Synthesis of non-proteinogenic amino acids from N-(4-toluenesulfonyl)dehydroamino acid derivatives

Article abstract of DOI:10.1016/S0040-4039(02)00811-0

By treating N-(4-toluenesulfonyl)-N-(tert-butyloxycarbonyl)-dehydroamino acid derivatives with different reactants under different conditions, a variety of new amino acids are obtained, viz. (i) α-alcoxy-α-amino acids, (ii) α,α-diamino acids and (iii) novel β-substituted dehydroamino acids.

Full text of DOI:10.1016/S0040-4039(02)00811-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4495–4497
Synthesis of non-proteinogenic amino acids from
N-(4-toluenesulfonyl)dehydroamino acid derivatives
Paula M. T. Ferreira, Hernaˆni L. S. Maia and Lu´ıs S. Monteiro*
Department of Chemistry, University of Minho, Gualtar, P-4700-320 Braga, Portugal
Received 4 April 2002; accepted 25 April 2002
Abstract—By treating N-(4-toluenesulfonyl)-N-(tert-butyloxycarbonyl)-dehydroamino acid derivatives with different reactants
under different conditions, a variety of new amino acids are obtained, viz. (i) a-alcoxy-a-amino acids, (ii) a,a-diamino acids and
(iii) novel b-substituted dehydroamino acids. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
tain carbon nucleophiles the addition product suffers
cyclization to give 2,3-dihydrofuran derivatives.2
Non-proteinogenic amino acids have several applica-
tions either as biologically active substrates or as com-
ponents for the synthesis of peptidomimetics and for
the modification of natural peptides. We have found
that N,N-disubstituted dehydroamino acid derivatives
are excellent substrates in Michael addition reactions
for the synthesis of a variety of such compounds. We
have previously described the synthesis of b-substituted
amino acid and b-substituted dehydroamino acid
derivatives by reacting the methyl esters of N-(4-tolu-
enesulfonyl)-N-(tert-butyloxycarbonyl)-dehydroamino
acids with several types of nucleophiles (nitrogen hete-
rocycles, thiols, carbon nucleophiles and amines).1,2
Using the corresponding dehydroalanine derivative as
substrate [Tos-DAla(N-Boc)-OMe] with the above
nucleophiles in the presence of K2CO3, in all cases
addition to the b-carbon atom occurs to give b-substi-
tuted alanine derivatives. When the nucleophile is a
nitrogen heterocycle or a thiol the b-substituted alanine
obtained undergoes elimination of p-toluenesulfinic
acid with regeneration of the a,b-double bond, yielding
the corresponding dehydroalanine derivative. With cer-
2. Results and discussion
In view of the results obtained we decided to further
investigate the reactivity of N-(4-toluenesulfonyl)-N-
(tert-butyloxycarbonyl)-dehydroamino acids. Thus by
treating Tos-DAla(N-Boc)-OMe (1) with base in aceto-
nitrile a rearrangement occurs with the formation of the
E-isomer of a b-sulfinated dehydroalanine derivative
(compound 2, Scheme 1). This derivative had been
previously detected as a by-product formed in reactions
of Tos-DAla(N-Boc)-OMe with weak nucleophiles in
which longer reaction times were required.1 By substi-
tuting acetonitrile for methanol as solvent and DMAP
for K2CO3 as base it was possible to obtain in 91%
yield the methyl ester of N-tert-butyloxycarbonyl a,b-
dimethoxyalanine (compound 3, Scheme 1).3
Due to the electron-withdrawing effect of the b-substi-
tuting group in compound 2 it was possible to synthe-
size several a,a-disubstituted amino acids. In fact,
Scheme 1.
Keywords: dehydroalanine; a-alcoxy-a-amino acids; a,a-diamino acids; b-substituted dehydroamino acids.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00811-0

