Solid-phase synthetic method for (±)-α-amino acids via phase-transfer catalytic alkylation

Article abstract of DOI:10.1016/j.tetlet.2004.11.020

A solid supported glycineimine t-butyl ester was designed and successfully applied to the synthesis of (±)-α-amino acids. The phase-transfer catalytic alkylation, followed by acidic hydrolysis and benzoylation gave N-benzoyl-α-amino acid tert-butyl esters in high yields (up to 92%).

Full text of DOI:10.1016/j.tetlet.2004.11.020

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 93–95
Solid-phase synthetic method for ( )-a-amino acids via
phase-transfer catalytic alkylation
Hyeung-geun Park,* Mi-Jeong Kim, Mi-Kyung Park, Hyun-Ju Jung, Jihye Lee,
Yeon-Ju Lee, Byeong-Seon Jeong, Jeong-Hee Lee, Mi-Sook Yoo,
Jin-Mo Ku and Sang-sup Jew*
Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Korea
Received 4 October 2004; revised 27 October 2004; accepted 4 November 2004
Abstract—A solid supported glycineimine t-butyl ester was designed and successfully applied to the synthesis of ( )-a-amino acids.
The phase-transfer catalytic alkylation, followed by acidic hydrolysis and benzoylation gave N-benzoyl-a-amino acid tert-butyl
esters in high yields (up to 92%).
ꢀ 2004 Elsevier Ltd. All rights reserved.
Natural and nonnatural ( )-a-amino acids have been re-
garded as one of the important components for the drug
design of peptidomimetics, due to their important role in
activity, stability and bioavailability.1 Among the syn-
thetic methodologies, the solid-phase synthetic methods
have been extensively developed and applied to the com-
binatorial synthesis or parallel synthesis of a-amino
acids and peptides.2 Recently, OꢀDonnell and Scott re-
ported very efficient solid-phase synthetic methods for
a-amino acids and peptides by the phase-transfer alkyla-
tion.3 They used the resin bound diphenylimine-glycine
ester (1) and successfully applied to the synthesis of nat-
ural and nonnatural a-amino acids (Scheme 1). In this
letter, we report a new solid-phase synthetic method
for a-amino acids via phase-transfer catalytic alkylation.
final stage of the synthesis. Among the various linkers
developed over the past 20 years, most of the linkers
for the synthesis of a-amino acids and peptides were es-
ter (Scheme 1).2 Imines have not been popular linkers
due to their instability in acidic condition. But it was
presumed that aromatic imines could be stable enough
to prevent the hydrolysis in the basic conditions of the
phase-transfer alkylation. In addition, the aromatic
imine linkers themselves could take place of the role of
imine moieties in diphenylimine-glycine esters, which
could make the a-hydrogen acidic enough to form the
corresponding enolate by weak alkali bases.4 Therefore,
the linker was changed from an ester group (1) to an
imine group (3) and the resin bound ester was replaced
with t-butyl ester, as shown in Scheme 2.
The connecting point of the linker to the solid support
should be chemically stable during the synthesis. Also,
its cleavage should be as quantitative as possible at the
Resin bound t-butyl imine esters 8A and 8B were
prepared from Merrifield resin.5 The Merrifield resin
was oxidized to the corresponding aldehyde 6A by
O
O
PTC
H+
H2N
CO2H
Ph
N
Ph
N
O
W
O
W
alkylation
R
Ph
Ph
R
α-amino acid
1
2
= Wang resin
W
Scheme 1.
Keywords: Phase-transfer catalytic alkylation; Solid-phase synthesis; a-Amino acid.
*
Corresponding authors. Tel.: +82 28807871; fax: +82 28729129 (H.P.); e-mail: hgpk@plaza.snu.ac.kr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.020

