Efficient synthesis of α-substituted amino acid ester: Alkylation and hydrogenation removal of Schiff's base protecting group

Article abstract of DOI:10.1080/00397910802138611

A general and efficient synthetic route to α-amino acids by alkylation of the sodium salt of Schiff base ester 1 has been described previously. The α-substituted ethyl glycinates 4a-g are prepared in excellent yield by a two-step sequence involving regios

Full text of DOI:10.1080/00397910802138611

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Efficient Synthesis of α-
Substituted Amino Acid Ester:
Alkylation and Hydrogenation
Removal of Schiff's Base
Protecting Group
Aslam M. Ansari a & Sydney O. Ugwu a
a NeoPharm Inc. , Waukegan, Illinois, USA
Published online: 11 Jul 2008.
To cite this article: Aslam M. Ansari & Sydney O. Ugwu (2008) Efficient Synthesis of
α-Substituted Amino Acid Ester: Alkylation and Hydrogenation Removal of Schiff's
Base Protecting Group, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 38:14, 2330-2340, DOI:
10.1080/00397910802138611
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Synthetic Communications1, 38: 2330–2340, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802138611
Efficient Synthesis of a-Substituted Amino Acid
Ester: Alkylation and Hydrogenation Removal
of Schiff’s Base Protecting Group
Aslam M. Ansari and Sydney O. Ugwu
NeoPharm Inc., Waukegan, Illinois, USA
Abstract: A general and efficient synthetic route to a-amino acids by alky-
lation of the sodium salt of Schiff base ester 1 has been described previously.
The a-substituted ethyl glycinates 4a–g are prepared in excellent yield by a
two-step sequence involving regioselective alkylation of the anionic glycine syn-
thon 2 with various alkyl halides, followed by purification of the alkylated
Schiff base on florisil and cleavage by catalytic hydrogenolysis. Reducible
groups on the side chain may be reduced or preserved depending upon the
deprotecting method utilized.
Keywords: Alkylation; Base; Ethyl; Glycinates; Schiff
INTRODUCTION
There is a great demand for an efficient method for the synthesis of
natural and synthetic biologically active a-amino acids. Several appro-
aches recently have been reported for highly stereospecific synthesis of
amino acids from a bis-lactum.[1–4] Among the conventional methods for
the preparation of a-amino acids, alkylation of glycine ester derivative
has a particular advantage to prepare structurally diversified a-amino
acids from a single starting material by the choice of alkylating agents.
A number of higher homologs of amino acids have successfully been pre-
pared by the alkylating route.[5–7] The standard condition employed in
this technique involves generation of an anionic synthon either in the pres-
ence of a strong base or under various phase-transfer conditions.[8–12] The
Received in the USA March 23, 2008
Address correspondence to Sydney O. Ugwu, NeoPharm Inc., 101 Waukegan
Road, Suite 970, Lake Bluff, IL 60044. E-mail: sugwu@aol.com
2330

a-Substituted Amino Acid Ester
2331
Scheme 1.
anion, thus generated, reacts with alkyl halides, giving a-substituted
amino acids. The main limitation of this method is the instability of
the ketimine or aldimine intermediate toward silica gel, making it neces-
sary to hydrolyze the alkylated adduct immediately to the corresponding
amino acids or esters without any purification.[8,13] Achqar et al.[14]
used 2-hydroxypinane-3-one in which the OH group ortho to the
carbonyl carbon prevented decomposition by chelating with the N-atom
of the amine.
Our initial target was to find a synthetic route that would overcome
these limitations and extend the scope and generality of the technique.
This synthetic approach to a-substituted amino acids draws on the Stork
et al.[7] procedure using NaH. Saturated and unsaturated amino acid
esters were obtained in good to excellent yield by adding 0.98 equivalent
alkyl halide derivative in benzene to a solution of anion in benzene.
Because benzene is toxic, it should be properly disposed of. Alternatively,
the reaction could be run in anhydrous dimethoxyethane. After gentle
refluxing, the reaction mixture was cooled, quenched with ethanol, and
worked up. The Schiff base was purified by flash chromatography over
florisil, on which it was stable. Prior to our work, there was not a single
example in the literature of cleavage of ketimine by catalytic hydrogeno-
=
lysis. The C N bond was conventionally hydrolyzed by refluxing with
aqueous acid. In our hands, the ketimine was rapidly removed at room
temperature by hydrogenolysis under neutral conditions using 10%
palladium=charcoal. Addition of 2 mol excess of conc. HCl halved the
reaction time. The esters (4d–f) were characterized as their stable oxalate
salts, because the hydrochlorides were hygroscopic.

