Synthesis of cis- and trans-(±)-3-mercaptoproline and pipecolic acid derivatives via thio-Michael addition

Article abstract of DOI:10.1016/j.tetlet.2018.03.057

The reactivity of 2,3-dehydroproline and 2,3-dehydropipecolic acid methyl ester derivatives with S-nucleophiles in the thio-Michael addition reaction has been explored. The addition of triphenylmethanethiol and subsequent trityl cleavage led to the corres

Full text of DOI:10.1016/j.tetlet.2018.03.057

Accepted Manuscript
Synthesis of cis- and trans-(±)-3-mercaptoproline and pipecolic acid derivatives
via thio-Michael addition
Alejandro Gutiérrez, Iñaki Osante, Carlos Cativiela
PII:
S0040-4039(18)30371-X
https://doi.org/10.1016/j.tetlet.2018.03.057
TETL 49826
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
30 January 2018
8 March 2018
19 March 2018
Please cite this article as: Gutiérrez, A., Osante, I., Cativiela, C., Synthesis of cis- and trans-(±)-3-mercaptoproline
and pipecolic acid derivatives via thio-Michael addition, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.03.057
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pipecolic acid derivatives via thio-Michael addition
Alejandro Gutiérrez,a Iñaki Osante,a,* and Carlos Cativielaa,*
aDepartamento de Química Orgánica. "Instituto de Síntesis Química y Catálisis Homogénea-ISQCH, CSIC-Universidad de Zaragoza" Pedro Cerbuna,
12, 50009 Zaragoza (Spain).

1
Tetrahedron Letters
Synthesis of cis- and trans-(±)-3-mercaptoproline and pipecolic acid derivatives
via thio-Michael addition
Alejandro Gutiérreza , Iñaki Osantea,  and Carlos Cativielaa, *
aDepartamento de Química Orgánica. "Instituto de Síntesis Química y Catálisis Homogénea-ISQCH, CSIC-Universidad de Zaragoza" Pedro Cerbuna, 12,
50009 Zaragoza (Spain).
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The reactivity of 2,3-dehydroproline and 2,3-dehydropipecolic acid methyl ester derivatives with S-
nucleophiles in the thio-Michael addition reaction has been explored. The addition of
triphenylmethanethiol and subsequent trityl cleavage led to the corresponding cis- and trans-(±)-3-
mercaptoproline and pipecolic acid derivatives in good yields.
Available online
Keywords:
Thio-Michael addition
Proline derivatives
Pipecolic acid derivatives
Cysteine derivatives
Medicinal chemistry
2009 Elsevier Ltd. All rights reserved.
Introduction
knowledge, the synthesis of 3-mercaptoproline (3-MP)
derivatives remains scarcely explored.8 In order to obtain the
The preparation of modified amino acids (e.g. cyclic
desired (±)-3-MP derivatives (Scheme 1), a suitable strategy
could involve the thio-Michael addition of an appropriate S-
nucleophile to 2,3-dehydroproline derivatives and selective
deprotection to deliver the thiol functionality. In fact, the addition
of selected nucleophiles, including S-nucleophiles, to this
dehydroamino acid has been previously explored.9 Furthermore,
the thio-Michael addition10 to more complex molecules
containing the 2,3-dehydroproline unit (e.g. carbapenems) has
been employed in the development of more potent antibiotic
analogs.11 In this sense, pipecolic acid (a non-proteinogenic
amino acid analogous to proline) and 2,3-dehydropipecolic acid
as dehydroalanine analogs are important constituents of various
alkaloids or carbacephem antibiotics (e.g. cefaclor)12 which
possess interesting biological activities.
and/or quaternary amino acids)1 represents an interesting field of
research in organic synthesis, and plays crucial roles in biological
and medicinal chemistry.2 The incorporation of non-
proteinogenic amino acids into bioactive peptides often provides
compounds with improved pharmaceutical profiles, as
a
consequence of increased resistance towards enzymatic
hydrolysis as well as better recognition by the receptor due to
reduced conformational flexibility.3 It has been demonstrated that
modification of the core structure of an amino acid plays a
fundamental role and it is interesting to prepare new amino acids
related to the proteinogenic ones to control the structure of the
new compounds and improve the macroscopic properties of
compounds that contain them.
Taking this into account, our research has focused on
the synthesis of proline hybrids and cysteine derivatives, a priori,
unnatural amino acids with interesting biological and medicinal
activities. Proline, the only conformationally rigid proteinogenic
amino acid due to the presence of a cyclic moiety in its structure,
has a profound influence on the three-dimensional structure of
peptides and proteins, allowing the formation of β-turns.4 On the
other hand, cysteine is present in the catalytic site of many
enzymes and antioxidant compounds due to the nucleophilicity
and redox properties of the thiol group.5
Herein, we report the synthesis of orthogonally
protected cis- and trans-(±)-3-MP and (±)-3-MPip derivatives,
which represent potentially useful building blocks for both
solution and solid peptide synthesis. These compounds could be
obtained via a thio-Michael addition reaction, a powerful
synthetic tool to create C-X (X = O, S, N) bonds.13 However, the
dehydroamino acids used as starting material are known to be
generally poor Michael acceptors14 (Scheme 1).
Mercaptoproline (MP) is part of an interesting class of
compound which combines the properties of both previously
mentioned amino acids.6 Whereas 4-mercaptoproline (4-MP)
derivatives have been known for a long time and their syntheses
from 4-hydroxyproline are well-established,7 to the best of our
Scheme 1. Retrosynthetic pathway towards (±)-3-MP and (±)-3-
MPip.
———
 Corresponding authors. e-mail:cativiela@unizar.es and iosante@unizar.es

