (3 H, s), 4.11 (1 H, s), 5.18 (1 H, s), 6.61 (2 H, d,
J = 8.8 Hz), 7.01 (2 H, d, J = 8.8 Hz), 7.27–7.36 (5 H, m).
13C NMR (CDCl3, 100 MHz): d = 9.43, 22.1, 26.8, 55.5, 57.8, 60.4,
60.8, 86.5, 105.4, 120.2, 125.0, 126.1, 128.2, 128.4, 138.6, 157.0,
158.8, 170.1.
25
(1.94 mmol, 94%) of 9a as white crystals; mp 112–113 °C; [a]D
+80.8 (c = 1.2, CHCl3).
HRMS (FAB): m/z calcd for C21H25NO4, 355.1784; found,
355.1780.
IR (film): 2984, 1726, 1607, 1509, 1385, 1230, 1179, 1115, 985,
762 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.38 (3 H, s), 1.40 (3 H, s), 4.11
(1 H, s), 5.01 (1 H, s), 5.05 (2 H, s), 6.65 (1 H, s), 6.96 (1 H, a), 7.25–
7.47 (12 H, m).
13C NMR (CDCl3, 100 MHz): d = 22.2, 26.8, 60.6, 60.8, 70.0, 86.5,
114.5, 115.2, 127.4, 128.0, 128.3, 128.6, 128.8, 130.7, 131.6, 136.7,
138.3, 158.5, 169.6.
(3S,5S)-6,6-Dimethyl-5-phenyl-3-(2,4,6-trimethoxyphenyl)mor-
pholin-2-one (6i)
In a manner similar to that used in the preparation of 6a, 5i (121 mg,
0.719 mmol) gave 262 mg of 6i (98%) as white crystals: mp 147–
148 °C; [a]D21 +98.9 (c = 4.9, CHCl3).
IR (film): 3339, 2925, 2840, 1726, 1609, 1456, 1386, 1291, 1121,
989, 921, 756, 665 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.51 (3 H, s), 1.54 (3 H, s), 3.82
(3 H, s), 3.83 (3 H, s), 3.87 (3 H, s), 4.11 (1 H, s), 5.10 (1 H, s), 6.93
(1 H, s), 6.95 (1 H, s), 7.26–7.41 (5 H, m).
13C NMR (CDCl3, 100 MHz): d = 21.9, 26.5, 51.5, 55.2, 55.6, 61.6,
76.7, 85.4, 91.2, 110.4, 127.8, 127.9, 128.4, 139.2, 158.4, 161.0,
171.0.
HRMS (FAB): m/z calcd for C25H25NO3, 387.1834; found,
387.1853.
(3S,5S)-3-(4-Methoxyphenyl)-6,6-dimethyl-5-phenylmorpho-
lin-2-one (9b)
In a manner similar to that used in the preparation of 6a, 8b (115
25
mg, 0.757 mmol) gave 200 mg 9b (85%) as a white foam; [a]D
+60.8 (c = 3.1, CHCl3).
HRMS (FAB): m/z calcd for C21H26NO5 (M + H)+, 372.1811; found,
372.1821.
IR (film): 2984, 1729, 1608, 1511, 1252, 1115, 1032, 985, 760 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.43 (3 H, s), 1.44 (3 H, s), 3.80
(3 H, s), 4.21 (1 H, s), 5.02 (1 H, s), 6.88 (1 H, d, J = 3.2 Hz), 6.90
(1 H, d, J = 2.0 Hz), 7.26–7.47 (7 H, m).
13C NMR (CDCl3, 100 MHz): d = 22.1, 26.7, 55.2, 60.5, 60.7, 86.5,
114.2, 128.3, 131.2, 138.3, 159.2, 169.5.
(3S,5S)-3-(4-Aminophenyl)-6,6-dimethyl-5-phenylmorpholin-
2-one (6j)
In a manner similar to that used in the preparation of 6a, 5j (106 mL,
1.16 mmol) gave 268 mg of 6j (78%) as a yellow oil; [a]D23 +54.0
(c = 2.6, CHCl3).
