Synthesis of non-natural amino acids from N-(p-tolylsulfonyl)-α,β-didehydroamino acid derivatives

Article abstract of DOI:10.1002/ejoc.200300103

Carbon nucleophiles, amines, and oxygen nucleophiles were treated with the methyl ester of N-(tert-butoxycarbonyl)-N-(p-tolylsulfonyl)-α,β-didehydroalanine, and also with the methyl esters of N-(tert-butoxycarbonyl)-O-(p-tolylsulfinyl)-α,β-didehydroserine

Full text of DOI:10.1002/ejoc.200300103

FULL PAPER
Synthesis of Non-Natural Amino Acids from N-(p-Tolylsulfonyl)-α,β-
didehydroamino Acid Derivatives
[a]
[a]
[a]
ˆ
´
Paula M. T. Ferreira,* Hernani L. S. Maia, and Luıs S. Monteiro
Keywords: Amino acids / Synthesis design / Nitrogen heterocycles / α,β-Didehydroamino acids / Dihydrofurans
Carbon nucleophiles, amines, and oxygen nucleophiles were
treated with the methyl ester of N-(tert-butoxycarbonyl)-N-
(p-tolylsulfonyl)-α,β-didehydroalanine, and also with the
methyl esters of N-(tert-butoxycarbonyl)-O-(p-tolylsulfinyl)-
α,β-didehydroserine and N-(tert-butoxycarbonyl)-β-(1,2,4-
triazol-1-yl)-α,β-didehydroalanine, both of which were ob-
tained from the former substrate. Carbon nucleophiles of the
β-dicarbonyl type gave furanic amino acids, which were con-
verted into the corresponding pyrrole derivatives (dehy-
droprolines) in high yields, while use of amines allowed the
synthesis of α,α-diamino acids and β-amino-α,β-didehy-
droamino acids. Different types of alkoxyamino acids were
obtained by treatment of the above substrates with oxygen
nucleophiles. The reactivities of the α,β-didehydroaminobu-
tyric and α,β-didehydrophenylalanine analogues were also
tested. Some of the methods developed were applied to the
synthesis of cross-linked amino acids, namely didehydrolant-
hionine and histidino-α,β-didehydroalanine derivatives.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
sults encouraged us to investigate the reactivities of N-(p-
tolylsulfonyl)-α,β-didehydroamino acids further in order to
obtain new non-natural amino acids, as described below.
Research towards new practical methods for the prep-
aration of non-natural amino acids that can serve as build-
ing blocks in combinatorial chemistry and drug discovery
has become a major field in peptide chemistry.[1] In recent
years we have developed an efficient synthesis of N,N-di-
acyl-α,β-didehydroamino acids[2] and promoted their sub-
sequent use as precursors of other novel amino acids.[3Ϫ5]
We found that N,N-diacyl-α,β-didehydroamino acid deriva-
tives are excellent substrates in Michael addition reactions,
allowing the preparation of a variety of new β-substituted
amino acids.[3] When one of the protecting groups is p-tolyl-
sulfonyl, addition of several types of nucleophile (nitrogen
heterocycles, thiols, carbon nucleophiles, and amines) en-
ables the synthesis not only of β-substituted amino acid de-
rivatives but also, in some cases, of β-substituted α,β-dide-
hydroamino acid derivatives.[4,5] Therefore, on treatment of
the methyl ester of N-(tert-butoxycarbonyl)-N-(p-tolylsul-
fonyl)-α,β-didehydroalanine [Tos(Boc)-∆Ala-OMe[6]] with
the above nucleophiles in the presence of K2CO3, addition
to the β-carbon atom occurs in all cases to give β-substi-
tuted alanine derivatives. When the nucleophile is a nitrogen
heterocycle or a thiol, the obtained β-substituted alanine
undergoes elimination of p-tolylsulfinic acid with regener-
ation of the α,β-double bond to yield the corresponding β-
substituted α,β-didehydroalanine derivative.[4,5] With cer-
tain carbon nucleophiles the addition product undergoes
cyclization to give 2,3-dihydrofuran derivatives.[5] These re-
Results and Discussion
We have reported that the initial products of reactions
between Tos(Boc)-∆Ala-OMe[6] (compound 1) and carbon
nucleophiles of the β-dicarbonyl type, with a methyl group
bonded to one of the carbonyl groups, undergo spon-
taneous elimination of tosyl groups with cyclisation to give
5-methyl-2,3-dihydrofuran derivatives in good yields.[5,7] We
now report the synthesis of a few more such compounds,
which were carried out with the aim of exploring possible
applications for these adducts (compounds 3aϪ3e,
Scheme 1). Deprotection of dihydrofurans 3aϪ3e with tri-
fluoroacetic acid (TFA) resulted in a new rearrangement
followed by elimination of a water molecule to give the cor-
responding pyrrole derivatives 4aϪ4e (Scheme 1) in high
yields.
It had previously been found that reactions between com-
pound 1 and amines proceed as typical Michael additions
without elimination of tosyl groups, thus affording the ex-
pected β-substituted alanines.[5] We now report the syn-
thesis of the E isomers of the corresponding α,β-didehydro
analogues (compounds 9aϪ9c, Scheme 2, Table 1) by treat-
ment of the E isomer of Boc-∆Ala[β-(1,2,4-triazol-1-yl)]-
OMe[4] (compound 6) with amines. These reactions proceed
with replacement of the triazole group by the amines, giving
the E isomers of the corresponding β-amino-α,β-didehy-
droalanine derivatives.
[a]
´
Departamento de Quımica-Universidade do Minho
4710-057 Braga, Portugal
Fax: (internat.) ϩ 351/253678983
E-mail: pmf@quimica.uminho.pt
Eur. J. Org. Chem. 2003, 2635Ϫ2644
DOI: 10.1002/ejoc.200300103
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P. M. T. Ferreira, H. L. S. Maia, L. S. Monteiro
FULL PAPER
Scheme 1
Scheme 2
Table 1. Yields obtained in the synthesis of β-aminodehydroamino acid derivatives
Subst.
R1NH2
Product
Yield (%)
6
benzylamine 8a
(E)-Boc-∆Ala(β-benzylamino)-OMe 9a
87
82
90
95
92
49
6
propargylamine 8b
1,2-ethylenediamine 8c
benzylamine 8a
(E)-Boc-∆Ala(β-propargylamino)-OMe 9b
(E)-Boc-∆Ala{β-[N-(2-aminoethyl)amino]}-OMe 9c
(E)-Boc-∆Abu(β-benzylamino)-OMe 10a[9]
(E)-Boc-∆Abu(β-propargylamino)-OMe 10b
(E)-Boc-∆Abu{β-[N-(2-aminoethyl)amino]}-OMe 10c
6
(E)-7
(Z)-7
(Z)-7
Ppropargylamine 8b
1,2-ethylenediamine 8c
In attempts to induce reactions between amines and of (p-tolylsulfinyl)-α,β-didehydroserine[4,5] (compound 12a,
N-(tert-butoxycarbonyl)-N-(p-tolylsulfonyl)-α,β-dehydro- Scheme 3). By extending the reaction time during the dehy-
aminobutyric acid [Tos(Boc)-∆Abu-OMe,[2] 5] no products dration of Tos-Ser-OMe,[2] it was possible to obtain this sul-
could be obtained, which we have attributed to the low re- finyl derivative as the major product. This compound was
activity of the substrate.[5] However, by taking advantage of treated with amines 8a and 8b, yielding the corresponding
Boc-∆Abu[β-(1,2,4-triazol-1-yl)]-OMe[4] (compounds (E)-7 α-amino-O-(p-tolylsulfinyl)serine derivatives (compounds
and (Z)-7), we were able to synthesize several α,β-diamino- 13a and 13b, Scheme 3, Table 2). We believe that the attack
α,β-didehydroaminobutyric acid derivatives (compounds at the α-carbon atom is due to the strongly electron-with-
10a,[9] 10b and 10c, Scheme 2, Table 1). The reactions were drawing effect of the sulfinyl group, which would render the
stereoselective, yielding only the E isomers either from the α-carbon less negative than the β-carbon atom. With 1,2-
E or from the Z isomer of the starting material. Unfortu- ethylenediamine (8c), addition to the α-carbon atom was
nately, neither the E nor the Z isomer of Boc-∆Phe[β-(1,2,4- followed by intramolecular aminolysis to give the lactone
triazol-1-yl)]-OMe[4] [compounds (E)-11 and (Z)-11] re- 15a (Scheme 3, Table 2) in high yield. The same reactions
acted with amines under these conditions, possibly due to as above were carried out with substrates in which a 4-nitro-
stabilization of the substrate through conjugation with the phenylsulfonyl (nosyl, Nos) moiety substituted for p-tolyl-
aromatic ring.