2
Tetrahedron
aReactions were performed on a 0.5 mmol scale in 5 mL of solvent. bIsolated yield;
Results and Discussion
cis/trans ratio is given in parentheses. cNo detectable product formation. dReaction
carried out at 50 ºC. e2-(Boc-amino)cysteamine (NBC).
Synthesis of (±)-3-mercaptoproline derivatives.
Initial attempts at the thio-Michael reaction between
dPro 1 and TrtSH were carried out in CH2Cl2 as an aprotic
solvent and NEt3 as a base at room temperature. The reaction
using a catalytic amount of base and an equimolecular amount of
TrtSH failed (Entry 1). The use of one equivalent of base resulted
Initially, the synthesis of 2,3-dehydroproline (dPro)
derivative 1 with the amino and carboxylic acid groups
orthogonally protected was carried out according to the previous
work of Schmalz and co-workers.15 The next step consisted of
exploring the thio-Michael addition between an appropriate S-
nucleophile and dPro derivative 1 as an electrophile (Table 1).
For this purpose, triphenylmethanethiol (TrtSH), thioacetic acid
(AcSH) and 2-(Boc-amino)cysteamine (NBC) were selected due
to the fact that the triphenylmethane and acetyl protecting groups
are easily removed under mild conditions16 and that the 2-(Boc-
amino)ethanethioether moiety represents a versatile group to
carry out additional structural modifications and to build more
complex molecules. A wide range of conditions were studied and
the effect of the solvent, base, temperature, stoichiometry and
time were evaluated in order to determine the best conditions in
terms of yield and diastereoselectivity (Table 1).
1
in formation of the Michael adduct, which was observed by H
NMR spectroscopy (<10%). However, it was not possible to
isolate the desired product from the complex reaction mixture
(Entry 2). Unfortunately, the result was not as expected when an
excess of thiol (10 eq.) and NEt3 (10 eq.) was employed (Entry
3). At this point, we decided to change the base and the nature of
the aprotic solvent. The use of an equivalent of the inorganic base
K2CO3 in THF/DMF (5:1) at room temperature resulted in the
formation of both diastereoisomers in low yield after 96 h (Entry
4). When the reaction was carried out at 50 ºC, no product
formation was observed, possibly due to decomposition of the
Michael adducts by β-elimination,17 affording recovered starting
materials after work-up (Entry 5). Fortunately, when excess thiol
(10 eq.) and base (10 eq.) were employed, the reaction occurred
smoothly; the conversion was complete and both
diastereoisomers cis-(±)-2a and trans-(±)-2b (d.r. 37/63) were
obtained in excellent yield after chromatography (Entry 6).
Finally, the use of DBU (10 eq.) in MeCN exclusively led to the
trans-(±)-2b thio-Michael adduct, not only in excellent yield but
also with remarkably shorter reaction times (Entry 7). These
results indicated the crucial importance of the generated enolate
intermediate whose stability depends on the counterion, since it
determines the rate of β-elimination and therefore the recovery of
the starting materials and/or the diastereoselectivity of the
reaction owing to the volume of the counterion. In fact, the
results were different depending on the cation nature and steric
hindrance of the counterion of the enolate (e.g. potassium and the
ammonium salts derived from Et3N and DBU). The lowest yields
generally corresponded to protonation of the enolate intermediate
with the hydrogen triethylammonium salt as a counterion (Entries
1-3). Protonation of the potassium enolate depends on the
reaction temperature and the amount of base and thiol (Entries 4-
6). The enolate with the ammonium salt of DBU as a counterion
was protonated, exclusively giving the trans-adduct in good
yield, probably due to the bulky counterion blocking the face of
the double bond opposite to the thioether group at C3 position of
the proline unit (Entry 7) (Scheme 2).
Table 1.
Optimization of the thio-Michael addition to 1.a
Entry
Base (eq.)
NEt3 (cat.)
RSH (eq.)
Solvent
Time (h)
Yield
(%)b
1
2
TrtSH (1 eq.)
CH2Cl2
CH2Cl2
120
96
96
96
96
72
6
0c
NEt3 (1 eq.)
NEt3 (10 eq.)
K2CO3 (1 eq.)
K2CO3 (1 eq.)
K2CO3 (10 eq.)
DBU (10 eq.)
NEt3 (10 eq.)
NEt3 (10 eq.)
TrtSH (1 eq.)
TrtSH (10 eq.)
TrtSH (1 eq.)
TrtSH (1 eq.)
TrtSH (10 eq.)
TrtSH (10 eq.)
TrtSH (10 eq.)
TrtSH (10 eq.)
TrtSH (10 eq.)
AcSH (10 eq.)
AcSH (10 eq.)
AcSH (10 eq.)
NBCe (10 eq.)
NBCe (10 eq.)
< 10c
3
THF/DMF
THF/DMF
THF/DMF
THF/DMF
MeCN
19 (49/51)
16 (37/63)
0c,d
4
5
Scheme 2. Stereochemical outcome of the thio-Michael addition.
6
97 (37/63)
96 (1/99)
95 (1/99)
98 (1/99)
10 (41/59)
40 (1/99)
16 (1/99)
94 (1/99)
7
Next, the thio-Michael reaction between dPro 1 and
TrtSH was examined in protic solvents (Entries 8-10).
Surprisingly, the reaction was diastereoselective using NEt3 (10
eq.) as a base in MeOH, exclusively affording the trans-(±)-2b
adduct in excellent yield (Entry 8). The addition of water had a
remarkable rate acceleration effect (entry 8 vs. entry 9) without
decreasing the diastereoselectivity towards the trans-(±)-2b
adduct (Entry 9).18 In comparison, the thio-Michael reaction
carried out in an aprotic solvent and NEt3 was worse in terms of
diastereoselectivity and yield (entry 3 vs. entries 8 and 9). The
reaction carried out using K2CO3 in MeOH/H2O (3:2) at room
temperature afforded a diastereoisomeric mixture (d.r. 41/59) and
poor yield (Entry 10). Instead, the reaction in aprotic solvents
gave better yield and diastereoselectivity (d.r. 37/63) (entry 6 vs.
entry 10). These results point to the stability of the enolate
intermediate being dependent on the effective combination of its
8
MeOH
96
60
96
96
72
12
6
9
MeOH/H2O
MeOH/H2O
MeOH/H2O
THF/DMF
MeCN
10
11
12
13
14
15
K2CO3 (10 eq.)
NEt3 (10 eq.)
K2CO3 (10 eq.)
DBU (10 eq.)
MeCN
DBU (10 eq.)
63 (1/99)
97 (1/99)
K2CO3 (10 eq.)
THF/DMF
12

