Stereoselective synthesis of (S)-MPPG, (S)-MTPG and (S)-(+)-αM4CPG from (R)-4-hydroxyphenylglycine

Article abstract of DOI:10.1039/a704704e

(R)-4-Hydroxyphenylgrycine was protected with a benzyl group and a methyl group was introduced at the α position by using the self-regeneration-of-stereocentre method. After the 4-hydroxy group had been converted into the corresponding trifluoromethanesulfonate (triflate), three palladium-catalyzed reactions were employed to furnish (S)-α-methyl-4-phosphonophenylglycine [(S)-MPPG], (S)-α-methyl-4-(tetrazol-5-yl)phenylglycine [(S)-MTPG] and (S)-4-carboxyphenyl-α-methylglycine [(S)-αM4CPG], a class of new and selective antagonists of metabotropic glutamate receptors.

Full text of DOI:10.1039/a704704e

View Article Online / Journal Homepage / Table of Contents for this issue
Stereoselective synthesis of (S)-MPPG, (S)-MTPG and
(S)-(؉)-áM4CPG from (R)-4-hydroxyphenylglycine
Dawei Ma* and Hongqi Tian
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
(R)-4-Hydroxyphenylglycine was protected with a benzyl group and a methyl group was introduced at
the á position by using the self-regeneration-of-stereocentre method. After the 4-hydroxy group had been
converted into the corresponding trifluoromethanesulfonate (triflate), three palladium-catalyzed reactions
were employed to furnish (S)-á-methyl-4-phosphonophenylglycine [(S)-MPPG], (S)-á-methyl-4-(tetrazol-
5-yl)phenylglycine [(S)-MTPG] and (S)-4-carboxyphenyl-á-methylglycine [(S)-áM4CPG], a class of new
and selective antagonists of metabotropic glutamate receptors.
Me
Me
The metabotropic glutamate receptor (mGluR) family consists
at least eight distinct subtypes termed mGluR1 to mGluR8.
Based on their sequence homology, transduction mechanism,
and agonist selectivity, these subtypes have been classified into
three subgroups.1 Group I includes mGluR1 and mGluR5,
which are coupled to phospholipase C (PLC) and show very
similar agonist selectivity for quisqualate. In contrast, group II,
which contains mGluR2 and mGluR3, and group III, including
mGluR4, mGluR6, mGluR7, mGluR8 negatively couple to
adenylate cyclase and, thereby, depress elevations in cyclic
adenosine monophosphate (cAMP) levels. However, group II
and group III can be distinguished by their marked agonist-
selectivity. The former group effectively interact with
(2S,1ЈS,2ЈS)-2-(2-carboxycyclopropyl)glycine (-CCG-I) and
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-
ACPD], whereas the latter potently interact with (S)-2-amino-
4-phosphonobutyric acid (-AP4).1 In order better to charac-
terize the different synaptic functions for different subtypes,
antagonists, in particular those with subtype selectivity for
metabotropic glutamate receptors, are very much required.
Owing to Watkins’ pioneering work, a number of phenylglycine
derivatives have been identified as selective antagonists for
mGluRs.2 Among them, (S)-α-methyl-4-carboxyphenylglycine
[(S)-αM4CPG], was described as an antagonist of group I and
group II mGluRs,3 while α-methyl-4-phosphonophenylglycine
(MPPG) and α-methyl-4-(tetrazol-5-yl)phenylglycine (MTPG)
were identified as potent antagonists for group II and group III
mGluRs with different selectivities.4 In the past three years,
these compounds have found very immediate applications in
investigations of the functions of mGluRs in synaptic activ-
ity.1,5 In a preliminary communication,6 we reported the first
asymmetric synthesis of (S)-αM4CPG and the configurational
assignment of this compound. Although no report about the
activity of optical isomers of either MPPG or MTPG has
appeared, it is obvious that S-isomers for both compounds
should be active isomers. Recently, we found that our synthetic
protocol for (S)-αM4CPG was also suitable for asymmetric
synthesis of (S)-MPPG and (S)-MTPG. Herein, we detail our
results.