sulfonyl. Thus, treatment of 12b with amines 8a and 8b gave
In previous work it had been found that compound 1, in the corresponding α-amino-O-(4-nitrophenylsulfinyl)serine
the presence of dimethylaminopyridine (DMAP), under- derivatives (compounds 14a and 14b, Scheme 3, Table 2).
went a rearrangement to give the fully protected E isomer With 1,2-ethylenediamine, compound 12b gave the corre-
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Eur. J. Org. Chem. 2003, 2635Ϫ2644

Non-Natural Amino Acids from N-(p-Tolylsulfonyl)-α,β-didehydroamino Acid Derivatives
FULL PAPER
Scheme 3
Table 2. Results obtained on treatment of O-(p-tolylsulfinyl)-α,β-didehydroserine derivatives with nitrogen nucleophiles
Subst. NuH
Product
Yield (%)
12a
12a
12b
12b
12a
12b
12a
12a
12a
benzylamine, 8a
propargylamine, 8b
benzylamine, 8a
Boc-Ser[α-benzylamino, O-(p-tolylsulfinyl)]-OMe, 13a[9]
92
87
91
75
89
Boc-Ser[α-propargylamino, O-p-(tolylsulfinyl)]-OMe, 13b
Boc-Ser[α-benzylamino, O-(4-nitrophenylsulfinyl)]-OMe, 14a
Boc-Ser[α-propargylamino, O-(4-nitrophenylsulfinyl)]-OMe, 14b
3-(tert-butoxycarbonylamino)-2-oxo-3-[(p-tolylsulfinyl)oxymethyl]piperazine, 15a
propargylamine, 8b
1,2-ethylenediamine, 8c
1,2-ethylenediamine, 8c
3-(tert-butoxycarbonylamino)-2-oxo-3-[(4-nitrophenylsulfinyl)oxymethyl]piperazine, 15b 59
methylsulfanyl acetate, 16 (E)-Boc-∆Ala(β-methoxycarbonylmethylsulfanyl)-OMe, 19[5]
54
75
83
4-bromothiophenol, 17
1,2,4-triazole, 18
(E)-Boc-∆Ala[β-(4-bromophenylsulfanyl)]-OMe, 20[9]
(E)-Boc-∆Ala(1,2,4-triazol-1-yl)-OMe, 6
sponding lactone (compound 15b, Scheme 3, Table 2). OMe[12] (compound 21) with sodium methoxide and so-
These results differ from those reported by Nakazawa et dium ethoxide under similar conditions resulted in a typical
al.,[10,11] who found that treatment of an O-(p-tolylsulfonyl)- Michael addition to give the corresponding β-alkoxyalanine
α,β-didehydroserine derivative with amines gave the corre- derivatives 23a and 23b (Table 3).
sponding β-amino-α,β-didehydroalanine derivatives.
Being poor Michael substrates, Boc2-∆Abu-OMe[2] and
Treatment of 12a with sulfur nucleophiles (methylsulfanyl Boc2-∆Phe-OMe[5] reacted differently with sodium methox-
acetate 16 and 4-bromothiophenol 17) as well as with 1,2,4- ide, undergoing competitive nucleophilic cleavage of one of
triazole (18) resulted in substitution of the O-sulfinyl group the Boc groups, which prevented addition from taking
to give the corresponding β-substituted α,β-didehydroala- place. Treatment of compound 1 with the oxygen nucleo-
nine derivatives (compounds 19, 20 and 6; Scheme 3, phile sodium methoxide gave the methyl ester of N-(tert-
Table 2). These results seem to indicate that attack at the β- butoxycarbonyl)-α,β-dimethoxyalanine (compound 24a,[9]
carbon atom of substrate 12a requires powerful nucleo- Scheme 4, Table 3). The same reaction but with sodium
philes, whilst amines add at the α-carbon atom.
ethoxide gave the ethyl ester of N-(tert-butoxycarbonyl)-
With oxygen nucleophiles (sodium methoxide and so- α,β-diethoxyalanine (compound 24b, Scheme 4, Table 3).
dium ethoxide), in a pattern similar to that observed in the Differently from what was reported above for the case of
case of the reactions with amines, sulfinyl derivative 12a amines, Tos(Boc)-∆Phe-OMe[5] (compound 25), the de-
underwent addition of alkoxide at the α-carbon atom to hydrophenylalanine analogue of 1, reacted with sodium me-
give the α-alkoxyamino acid derivatives 22a and 22b, thoxide to give the corresponding α,β-dimethoxyphenyalan-
respectively (Scheme 4, Table 3). Treatment of Boc2-∆Ala- ine derivative (compound 26) as a racemic mixture. With
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P. M. T. Ferreira, H. L. S. Maia, L. S. Monteiro
FULL PAPER
Scheme 4
Table 3. Yields obtained on treatment of several dehydroamino acid derivatives with oxygen nucleophiles
Subst.
NaOR
Product
Yield (%)
12a
12a
21
21
1
1
25
6
NaOMe
NaOEt
NaOMe
NaOEt
NaOMe
NaOEt
NaOMe
NaOMe
NaOEt
NaOMe
Boc-Ser[α-methoxy, O-(p-tolylsulfinyl)]-OMe 22a
Boc-Ser[α-ethoxy, O-(p-tolylsulfinyl)]-OEt 22b
Boc-Ala(N-Boc, β-methoxy)-OMe 23a
Boc-Ala(N-Boc, β-ethoxy)-OEt 23b
Boc-Ala(α,β-dimethoxy)-OMe 24a[9]
Boc-Ala(α,β-diethoxy)-OEt 24b
77
52
80
38
91
60
87
88
27
33
Boc-Phe(α,β-dimethoxy)-OMe 26
Boc-Ala(β,β-dimethoxy)-OMe 27a
Boc-Ala(β,β-diethoxy)-OEt 27b
(E)-Boc-∆Abu(β-methoxy)-OMe 28
6
(E)-7
Tos(Boc)-∆Abu-OMe (compound 5), however, a complex tives (compound 27a and 27b, respectively). These products
mixture of products that could not be purified was formed, suggest that in this case 1,2,4-triazole is replaced by an al-
although 1H NMR indicated that it contained dia- koxide ion, leaving a α,β-double bond, which allows ad-
stereomers of the expected α,β-dimethoxy derivative. We be- dition of a second alkoxide ion. Treatment of the E isomer
lieve that the above reactions involve the initial addition of of Boc-∆Abu[β-(1,2,4-triazol-1-yl)]-OMe with sodium me-
a methoxy group at the β-carbon atom, followed by elimi- thoxide in methanol gave the corresponding β-methoxy-
nation of tosyl and subsequent attack at the α-carbon of α,β-didehydroaminobutyric acid derivative (compound 28)
the resulting imine by a methoxide ion (Scheme 5).
but in a low yield (33%). The fact that this product did not
Finally, treatment of the triazole derivative 6 with either undergo addition of a second alkoxide ion shows that it is
sodium methoxide or sodium ethoxide in the corresponding not a sufficiently strong Michael acceptor and reflects the
alcohol gave the corresponding β,β-dialkoxyalanine deriva- electron-donating effect of the β-methyl group. As pre-
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Non-Natural Amino Acids from N-(p-Tolylsulfonyl)-α,β-didehydroamino Acid Derivatives
FULL PAPER
Scheme 5
viously observed with amines, Boc-∆Phe[β-(1,2,4-triazol-1- 1 gave the corresponding lysinoalanine derivative as a dia-
yl)]-OMe also did not react with sodium methoxide, again stereomeric mixture.
possibly due to stabilization by conjugation with the phe-
nyl group.