3
counterion and the solvent employed (entry 3 vs. entries 8 and
entry 9; entry 6 vs. entry 10).
Table 2.
Optimization of the thio-Michael addition to 4.a
The synthesis of cis-(±)-2a from trans-(±)-2b, a priori,
the less stable diastereoisomer, was postulated to proceed under
kinetic reaction conditions (e.g. -78 ºC or -90 ºC and using LDA
or LHMDS). Unfortunately, various attempts to isomerize the
trans into the cis isomer product failed,19 most probably due to
its higher stability and β-elimination processes.
Next, we examined the scope of the thio-Michael
reaction under the optimized conditions using AcSH as a S-
nucleophile (Table 1). The addition also was completely
diastereoselective towards the formation of trans-(±)-2c, but in
moderate yield (Entries 11 and 12). Nevertheless, trans-(±)-2c
was exclusively obtained in excellent yield and in shorter
reaction time with DBU and MeCN (Entry 13). The low
nucleophilicity of AcSH or the corresponding salts (Entries 11
and 12) as well as the instability of the enolate intermediates
previously discussed are most probably responsible for the
limited success of this reaction.
Entry
1
Base (eq.)
RSH (eq.)
Solvent
MeCN
Time (h)
48
Yield
(%)b
DBU (10 eq.)
TrtSH (10 eq.)
54
(44/56)
2
3
4
THF/DMF
MeCN
48
72
72
K2CO3
eq.)
(10
TrtSH (10 eq.)
NBCc (10 eq.)
NBCc (10 eq.)
57
(60/40)
DBU (10 eq.)
10
(1/99)
THF/DMF
K2CO3 (10 eq.)
94
The use of 2-(Boc-amino)cysteamine (NBC) as a S-
nucleophile was also explored(Table 1). Selective deprotection of
the Boc protecting group in this thiol could be carried out without
cleavage of the other protecting groups (Cbz and methyl ester),
allowing more complex molecules to be attached. Thus, the thio-
Michael reaction under both optimized conditions was
diastereoselective towards the trans-(±)-2d adduct (Entries 14
and 15), but a higher yield was obtained when a less sterically
hindered enolate intermediate (K2CO3 vs. DBU) was formed.
Thus, proton transfer from the bulky S-nucleophile to the enolate
was more efficient (Scheme 3).
(50/50)
aReactions were performed on a 0.5 mmol scale in 5 mL of solvent. bIsolated yield;
cis/trans ratio is given in parentheses. c2-(Boc-amino)cysteamine (NBC).
The preparation of 2,3-dehydropipecolic acid derivative
4 from Cbz-Pip-OMe24 with the amino and carboxylic groups
orthogonally protected was carried out according to the
conditions described by Toyooka and co-workers.25 The next step
consisted of thio-Michael addition of TrtSH employing the
optimal conditions found for dPro 1. Thus, separable mixtures of
cis-(±)-5a and trans-(±)-5b were obtained in moderate yield
(Table 2, entries 1 and 2). The conversion was incomplete and no
significant diastereoselectivity was observed. Hence, the thio-
Michael addition appeared to be more difficult compared to the
addition of TrtSH to dPro 1 and increasing the reaction time did
not improve the yield. The change of the ring size (pyrrolidine vs.
piperidine) resulted in significantly decreased reactivity and
diastereoselectivity, probably due to increased steric hindrance
and conformational freedom of the six-membered ring.26
Scheme 3. Enolate protonation to obtain trans-(±)-2d.
