Novel sulfur and selenium containing bis-α-amino acids from 4-hydroxyproline

Article abstract of DOI:10.1007/s00726-009-0251-x

The synthesis of new substituted prolines carrying at C-4 a second α-amino acid residue is reported. The amino acid, l-cysteine or l-selenocysteine, is linked to the proline ring through the sulfur or the selenium atom, respectively. The products were prepared with different stereochemistry at C-4, in few and clean high-yielding steps, with suitable protections for solid phase applications. The introduction of both sulfur and selenium atoms at C-4 of the proline ring seems to enhance significantly the cis geometry at the prolyl amide bond.

Full text of DOI:10.1007/s00726-009-0251-x

Amino Acids (2010) 38:305–310
DOI 10.1007/s00726-009-0251-x
ORIGINAL ARTICLE
Novel sulfur and selenium containing bis-a-amino acids
from 4-hydroxyproline
Romualdo Caputo Æ Marina DellaGreca Æ
Ivan de Paola Æ Domenico Mastroianni Æ
Luigi Longobardo
Received: 19 May 2008 / Accepted: 17 September 2008 / Published online: 12 February 2009
Ó Springer-Verlag 2009
Abstract The synthesis of new substituted prolines car-
rying at C-4 a second a-amino acid residue is reported. The
amino acid, L-cysteine or L-selenocysteine, is linked to the
proline ring through the sulfur or the selenium atom,
respectively. The products were prepared with different
stereochemistry at C-4, in few and clean high-yielding
steps, with suitable protections for solid phase applications.
The introduction of both sulfur and selenium atoms at C-4
of the proline ring seems to enhance significantly the cis
geometry at the prolyl amide bond.
and trans prolyl amide isomers that makes them nearly
isoenergetic (Fischer 2000). The result is the higher cis-
amide content relative to the other a-amino acids,
whereas the cis conformation appears with a frequency
of 5–6% in protein structures (Pal and Chakrabarti
1999). The cis/trans equilibrium of the prolyl amide
bond has been reported to be the rate-determining step in
the folding pathways of many peptides and proteins (Lu
et al. 2007; Halab and Lubell 2002): in particular, var-
ious substituted proline derivatives exhibit strong and
disparate conformational biases that are dependent on the
stereochemistry and the electronics of the substitution
(Thomas et al. 2005). Such effects on peptide confor-
mations have aroused a great interest towards design and
synthesis of substituted proline analogues, although the
conformational restrictions induced by the substitution
have not received broad attention in the context of
peptide secondary structures.
Keywords 4-Substituted proline ꢀ
Cysteine thioalkylation ꢀ Selenocystine ꢀ
Bis-a-amino acids ꢀ Unnatural amino acids
Introduction
Proline and its (R)-4-hydroxyl derivative (Hyp) are
unique among the protein amino acids, characterized by
limited rotation of the / dihedral angle as their side
chain is fused to the peptide backbone. Consequently,
there is a reduction in the energy difference between cis
Therefore, we considered worthy of note the prepara-
tion we have devised of an undoubtedly new class of
substituted prolines carrying at C-4 a second a-amino acid
residue, namely L-cysteine or L-selenocysteine, linked to
the proline ring through the sulfur or the selenium atom,
respectively.
In fact, pursuing our current interest for the synthesis of
new non-natural amino acids containing chalcogen atoms
(Bolognese et al. 2006; Caputo et al. 2007), we have per-
formed a simple and fully stereoselective synthesis of the
new bis-a-amino acids 1 and 2 that can be obtained (vide
infra) protected with the common groups used in peptide
synthesis and, hence, ready for being incorporated in
growing peptide chains.
R. Caputo ꢀ M. DellaGreca ꢀ I. de Paola ꢀ L. Longobardo (&)
Dipartimento di Chimica Organica e Biochimica,
`
Universita di Napoli Federico II,
Via Cynthia 4, 80126 Naples, Italy
e-mail: luilongo@unina.it
D. Mastroianni
Tecnogen SpA, Localita la Fagianeria,
A retrosynthetic analysis showing the preparation of the
backbones of both 1 and 2, starting from trans-L-4-
hydroxyproline (Hyp) is reported in Scheme 1.
