A new highly versatile handle for chemistry on a solid support: The pipecolic linker

Article abstract of DOI:10.1002/chem.201201452

The versatility of the pipecolic linker (Pip-linker) is illustrated by the synthesis of modified amino acids, C-terminal-modified pseudopeptides, and cyclic peptides, through side-chain anchoring of a lysine residue (see figure). Introduction of the first residue was easily accomplished and the Pip-linker revealed to be robust enough to support various chemical modifications. Copyright

Full text of DOI:10.1002/chem.201201452

COMMUNICATION
DOI: 10.1002/chem.201201452
A New Highly Versatile Handle for Chemistry on a Solid Support: The
Pipecolic Linker**
Nicolas Masurier,*[a] Paweł Zajdel,[b] Pascal Verdiꢀ,[a] Maciej Pawłowski,[b]
Muriel Amblard,[a] Jean Martinez,[a] and Gilles Subra[a]
Peptides have drawn considerable attention as therapeu-
tics[1] due to their roles as mediators of key biological func-
tions associated with their low toxicity and high specificity.
In 2010, about 60 peptide drugs were on the market (four of
them have reached global sales over US$ 1 billion), and
more than 500 peptides are in clinical development.[2] De-
spite their high potentials, peptides demonstrate some thera-
peutic limits: short half-life, rapid metabolism, poor oral
However, these handles suffer from low yields of anchor-
ing[7] and high sensitivity to acidic conditions, limiting the
use of other orthogonal acid-labile protecting groups. Re-
cently, we proposed the pipecolic linker (Pip-linker), a novel
trifluoroacetic acid (TFA)-labile linker based on the pipecol-
ic acid scaffold, which can be readily activated to anchor ef-
fectively and simply alcohol and amine groups.[8] Anchoring
of hydrazine is also possible, which constitutes an efficient
way for the preparation of C-terminal hydrazide peptides by
conventional Fmoc solid-phase peptide synthesis (SPPS).[8]
After anchoring and synthesis of target compound, the
acidic treatment by TFA or acetic acid can easily release the
target molecule from the Pip-linker (Scheme 1). The cleav-
bioACHTUNGTRENNUNG
availability, and so forth.[3] Nevertheless, development of
pseudopeptides by different chemical modifications can
avoid these disadvantages. Various peptidomimetic ap-
proaches used for the design and synthesis of peptide-de-
rived compounds with improved pharmacological and phar-
macokinetic properties were proposed.[4]
In research, peptide synthesis is performed mostly by
solid-phase procedures owing to the speed, ease of automa-
tion, and improvement of yields by use of excess of reac-
tants and easy removal of reactants. In production, the ma-
jority of peptide synthesis is still performed in solution.
However, the use of resins tends to gain popularity since the
development of Fuzeon.[5] Solid-phase synthesis is normally
performed from C to N terminus, requiring the anchoring of
the carboxylic function of the first amino acid to the linker.
However, for some modifications and pseudopeptide synthe-
sis, nonconventional N-terminal anchoring is required to
perform chemical modifications on the carboxylic function.[6]
Several commercially available linkers are currently used to
immobilize amino derivatives. Among them, the trityl-based
linkers or carbamate/carbonate linkers are the most popular.
Scheme 1. Use of the pipecolic linker anchored on the aminomethyl poly-
styrene (PS) resin.
[a] Dr. N. Masurier, Dr. P. Verdiꢀ, Dr. M. Amblard, Prof. J. Martinez,
Prof. G. Subra
Institut des Biomolꢀcules Max Mousseron IBMM
UMR CNRS 5247, 15 avenue Charles Flahault
34000 Montpellier (France)
Fax : (+33)467548654
E-mail: nicolas.masurier@univ-montp1.fr
age mechanism was assumed to involve an oxazolonium in-
termediate. This intermediate can then lead to the target
molecule, in the presence of water, and the free carboxylic
acid function of the pipecolic acid residue is recovered. This
original mechanism of cleavage allows efficient and easy re-
cycling of the Pip-linker.[9]
In this study, our aim was to enlarge the use of the Pip-
linker to pseudopeptide and cyclic-peptide synthesis, as well
as to the preparation of modified amino acids, on solid sup-
port. These different focuses are illustrated by the synthesis
of a vinylogous g-amino acid, urea-derived peptides, and
peptide alcohols. The synthesis of an Na-Lys anchoring
[b] Dr. P. Zajdel, Prof. M. Pawłowski
Department of Medicinal Chemistry
Jagiellonian University Medical College
9 Medyczna Street, 30-688 Krakꢁw (Poland)
[**] Part 2; for Part 1, see: P. Zajdel, G. Nomezine, N. Masurier, M. Am-
blard, M. Pawłowski, J. Martinez, G. Subra, Chem. Eur. J. 2010, 16,
7547–7553.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201452.
