DBU-Catalyzed transprotection of N-Fmoc-cysteine di- and tripeptides into S-Fm-cysteine di- and tripeptides

Article abstract of DOI:10.1039/c0ob00663g

The transprotection of N-Fmoc-cysteine containing di- and tripeptides possessing a free SH group to produce the corresponding S-Fm-cysteine di- and tripeptides bearing a free amino group is accomplished efficiently with DBU in dry THF. The N-Fmoc to S-Fm

Full text of DOI:10.1039/c0ob00663g

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 596
www.rsc.org/obc
PAPER
DBU-Catalyzed transprotection of N-Fmoc-cysteine di- and tripeptides into
S-Fm-cysteine di- and tripeptides†
Alan R. Katritzky,*a Nader E. Abo-Dya,a,b Abdelmotaal Abdelmajeid,a,c Srinivasa R. Tala,a M. S. Aminec and
Said A. El-Fekyb
Received 3rd September 2010, Accepted 21st September 2010
DOI: 10.1039/c0ob00663g
The transprotection of N-Fmoc-cysteine containing di- and tripeptides possessing a free SH group to
produce the corresponding S-Fm-cysteine di- and tripeptides bearing a free amino group is accomp-
lished efficiently with DBU in dry THF. The N-Fmoc to S-Fm transformation mechanism is discussed.
S-Fm-Cysteine di- and tripeptides readily form amide bonds on coupling with N-(Pg-a-aminoacyl)-
benzotriazoles and N-(Pg-a-dipeptidoyl)benzotriazoles to give larger peptides.
Introduction
Results and discussion
Protecting groups play important roles in organic synthesis and the
development of new selective methodologies for the protection and
deprotection of sensitive functionalities is ongoing.1 9-Fluorenyl-
methyloxycarbonyl (Fmoc) is widely used as a protecting group
in peptide chemistry, since it is easily removed by base, provides
good orthogonality and is inexpensive with many Fmoc-protected
amino acids sold commercially. The 9-fluorenylmethyl (Fm) group
is used for thiol protection2 and has been preferred for the
orthogonal protection of cysteine in Boc/benzyl-based synthetic
strategies.3
Transprotections, which combine deprotection and protection
into a single step, can be highly valuable in organic synthesis.
Known transprotections include the well-known, useful trans-
formation of enol ethers into ketals,4 the conversions of allyl
carbamates into amides or dipeptides,5 thioesters into thioethers
or thioketals,6 silyl ethers into benzyl ethers or esters,7 enol ethers
into thioketals,8 and nucleosidic silyl ethers into acetates.9 We now
report transprotections of N-Fmoc-protected cysteine peptides
possessing free sulfhydryl groups into S-Fm-protected cysteine
peptides having free amino groups corresponding to simultaneous
N-Fmoc deprotection of the amino group and S-Fm protection
of the thiol group.
1. Preparation of N-Fmoc-protected cysteine dipeptides 3a–f
The starting N-(protected-a-aminoacyl)benzotriazoles 2a–i (N-
Fmoc-L-Phe-Bt 2a, N-Fmoc-L-Met-Bt 2b, N-Fmoc-L-Ala-Bt 2c,
N-Fmoc-L-Leu-Bt 2d, N-Fmoc-Gly-Bt 2e, N-Fmoc-L-Lys(N-
Boc)-Bt 2f, N-Cbz-L-Ala-Bt 2g, N-Cbz-Gly-Bt 2h, N-Cbz-L-Leu-
Bt 2i were prepared from corresponding N-protected amino acids
following our previously published one-step procedure.10
Peptide coupling of N-(Fmoc-a-aminoacyl)benzotriazoles 2a–f
with L-cysteine in partially aqueous solution (MeCN–H2O 7 : 3)
in the presence of Et3N for one hour at room temperature gave
novel N-Fmoc-protected cysteine dipeptides 3a–f (78–98%), which
were characterized by 1H, 13C NMR spectroscopy and elemental
analyses (Scheme 1, Table 1).11
Scheme 1 Synthesis of N-Fmoc-cysteine dipeptides 3a–f.
