Synthesis of (S)-α-cyclopropyl-4-phosphonophenylglycine

Full text of DOI:10.1021/jo0013711

348
J . Org. Chem. 2001, 66, 348-350
Syn th esis of (S)-r-Cyclop r op yl-4-
p h osp h on op h en ylglycin e
Dawei Ma* and Wei Zhu
State Key Laboratory of Bioorganic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
madw@pub.sioc.ac.cn
Received September 15, 2000
Since it was discovered that some phenylglycine ana-
logues could selectively modulate the activity of metabo-
tropic glutamate receptors (mGluRs),1 many efforts have
been directed to the development of more selective
agonists or antagonists based on the phenylglycine
skeleton.2 By varying the substituents on either the
R-position or aromatic ring, several subtype-selective
antagonists 1a -h (Figure 1) were reported.3-9 Among
these antagonists, CPPG (R-cyclopropyl-4-phosphono-
phenylglycine 1d ), an analogue of phenylglycine with a
4-phosphono group and a R-cyclopropyl group, was found
to be a most potent and selective antagonist for group
III mGluRs. Recently this compound has been widely
used in probing the neurotransmission mechanism and
physiological functions of mGluRs.10 Because only S-
isomers of this class of analogues showed selective
antagonist activity,2 an efficient synthetic route for
preparing enantiopure CPPG is highly required in order
to check if it displayed similar stereoselective recognition
to mGluRs. Herein, we report the first asymmetric
synthesis of (S)-CPPG.
F igu r e 1. Structures of phenylglycine-type antagonists of
metabotropic glutamate receptors.
Sch em e 1a
a
Our synthesis started from (R)-4-benzoxyphenylglycine
2, which was prepared using (R)-4-hydroxyphenylglycine
as the starting material (Scheme 1).11 After the amino
Reagents and conditions: i. ClCOOMe/NaHCO3; ii. Ph-
CH(OMe)2, BF3‚Et2O; iii. NaHMDS then BrCH2CH2OTf; iv. LiOH,
H2O, THF; v. MeOH/HCl.
group was protected with methyl chloroformate, the
carbamate generated was reacted with benzaldehyde
dimethyl acetal in ether in the presence of boron trifluo-
ride etherate to produce trans-oxazolidinone 3.12 The pure
product was obtained in 73% overall yield after recrys-
tallization, and its stereochemistry was confirmed by its
NOESY spectra. With the oxazolidinone 3 in hand, we
planned to introduce a dicarbon functional group at the
R-position of amino acid moiety using the self-regenera-
tion of stereocenter strategy.13 Initially, reaction of
lithium enolate of 3 with ethylene oxide was attempted.14
Under several literature conditions such as direct cou-
pling or using trifluoride etherate as an additive, we did
not detect any coupling product. This problem might
result from the lower reactivity of the present enolate
compared with those reported in the literature.14 By
using a more reactive electrophile, we obtained the
alkylation product 4 successively. It was found that only
one diastereomer formed in this step as shown by either
(1) Watkins, J .; Collingridge, G. Trends Pharmacol. Sci. 1994, 15,
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Tse, H.-W.; Birse, E. F.; Watkins, J . C. Br. J . Pharmacol. 1996, 117,
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B.; J akobsen, P.; Kanstrup, A.; Lombardi, G.; Moroni, F.; Thomsen,
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(7) (a) Ma, D.; Tian, H.; Sun, H.; Kozikowski, A. P.; Pshenichkin,
S.; Wroblewski, J . T. Bioorg. Med. Chem. Lett. 1997, 7, 1195. (b) Ma,
D.; Tian, H.; Zou, G. J . Org. Chem. 1999, 64, 120.
(8) Clark, B. P.; Baker, S. R.; Goldsworthy, J .; Harris, J . R.;
Kingston, A. E. Bioorg. Med. Chem. Lett. 1997, 7, 2777.
(9) Doherty, P.; Palmer, M. J .; Henley, J . M.; Collingridge, G. L.;
J ane, D. E. Neuropharmacology 1997, 36, 265.