The above results show that N-(tert-butoxycarbonyl)-N-
(p-tolylsulfonyl)-α,β-didehydroamino acid esters and their
These results suggested the possibility of using a similar triazole and tolylsulfinyl derivatives are versatile reagents
approach in order to obtain cross-linked amino acids. for the synthesis of a variety of non-proteinogenic amino
Cross-linking in peptides causes conformational con- and dehydroamino acids. Thus, TosN(Boc)-∆Ala-OMe pro-
straints, resulting in increased molecular rigidity and thus ved to be an excellent substrate for synthesis of furanic am-
determining the final shape of these molecules. By using ino acids and, subsequently, tetradehydroproline deriva-
amino acid derivatives containing thiol, imidazole, and tives. This method may have great synthetic importance,
amine side chains as nucleophiles Ϫ namely, Boc-Cys-OMe since most approaches to pyrrole derivatives are multistep
(29), Boc-His-OMe (30), and Z-Lys-OMe (31) Ϫ and by and low-yielding.[13Ϫ15]
treating them with compound 1 we were able to obtain sev-
Treatment of amines with the above triazole and tolylsul-
eral cross-linked amino acids in good yields. Treatment of finyl substrates allowed the synthesis of different diamino
compound 1 with nucleophiles 29 and 30 resulted in the acid derivatives. The use of the dehydroaminobutyric acid
formation of didehydrolanthionine and histidino-α,β-dide- analogue of the above triazole substrate allowed the syn-
hydroalanine derivatives (compounds 32 and 33, respec- thesis of several β-amino-α,β-didehydroaminobutyric acid
tively, Scheme 6). Addition of nucleophile 31 to compound derivatives. In a similar way, sulfanylamino acid derivatives
Scheme 6
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P. M. T. Ferreira, H. L. S. Maia, L. S. Monteiro
FULL PAPER
3 H, OCH3), 3.48Ϫ3.61 (m, 2 H, βCH2), 3.96 (broad s, 1 H, αCΗ),
5.10 (t, J ϭ 5.7 Hz, 1 H, OH), 8.03 (d, J ϭ 9.0 Hz, 2 H, ArH),
8.39 (d, J ϭ 9.0 Hz, 2 H, ArH), 8.71 (s, 1 H, αNH) ppm; δC
(DMSO) 51.9, 58.1, 61.9, 124.4, 128.1, 146.7, 149.5, 170.2 ppm.
were obtained from treatment of the tolylsulfinyl substrate
with sulfur nucleophiles. Taking advantage of the above
substrates, we were able to develop a strategy enabling the
synthesis of a variety of alkoxy and dialkoxyalanine deriva-
tives. Thus, from (E)-Boc-∆Ser(p-tolylsulfinyl)-OMe it was
possible to obtain the corresponding α-alkoxy-β-sulfinyl
product, while β-alkoxyalanine derivatives were obtained
from Boc2-∆Ala-OMe. Use of Tos(Boc)-∆Ala-OMe gave
α,β-dialkoxy compounds, whilst (E)-Boc-∆Ala[β-(1,2,4-tria-
zol-1-yl)]-OMe yielded the corresponding β,β-dialkoxy iso-
mers. β,β-Dimethoxyalanine derivatives have been used in
a variety of synthetic transformations, namely the synthesis
of ifetroban, a cardiovascular drug, and of several capreo-
mycins and tuberactinomycins.[16,17]
Preparation of α,β-Didehydroamino Acid Derivatives
Synthesis of Tos(Boc)-∆Ala-OMe[6] (1), Tos(Boc)-∆Abu-OMe[2] (5),
Boc2-∆Ala-OMe[12] (21), Tos(Boc)-∆Phe-OMe[5] (25), Boc2-∆Abu-
OMe,[2] and Boc2-∆Phe-OMe:[5] The syntheses of these compounds
were described in refs.[2,5,6,12]
Preparation of β-Substituted α,β-Didehydroamino Acid Derivatives
Synthesis of (E)-Boc-∆Ala[β-(1,2,4-triazol-1-yl)]-OMe (6), (E)-Boc-
∆Abu[β-(1,2,4-triazol-1-yl)]-OMe [(E)-7], (Z)-Boc-∆Abu[β-(1,2,4-
triazol-1-yl)]-OMe [(Z)-7], (E)-Boc-∆Phe[β-(1,2,4-triazol-1-yl)]-
OMe [(E)-11] and (Z)-Boc-∆Phe[β-(1,2,4-triazol-1-yl)]-OMe [(Z)-
11]: The syntheses of these compounds were described in ref.[4]
The application of the methods described in this work to
provision of cross-linked amino acids was demonstrated by
the syntheses of didehydrolanthionine and histidino-α,β-di-
dehydroalanine derivatives in good yields.
Preparation of O-Sulfinyl-α,β-didehydroserine Derivatives
Synthesis of (E)-Boc-∆Ser(p-tolylsulfinyl)-OMe (12a): DMAP (0.1
equiv.) was added at room temperature with rapid stirring to a
solution of Tos-Ser-OMe (5 mmol, 1.37 g) in acetonitrile (1
mol·dmϪ3), followed by tert-butyl pyrocarbonate (2.2 equiv.). The
reaction mixture was stirred for 36 hours with monitoring by TLC
(diethyl ether/n-hexane, 1:1). Evaporation at reduced pressure gave
a residue that was partitioned between diethyl ether (200 cm3) and
KHSO4 (1 mol·dmϪ3, 100 cm3). The organic phase was thoroughly
washed with KHSO4 (1 mol·dmϪ3), NaHCO3 (1 mol·dmϪ3) and
brine (3 ϫ 50 cm3 each), and dried with MgSO4. Removal of the
solvent afforded pure product (1.67 g, 94%), m.p. 102Ϫ103.5 °C
(from ethyl acetate/n-hexane), C16H21NO6S (355.41): calcd. C
54.07, H 5.96, N 3.94, S 9.02; found C 53.93, H 6.11, N 4.01, S
8.83%. δH ϭ 1.48 (s, 9 H, Boc), 2.45 (s, 3 H, Ar-CH3), 3.81 (s, 3
H, OCH3), 5.68 (s, 1 H, βCH), 7.35 (d, J ϭ 8.4 Hz, 2-H, ArH),
Experimental Section
General Remarks: All melting points were measured on a Gallenk-
amp melting point apparatus and are uncorrected. TLC analyses
were carried out on 0.25 mm thick precoated silica plates (Merck
Fertigplatten Kieselgel 60F254) and spots were viewed either under
UV light or through exposure to vaporized iodine. Preparative
chromatography was carried out on Merck Kieselgel 60 (230Ϫ400
mesh). 1H NMR spectra were recorded on a Varian Unit Plus spec-
trometer at 300 MHz at 25 °C in ഠ5% CDCl3 solution when not
otherwise stated. All shifts are given in δ ppm with δH Me4Si ϭ 0
as reference. J Values are given in Hz. Spin-spin decoupling tech-
niques were used to attribute the signals. The stereochemistries of
the products were determined by NOE experiments. 13C NMR
spectra were recorded with the same instrument at 75.4 MHz and
with use of the solvent peak as internal reference (DEPT θ 45°).
The elemental analyses of crystalline compounds and of some oils
were carried out on a Leco CHNS 932 instrument.
7.77 (d, J ϭ 8.4 Hz, 2 H, ArH), 8.86 (s, 1 H, αNH) ppm; δC
ϭ
21.7, 28.0, 53.3, 83.2, 109.3, 127.2, 130.1, 137.8, 139.9, 145.2, 150.7,
163.3 ppm.
Synthesis of (E)-Boc-∆Ser(4-nitrophenylsulfinyl)-OMe (12b): The
same procedure as described above for the synthesis of 12a was
followed, with substitution of Nosyl-Ser-OMe (5 mmol, 1.52 g) for
Tos-Ser-OMe to afford 12b (1.24 g, 64%), m.p. 128.5Ϫ130 °C (from
diethyl ether/n-hexane), C15H18N2O8S (386.37): calcd. C 46.63, H
4.70, N 7.25, S 8.30; found C 46.86, H 4.99, N 7.35, S 8.00%. δH ϭ
1.47 (s, 9 H, Boc), 3.95 (s, 3 H, OCH3), 6.81 (s, 1 H, αNH), 7.16
(s, 1 H, βCH), 8.15 (d, J ϭ 9.0 Hz, 2 H, ArH), 8.38 (d, J ϭ 9.0 Hz,
2 H, ArH) ppm; δC ϭ 27.9, 53.8, 83.7, 110.3, 124.2, 128.6, 141.4,
147.8, 150.2, 150.6, 162.3 ppm.