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amino acid for the preparation of biotin-derived peptide
and cyclic peptides was also undertaken.
followed by reaction with H-Phe-OMe as nucleophile. The
b-alanine derivative TFA-mediated cleavage released the
ureidodipeptide 12 in 92% yield and 83% purity
(Scheme 3). When the leucine derivative was used, only the
Vinylogous amino acid derivatives are found in certain
natural cyclic peptides.[10] Moreover, incorporation of a vi-
nylogous g-amino acid derivative into a peptide sequence
proved to be efficient to develop protease inhibitors[11] or to
introduce conformational changes into a peptide back-
bone.[12] The use of the Pip-linker for the synthesis of modi-
fied amino acids was demonstrated by synthesizing a phenyl-
alanine vinylogous g-amino acid derivative (Scheme 2). For
Scheme 3. Synthesis of ureidodipeptides. BTIB=(bistrifluoroacetoxy)-
AHCTUNGTREGUNiNN odobenzene.
Scheme 2. Synthesis of vinylogous g-phenylalanine derivative 4. AM-
PS=aminomethyl polystyrene, BOP=benzotriazolyl-1-oxytris(dimethyl-
ACHTUNGTRENNUNG
N-monosubstituted urea derivative 11 was obtained with
99% yield and 91% purity. The structure of compound 11
was ascertained by 1H NMR and ESI-mass spectroscopy
(m/z=223.1). The ureidodipeptide was not stable enough to
be observed, contrary to the behavior of the corresponding
monoacyl gem-diamino derivative.[8] This result can be ex-
plained by the well-known weak stability of pseudo gem-di-
ACHTUNGTRENNUNG
the synthesis of such building blocks, the phenylalanine
Weinreb amide derivative[13] was anchored on the support
and was reduced in THF at 08C. Mixing with ten equivalents
of hydride for 45 min were necessary to complete the reac-
tion. To access the vinylogous derivative, a Wittig reaction
was used, by using carboethoxymethylene triphenylphos-
phorane in DMF at 808C. After cleavage with TFA, com-
pound 4 was obtained in 91% overall yield and 95% purity,
which is better than the results obtained with the p-nitro-
phenylcarbonate derivatized Wang resin.[6b] The 1H NMR
spectrum of compound 4 reveals only the trans configuration
for the double bound (coupling constant of 15.8 Hz).
Pseudopeptides containing urea moieties appeared to be
useful to access various peptidomimetic foldamers.[14] Re-
placement of an amide bond by a urea was also used to de-
velop enzyme inhibitors.[15] Generally, to synthesize urea de-
rivatives, azido, carbamate, or protected isocyanate building
blocks are needed.[16] To prepare such compounds, one or
several steps performed in solution are required and toxic
reactants are currently used. To avoid these disadvantages,
we set up a solid-phase procedure based on the Hofmann
rearrangement of C-terminal aminoamides to yield support-
ed isocyanates that can readily be converted into ureas. To
this end, H-Leu-NH2 or H-b-Ala-NH2 was coupled to the
Pip-linker. Subsequent treatment with BTIB and pyridine in
dry THF afforded the presumed isocyanate intermediate,
AHCTUNGTRENNUNG
amino compounds,[17] which lead to the N-monosubstituted
urea derivative 11 after loss of isobutylamine. In compound
12, the presence of a supplementary methylene increased
the stability of the urea derivative and the ureidodipeptide
could be isolated.
Anchoring of an amino acid through its side chain could
represent a method of choice for the synthesis of N- to C-
cyclic peptides, for the coupling of peptide fragments, or for
generation of C-terminus-modified peptides. Anchoring of
serine, threonine, or tyrosine by the side chains proved to be
efficient with the Pip-linker.[8] We now explored the anchor-
ing of the lysine side chain to access C-terminus-modified
peptides and to synthesize cyclic peptides.