Table 1 Preparation N-Fmoc- Cysteine dipeptides 3a–f
2
Product 3
Yielda (%)
Mp/◦C
aCenter for Heterocyclic Compounds, Department of Chemistry, Univer-
sity of Florida, Gainesville, FL 32611-7200, USA. E-mail: katritzky@
chem.ufl.edu; Fax: +1 352-392-9199; Tel: +1 352-392- 0554
2a
2b
2c
2d
2e
2f
N-Fmoc-Phe-L-Cys-OH 3a
N-Fmoc-Met-L-Cys-OH 3b
N-Fmoc-Ala-L-Cys-OH 3c
N-Fmoc-Leu-L-Cys-OH 3d
N-Fmoc-Gly-L-Cys-OH 3e
N-Fmoc-Lys(N-Boc)-L-Cys-OH 3f
98
88
84
86
84
78
164–166
110–111
167–169
68–70
90–91
88–90
bDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy,
Zagazig University, Zagazig, 44519, Egypt
cDepartment of Chemistry, Faculty of Science, Benha University, Benha,
Egypt
† Electronic supplementary information (ESI) available: (1) characteriza-
tion data for compounds 3b–f, 4b–f, 9b–d, 10a–c and 11, and (2) 1H NMR,
13C NMR spectra of compounds. See DOI: 10.1039/c0ob00663g
a Isolated yield.
596 | Org. Biomol. Chem., 2011, 9, 596–599
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 2 Transprotection of N-Fmoc-dipeptides 3a–f to form S-Fm-
dipeptides 4a–f
3
Product 4
Yielda (%)
Mp ◦
C
3a
3b
3c
3d
3e
3f
H-L-Phe-L-Cys(S-Fm)-OH 4a
H-L-Met-L-Cys(S-Fm)-OH 4b
H-L-Ala-L-Cys(S-Fm)-OH 4c
H-L-Leu-L-Cys(S-Fm)-OH 4d
H-Gly-L-Cys(S-Fm)-OH 4e
81
76
70
87
78
69
233–235
205–207
202–204
207–209
230–232
165–167
H-L-Lys(N-Boc)-L-Cys(S-Fm)-OH 4f
a Isolated yield
2. Transprotection of N-Fmoc-protected cysteine dipeptides 3a–f
N-Fmoc-protected cysteine dipeptides 3a–f were each treated
with three equivalents of DBU in dry THF at 0 ◦C for 15 min
to afford the corresponding S-Fm-transprotected dipeptides 4a–
f in (69–87%) yields (Scheme 2, Table 2). These compounds
were characterized by 1H, 13C- NMR spectroscopy and elemental
analyses.
Scheme 3 Mechanism of N-Fmoc to S-Fm transformation.
Scheme
2 Transprotection of N-Fmoc-dipeptides 3a–f to form
S-Fm-dipeptides 4a–f.
The mechanism of the transprotection (Scheme 3) involves three
steps: (i) one equivalent of DBU catalyses the E1cB reaction, which
liberates dibenzofulvene (DBF) and forms DBU carbamate, two
additional equivalents of DBU are consumed in formation of DBU
mercaptide and DBU carboxylate; (ii) the mercaptide anion adds
by Michael reaction to dibenzofulvene (DBF); (iii) carbamic acid
is formed and rapidly decarboxylated on acidification with HCl.
When less than three equivalents of DBU was used, the reaction
rate was decreased. The successful transprotection of 3f into 4f
where the lysine side chain is protected with N-Boc acid labile
group extends the scope of this methodology to examples of amino
acids which require side chain protection by an acid labile group.
One step deprotection of amino group of 3a–f and protection of
thiol group was thus achieved to afford S-Fm-protected dipeptides
4a–f.
Scheme 4 Synthesis of N-Fmoc cysteine tripeptides 7a,b and their
transprotection into S-Fm cysteine tripeptides 8a,b.