(10) (a) Matsumura, K.; Tsuchihashi, T.; Kagiyama, S.; Abe, I.;
Fujishima, M. Brain Res. 1999, 842, 461. (b) Ren, J .; Hu, H.-Z.; Liu,
S.; Xia, Y.; Wood, J . D. NeuroReport 1999, 10, 3045. (c) Lin, W.;
Kinnamon, S. C. J . Neurophysiol. 1999, 82, 2061. (d) Von Gersdorff,
H.; Schneggenburger, R.; Weis, S.; Neher, E. J . Neurosci. 1997, 17,
8137.
(12) O’Donnell, M. J .; Fang, Z.; Ma, X.; Huffman, J . C. Hetercycles
1997, 46, 617.
(13) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2708.
(14) (a) Smith, A. B.; Pasternak, A.; Yokoyama, A.; Hirschmann, R.
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(11) (a) Ma, D.; Tian, H. J . Chem. Soc., Perkin Trans 1 1997, 3493.
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10.1021/jo0013711 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/16/2000

Notes
J . Org. Chem., Vol. 66, No. 1, 2001 349
Sch em e 2a
hydrochloride salt. Upon purification by a Dowex-50W
column, the pure (S)-CPPG was obtained in 99% yield.
In conclusion, we developed a stereospecific route to
synthesize (S)-CPPG. The biological evaluation of this
compound and amino acid 11 is in progress.
Exp er im en ta l Section
(2R,4R)-2-P h en yl-4-((4-p h en ylm eth oxy)p h en yl)-5-oxo-3-
oxa zolid in in eca r boxylic Acid , Meth yl Ester 3. To a suspen-
sion solution of (R)-4-benzoxyphenylglycine (25 g, 97.3 mmol),
NaHCO3 (16.3 g, 194.6 mmol) in 150 mL of water, and 25 mL of
chloroform was added methyl chloroformate (15.0 mL, 194.6
mmol) in a dropwise manner. After the solution was stirred for
another 24 h, 1 N HCl was added to adjust pH ) 4. The mixture
was extracted with ethyl acetate. The organic layer was washed
with brine, dried over MgSO4, and concentrated to yield a crude
solid, which was dissolved in 150 mL of dry ether. To this stirring
solution were added benzaldehyde dimethyl acetal (14.8 mL,
107.0 mmol) and boron trifluoride etherate (50.9 mL, 414.5
mmol) by syringe. After it was stirred for 72 h, the reaction
mixture was filtered. The filter cake was washed with ether to
give 28.6 g (73%) of 3 as a white solid. Mp: 229-231 °C (ethyl
a
Reagents and conditions: i. (PhSe)2, NaBH4; ii. CH2N2; iii. O3;
iv. CCl4, reflux; v. CH2N2, Pd(acac)2; vi. Pd/C, H2; vii. Tf2O, Et3N;
viii. Pd(Ph3P)4, HP(O)(OEt)2, Et3N; ix. 2 N NaOH, reflux, then
Dowex-50W; x. 2 N HCl, 80 °C, then Dowex-50W.
acetate); [R]24 -165 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3)
D
δ 7.41-7.27 (m, 12H), 7.00 (d, J ) 8.7 Hz, 2H), 6.69 (s, 1H),
5.36 (s, 1H), 5.05 (s, 2H), 3.43 (s, 3H); MS m/z 403 (M+); HRMS
found m/z 403.1420 (M+); C24H21NO5 requires 403.1421.