HRMS (FAB): m/z calcd for C19H21NO3, 311.1521; found,
311.1536.
IR (film) 3365, 2985, 2934, 1722, 1623, 1515, 1283, 1117, 985,
827, 758 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.25 (3 H, s), 1.25 (3 H, s), 4.16
(1 H, s), 4.96 (1 H, s), 6.66 (2 H, d, J = 8.0 Hz), 7.13 (2 H, d, J = 8.8
Hz), 7.31–7.39 (5 H, m).
13C NMR (CDCl3, 100 MHz): d = 22.2, 26.7, 60.6, 60.8, 86.4, 115.0,
115.2, 128.2, 128.3, 128.4, 129.0, 138.4, 146.2, 169.8.
(3S,5S)-3-(4-Hydroxyphenyl)-6,6-dimethyl-5-phenylmorpho-
lin-2-one (6g)
A solution of 9b (52 mg, 0.13 mmol) in EtOH (0.5 mL) was hydro-
genated over 5% Pd/C (58 mg, 0.06 mmol) at 1 atm of hydrogen at
r.t. for 1 h. The reaction mixture was filtered through a pad of Celite,
and solvent removed under reduced pressure. Purification by silica
gel chromatography (EtOAc→30% EtOAc–hexane) afforded 38 mg
(0.13 mmol, 99%) of 6g as white crystals.
HRMS (FAB): m/z calcd for C18H20N2O2, 296.1525, found:
296.1538.
Synthesis 2004, No. 6, 909–917 © Thieme Stuttgart · New York

PAPER
A New Chiral Template – Synthesis of Optically Active a-Arylglycine Derivatives
915
(3S,5S)-6,6-dimethyl-3-{4-[(triflouromethane)sulfonyl]oxyphe-
nyl}-5-phenylmorpholin-2-one (10)
IR (film): 3343, 2978, 1722, 1452, 1373, 1301, 1275, 1191, 1117,
1088, 972, 820, 791, 760 cm–1.
Pyridine (0.15 mL, 1.9 mmol) and 6g (188 mg, 0.63 mmol) were
dissolved in CH2Cl2 (2 mL). Tf2O (0.13 mL, 0.76 mmol) was added
to the solution at 0 °C. The reaction mixture was poured into sat. aq
NaHCO3, and extracted with EtOAc. The extracts were washed
with brine, dried over anhyd MgSO4, filtered, and evaporated under
reduced pressure. Purification by silica gel chromatography
(EtOAc→10% EtOAc–hexane) afforded 248 mg (0.58 mmol, 92%)
of 10 as a colorless oil; [a]D25 +42.2 (c = 5.9, CHCl3).
1H NMR (CDCl3, 400 MHz): d = 1.31 (3 H, s), 1.35 (3 H, s), 1.49
(3 H, d, J = 9.6 Hz), 4.04–4.09 (1 H, m), 4.13 (1 H, s), 7.33–7.43 (5
H, m).
13C NMR (CDCl3, 100 MHz): d = 19.8, 21.4, 26.6, 52.0, 61.0, 76.7,
85.7, 128.1, 128.1, 138.3, 172.0.
HRMS (FAB): m/z calcd for C13H17NO2 (M + 1)+, 220.1337; found,
220.1336.
IR (film): 3343, 2987, 1727, 1499, 1425, 1250, 1214, 1117, 1069,
986, 890, 758 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.40 (3 H, s), 1.43 (3 H, s), 4.10
(1 H, s), 5.08 (1 H, s), 7.29 (2 H, d, J = 6.8 Hz), 7.33–7.39 (5 H, m),
7.31 (2 H, d, J = 8.8 Hz).