4. Utility of the S-Fm protecting group
3. Transprotection of N-Fmoc-cysteine tripeptides 7a,b
The Fm-group is stable towards hydrogenation,13 and several
reagents frequently used in solid-phase synthesis including HF and
diisopropylethylamine (DIPEA).14 However, Fm is readily cleaved
by ammonia in methanol or organic bases, e.g. a 20% piperidine
in dimethylformamide,13 and hence S-Fm-protected cysteine pep-
tides having a free amino group could be valuable building blocks
in peptide synthesis in solid or solution phase. Indeed, the S-Fm
protected cysteine residues have served as reliable thiol precursors
during the synthesis of cyclic tripeptides,15 cyclic disulfide-peptides
such as oxytocin,16 bicyclo[2,3]-Leu-enkephalin analogues,17 and
bis-cystine peptides.14
N-(Fmoc-Dipeptidoyl)benzotriazoles 6a,b, which were prepared
by our previously published procedure12 are reacted with L-
cysteine in acetonitrile–water (3 : 1) in the presence of one
equivalent of TEA to give N-Fmoc-cysteine tripeptides 7a,b
in 88%, 96% yields respectively (Scheme 4). Then, treatment
of 7a,b with three equivalents of DBU in dry THF at 0 ◦C
for 15 min afforded transprotected S-Fm-cysteine tripeptides
8a,b in 80%, 78% yields respectively (Scheme 4). S-Fm-Cysteine
tripeptides 8a,b were characterized by 1H, 13C-NMR spectroscopy
and elemental analyses.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 596–599 | 597
©

View Article Online
Table 3 Peptide coupling reactions of S-Fm-cysteine peptides 4a–e with N-(Pg-a-aminoacyl)benzotriazoles 2e,g–i and N-(Pg-dipeptidoyl)benzotriazole
6c,d
Entry
RCOBt 2 or 6
S-Fm-peptide 4
N-Pg-S-Fm-Cysteine peptide 9 or 10, Yielda (%)
1
2
3
4
5
6
7
N-Fmoc-Gly-Bt 2e
N-Cbz-Ala-Bt 2g
H-Phe-Cys(S-Fm)-OH 4a
H-Gly-Cys(S-Fm)-OH 4e
H-Ala-Cys(S-Fm)-OH 4c
H-Met-Cys(S-Fm)-OH 4b
H-Gly-Cys(S-Fm)-OH 4e
H-Ala-Cys(S-Fm)-OH 4c
H-Leu-Cys(S-Fm)-OH 4d
Fmoc-Gly-Phe-Cys(S-Fm)-OH 9a, 75
Cbz-Ala-Gly-Cys(S-Fm)-OH 9b, 70
Cbz-Gly-Ala-Cys(S-Fm)-OH 9c, 60
Cbz-Leu-Met-Cys(S-Fm)-OH 9d, 65
Cbz-Leu-Met-Gly-Cys(S-Fm)-OH 10a, 75
Cbz-Ala-Phe-Ala-Cys(S-Fm)-OH 10b, 72
Cbz-Ala-Phe-Leu-Cys(S-Fm)-OH 10c, 79
N-Cbz-Gly-Bt 2h
N-Cbz-Leu-Bt 2i
N-Cbz-Leu-Met-Bt 6c
N-Cbz-Ala-Phe-Bt 6d
N-Cbz-Ala-Phe-Bt 6d
a Isolated yield.
5. Solution-phase peptide coupling reactions of S-Fm-cysteine
peptides 4a–e, 8a with N-(protected-a-aminoacyl)benzotriazoles
2e, 2g–i and N-(protected-dipeptidoyl)benzotriazole 6c,d
S-Fm-Protected dipeptides 4a–e on treatment with N-
(Pg-a-aminoacyl)benzotriazoles
2e,g–i
and
N-(Cbz-a-
dipeptidoyl)benzotriazoles 6c,d (compounds 6c,d were prepared
by our previously published procedure12) in the presence of
diisopropyl ethylamine at 20 ◦C in acetonitrile–water afforded
cysteine tripeptides 9a–d (65–75%) and tetrapeptides 10a–c
(72–79%) respectively (Scheme 5, Table 3). N-Pg-S-Fm-Cysteine
1
containing tri- and tetrapeptides were characterized by H, 13C
NMR spectroscopy and elemental analyses.
Scheme 6 Preparation of cysteine containing pentapeptide 11.
of the introduction of S-Fm protection with 9-fluorenylmethanol18
or using expensive amino acids such as H-cysteine(S-Fm)-OH.
These free amino S-Fm-cysteine di- and tripeptides can be
readily used to form amide bonds in the synthesis of larger
peptides.