HPLC (DIKMA C18, 4.6 × 150 mm, 1/1-1/0 MeCN/H2O
1
(2R,4S)-2-P h en yl-4-(2-br om oeth yl)-4-((4-ph en ylm eth oxy)-
p h en yl)-5-oxo-3-oxa zolid in in eca r boxylic Acid , Meth yl Es-
ter 4. A solution of 3 (5.0 g, 12.4 mmol) in 350 mL of anhydrous
THF was cooled to -78 °C. To this solution was added NaHMDS
(1 M in THF, 14.9 mL, 14.9 mmol) at -78 °C under argon
atmosphere. After the stirring was continued for 30 min, BrCH2-
CH2OTf (4.14 g, 16.1 mmol) was added by syringe. The reaction
mixture was stirred for another 45 min at the same temperature,
and then 50 mL of saturated aqueous NH4Cl was added to
quench the reaction. The mixture was extracted with ethyl
acetate, and the organic layer was washed with brine and dried
over MgSO4. After the solvent was evaporated, the residual oil
was purified by flash chromatography (silica gel, 2/1 petroleum
ether/ethyl acetate as eluent) to afford 5.6 g (88%) of 4 as a
as eluent) or H NMR. Treatment of the bromide 4 with
aqueous lithium hydroxide in THF provided the desired
lactone 6 in 54% yield, together with a byproduct 5 in
46% yield, which was converted into the lactone 6 by
refluxing in methanolic hydrochloride. Next, lactone
cleavage of 6 with benzeneselenolate anion followed by
oxidation/pyrolysis produced the olefin 7 in 80% overall
yield (Scheme 2).15 Cyclopropanation of 7 with diazo-
methane under the action of various catalysts such as
Pd(OAc)2, Pd(acac)2, CuI, Cu(acac)2, and PdCl2 was
tried.16 In most cases the reaction occurred with low
conversion. The highest conversion (23%) was observed
when Pd(acac)2 was used as catalyst. In this case 85%
yield was reached based on the recovery of the starting
material. The reason for this low conversion is unclear,
but one possible explanation is the steric hindrance of
olefin 7. It was notable that under Simmons-Smith
condition17 less 10% conversion was observed. By careful
column chromatography, the pure cyclopropanation prod-
uct 8 was isolated, which was deprotected by Pd/C-
catalyzed hydrogenation and then transformed into
triflate 9 with Tf2O. Finally, coupling of the triflate 9 with
diethyl phosphite catalyzed by Pd(Ph3P)4 afforded phos-
phonate 10.11a The deprotection of 10 was found to be
another challenging step in this synthesis. Under higher
reaction temperatures (>100 °C), hydrolysis of 10 with
aqueous hydrochloride provided the ring-opened prod-
ucts, while under lower reaction temperature it gave
incomplete deprotection products. After some experimen-
tation, we found that this problem could be solved by
stepwise hydrolysis. Accordingly, refluxing the phospho-
nate 10 in 2 N NaOH for 2 days afforded amino acid 11
as a single product, which was further hydrolyzed in 2
N HCl at 80 °C for 3 days, providing crude 1 as the
colorless oil. [R]20 +44 (c 1.3, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.43-7.27 (m, 12H), 6.95 (d, J ) 8.4 Hz, 2H), 6.61 (s,
1H), 5.06 (s, 2H), 3.70 (s, 3H), 3.40 (m, 2H), 3.05 (m, 1H), 2.38
(m, 1H); MS m/z 509 (M+, 79Br); HRMS found m/z 509.0838 (M+,
79Br); C26H24BrNO5 requires 509.0833.
(S)-r-(2-Hydroxyethyl)-r-((methylcarboxy)amino)-4-(phen-
ylm eth oxy)ben zen ea cetic Acid 5 a n d (S)-2-Oxo-3-(4-p h en -
ylm eth oxy)p h en yl-3-(m eth oxyca r bon yl)a m in otetr a h yd r o-
fu r a n 6. A mixture of 4 (5.6 g, 10.9 mmol) and LiOH (1.0 g,
19.4 mmol) in 50 mL of THF and 10 mL of H2O was stirred at
room temperature until the starting material was consumed.
The mixture was added 1 N HCl to adjust pH ) 5 before it was
extracted with ethyl acetate. The organic layer was washed with
brine, dried over MgSO4, and concentrated. The residual oil was
purified by flash chromatography (silica gel, 2/1 petroleum ether/
ethyl acetate as eluent) to afford 2.0 g (54%) of 6 as a white
solid, together with 1.8 g (46%) of alcohol 5.