94
H. Park et al. / Tetrahedron Letters 46 (2005) 93–95
O
O
PTC
hydrolysis
H2N
CO2H
N
N
O
O
alkylation
R
X
X
R
α-amino acid
3
X = H or Ph
4
Scheme 2.
dimethylsulfoxide in the presence of NaHCO3.6 The
addition of phenyl Grignard reagent to 6A, followed
by oxidation gave 6B. The condensation of 6A and 6B
with glycine t-butyl ester gave the corresponding imines
8A and 8B, respectively. Their efficiencies for phase-
transfer alkylation were evaluated by benzylation.7
The phase-transfer benzylations of 8A and 8B were per-
formed by using 10mol% of tetrabutylammonium bro-
mide with benzyl bromide (5equiv) and 50% aqueous
KOH (10equiv) in toluene/chloroform (volume ra-
tio = 7:3) at room temperature for 48h. The hydrolysis
of the a-benzylated ketimine 9B with 1N HCl, followed
by benzoylation afforded 10 (27%) along the correspond-
ing nonalkylated product (52%). In the case of the a-
benzylated aldimine 9A, 10 (85%) was obtained without
any nonalkylated product, showing that the aldimine
(8A) is a more appropriate substrate than the ketimine
(8B) in solid-phase alkylation. Notably, there was no
dibenzylated product from 8A in the presence of excess
base. Generally, the aldimines have been applied to the
synthesis of a,a-dialkylamino acids in solution-phase
system.8 Once the aldimines are alkylated, another a-
hydrogen still acidic enough to form the corresponding
enolates for the second alkylation in the presence of ex-
cess base. However, the solid supported aldimine (8A)
gave only mono-alkylation. We tentatively propose that
the second alkylation might be inhibited by the steric
hinderance, involved in solid-supported polymer itself.
8A was chosen for further investigation with various al-
kyl halides.9 The high yields (up to 92%) shown in Table
1 indicate that this solid-phase synthetic method is a
very efficient synthetic method for natural and nonnatu-
ral ( )-a-amino acids. As one of merits compared to
OꢀDonnell and Scottꢀs method, 6A could be recovered
a
O
O
N
N
O
O
R
R
R
6
8
A
B
R = H
R = Ph
b
O
O
c
BzHN
O
R'
R'
10
9
Scheme 4. Reagents and conditions: (a) glycine t-butyl esterÆHCl,
Et3N, C6H6, reflux, 27h, (b) 50% aq KOH, RX, toluene–CHCl3 (7:3),
rt (c) (i) 1N HCl, THF, rt, (ii) BzCl, TEA, CH2Cl2, rt, 50–92% from 8.
Table 1. Phase-transfer catalytic alkylationa
O
O
TBAB, RX i) 1N-HCl
BzHN
N
O
O
50% KOH
ii) BzCl
R
10
8A
Entry
a
RX
Yieldb (%)
CH3(CH2)4CH2I
50
Br
b
c
82
80
Br
Br
d
85
Br
e
f
82
78
88
F
Br
NC
a
Br
O
g
Cl
H3C
5
6A
Br
Br
h
i
87
92
b
c
OH
Cl
O
j
85
6B
7
a The reaction was carried out with 5.0equiv of benzyl bromide and
10.0equiv of 50% aqueous KOH in the presence of 10.0mol% of
catalyst in toluene/chloroform (7:3) at room temperature for 48h.
b Isolated yield (10).
Scheme 3. Reagents and conditions: (a) NaHCO3, DMSO, 150ꢁC,
15h; (b) PhMgBr, THF, 0ꢁC; (c) Dess-martin periodinane, CH2Cl2,
0ꢁC.