`
Piana di Monte Verna,
81015 Caserta, Italy
123

306
R. Caputo et al.
(2S,4S)-2-benzyl 1-tert-butyl 4-iodopyrrolidine-1,2-dicar-
boxylate (4) Pure 4 was prepared according to a reported
general procedure (Bolognese et al. 2006; Caputo et al.
1995b): colorless oil (80%) solidifying upon standing at
4°C, m.p. = 71–72°C (Et2O-hexane); [a]2D5 = - 27.1
1
(c = 0.75, MeOH). H NMR (500 MHz, CD3OD) (Ktrans/
= 1.51): d 1.30 and 1.45 (2s, 9H); 2.29 (m, 1H); 2.92
cis
(m, 1H); 3.59 (m, 1H); 4.03 (m, 1H); 4.28 (m, 1H); 4.35
(m, 1H); 5.12 and 5.19 (d, J = 12.7, 1H); 5.21 and 5.25 (d,
J = 12.7, 1H); 7.28–7.43 (m, 5H). 13C NMR (125 MHz,
CD3OD): d 13.7 and 14.6; 28.9 and 29.1; 43.6 and 44.5;
58.9 and 59.3; 60.7 and 61.0; 68.6 and 68.7; 82.3 and 82.6;
129.8, 130.0; 130.3; 137.6; 155.3 and 155.6; 173.4 and
173.6.
Scheme 1 Retrosynthetic analysis for bis-a-amino acids 1 and 2
from Hyp
Materials and methods
(2S,4R)-2-benzyl 1-tert-butyl 4-(tosyloxy) pyrrolidine-1,2-
dicarboxylate (5) The compound
5 was prepared
General
according to a reported procedure (Kondo et al. 2007):
colorless solid (82%), m.p. = 79–81°C (Et2O-hexane);
[a]2D5 = - 35.9 (c = 1.30, EtOH). 1H NMR (300 MHz,
CD3OD) spectrum was consistent with that reported: split
signals d 1.29 and 1.40 (2s, 9H); (Ktrans/cis = 1.64). 13C
NMR (125 MHz, CD3OD): d 22.1; 28.9 and 29.0; 37.4 and
38.3; 53.6 and 53.9; 59.2 and 59.4; 68.6 and 68.7; 80.8 and
81.6; 82.7 and 82.8; 129.4; 129.7; 129.8; 130.1; 130.2;
131.8; 137.5; 147.4; 156.0 and 156.3; 173.7 and 173.9.
Inorganics, organic reagents, and solvents were com-
mercial pure compounds (Fluka, Aldrich) and used
without further purification. Melting points were mea-
sured with a Kofler apparatus and are uncorrected. TLC
analyses were performed using silica gel plates (E. Merck
silica gel 60 F-254) visualized by UV light, iodine, and
ninhydrin spray. Column chromatography was carried out
on silica gel (E. Merck, 70-230 mesh). RP-HPLC was
carried out with Agilent 1100 system, photodiode-array
detector, using a binary solvent system [0.01% TFA in
H2O and 0.01% TFA in MeCN] on analytical C18 col-
(2S,4R)-2-benzyl 1-tert-butyl 4-((R)-2-amino-3-ethoxy-3-
oxopropylsulfanyl)pyrrolidine-1,2-dicarboxylate (6) To a
stirred solution of 4 (0.4 g, 1 mmol) and L-cysteine ethyl
ester hydrochloride (0.2 g, 1 mmol) in dry DMF (5 ml),
under nitrogen, solid Cs2CO3 (0.6 g, 2 mmol) was added in
one portion. Stirring was continued in the dark at room
temperature for 3 h. Most of the solvent was then carefully
(\45°C) evaporated in vacuo and the residue was suspended
in EtOAc (75 ml) and shaken with H2O (3 9 20 ml). The
organic layer was then dried (Na2SO4) and the solvent
evaporated in vacuo. Column chromatography (0–5%
MeOH in CH2Cl2) of the residue gave pure 6, as colorless oil
(85%), [a]2D5 = - 33.1 (c = 0.34, CHCl3). 1H NMR
(500 MHz, CD3OD) (Ktrans/cis = 1.65): d 1.27 (t, J = 6.8,