Preparation of N-Acyl Amino Acid Esters
Synthesis of Tos-Ser-OMe, Boc-Ser-OMe, and Tos-Thr-OMe: The
syntheses of these compounds were described in ref.[2]
Synthesis of Tos-Phe(β-OH)-OMe: This compound was prepared
from HCl·H-Phe(β-OH)-OMe (10 mmol, 3.23 g) and p-tolylsul-
fonyl chloride according to the procedure described in ref.[2] for
the compounds above (2.72 g, 78%), m.p. 175Ϫ177 °C (from ethyl
acetate), C17H19NO5S (349.40): calcd. C 58.44, H 5.48, N 4.01, S
9.18; found C 58.39, H 5.60, N 4.07, S 9.16%. δH ϭ 2.39 (s, 3 H,
4-CH3 Tos), 2.77 (d, J ϭ 3.6 Hz, 1 H, OH), 3.50 (s, 3 H, OCH3),
4.10 (dd, J ϭ 3.9, J ϭ 9.9 Hz, 1 H αCH), 5.04 (dd, J ϭ 3.6, J ϭ
3.9 Hz, 1 H, βCH), 5.43 (d, J ϭ 9.9 Hz, 1 H, αNH), 7.16 (d, J ϭ
8.4 Hz, 2 H, ArH Tos), 7.28 (broad s, 5 H, ArH), 7.51 (d, J ϭ
8.4 Hz, 2 H, ArH Tos) ppm; δC ϭ 21.5, 52.6, 61.8, 74.2, 126.1,
127.0, 128.3, 128.4, 129.5, 136.4, 138.5, 143.5, 170.4 ppm.
Synthesis of 2,3-Dihydrofuran Derivatives
Synthesis of 4-Acetyl-2-(tert-butoxycarbonylamino)-2-methoxycar-
bonyl-5-methyl-2,3-dihydrofuran[5] (3a), 2-(tert-Butoxycarbonylam-
ino)-2,4-bis(methoxycarbonyl)-5-methyl-2,3-dihydrofuran[5] (3b), and
2-(tert-Butoxycarbonylamino)-4-benzyloxycarbonyl-2-
methoxycarbonyl-5-methyl-2,3-dihydrofuran[7] (3d): The synthesis of
these compounds was described in refs.[5,7]
Synthesis of 4-Benzoyl-2-(tert-butoxycarbonylamino)-2-methoxycar-
bonyl-5-methyl-2,3-dihydrofuran (3c): Cs2CO3 (1 equiv.) was added
at room temperature with rapid stirring to a solution of Tos(Boc)-
∆Ala-OMe (2 mmol, 0.71 g) in acetonitrile (0.1 mol·dmϪ3), fol-
lowed by benzoyl acetone (1 equiv.). The reaction was monitored
by TLC and when no starting material was detected, the solution
was filtered and the solvent was evaporated at reduced pressure to
Synthesis of Nosyl-Ser-OMe: This compound was prepared from
HCl·H-Ser-OMe (10 mmol, 2.47 g) and 4-nitrophenylsulfonyl chlo-
ride according to the procedure described elsewhere for the com-
pounds above (2.70 g, 89%), m.p. 172.5Ϫ173.5 °C (from methanol),
C10H12N2O7S (304.27): calcd. C 39.47, H 3.97, N 9.21, S 10.54;
found C 39.62, H 4.08, N 9.24, S 10.59%. δH (DMSO) ϭ 3.41 (s,
2640
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 2635Ϫ2644

Non-Natural Amino Acids from N-(p-Tolylsulfonyl)-α,β-didehydroamino Acid Derivatives
FULL PAPER
give 3c (0.58 g, 80%), m.p. 120Ϫ121 °C (from diethyl ether/n-hex- OCH3), 4.08 (d, J ϭ 6.3 Hz, 2 H, CH2), 7.26 (d, J ϭ 2.7 Hz, 1 H,
ane), C19H23NO6 (361.39): calcd. C 63.15, H 6.41, N 3.88; found: CH), 9.65 (s, 1 H, αNH) ppm; δC ϭ 13.5, 19.2, 27.9, 51.7, 70.0,
62.92, H 6.20, N 3.86%. δH ϭ 1.47 (s, 9 H, CH3 Boc), 1.89 (s, 3 H,
CH3), 3.37 (q, J ϭ 14.6 Hz, 2 H, CH2), 3.88 (s, 3 H, OCH3), 5.88
(s, 1 H, αNH), 7.40Ϫ7.61 (m, 5 H, ArH) ppm; δC ϭ 28.0, 39.8,
53.4, 67.1, 81.3, 91.2, 100.6, 128.0, 128.3, 128.4, 128.5, 129.8, 136.2,
153.2, 164.7, 167.0, 168.7 ppm.
114.3, 117.4, 120.3, 139.4, 164.7, 170.8 ppm.
Synthesis of β-Amino-α,β-didehydroamino Acid Derivatives
Synthesis of (E)-Boc-∆Ala(β-benzylamino)-OMe (9a): Benzylamine
(2.5 equiv.) was added to solution of (E)-Boc-∆Ala[β-(1,2,4-triazol-
1-yl)]-OMe (1 mmol, 0.27 g) in methanol (0.1 mol·dmϪ3). After
overnight stirring, TLC still indicated some starting material, so a
further 2.5 equiv. of benzylamine were added. When no starting
material was detected, ethyl acetate (100 cm3) was added and the
organic layer was washed with KHSO4 (1 mol·dmϪ3) and brine (2
ϫ 30 cm3 each). Drying with MgSO4 and evaporation of the sol-
vent at reduced pressure afforded 9a (0.27 g, 87%), m.p. 90Ϫ91.5
°C (from diethyl ether/n-hexane), C16H22N2O4 (306.36): calcd. C
62.73, H 7.24, N 9.14; found C 62.75, H 7.18, N 9.03%. δH ϭ 1.46
(s, 9 H, Boc), 3.70 (s, 3 H, OCH3), 4.41 (d, J ϭ 6.3 Hz, 2 H, CH2),
5.68 (s, 1 H, NH), 5.93 (s, 1 H, NH), 7.29Ϫ7.41 (m, 6 H, βCH ϩ
ArH) ppm; δC ϭ 28.2, 51.3, 52.0, 80.2, 98.3, 127.0, 127.2, 127.57,
127.63, 128.7, 138.6, 141.7, 166.6 ppm.
Synthesis of 2-(tert-Butoxycarbonylamino)-4-isobutoxycarbonyl-2-
methoxycarbonyl-5-methyl-2,3-dihydrofuran (3e): The same pro-
cedure as used above for the synthesis of 3c was followed, with
substitution of isobutoxycarbonyl acetone for benzoyl acetone to
afford 3e (0.59 g, 82%), m.p. 109.5Ϫ111 °C (from diethyl ether/n-
hexane), C17H27NO7 (357.40): calcd. C 57.13, H 7.61, N 3.92;
found C 57.13, H 7.61, N 3.99%. δH ϭ 0.95 (d, J ϭ 6.9 Hz, 6 H,
2 CH3), 1.45 (s, 9 H, Boc), 1.93Ϫ2.01 (m, 1 H, CH), 2.27 (s, 3 H,
CH3), 3.17 (q, J ϭ 17.4 Hz, 2 H, CH2), 3.85 (s, 3 H, OCH3), 3.90
(d, J ϭ 6.9 Hz, 2 H, CH2), 5.83 (s, 1 H, αNH) ppm; δC ϭ 14.1,
19.2, 28.1, 30.9, 40.0, 53.5, 70.1, 81.5, 91.1, 101.1, 153.3, 165.0,
166.2, 168.9 ppm.