To a solution of 5 (1.8 g, 5 mmol) in 20 mL of methanol was
introduced gaseous hydrogen chloride until the starting material
was consumed. The mixture was evaporated, and the residual
oil was purified by flash chromatography (silica gel, 2/1 petro-
leum ether/ethyl acetate as eluent) to provide 1.4 g (82%) of 6.
5: [R]16 +55 (c 1.4, CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
7.45-7.31 (m, 7H), 6.95 (d, J ) 8.1 Hz, 2H), 5.60 (br s, 1H),
5.02 (s, 2H), 3.65 (s, 3H), 3.41-2.53 (m, 4H); MS (ESI) m/z 382
(M+ + Na+).
6: Mp: 103-105 °C (ethyl acetate/hexane); [R]20D +50 (c 0.43,
1
(15) (a) Pedersen, M. L.; Berkowitz, D. B. J . Org. Chem. 1993, 58,
6966. (b) Berkowitz, D. B. Synth. Commun. 1990, 20, 1819.
(16) (a) Suda, M. Synthesis, 1981, 714. (b) Tomilov, Yu. V.; Dokichev,
V. A.; Dzhemilev, U. M.; Nefedov, O. M. Russ. Chem. Rev. 1993, 62,
799.
(17) Simmons, H. E.; Cairns, T. L.; Vladuchick, S. A. Org. React.
1973, 20, 1.
CHCl3); H NMR (300 MHz, CDCl3) δ 7.47-7.31 (m, 7H), 7.00
(d, J ) 8.1 Hz, 2H), 5.53 (s, 1H), 5.08 (s, 2H), 4.50 (t, J ) 9.0
Hz, 1H), 4.10 (dt, J ) 9.1, 5.7 Hz, 1H), 3.66 (s, 3H), 3.11 (dd,
J ) 13.0, 9.4 Hz, 1H), 2.95 (dd, J ) 13.0, 5.6 Hz, 1H); MS m/z
341 (M+); HRMS found m/z 341.1263 (M+); C19H19NO5 requires
341.1260.

350 J . Org. Chem., Vol. 66, No. 1, 2001
Notes
(S)-r-Vin yl-r-(m eth oxycar bon yl)am in o-4-ph en ylm eth oxy-
ben zen ea cetic Meth yl Ester 7. A 250 mL two-neck flask
containing sodium borohydride (1.2 g, 31.7 mmol) was fitted with
a no. 17 needle as gas outlet and purged with argon over a period
of 1 h. Solutions of diphenyl diselenide (4.9 g, 15.6 mmol) in dry
DMF (100 mL) and compound 6 (8.9 g, 26 mmol) in dry DMF
(100 mL) were prepared and cooled to -78 °C. Each frozen
solution was subjected to 20 cycles of argon purging followed by
evacuating to 0.1 Torr. Finally each solution was allowed to thaw
to room temperature under vacuum and then placed under argon
atmosphere. The diphenyl diselenide solution was rapidly
transferred to the solid NaBH4 via cannula and stirred to
produce a clear faint yellow solution. To this solution was added
in an identical manner the solution of compound 6 in DMF. The
reaction mixture was then heated at 110 °C for 30 min. The
reaction mixture was cooled to 0 °C, and methanol was added
to destroy the borane formed in the reaction. After the solvent
was removed on a rotary evaporator, the residue was adjusted
to pH ) 2.5 and extracted with ethyl acetate. The organic layer
was washed with brine, dried over MgSO4, and concentrated to
give a crude acid, which was put into a 100 mL flask, and then
diazomethane ether solution (about 1 M) was added. After the
acid was consumed monitored by TLC, the reaction was quenched
with acetic acid. The solvent was evaporated in vacuo, and the
crude oil was purified by flash chromatography (silica gel, 4/1
petroleum ether/ethyl acetate as eluent) to give the correspond-
ing ester.