3H); 1.31 and 1.45 (2s, 9H); 2.16–2.30 (m, 2H); 2.90 (m,
2H); 3.31 (m, 1H); 3.45 (m, 1H); 3.63 (m, 1H); 3.83 (m, 1H);
4.17 (q, J = 6.8, 2H); 4.37 and 4.42 (2dd, J = 4.9 and 8.8,
J = 3.9 and 8.8, 1H); 5.12 and 5.15 (d, J = 12.7, 1H); 5.20
and 5.22 (d, J = 12.7, 1H); 7.29–7.42 (m, 5H). 13C NMR
(125 MHz, CD3OD): d 15.0; 28.9 and 29.2; 37.3; 38.7; 42.5
and 43.0; 54.2 and 54.6; 55.6; 60.3 and 60.5; 62.9; 68.5; 82.2
and 82.3; 129.7; 129.8; 130.1; 130.2; 137.6; 155.8 and
156.2; 174.1 and 174.3; 175.3. ES-MS (EI): 353.2 (30);
453.0 (100), 475.2 (10); 904.5 (55). Calculated for
C22H32N2O6S: C, 58.39%; H, 7.13%; N, 6.19%; S, 7.09%;
found: C, 58.45%; H, 7.29%; N, 6.12%; S, 7.11%.
1
umn (Gemini 100 9 4.6 mm), flow rate 0.5 ml/min). H
and 13C NMR spectra were recorded on Varian Inova
500 and Varian Gemini 300 spectrometers: chemical
shifts are in ppm (d) and J coupling constants in Hz; split
signals denote the presence of two rotamers of the car-
bamate bond, trans (major) and cis (minor). Low-
resolution MS spectra were recorded on Thermo-Finnigan
LXQ linear trap. Optical rotations were measured with
Jasco 1,010 polarimeter (k = 589 nm). All compounds
for which analytical and spectroscopic data are quoted
were homogeneous by TLC and HPLC, and solids were
crystallized.
(2S,4R)-2-benzyl 1-tert-butyl 4-hydroxypyrrolidine-1,2-
dicarboxylate (3) The title compound 3 was already
known (Qiu and Qing 2002) and was prepared from com-
mercial Hyp by modification of the reported procedure,
using benzyl bromide in DMF and K2CO3 as the base for
the esterification of the carboxyl group: colorless oil (92%).
[a]D20 = - 59.4 (c = 1.10, CHCl3). [Lit., [a]2D0 = - 58.0
(c = 1.24, CHCl3]. 1H NMR (300 MHz, CD3OD) spectrum
was consistent with that reported: split signals d 1.31 and
1.44 (2s, 9H); (Ktrans/cis = 2.03).
123

Novel sulfur and selenium containing bis-a-amino acids
307
(2S,4S)-2-benzyl 1-tert-butyl 4-((R)-2-amino-3-ethoxy-3-
oxopropylsulfanyl)pyrrolidine-1,2-dicarboxylate (7) The
title compound 7 was prepared from L-cysteine ethyl ester
hydrochloride (0.2 g, 1 mmol) and tosylate 5 (0.5 g,
1 mmol) under the conditions reported for the preparation
of 6, but the temperature that was kept at 50°C for 3 h:
colorless oil (88%), [a]2D5 = - 37.2 (c = 0.85, CHCl3). 1H
NMR (300 MHz, CD3OD) (Ktrans/cis = 1.52): d 1.28 (t,
J = 7.5, 3H); 1.31 and 1.44 (2s, 9H); 1.90 (m, 1H); 2.69
(m, 1H); 2.88 (m, 2H); 3.18 (m, 1H); 3.41 (m, 1H); 3.62
(m, 1H); 3.91 (m, 1H); 4.20 (q, J = 7.5, 2H); 4.35 (dd,
J = 7.5 and 7.5, 1H); 5.09 and 5.16 (d, J = 12.3, 1H); 5.19
and 5.23 (d, J = 12.3, 1H); 7.37 (m, 5H). 13C NMR
(75 MHz, CD3OD): d 15.0; 28.9 and 29.2; 37.5; 39.1; 42.5
and 43.4; 54.5 and 54.8; 55.8; 60.4 and 60.7; 62.8; 68.6;
82.3 and 82.4; 129.8; 130.1; 130.2; 137.6; 155.7 and 156.1;
174.0 and 174.2; 175.2. ES-MS (EI): 453.13 (M ? H?).