Synthesis of Pyrrole Derivatives
Synthesis of (E)-Boc-∆Ala(β-propargylamino)-OMe (9b): The same
procedure as described for the preparation of 9a was followed, with
Synthesis of 4-Acetyl-2-methoxycarbonyl-5-methylpyrrole[8] (4a):
TFA (10%) was added at room temperature with rapid stirring to substitution of propargylamine for benzylamine, to afford 9b in
a
solution of 3a (1 mmol, 0.30 g) in dichloromethane (0.1
(0.21 g, 82%), m.p. 60Ϫ61.5 °C (from diethyl ether), C12H18N2O4
(254.28): calcd. C 56.68, H 7.13, N 11.02; found C 56.43, H 7.12,
N 10.70%. δH ϭ 1.45 (s, 9 H, Boc), 2.35 (m, 1 H, CH), 3.70 (s, 3
H, OCH3), 3.96 (m, 2 H, CH2), 5.61 (s, 1 H, NH), 6.05 (s, 1 H,
NH), 7.24 (d, J ϭ 6.3 Hz, 1 H, βCH) ppm; δC ϭ 28.5, 37.4, 51.8,
73.2, 79.8, 80.7, 100.2, 139.6, 150.3, 166.6 ppm.
mol·dmϪ3). The reaction was monitored by TLC and when no
starting material was detected, dichloromethane (30 cm3) was ad-
ded and the solution was washed with NaHCO3 (1 mol·dmϪ3) and
brine (3 ϫ 10 cm3 each) and dried with MgSO4. Removal of the
solvent at reduced pressure afforded 4a (0.17 g, 92%), m.p.
177.5Ϫ179 °C (from diethyl ether/n-hexane), C9H11NO3 (181.19):
calcd. C 59.66, H 6.12, N 7.73, found C 59.55, H 6.11, N 7.77%.
δH ϭ 1.62 (s, 3 H, CH3), 2.43 (s, 3 H, CH3), 3.88 (s, 3 H, OCH3),
7.21 (d, J ϭ 3.0 Hz, 1 H, CH), 9.23 (s, 1 H, αNH) ppm; δC ϭ 14.0,
28.2, 51.7, 117.4, 119.9, 122.5, 139.5, 161.5, 194.8 ppm.
Synthesis of (E)-Boc-∆Ala{β-[N-(2-aminoethyl)amino]}-OMe (9c):
1,2-Ethylenediamine (10 equiv.) was added to a solution of (E)-
Boc-∆Ala[β-(1,2,4-triazol-1-yl)]-OMe (1 mmol, 0.27 g) in methanol
(0.1 mol·dmϪ3). The solution was heated at reflux for 2 hours and
the solvent was then evaporated at reduced pressure. The residue
was dissolved in dichloromethane (100 cm3) and washed with
Na2CO3 (1 mol·dmϪ3) (3 ϫ 30 cm3). The organic phase was dried
with MgSO4 and the solvents were evaporated at reduced pressure
to afford 9c (0.23 g, 90%), oil; δH ϭ 1.47 (s, 9 H, Boc), 2.85 (t, J ϭ
Synthesis of 2,4-Bis(methoxycarbonyl)-5-methylpyrrole (4b): This
compound was prepared from compound 3b (1 mmol, 0.32 g) by
the same procedure as described above for 4a, to give 4b (0.18 g,
90%), m.p. 175Ϫ176 °C (from diethyl ether/n-hexane), C9H11NO4
(197.19): calcd. C 54.82, H 5.62, N 7.10; found C 54.75, H 5.62, N 5.4 Hz, 2 H, CH2), 3.25 (q, J ϭ 5.4 Hz, 2 H, CH2), 3.70 (s, 3 H,
7.11%. δH ϭ 2.58 (s, 3 H, CH3), 3.82 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 3.46 (broad s, 2 H, NH2), 5.38 (broad s, 1 H, NH), 5.92
OCH3), 7.24 (d, J ϭ 2.7 Hz, 1 H, CH), 9.23 (s, 1 H, αNH) ppm;
(broad s, 1 H, NH), 7.24 (d, J ϭ 13.2 Hz, 1 H, βCH) ppm; δC ϭ
δC ϭ 13.3, 51.0, 51.7, 113.8, 117.5, 120.3, 140.0, 161.7, 165.1 ppm. 28.2, 31.5, 42.8, 51.2, 80.2, 97.9, 128.2, 144.2, 166.7 ppm.
Synthesis of 4-Benzoyl-2-methoxycarbonyl-5-methylpyrrole[8] (4c):
This compound was prepared from compound 3c (1 mmol, 0.36 g)
by the same procedure as described for 4a, to give 4c (0.19 g, 77%),
m.p. 153Ϫ154.5 °C (from diethyl ether/n-hexane), C14H13NO3
(243.26): calcd. C 69.13, H 5.39, N 5.76; found C 69.39, H 5.39, N
5.62%. δH ϭ 2.38 (s, 3 H, CH3), 3.86 (s, 3 H, OCH3), 7.36 (d, J ϭ
3.0 Hz, 1 H, CH), 7.44Ϫ7.46 (m, 3 H, ArH), 7.58Ϫ7.61 (m, 2 H,
ArH), 9.48 (s, 1 H, αNH) ppm; δC ϭ 28.9, 51.9, 117.9, 121.8, 123.0,
128.4, 129.1, 129.4, 131.0, 139.8, 161.3, 193.8 ppm.
Synthesis of (E)-Boc-∆Abu(β-benzylamino)-OMe (10a): The syn-
thesis of this compound was described in ref.[9]
Synthesis of (E)-Boc-∆Abu(β-propargylamino)-OMe (10b): The
same procedure as described for the preparation of 9b was fol-
lowed, with substitution of (E)-Boc-∆Abu[β-(1,2,4-triazol-1-yl)]-
OMe (1 mmol, 0.28 g) for (E)-Boc-∆Ala[β-(1,2,4-triazol-1-yl)]-
OMe, to afford 10b (0.24 g, 90%), m.p. 75Ϫ77 °C (from diethyl
ether/n-hexane), C13H20N2O4 (268.31): calcd. C 58.19, H 7.51, N
10.44; found C 57.85, H 7.36, N 10.07%. δH ϭ 1.46 (s, 9 H, Boc),
2.09 (s, 3 H, γCH3), 2.28 (t, J ϭ 2.4 Hz, 1 H, CH), 3.66 (s, 3 H,
OCH3), 3.98 (2d, J ϭ 2.4, J ϭ 6.2 Hz, 2 H, CH2), 5.39 (broad s, 1
H, NH), 9.11 (s, 1 H, NH) ppm; δC ϭ 14.0, 28.0, 32.8, 54.0, 72.0,
79.6, 84.0, 94.2, 109.7, 156.0, 168.1 ppm. The same procedure with
(Z)-Boc-∆Abu[β-(1,2,4-triazol-1-yl)]-OMe again gave the E isomer
of 10b, in 92% yield (0.25 g).
Synthesis 4-Benzyloxycarbonyl-2-methoxycarbonyl-5-methylpyrrole
(4d): The synthesis of this compound was described in ref.[7]
Synthesis of 4-Isobutoxycarbonyl-2-methoxycarbonyl-5-methylpyr-
role (4e): This compound was prepared from compound 3e
(1 mmol, 0.36 g) by the same procedure as described above for 4a,
to give 4e (0.21 g, 88%) as an oil, which solidified on standing m.p.
137Ϫ138.5 °C, C12H17NO4 (239.27): calcd. C 60.24, H 7.16, N 5.85; Synthesis of (E)-Boc-∆Abu{β-[N-(2-aminoethyl)amino]}-OMe (10c):
found C 60.15, H 7.12, N 5.91%. δH ϭ 1.06 (d, J ϭ 6.9 Hz, 6 H, The same procedure as described for the preparation of 9c was
2 CH3), 1.98Ϫ2.17 (m, 1 H, CH), 2.64 (s, 3 H, CH3), 3.93 (s, 3 H, followed, with substitution of (E)-Boc-∆Abu[β-(1,2,4-triazol-1-yl)]-
Eur. J. Org. Chem. 2003, 2635Ϫ2644
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2641

P. M. T. Ferreira, H. L. S. Maia, L. S. Monteiro
FULL PAPER
OMe (1 mmol, 0.28 g) for (E)-Boc-∆Ala[β-(1,2,4-triazol-1-yl)]-
S 7.26; found C 49.04, H 5.38, N 9.48, S 7.14%. δH ϭ 1.23 (s, 9 H,
OMe, to afford 10c (0.11 g, 39%), oil; δH ϭ 1.45 (s, 9 H, Boc), 2.01 Boc), 2.20 (t, J ϭ 2.4 Hz, 1 H, CH), 3.05 (s, 1 H, NH), 3.19Ϫ3.24
(s, 3 H, γCH3), 2.87 (t, J ϭ 5.7 Hz, 2 H, CH2), 3.28 (q, J ϭ 5.7 Hz,
2 H, CH2), 3.64 (s, 3 H, OCH3), 3.90 (d, J ϭ 5.7 Hz, 2 H, NH2),
(m, 2 H, CH2), 3.96 (s, 3 H, OCH3), 3.99 (d, J ϭ 15.0 Hz, 1 H,
CH2), 4.49 (d, J ϭ 15.0 Hz, 1 H, CH2), 6.02 (s, 1 H, NH), 8.07 (d,
5.11 (broad s, 1 H, NH), 5.40 (broad s, 1 H, NH) ppm; δC ϭ 14.4, J ϭ 8.7 Hz, 2 H, ArH), 8.38 (d, J ϭ 8.7 Hz, 2 H, ArH) ppm; δC ϭ
28.2, 42.0, 46.3, 52.2, 79.4, 92.6, 143.7, 151.3, 162.2 ppm. The same 28.0, 31.4, 54.0, 59.6, 71.6, 71.9, 80.2, 81.0, 124.3, 129.9, 145.4,
procedure with (Z)-Boc-∆Abu[β-(1,2,4-triazol-1-yl)]-OMe again 150.8, 153.6, 168.7 ppm.
gave the E isomer of 10c, in 49% yield (0.13 g).