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P. M. T. Ferreira et al. / Tetrahedron Letters 43 (2002) 4495–4497
It has been found that addition of amines to compound
1 proceeds without elimination of the Tos group. Thus,
only b-substituted alanines could be obtained with this
type of nucleophiles. In order to circumvent this limita-
tion, the E-isomer of Boc-DAla(1,2,4-triazol-1-yl)-
OMe1 obtained from compound 1 was reacted with
amines a and b and replacement of the triazole group
for the amine takes place to give the E-isomer of the
corresponding b-aminodehydroalanine derivative (com-
pounds 7a and 7b, Scheme 3).6
reaction with primary amines (benzylamine, a; propar-
gylamine, b) in methanol resulted in addition of the
amine function to the a-carbon atom of the dehy-
droamino acid derivative to give compounds 4a4 and
4b, respectively (Scheme 2).
Using a poor nucleophile such as the sterically hindered
tert-butylamine, the saturated a-methoxyamino acid 5
was obtained (Scheme 2). This compound can also be
obtained from compound 2 using an excess of K2CO3
(77% yield).
Derivatives of dehydroaminobutyric acid have shown a
lower reactivity towards Michael additions than the
corresponding dehydroalanines,2 since only the more
powerful nucleophiles, viz. 1,2,4-triazole, imidazole and
3-formylindole were suitable to react with these sub-
strates. However, with the strategy used above, i.e. by
using both E or Z-isomers of Boc-DAbu[b-(1,2,4-tria-
zol-1-yl)]-OMe as intermediate compounds, we were
now able to stereoselectively synthesize the E-isomer of
Reaction of 2 with thiols in methanol gave a different
result, as in this case the sulfinic group was replaced by
the sulfur nucleophile. This allowed the preparation of
the previously described Boc-DAla(b-methoxycarbonyl-
methylsulfanyl)-OMe2 and also of Boc-DAla[b-(p-bromo-
phenylsulfanyl)]-OMe (compound 6, Scheme 2).5 The
stereochemistry of the starting material was preserved
(E-isomer),6 which indicates addition of the nucleophile
followed by spontaneous elimination of the sulfinate
group.
Boc-DAbu(b-benzylamino)-OMe6,8
(compound
8,
Scheme 3). In view of this result it seems possible to
expand the range of b-substituted dehydroaminobutyric
acid derivatives that we had been able to obtain.
Nakazawa et al. reported the synthesis of b-aminodehy-
droalanines by reaction of the b-toluenesulfonate of
dehydroalanine with primary amines.7 Our results show
a different reactivity for the b-sulfinate dehydroalanine
derivative from that of the b-sulfonate dehydroalanine
since elimination of the sulfinic group only occurs with
thiols. With primary amines addition to the a-carbon
atom takes place.
The present results supply not only an appropriate
route to new classes of compounds such as a-alcoxy-a-
amino, a,b-dialcoxy-a-amino and a,a-diamino acids, as
well as novel b-substituted dehydroamino acids, but
also an efficient route to the synthesis of the sterically
crowded b-substituted dehydroaminobutyric acid
derivatives. This shows that N-(4-toluenesulfonyl)-N-
Scheme 2.
Scheme 3.