Calculated for C22H32N2O6S: C, 58.39%; H, 7.13%; N,
6.19%; S, 7.09%; found:C, 58,18%; H, 7.20%; N, 6.15%;
S, 7.01%.
d 1.39 and 1.43 (2s, 9H); 2.34 (m, 2H); 2.98 (m, 1H); 3.16
(m, 1H); 3.40 (m, 1H); 3.61 (m, 1H); 3.71 and 3.72 (2s,
3H); 3.86 (m, 1H); 4.26 (t, J = 6.8, 1H); 4.36 (m, 2H);
4.41 (m, 2H); 7.31 (t, J = 7.8, 2H); 7.39 (t, J = 7.8, 2H);
7.69 (d, J = 7.8, 2H); 7.79 (d, J = 7.8, 2H). 13C NMR
(125 MHz, CD3OD): d 26.2; 29.0 and 29.1; 35.0 and 35.6;
39.0 and 39.6; 48.9; 53.3; 54.9 and 55.2; 56.6; 60.4 and
60.7; 68.6; 82.4; 121.4; 126.8; 128.7; 129.3; 143.1; 145.8;
155.8; 158.9; 174.3 and 174.9; 175.2. ES-MS (EI): 517.19
(56); 519.21 (100); 641.17(10); 657.17 (6); 1256.56 (10);
1272.09 (9); Calculated for C29H34N2O8Se: C, 56.40%; H,
5.55%; N, 4.54%; Se, 12.79%; found: C, 56.24%; H,
5.34%; N, 4.44%.
(R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-((3S,
5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrroli-
din-3-ylselanyl)propanoic acid (13) The title compound
13 was prepared from L-selenocystine (0.3 g, 1 mmol) and
tosylate 9 (0.8 g, 2 mmol) under the conditions reported
for the preparation of 12: colorless solid (77%), m.p. =
134–136°C (CH2Cl2-hexane); [a]2D5 = 18.0 (c = 0.47,
1
(2S,4S)-2-methyl 1-tert-butyl 4-iodopyrrolidine-1,2-dicar-
boxylate (8) The title compound was already reported
(Schumacher et al. 1998) and was prepared by the same
procedure described above for the iodide 4, starting from
commercial Boc-L-Hyp-OMe: colorless oil (80%) solidi-
fying upon standing at 4°C, m.p. = 63–65°C (Et2O-petrol
ether); [a]2D5 = - 22.1 (c = 0.92, CHCl3). [Lit.,
m.p. = 64° C, [a]D20 = - 20.9 (c = 1.24, CHCl3)].
CHCl3). H NMR (500 MHz, CD3OD) (Ktrans/cis = 1.26):
d 1.39 and 1.43 (2s, 9H); 2.31 (m, 2H); 3.00 (m, 1H);
3.18 (m, 1H); 3.38 (m, 1H); 3.57 (m, 1H); 3.69 and 3.70
(s, 3H); 3.84 (m, 1H); 4.20–4.32 (m, 4H); 4.43 (m, 1H);
7.23 (t, J = 7.5, 2H); 7.38 (t, J = 7.5, 2H); 7.67 (m, 2H);
7.78 (d, J = 8.0, 2H). 13C NMR (125 MHz, CD3OD): d
28.0; 29.1 and 29.2; 34.8 and 35.3; 39.1 and 39.7; 53.3;
55.0 and 55.4; 57.9; 60.5 and 60.7; 68.6; 79.9 and 82.3;
121.4; 126.9; 128.7; 129.3; 143.1; 145.8; 156.0 and 156.5;
158.7; 174.9 and 175.3; 178.2. ES-MS (EI): 517.20 (20);
519.22 (100); 641.19 (13); 657.17 (6); 1254.23 (20);
1272.99 (8). Calculated for: C29H34N2O8Se: C, 56.40%;
H, 5.55%; N, 4.54%; Se, 12.79%; found: C, 56.14%; H,
5.29%; N, 4.46%.