Synthesis of 3-(tert-Butoxycarbonylamino)-2-oxo-3-[(4-nitrophe-
nylsulfinyl)oxymethyl]piperazine (15b): The same procedure as de-
scribed for the preparation of 15a was followed, with substitution
of (E)-Boc-∆Ser(4-nitrophenylsulfinyl)-OMe (1 mmol, 0.39 g) for
(E)-Boc-∆Ser(p-tolylsulfinyl)-OMe, to afford 15b (0.24 g, 59%),
m.p. 156Ϫ157 °C (from ethyl acetate/n-hexane), C16H22N4O7S
(414.44): calcd. C 46.37, H 5.35, N 13.52, S 7.74; found C 46.30,
H 5.44, N 13.34, S 7.66%. δH ϭ 1.33 (s, 9 H, Boc), 2.63Ϫ3.22 (m,
5 H, 2 CH2 ϩ NH), 4.01 (d, J ϭ 14.7 Hz, 1 H, CH2), 4.15 (d, J ϭ
14.7 Hz, 1 H, CH2), 7.38 (s, 1 H, NH), 7.90 (s, 1 H, NH), 8.13 (d,
J ϭ 9.0 Hz, 2 H, ArH), 8.40 (d, J ϭ 9.0 Hz, 2 H, ArH) ppm; δC ϭ
28.0, 36.4, 41.1, 59.7, 70.0, 79.1, 123.9, 130.0, 146.5, 150.1, 154.4,
164.9 ppm.
Synthesis of α-Amino-Ο-Sulfinylserine Derivatives
Synthesis of Boc-Ser[α-benzylamino,Ο-(p-tolylsulfinyl)]-OMe (13a):
The synthesis of this compound was described in ref.[9]
Synthesis of Boc-Ser[α-propargylamino,Ο-(p-tolylsulfinyl)]-OMe
(13b): Propargylamine (2.5 equiv.) was added at room temperature,
with rapid stirring, to a solution of (E)-Boc-∆Ser(p-tolylsulfinyl)-
OMe (1 mmol, 0.36 g) in methanol (0.1 mol·dmϪ3). The reaction
was monitored by TLC and when no starting material was de-
tected, ethyl acetate (100 cm3) was added. The organic phase was
then washed with water and brine (2 ϫ 30 cm3 each) and dried
with MgSO4, and the solvents were evaporated at reduced pressure
to afford 13b (0.36 g, 87%), m.p. 117Ϫ119 °C (from diethyl ether/
n-hexane), C19H26N2O6S (410.49): calcd. C 55.59, H 6.38, N 6.82,
S 7.81; found C 55.52, H 6.39, N 6.73, S 7.69%. δH ϭ 1.27 (s, 9 H,
Boc), 2.17 (t, J ϭ 2.4 Hz, 1 H, CH), 2.43 (s, 3 H, Ar-CH3), 3.09 (s,
1 H, NH), 3.21 (dq, J ϭ 2.4, J ϭ 16.8 Hz, 2 H, CH2), 3.89 (d, J ϭ
14.7 Hz, 1 H, β-CH2), 3.90 (s, 3 H, OCH3), 4.36 (d, J ϭ 14.7 Hz,
1 H, CH2), 6.02 (s, 1 H, NH), 7.32 (d, J ϭ 8.1 Hz, 2 H, ArH), 7.73
(d, J ϭ 8.1 Hz, 2 H, ArH) ppm; δC ϭ 21.6, 28.0, 31.4, 53.8, 59.5,
71.7, 80.4, 128.2, 129.8, 137.1, 144.6, 153.7, 169.1 ppm.
Synthesis of β-Sulfanyl α,β-Didehydroalanine Derivatives
Synthesis of (E)-Boc-∆Ala(β-methoxycarbonylmethylsulfanyl)-OMe
(19): The same procedure as described above for the synthesis of
13b was followed, with substitution of methylsulfanyl acetate (1
equiv.) for propargylamine and addition of triethylamine (2.5
equiv.), to give 19[5] (0.16 g, 54%).
Synthesis of (E)-Boc-∆Ala[β-(4-bromophenylsulfanyl)]-OMe (20):
The same procedure as described above for the synthesis of 19 was
followed, with substitution of 4-bromothiophenol for methylsul-
fanyl acetate, to give 20[9] (0.29 g, 75%).
Synthesis of 3-(tert-Butoxycarbonylamino)-2-oxo-3-[(p-tolylsulfiny-
l)oxymethyl]piperazine (15a): The same procedure as described for
the preparation of 13b was followed, with substitution of 1,2-ethyl-
enediamine for benzylamine, to afford 15a (0.34 g, 89%), m.p.
118Ϫ119.5 °C (from methanol/diethyl ether), C17H25N3O5S
(383.47): calcd. C 53.25, H 6.57, N 10.96, S 8.36; found C 53.27,
H 6.42, N 11.08, S 8.37%. δH ϭ 1.41 (s, 9 H, Boc), 2.44 (s, 3 H,
Ar-CH3), 2.90Ϫ2.95 (m, 1 H, CH2), 3.14Ϫ3.26 (m, 2 H, CH2), 3.49
(broad s, 1 H, NH), 3.62Ϫ3.71 (m, 1 H, CH2), 3.95 (d, J ϭ 14.4 Hz,
1 H, CH2), 4.04 (d, J ϭ 14.4 Hz, 1 H, CH2), 5.46 (s, 1 H, NH),
6.15 (broad s, 1 H, NH), 7.32 (d, J ϭ 8.1 Hz, 2 H, ArH), 7.82 (d,
J ϭ 8.1 Hz, 2 H, ArH) ppm; δC ϭ 21.6, 28.2, 37.2, 42.3, 60.5, 71.5,
80.6, 128.3, 129.4, 138.4, 144.2, 154.5, 167.4 ppm.
Synthesis of (E)-Boc-∆Ala[β-(1,2,4-triazol-1-yl]-OMe: The same
procedure as described above for the synthesis of 19 was followed,
with substitution of 1,2,4-triazole for methylsulfanyl acetate, to give
6[4] (0.12 g, 42%).
Synthesis of Alkoxyamino Acid Derivatives
Synthesis of Boc-Ser[α-methoxy-O-(p-tolylsulfinyl)]-OMe (22a):
NaOMe (2 equiv.) was added with rapid stirring at room tempera-
ture to a solution of (E)-Boc-∆Ser(p-tolylsulfinyl)-OMe (1 mmol,
0.36 g) in methanol (0.1 mol·dmϪ3). The reaction was monitored
by TLC and, when no starting material was detected, ethyl acetate
(100 cm3) was added. The organic phase was then washed with
water and brine (2 ϫ 30 cm3 each) and dried with MgSO4, and the
solvents were evaporated at reduced pressure to give 22a (0.30 g,
77%), m.p. 89.5Ϫ90.5 °C (from diethyl ether/n-hexane),
C17H25NO7S (387.45): calcd. C 52.70, H 6.50, N 3.62, S 8.28; found
C 52.43, H 6.58, N 3.66, S 7.75%. δH ϭ 1.30 (s, 9 H, Boc), 2.44 (s,
3 H, Ar-CH3), 3.11 (s, 3 H, CH3), 3.83 (d, J ϭ 14.7 Hz, 1 H, βCH2),
3.92 (s, 3 H, OCH3), 4.68 (d, J ϭ 14.7 Hz, 1 H, βCH2), 6.27 (s, 1
H, αNH), 7.33 (d, J ϭ 8.1 Hz, 2 H, ArH), 7.75 (d, J ϭ 8.1 Hz, 2
H, ArH) ppm; δC ϭ 21.5, 27.9, 50.2, 53.7; 58.3, 80.5, 83.6, 128.3,
129.6, 136.8, 144.6, 152.6, 168.0 ppm.