P. M. T. Ferreira et al. / Tetrahedron Letters 43 (2002) 4495–4497
4497
(tert-butyloxycarbonyl)-dehydroamino acid derivatives
are versatile starting materials for the synthesis of dif-
ferent types of non-proteinogenic amino acids.
(1H, d, J=12.0 Hz, bCH2), 3.85 (3H, s, CH3OMe), 3.95
(1H, d, J=14.7 Hz, CH2), 4.38 (1H, d, J=14.7 Hz, CH2),
6.10 (1H, s, aNH), 7.20–7.34 (7H, m, ArH), 7.75 (2H, d,
J=8.4 Hz ArH); lC (75.4 MHz; CDCl3) 21.57, 28.02,
46.34, 53.69, 59.69, 71.97, 80.15, 127.28, 128.19, 128.35,
128.38, 129.70, 137.18, 138.32, 144.45, 153.53, 169.52.
5. The same procedure as described above was followed
substituting triethylamine (2.5 equiv.) for K2CO3 and
adding 4-bromothiophenol (1 equiv.) to give 6 (75%), mp
114.5–116.0°C (from diethyl ether), (found: C, 46.28; H,
4.77; N, 3.62; S, 8.28. Calcd for C15H18BrNO4S: C, 46.40;
H, 4.67; N, 3.61; S, 8.26%); lH (300 MHz; CDCl3; Me4Si)
1.51 (9H, s, CH3Boc), 3.80 (3H, s, CH3OMe), 6.35 (1H, s,
aNH), 7.33 (2H, d, J=8.1 Hz, ArH), 7.34 (1H, s, bCH),
7.49 (2H, d, J=8.1 Hz, ArH); lC (75.4 MHz; CDCl3)
28.13, 52.59, 81.23, 122.27, 122.93, 129.33, 132.39, 133.70,
152.35, 163.46.
Acknowledgements
We wish to thank the Fundac¸a˜o para a Cieˆncia e a
Tecnologia for financial support (project no. POCTI/
1999/QUI/32689).
References
1. Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S.;
Sacramento, J. Tetrahedron Lett. 2000, 41, 7437–7441.
2. Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S.;
Sacramento, J. J. Chem. Soc., Perkin Trans. 1 2001, 3167–
3174.
6. The stereochemistry was determined using differential
NOE enhancements between the b (DAla) or g (DAbu)
protons and the a-NH.
7. Nakazawa, T.; Suzuki, T.; Ishii, M. Tetrahedron Lett.
1997, 38, 8951–8954.
3. To a solution of Tos-DAla(N-Boc)-OMe (1 mmol) in
methanol (0.1 mol dm−3), K2CO3 (6 equiv.) was added
with rapid stirring at room temperature. The reaction was
monitored by TLC and, when no starting material was
detected, 100 cm3 of ethyl acetate were added. The organic
phase was then washed with water and brine (2×30 cm3
each), dried over MgSO4 and evaporated at reduced pres-
sure to give 3 (91%), mp 57.5–58.5°C (from diethyl ether/
n-hexane), (found: C, 50.32; H, 7.79; N, 5.32. Calcd for
C11H21NO6: C, 50.18; H, 8.04; N, 5.32%); lH (300 MHz;
CDCl3; Me4Si) 1.47 (9H, s, CH3 Boc), 3.30 (3H, s, OCH3),
3.40 (3H, s, OCH3), 3.71 (1H, d, J=9.6 Hz, bCH2), 3.85
(3H, s, CH3 OMe), 4.07 (1H, d, J=9.6 Hz, bCH2), 5.96
(1H, s, aNH); lC (75.4 MHz; CDCl3) 28.11, 51.27, 53.12,
59.60, 73.22, 80.30, 86.77, 153.48, 169.48.
4. The same procedure as described above was followed
substituting benzylamine (2.5 equiv.) for K2CO3 to give 4a
(92%), mp 112.0–112.5°C (from diethyl ether), (found: C,
59.71; H, 6.77; N, 6.06; S, 6.88. Calcd for C23H31N2O6S:
C, 59.59; H, 6.74; N, 6.04; S, 6.92%); lH (300 MHz;
CDCl3; Me4Si) 1.31 (9H, s, CH3 Boc), 2.44 (3H, s, 4-CH3),
3.00 (1H, s, NH), 3.34 (1H, d, J=12.0 Hz, bCH2), 3.60
8. To a solution of Boc-E-DAbu[b-(1,2,4-triazol-1-yl)]-OMe
(1 mmol) in methanol (0.1 mol dm−3), benzylamine (2.5
equiv.) was added. After stirring overnight, TLC still
indicated some starting material so, a further 2.5 equiv. of
benzylamine were added. When no starting material was
detected, 100 cm3 of ethyl acetate were added and the
organic layer was washed with KHSO4 1 M and brine
(2×30 cm3 each). After drying over MgSO4 and evaporat-
ing the solvent at reduced pressure the E-isomer of 8 was
obtained (95%), mp 136.5–137.0°C (from diethyl ether),
(found: C, 63.80; H, 7.46; N, 8.78. Calcd for C17H24N2O4:
C, 63.73; H, 7.55; N, 8.74%); lH (300 MHz; CDCl3;
Me4Si) 1.47 (9H, s, CH3 Boc), 2.02 (3H, s, gCH3), 3.67
(3H, s, CH3 OMe), 4.44 (2H, d, J=6.3 Hz, CH2), 5.38
(1H, s, aNH), 7.26–7.34 (5H, m, ArH), 9.38 (1H, s, NH);
lC (75.4 MHz; CDCl3) 14.25, 28.24, 28.36, 47.36, 50.61,
79.38, 126.82, 127.39, 127.56, 128.41, 128.81, 138.41,
161.99, 169.11. The same procedure using Boc-Z-DAbu[b-
(1,2,4-triazol-1-yl)]-OMe gave the E-isomer of 8 in 79%
yield.