Click chemistry: A straightforward route to decorated prolines

Article abstract of DOI:10.1055/s-2007-991065

The synthesis of α-substituted prolines has been accomplished by microwave-assisted Huisgen 1,3-dipolar cycloaddition between azides and orthogonally protected α-propynyl proline in the presence of Cu(I). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-991065

2882
LETTER
Click Chemistry: A Straightforward Route to Decorated Prolines
A
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traightforw
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Prolines rica Pisaneschi, Franca M. Cordero,* Marco Lumini, Alberto Brandi
Dipartimento di Chimica Organica ‘Ugo Schiff’, Università di Firenze, Laboratorio di Progettazione,
Sintesi e Studio di Eterocicli Biologicamente Attivi – HeteroBioLab, via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax +39(055)4573531; E-mail: franca.cordero@unifi.it
Received 23 July 2007
and terminal acetylenes to afford 1,2,3-triazoles appeared
to be one of the best choices, because the partners are
easily set up, albeit they react together in a very slow man-
ner under thermal conditions. The introduction of Cu(I)
catalysis in the reaction of terminal alkynes, which
favours a stepwise mechanism rather than a concerted
one, increases the reaction rate up to 107 times and dra-
matically improves the scope and the regioselectivity of
the process with exclusive formation of the 1,4-regioiso-
mers.8,9 Finally, the use of microwaves as heating source
highlights the sustainability of this process.10 According-
ly, we decided to investigate Huisgen cycloaddition be-
tween a 2-prop-2-ynylproline derivative and azides as a
suitable tool for decorating proline with different
chains.11,12
Abstract: The synthesis of a-substituted prolines has been accom-
plished by microwave-assisted Huisgen 1,3-dipolar cycloaddition
between azides and orthogonally protected a-propynyl proline in
the presence of Cu(I).
Key words: alkynes, amino acids, azides, a-substituted prolines,
1,2,3-triazoles
Due to its cyclic nature and its limited conformational
freedom, proline plays a crucial role in peptides and,
therefore, in peptidomimetics. Proline can induce a b-
turn, particularly if preceded by tyrosine or followed by
phenylalanine and tryptophan residues. Proline-rich se-
quences are relatively rigid and they are commonly found
in binding sites. Proline can induce bends in transmem-
brane helices and can act as a conformational ‘switch’,
allowing parts of the proteins to adopt alternative confor-
mations.
Taking advantage of the Seebach et al. methodology of
self-reproduction of chirality,13 we have synthesised the
propargyl proline 4, unknown in the literature to the best
of our knowledge. Proline 4 bears the terminal acetylene
moiety that is ready to be coupled with different azides, as
well as suitable protecting groups for the C-terminus and
the N-terminus for its application in peptide synthesis.
Relating to the importance of this amino acid, the set up
of new and powerful methodologies for the synthesis of
proline analogues is one of the major goals of peptide
chemists. Modified prolines, including a-substituted
prolines,1,2 are attracting increasing interest as discrete
molecules as well. For instance, a-methylproline stimu-
lates collagen synthesis,3 an N-hydroxy-2-[(arylsul-
fonyl)methyl]prolinamide has been shown to be a potent
and selective MMP inhibitor,4 1-acyl-2-isopropyl-5-
arylpyrrolidine-2,4-dicarboxylic acids seemed to be ef-
fective inhibitors of the Hepatitis C virus,5 and the natural
kaitocephalin is a potent antagonist for NMDA and
AMPA/KA receptors.6
The optically pure proline derivative 2 was obtained from
L-proline (1) by protection of the carboxylic and amine
functions with trichloroacetaldehyde as previously
described.14 Oxazolidinone 2 was treated in sequence with
LDA and 3-bromoprop-1-yne in anhydrous THF to afford
oxazolidinone 3 as a single isolated diastereomer in low
yield (24% yield based on converted oxazolidinone;
Scheme 1). The configuration of 3 was assigned as
3R,7aR on the basis of the well-documented stereocontrol
during alkylation of the enolate of oxazolidinones such
as 2.13a,14c
During our research, we became interested in preparing
small libraries of 2-alkylprolines employing common
advanced building blocks that could be easily decorated
with different substituents, exploiting inexpensive start-
ing materials and very efficient reactions.
