A new method for the preparation of functionalized unnatural α-H-α-amino acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2006.08.096

A new method for the preparation of α-H-α-amino acids is reported based on the α-alkylation of iminoacetic acid esters or amides. These imines are readily available by the reaction of glyoxylic acid esters with branched primary amines. The subsequent reaction with methanolic ammonia gave the corresponding iminoacetic acid amides. α-Alkylation of these imines with various electrophiles under basic conditions, followed by an acidic hydrolysis, gave α-amino acids, esters, or amides in up to 93% yield. α-Alkylation under chiral PTC conditions resulted in mono-alkylated amino acids with 90% ee.

Full text of DOI:10.1016/j.tetlet.2006.08.096

Tetrahedron Letters 47 (2006) 7771–7774
A new method for the preparation of functionalized unnatural
a-H-a-amino acid derivatives
`
David J. Hyett, Mara Didone, Thierry J. A. Milcent, Quirinus B. Broxterman
and Bernard Kaptein*
DSM Research, Life Sciences-Advanced Synthesis and Catalysis, PO Box 18, 6160 MD Geleen, The Netherlands
Received 18 July 2006; revised 15 August 2006; accepted 23 August 2006
Available online 15 September 2006
Abstract—A new method for the preparation of a-H-a-amino acids is reported based on the a-alkylation of iminoacetic acid esters
or amides. These imines are readily available by the reaction of glyoxylic acid esters with branched primary amines. The subsequent
reaction with methanolic ammonia gave the corresponding iminoacetic acid amides. a-Alkylation of these imines with various elec-
trophiles under basic conditions, followed by an acidic hydrolysis, gave a-amino acids, esters, or amides in up to 93% yield. a-Alkyl-
ation under chiral PTC conditions resulted in mono-alkylated amino acids with 90% ee.
Ó 2006 Elsevier Ltd. All rights reserved.
Of the various routes described to synthesize (enantio-
pure) a-H-a-amino acids, a-alkylation of glycine deriva-
tives has gained an increasing interest in recent years.
The method initially developed by O’Donnell has found
widespread application in the laboratory, especially
for the preparation of amino acids with function-
alized side chains.1–3 Thus glycine esters, activated as
their benzophenone imines, can be selectively mono-
alkylated as a result of an increase in the pKa of the
product after the first alkylation because of 1,3-allylic
strain (Scheme 1).4 A drawback of this procedure is
the troublesome preparation of the benzophenone
imine. A direct formation with benzophenone is a slug-
gish and low-yielding reaction requiring BF3ÆEt2O catal-
ysis, whilst transimination using an expensive benzo-
phenone imine is less attractive for a large-scale
application.1
on activation using imines that are both easily prepared
and derived from low-cost starting materials. We identi-
fied a good procedure using imines formed by reacting
branched primary amines 1a–c with glyoxylic acid ester
derivatives, for example, hemi-acetal 2.5–7 These esters
are readily available on a large scale (indeed some of
them are produced annually on a multi-ton scale8) and
react smoothly to form imines (e.g., 3a–c) in 86–95%
yields (Scheme 2).
R2
OCH3
OCH3
R2
40 - 50 oC
OCH3
R1
NH2
HO
R1
N
+
toluene
or
CH2Cl2
O
O
1a: R1 = R2 = Ph
1b: R1 = Ph, R2 = CH3
1c: R1 = R2 = CH3
2
3a-c
In order to develop an alternative to this alkylation
process suitable for the industrial scale, we concentrated
Scheme 2. Imine formation by reaction of branched amines with
methyl glyoxylate hemi-acetal.
R-Br
OtBu
R
*
R
R
OtBu
OtBu
PTC*
N
N
N
*
O
O
O
Scheme 1. Selective (asymmetric) mono-alkylation of the benzophenone imine of glycine esters.