Scheme 5 Solution-phase peptide coupling reactions of S-Fm-cysteine
peptides 4a–e with N-(Pg-a-aminoacyl)benzotriazoles 2e,g–i and
N-(Pg-dipeptidoyl)benzotriazole 6c,d.
Experimental
Starting materials and solvents were purchased from commercial
sources and used without further purification. Melting points were
determined on a Fisher melting apparatus and are uncorrected. 1H
NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded
on a 300 MHz NMR spectrometer with CDCl3 or DMSO-d6 as
solvents. J values are given in Hz. [a]D values are given in 10-1 deg
cm2 g-1. Elemental analyses were performed on a Carlo Erba–1106
instrument.
Similarly, treatment of S-Fm-protected tripeptide 8a with N-
(Fmoc-a-dipeptidoyl)benzotriazole 6a in the presence of diiso-
propyl ethylamine at 20 ◦C in acetonitrile–water afforded cysteine
containing pentapeptide 11 in 69% yield (Scheme 6). Pentapeptide
11 was characterized by 1H, 13C NMR spectroscopy and elemental
analysis.
Conclusion
General procedure for preparation of N-Fmoc-cystiene dipeptides
3a–f and tripeptides 7a,b
In conclusion we have demonstrated useful and convenient
transprotections of N-Fmoc-cysteine di- and tripeptides contain-
ing a free SH group into S-Fm-cysteine di- and tripeptides bearing
free amino and carboxylic groups under mild conditions. The base-
induced cleavage of the Fmoc protecting group of a N-Fmoc-
cysteine di- or tripeptide provides dibenzofulvene, which is then
attacked by the highly nucleophilic sulfur of a cysteine side chain
to provide S-Fm-cysteine di- and tripeptides bearing free amino
and carboxylic groups. Thus, in the present method, we not only
deprotected the N-Fmoc group in a peptide, but also free SH group
was protected with Fm group in the same peptide in a single step.
This could be an efficient alternative to the usual two step process
N-(Protected-a-aminoacyl)benzotriazoles 2a–f and N-Fmoc-
dipeptidoylbenzotriazole 6a,b were suspended in acetonitrile and
a solution of cysteine in water containing equivalent amount of
◦
triethylamine was added. The mixture was stirred at 20 C until
the TLC revealed complete consumption of the starting materials.
After acidifiacation with HCl (4 N) acetonitrile was removed under
reduced pressure and the residue formed was taken in ethyl acetate,
extracted with HCl (2 N) and brine. Ethyl acetate was concentrated
under reduced pressure and hexanes were added. The turbid solu-
tion was left to crystallize overnight at -20 ◦C. The solid obtained
was filtered, dried to give the corresponding di- or tripeptides.
598 | Org. Biomol. Chem., 2011, 9, 596–599
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
N-Fmoc-L-Phe-L-Cys-OH◦ (3a)11a
.
(0.19 g, 98%). White mi-
-20 ◦C. The solid formed was filtered out and dried under reduced
pressure to give the corresponding coupling products.
crocrystals; mp 164.0–166.0 C (EtOAc/hexanes). [a]2D3 -13.0 (c
1.0 in MeOH). (Found: C, 65.98; H, 5.41; N, 5.51%. Calcd for
C27H26N2O5S: C, 66.10; H, 5.34; N, 5.71%). dH (300 MHz; DMSO-
d6; Me4Si) 8.37 (1 H, d, J 7.7), 7.87 (2 H, d, J 7.6), 7.71–7.62 (3
H, m), 7.43–7.16 (9H, m), 4.50–4.44 (1H, m), 4.38–4.32 (1 H, m),
4.19–4.15 (3 H, m), 3.06 (1 H, dd, J 13.6, 3.3), 2.97–2.77 (3 H, m),
2.44 (1 H, t, J 8.1); dC (75 MHz; DMSO-d6; Me4Si) 171.6, 171.4,
155.7, 143.7, 143.6, 140.6, 138.0, 129.1, 127.9, 127.5, 127.0, 126.2,
125.3, 125.2, 120.0, 65.6, 55.9, 54.3, 46.5, 37.3 and 25.5.