Sharpless and co-workers7 have recently defined ‘click
chemistry’ as a set of powerful and selective reactions that
are wide in scope, give high yields, generate inoffensive
by-products and use simple reaction conditions, readily
available starting materials and benign solvents, or even
no solvent where possible. Among these near-perfect re-
actions, the Huisgen dipolar cycloaddition between azides
Protected proline 3 was then treated with MeOH and
trimethylsilylchloride (TMSCl) in a microwave reactor at
40 °C to remove the oxazolidinone moiety and to protect
the carboxylic acid as methyl ester. The product was
directly treated with CbzCl and an aqueous solution of
NaHCO3 at room temperature to obtain, after purification
on silica gel, the orthogonally protected proline 4 in 40%
overall yield from 3. The choice of Cbz protecting group
was driven by the failure in the introduction of more
hindered protecting groups such as Boc or Fmoc.
In an effort to improve the overall yield, an alternative ap-
proach to 4 was examined. Propargylation of 2 with 3-bro-
mo-1-(trimethylsilyl)-1-propyne under the previously
described conditions was slightly more efficient than with
SYNLETT 2007, No. 18, pp 2882–2884
Advanced online publication: 25.09.2007
DOI: 10.1055/s-2007-991065; Art ID: D22707ST
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© Georg Thieme Verlag Stuttgart · New York

LETTER
A Straightforward Route to Decorated Prolines
2883
3-bromoprop-1-yne and afforded the trimethylsilyl Table 1 Synthesis of Modified Prolines by Cu(I)-Catalysed Azide
propargyl derivative 515 in 42% yield based on converted
Cycloadditions
oxazolidinone 2 (Scheme 1). Hydrolysis of the oxazolidi-
N
N
none 5 followed by protection of the carboxylic acid and
N
X
+
( )n
X(CH2)nN3
the amino groups as before, gave derivative 7 in 73%
yield. Eventually, treatment of 7 with TBAF in THF gave
the 2-prop-2-ynyl-L-proline 4 in 55% yield (Scheme 1).16
CO2Me
N
N
CO2Me
Cbz
Cbz
4
8
9
Azide
Product
Yield (%)
64
CO2H
N
N
NH
N
N
1
PhCH2N3
8a
Ph
N
a)
CO2Me
Cbz
O
O
H
N
9a
CO2Me
Cbz
c)
b)
1
3
6
N
N
O
O
N
N
CH2=CH(CH2)9N3
8b
79
65
7
CCl3
2
N
CCl3
3
4
CO2Me
Cbz
d)
g)
9b
TMS
TMS
f)
TMS
N
N
N
O
EtO2C(CH2)3N3
8c
CO2Et
e)
CO2Me
NH2
CO2Me
Cbz
N
O
CO2Me
N
N
Cl–
Cbz
CCl3
6
7
5
9c
N
N
N
OAc
Scheme 1 Reagents and conditions: (a) Cl3CCHO, MeCN, r.t.,
overnight, 82%; (b) LDA, BrCH2C≡CH, –78 °C to –30 °C, 2 h, 24%
(63% conv.); (c) (i) TMSCl, MeOH, MW (150 W), 40 °C; (ii) CbzCl,
sat. aq NaHCO3, 0 °C to r.t., 2 d, 40%; (d) LDA, BrCH2C≡C–TMS,
–78 °C to –30 °C, 2 h, 42% (87% conv.); (e) TMSCl, MeOH, MW
(150 W), 2.5 h, 40 °C; (f) CbzCl, sat. aq NaHCO3, 0 °C to r.t., 12 h,
73% over two steps; (g) 1 M TBAF, THF, 2 h, r.t., 55%.