To access C-terminus-modified peptides, the lysine was
anchored to the solid support through its Ne-amino function.
In this respect, the Na-amino function constituted the start-
ing point for the peptide elongation and the carboxylic acid
function allowed C-terminal modification of the peptide
without epimerization. In a first instance, we explored the
introduction of a biotinylated probe onto the C-terminal po-
sition of a bioactive peptide by using the Pip-linker. For this
purpose, Fmoc-Lys-OAll[18] was anchored on the Pip-linker
and a biotin derivative[19] was introduced on compound 13
after deprotection of the allyl ester (Scheme 4). During acti-
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The Pipecolic Linker
COMMUNICATION
Scheme 4. Synthesis of C-terminal-modified endomorphin-1 derivative.
Fmoc=9-fluorenylmethoxycarbonyl (coupling step: BOP, DIEA, Fmoc-
Lys
or Boc-Tyr
TIS=triisopropylsilane.
G
ACHTUNGERTN(NUNG Boc)-OH or Fmoc-Pro-OH
ACHTUNGTRENNUNG
Scheme 5. Synthesis of cyclic peptides, Trt=trityl (triphenylmethyl) (cou-
pling step: BOP, DIEA, Fmoc-dPhe-OH or Fmoc-Phe-OH or Fmoc-Leu-
vation of the C-terminal carboxylic acid function, the lysine
residue is N-urethane protected, avoiding epimerization via
oxazolone formation. After N-Fmoc removal, the lysine Na-
amino group was used for the target peptide elongation.
The endogenous opioid peptide endomorphin-1 (H-Tyr-Pro-
Trp-Phe-NH2) was chosen as the bioactive peptide model.
TFA-mediated cleavage released biotinylated peptide 15 in
70% overall yield and 61% purity.
OH or Fmoc-dTrp
ACHUTGTNRNEUG(N Boc)-OH or Fmoc-LysACHUTNGTRENN(UGN Boc)-OH; deprotection step:
DMF/piperidine 80:20 v/v).
cyclized by BOP/DIEA activation. After TFA/TIS/H2O
cleavage, the crude cyclic peptide 20 was obtained and puri-
fied by preparative HPLC. Peptide fragments lead to a cer-
tain extent of epimerization upon activation. Special atten-
tion was paid to evaluate this side reaction on the lysine res-
idue. To this purpose, the diastereoisomer of compound 20,
cyclo(Lys-d-Trp-Leu-d-Phe-Phe-Lys) (20’), was synthesized.
Epimerization was estimated to 2% by HPLC (see the Sup-
porting Information).
Last but not least, we envisaged application of the Pip-
linker for the synthesis of C-terminal peptide alcohols. Pep-
tide alcohols constitute an important class of compounds
and present a range of biological properties.[22] Recently, an
efficient synthesis of peptide alcohols was reported, with a
trityl chloride resin and a O–N acyl transfer reaction as the
key step.[23] Based on this study, we propose a strategy in
which the aminoalcohol is prepared directly on solid support
from a supported aminoester. We applied this method to
prepare the antibiotic trichogin GA IV (24, Scheme 6) on
the Pip-linker. In a first step H-Leu-OMe was anchored, by
BOP/DIEA coupling. The effectiveness of the coupling re-
action was verified by using a malachite green colorimetric
test. Reduction of the ester function by lithium borohydride
led to the aminoalcohol derivative 22. The free hydroxyl
function was then acylated with Fmoc-Ile-OH in the pres-
ence of DIC/DMAP. As already mentioned, no epimeriza-
tion was detected in the DIC/DMAP acylation.[23] Standard
SPPS afforded the corresponding isopeptide as a TFA salt,
Immobilization of a lysine side chain could also constitute
a simple way to access N- to C-cyclic peptides. As an exam-
ple, the cyclic hexapeptide cyclo(Lys-d-Trp-Leu-d-Phe-Phe-
d-Lys) (20), displaying high activity against multiresistant
Staphylococcus aureus (MRSA) strains,[20] was synthesized
by using the Pip-linker. In a first step, Fmoc-Lys-OAll[18] was
anchored to the Pip resin, by BOP/DIEA activation
(Scheme 5). The resin loading was evaluated based on Fmoc
released, monitored by UV absorption at 290 nm
(0.34 mmolgÀ1, quantitative yield). To prevent diketopipera-
zine formation, Trt-Phe-OH was introduced as the second
residue to give 17. A first attempt to remove the trityl group
was performed with the CH2Cl2/TFA/H2O cocktail
(98.8:0.2:1 v/v/v), as reported by Alsina et al.[21] However,
trityl-group removal was not complete and a 97:2:1 (v/v/v)
CH2Cl2/TFA/H2O solution was required to achieve complete
trityl removal. With these conditions, no premature peptide
cleavage was observed from the Pip-linker; this would have
happened on trityl-based linker. At this step, a cleavage of a
resin aliquot confirmed the absence of diketopiperazine for-
mation. The peptide sequence was then elongated by using
a standard SPPS strategy to yield the supported linear pep-
tide 18. After removal of the Fmoc group and the allyl
group by using PdACHTUNGTRENNUNG(PPh3)4 and phenylsilane, the peptide was
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N. Masurier et al.
