New pyrrole-based amino acids for the synthesis of peptidomimetic constrained scaffolds

Article abstract of DOI:10.1016/j.tetlet.2005.07.155

A new family of pyrrole-based amino acids have been prepared through the microwave assisted Paal-Knorr reaction of 1-4 ketoesters derived from the corresponding β-ketoester with a functional homologation. The carboxylic group is located in position 3 of the pyrrole, whereas the amino group, protected with the Cbz moiety, is present on the side chain in positions 1 or 2. These compounds were used to prepare constrained oligopeptides.

Full text of DOI:10.1016/j.tetlet.2005.07.155

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7069–7072
New pyrrole-based amino acids for the synthesis
of peptidomimetic constrained scaffolds
Maddalena Alongi, Giacomo Minetto and Maurizio Taddei*
`
Dipartimento Farmaco Chimico Tecnologico, Universita degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
Received 27 June 2005; revised 26 July 2005; accepted 29 July 2005
Available online 26 August 2005
Abstract—A new family of pyrrole-based amino acids have been prepared through the microwave assisted Paal–Knorr reaction of
1–4 ketoesters derived from the corresponding b-ketoester with a functional homologation. The carboxylic groupis located in posi-
tion 3 of the pyrrole, whereas the amino group, protected with the Cbz moiety, is present on the side chain in positions 1 or 2. These
compounds were used to prepare constrained oligopeptides.
Ó 2005 Elsevier Ltd. All rights reserved.
The development and the synthesis of new amino acids
and peptidomimetics have attracted considerable inter-
est with the aim of finding new bioactive molecules
based on natural peptide structures.1 A widespread ap-
proach for designing of peptidomimetics is the introduc-
tion of conformationally constrained scaffolds, which
may helpto introduce turns in a short peptide, often a
requisite to bioactive structures.2 In connection with
our interest in the synthesis of rare and unnatural amino
acids and their application as peptidomimetic structural
templates,3 we considered a pyrrole-based amino acid as
a suitable building block for the preparation of drug like
scaffolds for combinatorial chemistry. Amino acids con-
taining five member heterocyclic rings are present in sev-
eral naturally occurring peptides isolated from marine
organisms4 and analogues compounds have been de-
scribed as peptidomimetics,5 macromolecular scaffolds6
or building blocks for high throughput synthesis.7
O
COOMe
R2
COOMe
R2
O
O
R1
R1
R1
OMe
O
N
NH2
R3
R3
Scheme 1.
As the carboxylic groupwas already installed in the het-
erocycle in position 3 during the synthesis, the possibil-
ity of having an amino groupon R 1, R2 or R3 was
explored. In order to introduce a NHCbz moiety in
the R1 substituent, N–Cbz–b-ketoester 2 was prepared
from N–CbzPheOMe (1) through a Claisen cross con-
densation with EtOAc.9 The product was submitted to
functional homologation with Et2Zn/CH2I2 followed
by addition of benzaldehyde, but exclusively the product
of simple homologation (3) was obtained, probably for
the presence of the acid proton on the NHCbz group
(Scheme 2).10 We tried to use the N,N-dibenzyl deriva-
tive 4, but its reaction with Et2Zn/CH2I2 and PhCHO
gave compound 5 in low yield. Moreover oxidation with
PCC gave degradation of the product and other oxi-
dants did not induce any transformation in the starting
material.
We report here the synthesis of new short peptides con-
taining highly functionalised pyrroles designed to be
incorporated into longer strands through their NH2
and COOH groups. Recently, we described a convenient
preparation of pyrroles based on a microwave assisted
Paal–Knorr reaction8 and we started to explore this
reaction for the preparation of pyrrole amino acids
(Scheme 1).
Disappointed by the result on position 5, the introduc-
tion of an amino groupin the substituent R was at-
2
tempted. As observed before, starting from ketoester
6, the use of an NHCbz amino aldehyde as the electro-
phile gave exclusively the homologated compound 6a
(Scheme 3). As the undesired reactivity was attributed
Keywords: Paal–Knorr reaction; Cyclocondensation; Microwaves;
Peptides.
*
Corresponding author. Tel.: +39 0577 234280; fax: +39 0577
234333; e-mail: taddei.m@unisi.it
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.155