OAc
OAc
OAc
AcO
N3
OAc
OAc
N
CO2Me
O
62
Cbz
O
OAc
8d
9d
The propargyl proline 4 was tested in the ‘click cyclo-
addition’ with four variably functionalised azides 8a–d
(Table 1) including one decorated with a sugar moiety
(8d).17 The azides 8a and 8c were prepared from the cor-
responding bromides using NaN3 in DMF at 40 °C over-
night, while 8b was obtained from the corresponding
mesylated alcohol following the above procedure. Azide
8d is commercially available or can be synthesised as re-
ported in the literature.18 The click chemistry reaction was
performed in a microwave reactor with 1:1 mixtures of
proline 4 and the appropriate azide 8 in t-BuOH–H2O so-
lution.10 After addition of CuSO4 and Cu(0) the reaction
Moreover, the triazole moiety serves as a rigid linking
unit, but, at the same time, is isosteric to a peptide bond,
and, due to its aromatic nature, is very stable and cannot
be cleaved.22
The reported preliminary results appear to be wide in
scope and further studies for the use of these interesting
compounds as mimics of amino acids are in progress in
our laboratories.
Acknowledgment
mixture was stirred under microwave heating (100 W) at Authors thank MiUR-COFIN 2005 and Università degli Studi di
125 °C for 15–20 min.19 Analytically pure triazoles 9a–d
were recovered after chromatography on silica gel in good
Firenze for financial support. Maurizio Passaponti and Brunella
Innocenti are gratefully acknowledged for their technical support.
Ente Cassa di Risparmio is acknowledged for granting a 400 MHz
yields (Table 1).20
NMR instrument.
Albeit a more efficient synthetic route to the key interme-
diate 4 needs further studies, the collected experimental
data prove that the well-known click chemistry cycloaddi-
References and Notes
tion can be used as a powerful tool to decorate prolines.
The examples obtained in this study constitute a small
library of a-substituted prolines bearing chains with func-
tional groups that mimic the side chains of natural amino
acids (9a and 9c) or sugar moieties (9d)21 or groups ame-
nable to further transformations (9b).
(1) For a review on the stereoselective synthesis of a-alkyl-
prolines, see: Cativiela, C.; Díaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 2000, 11, 645.
(2) For other reviews on a,a-disubstituted a-amino acids, see:
(a) Cativiela, C.; Díaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517. (b) Nájera, C. Synlett 2002,
1388. (c) Park, K.-H.; Kurth, M. J. Tetrahedron 2002, 58,
Synlett 2007, No. 18, 2882–2884 © Thieme Stuttgart · New York

2884
F. Pisaneschi et al.
LETTER
8629. (d) Kotha, S. Acc. Chem. Res. 2003, 36, 342.
(e) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 5127.
(f) Toniolo, C.; Formaggio, F.; Kaptein, B.; Broxterman, Q.
B. Synlett 2006, 1295. (g) Vogt, H.; Bräse, S. Org. Biomol.
Chem. 2007, 5, 406.
The crude product was purified by chromatography on silica
gel (eluent: PE–Et2O, 1:1) to give pure 7 (154 mg, 73%;
