Soluble Polymer-Supported Synthesis of α-Amino Acid Derivatives

Article abstract of DOI:10.1081/SCC-120027256

A practical and efficient synthesis of N-substituted α-amino acid derivatives on soluble polymer support is described.

Full text of DOI:10.1081/SCC-120027256

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Soluble Polymer-Supported Synthesis of α-Amino
Acid Derivatives
Chunling Hu a , Zuxing Chen a & Guichun Yang a
a Faculty of Chemistry & Material Science, Hubei University, Wuhan, Hubei, 430062, P.R.
China
Version of record first published: 18 Oct 2011.
To cite this article: Chunling Hu, Zuxing Chen & Guichun Yang (2004): Soluble Polymer-Supported Synthesis of α-Amino
Acid Derivatives, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 34:2, 219-224
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 2, pp. 219–224, 2004
Soluble Polymer-Supported Synthesis of
a-Amino Acid Derivatives
*
Chunling Hu, Zuxing Chen, and Guichun Yang
Faculty of Chemistry & Material Science, Hubei University, Wuhan,
Hubei, P.R. China
ABSTRACT
A practical and efficient synthesis of N-substituted a-amino acid
derivatives on soluble polymer support is described.
Key Words: a-Amino acid derivatives; Soluble polymer support;
Synthesis; LPOS; SPOS.
Due to the central role played by a-amino acid in chemistry and biology,
the development of versatile and new methodology for the synthesis of natural
and unnatural a-amino acid has emerged as an important and challenging
synthetic endeavour for organic chemists.[1] Similarly, the preparation of
N-substituted a-amino acids and their derivatives has also been attracted
considerable attention recently owing to their use as building block for many
*
Correspondence: Zuxing Chen, Faculty of Chemistry & Material Science, Hubei
University, Wuhan, Hubei 430062, P.R. China; E-mail: chzux@163.net.
219
DOI: 10.1081/SCC-120027256
0039-7911 (Print); 1532-2432 (Online)
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Copyright # 2004 by Marcel Dekker, Inc.

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Hu, Chen, and Yang
peptides, depsipeptides,[2] alkaloids and other compounds with therapeutic
activity.[3] Among the various methodologies reported for a-amino acid
synthesis,[4] the solid-phase organic synthesis (SPOS) has served as an
important approach.[5] Molecules are synthesized on an insoluble solid
support where reactions are driven to completion by using excess of reagents,
which can be removed by washing with various solvents. However, inherent
problems on solid supports are reactive site accessibility, site–site interaction,
and monitoring of the reaction.
One alternative to the SPOS is the liquid-phase organic synthesis (LPOS)
where soluble polymers such as poly (ethylene glycol) (PEG) are utilized as
supports.[6] The PEG support solubilizes the reacting center in the reaction
solvent. After completion of the reactions, purification is performed by
precipitation, filtration, and washing of the polymer. Characterization of the
polymer-supported molecule is performed without preliminary cleavage of the
growing structure by UV, TLC, IR and NMR.
As a continuation of our efforts to utilize soluble polymer-supported
systems in organic synthesis,[7] herein we report a promising liquid-phase
approach for the synthesis of N-substituted a-amino acid derivatives on
soluble poly(ethylene glycol) (PEG) support. The synthesis route is illustrated
in Sch. 1. The PEG-bound product was prepared from PEG3400, bromoacetyl
bromide via ester linkage. The resulting polymer-supported product I, which
was obtained by precipitation and washing with cold ether, reacted readily
with a variety of amines at r.t. to afford II. Subsequently, the PEG-bound
product II was isolated by adding icy-cold dry Et2O (10 folds of the solution),
filtering and washing to remove excessive starting materials and by-products.
TLC (silica gel, acetone/petroleum ether ¼ 1 : 3 as eluent) showed that the
polymer II contained little small molecular and impurities. Herein PEG-bound
product II was cleaved under different conditions. One reaction proceeded
under 1% KCN/CH3OH, which provided a-amino acid ester III. The other
Scheme 1.