and filtration, the resin was washed with DMF (3x), MeOH (2x), and
CH2Cl2 (3x). After TFA-cleavage for 2 h under gentle stirring, the resin
was filtered off and the TFA solution was concentrated to dryness to
offer 24 mg of compound 4 (yield 91%, purity 95%). NMR data are in
agreement with the literature.[24] Rt =0.95 min; MS (ESI+): m/z: 220.3
[M+H]+.
Synthesis of ureidopeptides 11 and 12: After the Pip-PS resin (1, 100 mg,
0.045 mmol, 0.45 mmolgÀ1) had been left to swell in DMF for 15 min, it
was added to DMF (6 mL) containing BOP (60 mg, 0.14 mmol, 3 equiv),
DIEA (52 mg, 70 mL, 0.40 mmol, 9 equiv) and H-Leu-NH2 (18 mg,
0.14 mmol, 3 equiv) or H-b-AlaNH2 (12 mg, 0.14 mmol, 3 equiv). The
resin was gently stirred for 2 h and then washed with DMF (3x), MeOH
(2x), CH2Cl2 (3x), and dried. The resin was then treated with a dry THF
solution (5 mL) containing pyridine (40 mL, 39 mg, 0.49 mmol, 11 equiv)
and BTIB (58 mg, 0.13 mmol, 3 equiv) and stirred for 1 h. Then the resin
was filtered off and a mixture of H-Phe-OMe·HCl (29 mg, 0.13 mmol,
3 equiv), DIEA (17 mg, 24 mL, 0.13 mmol, 3 equiv) in dry THF (3 mL)
was added. The resin was gently stirred for overnight and subsequently
washed with DMF (3x), MeOH (2x), CH2Cl2 (3x). After TFA-cleavage
for 2 h under gentle stirring, the resin was filtered off and the TFA solu-
tion was concentrated to dryness to offer compound 11 (6 mg, yield 99%,
purity 91%) or compound 12 (15 mg, yield 92%, purity 83%). For NMR
analysis, crude compounds 11 and 12 were purified by preparative HPLC
to offer pure compounds as TFA salts.
Scheme 6. Synthesis of trichogin IV using Pip support. DIC=diisopropyl-
carbodiimide, DMAP=4-(dimethylamino)pyridine.
Compound 11: 1H NMR (300 MHz, [D6]DMSO): d=2.95 (m, 2H), 3.61
(s, 3H), 4.39 (d, J=7.1 Hz, 1H), 6.30 (d, J=7.1 Hz, 1H), 7.17–7.33 ppm
(m, 5H); 13C NMR (75 MHz, [D6]DMSO): d=37.6, 51.6, 53.8, 126.5,
128.2, 129.1, 137.1, 157.9, 173.0 ppm; Rt =1.09 min; MS (ESI+): m/z:
223.1 [M+H]+.
Compound 12: 1H NMR (300 MHz, [D6]DMSO): d=2.79 (m, 2H), 2.94
(m, 2H), 3.17 (m, 2H), 3.59 (s, 3H), 4.39 (dd, J=7.1, 8.1 Hz, 1H), 6.37
(brs, 1H), 6.58 (d, J=8.1 Hz, 1H), 7.17–7.32 (m, 5H), 7.72 ppm (brs,
2H); 13C NMR (75 MHz, [D6]DMSO): d=37.4, 37.5, 51.7, 54.3, 126.6,
128.2, 129.1, 137.0, 157.9, 172.9 ppm; Rt =0.82 min; MS (ESI+): m/z:
266.1 [M+H]+.
after TFA/TIS/H2O cleavage. Peptide alcohol 24 was then
obtained through an intramolecular O–N acyl transfer, after
alkaline treatment (DMF/piperidine 80:20 v/v). The tricho-
gin GA IV was isolated in 47% overall yield and 78%
purity.