Finally, selective deprotection of the S-protected (±)-3-
mercaptoproline derivatives (±)-2a-c was examined (Scheme 4).
Trityl cleavage of (±)-2a-b was achieved by employing Et3SiH in
CH2Cl2 (2% TFA v/v),21 while trans-(±)-2c was hydrolyzed
under basic conditions with 1M NaOH (aq.).22 In all the cases,
the yields were almost quantitative and provided the desired cis
and trans (±)-3-mercaptoprolines (±)-3a and (±)-3b after flash
chromatography.
Finally, the thio-Michael reaction between 2,3-
dehydropipecolic acid derivative 4 and the S-nucleophile 2-(Boc-
amino)cysteamine (NBC) was explored. To our surprise, very
low amounts of the addition products was obtained using
DBU/MeCN, affording recovered starting materials after work-
up (Table 2, entry 3). Nevertheless, the use of K2CO3/THF/DMF
gave the Michael adducts cis-(±)-5c and trans-(±)-5d in excellent
yield after chromatographic separation (Table 2, entry 4). These
results are in accordance with those previously described for the
synthesis of trans-(±)-2d (Table 1, entries 14 and 15). The lack of
diastereoselectivity could be due to higher conformational
freedom of the six-membered ring versus the five-membered ring
of the proline derivatives, where interactions of the 1,3-diaxial
type have crucial importance.
Finally, S-trityl deprotection provided the desired cis-
(±)-3-MPip-6a and trans-(±)-MPip-6b (Scheme 5), albeit in
lower yields than their proline analogues. Various by-products,
unreacted cis-(±)-5a and the corresponding disulphide derived
from trans-(±)-5b were also obtained.
Scheme 4. Deprotection of (±)-3-mercaptoprolines (±)-2a-c.
Synthesis of (±)-3-mercaptopipecolic acid derivatives.
The successful preparation of the cis- and trans-(±)-3-
mercaptoproline derivatives (±)-2a-d prompted us to extend this
methodology to the synthesis of (±)-3-mercaptopipecolic acid
derivatives which have only been previously reported by
Hanessian and co-workers.23
Scheme 5. Deprotection of (±)-3-mercaptopipecolic acid
derivatives cis-(±)-5a and trans-(±)-5b.

4
Tetrahedron
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Conclusion
A
practical synthesis of cis- and trans-(±)-3-
mercaptoprolines and (±)-3-mercaptopipecolic acid derivatives
from their corresponding 2,3-dehydroamino acids has been
achieved. Given the value of these compounds in medicine and
biology, this work provides a valuable route for the elaboration
of new mercaptoproline and mercaptopipecolic acid derivative-
based building blocks.
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Acknowledgements
The authors thank the Ministerio de Economía y
Competitividad (project number CTQ2013-40855-R) and DGA-
FSE (research group E40) for financial support.
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10. Enders D, Lüttgen K, Narine AA. Synthesis. 2007;959-980.
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5
Research Highlights:
 thio-Michael addition of thiols to 2,3-dehydroamino acids
 Practical synthesis of cis- and trans-(±)-3-mercaptoproline
acids derivatives
 First synthesis of cis- and trans-(±)-3-mercaptopipecolic acids
derivatives

Efficient synthetic route of building blocks for their
incorporation into peptides