13C NMR (CDCl3, 100 MHz): d = 22.0, 26.8, 59.9, 61.1, 86.9, 120.2,
121.7, 128.1, 128.4, 128.5, 129.1, 130.4, 137.6, 139.2, 149.0, 168.6.
(S)-(2-Hydroxy-3,5-dimethoxy-4-methylphenyl)-[(1S)-2-hy-
droxy-2-methyl-1-phenylpropylamino]acetic Acid Benzyl Ester
(13); Preparation of a-Arylglycines; Typical Procedure
To a stirred solution of 6a (1.23 g, 3.31 mmol) in of BnOH (20 mL)
was added dropwise SOCl2 (0.72 mL, 9.94 mmol) at 0 °C for 15
min. The reaction mixture was allowed to warmed to r.t. and was
stirred for 10 h until the starting material was consumed. The reac-
tion mixture was poured into sat. aq NaHCO3 solution, and extract-
ed with EtOAc. The extracts were washed with brine, dried over
anhyd MgSO4, filtered, and evaporated under reduced pressure. Pu-
rification by silica gel chromatography (EtOAc→30% EtOAc–hex-
ane) afforded 1.46 g (3.05 mmol, 92%) of 13 as a yellow solid;
[a]D25 +76.6 (c = 11.6, CHCl3).
HRMS (FAB): m/z calcd for C19H21F3NO3, 429.0857; found,
429.0865.
(3S,5S)-3-Allyl-6,6-dimethyl-5-phenylmorpholin-2-one (12a)
Prepared according to the general procedure for Mannich type reac-
tions except the reaction was conducted at ambient temperature
(See Table 3); colorless oil; [a]D23 +13.0 (c = 2.4, CHCl3).
IR (film): 2936, 2359, 1733, 1465, 1365, 1129, 1036, 956, 753 cm–1.
IR (film) 3453, 3326, 3063, 2982, 2923, 2852, 1731, 1639, 1604,
1495, 1455, 1386, 1372, 1272, 1210, 1189, 1119, 1059, 1002, 922,
861, 839, 807, 763, 705 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.29 (3 H, s), 1.35 (3 H, s), 2.60–
2.71 (2 H, m), 3.90 (1 H, q), 4.05 (1 H, s), 5.15 (1 H, d, J = 16.8 Hz),
5.18 (1 H, d, J = 16.8 Hz), 5.72–5.83 (1 H, m), 7.26–7.42 (5 H, m).
1H NMR (CDCl3, 400 MHz): d = 1.02 (3 H, s), 1.35 (3 H, s), 2.15
(3 H, s), 3.39 (1 H, s), 3.63 (3 H, s), 3.81 (3 H, s), 4.12 (1 H, s), 5.05
(1 H, d, J = 12.8 Hz), 5.13 (1 H, d, J = 12.8 Hz), 6.08 (1 H, s), 7.10–
7.38 (10 H, m).
13C NMR (CDCl3, 100 MHz): d = 9.01, 27.7, 27.9, 56.0, 60.3, 61.6,
66.9, 67.9, 72.5, 107.5, 118.1, 120.8, 127.3, 127.9, 128.0, 128.4,
128.5, 128.6, 135.4, 138.3, 143.8, 146.9, 150.9, 171.6.
13C NMR (CDCl3, 100 MHz): d = 21.9, 26.6, 36.2, 54.9, 61.9, 76.7,
84.8, 120.5, 128.3, 128.6, 132.3, 135.0, 168.5.
HRMS (FAB): m/z calcd for C28H33NO6, 479.2308; found,
479.2309.
HRMS (FAB): m/z calcd for C15H19NO2, 245.1416; found,
245.1421.