2332
A. M. Ansari and S. O. Ugwu
The use of florisil for purification of the alkylated Schiff base
followed by catalytic hydrogenolysis under neutral or acidic condition is
therefore an attractive approach to synthesis of a variety of amino acids.
EXPERIMENTAL SECTION
Melting points (Pyrex1 capillary) were determined on a Thomas Hoover
1
capillary melting-point apparatus and were uncorrected. H NMR spec-
tra were recorded on a GE,QE 300-MHz instrument and are reported in
parts per million (ppm) relative to tetramethylsilane (TMS) (1%) as an
internal standard. Fourier transform infrared (FTIR) spectra were
recorded on a Nicolet 5DX spectrometer using KBr pellets unless other-
wise specified. Elemental analyses were performed by the Microanalytical
Laboratory, Department of Chemistry, University of California,
Berkeley. All reactions were followed by thin-layer chromatography
(TLC) carried out on Uniplate silica-gel GF (Analtech) plates. For purity
tests of all compounds, a single spot (visualized by UV light and iodine
vapor) was obtained. Florisil (200–300 mesh, Fluka) was used for flash
chromatographic separation. Solutions were dried over Na2SO4 and con-
centrated using a Buchi rotary evaporator under water aspirator vacuum.
¨
Alkylation of Schiff’s Base Ester (1): General Procedure
A solution of 1 (1.0 g, 3.75 mmol) in dry benzene (5 mL) was added to a
stirred suspension of NaH (0.098 g, 4.1 mmol; 60% oil dispersion) in
dry benzene (1.5 mL) under argon. The mixture was refluxed gently at
90–95 ꢀC for 1 h. The flask was removed from the heating bath, and a
solution of alkyl halide (3.59 mmol) dissolved in a minimum quantity of
benzene (ꢁ20 mL) was added through a dropping funnel. After the
addition, the reaction mixture was gently refluxed with stirring until the
starting material disappeared (checked by TLC analysis). The reaction
mixture was cooled, and a small quantity of ethanol (ꢁ2 mL) was added
to destroy unreacted NaH. The solution was concentrated, and the residue
was partitioned between water and ether. The ether fraction was dried
(MgSO4), filtered, and concentrated to yield a gummy brown liquid. Flash
chromatography on florisil gave monoalkylated Schiff base (3a–g).
Ethyl-N-(diphenylmethylene)phenylalaninate (3a)
Flash chromatography (5% ethyl acetate–benzene) gave an orange solid
crystallized from benzene–pentane into pale yellow crystals, mp 65–67 ꢀC
(lit.[15] mp 68.5–69 ꢀC).