mixture of two rotamers at r.t.) as a colourless oil. TBAF (1
M, 0.62 mmol, 0.6 mL) was added dropwise to a solution of
proline 7 (0.41 mmol, 154 mg) in THF (10 mL). The mixture
was stirred at r.t. for 2 h, and then the solvent was removed
at reduced pressure. The residue was dissolved in CH2Cl2
and H2O and the two layers were separated. The aqueous
layer was extracted with CH2Cl2 and the combined organic
layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by
chromatography on silica gel (eluent: PE–Et2O, 1:1) to give
pure 4 (67 mg, 55%; mixture of two rotamers at r.t.) as a
colourless oil. Compound 4: Rf 0.37. 1H NMR (400 MHz,
DMSO-d6, 110 °C): d = 7.28–7.40 (m, 5 H, Ph), 5.09 (br s, 2
H, CH2Ph), 3.66 (ddd, J = 5.3, 7.8, 10.2 Hz, 1 H, 5-Ha), 3.59
(br s, 3 H, OMe), 3.51 (dt, J = 7.3, 10.2 Hz, 1 H, 5-Hb), 3.05–
3.17 (m, 1 H, CHHC≡), 2.81 (dd, J = 2.6, 17.0 Hz, 1 H,
CHHC≡), 2.64 (t, J = 2.6 Hz, 1 H, ≡CH), 2.32 (m, 1 H, 3-Ha),
2.15 (m, 1 H, 3-Hb), 1.97–2.07 (m, 1 H, 4-Ha), 1.89–1.96 (m,
1 H, 4-Hb). Anal. Calcd for C17H19NO4: C, 67.76; H, 6.36; N,
4.65. Found: C, 67.57; H, 6.63; N, 4.93.
(3) Lubec, G.; Labudova, O.; Seebach, D.; Beck, A.; Hoeger,
H.; Hermon, M.; Weninger, M. Life Sci. 1995, 57, 2245.
(4) Becker, D. P.; DeCrescenzo, G.; Freskos, J.; Getman, D. P.;
Hockerman, S. L.; Li, M.; Mehta, P.; Munie, G. E.;
Swearingen, C. Bioorg. Med. Chem. Lett. 2001, 11, 2723.
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Lin-Goerke, J.; Baker, A.; Earnshaw, D. L.; Hofmann, G. A.;
Keenan, R. M.; Dhanak, D. Bioorg. Med. Chem. Lett. 2005,
15, 1553.
(6) (a) Shin-ya, K.; Kim, J.-S.; Furihata, K.; Hayakawa, Y.;
Seto, H. Tetrahedron Lett. 1997, 38, 7079. (b) Watanabe,
H.; Okue, M.; Kobayashi, H.; Kitahara, T. Tetrahedron Lett.
2002, 43, 861.
(7) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int.
Ed. 2001, 40, 2004.
(8) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org.
Chem. 2002, 67, 3057. (b) Rostovtsev, V. V.; Green, L. G.;
Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002,
41, 2596.
(17) (a) Alvarez, S. G.; Alvarez, M. T. Synthesis 1997, 413.
(b) Ju, Y.; Kumar, D.; Varma, R. S. J. Org. Chem. 2006, 71,
6697. (c) Hu, X.; Nguyen, K. T.; Jiang, V. C.; Lofland, D.;
Moser, H. E.; Pei, D. J. Med. Chem. 2004, 47, 4941.
(18) (a) Szarek, W. A.; Achmatowicz, O. Jr.; Plenkiewicz, J.;
Radatus, B. K. Tetrahedron 1978, 34, 1427. (b) Esteves, A.
P.; Rodrigues, L. M.; Silva, M. E.; Gupta, S.; Oliveira-
Campoça, A. M. F.; Machalickyb, O.; Mendonça, A. J.
Tetrahedron 2005, 62, 8625.
(19) General Procedure: To a mixture of proline 4 (1 equiv) and
azide 8 (1.2 equiv) in a mixture of H2O and t-BuOH (1:1) in
a microwave reaction tube were added copper turnings (0.2
equiv) and copper sulfate (0.7 equiv). The mixture was
stirred for 15–20 min at 125 °C, using an irradiation power
of 100 W with simultaneous cooling. It was then diluted with
H2O and CH2Cl2 and the two layers were separated. The
aqueous layer was extracted with CH2Cl2 and the combined
organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by chromatography on silica gel to afford
(9) For a recent review, see: Bock, V. D.; Hiemstra, H.; van
Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51.
(10) (a) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der
Eychen, E. Org. Lett. 2004, 6, 4223. (b) Khanetskyy, B.;
Dallinger, D.; Kappe, C. O. J. Comb. Chem. 2004, 6, 884.
(11) For the synthesis of other proline-derived triazoles by azide–
alkyne cycloadditions, see: (a) Yan, Z.-Y.; Niu, Y.-N.; Wei,
H.-L.; Wu, L.-Y.; Zhao, Y.-B.; Liang, Y.-M. Tetrahedron:
Asymmetry 2006, 17, 3288. (b) Paul, A.; Bittermann, H.;
Gmeiner, P. Tetrahedron 2006, 62, 8919.
(12) During our study, the preparation of racemic a-trifluoro-
methyl azahistidine analogues using the same approach has
been reported: Shchetnikov, G. T.; Peredukov, A. S.;
Osipov, S. N. Synlett 2007, 136.
