A novel four-component synthesis of N-substituted amino acid esters

Article abstract of DOI:10.1055/s-2002-34864

A library of N-substituted amino acid esters was synthesized using a solid phase bound organic isocyanide that provides a C1 synthon to the final molecule. This novel four-component, one-pot reaction delivers the final products in acceptable yields with high purities of the crude reaction products, facilitating the final purification. The preparation of the isocyano resin is also described the intermediates being controlled by ATR-spectroscopy.

Full text of DOI:10.1055/s-2002-34864

LETTER
1877
A Novel Four-Component Synthesis of N-Substituted Amino Acid Esters
F
our-Component
e
Synthesis
o
f
N
-Sub
n
stituted Ami
dno Acid Esters Henkel,* Lutz Weber
Morphochem AG, Gmunder Strasse 37-37a, 81379 München, Germany
Fax +49(89)78005555; E-mail: Bernd.Henkel@morphochem.de
Received 6 August 2002
Similar to carbon monoxide, organic isocyanides contain
a carbon atom in a monodentate, CII oxidation state. Thus,
it seemed reasonable to investigate, whether isocyanides
could be used as an equivalent of Strecker’s cyanide an-
Abstract: A library of N-substituted amino acid esters was synthe-
sized using a solid phase bound organic isocyanide that provides a
C1 synthon to the final molecule. This novel four-component, one-
pot reaction delivers the final products in acceptable yields with
high purities of the crude reaction products, facilitating the final pu- ion.
rification. The preparation of the isocyano resin is also described the
intermediates being controlled by ATR-spectroscopy.
The Ugi-type four-component addition of isocyanides
with aldehydes and amines in methanol usually yields -
amino acid amides 2 through a postulated imino-ether in-
termediate 1 (Scheme 1).5
Key words: multi-component reaction, amino acids, polymer-sup-
ported synthesis, combinatorial chemistry, Lewis acids
On the other hand, it is known that the aqueous cleavage
of imino-ethers depends on reaction conditions, yielding
in most cases the respective amides as above, or, more
rarely, carboxylic acid esters.6 Combining this alternative
imino-ether cleavage towards carboxylic acid esters with
the Ugi-four component reaction, we developed a novel
procedure for the synthesis of N-substituted -amino acid
esters using aldehydes, alcohols, amines and solid-phase
bound isocyanides. Polymer bound isocyanide was ob-
tained from aminomethyl polystyrene or TentaGel-NH2
through treatment with formic acid/acetic anhydride and
subsequent dehydration of the polymer bound formamide
with tosylchloride/pyridine.7 The completion of the
formylation was followed by the Kaiser-test8 and ATR-IR
spectroscopy (Figure 1).
The discovery of novel synthetic routes towards amino
acid derivatives is an area of continued interest and cre-
ativity of organic chemists. The Strecker three-component
reaction, a corner stone amino acid synthesis procedure
using aldehydes, amines and cyanide, has been an early
example of multi-component reactions in organic chemis-
try. Improved multi-component variants of this reaction
have been introduced since, using trimethylsilylcyanide
together with lanthanide triflates as Lewis acid catalyst,1
or using carbon monoxyde as the source of the carboxylic
acid carbon atom under palladium catalysis instead of
Strecker’s cyanide.2 Exploring other compound classes
that can replace the cyanide or carbon monoxyde and
comprising a nucleophilic carbon atom allowed for dis-
covery of novel three-component reactions, for example
reacting alkynes3 or -alkenyl boronic acids4 with a suit-
able carbonyl and amine component.
The conversion of the formamide to the polymer bound
isocyanide was determined by reacting the polymer with
a tenfold excess of N-benzylidene aniline and Fmoc-gly-
cine in methanol/dichlormethane = 1:1. The Fmoc-group
Scheme 1 Mechanism of the synthesis of N-substituted -amino acids methyl esters using polymer bound isocyanide; PS = polystyrene resin.