Synthesis of Boc-Ser[α-benzylamino,O-(4-nitrophenylsulfinyl)]-OMe
(14a): The same procedure as described for the preparation of 13b
was followed, with substitution of (E)-Boc-∆Ser(4-nitrophenylsulfi-
nyl)-OMe (1 mmol, 0.39 g) for (E)-Boc-∆Ser(p-tolylsulfinyl)-OMe
and benzylamine for propargylamine, to afford 14a (0.45 g, 91%),
m.p. 141Ϫ143 °C (from diethyl ether), C22H27N3O8S (493.53):
calcd. C 53.54, H 5.51, N 8.51, S 6.50; found C 53.63, H 5.49, N
8.86, S 6.90%. δH ϭ 1.25 (s, 9 H, Boc), 2.94 (s, 1 H, NH), 3.33 (d,
J ϭ 12.0 Hz, 1 H, CH2), 3.56 (d, J ϭ 12.0 Hz, 1 H, CH2), 3.88 (s,
3 H, OCH3), 4.04 (d, J ϭ 14.7 Hz, 1 H, CH2), 4.49 (d, J ϭ 14.7 Hz,
1 H, CH2), 6.08 (s, 1 H, NH), 7.18Ϫ7.31 (m, 5 H, ArH Bzl), 8.07
(d, J ϭ 9.0 Hz, 2 H, ArH), 8.38 (d, J ϭ 9.0 Hz, 2 H ArH) ppm;
δC ϭ 28.0, 46.4, 53.9, 59.7, 71.9, 80.8, 124.2, 127.5, 128.3, 128.5,
128.6, 129.8, 138.0, 145.5, 150.7, 153.5, 169.2 ppm.
Synthesis of Boc-Ser[α-ethoxy,O-(p-tolylsulfinyl)]-OEt (22b): The
same procedure as described above for the synthesis of 22a was
followed, with substitution of NaOEt (3 equiv.) for NaOMe and
ethanol for methanol, to give 22b (0.22 g, 52%), m.p. 81.5Ϫ82.5 °C
(from diethyl ether/n-hexane), C19H29NO7S (415.50): calcd. C
54.92, H 7.03, N 3.37, S 7.72; found C 54.96, H 6.89, N 3.39, S
Synthesis of Boc-Ser[α-propargylamino,Ο-(4-nitrophenylsulfinyl)]-
OMe (14b): The same procedure as described for the preparation
of 14a was followed, with substitution of propargylamine for ben-
zylamine, to afford 14b (0.33 g, 75%), m.p. 131Ϫ133 °C (from di- 7.72%. δH ϭ 1.08 (t, J ϭ 7.2 Hz, 3 H, CH3 OEt), 1.29 (s, 9 H,
ethyl ether), C18H23N3O8S (441.46): calcd. C 48.97, H 5.25, N 9.52, Boc), 1.39 (t, J ϭ 7.2 Hz, 3 H, CH3 OEt), 2.43 (s, 3 H, Ar-CH3),
2642
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 2635Ϫ2644

Non-Natural Amino Acids from N-(p-Tolylsulfonyl)-α,β-didehydroamino Acid Derivatives
3.21Ϫ3.46 (m, 2 H, CH2 OEt), 3.85 (d, J ϭ 14.7 Hz, 1 H, βCH2), 5.24 (d, J ϭ 8.4 Hz, 1 H, αNH) ppm; δC ϭ 28.2, 52.5, 55.3, 55.5,
FULL PAPER
4.36 (q, J ϭ 7.2 Hz, 2 H, CH2 OEt), 4.64 (d, J ϭ 14.7 Hz, 1 H,
βCH2), 6.30 (broad s, 1 H, αNH), 7.32 (d, J ϭ 8.1 Hz, 2 H, ArH),
7.75 (d, J ϭ 8.1 Hz, 2 H, ArH) ppm; δC ϭ 14.0, 14.8, 21.6, 28.0,
58.6, 63.1, 80.3, 83.1, 109.7, 128.3, 129.6, 137.1, 144.5, 152.7,
167.9 ppm.
55.7, 80.0, 103.7, 155.6, 170.2 ppm.
Synthesis of Boc-Ala(β,β-diethoxy)-OEt (27b): The same procedure
as described above for the synthesis of 22b was followed, with sub-
stitution of (E)-Boc-∆Ala(1,2,4-triazol-1-yl)-OMe (1 mmol, 0.27 g)
for (E)-Boc-∆Ser(p-tolylsulfinyl)-OMe, to give 27b (0.08 g, 27%),
oil, C14H27NO6 (305.37): calcd. C 55.07, H 8.91, N 4.59; found C
55.22, H 8.64, N 4.50%. δH ϭ 1.17 (t, J ϭ 7.2 Hz, 3 H, CH3 OEt),
1.23 (t, J ϭ 7.2 Hz, 3 H, CH3 OEt), 1.28 (t, J ϭ 7.2 Hz, 3 H, CH3
OEt), 1.45 (s, 9 H, Boc), 3.47Ϫ3.80 (m, 4 H, 2 CH2 OEt),
4.16Ϫ4.28 (m, 2 H, CH2 OEt), 4.51 (dd, J ϭ 3.3, J ϭ 9.0 Hz, 1 H,
αCH), 4.75 (d, J ϭ 3.3 Hz, 1 H, βCH), 5.26 (d, J ϭ 9.0 Hz, 1 H,
αNH) ppm; δC ϭ 14.1, 14.8, 15.0, 28.2 56.0, 61.3, 63.5, 63.6, 79.8,
101.1, 155.7, 169.7 ppm.
Synthesis of Boc2-Ala(β-methoxy)-OMe (23a): The same procedure
as described above for the synthesis of 22a was followed, with sub-
stitution of Boc2-∆Ala-OMe (1 mmol, 0.30 g) for (E)-Boc-∆Ser(p-
tolylsulfinyl)-OMe, to give 23a (0.27 g, 80%), oil, C15H27NO7
(333.38): calcd. C 54.04, H 8.16, N 4.20; found C 53.83, H 7.97, N
4.53%. δH ϭ 1.51 (s, 9 H, Boc), 3.37 (s, 3 H, βOCH3), 3.74 (s, 3 H,
COOCH3), 3.83 (dd, J ϭ 8.4, J ϭ 10.7 Hz, 1 H, βCH2), 3.99 (dd,
J ϭ 5.1, J ϭ 10.7 Hz, 1 H, βCH2), 5.19 (dd, J ϭ 5.1, J ϭ 8.4 Hz,
1 H, αCH2) ppm; δC ϭ 27.9, 52.2, 57.4, 58.9, 71.1, 83.2, 152.0,
169.6 ppm.
Synthesis of (E)-Boc-∆Abu(β-methoxy)-OMe (28): The same pro-
cedure as described above for the synthesis of 22a was followed,
with substitution of (E)-Boc-∆Abu[β-(1,2,4-triazol-1-yl)]-OMe
(1 mmol, 0.28 g) for (E)-Boc-∆Ser(p-tolylsulfinyl)-OMe, to give 28
(0.08 g, 33%), m.p. 126Ϫ127 °C (from diethyl ether/n-hexane),
C11H19NO5 (245.27): calcd. C 53.87, H 7.81, N 5.71; found C
53.84, H 7.94, N 5.69%. δH ϭ 1.46 (s, 9 H, Boc), 2.38 (s, 3 H,
γCH3), 3.74 (s, 3 H, OCH3), 3.76 (s, 3 H, OCH3), 5.64 (s, 1 H,
αNH) ppm; δC ϭ 13.7, 28.2, 51.6, 55.3, 80.0, 109.2, 154.1, 166.5
ppm.