*
Corresponding author. Tel.: +31 46 4767416; fax: +31 46 4767604; e-mail: bernard.kaptein@dsm.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.096

7772
D. J. Hyett et al. / Tetrahedron Letters 47 (2006) 7771–7774
Although iminoacetates have been frequently used as
electrophiles for the addition of organometallic re-
agents6 or as dienophiles in Diels–Alder reactions,7 to
our knowledge deprotonation and use as nucleophilic
reagents has never been described. The alkylation of imi-
nes 3a–c with various electrophiles, using either PTC
conditions9 or, for example, with KOtBu as base, gave
imines 5a–i of a-mono-alkylated a-amino acid methyl
esters in 56–91% unoptimized yields (Table 1).10 Differ-
ent electrophiles were tested, varying from activated spe-
cies such as allylic, propargylic or benzylic chlorides and
bromides through 1,4-acceptors, such as acrylonitrile
and crotonitrile, to unactivated n-butyl iodide. Our ini-
tial attempts focused on the use of N-benzhydrylimines
in order to obtain mono-alkylation. However, the use
of other branched primary amines also resulted in
selective mono-alkylation. The application of (racemic)
N-1-phenylethyl- or N-i-propyl-imino substrates (3b/3c,
respectively) proved to be advantageous from an indus-
trial perspective; the corresponding amines are cheap,
readily available and have a lower molecular weight
than benzhydrylamine. As a result of this lower molecu-
lar weight, the intermediate imines contain a higher
weight percentage of ‘amino acid end-product’. Thus a
higher productivity is possible since (assuming identical
molar yields) less kgs of intermediate imine would
have to be processed in order to produce 1 kg of end-
product.
The acidic hydrolysis of mono-alkylated imines 5a–i
with dilute hydrochloric acid gave the hydrochloride
salts of the corresponding mono-alkylated amino acids
6 or amino acid methyl esters 7, depending on the
hydrolysis conditions.1
In addition to the alkylation of methyl esters 3a–c, we
also studied the alkylation of amides 4a–c, which could
be readily formed by the reaction of 3a–c with methan-
olic NH3 (Scheme 3). Amide 4a could be mono-alkyl-
ated in high yields and the subsequent acidic
hydrolysis of the imines resulted in amino acid amides
8a–n (Table 1). Amides 4b and 4c resisted alkylation un-
der the reaction conditions studied, most likely because
of higher pKa values.
The remarkably fast amidation reaction of methyl esters
3a–c to amides 4a–c is most likely the result of the induc-
tive effect of the imino functional group. Using 7 M
NH3 in methanol at an ambient temperature, the amida-
tion was complete within 30 min. The alternative expla-
nation for this fast reaction, namely initial (mixed)
aminal formation followed by an intramolecular amida-
Table 1. Alkylation of the imines of glyoxylic acid esters 3a–c and amide 4a
R2
R2
R
R
R
electrophile
base
HCl
OH/OCH3
NH2
Y
Y
or
R1
N
HCl.H2N
6/7
Methoda
HCl.H2N
8a-n
R
1
N
H2O
O
O
O
O
3a-c, 4a
5
Entry
Substrate
R1
R2
Y
Electrophile (R–X)b
Yield (%)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3b
3b
3b
3c
3c
3c
Ph
Ph
Ph
Ph
Ph
Ph
CH3
CH3
CH3
Ph
Ph
Ph
CH3
CH3
CH3
CH3
CH3
CH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
A
A
B
A
B
H2C@CH–CH2–Br
HC„C–CH2–Br
H2C@CH–CN
H2C@CH–CH2–Br
H2C@CH–CN
CH3–CH@CH–CN
H2C@CH–CH2–Br
n-C4H9–I
88 5a
73 5b
90 5c
56 5d
64 5e
68 5f (60:40)
90 5g
85 5h
91 5i
B
A
A
A
Ph–CH2–Br
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
C
C
H2C@CH–CH2–Br
HC„C–CH2–Br
H2C@CH–CH2–Br
PhCH2–Br
88 8a
85 8b
93 8a
89 8c
65 8d
81 8e
78 8f
66 8g
62 8h
62 8i
73 8j
71 8k
72 8l
77 8m
80 8n
D
D
D
D
D
D
D
D
D
D
D
D
D
3-F–C6H4CH2–Br
3-MeO–C6H4CH2–Br
4-Br–C6H4CH2–Br
4-CN–C6H4CH2–Br
4-NO2–C6H4CH2–Br
4-Ph–C6H4CH2–Cl
1-Napht–CH2–Cl
2-Napht–CH2–Br
9-Anthr–CH2–Cl
3-Py–CH2–Br
Ph2CH–Br
a Reaction at ambient temperature of a solution of 1 equiv of 3/4 and 1.1–1.2 equiv of electrophile; method A, in MTBE by the addition of 1.1 equiv
of KOtBu; method B, in MTBE by the addition of 0.1–0.3 equiv of KOtBu; method C, in CH2Cl2 by the addition of 1.2 equiv of KOtBu; method D,
PTC conditions: CH2Cl2/10 M NaOH solution/5–10 mol % Bu4NHSO4.
b All reactions proceeded via an SN2 mechanism, except for entries 3, 5 and 6, which gave the 1,4-addition products 5c, 5d and 5f. Compound 5f was
obtained in a 60:40 diastereomeric ratio according to 1H NMR.