After the purified ester was dissolved in 150 mL of CH2Cl2,
ozone was bubbled into the solution at -78 °C until a light blue
color persisted. To this mixture was added 1-hexene to give a
colorless solution. The cold solution was then added dropwise
to refluxing CCl4, and the refluxing was continued for 30 min.
The mixture was concentrated in vacuo, and the residual oil was
purified by flash chromatography (silica gel, 4/1 petroleum ether/
ethyl acetate as eluent) to provide 7.4 g (80%) of 7 as a colorless
oil. [R]16D +18 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.40-
7.30 (m, 7H), 6.90 (d, J ) 6.9 Hz, 2H), 6.55 (dd, J ) 17.3, 10.5
Hz, 1H), 5.97 (s, 1H), 5.39 (d, J ) 10.5 Hz, 1H), 5.31 (d, J )
17.3 Hz, 1H), 5.01 (s, 2H), 3.71 (s, 3H), 3.59 (s, 3H); MS m/z 355
(M+); HRMS found m/z 355.1411 (M+); C20H21NO5 requires
355.1416.
solution of Tf2O (1.6 mL, 11.3 mmol) in 10 mL of methylene
chloride at -30 °C, respectively. After the reaction mixture was
stirred for another 2 h, it was concentrated, and the residual oil
was purified by flash chromatography (silica gel, 3/1 petroleum
ether/ethyl acetate as eluent) to provide 3.4 g (96%) of 9 as a
1
pale yellow oil. [R]16 +10 (c 0.77, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 7.67 (d, J ) 8.1 Hz, 2H), 7.23 (d, J ) 8.1 Hz, 2H), 6.09
(s, 1H), 3.70 (s, 3H), 3.56 (s, 3H), 1.89 (m, 1H), 0.68 (m, 2H),
0.52 (m, 2H); MS m/z 411 (M+); HRMS found m/z 411.0600 (M+);
C15H16F3NO7S requires 411.0597.
(S)-r-Cyclop r op yl-r-(m eth oxyca r bon yl)a m in o-4-(d ieth -
ylp h osp h on o)ben zen ea cetic Meth yl Ester 10. To a solution
of 9 (3.0 g, 7.2 mmol) in 30 mL of Et3N were added diethyl
phosphite (1.8 mL, 10.8 mmol) and Pd(PPh3)4 (800 mg, 0.72
mmol) under argon. After the resultant mixture was refluxed
for 3 h, the cooled solution was concentrated, and the residue
was partitioned between 5 mL of water and 50 mL of ethyl
acetate. The organic layer was dried over MgSO4 and concen-
trated. The residual oil was purified by flash chromatography
(silica gel, 1/1 petroleum ether/ethyl acetate as eluent) to afford
2.5 g (87%) of 10 as a pale yellow oil. [R]16D +16 (c 0.55, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.78 (dd, J ) 12.8, 8.2 Hz, 2H),
7.66 (dd, J ) 8.1, 2.3 Hz, 2H), 6.10 (s, 1H), 4.13 (m, 4H), 3.68 (s,
3H), 3.55 (s, 3H), 1.91 (m, 1H), 1.26 (t, J ) 6.3 Hz, 6H), 0.69 (m,
2H), 0.48 (m, 2H); MS m/z 399 (M+); HRMS found m/z 399.1447
(M+); C18H26NO7P requires 399.1443.
(S)-r-Cyclop r op yl-4-(eth ylp h osp h on o)p h en ylglycin e 11.
A mixture of 10 (1.0 g, 2.5 mmol) in 10 mL of 2 N NaOH was
heated at reflux for 2 days. The cooled solution was concentrated
in vacuo to dryness, and the residue was extracted by ethanol.