Synthesis of Boc2-Ala(β-ethoxy)-OEt (23b): The same procedure as
described above for the synthesis of 22b was followed, with substi-
tution of Boc2-∆Ala-OMe (1 mmol, 0.30 g) for (E)-Boc-∆Ser(p-to-
lylsulfinyl)-OMe, to give 23b (0.14 g, 38%), m.p. 36.5Ϫ38 °C,
C17H31NO7 (361.43): calcd. C 56.49, H 8.64, N 3.88; found C
56.33, H 8.35, N 3.96%. δH ϭ 1.17 (t, J ϭ 7.2 Hz, 3 H, CH3 OEt),
1.27 (t, J ϭ 7.2 Hz, 3 H, CH3 OEt), 1.51 (s, 18 H, Boc), 3.43Ϫ3.59
(m, 2 H, CH2 OEt), 3.88 (dd, J ϭ 8.4, J ϭ 10.7 Hz, 1 H, βCH2),
4.03 (dd, J ϭ 4.8, J ϭ 10.7 Hz, 1 H, βCH2), 4.19 (q, J ϭ 7.2 Hz,
2 H, CH2 OEt), 5.16 (dd, J ϭ 4.8, J ϭ 8.4 Hz, 1 H, αCH) ppm;
Synthesis of Cross-linked Amino Acid Derivatives
Synthesis of N,NЈ-Bis-Boc-cysteino-(E)-α,β-didehydroalanine Di-
methyl Ester (32): K2CO3 (6 equiv.) was added to a solution of
Tos(Boc)-∆Ala-OMe (1 mmol, 0.36 g) in acetonitrile (0.2
mol·dmϪ3), followed by Boc--Cys-OMe (1 equiv.), with fast stir-
ring at room temperature. The reaction was monitored by 1H NMR
and when no starting material was detected, the solution was fil-
tered and the solvent was evaporated at reduced pressure to give
32 (0.33 g, 75%), oil; δH ϭ 1.45 (s, 9 H, Boc), 1.47 (s, 9 H, Boc),
3.29 (d, J ϭ 4.2 Hz, 2-H, βCH2 Cys), 3.77 (s, 6 H, 2OCH3), 4.62
(m, 1 H, αCH Cys), 5.44 (d, J ϭ 7.2 Hz, 1 H, αNH Cys), 6.07
δ
C ϭ 14.1, 15.1, 27.9, 57.7, 61.2, 66.3, 68.9, 82.9, 152.1, 169.2 ppm.
Synthesis of Boc-Ala(α,β-dimethoxy)-OMe (24a): The synthesis of
this compound was described in ref.[9]
Synthesis of Boc-Ala(α,β-diethoxy)-OEt (24b): The same procedure
as described above for the synthesis of 22b was followed, with sub-
stitution of Tos(Boc)-∆Ala-OMe (1 mmol, 0.36 g) for (E)-Boc-
∆Ser(p-tolylsulfinyl)-OMe and use of 4 equiv. of NaOEt, to give
24b (0.18 g, 60%), m.p. 29Ϫ30.5 °C, C14H27NO6 (305.37): calcd. C
55.07, H 8.91, N 4.59; found C 55.42, H 8.88, N 4.43%. δH ϭ 1.15
(t, J ϭ 7.2 Hz, 3 H, CH3 OEt), 1.20 (t, J ϭ 7.2 Hz, 3 H, CH3 OEt),
1.31 (t, J ϭ 7.2 Hz, 3 H, CH3 OEt), 1.45 (s, 9 H, Boc), 3.35Ϫ3.63
(m, 4 H, 2 CH2 OEt), 3.72 (d, J ϭ 9.3 Hz, 1 H, βCH2), 4.17 (d,
J ϭ 9.3 Hz, 1 H, βCH2), 4.23Ϫ4.34 (m, 2 H, CH2 OEt), 6.04 (broad
s, 1 H, αNH) ppm; δC ϭ 14.1, 14.9, 15.2, 28.2, 59.3, 62.2, 67.1,
71.0, 80.0, 86.7, 153.4, 169.6 ppm.
(broad s, 1 H, αNH ∆Ala), 7.17 (s, 1 H, βCH ∆Ala) ppm; δC
ϭ
28.1, 28.2, 37.2, 52.3, 52.7, 59.0, 80.4, 80.9, 122.8, 134.9, 144.4,
154.9, 163.3, 170.4 ppm.
Synthesis of N,NЈ-Bis-Boc-histidino-(E)-α,β-didehydroalanine Di-
methyl Ester (33): The same procedure as described above for the
synthesis of 32 was followed, with substitution of Boc--His-OMe
(1 mmol, 0.27 g) for Boc--Cys-OMe, to give 33 (0.40 g, 85%), m.p.
70Ϫ71.5 °C, C21H32N4O8 (468.50): calcd. C 53.84, H 6.88, N 11.96;
found C 53.51, H 6.88, N 11.68%. δH ϭ 1.41 (s, 9 H, Boc), 1.43 (s,
9 H, Boc), 3.00Ϫ3.12 (m, 2 H, βCH2 His), 3.71 (s, 3 H, OCH3),
3.85 (s, 3 H, OCH3), 4.55Ϫ4.58 (m, 1 H, αCH), 5.73 (d, J ϭ 8.1 Hz,
1 H, αNH His), 6.04 (s, 1 H, αNH ∆Ala), 7.15 (s, 1 H, βCH ∆Ala),
7.63 (s, 1 H, 2-H or 4-H imid.), 7.76 (s, 1 H, 2-H or 4-H imid.)
ppm; δC ϭ 28.0, 29.3, 52.3, 52.6, 52.8, 53.2, 79.7, 81.8, 116.1, 126.6,
136.9, 138.3, 139.1, 152.9, 165.2, 172.3 ppm.
Synthesis of Boc-Phe(α,β-dimethoxy)-OMe (26): The same pro-
cedure as described above for the synthesis of 22a was followed,
with substitution of Tos(Boc)-∆Phe-OMe (1 mmol, 0.43 g) for (E)-
Boc-∆Ser(p-tolylsulfinyl)-OMe and use of 3 equiv. of NaOMe, to
give 26 (0.30 g, 87%), m.p. 80Ϫ81 °C (from diethyl ether/n-hexane),
C17H25NO6 (339.39): calcd. C 60.16, H 7.42, N 4.13; found C
59.92, H 7.30, N 4.07%. δH ϭ 1.42 (s, 9 H, Boc), 3.21 (s, 3 H,
αOCH3 or βOCH3), 3.36 (s, 3 H, αOCH3 or βOCH3), 3.77 (s, 3 H,
COOCH3), 4.61 (s, 1 H, βCH), 5.05 (broad s, 1 H, αNH),
7.38Ϫ7.47 (m, 5 H, ArH) ppm; δC ϭ 28.1, 52.1, 52.6, 57.5, 68.9,
86.6, 87.5, 128.3, 128.9, 129.1, 134.8, 153.9, 169.1 ppm.
Synthesis of Tos-Ala[N-Boc-β-{[(Z)-lysin-ω-yl]-OMe}]-OMe: The
same procedure as described above for the synthesis of 32 was fol-
lowed, with substitution of (Z)--Lys-OMe (1 mmol, 0.29 g) for
Boc--Cys-OMe, to give a mixture of diastereomers (0.55 g, 84%)
that could not be separated by column chromatography.
Synthesis of Boc-Ala(β,β-dimethoxy)-OMe (27a): The same pro-
cedure as described above for the synthesis of 22a was followed,
with substitution of (E)-Boc-∆Ala[β-(1,2,4-triazol-1-yl)]-OMe
(1 mmol, 0.27 g) for (E)-Boc-∆Ser(p-tolylsulfinyl)-OMe and use of
3 equiv. of NaOMe, to give 27a (0.23 g, 88%), oil; C11H21NO6
(263.29): calcd. C 50.18, H 8.04, N 5.32; found C 50.16, H 7.85, N
5.31%. δH ϭ 1.44 (s, 9 H, Boc), 3.41 (s, 3 H, OCH3), 3.43 (s, 3 H,
OCH3), 3.76 (s, 3 H, OCH3), 4.49Ϫ4.57 (m, 2 H, αCH ϩ βCH),
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www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2643

P. M. T. Ferreira, H. L. S. Maia, L. S. Monteiro
FULL PAPER
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Received February 18, 2003
2644
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2635Ϫ2644