D. J. Hyett et al. / Tetrahedron Letters 47 (2006) 7771–7774
7773
NH3
R2
R2
7M NH3
MeOH
NH2
OCH3
R1
N
R1
N
O
O
4a: R1 = R2 = Ph (83%)
3a-c
4b: R1 = Ph, R2 = CH3 (76%)
4c: R1 = R2 = CH3 (84%)
R2 NH2
OCH3
R1
N
H
O
Scheme 3. Amidation reaction of iminoacetic acid methyl esters 3a–c.
PhCH2Br
10 mol% PTC*
6 M HCl
O
CH2Cl2
N
OH
O
reflux
HCl.H2N
N
10 M NaOH
O
O
O
9a
(S)-10
90% e.e
Scheme 4. Asymmetric PTC alkylation of L-menthyl N-benzhydryliminoacetate 9a using the Lygo PTC* catalyst N-(9-anthracenylmethyl)cinchon-
idinium chloride.
tion, seems unlikely because only primary amides were
formed. A mixed aminal mechanism would be expected
to lead to product mixtures containing both primary
amides (resulting from intramolecular amidation by
–NH2) and substituted amides (resulting from intra-
molecular amidation by –NHiPr, –NHCH(CH3)Ph or
–NHCHPh2). The amidation of 3a–c can also be
performed with primary amines but secondary amines
reacted very sluggishly (results not shown).
menthyl moiety provides a comparable steric interaction
to that of a tert-butyl ester (which has been used success-
fully in related reactions, see Scheme 1).3,12 The menthyl
ester is preferred in this case because tert-butyl glyoxy-
late is not readily available on an industrial scale.
In conclusion, a new method for the preparation of a-H-
a-amino acid derivatives by the selective a-mono-alkyl-
ation of iminoacetic acid esters or amides has been iden-
tified.13 The benefit of this method results from the
availability of the starting materials and an easy prepa-
ration of the iminoacetic acid derivatives compared to
the N-benzhydrylidene-glycine esters. The formation
and alkylation of the iminoacetic acid derivatives pro-
ceeds in high yields and gives access to enantiopure ami-
no acids, either by asymmetric PTC alkylation or by
enzymatic resolution of the racemic amino acid amides.
The formation of the racemic amino acid amides 8a–n
is especially attractive because it can be combined with
the enzymatic resolution process developed at DSM
Research some years ago. For example, the resolution
of amides 8a and 8b using the L-aminopeptidase from
Pseudomonas putida ATCC 12633 has been described
previously.11
Initial studies into an asymmetric alkylation procedure
have been performed using iminoacetate 9a, obtained
in a 98% yield as a colourless solid from commercially
available L-menthyl glyoxylate hydrate8 and benzhydr-
ylamine 1a. Although the asymmetric induction by the
chiral menthyl ester moiety upon alkylation with benzyl
bromide using KOtBu in CH2Cl2 (method C, ee 10%
(S)) or achiral PTC alkylation conditions (method D,
ee 18% (S)) is rather limited, the combination of this
moiety and a chiral PTC catalyst resulted in good ees.
Using the phase transfer catalyst N-(9-anthracenyl-
methyl)cinchonidinium chloride, developed by Lygo,12
benzylation in CH2Cl2/10 M NaOH solution at 0 °C
gave (S)-phenylalanine 10 in an 81% yield and 90% ee
(Scheme 4). The enantiopurity of this material was
improved to 98% ee by crystallization from aqueous
2-propanol.
Acknowledgements
We thank Math Boesten for the chiral HPLC determi-
nations and Bert Zeegers and Daniel Mink for their
helpful discussions.
References and notes
1. O’Donnell, M. J. Aldrichim. Acta 2001, 34, 3–15.
2. Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013–3028.