CO2H
NH2
CO2H
NH2
HO2C
X
X = P(O)(OH)2, MPPG
(S)-α-M4CPG
N
N
, MTPG
X =
N
N
H
Structures of (S)-α-M4CPG, MPPG and MTPG
NH2
NH2
CO2H
i, ii, iii
CO2H
60%
HO
BnO
2
1
iv, v
81%
NH2
But
N
PhCO
N
Me
vi, vii
88%
CONHMe
O
BnO
BnO
3
4
viii
92%
But
N
But
N
PhCO
PhCO
N
N
Me
Me
ix, x
95%
Me
Me
O
O
BnO
TfO
6
5
Scheme 1 Synthesis of key intermediate 6. Reagents: i, NaOH, then
CuSO4; ii, NaOH, then BnBr; iii, HCl; iv, MeOH, HCl; v, MeNH2; vi,
tBuCHO, then HCl, MeOH; vii, PhCOCl, Et3N; viii, LDA, then MeI;
ix, Pd/C, H2; x, Tf2O, 2,6-lutidine, DMAP.
Results and discussion
As outlined in Scheme 1, we started our total synthesis from
commercially available (R)-4-hydroxyphenylglycine 1. To avoid
problems from the hydroxy group in the following steps, we
needed a suitable protecting group. We found that a method
similar to that used for the protection of tyrosine7 could be
successfully extended to this case. Thus, (R)-4-hydroxy-
phenylglycine was treated with one mole equivalent of NaOH
and the resulting salt was mixed with CuSO4 to form an amino
acid–copper complex. This complex was treated with another
J. Chem. Soc., Perkin Trans. 1, 1997
3493

View Article Online
mole equivalent of NaOH, followed by reaction with benzyl
bromide, and then the product was triturated with 1  HCl to
release the free benzyl-protected (R)-4-hydroxyphenylglycine 2.
This operation could be carried out in one pot and gave com-
pound 2 in ~60% overall yield. We then used Seebach’s self-
regeneration-of-stereocentre strategy8 to introduce a methyl
group at the α position of this amino acid. Therefore, com-
pound 2 was converted into the corresponding methyl ester and
this was treated with methylamine to obtain amide 3 in 81%
yield. Amide 3 was allowed to react with tert-valeraldehyde, and
then the imine product was treated with methanol saturated
with gaseous HCl followed by the reaction with benzoyl chlor-
ide to afford 4 in ~88% overall yield. The trans-isomer is the
major product and only a small amount of cis-isomer was sep-
arated by silica gel chromatography. After treatment of trans-
isomer with lithium diisopropylamide (LDA), the resulting
anion was trapped with methyl iodide to produce compound 5.
The configuration of the new stereogenic centre should be S,
ide (TMSCN) as cyanide source produced the corresponding
nitrile, which was elaborated to the tetrazole 8 by heating of
a solution of the nitrile with 2 mol equiv. of azidotri-n-
butylstannane in the absence of solvent.13 The tetrazole 8 was
deprotected with 6  HCl to afford (S)-MTPG after ion-
exchange chromatography (Dowex 50-X-8). Finally, we could
obtain ester 9 by employing a palladium-catalyzed carbonyl-
ation,14 and the ester was hydrolyzed with 6  HCl, followed
by treatment with propylene oxide to afford (S)-αM4CPG.
To conclude, we have developed a general and asymmetric
route to (S)-MPPG, (S)-MTPG and (S)-αM4CPG. The syn-
theses of other phenylglycine derivatives by using this method,
together with their biological evaluation, are underway in this
group and will be reported in due course.
Experimental
General procedures
1
and H NMR spectroscopy showed that only one isomer was
Mps were measured on a capillary melting point apparatus and
are uncorrected. IR spectra were measured on a Shimadzu 440
spectrometer. 1H NMR spectra were recorded with SiMe4 as an
internal standard in a Bruker AM-300 spectrometer. J-Values
are given in Hz. MS spectra were determined on a Finnigan
4201 spectrometer or a VG Quattro MS/MS spectrometer.
Optical rotations were obtained on a Perkin-Elmer 241 Autopol
formed. It is worth noting that the present methodology should
permit the preparation of a wide variety of analogous com-
pounds, some of which have been previously reported,9 just by
employing different electrophiles. After removal of the benzyl
protecting group of compound 5 by Pd/C-catalyzed hydrogen-
ation, the resulting free hydroxy group was converted into the
triflate 6 by reaction with trifluoromethanesulfonic anhydride
(Tf2O).10
polarimeter, with [α]D-values, given in units of 10Ϫ1 deg cm2 gϪ1
.