Fmoc-Gly-L-Phe-Cys(S-Fm)-OH (9a). (0.15 g, 75%). White
micrcrystals; mp 103.0–105.0 ◦C (EtOAc/hexanes). [a]2D3 -15.0 (c
1.0 in MeOH). (Found: C, 65.97; H, 5.76; N, 5.05%. Calcd for
C43H39N3O6S·3H2O: C, 66.22; H, 5.82; N, 5.39%). dH (300 MHz;
DMSO-d6; Me4Si) 9.06 (1 H, d, J 8.1), 8.24 (2 H, br s), 7.88 (4 H,
t, J 7.8), 7.77–7.70 (3 H, m), 7.65 (1 H, t, J 6.6), 7.45–7.31 (12 H,
m), 4.53–4.49 (1 H, m), 4.31–4.18 (4 H, m), 4.09 (1 H, br s), 3.67 (2
H, d, J 6.3), 3.21 (2 H, d, J 6.3), 3.15 (1 H, d, J 5.1), 3.01–2.85 (3
H, m); dC (75 MHz; DMSO-d6; Me4Si) 171.5, 171.3, 168.1, 156.5,
145.8, 143.8, 140.7, 140.5, 134.8, 129.7, 128.4, 127.6, 127.4, 127.1,
127.0, 125.2, 125.0, 120.1, 120.0, 65.7, 53.2, 52.7, 46.6, 46.4, 42.1,
36.7, 35.9 and 33.9.
General procedure for transprotection of N-Fmoc-cystiene di- and
tripeptides 3a–f, 7a,b into S-Fm-protected cysteine di- and
tripeptides 4a–f, 8a,b
N-Fmoc-Di- or tripeptide (0.5 mmol) was dissolved in dry THF
(5 mL) under argon at 0 ◦C. DBU (152 mg, 1 mmol) was
dissolved in (1 mL) THF and added dropwise over 5 min to the
Fmoc-dipeptide solution. The solution was left to stir for 10 more
minutes and a sticky solid was precipitated. THF was evaporated
under reduced pressure and the solid was dissolved in 1 N HCl
(3 mL) under cooling. When the pH of the solution was adjusted
to 5 using Na2HPO4 solution (1M), a solid precipitated. The solid
was collected by filtration, washed with water (1 ¥ 3 mL), ether (3 ¥
5 mL), dried to give the corresponding S-Fm-protected cysteine
di- or tripeptide.
Notes and references
1 (a) A. C. Spivey and R. Srikaran, Annu. Rep. Prog. Chem., Sect. B, 2001,
97, 41–59; (b) J. Robertson, Protecting Group Chemistry, S. G. Davies,
Ed., Oxford University Press, Oxford, 2000; (c) T. W. Greene and P.
G. M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley-
Intersience, Hoboken, New Jersey, 2007; (d) P. J. Kocienski, Protecting
Groups, Thieme, Stuttgart, 2005.
2 (a) E. J. Corey, D. Y. Gin and R. S. Kania, J. Am. Chem. Soc., 1996,
118, 9202–9203; (b) C. W. West, M. A. Estiarte and D. H. Rich, Org.
Lett., 2001, 3, 1205–1208.
3 B. Ponsati, E. Giralt and D. Andreu, Tetrahedron, 1990, 46, 8255–8266.
4 S. Lee and J. P. N. Rosazza, Org. Lett., 2004, 6, 365–368.
5 (a) E. C. Roos, P. Bernabe´, H. Hiemstra, W. N. Speckamp, B. Kaptein
and W. H. J. Boesten, Tetrahedron Lett., 1991, 32, 6633–6636; (b) E. C.
Roos, P. Bernabe´, H. Hiemstra, W. N. Speckamp, B. Kaptein and W.
H. J. Boesten, J. Org. Chem., 1995, 60, 1733–1740; (c) For related work,
see: R. Beugelmans, L. Neuville, M. Bois-Choussy, J. Chastanet and J.
Zhu, Tetrahedron Lett., 1995, 36, 3129–3132.
6 S. Iimura, K. Manabe and S. Kobayashi, Org. Lett., 2003, 5, 101–103.
7 S. Iimura, K. Manabe and S. Kobayashi, J. Org. Chem., 2003, 68, 8723–
8725.
8 A. Martel, S. Chewchanwuttiwong, G. Dujardin and E. Brown,
Tetrahedron Lett., 2003, 44, 1491–1494.