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Synthesis of a-Amino Acid Derivatives
221
proceeded under sodium hydroxide, followed by acidification to obtain a-
amino acid IV. Lastly, each crude product was analysed by HPLC and give
1
excellent purity (73–97%) (Table 1). Products show satisfactory IR and H
NMR data, which are consistent with the proposed structure.
It is worthy of note that, in sharp contrast to the corresponding reaction in
the solid phase, it was not necessary to use excess reagents in order to obtain
Table 1. Yield and purity for various N-substituted a-amino acid derivatives.
Entry
Substrate (R1R2NH)
Crude yielda (%)
Crude purityb (%)
85.5(IIIa)
83.5(IVa)
90.1
94.2
a
83.5(IIIb)
79.8(IVb)
85.4
78.6
b
c
d
e
f
81.3(IIIc)
82.5(IVc)
85.5
84.3
84.8(IIId)
83.7(IVd)
94.6
85.7
92.1(IIIe)
76.8(IVe)
97.1
73.3
89.3(IIIf)
80.8(IVf)
94.5
85.6
79.1(IIIg)
83.4(IVg)
81.3
95.4
g
h
i
86.3(IIIh)
75.1(IVh)
86.7
80.2
90.1(IIIi)
82.2(IVi)
92.9
82.9
91.5(IIIj)
85.5(IVj)
86.1
76.2
j
82.9(IIIk)
81.2(IVk)
90.9c
83.2c
k
l
78.5(IIIl)
80.5(IVl)
78.3c
90.5c
CH3(CH2)3NH2
aDetermined based on weight of crude sample.
bPurity determined by HPLC analysis of crude product.
cIsolated purity of product k, l.

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Hu, Chen, and Yang
completion of the reaction in a reasonable amount of time. Also, this reaction
does not require the use of expensive base or sophisticated conditions. More-
over, liquid phase synthesis allow routine analytical method (UV, IR, NMR,
TLC) to monitor reaction progress without following cleavage-and-analysis
technique.[8] This non-destructive method makes LPOS even more valuable.
In summary, a novel liquid phase combinatorial synthesis of N-substituted
a-amino acid derivatives has been developed. All reactions are efficient to
give the desired compounds in high yield and excellent purity by simple
precipitation and washing. Further applications of this technology to other
transformations are going and will be reported in later paper.
EXPERIMENTAL
All organic solvents were dried by standards. All PEG samples were
melted at 808C in vacuum for 30 min before use to remove traces of moisture.
IR was recorded using KBr Pellets on an IR-Spectrum One (PE). 1H NMR was
recorded on Bruker XL 300 (300 MHz) instruments using TMS as internal
standard. HPLC was recorded on Shimadzu LC-6AD with a Shim-pack PREP-
SIL (H) KIT column (2 Â 250 mm).
Preparation of PEG-Bound Bromoacetylate (I)
To a solution of PEG3400 (1 g, 0.3 mmol) in dry CH2Cl2 (5 mL) was added
bromoacetyl bromide (0.06 mL, 0.7 mmol) and DIPEA (0.1 mL, 0.6 mmol) at
08C. The resulting solution was stirred at r.t. for overnight. After completion,
the solution was concentrated in vacuum and precipitated by adding icy-cold
Et2O with stirring. The PEG-bound product I was obtained by filtering and
washing with cold Et2O (3 Â 10 mL), which was analysed on the thin-layer
chromatography (acetone/petroleum ether ¼ 1/3 as eluent) to show contain-
ing no bromoacetyl bromide and other impurities. IR (KBr): 1738 cm21 (s);
1H NMR (CD3Cl): d ¼ 3.50 ꢀ 3.85 (s, H PEG), 3.90 ꢀ 4.05 (s, 2H),
4.30 ꢀ 4.40 (m, 2H).
General Procedure for the Preparation of PEG-Bound
Amino Ester (II)
The PEG-bound product I (1.1 g, 0.28 mmol) was dissolved in a mixture
of CH2Cl2 (5 mL) and NHR1R2 (which could be illustrated by NH2CH2Ph,
0.3 mmol, 0.03 mL). The mixture was precipitated by icy-cold ether after