CH2Cl2 was distilled from CaH2, and tetrahydrofuran (THF)
was distilled from a deep blue ketyl prior to use. All other
solvents were reagent-grade quality and were used as received.
Na2SO4 was used as the drying agent in all work-up procedures.
All reactions were run in flame-dried glassware under nitrogen
atmosphere unless stated otherwise. Light petroleum refers to
the fraction distilled between 60–90 ЊC.
With the key intermediate 6 in hand, we could use three Pd-
catalyzed reactions to generate our desired functional groups.
Thus, as shown in Scheme 2, treatment of triflate 6 with diethyl
But
PhCO
Me
CO2H
NH2
N
N
O
Me
ii
i
(R)-4-Benzyloxyphenylglycine 2
6
99%
78%
25 g (0.15 mol) of (R)-4-hydroxyphenylglycine 1 was dissolved
in 75 ml of 2  NaOH and then a solution of 35.7 g of
CuSO4ؒ5H2O (0.15 mol) in 40 ml of water was added to the
stirred solution. After stirring of this mixture for a further 20
min, 75 ml of 2  NaOH, 560 ml of methanol and 22 ml (0.19
mol) of benzyl bromide were added. The resulting solution was
stirred vigorously for 3 h and then the blue precipitate was
filtered off, and washed with 200 ml of methanol–water (3.5:1).
After trituration of the precipitate with 10 ml of 1  hydrochloric
acid, the mixture was filtered again and the operation was
repeated several times until the precipitate turned white. This
solid was washed successively with 50 ml of NH4OH, 50 ml of
water and 50 ml of methanol, and dried in vacuo to afford crude
title compound 2. Without further purification, this amino acid
was used directly for the next step; δH(300 MHz; CD3SOCD3)
7.45 (m, 5 H, C6H5CH2), 7.28 (d, J2,3 7.8, 2 H, ArH), 6.91 (d, J3,2
7.8, 2 H, ArH), 5.14 (s, 2 H, PhCH2) and 5.08 (s, 1 H, CHNH2).
Me
(HO)2(O)P
(EtO)2(O)P
(S)-MPPG
7
But
PhCO
Me
N
CO2H
NH2
N
O
Me
iii
iv, ii
66%
6
Me
98%
NC
N
N
N
N
H
8
(S)-MTPG
But
N
PhCO
N
Me
CO2H
NH2
Me
(R)-4-Benzyloxyphenyl-N-methylglycinamide 3
v
ii
6
Through a suspension of (R)-4-benzyloxyphenylglycine (40.0 g,
0.156 mol) in 350 ml of anhydrous methanol was introduced
gaseous hydrogen chloride until no more gas was absorbed. The
resulting solution was stirred overnight at room temperature
before the solvent was removed. The residue was dissolved with
50 ml of methanol and the solution was concentrated again to
remove remaining hydrochloride. Without further purification,
this ester was dissolved in 100 ml of anhydrous methanol. To
this solution, cooled to 0 ЊC, was added 300 ml of methylamine
in ethanol (300 ml). After the addition the solution was stirred
for 30 h at room temp. The solvent was removed on a Rotavapor
and the residue was treated with 100 ml of methylene dichloride.
The resulting suspension was filtered and the filtrate was con-
centrated. Column chromatography (silica gel; elution with
20:1 methylene dichloride–methanol) of the residual oil
afforded compound 3 (26.0 g, 71%) as a solid, mp 103–105 ЊC;
Me
94%
O
80%
HO2C
EtO2C
9
(S)-α-M4CPG
Scheme 2 Pd-catalyzed route to (S)-MPPG, (S)-MTPG and (S)-α-
M4CPG. Reagents: i, (Ph3P)4Pd, HP(O)(OEt)2, Et3N; ii, 6  HCl, then
propylene oxide, or ion-exchange chromatography; iii, (Ph3P)4Pd,
TMSCN, Et3N; iv, Bu3SnN3; v, Pd(OAc)2, DPPP, CO, EtOH.
hydrogen phosphite under catalysis by tetrakis(triphenyl-
phosphine)palladium11 afforded the diethyl arylphosphonate 7.