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1877,1879,ftx,en;G21902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1878
B. Henkel, L. Weber
LETTER
Figure 2 ATR-IR spectrum of the intermediate iminoether: Spec-
trum A shows the starting isocyanomethyl polystyrene, spectrum B
the polymer bound iminoether intermediate after reaction with the
imine, an alcohol and boron trifluoride etherate. In the spectrum B the
isocyanide band at 2145 cm–1 disappeared and a new band at 1701
cm–1 for the C=N stretch vibration of the iminoether is visible. The
ether C-O-C band is visible at 1058 cm–1. Spectrum A = isocyanome-
thyl polystyrene, spectrum B = polymer bound iminoether interme-
diate, 1 = isocyanide band, 2 = CN-band, 3 = C-O-C-band
Figure 1 ATR-IR spectra of isocyanide resin formation: Spectrum
A shows the starting aminomethyl polystyrene resin, spectrum B the
carbonyl band of the respective formamide 1674 cm–1, and spectrum
C the isocyanide band at 2145 cm–1. It is also seen that the isocyanide
formation was not complete as revealed by the still prevalent carbonyl
band in spectrum C. A = aminomethyl polystyrene, B = formamido-
methyl polystyrene, C = isocyanomethyl polystyrene, 1 = carbonyl
band, 2 = isocyanide band. A Thermo Nicolet Nexus instrument with
the ATR unit Smart DuraSamplIR was used.
expected N-substituted -amino acid methyl esters 3
when using methanol as the alcohol component. The for-
mation of the iminoether 1 could be observed by ATR-IR-
spectroscopy (Figure 2).
was cleaved and quantified according to Meienhofer.9 The
loading of the polymer was calculated to be 0.61 mmol/g.
In the uncatalyzed reaction, using a polymer bound isocy-
anide derived from aminomethyl polystyrene resin, we
did not obtain any observable product 3 in solution.
Therefore, we tested the effect of several Lewis acid cata-
lysts and various reaction conditions. From all catalysts
tested [Yb(OTf)3, InCl3, ZnCl2, FeCl3, BF3 Et2O], only
boron trifluoride etherate gave significant amounts of the
This imino-ether is than cleaved by a acetone/water mix-
ture to the corresponding N-alkyl, N-aryl- or N-hetaryl
amino acid methyl ester 3 (Scheme 1). The respective by-
product -amino acid amide 2 would remain bound on
solid support, allowing for a facile separation of the de-
sired products.10
Table 1 Yields and Purities (in Parenthesis) of the N-Substituted -Amino Acids Methyl Esters Obtained from the Boron Trifluoride Cata-
lyzed Reaction of Methanol and Cyanomethyl Polystyrene with the Corresponding Aldehydes and Amines after Subsequent Treatment with
Watera
O
H
O
H
O
H
O
H
O
H
O
O
N
Cl
Starting Materials
S
H
56 (95)
15 (96)
64 (94)
Traces
24 (88)
20 (40)
–
53 (94)
15 (94)
56 (97)
Traces
53 (82)
45 (95)
40 (94)
Traces
19 (92)
16 (45)
21 (95)
Traces
32 (68)
30 (91)
28 (92)
NH2
O
NH2
NH2
Cl
Traces
18.3 (23)
20 (62)
19 (90)
NH2
24 (30)
34 (96)
–
27 (28)
29 (97)
Traces
18 (93)
–
NH2
42 (94)
Traces
NH2
N
a Yields were calculated based on the loading of the resin, purities were determined by reversed phase HPLC [Agilent 1100 HPLC-system,
YMC ODS-A column, 50 2 mm with guard column 10 2 mm; detector wavelength: 220 nm; flow: 0.6 mL/min; gradient: 0 min (10% ac-
etonitrile, 80% water, 10% 0.1 M HCOOH), 2.5 min (90% acetonitrile, 10% 0.1 M HCOOH), 4 min (90% acetonitrile, 10% 0.1 M HCOOH),
6 min (10% acetonitrile, 80% water, 10% 0.1 M HCOOH)].
Synlett 2002, No. 11, 1877–1879 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Four-Component Synthesis of N-Substituted Amino Acid Esters
1879
(4) (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997,
119, 445. (b) Petasis, N. A.; Goodman, A.; Zavialov, I. A.
Tetrahedron 1997, 53, 16463.
(5) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
(6) Gröbke, K.; Ji, Y.-H.; Wallbaum, S.; Weber, L. Eur. Pat.
Appl. EP 0921116 A1, 1999; Chem. Abstr. 2001, 131,
44656.
(7) Arshady, R.; Ugi, I. Polymer 1990, 31, 1164.
(8) Kaiser, E.; Colescott, R. L.; Bossinger, C. D.; Cook, P. I.
Anal. Biochem. 1970, 34, 595.