The unsolved solid was filtered off, and the filtrate was concen-
trated. The residue was purified by Dowex-50W using water as
eluent to provide 740 mg (99%) of 11 as a white solid. Mp: 246
°C (dec); [R]27 +10 (c 1.05, H2O); 1H NMR (300 MHz, D2O) δ
D
7.79-7.66 (m, 4H), 3.81 (m, 2H), 1.51 (m, 1H), 1.17 (t, J ) 7.5
Hz, 3H), 0.84 (d, J ) 8.3 Hz, 2H), 0.71 (m, 1H), 0.48 (m, 1H);
31P NMR (121 MHz, D2O) δ 15.32; 13C NMR (75 MHz, D2O) δ
178.86, 141.74, 136.60 (d, J ) 135.0 Hz), 134.23 (d, J ) 7.5 Hz),
129.57 (d, J ) 10.6 Hz), 69.69, 64.25 (d, J ) 3.9 Hz), 18.40, 18.00,
5.3; MS (ESI) m/z 300 (M+ + H+).
(S)-r-Cyclop r op yl-4-p h osp h on op h en ylglycin e 1d . A solu-
tion of 11 (600 mg, 2.0 mmol) in 10 mL of 2 N HCl was heated
to 80 °C for 3 days. The cooled solution was concentrated, and
the residue was purified by Dowex-50W using water as eluent
to provide 540 mg (99%) of 1d as a white solid. Mp: 243 °C (dec);
[R]27D +17 (c 1.05, 10% NaOH/H2O); 1H NMR (300 MHz, D2O) δ
7.82 (dd, J ) 12.5, 8.0 Hz, 2H), 7.71 (dd, J ) 7.6, 1.5 Hz, 2H),
1.70 (m, 1H), 0.89 (d, J ) 8.2 Hz, 2H), 0.75 (dd, J ) 10.3, 5.7
Hz, 1H), 0.53 (dd, J ) 10.0, 5.6 Hz, 1H); 31P NMR (121 MHz,
D2O) δ 11.91; 13C NMR (75 MHz, D2O) δ 185.38, 148.68, 141.88
(d, J ) 125.4 Hz), 132.80 (d, J ) 6.8 Hz), 128.78 (d, J ) 9.6 Hz),
66.73, 20.76, 3.85, 2.81; MS (ESI) m/z 272 (M+ + H+).
(S)-r-Cyclop r op yl-r-(m eth oxyca r bon yl)a m in o-4-(p h en -
ylm eth oxy)ben zen ea cetic Meth yl Ester 8. An excess of
ethereal diazomethane was added slowly to a solution of
compound 7 (7.4 g, 20.8 mmol) and Pd(acac)2 (300 mg, 0.98
mmol) in 50 mL of ether. After the solution was stirred for 10 h
at room temperature, the excess diazomethane was removed
using a stream of nitrogen. The mixture was evaporated, and
the residual oil was purified by flash chromatography (silica gel,
4/1 petroleum ether/ethyl acetate as eluent) to afford 5.4 g (73%)
of starting material and 1.77 g (23%) of 8. [R]16 +16 (c 1.0,
D
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.45-7.34 (m, 7H), 6.93
(d, J ) 8.8 Hz, 2H), 5.97 (s, 1H), 5.01 (s, 2H), 3.70 (s, 3H), 3.59
(s, 3H), 1.93 (m, 1H), 0.62 (m, 2H), 0.48 (m, 2H); MS m/z 369
(M+); HRMS found m/z 369.1578 (M+); C21H23NO5 requires
369.1572.
(S)-r-Cyclop r op yl-r-(m eth oxyca r bon yl)a m in o-4-((tr iflu -
or om eth yl)su lfon yloxy)ben zen ea cetic Meth yl Ester 9. To
solution of 8 (3.2 g, 8.6 mmol) in 50 mL of methanol was added
Pd/C (10%, 320 mg). The suspension solution was stirred for 3
h under H2 atmosphere at ambient temperature before it was
filtered. The filtrate was evaporated to yield a crude oil, which
was dissolved in 50 mL of methylene chloride. To this stirring
solution was added triethylamine (2.3 mL, 17 mmol) and a
Ack n ow led gm en t. The authors are grateful to the
Chinese Academy of Sciences, National Natural Science
Foundation of China (grant 29725205), and Qiu Shi
Science & Technologies Foundation for their financial
support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 3 and 6-10. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0013711