After heating of a solution of compound 7 in 6  HCl at
150 ЊC, all the protecting groups were removed and the result-
ing hydrochloride salt of the amino acid was treated with pro-
pylene oxide to release the free (S)-MPPG. Next, palladium-
catalyzed cyanation12 of triflate 6 by using trimethylsilyl cyan-
3494
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
[α]2D2 Ϫ22.3 (c 0.22, CHCl3); νmax(KBr)/cmϪ1 3380 (NH), 3030
(ArH) and 1650 (CO); δH(300 MHz; CDCl3) 7.46–7.27 (m, 7 H,
ArH), 7.05 (br s, 1 H, NH), 6.79 (d, J3,2 8.5, 2 H, ArH), 5.08
(s, 2 H, PhCH2), 4.54 (m, 1 H, CHNH2), 2.84 (d, J 4.9, 3 H,
NHCH3) and 1.65 (br s, 2 H, NH2); m/z (EI) 254 (Mϩ Ϫ 16)
(Found: Mϩ Ϫ CONHMe, 212.109. C14H14NO requires m/z,
212.108).
amino)pyridine (DMAP) (1.32 g, 10.8 mmol). The stirred
solution was cooled to Ϫ30 ЊC and triflic anhydride (Tf2O)
(9 ml, 53.5 mmol) was added. After being stirred for 2 h the
solution was warmed to room temp. and was then poured into
150 ml of ice–water. The organic layer was separated, washed
with water, dried over anhydrous Na2SO4, and concentrated.
The residual oil was allowed to pass through a short column of
silica gel with elution by 1:4 ethyl acetate–light petroleum to
afford compound 6 (17.4 g, 95%). Without further purification,
this triflate was directly used for the next step.
(2R,5R)-1-Benzoyl-5-(4-benzyloxyphenyl)-2-tert-butyl-3-
methylimidazolidin-4-one 4
A mixture of compound 3 (26.0 g, 96 mmol), trimethylacetal-
dehyde (13 ml, 120 mmol) and 80 ml of n-pentane was refluxed
with removal of water (Dean–Stark) for 3 h. After being cooled
the resulting suspension was concentrated at reduced pressure
and the residual oil was dissolved in 30 ml of anhydrous meth-
anol and then 60 ml of methanol saturated with gaseous HCl
was added at 0 ЊC. After being stirred for 3 h at room temp., the
solution was concentrated to dryness. The residue was dissolved
in 30 ml of anhydrous methanol and the solution was concen-
trated again to remove remaining hydrochloride. The resultant
yellow solid was dissolved in 250 ml of methylene dichloride
and then 200 ml of triethylamine was added, with cooling in an
ice–water-bath. After the mixture had been stirred for 20 min,
35 ml (300 mmol) of benzoyl chloride was added and the solu-
tion was stirred for 6 h at room temp. To quench the reaction
200 ml of ice–water was added. The organic layer was separated
and the aqueous layer was extracted with methylene dichloride
(3 × 150 ml). The combined organic layers were washed succes-
sively with water and brine, dried over Na2SO4, and concen-
trated. The residue was loaded on a column of silica gel and
eluted with 1:3 ethyl acetate–light petroleum to afford com-
pound 4 (37.5 g, 88% from 3), mp 203–205 ЊC (Found: C, 75.52;
H, 6.67; N, 6.12. C28H30N2O3 requires C, 75.98; H, 6.83; N,
6.33%); [α]2D2 Ϫ137.5 (c 1.02, CHCl3); νmax(KBr)/cmϪ1 3030
(ArH), 1700 (CO) and 1650 (CO); δH(300 MHz; CDCl3) 7.49–
7.16 (m, 12 H, ArH), 6.57 (m, 2 H, ArH), 5.85 (s, 1 H, ArCHN),
5.05 (s, 1 H, ButCH), 4.95 (s, 2 H, PhCH2), 3.17 (s, 3 H, NCH3)
and 1.14 (s, 9 H, But); m/z (EI) 385 (Mϩ Ϫ 57).