(S)-(2-Benzyloxy-3,5-dimethoxy-4-methylphenyl)-[(1S)-(2-hy-
droxy-2-methyl-1-phenylpropylamino)acetic Acid Benzyl Ester
(14)
To a stirred solution of 13 (322 mg, 0.670 mmol), BnOH (0.14 mL,
1.34 mmol), and PPh3 (352 mg, 1.34 mmol) in benzene (8 mL) was
added DEAD (0.61 mL, 1.34 mmol) at 0 °C. The resulting mixture
was allowed to warm to r.t. After 20 min, the mixture was concen-
trated in vacuo. The residue was purified by flash chromatography
(10–20% EtOAc–hexane) to give 336 mg (0.590 mmol, 88%) of 14
as a yellow solid; [a]D24 +82.4 (c = 1.2, CHCl3).
(3S,5S)-3-(1-Methoxycarbonyl-1-methylethyl)-6,6-dimethyl-5-
phenylmorpholin-2-one (12b)
Prepared according to the general procedure for Mannich type reac-
tions except the reaction was conducted at ambient temperature
(See Table 3); colorless crystals; mp 128–129 °C; [a]D +7.6
(c = 1.8, CHCl3).
23
IR (film): 3364, 2981, 2948, 2877, 1738, 1732, 1716, 1470, 1388,
1265, 1190, 1116, 1003, 869, 750 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.23 (3 H, s), 1.25 (3 H, s), 1.42
(3 H, s), 1.44 (3 H, s), 3.66 (3 H, s), 4.23 (1 H, s), 5.23 (1 H, s), 7.30
(5 H, m).
13C NMR (CDCl3, 100 MHz): d = 20.0, 21.4, 23.4, 27.0, 47.7, 52.1,
60.6, 64.4, 85.1, 127.9, 128.4, 128.5, 138.0, 169.7, 176.8.
IR (film): 3481, 3030, 2967, 2906, 1733, 1602, 1482, 1455, 1328,
1218, 1129, 1026, 848, 744 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.02 (3 H, s), 1.03 (3 H, s), 2.08
(3 H, s), 3.30 (1 H, s), 3.66 (3 H, s), 3.68 (3 H, s), 4.57 (1 H, d,
J = 10.8 Hz), 4.59 (1 H, s), 4.71 (1 H, d, J = 11.6 Hz), 4.90 (1 H, d,
J = 11.6 Hz), 4.97 (1 H, d, J = 12.8 Hz), 6.48 (1 H, s), 6.95–7.22 (15
H, m).
HRMS (FAB): m/z calcd for C17H23NO4, 305.1627; found,
305.1641.
13C NMR (CDCl3, 100 MHz): d = 9.0, 24.7, 27.5, 55.7, 56.6, 60.4,
66.6, 68.7, 72.3, 74.7, 76.8, 104.5, 120.8, 126.9, 127.4, 127.4,
127.5, 127.9, 128.1, 128.2, 128.5, 128.7, 128.8, 135.6. 137.8, 139.1,
144.7, 152.1, 154.5, 172.7.
(3S,3S)-3,6,6-Trimethyl-5-phenyl-morpholin-2-one (12c)
To a stirred solution of 4 (225 mg, 1.11 mmol) in THF (5 mL) was
added (0.141 mL, 2.22 mmol) BF3·OEt2 at –78 °C, followed by
MeMgBr (3.0 M; 0.74 mL, 2.22 mmol) in Et2O solution at the same
temperature. After a few minutes, the mixture was quenched with
sat. aq NH4Cl, and was allowed to warm to r.t. The reaction mixture
was extracted with EtOAc. The extracts were washed with sat. aq
NaHCO3 solution, brine, dried over anhydrous MgSO4, filtered, and
evaporated under reduced pressure. Purification by silica gel chro-
matography (EtOAc→10% EtOAc–hexane) afforded 214 mg (0.98
mmol, 88%) of 12c as a white foam; [a]D24 +46.7 (c = 3.0, CHCl3).
HRMS (FAB): m/z calcd for C35H39NO6, 569.2777; found,
569.2770.