(2S,4R)-2-methyl 1-tert-butyl 4-(tosyloxy) pyrrolidine-1,2-
dicarboxylate (9) The title compound was prepared
according to a reported procedure (Lowe and Vilaivan
1997), starting from commercial Boc-L-Hyp-OMe: color-
less solid (84%), m.p. = 76–78°C (Et2O-petrol ether);
[a]2D5 = - 36.5 (c = 0.85, CHCl3). [Lit., m.p. = 78–79°C,
[a]2D5 = -37.4 (c = 0.70, CHCl3)].
(R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-((3R,
5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrroli-
din-3-ylselanyl) propanoic acid (12) L-Selenocystine
(0.3 g, 1 mmol) was suspended in anhydrous EtOH
(10 ml) under nitrogen atmosphere. Solid NaBH4 (0.2 g,
5 mmol) was added in one portion and the yellow mixture
refluxed for 5 min, until clear and colorless. Iodide 8
(0.7 g, 2 mmol) dissolved in anhydrous EtOH (4 ml) was
then added in one portion and the reaction mixture was
slowly cooled to room temperature (1 h). After evaporation
of the solvents in vacuo, the residue was dissolved in THF
(10 ml), cooled at 0°C, and treated with Fmoc-Cl (0.3 g,
1 mmol) under standard conditions. Column chromatog-
raphy of the residue afforded the pure acid 12 (81%), m.p.
124–126°C (CH2Cl2-hexane); [a]2D5 = 67.2 (c = 0.23,
Results and discussion
The S-alkylation reaction of the trans-4-hydroxy-L-proline
ring at C-4 by the cysteinyl residue is a SN2 process
involving the existing hydroxyl group that, therefore, needs
to be converted into a good leaving group. The stereo-
chemical outcome of the replacement can be controlled at
this stage: as a matter of fact, the hydroxyl group can be
either transformed into its tosyl ester, thus maintaining the
trans configuration, or replaced by an iodine atom, using
triphenylphosphine-iodine complex (Caputo et al. 1995a).
This way leads to cis-4-iodo-L-proline.
Under these circumstances, the subsequent attack by the
proper cysteinyl nucleophile may afford either trans-4-S-
cysteinyl-L-proline (from iodide) or cis-4-S-cysteinyl-L-
proline (from tosylate).
1
CHCl3). H NMR (500 MHz, CD3OD) (Ktrans/cis = 1.47):
123

308
R. Caputo et al.
Scheme 2 Conversion of Hyp
into cis-4-iodo and trans-4-
tosyloxy derivatives
Scheme 3 S-alkylation of
L-cysteine with cis 4-iodo or
trans 4-tosyloxy proline
derivatives
In the same way, two diastereomeric trans- and cis-4-
Se-selenocysteinyl-L-prolines are obtained from the attack
of a suitable selenocysteinyl nucleophile.
reaction mixture at nearly 50°C for three hours enabled the
formation of 7 (2S,4S,20R) in 88% yield (Scheme 3).
It is noteworthy that the synthetic route we have chosen
leads to both the bis-a-amino acids 6 and 7 as tri-protected
forms, i.e. still having a free a-amino group. Consequently,
they can be further converted into orthogonally protected
derivatives (N-Boc, N-Fmoc), via ethyl ester hydrolysis and
Na-Fmoc protection (Bolognese et al. 2006), ready for use
in solid phase peptide synthesis. Obviously, they can also
be directly exploited for couplings with N-protected a-
amino acids in solution peptide synthesis. For example the
bis-a-amino acid 6 was condensed, under mixed anhydride
conditions, with Boc-Val-OH and Fmoc-Phe-OH, while 7
was condensed with Boc-Pro-OH, to give the correspond-
ing peptides in good yields.
The reactions described so far are reported in detail in
Schemes 2–4: commercial 4-hydroxy-L-proline (Hyp) was
first converted, under standard conditions, into its corre-
sponding N-Boc benzyl ester 3. This was divided in two
aliquots: one was treated with triphenylphosphine-iodine
complex and imidazole, in anhydrous dichloromethane
(Caputo et al. 1995b), to get the cis-4-iodo derivative 4,
whereas the other aliquot was treated under usual condi-
tions with tosyl chloride in pyridine to afford the trans-4-
tosyloxy derivative 5 (Scheme 2).