Pd-catalyzed coupling of triflate 6 with diethyl hydrogen
phosphite
A
mixture of triflate 6 (1.23 g, 2.48 mmol), tetrakis-
(triphenylphosphine)palladium (0.61 g, 0.51 mmol), diethyl
hydrogen phosphite (1.9 ml, 14.5 mmol) and 4 ml of triethyl-
amine was heated at 100 ЊC under nitrogen for 8 h. After having
cooled to room temp. the mixture was partitioned between 100
ml of ethyl acetate and 50 ml of water. The organic layer was
separated, washed successively with water and brine, dried over
anhydrous Na2SO4, and concentrated by Rotavapor. Chroma-
tography of the residual oil with 1:2 ethyl acetate–light petrol-
eum as eluent afforded phosphonate 7 (1.01 g, 84%); [α]2D2
ϩ141.3 (c 1.33, CHCl3); νmax(KBr)/cmϪ1 3050 (Ar᎐H), 1776
(C᎐O), 1728 (C᎐O) and 1410 (Ar᎐P); δ (300 MHz; CDCl ) 8.10
᎐
᎐
H
3
(m, 4 H, ArH), 7.43 (m, 5 H, ArH), 5.52 (s, 1 H, ButCH), 4.15 (q,
J 7.6, 4 H, OCH2CH3), 3.15 (s, 3 H, NCH3), 1.91 (s, 3 H, CH3),
1.36 (t, J 7.6, 6 H, OCH2CH3) and 0.86 (s, 9 H, But); m/z
(EI) 429 (Mϩ Ϫ 57) (Found: Mϩ Ϫ But, 429.160. C22H26N2O5P
requires m/z, 429.158).
(S)-á-Methyl-4-phosphonophenylglycine [(S)-MPPG]
The phosphonate 7 (0.48 g, 0.99 mmol) and 10 ml of 6  HCl
were placed in a sealed tube. This mixture was heated at 160 ЊC
for 24 h. After being cooled to room temp. it was extracted with
methylene dichloride (3 × 10 ml). The aqueous layer was con-
centrated to dryness at reduced pressure and the resulting pale
yellow solid was loaded onto an ion-exchange column (Dowex
50WX2-200) and eluted with water to afford (S)-MPPG (0.19
g, 78%); [α]2D2 ϩ58 (c 0.014, 6  HCl); νmax(KBr)/cmϪ1 3857–
2050br (CO2H, NH, OH), 1612 (NH3ϩ) and 1548 (CO2Ϫ);
δH(300 MHz; D2O) 7.73 (dd, JP-H 12.4, J3,2 8.3, 2 H, 3,5-ArH),
7.55 (dd, J2,3 8.3, JP-H 2.8, 2 H, 2,6-ArH) and 1.75 (s, 3 H, CH3);
m/z (FAB) 246 (Mϩ).
(2R,5S)-1-Benzoyl-5-(4-benzyloxyphenyl)-2-(tert-butyl)-3,5-
dimethylimidazolidin-4-one 5
To a solution of compound 4 (17.2 g, 38.9 mmol) in 400 ml of
anhydrous THF was added a solution of LDA (40 mmol) in
THF at Ϫ78 ЊC. The resulting solution was stirred for 1 h at the
same temperature and then methyl iodide (4 ml, 65 mmol) was
added. Stirring was continued for 2 h at Ϫ78 ЊC before the
solution was warmed to room temp. Saturated aq. ammonium
chloride (400 ml) was added to quench the reaction. The
organic layer was separated and the aqueous layer was
extracted with methylene dichloride. The combined organic
layers were washed successively with water and brine, and dried
over anhydrous Na2SO4. After removal of the solvent, the
residual oil was chromatographed (silica gel; 1:3 ethyl acetate–
light petroleum as eluent) to afford title compound 5 (16.2 g,
92%), mp 202–204 ЊC (Found: C, 75.98; H, 7.13; N, 5.81.
C29H32N2O3 requires C, 76.29; H, 7.06; N, 6.14%); [α]2D2 ϩ141.3
(c 1.33, CHCl3); νmax(KBr)/cmϪ1 3050 (ArH), 1690 (CO) and
1650 (CO); δH(90 MHz; CDCl3) 7.6–7.4 (m, 12 H, ArH), 6.9 (d,
J 8.4, 2 H, ArH), 5.4 (s, 1 H, ButCH), 5.0 (s, 2 H, PhCH2), 3.0 (s,
3 H, NCH3), 1.7 (s, 3 H, CH3) and 0.8 (s, 9 H, But); m/z (EI) 399
(Mϩ Ϫ 57).
Nitrile 8
To a solution of triflate 6 (1.30 g, 2.61 mmol) and TMSCN
(0.52 g, 5.22 mmol) in 6 ml of triethylamine was added
tetrakis(triphenylphosphine)palladium (0.15 g, 0.13 mmol).