(S)-Amino-(2-benzyloxy-3,5-dimethoxy-4-methylphenyl)acetic
Acid Benzyl Ester (16)
To a solution of 14 (103 mg, 0.181 mmol) in MeOH (2 mL) and
H2O (0.5 mL), H5IO6 (228 mg, 0.543 mmol) was added at r.t., and
the mixture was heated at 70 °C for 3 h. After cooling, the reaction
Synthesis 2004, No. 6, 909–917 © Thieme Stuttgart · New York

916
S. Tohma et al.
PAPER
mixture was poured into a sat. aq NaHCO3 solution, and extracted
with EtOAc. The extracts were washed with brine, dried over anhyd
MgSO4, filtered, and evaporated under reduced pressure. Purifica-
tion by silica gel chromatography (EtOAc→70% EtOAc–hexane)
(3S,5S)-3-[4-(benzylamino)phenyl]-6,6-dimethyl-5-phenylmor-
pholin-2-one (18)
To a solution of 6j (414 mg, 1.40 mmol) of and Et3N (0.23 mL, 1.65
mmol) in CH2Cl2 (3 mL) was added BzCl (0.18 mL, 1.54 mmol) at
0 °C. The reaction mixture was stirred for 10 min, poured into sat.
aq NH4Cl solution, and diluted with CH2Cl2. The organic layer was
separated and washed with sat. aq NaHCO3 solution, brine, dried
over anhyd MgSO4, filtered, and evaporated under reduced pressure
to afford 562 mg (1.40 mmol, quant.) as a yellow solid. The result-
ing crude product 18 was used in next reaction without purification;
[a]D25 +56.2 (c = 3.0, CHCl3).
24
afforded 62.5 mg (0.148 mmol, 82%) of 16 as a white foam; [a]D
+21.9 (c = 1.3, CHCl3).
IR (film): 2359, 1733, 1516, 1456, 1410, 1219, 11129, 1047, 771
cm–1.
1H NMR (CDCl3, 400 MHz): d = 2.08 (3 H, s), 3.64 (3 H, s), 3.75
(3 H, s), 4.87–5.05 (4 H, m), 5.05 (1 H, s), 6.39 (1 H, s), 6.93–7.32
(10 H, m).
13C NMR (CDCl3, 100 MHz): d = 8.9, 53.2, 55.7, 60.5, 66.8, 75.2,
103.9, 120.9, 128.0, 128.1, 128.1, 128.4, 128.4, 128.4, 131.4, 135.6,
137.6, 143.1, 152.0, 154.5, 174.0.
IR (film): 3326, 2988, 1718, 1653, 1602, 1527, 1409, 1269, 1186,
1014, 958, 829, 753 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.37 (3 H, s), 1.40 (3 H, s), 4.15
(1 H, s), 5.04 (1 H, s), 5.30 (2 H, s), 7.13–8.05 (9 H, m).
13C NMR (CDCl3, 100 MHz): d = 22.1, 26.6, 60.6, 60.9, 76.7, 86.8,
120.8, 127.2, 127.6, 128.2, 128.3, 128.5, 131.7, 134.5, 134.6, 137.9,
138.0, 165.9, 169.7.
HRMS (FAB): m/z calcd for C25H27NO5, 421.1889; found,
421.1894.
(S)-Amino-(2-hydroxy-3,5-dimethoxy-4-methylphenyl)acetic
Acid (17a)
HRMS (FAB): m/z calcd for C25H24N2O3, 400.1787; found,
A solution of 16 (41.1 mg, 0.097 mmol) in EtOH (1.0 mL) was hy-
drogenated over 5% Pd/C (20 mg, 1 atm) at r.t. for 4 h. The reaction
mixture was filtered through a pad of Celite, and evaporated under
reduced pressure to afford 18.3 mg (0.076 mmol, 78%) of 17a as a
yellow solid; [a]D25+ 13.6 (c = 0.73, CH3OH).
400.1787.