Both yields and purities of the final products were signif-
icantly higher when the aldehyde and amine were precon-
densed to the respective imine and solid phase bound
isocyanide, boron trifluoride etherate and alcohol were
added sequentially, as compared to a true four-component
reaction protocol. Out of 36 tested aldehyde-amine com-
binations, 17 crude reaction products were obtained with
a purity higher than 90% (Table 1).
While aliphatic amines gave only poor results, aromatic
amines yielded the respective products in both satisfacto-
ry yields and purities. Using the more water compatible
isocyano-TentaGel instead of the isocyanomethyl poly-
styrene resin, both yields and purities of the crude reaction
products could be improved by about twofold for unsatis-
factory cases as N-benzyl phenyl-glycine methylester and
N-benzyl 4-chlorophenyl-glycine methyl ester, giving
53.5% (61% purity) and 44.5% yield (65% purity), re-
spectively. Replacing methanol with isopropanol and 5-
phenylpentanol as the hydroxy component yielded in sim-
ilarly satisfactory results.
(9) Meienhofer, J.; Waki, M.; Heimer, E. P.; Lambros, T. J.;
Makofske, R. C.; Chang, C. D. Int. J. Peptide Protein Res.
1979, 13, 35.
(10) Synthesis of N-(4-Methoxyphenyl)-(R,S)-valine
methylester: 0.044 mL Isobutyraldehyde (0.48 mmol) and
60 mg p-anisidine (0.48 mmol) were dissolved in 2 mL dry
dichloromethane and 50 mg molecular sieves (0.4 nm) was
added. The reaction mixture was stirred at room temperature
for one hour. The molecular sieve was filtered off and 0.195
mL dry methanol (4.8 mmol), 0.183 mL boron trifluoride
etherate (1.44 mmol) and 400 mg isocyanomethyl
polystyrene (0.24 mmol) were added together with 2 mL dry
dichloromethane. The reaction mixture was shaken at room
temperature for two hours. The resin was filtered off and
washed twice with dry dichloromethane and dry acetone.
The cleavage was performed by shaking the resin with a
mixture of acetone/water = 4:1 for 4 h at room temperature.
The resin was filtered off and washed several times with
acetone. The combined filtrates were combined and the
solvent was evaporated, yielding 22.8 mg N-(4-
In summary, the described reaction sequence provides a
novel and facile, four-component synthesis route to unnat-
ural amino acid esters. Remarkably, only the carbon atom
of the polymer bound isocyanide, which acts as a C1 syn-
thon, appears in the final product. The use of other nucleo-
philes like amines or C-nucleophiles that could replace the
alcohol in the described process above is under current in-
vestigation.
methoxyphenyl)-(R,S)-valine methylester as a yellow oil
(40% yield, calculated based on the loading of the resin).
Satisfactory analytical data were obtained. 1H NMR (400
MHz, CDCl3, 25 °C): (ppm) 1.00 [d, 3J(H,H) = 6.3 Hz, 3 H,
CH3CH], 1.09 [d, 3J(H,H) = 6.3 Hz, 3 H, CH3CH], 2.33 (m,
1 H, CH3CHCH3), 3.72 (s, 3 H, CH3O), 3.79 (s, 3 H, CH3O),
4.06 (m, 1 H, CHNH), 6.88 [d, 3J(H,H) = 8.6 Hz, 2 H, ArH],
7.43 [d, 3J(H,H) = 8.6 Hz, 2 H, ArH]. 13C NMR (100 MHz,
CDCl3, 25 °C): (ppm) 16.3 CH3CH), 19.5 (CH3CH), 28.4
(CH3CH), 53.1 (CH3O), 55.5 (CH3O), 71.4 (CHNH), 115.2
(m-CAr), 124.7 (i-CAr), 125.6 (o-CAr), 160.5 (p-CAr),
167.0 (CO).
References
(1) (a) Kobayashi, S.; Ishitani, H.; Ueno, M. Synlett 1997, 115.
(b) Kobayashi, S.; Busujima, T.; Nagayama, S. Chem.
Commun. 1998, 981.
(2) Beller, M.; Eckert, M.; Vollmüller, F.; Bogdanovic, S.;
Geissler, H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1494.
(3) Sakaguchi, S.; Kubo, T.; Ishii, Y. Angew. Chem. Int. Ed.
2001, 40, 2534.
Synlett 2002, No. 11, 1877–1879 ISSN 0936-5214 © Thieme Stuttgart · New York