The resulting mixture was stirred at reflux for 6 h under nitro-
gen, when TLC indicated complete conversion to nitrile. The
solution was partitioned between 150 ml of methylene di-
chloride and 50 ml of water. The organic layer was separ-
ated, washed successively with water and brine, and dried over
Na2SO4. After removal of solvent, the residual oil was chrom-
atographed to afford nitrile 8 (0.95 g, 98%), [α]2D2 ϩ167 (c
0.019, CHCl3); νmax(KBr)/cmϪ1 2235 (CN), 1702 (CO) and 1648
(CO); δH(300 MHz; CDCl3) 8.09 (d, J3,2 8.3, 2 H, ArH), 7.64 (d,
J2,3 8.3, 2 H, ArH), 7.44 (m, 5 H, ArH), 5.37 (s, 1 H, ButCH),
3.10 (s, 3 H, NCH3), 1.99 (s, 3 H, CH3) and 0.62 (s, 9 H, But);
m/z (EI) 376 (Mϩ) (Found: Mϩ Ϫ But, 318.122. C19H16N3O2
requires m/z, 318.124).
Triflate 6
A mixture of the benzyl ether 5 (16.3 g, 35.7 mmol), 0.5 g of
10% Pd/C and 250 ml of methanol was stirred under hydrogen
(ordinary pressure) for 3 h. After filtration to remove Pd/C, the
filtrate was concentrated to furnish the deprotected product,
which was dissolved in 250 ml of anhydrous methylene di-
chloride, and this was followed by addition of 2,6-dimethyl-
pyridine (2,6-lutidine) (5 ml, 42.9 mmol) and 4-(dimethyl-
(S)-á-Methyl-4-(tetrazol-5-yl)phenylglycine [(S)-MTPG]
A mixture of the nitrile 8 (200 mg, 0.55 mmol) and azidotri-
butylstannane (366 mg, 1.1 mmol) was heated at 80 ЊC under
N2 for 12 h. After being cooled to room temp. it was treated with
6  HCl. The resulting mixture was stirred for 2 h and was then
concentrated to dryness in vacuo. The residue was placed in a
sealed tube and 5 ml of 6  HCl were added. After the mixture
J. Chem. Soc., Perkin Trans. 1, 1997
3495

View Article Online
had been heated at 160 ЊC for 24 h it was cooled to room temp.
and extracted with methylene dichloride (3 × 10 ml). The aque-
ous layer was concentrated and the residue was purified on an
ion-exchange column (Dowex 50WX2-200; elution with water)
HCl)}; νmax(KBr)/cmϪ1 3424–2500 (NH, CO H), 1687 (C᎐O),
᎐
2
1602 (NH3ϩ) and 1540 (CO2Ϫ); δH(300 MHz; CDCl3) 7.88
(d, J3,2 8.4, 2 H, ArH), 7.50 (d, J2,3 8.4, 2 H, ArH) and 1.94
(s, 3 H, CH3); m/z (FAB) 210 (Mϩ).
to afford (S)-MTPG (89 mg, 66%), [α]2D2 Ϫ72.4 (c 0.009, 6 
ϩ
)
HCl); νmax(KBr)/cmϪ1 3400–2340br (CO2H, NH2), 1620 (NH3
Acknowledgements
We are grateful to the Chinese Academy of Sciences and
National Natural Science Foundation of China for their finan-
cial support.
and 1531 (CO2Ϫ); δH(300 MHz; D2O) 7.87 (d, J3,2 8.2, 2 H,
ArH), 7.48 (d, J2,3 8.2, 2 H, ArH) and 1.78 (s, 3 H, CH3); m/z
(FAB) 272 (Mϩ ϩ Kϩ).
Pd-catalyzed carbonylation of triflate 6
To a solution of triflate 6 (17.4 g, 35.4 mmol), 1,3-bis-
(diphenylphosphino)propane (DPPP) (1.51 g, 3.64 mmol) and
palladium diacetate (0.51 g, 2.25 mmol) in 100 ml of anhydrous
ethanol were added 20 ml of triethylamine. The mixture was
stirred under carbon monoxide (1 atm) at 70 ЊC for 3 h. After
being cooled to room temp., the mixture was partitioned
between 400 ml of water and 600 ml of methylene dichloride.
The organic layer was separated, washed successively with
water and brine, and dried over Na2SO4. After removal of the
solvent the residual oil was chromatographed (silica gel; elution
with 1:3 ethyl acetate–light petroleum) to afford ester 9 (14.4 g,
97%), mp 58–60 ЊC (Found: C, 69.74; H, 7.11; N, 6.20.