N-{4-[(S)-Benzylcarbamoyl-(S-2-hydroxy-2-methyl-1-phenyl-
propylamino)methyl]phenyl}benzamide
To a solution of 18 (562 mg, 1.40 mmol) and BnNH2 (0.23 mL, 2.11
mmol) in toluene (4 mL) was added 2-hydroxypyridine (670 mg,
7.05 mmol) at r.t., and the mixture was heated to 80 °C. The mixture
was stirred for 4.5 h at the same temperature, cooled to r.t., and di-
rectly passed through a neutral silica gel column (EtOAc–
hexane 3:2) to afford 612.2 mg (1.22 mmol, 86.6%, 2 steps from 6j)
of the above amide as colorless crystals mp 169–170 °C (decomp);
[a]D25 +55.5 (c = 3.0, CHCl3).
IR (film): 2941, 1626, 1467, 1391, 1375, 1238, 1187, 1125, 925,
800, 716, 679 cm–1.
1H NMR (CD3OD, 400 MHz): d = 2.11 (3 H, s), 3.72 (3 H, s), 3.75
(3 H, s), 4.90 (1 H, s), 6.65 (1 H, s).
13C NMR (CD3OD, 100 MHz): d = 175.8, 155.2, 151.0, 146.2,
124.7, 123.0, 109.4, 109.3, 63.7, 58.9, 52.1, 13.9.
IR (film): 3316, 3028, 2930, 1955, 1652, 1602, 1579, 1493, 1359,
1267, 1217, 1162, 1066, 997, 838, 796 cm–1.
HRMS (FAB): m/z calcd for C11H15NO5, 241.0950; found,
241.0948.
1H NMR (CDCl3, 400 MHz): d = 1.01 (3 H, s), 1.19 (3 H, s), 3.47
(S)-Amino-(7-hydroxy-6-methanesulfonyloxybenzo[1,3]dioxol-
4-yl)acetic Acid (17b)
In a manner similar to that used in the preparation of 17a, treatment
of 6b (150 mg, 0.345 mmol) gave 33.6 mg (32%, 4 steps) 17b as a
yellow solid; [a]D25 +20.0 (c = 1.0, CH3OH).
(1 H, s), 3.94 (1 H, s), 4.44 (2 H, s), 7.17–8.02 (19 H, m).
13C NMR (CDCl3, 100 MHz) 14.1, 26.0, 27.8, 43.2, 60.3, 64.2, 70.3,
72.5, 121.1, 127.3, 127.4, 127.6, 127.7, 128.2, 128.4, 128.6, 131.6,
134.7, 135.1, 137.9, 138.3, 139.1, 166.0, 172.5.
HRMS (FAB): m/z calcd for C32H33N3O3, 507.2522; found,
507.2500.
IR (film): 2924, 1638, 1499, 1458, 1353, 1261, 1170, 1045, 914,
802, 735 cm–1.
1H NMR (CD3OD, 400 MHz): d = 3.21 (3 H, s), 4.73 (1 H, s), 6.12
N-{4-[(S)-Benzylcarbamoyl(benzylideneamino)methyl]phe-
nyl}benzamide
(2 H, s), 7.14 (1 H, s).
13C NMR (CD3OD, 400 MHz): d = 147.8, 143.1, 141.7, 125.1,
112.1 107.7, 104.7, 48.4.
To a solution of the above amide (502 mg, 0.980 mmol) in MeCN
(20 mL) was added (540 mg, 1.22 mmol) of Pb(OAc)4 (purity ca.
95%) at r.t., the reaction was stirred for 15 min, then pinacol (67 mg,
0.570 mmol) was added and the solution was diluted with EtOAc.
The mixture was filtered through a pad of Celite and the solvent re-
moved under reduced pressure. The resulting crude product was un-
stable in water and partially hydrolyzed to the imine, therefore, it
was used immediately in next reaction without purification.
HRMS (FAB): m/z calcd for C10H11NO8S, 305.0205; found,
305.0203.