In conclusion, we have demonstrated that the Pip-linker
could be regarded as a versatile handle for the synthesis of
modified amino acids (a vinylogous g-amino acid and an N-
monosubstituted urea derivative), pseudopeptides (an urei-
dodipeptide and two functionalized C-terminal peptides).
The Pip-linker was also efficient to access cyclic peptides,
through side-chain anchoring of a lysine residue. Introduc-
tion of the first residue was easily accomplished by simple
BOP/DIEA activation and the Pip-linker revealed to be
robust enough to support various chemical modifications. Fi-
nally, the Pip-linker proved its usefulness for the synthesis
of peptide alcohols through the O–N acyl transfer reaction.
Lysine side-chain anchoring on Pip-PS resin: After the Pip-PS resin (1,
200 mg, 0.09 mmol, 0.45 mmolgÀ1) had been left to swell in DMF for
15 min, it was added to DMF (6 mL) containing BOP (120 mg,
0.27 mmol, 3 equiv), DIEA (105 mg, 141 mL, 0.81 mmol, 9 equiv), and
Fmoc-Lys-OAll[18] (110 mg, 0.27 mmol, 3 equiv). The resin was gently stir-
red for 2 h and then washed with DMF (3x), MeOH (2x), CH2Cl2 (3x)
and dried.
All other synthetic procedures, as well as characterization of the products
(LC/MS, NMR spectroscopy analysis) are available in the Supporting In-
formation.
Experimental Section
Acknowledgements
Synthesis of g-vinylogous phenylalanine (4): The Weinreb amide of N-
Boc phenylalanine was prepared in solution, as previously described.[13]
This compound (72 mg, 0.23 mmol) was stirred at room temperature in a
mixture of TFA/CH2Cl2 (2.5 mL, 4:1 v/v) for 1 h and then evaporated
under reduced pressure, to offer the deprotected Weinreb amide of phe-
nylalanine as a TFA salt. The Pip-AM-PS resin (1, 200 mg, 0.08 mmol,
0.40 mmolgÀ1) was left in DMF for 15 min to swell. DMF (6 mL) con-
taining BOP (106 mg, 0.24 mmol, 3 equiv), DIEA (93 mg, 125 mL,
0.72 mmol, 9 equiv) was added, along with the deprotected Weinreb
amide of phenylalanine previously synthesized (0.23 mmol, 3 equiv). The
resin was gently stirred for 3 h and then washed with DMF (3x), MeOH
(2x), CH2Cl2 (3x), to give resin 2. The Weinreb amide was reduced in dry
THF at 08C with 30 mg of AlLiH4 (0.79 mmol, 10 equiv) for 1 h. The re-
action mixture was then hydrolyzed with a KHSO4 solution (1m). After
filtration, the resin was washed successively with a saturated NaHCO3
solution, water, MeOH, and CH2Cl2. A solution of carboethoxymethy-
lene triphenylphosphine in dry DMF (5 mL) was then added. The sus-
pension was stirred at 808C for 3 h. After cooling to room temperature
The authors thank the IBMM for support.
Keywords: C-terminal peptide alcohols · cyclic peptides ·
pipecolic linker · solid-phase synthesis · ureidopeptides
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The Pipecolic Linker
COMMUNICATION
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Received: April 27, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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N. Masurier et al.
The versatility of the pipecolic linker
(Pip-linker) is illustrated by the syn-
thesis of modified amino acids, C-ter-
minal-modified pseudopeptides, and
cyclic peptides, through side-chain
anchoring of a lysine residue (see
figure). Introduction of the first resi-
due was easily accomplished and the
Pip-linker revealed to be robust
enough to support various chemical
modifications.
Solid-Phase Synthesis
N. Masurier,* P. Zajdel, P. Verdiꢀ,
M. Pawłowski, M. Amblard,
J. Martinez, G. Subra ........ &&&& — &&&&
A New Highly Versatile Handle for
Chemistry on a Solid Support: The
Pipecolic Linker
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www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!