C25H30N2O4 requires C, 71.06; H, 7.16; N, 6.63%); [α]2D2 ϩ147.5
(c 1.48, CHCl3); νmax(KBr)/cmϪ1 3050 (ArH), 1710 (CO) and
1650 (CO); δH(300 MHz; CDCl3) 8.05 (m, 4 H, ArH), 7.52
(m, 5 H, ArH), 5.49 (s, 1 H, CHBut), 4.45 (q, J 7.2, 2 H,
CO2CH2CH3), 3.08 (s, 3 H, NCH3), 1.95 (s, 3 H, CH3), 1.24
(t, J 7.2, 3 H, CO2CH2CH3) and 0.81 (s, 9 H, But); m/z (EI)
365 (Mϩ Ϫ 57).
References
1 For reviews, see: T. Knopfel, R. Kuhn and H. Allgeier, J. Med.
Chem., 1995, 38, 1418; P. L. Ornstein, D. D. Schoepp and J. A.
Monn, Curr. Pharm. Design, 1995, 1, 355; T. Knopfel and
F. Gasparini, Drug Discovery Today, 1996, 1, 103.
2 J. C. Watkins and G. Collingridge, Trends Pharmacol. Sci., 1994, 15,
333; J.-P. Pin and R. Duvoisin, Neuropharmacology, 1995, 34, 1.
3 Y. Hayashi, N. Sekiyama, S. Nakanishi, D. E. Jane, D. C. Sunter,
E. F. Birse, P. M. Udvarhelyi and J. C. Watkins, J. Neurosci., 1994,
14, 3370.
4 D. E. Jane, K. Pittaway, D. C. Sunter, N. K. Thomas and J. C.
Watkins, Neuropharmacology, 1995, 34, 851.
5 J. J. O’Connor, M. J. Rowan and R. Anwyl, Nature, 1994, 367, 557;
Z. A. Bortolotto, Z. I. Bashir, C. H. Davies and G. L. Collingridge,
Nature, 1994, 368, 740.
6 D. Ma and H. Tian, Tetrahedron: Asymmetry, 1996, 6, 1567.
7 E. Wunsch, G. Fries and W. Siedel, Chem. Ber., 1958, 91, 542.
8 D. Seebach, J. D. Aebi, R. Neaf and T. Weber, Helv. Chim. Acta,
1985, 68, 144; for a review, see: D. Seebach, A. R. Sting and
M. Hoffmann, Angew. Chem., Int. Ed. Engl., 1996, 35, 2708.
9 N. Sekiyama, Y. Hayashi, S. Nakanishi, D. E. Jane, H.-W. Tse,
E. F. Birse and J. C. Watkins, Br. J. Pharmacol., 1996, 117, 1493, and
references cited therein.
(S)-4-Carboxyphenyl-á-methylglycine
10 R. E. Dolle, S. J. Schmidt and L. I. Kruse, J. Chem. Soc., Chem.
Commun., 1987, 904.
11 X. Lu and J. Zhu, Synthesis, 1987, 726.
12 N. Chatani and T. Hanafusa, J. Org. Chem., 1986, 51, 4714.
13 P. L. Ornstein, D. D. Schoepp, M. B. Arnold, J. D. Leander,
D. Lodge, J. W. Paschal and T. Elzey, J. Med. Chem., 1991, 34, 90.
14 S. Cacchi, P. G. Cittini, E. Morera and G. Ortar, Tetrahedron Lett.,
1986, 27, 3931.
The ester 9 (2.0 g, 4.7 mmol) and 30 ml of 6  HCl were placed
in a sealed tube. This mixture was heated at 150 ЊC for 18 h, by
which time the solution had clarified. After being cooled to
room temp. it was extracted with methylene dichloride (3 × 30
ml). The aqueous layer was concentrated to dryness at reduced
pressure and the resulting pale yellow solid was dissolved in 40
ml of ethanol. To this solution were added 10 ml of propylene
oxide and the mixture was heated at 50 ЊC for 10 min. After
storage overnight, the precipitate was filtered off, washed with
ethanol, and dried in vacuo to afford (S)-αM4CPG (0.82 g,
83%), [α]2D5 ϩ90 (c 0.53, 6  HCl) {lit.,3 [α]1D8 ϩ93 (c 0.53, 6 
Paper 7/04704E
Received 3rd July 1997
Accepted 11th August 1997
3496
J. Chem. Soc., Perkin Trans. 1, 1997