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Synthesis of a-Amino Acid Derivatives
223
agitated for overnight at r.t. The polymer was filtered, dissolved with
CH2Cl2 (4 mL), precipitated once and dried in vacuum to give II. IR (KBr):
1
1718 cm21 (s), 2880 ꢀ 3100 cm21 (m), 3440 cm21 (m); H NMR (CD3Cl):
d ¼ 3.50 ꢀ 3.70 (m, H PEG), 3.51 (d, 2H), 3.80 (s, 2H), 6.95 ꢀ 7.60
(m, 5H).
General Procedure for the Preparation of a-Amino Ester (III)
A portion of the PEG-bound product II (0.6 g, 0.13 mmol) was dissolved
in 5 ml 1% KCN/CH3OH solution and stirred at r.t. for overnight. The
solution was evaporated under vacuum to remove methanol and dissolved in
2 ml CH2Cl2, then precipitated into icy-cold Et2O. The polymer was filtered
and the combined filtrate was dried to give III. The purity of this compound
was determined to be 90.1% by HPLC. IR (KBr): 1720 cm21 (s),
2850 ꢀ 3030 cm21 (m), 3450 cm21 (m); 1H NMR (CD3Cl): d ¼ 3.40
(d, 2H), 3.67 (s, 3H), 4.10 (m, 2H).
General Procedure for the Preparation of a-Amino Acid (IV)
1
The PEG-bound product II (0.6 g, 0.15 mmol) was dissolved in 5 mL N
NaOH aqueous solution and heated at 608C for 3 h (tested by TLC until the
original point disappeared). After cooled to room temperature, the solution
was acidified with 5N HCl aqueous solution to pH ¼ 3 ꢀ 4. The purity of
crude product was determined to be 94.2% by HPLC. IR (KBr): 1650 cm21
1
(s), 2850 ꢀ 3100 cm21 (m), 3450 cm21 (m); H NMR (CD3Cl): d ¼ 3.41
(d, 2H), 4.00 (s, 2H), 6.80 ꢀ 7.81 (m, 5H).
ACKNOWLEDGMENT
Financial supports were provided by Education Department of Hubei
Province and Hubei University.
REFERENCES
1. (a) Boto, A.; Hernandez, R.; Montoya, A. One-pot synthesis of aryl
glycines and other unnatural amino acids from serine derivatives.
Tetrahedron Lett. 2002, 43, 8269; (b) Reichwein, J.; Liskamp, R. Site-
specific N-alkylation of peptides on the solid phase. Tetrahedron Lett.
1998, 39, 1243; (c) Spengler, J.; Burger, K. An efficient synthesis of N-
methylamino acids and some of their derivatives. Synthesis 1998, 67; (d)

ORDER
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Hu, Chen, and Yang
Reddy, G.V.; Rao, G.V.; Iyengar, D.S. A practical approach for the
optically pure N-methyl-a-amino acids. Tetrahedron Lett. 1998, 39, 1985.
2. Humphrey, J.M.; Chamberlin, A.R. Chemical synthesis of natural
products: coupling methods for the incorporation of noncoded amino
acids into peptides. Chem. Rev. 1997, 97, 2243.
3. (a) Beck, G. Synthesis of chiral drug substances. Synlett. 2002, 837; (b)
Berkowitz, D.B.; Chisowa, E. Stereo-phase synthesis of quaternary b,g-
unsaturated amino acids: chain extension of d- and l- a-(2-tributylstan-
nyl)vinyl amino acids. Tetrahedron 2001, 57, 6329.
4. (a) Lloyd-Joned, G.C. Palladium-catalyzed a-arylation of esters: ideal new
methodology for discovery chemistry. Angew. Chem. Int. Ed. 2002, 41,
953; (b) Ge, C.-S.; Chen, Y.-J.; Wang, D. Highly diastereoselective
synthesis of N-protected arylglycine derivatives via TiCl4-promoted
Friedel-Crafts reaction of phenols with chiral N,O-hemiacetal. Synlett.
2002, 37; (c) Sakai, N.; Hamajima, T.; Konakahara, T. Friedel-Crafts
reaction of indoles with N-silyl-N,O-acetal catalyzed by Cu(OTf)2 in the
presence of TmSCl leading to indolyl primary amines. Tetrahedron Lett.
2002, 43, 4821; (d) Janczuk, A.; Zhang, W.; Xie, W.; Lou, S.; Cheng, J.-P.;
Wang, P.G. Ytterbium triflate catalyzed electrophilic substitution of
indoles: the synthesis of unnatural tryptophan derivatives. Tetrahedron
Lett. 2002, 43, 4271.
5. O’Donnell, M.J.; Delgado, F.; Drew, M.D. Solid-phase synthesis of
unnatural a-amino acid derivatives using a resin-bound glycine cation
equivalent. Tetrahedron Lett. 1999, 40, 5831.
6. Parrick, H.Y.; Kim, D.J. Soluble polymer-supported organic synthesis.
Acc. Chem. Res. 2002, 33, 546.
7. (a) Yang, G.C.; Chen, Z.X.; Zhang, Z.J. Novel synthesis of monoethers of
hydroquinone and resorcinol on soluble polymer-supports. Synth.
Commun. 2002, 32, 3637; (b) Yang, G.C.; Chen, Z.X.; Zhang, Z.J.
Synthesis of thiourea derivatives on soluble polymeric support. Chin. J.
Chem. 2002, 20, 178; (c) Chen, Z.X.; Yang, G.C.; Zhang, Z.J. Synthesis of
a library of N-p-hydroxybenzoyl thioureas using a poly(ethylene glycol)
support. Synthesis 2001, 1483.
8. Luo, Y.; Ouyang, X.H.; Robert, W.A.; Murphy, M.M. A case study of
employing spectroscopic tools for monitoring reactions in the develop-
mental stage of a combinatorial chemistry library. J. Org. Chem. 1998, 63,
8719.
Received in Japan May 12, 2003

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