a-Substituted Amino Acid Ester
2333
Ethyl-N-(diphenylmethylene)-p-nitrophenylalaninate (3b)
Flash chromatography (4% ethyl acetate–benzene) gave an oil. It was
then crystallized from ethanol into orange crystals, mp 104–105 ꢀC,
Rf ¼ 0.48 (10% ethyl acetate–benzene). IR (KBr) 3071.9, 2987.5, 2959.4
=
=
(CH CH, & CH2-CH2), 1743.0 (CO2CH2-), 1623.4 (N C), 1595.3,
1
1567.2 (C C) cmꢂ1; H NMR (CDCl3) d 1.21 (t, 3H, CH3), 3.4 (t, 2H,
=
OCH2), 4.5 (m, 1H, CH), 7.4–8.1 (m, 14H, aromatic). Anal. calcd.
for C24H22N2O4: C, 71.62; H, 5.47; N, 6.96. Found: C, 71.41; H, 5.51;
N, 6.73.
Ethyl-N-(diphenylmethylene) Cyclohexylalaninate (3c)
Flash chromatography (4% ethyl acetate–benzene) gave an oil. It was
then crystallized from ethanol into orange crystals, mp 104–105 ꢀC,
Rf ¼ 0.56 (20% ethyl acetate–benzene). IR (neat) 3057, 2924.2, 2851.2
1
(CH2-CH2), 1622.4 (N C) cmꢂ1; H NMR (CDCl3) d1.2 (t, 3H, CH3),
=
0.9–1 and 1.8–1.9 (m, 11H, alicyclic), 4.1–4.3 (m, 3H, CH, OCH2-),
7.2–7.9 (m, 10H, aromatic); HRMS m=z (relative intensity) 363 (Mþ ,
41.0), 362 (51.1), 291 (23.0), 290 (100), 286 (12.7), 280 (17.5), 276
(99.4), 267 (13.8), 266 (20.1), 264 (6.0), 263 (32.0), 262 (73.7), 252 (8.1),
238 (31.4), 208 (43.2), 206 (22.5), 194 (28.6), 193 (65.0), 192 (12.8), 182
(64.5), 180 (20.4), 167 (29.3), 166 (22.7), 165 (56.2), 104 (21.9), 103
(18.9), 91 (16.5); HRMS calcd. for C24H29NO2: (Mþ) 363.1958, obsd.
363.2185, Anal. calcd for C24H29NO2: C, 79.33; H, 8.04; N, 3.85, Found:
C, 80.91; H, 7.70; N, 3.23.
Ethyl-N-(diphenylmethylene) Hexanoate (3d)
Flash chromatography (10% ethyl acetate–hexane) gave a pale yellow oil,
Rf ¼ 0.48 (20% ethyl acetate–hexane). IR (neat) 3057, 2957.4, ꢂ21924.2
1H
=
(CH2-CH2-CH3), 1735.5 (CO2CH2-), 1662.5, 1596.1 (N C) cm
;
NMR (CDCl3) d 0.82–0.87 (t, 3H, CH3), 1.12–1.27 (m, 5H, -CH2-
CH3), 1.91 (m, 2H, -CH2-), 4.10 (q, 2H, OCH2), 4.22 (m, 1H, -CH),
7.15–7.82 (m, 10H, aromatic); HRMS m=z (relative intensity) 333
(Mþ , 11.9), 322 (20.2), 266 (7.1), 251 (20.8), 250 (100), 238 (7.0), 223
(6.9), 222 (19.2), 208 (20.1), 206 (8.9), 194 (8.0), 193 (22.8), 183 (8.7),
182 (52.3), 108 (9.0), 166 (11.1), 165 (33.4), 105 (99.1), 104 (15.9), 91
(40.8), 84 (12.6), 77 (60.5); HRMS calcd. for C21H25NO2 (Mþ )
323.1678, obsd. 323.1885, Anal. calcd. for C21H25NO2; C, 78.01; H,
7.79; N, 4.33, Found: C, 78.5; H, 7.57; N, 4.12.

2334
A. M. Ansari and S. O. Ugwu
Ethyl-N-(diphenylmethylene) Pentanoate (3e)
Flash chromatography (10% ethyl acetate–hexane) gave a yellow oil,
Rf ¼ 0.63 (20% ethyl acetate–hexane). IR (neat) 3057.8, 2952.3,ꢂ21868.0
1H
=
(CH2-CH2-CH3), 1735.9 (CO2CH2-), 1616.4, 1574 (N C) cm
;
NMR (CDCl3) d 0.83 (t, 3H, CH3), 1.22 (m, 5H), 1.89 (m, 2H), 4.05
(q, 2H, OCH2-), 4.14 (m, 1H, -CH), 7.15–7.66 (m, 10H, aromatic);
HRMS m=z (relative intensity) 309 (Mþ , 7.2), 308 (3.8), 267 (4.0), 266
(5.3), 238 (5.0), 237 (19.0), 236 (100), 209 (4.3), 208 (8.9), 206 (3.8), 194
(6.8), 193 (15.5), 192 (4.5), 166 (6.8), 165 (22.7), 105 (7.9), 165 (33.4),
104 (10.6), 91 (41.7), 77 (10.5); HRMS calcd. for C20H23NO2 (Mþ )
309.1722, obsd 309.1730.
Ethyl-N-(diphenylmethylene) Pentynoate (3f)
Flash chromatography (15% benzene–hexane) gave an oil, Rf ¼ 0.48
(5% ethyl acetate–benzene). IR (neat) 3096.9 (CꢃCH), 3057, 2980.5
(CH2-CꢃCH), 1728.9 (CO2CH2-), 1658.6 (N C) cmꢂ1; 1H NMR (CDCl3)
=
=
d 1.23–1.28 (t, 3H, CH3, J 7.0 Hz), 1.94–1.96 (t, 1H, CꢃCH), 2.79–2.89
(m, 2H), 4.16–4.2 (q, 2H, OCH2-), 4.26–4.31 (m, 1H, -CH), 7.25–7.82 (m,
10H, aromatic); HRMS m=z (relative intensity) 305 (Mþ , 1.1), 304 (4.5),
266 (3.8), 238 (1.5), 233 (1.3), 232 (7.9), 194 (2.3), 193 (8.2), 192 (7.3), 191
(1.2), 184 (1.4), 183 (6.5), 165 (10.7), 164 (1.3), 163 (2.5), 154 (3.1), 152
(4.4), 144 (4.1), 128 (4.1), 127 (2.6), 115 (3.2), 106 (6.7), 105 (100); HRMS
calcd. for C20H19NO2 (Mþ) 305.1258, obsd. 305.1342. Anal. calcd. for
C20H19NO2: C, 78.68; H, 6.27; N, 4.59. Found: C, 79.29; H, 6.22; N, 4.12.
Ethyl-N-(diphenylmethylene) pentenoate[16] (3g)
Flash chromatography (15% benzene–hexane) gave an oil, Rf ¼ 0.45
(5% ethyl acetate–benzene). Yield 89%, IR (film) 3020, 1735, 1645,
1
1670, 1580, 1495, 1200, 1115, 995, 925, 75, 700 cmꢂ1; H NMR(CDCl3)
=
1.2 (3H, CH3), 2.5 (2H, CH2), 4.00 (2H, OCH2), 5.10 (2H, CH CH2),
=
=
5.60 (1H, CH CH2), 7.3–7.70 (5H, C6H5), 8.30 (1H, N CH); m=z
230 (Hþ) (C14H17NO2 requires 231).
Hydrogenolysis: General Procedure
Method A
A mixture of 3a–g (3.27 mmol) and 10% Pd-C (1.12 g) in ethanol (83 mL)
was stirred under a balloon of H2 gas at room temperature (see Table 1),