(S)-Amino-(6-hydroxy-7-methanesulfonyloxybenzo[1,3]dioxol-
4-yl)acetic Acid (17c)
In a manner similar to that used in the preparation of 17a, treatment
of 6c (221 mg, 0.551 mmol) gave 25.2 mg (15%, 5 steps) 17c as a
yellow solid; [a]D25 +20.1 (c = 0.9, CH3OH).
(S)-2-Amino-N-benzyl-2-[4-(benzylamino)phenyl]acetamide
(19)
IR (film): 2924, 1732, 1716, 1698, 1652, 1558, 1540, 1456, 1362,
1189, 1067, 980, 668.
1H NMR (CD3OD, 400 MHz): d = 3.34 (3 H, s), 5.05 (1 H, s), 6.08
(2 H, s), 6.47 (1 H, s).
13C NMR (CD3OD, 400 MHz): d = 173.0, 148.3, 138.2, 137.5,
136.3, 118.1, 109.5, 105.0, 54.5, 39.1.
To a solution of the crude product from the preceding step, (0.980
mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride
(354 mg, 5.10 mmol) and NaOAc (571 mg 6.96 mmol) at r.t. After
the reaction was stirred for 20 min, H2O was added to the solution
and the mixture was extracted with EtOAc. The combined organic
layer was washed with brine and dried over anhyd MgSO4. The sol-
vent was removed under reduced pressure, purification by silica gel
chromatography (CH2Cl2–MeOH, 10:1) afforded 334 mg (95%
HRMS (FAB): m/z calcd for C10H11NO8S, 305.0205; found,
305.0203.
24
from 2 steps) of 19; white solid; mp 179–180 °C; [a]D +19.2
(c = 4.1, CHCl3).
Synthesis 2004, No. 6, 909–917 © Thieme Stuttgart · New York

PAPER
A New Chiral Template – Synthesis of Optically Active a-Arylglycine Derivatives
917
IR (film): 3030, 1653, 1603, 1533, 1416, 1328, 1267, 1018, 840,
699, 665 cm–1.
1H NMR (CDCl3, 400 MHz): d = 4.36 (1 H, d, J = 17.6 Hz), 4.42 (1
H, d, J = 12.4 Hz), 4.91 (1 H, s), 7.17–7.95 (14 H, m).
see: Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1996, 61,
2044. (c) For its application to Mannich-type reactions see:
Chen, Y.-J.; Lei, F.; Liu, L.; Wang, D. Tetrahedron 2003,
59, 7609.
13C NMR (CDCl3, 100 MHz): d = 17.7, 21.7, 43.3, 43.4, 56.8, 57.5,
H
H
H2N
HO
Ph
N
Ph
121.3, 121.4, 127.2, 128.0, 128.4, 131.8, 134.3, 137.4, 139.0, 176.9.
HRMS (FAB): m/z calcd for C22H22N3O2 (M+ + 1), 360.1712;
O
O
found, 360.1720.
A
B
Scheme 5
Acknowledgment
(11) (a) For preparation of the phenol 5a see: Fukuyama, T.;
Sachleben, R. A. J. Am. Chem. Soc. 1982, 104, 4957.
(b) For preparation of phenols 5b see: ref. 6
(12) Compound 7 was prepared from 6a by treatment with MsCl
and Et3N in 85% yield. X-ray crystallographic data for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Date Base (Deposition No.
162231). Copies of the data can be obtained free of charge
on application to the CCDC 12 Union Road, Cambridge
CB21EZ UK [fax +44 (1223)336333; E-mail:
We wish to thank Mr. R. Akiyama (Graduate School of Pharmaceu-
tical Sciences, The University of Tokyo) for his kind contribution
of the X-ray analysis of 7.
References
(1) Williams, R. M. Synthesis of Optically Active a-Amino
Acids; Pergamon Press: Oxford, 1989.
(2) For a review of asymmetric syntheses of arylglycines see:
Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889.
(3) Watkins, J.; Collingridge, G. Trends Pharm. Sci. 1994, 15,
333.
deposit@ccdc.cam.ac.uk].