The S-alkylation reaction of cis iodide 4 was performed
in anhydrous DMF, at room temperature, with L-cysteine
ethyl ester hydrochloride (1 eq) and Cs2CO3 (2 eq) as the
base. The substitution product, 6 (2S,4R,20R), was obtained
within three hours in 85% yield.
Due to the high tendency of L-selenocysteine to undergo
oxidation, the procedure reported above could not be
applied as such to the synthesis of the selenium containing
analogues of bis-a-amino acids 6 and 7 and had to be
partially modified in order to form in situ the Se-cysteinyl
anion nucleophile. Actually, commercial L-selenocystine
was refluxed with NaBH4 in dry EtOH, under nitrogen
atmosphere (Caputo et al. 2007), to get (R)-2-amino-2-
carboxyethaneselenolate anion, whose formation could be
Such experimental conditions, indeed, were not satis-
factory for the S-alkylation of trans tosylate 5, likely due to
the combination of both the lower leaving tendency of
tosylate anion in comparison with iodide ion and the more
difficult attack by the nucleophile from the same side of the
carboxybenzyl group. In fact, a gentle heating of the
123

Novel sulfur and selenium containing bis-a-amino acids
309
Scheme 4 Se-alkylation of L-selenocysteine with cis 4-iodo or trans 4-tosyloxy proline derivatives
Table 1 Ktrans/cis of variously C-4 substituted prolines (1H NMR, 500 MHz, CD3OD)
Compound [subst.]
3 [OH]
5 [OTs]
6 [S(Cys)]
12 [Se(Sec)]
4 [I]
7 [S(Cys)]
13 [Se(Sec)]
4(S)
4(R)
–
–
–
–
1.51
1.52
1.26
2.03
1.64
1.65
1.47
–
–
–
monitored by the disappearance of the initial intense yel-
low colour of the selenocystine ethanolic solution (Block
et al. 2001).
although the 4(S) or 4(R) stereochemistry, as well as the
hindrance, of the C-4 substituents apparently should also be
considered.
At this stage, the addition of either the cis iodide 8 or the
trans tosylate 9 (Scheme 4), prepared as described above
from N-Boc-L-hydroxyproline methyl ester, followed by
slow cooling of the reaction mixture to room temperature
completed the coupling step and afforded the partially
protected bis-a-amino acids 10 (2S,4R,20R) and 11
(2S,4S,20R) respectively. They were not isolated as such,
but were directly converted by standard procedures into
their orthogonally protected derivatives 12 in 80% yield
and 13 in 77% yield, suitably protected for solid phase
applications.
In conclusion, this simple synthetic procedure may offer
an extraordinary opportunity to have access to new non-
natural peptides, in which two distinct peptide chains can
be grown from both proline and (seleno)cysteine residues.
In fact, the bis-a-amino acids 6, 7, 12, and 13 can be
regarded as prompt candidates to build up macromolecules
containing substituted proline residues with dendrimeric
architecture (Zhang and Schulter 2007). Furthermore, these
new proline derivatives are currently under investigation in
our lab as organocatalysts in enantioselective aldol and
Michael additions, in view of the well recognized catalytic
propensity of proline derivatives towards several organic
reactions (List 2006; Pellisier 2007).
The use of methyl rather than benzyl ester to protect the
starting hydroxyproline carboxyl group during the synthe-
sis of the selenium containing bis-a-amino acids 12 and 13
was dictated by the simple consideration that, according to
the above procedure, the selenocysteinyl residue is intro-
duced with the free carboxyl group and, therefore, the use
of benzylated proline derivatives becomes unnecessary.
The NMR spectra of the compounds described by this
paper deserve some comments as to the evidences of an
equilibrium between trans and cis conformations of the N-
prolyl carbamate bond. The equilibrium constants (Ktrans/
cis) were evaluated for the single compounds by integrating
and averaging as many distinct proton signals as possible
for both the major and minor isomers in the 1H NMR
spectra. Their trend (Table 1) seems to reinforce the
suggestion (Hodges and Raines 2005) that poorly electro-
negative atoms at C-4 of the proline ring lead to a reduction
of the trans/cis ratio between the amide bond rotamers,
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