2335

2336

a-Substituted Amino Acid Ester
2337
purged with N2 gas, and filtered through Celite1. The filtrate was
concentrated, and free base was purified from diphenylmethane by flash
chromatography (10% methanol–chloroform) over silica gel. Rf ¼ 0.51
(12% methanol–chloroform). The pure amino acid esters were analyzed
either as hydrochloride or oxalate salts.
Method B
The experiment was carried out in the same as described for method A
with 2 mol equivalent of HCl. At the end of the reaction, the filtrate
was concentrated and washed with dry ether, which removed diphenyl-
methane, leaving pure amino acid esters.
Phenylalanine Ethyl Ester Hydrochloride (4a)
Crystallized from ethanol ether into white crystals: mp 127 ꢀC (lit.[17]
mp 127 ꢀC).
p-Nitro-DL-phenylalanine Ethyl Ester Hydrochloride (4b)
Crystallized from ethanol-ether into white crystals mp 176–179 ꢀC (lit.[18]
mp 179–180 ꢀC).
p-Amino-DL-phenylalanine Ethyl Ester Hydrochloride (4b1)
HRMS m=z (relative intensity) 208 (Mþ , 3.3), 135 (8.5), 118 (4.9), 107
(10.6), 106 (100.0), 77 (3.7); HRMS calcd. for C11H16N2O2 (Mþ)
208.1206, obsd. 208.1216. The hydrochloride salt of p-amino-DL-
phenylalanine ethyl ester[18] was crystallized from ethanol ether into pale
yellow crystals: mp 232–233 ꢀC. Anal. calcd. for C11H16N2O2ꢄ2HCl: C,
46.97; H, 6.40; N, 9.96. Found: C, 45.81; H, 6.50; N, 9.66.
2-Amino Cyclohexyl Ethyl Propionate (4c)
Yellow oil, Rf ¼ 0.59 (20% ethyl acetate–hexane). IR (neat) 3388.3,
3310.9 (NH2), 1728.9 (CO2CH2-) cmꢂ1 1H NMR (CDCl3) d 0.9
.
(t, 3H, CH3), 1.12–1.78 (m, 15H), 3.44–3.46 (m, 1H, -CH-), 4.14 (m,
2H, OCH2). Hydrochloride salt crystallized from ethanol into white crys-
tals: mp 170–171 ꢀC. Anal. calcd. for C11H21NO2ꢄHCl: C, 55.98; H, 9.33;
N, 5.93. Found: C, 56.1; H, 9.42; N, 5.87.