(13) (a) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am.
Chem. Soc. 1983, 105, 5390. (b) Seebach, D.; Sting, A. R.;
Hoffmann, M. Angew. Chem. Int. Ed. 1996, 35, 2708.
(14) (a) Połoński, T. Tetrahedron 1985, 41, 603. (b) Orsini, F.;
Pellizzoni, F.; Forte, M.; Sisti, M.; Bombieri, G.; Benetollo,
F. J. Heterocycl. Chem. 1989, 26, 837. (c) Wang, H.;
Germanas, P. Synlett 1999, 33. (d) Amedjkouh, M.;
Ahlberg, P. Tetrahedron: Asymmetry 2002, 13, 2229.
(15) A related compound of 5 (NBoc instead of NCbz) has been
previously prepared in racemic form by propargylation of
Boc-Pro-OMe: Ikeda, M.; Kugo, Y.; Kondo, Y.; Yamazaki,
T.; Sato, T. J. Chem. Soc., Perkin Trans. 1 1997, 3339.
(16) 1-Benzyl 2-Methyl (2R)-2-Prop-2-ynylpyrrolidine-1,2-
dicarboxylate (4): To a solution of compound 5 (0.56 mmol,
197 mg) in MeOH (3 mL) in a microwave reaction tube was
added TMSCl (2.89 mmol, 365 mL). The mixture was stirred
for 2.5 h at 40 °C using an irradiation power of 150 W with
simultaneous cooling of the reaction vessel with a stream of
compressed air. The solvent was removed under reduced
pressure, and a sat. solution of NaHCO3 (3 mL) was added
followed by carbobenzyloxy chloride (CbzCl, 0.62 mmol,
87 mL) at 0 °C. The reaction mixture was allowed to warm to
r.t., stirred overnight at r.t., and diluted with EtOAc. The two
layers were separated, the aqueous layer was extracted with
EtOAc and the combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
analytically pure proline 9.
(20) 1-Benzyl 2-Methyl (2R)-2-{[1-(4-Ethoxy-4-oxobutyl)-1H-
1,2,3-triazol-4-yl]methyl}pyrrolidine-1,2-dicarboxylate
(9c): Rf 0.28 (PE–Et2O, 1:1). 1H NMR (400 MHz, DMSO-d6,
110 °C): d = 7.52 (s, 1 H, triazole), 7.29–7.41 (m, 5 H, Ph),
5.12 (s, 2 H, CH2Ph), 4.34 (t, J = 6.9 Hz, 2 H,
NCH2CH2CH2CO2Et), 4.08 (q, J = 7.1 Hz, 2 H, CH2CH3),
3.63 (br s, 3 H, OMe), 3.46–3.58 [m, 2 H, C(2)CHH + 5-Ha],
3.23 [d, J = 14.6 Hz, 1 H, C(2)CHH], 3.02–3.10 (m, 1 H, 5-
Hb), 2.24–2.32 (m, 1 H, 3-Ha), 2.27 (t, J = 7.3 Hz, 2 H,
CH2CO2Et), 2.02–2.10 (m, 3 H, 3-Hb + CH2CH2CO2Et),
1.67–1.79 (m, 1 H, 4-Ha), 1.29–1.41 (m, 1 H, 4-Hb), 1.20 (t,
J = 7.1 Hz, 3 H, CH2CH3). Anal. Calcd for C23H30N4O6: C,
60.25; H, 6.59; N, 12.22. Found: C, 59.98; H, 6.90; N, 11.98.
(21) For previous examples of triazole-linked glycosyl amino
acids and peptides, see: (a) Kuijpers, B. H. M.; Groothuys,
S.; Keereweer, A. (B.) R.; Quaedflieg, P. J. L. M.; Blaauw,
R. H.; van Delft, F. L.; Rutjes, F. P. J. T. Org. Lett. 2004, 6,
3123. (b) Lin, H.; Walsh, C. T. J. Am. Chem. Soc. 2004, 126,
13998.
(22) Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003,
8, 1128.
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