(13) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron
1997, 48, 16463.
(14) (a) Ishiyama, T.; Miyaura, N. J. Synth. Org. Chem., Jpn.
1999, 57, 503. (b) Ishiyama, T.; Miyaura, N. J. Organomet.
Chem. 2000, 611, 392.
(15) Unfortunately the hydroxyphenylglycines 17a–c had no
agonist and antagonist activity in mGluR1-5. Detailed
experimental procedures and results of the assay will be
reported elsewhere.
(4) (a) Bendingfield, J. S.; Kemp, M. C.; Jane, D. E.; Tse, H. W.;
Roberts, P. J.; Watkins, J. C. Br. J. Pharmacol. 1995, 116,
3323. (b) Sekiyama, N.; Hayashi, Y.; Nakanishi, S.; Jane, D.
E.; Tse, H. W.; Birse, E. F.; Watkins, J. C. Br J Pharmacol.
1996, 117, 1493. (c) Hayashi, Y.; Sekiyama, N.; Nakanishi,
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Watkins, J. C. J. Neurosci. 1994, 14, 3370.
(16) 2-Hydroxypyridine is a weak acid (pKa 11.7), used for the
conversion of aliphatic esters to the corresponding amides,
see: (a) Openshaw, H. T.; Whittaker, N. J. Chem. Soc. (C)
1969, 89. (b) Kametani, T.; Kanaya, N.; Ihara, M. J. Chem.
Soc., Perkin Trans. 1 1981, 959. (c) Jagers, E.; Steglich, W.
Angew. Chem., Int. Ed. Engl. 1981, 20, 1016. (d) Raduchel,
B. Tetrahedron Lett. 1983, 24, 3229. (e) Hoffmann, R. W.;
Eudesfelder, A. Liebigs Ann. Chem. 1986, 1823.
(17) (S)- or (R)-Phenylglycine methyl ester hydrochloride was
purchased from Aldrich Inc. Free methyl ester 1 is easily
obtained by treatment with gaseous ammonia in CH2Cl2,
followed by filtration, and evaporation. Alternatively (S)- or
(R)-phenylglycine can be converted to the methyl ester using
SOCl2 in MeOH (see also ref.18).
(5) (a) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F.
J. Am. Chem. Soc. 1986, 108, 6395. (b) Evans, D. A.;
Britton, T. C.; Dorow, R. L.; Dellaria, J. F. Tetrahedron
1988, 44, 5525.
(6) Caron, M.; Carlier, P. R.; Sharpless, K. B. J. Org. Chem.
1988, 53, 5185.
(7) Williams, R. M.; Hendrix, J. A. J. Org. Chem. 1990, 55,
3723.
(8) Endo, A.; Kan, T.; Fukuyama, T. Synlett 1999, 1103.
(9) For the first report of the iminolactone 4 see: (a) Tohma, S.;
Endo, A.; Kan, T.; Fukuyama, T. Synlett 2001, 1179.
(b) and for its application to the total synthesis of
ecteinascidin 743, see: Endo, A.; Yanagisawa, A.; Abe, M.;
Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002,
124, 6552.
(10) (a) During the course of this investigation the preparation of
the iminolactone B from phenylglycinol A and reaction with
a Grignard reagent was reported: Harwood, L. M.; Tyler, S.
N. G.; Anslow, A. S.; MacGlip, I. D.; Drew, M. G. B.
Tetrahedron: Asymmetry 1997, 8, 4007. (b) Similar
iminolactones were prepared from 2-substituted oxazolines
(18) Alternatively compound 2 can be prepared from D-phenyl-
glycine methyl ester hydrochloride by direct treatment with
MeMgI in Et2O in moderate yield (41% from methyl ester
hydrochloride): Davies, S. G.; Polywka, M. E. C.; Sanganee,
H. J. US 005801249A, 1998.
Synthesis 2004, No. 6, 909–917 © Thieme Stuttgart · New York