3. O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506–517.
4. O’Donnell, M. J.; Bennett, W. D.; Bruder, W. A.;
Jacobsen, W. N.; Knuth, K.; LeClef, B.; Polt, R. L.;
Bordwell, F. G.; Mrozack, S. R.; Cripe, T. A. J. Am.
Chem. Soc. 1988, 110, 8520–8525.
5. The iminoacetic acid esters are readily prepared by
addition of 1 equiv of the primary amine to a solution of
the hemi-acetal or hydrate of glyoxylic acid esters in an
inert solvent (toluene, CH2Cl2, MTBE, etc.). After stirring
Since the use of the chiral PTC catalyst with methyl ester
3a or amide 4a gave low ees, it can be postulated that the

7774
D. J. Hyett et al. / Tetrahedron Letters 47 (2006) 7771–7774
for 1 h at 40–50 °C, the water and alcohol by-products
9. PTC conditions: organic solvent (toluene, CH2Cl2 or
methyl t-butyl ether)/10 M NaOH or KOH solution/
5–10 mol Bu4NHSO4.
were removed by partial evaporation of the solvent. The
solution can be used directly for further reaction (option-
ally after drying over Na2SO4) or the solvent can be
removed to obtain the pure imine as a (coloured) oil.
Trituration with heptane gave methyl N-(diphenyl-
methyl)iminoacetate 3a as a stable white solid, mp 63–
10. Typical example: To a solution of 3c (1.00 g, 7.74 mmol)
and allyl bromide (1.12 g, 9.29 mmol) in MTBE (30 ml)
was added KOtBu (0.95 g, 8.5 mmol) in small portions
over 30 min. The suspension was stirred at room temper-
ature for 15 min and then the solvent was removed under
reduced pressure. The residue was dissolved in CH2Cl2
and the remaining undissolved salt (KBr) was removed by
filtration through decalite. The organic filtrate was washed
with water, dried (Na2SO4) and the solvent removed under
reduced pressure to give 5g as a brown oil (1.18 g,
7.0 mmol, 90%). 1H NMR (CDCl3), d (ppm): 5.78 (m,
1H, CH@CH2), 5.10 (m, 2H, CH@CH2), 4.17 (m, 1H, a-
CH), 3.72 (s, 3H, OCH3), 2.66 and 2.48 (2m, 2H, b-CH2),
2.09 and 1.88 (2s, 6H, (CH3)2C@N).
11. Wolf, L. B.; Sonke, T.; Tjen, K. C. M. F.; Kaptein, B.;
Broxterman, Q. B.; Schoemaker, H. E.; Rutjes, F. P. J. T.
Adv. Synth. Catal. 2001, 343, 662–674.
12. Lygo, B.; Crosby, J.; Lowdon, T. R.; Peterson, J. A.;
Wainwright, P. G. Tetrahedron 2001, 57, 2403–2409.
13. Hyett, D. J.; Mink, D.; Broxterman, Q. B.; Kaptein, B.;
Zeegers, H. J. M. PCT Int. Pat. Appl., WO 2004/078702,
to DSM Research (Chem. Abstr. 141, 243830).
1
66 °C. H NMR (CDCl3) d (ppm): 7.70 (s, 1H, N@CH),
7.20 (m, 10H, 2C6H5), 5.60 (s, 1H, Ph2CH), 3.79 (s, 3H,
OCH3). The imines that are liquid and do not solidify,
tend to decompose slowly. For the imine formation, it is
not necessary to start with the free glyoxylic acid esters as
is often described in the literature.6,7
6. (a) Fiaud, J.-C.; Kagan, H. B. Tetrahedron Lett. 1970,
1813–1816; (b) Yamamoto, Y.; Nishii, S.; Maruyama, K.;
Komatsu, T.; Ito, W. J. Am. Chem. Soc. 1986, 108, 7778–
7786; (c) Courtois, G.; Miginiac, L. J. Organomet. Chem.
1989, 376, 235–243.
7. (a) Stella, L.; Abraham, H.; Fereau-Dupont, J.; Tinant,
B.; Declercq, J. P. Tetrahedron Lett. 1990, 31, 2603–2606;
(b) Hashimoto, N.; Yasuda, H.; Hayashi, M.; Tanabe, Y.
Org. Proc. Res. Dev. 2005, 6, 105–109.
8. Methyl glyoxylate methyl hemi-acetal and L-menthyl
glyoxylate hydrate are produced by DSM Pharma Chem-
icals annually on multi-ton scale.