H. Park et al. / Tetrahedron Letters 46 (2005) 93–95
95
6A (18g) was obtained after drying under vacuum, IR
(KBr) 3440, 3022, 2913, 1698, 1602, 1489cmÀ1. To an
anhydrous benzene (140mL) mixture of the aldehyde resin
6A (18g) and glycine tert-butyl ester hydrochloride (9g,
52mmol) was added triethylamine (8.7g, 52mmol) and the
reaction mixture was refluxed for 10h at 80ꢁC. The resin
was filtrated and washed with a series of solvents: benzene,
dichloromethane, a mixture of dichloromethane and
methanol (1:1), methanol and dichloromethane. Pale
yellow resin 8A (18g, 0.26mmol/g) was obtained after
drying under vacuum, IR (KBr) 3441, 3025, 2920, 1736,
after hydrolysis of 9A and directly recycled to prepare
the substrate 8A, which could make the imine-linker
method more practical for industrial process10 (Schemes
3 and 4).
In conclusion, a new, efficient solid-phase synthetic
methodology for a-amino acids was developed using
the phase-transfer catalytic alkylation of resin bound t-
butyl glycine-imine ester (8A), and showed that the aro-
matic imines could be efficient linkers in the solid-sup-
ported phase transfer alkylation. The easy preparation
of the solid supported substrate, the high chemical yield,
the very mild reaction conditions and the recycling of 6A
could make this method applicable to the combinatorial
synthesis or parallel synthesis for a-amino acids.
1646, 1603cmÀ1
.
6. Frechet, J. M.; Schuerch, C. J. Am. Chem. Soc. 1971, 93,
492.
7. Representative procedure for the catalytic phase-transfer
alkylation of 8A (benzylation): To a mixture of aldimine
8A (300mg, 0.077mmol) and tetrabutylammonium bro-
mide (2.6mg, 0.008mmol) in 7:3 mixture of toluene and
chloroform (2mL) was added 50% aqueous potassium
hydroxide (0.3mL, 1.0mmol) and benzyl bromide
(0.045mL, 0.38mmol). The reaction mixture was stirred
vigorously at room temperature for 48h. The resin was
filtrated and washed with methylene chloride and meth-
anol. The yellow coloured resin 9A was dried under
vacuum. To the resin 9A in tetrahydrofuran (1mL) was
added 1N HCl (0.5mL) and the reaction mixture were
stirred at room temperature for 1h. The reaction mixture
was filtered and washed with tetrahydrofuran, methylene
chloride and methanol. The combined solvent was
removed under vacuum, basified with satd aq NaHCO3
(3mL) and extracted with methylene chloride (5 · 10mL).
The combined methylene chloride was dried over anhy-
drous MgSO4 and concentrated under vacuum. To the
methylene chloride (0.5mL) solution of the residue was
added triethylamine (0.032mL, 0.24mmol) and benzoyl
chloride (0.013mL, 0.12mmol) at 0ꢁC. The reaction
mixture was stirred for 0.5h and extracted with methylene
chloride (5 · 5mL). The combined methylene chloride was
washed with water, dried over anhydrous MgSO4 and
concentrated under vacuum. The residue was purified by
flash column chromatography (silica gel, hexane–
EtOAc = 10:1) to afford the desired product 10d as white
solid.
8. (a) OꢀDonnell, M. J.; Wu, S. Tetrahedron: Asymmetry
1992, 3, 591; (b) Lygo, B.; Crosby, J.; Perterson, J. A.
Tetrahedron Lett. 1999, 40, 8671; (c) Ooi, T.; Takeuchi,
M.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2000,
122, 5228; (d) Jew, S.-s.; Jeong, B.-S.; Lee, J.-H.; Yoo,
M.-S.; Lee, Y.-J.; Park, B.-s.; Park, H.-g. J. Org. Chem.
2003, 68, 4514.
9. All new compounds gave satisfactory analytical and
spectral data. Selected data for 10d: White solid; mp
61ꢁC (CHCl3); 1H NMR (CDCl3, 300MHz) d 7.67 (d,
J = 8.6Hz, 2H), 7.33–7.46 (m, 5H), 7.24–7.11 (m, 2H),
6.58 (d, J = 6.8Hz, 1H), 4.86–4.93 (m, 1H), 3.17 (d,
J = 5.3Hz, 2H), 1.37 (s, 9H) ppm; 13C NMR (CDCl3,
75MHz) d 170.8, 166.8, 133.7, 131.7, 130.2, 129.6,
128.6, 128.4, 127.0, 82.7, 53.9, 38.0, 28.0ppm; IR (KBr)
2978, 1723, 1645, 1530, 1488, 1453cmÀ1; MS (ESI) m/z
348 [M+Na]+, HRMS (FAB) calcd for [C20H22NO3]:
324.3936, found: 325.1679 [M+H]+.
Acknowledgements
This work was supported by a grant (01-PJ2-PG6-
01NA01-0002) from the Korea Health 21 R&D Project,
Ministry of Health&Welfare, Republic of Korea.
References and notes
1. For lead references, see: Asymmetric Synthesis of Novel
Sterically Constrained Amino Acids; Symposium-in-Print,
Hruby, V. J.; Soloshonok, V. A., Eds. Tetrahedron 2001,
57, 6329–6650.
2. (a) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2419; (b)
Merrifield, R. B. Science 1986, 232, 341; (c) Terrett, N. K.
Combinatorial Chemistry; Oxford University Press:
Oxford, 1998; Do¨rwald, F. Z. Organic Synthesis on Solid
Phase; Wiley-VCH Verlag: GmbH (Germany), 2000;
Bannwarth, W.; Felder, E. Combinatorial Chemistry;
Wiley-VCH Verlag: GmbH (Germany), 2000; Seneci, P.
Solid-Phase Synthesis and Combinatorial Technologies;
John Wiley and Sons: New York, 2000.
3. (a) OꢀDonnell, M. J.; Zhou, C.; Scott, W. L. J. Am. Chem.
Soc. 1996, 118, 6070; (b) Scott, W. L.; Zhou, C.; Fang, Z.;
OꢀDonnell, M. J. Tetrahedron Lett. 1997, 38, 3695; (c)
OꢀDonnell, M. J.; Lugar, C. W.; Pottorf, R. S.; Zhou, C.
Tetrahedron Lett. 1997, 38, 7163; (d) Griffith, D. L.;
OꢀDonnell, M. J.; Pottorf, R. S.; Scott, W. L.; Porco, J. A.,
Jr. Tetrahedron Lett. 1997, 38, 8821; (e) Dorminguez, E.;
OꢀDonnell, M. J.; Scott, W. L. Tetrahedron Lett. 1998, 39,
2167.
4. (a) OꢀDonnell, M. J.; Boniece, J. M.; Earp, S. E.
Tetrahedron Lett. 1978, 19, 2641; (b) OꢀDonnell, M. J.;
Eckrich, T. M. Tetrahedron Lett. 1978, 19, 4625; (c)
OꢀDonnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663;
(d) OꢀDonnell, M. J. Aldrichim. Acta 2001, 34, 3.
5. Procedure for the synthesis of 8A: To a dimethyl sulfoxide
(120mL) mixture of Merrifield resin (20g, 0.94mmol/g,
purchased from BEADTECH in Korea) were added
sodium bicarbonate (4g, 7.0mmol) and the reaction
mixture was stirred for 12h at 155ꢁC. The resin was then
filtrated and washed with a series of solvents: dimethyl
sulfoxide, water, a mixture of dioxane and water (2:1),
dioxane, acetone, ethanol, dichloromethane. White resin
10. The recovered resin 6A was confirmed by IR spectral
data and successfully applied for the synthesis of a-amino
acids.