2338
A. M. Ansari and S. O. Ugwu
2-Amino Ethyl Hexanoate (4d)
Yellow oil, Rf ¼ 0.62 (10% ethanol–chloroform). IR (neat) 3381.2,
3310.9 (NH2), 1728.9 (CO2CH2-) cmꢂ1 1H NMR (CDCl3) d 0.9
.
(t, 3H, CH3), 1.12–2.08 [m, 11H, CH3(CH2)3, NH2], 4.04 (m, 1H, -CH-),
4.26 (m, 2H, OCH2). HRMS m=z (relative intensity) 159 (Mþ, 10.6),
102 (10.6), 87 (8.1), 86 (100.0), 84 (2.7), 74 (7.1); HRMS calcd. for
C8H17NO2(Mþ) 159.1254, obsd. 159.1260. Oxalate salt Crystallized from
ethanol ether into white crystals, mp 119–120 ꢀC. Anal. calcd. for
C10H19NO6: C, 48.18; H, 7.68; N, 5.62. Found: C, 48.02; H, 7.64; N, 5.40.
2-Amino Ethyl Pentanoate (4e)
Yellow oil, Rf ¼ 0.62 (10% ethanol–chloroform). IR (neat) 3381.2,
3310.9 (NH2), 1735.9 (CO2CH2-) cm ꢂ 1 1H NMR (CDCl3) d 0.9
.
(t, 3H, CH3), 1.25–1.69 [m, 11H, CH3(CH2)3], 3.40 (m, 1H, -CH-), 4.22
(m, 2H, OCH2). HRMS m=z (relative intensity) 146 (Mþ , 0.5), 144
(1.0), 127 (2.6), 112 (0.5), 102 (0.8), 101 (1.2), 99(0.8), 98 (0.06),
83 (1.0), 74 (0.8), 73 (6.2), 72 (100.0), 71 (1.3), 70 (2.7); HRMS calcd.
for C7H16NO2 (Mþ) 146.1048, obsd. 146.1181. Oxalate salt: White crys-
tals: mp 115–116 ꢀC. Anal. calcd. for C9H17NO6: C, 45.95; H, 7.28; N,
5.96. Found: C, 45.97; H, 7.18; N, 5.83.
2-Amino Ethyl Pentynoate (4f)
Yellow liquid, Rf ¼ 0.50 (5% ethanol–ethyl acetate). IR (neat) 3381.2
(CꢃC), 3289.8, 3219.5 (NH2), 1728.9 (CO2CH2-) cm ꢂ 1
.
1H NMR
(CDCl3) d 1.26 (t, 3H, CH3), 1.77 (s, 2H, NH2), 2.08 (m, 1H, CꢃCH),
2.61 (m, 2H, CH2), 3.60 (t, 1H, CH), 4.19 (m, 2H, OCH2). Oxalate salt:
Crystallized from ethanol ether into white crystals: mp 146 ꢀC. Anal.
calcd. for C9H13NO6: C, 45.18; H, 5.62; N, 5.85. Found: C, 45.03;
H, 5.33; N, 5.59.
2-Amino Ethyl Pentenoate (4g)
Liquid, Rf ¼ 0.43 (5% ethanol–ethyl acetate). IR (neat) 3381.2, 3310.9
ꢂ 1
.
1H NMR (CDCl3) d
1.27 (t, 3H, CH3), 1.65 (s, 2H, CH2), 2.3 (m, 2H, CH2), 3.49–3.53
=
(NH2), 1728.9 (CO2CH2-), 913.28 C C) cm
=
(t, 1H, CH), 4.10–4.21 (m, 2H, OCH2), 5.68 (m, 1H, CH C). HRMS
m=z (relative intensity) 143 (Mþ , 0.2), 142 (0.6), 102 (100.0), 74 (77.7),
73 (6.2), 71 (16.1), 70 (20.1); HRMS calcd. for C7H13NO2(Mþ )

a-Substituted Amino Acid Ester
2339
143.0808, obsd. 143.094. Oxalate salt: Crystallized from ethanol ether
into white crystals, mp 111–112 ꢀC. Anal. calcd. for C9H15NO6; C,
43.02; H, 6.77; N, 5.57. Found: C, 42.86; H, 7.40; N, 5.32.
ACKNOWLEDGMENTS
This work was performed at the Department of Pharmaceutical
Chemistry, University of California at San Francisco.
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