9 J. R. Harjani, S. J. Nara and M. M. Salunkhe, Nucleosides, Nucleotides
Nucleic Acids, 2005, 24, 819–822.
H-L-Phe-L-Cys(S-Fm)-OH (4a). (0.18 g, 81%). White micro-
crystals; mp 233.0–235.0 ◦C. [a]2D3 -13.0 (c 1.0 in MeOH). (Found:
C, 65.15; H, 5.82; N, 5.66%. Calcd for C26H26N2O3S·2H2O: C,
64.71; H, 6.27; N, 5.80%). dH (300 MHz; DMSO-d6; Me4Si) 8.52
(1H, br s), 7.85 (2H, d, J 7.5), 7.75 (2H, d, J 6.9), 7.42–7.25 (9H,
m), 4.91 (2H, br s), 4.36 (1H, br s), 4.14 (1H, t, J 6.2), 3.78–
3.71 (1H, m), 3.17–2.81 (5H, m), 2.77–2.69 (1H, m); dC (75 MHz;
DMSO-d6; Me4Si) 171.8, 171.2, 145.9, 140.3, 137.0, 129.3, 128.1,
127.2, 126.8, 126.3, 124.9, 121.2, 119.8, 54.8, 52.8, 46.3, 35.8 and
34.6.
10 Compounds 2a–f were synthesized using our previously reported
procedure: A. R. Katritzky, A. Singh, D. N. Haase and M. Yoshioka,
Arkivoc, 2009, (viii), 47–56.
General procedure for peptide coupling reaction between S-Fm
protected cysteine peptides 4a–e and N-(Pg-a-aminoacyl)-
benzotriazole 2e,2g–i or N-(Cbz-a-dipeptidoyl)benzotriazole 6c–d
11 (a) A. R. Katritzky, N. E. Abo-Dya, S. R. Tala and Z. K. Abdel-Samii,
Org. Biomol. Chem., 2010, 8, 2316–2319; (b) See also: A. R. Katritzky,
S. R. Tala, N. E. Abo-Dya, K. Gyanda, B. E-D. M. El-Gendy, Z. K.
Abdel-Samii and P. J. Steel, J. Org. Chem., 2009, 74, 7165–7167.
12 A. R. Katritzky, N. E. Abo-Dya, S. R. Tala, K. Gyanda and Z. K.
Abdel-Samii, Org. Biomol. Chem., 2009, 7, 4444–4447.
13 M. Bodanszky and M. A. Bednarek, Int. J. Peptide Protein Res., 1982,
20, 434–437.
14 M. Ruiz-Gayo, M. Royo, I. Ferna´ndez, F. Albericio, E. Giralt and M.
Pons, J. Org. Chem., 1993, 58, 6319–6328.
15 C. W. West and D. H. Rich, Org. Lett., 1999, 1, 1819–1822.
16 M. Ruiz-Gayo, F. Albericio, E. Pedroso and E. Giralt, J. Chem. Soc.,
Chem. Commun., 1986, 1501–1502.
S-Fm protected cysteine di- or tripeptide (0.25 mmol) was
dissolved in water (1 mL) and N,N-diisopropyl-N-ethyl amine
(0.043 mL, 0.25 mmol). Then acetonitrile (7 mL) and N-(Pg-a-
aminoacyl)benzotriazole or N-(Cbz-a-dipeptidoyl)benzotriazole
(0.25 mmol) were added. The heterogeneous mixture was left to
stir at room temperature till the TLC shows complete consumption
of N-acylbenzotriazole (1–3 h). After that, 6 N HCl was used to
acidify the solution to pH 1 and acetonitrile was removed under
reduced pressure. Ethyl acetate was added and the organic layer
was extracted with 4 N HCl (2 ¥ 2 mL). Ethyl acetate was dried over
sodium sulfate and concentrated under reduced pressure. Hexanes
were added and the solution was left to crystallize over night at
17 X. Gu, J. Ying, R. S. Agnes, E. Navratilova, P. Davis, G. Stahl, F.
Porreca, H. Yamamura and V. J. Hruby, Org. Lett., 2004, 6, 3285–
3288.
18 F. Albericio, E. Nicolas, J. Rizo, M. Ruiz-Gayo, E. Pedroso and E.
Giralt, Synthesis, 1990, 119–122.
This journal is The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 596–599 | 599
©