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M. Alongi et al. / Tetrahedron Letters 46 (2005) 7069–7072
O
O
O
O
a
OEt
b
Ph
Ph
OMe
Ph
Ph
OEt
NHCbz
NHCbz
O
1
NHCbz
2
3
O
COOEt
Ph
O
O
c
Ph
OEt
NBn2
OH
NBn2
4
5
Scheme 2. Reagents and conditions: (a) EtOAc, LDA, À78 °C; (b) Et2Zn, CH2I2, DCM; (c) Et2Zn, CH2I2, DCM, PhCHO.
Scheme 3. Reagents and conditions: (a) Et2Zn, CH2I2, DCM, N–Cbz–Phe–CHO/Et2Zn; (b) PCC, DCM, SiO2; (c) Et2Zn, CH2I2, DCM,
R2–CH(NHCbz)CH2CHO, Et2Zn followed by PCC, DCM, SiO2; (d) R3–NH2, AcOH, MW, 130 °C, 5–12 m, 200 psi.
to the presence of an acidic NH, we tried to remove it
from the aldehyde by treatment with Et2Zn. Thus, when
the a-amino aldehyde was mixed with 1.2 equiv of dieth-
ylzinc and this mixture was added to the flask containing
the intermediate generated from 6–7, diethyl zinc and
CH2I2, products 8–9 were obtained in acceptable yields.
Oxidation with PCC gave ketones 10–11 that were iso-
lated pure after a passage on a short pad of silica gel.
Unfortunately, these compounds did not give the ex-
pected pyrroles following the classical Paal–Knorr reac-
tion conditions (MW, AcOH, 150 °C, 5 min). Attempts
to increase the temperature and the time of irradiation,
as changes in the nature of solvent, did not afford the
ring closing. In order to find a structure suitable for cyc-
lisation, compounds 12–15 were prepared using different
b-NHCbz-substituted aldehydes as the electrophile in
the functional homologation. Even in this case, the alde-
hyde must be treated with Et2Zn to remove the acid NH
proton.
When products 12–15, with a CH2 between the NHCbz
and the centre interested in the cyclisation, were submit-
ted to MW assisted Paal–Knorr reaction in the presence
of primary amines, pyrroles 16–20 were obtained in
good yields (Scheme 3).11
The introduction of the amine in the substituent in posi-
tion 1 was finally attempted using the Cbz protected
diamines 24–27 prepared from natural amino acids as
reported in Scheme 4.
Whereas compound 24 (formally derived from Gly) is
commercially available, the amino acids Phe, Ala and
Leu were reduced with LiAlH4 in THF and the crude

M. Alongi et al. / Tetrahedron Letters 46 (2005) 7069–7072
7071
very good yields. Cyclisation of 24–27 with diketones
28–31 was carried out under microwave irradiation pro-
viding compounds 32–37 in good yields (Scheme 5). The
transformation of the so obtained pyrrole-containing
amino acids into a peptidic backbone was carried out
starting from compounds 17 and 35. Thus, hydrolysis
of the methyl ester of 17 was carried out with LiOH in
THF/H2O and the acid coupled with H–Ala–OMe
(DMTMM,13 THF, NMM, 80%) to give 38. The Cbz
was removed by MW assisted transfer hydrogenolysis14
and the amine coupled with Boc–Phe–OH to give 39 in
88% overall yield.15 From 35, removing of the Cbz fol-
lowed by coupling with BocPheOH and ester hydrolysis
provided the acid 40 (72% yield from 35) that could be
coupled with other amino acids or peptides in solution
or solid phase synthesis (See Scheme 6).
NHCbz
NH2
NHCbz
N3
NH2
a
b
R3
R3
R3 COOH
24-27
21-23
R3 = H: 24
R3 = PhCH2-: 21 (72%); 25 (80%)
R3 = CH3-:
R3 = Me2CHCH2-: 23 (67%); 27 (78%)
22 (73%); 26 (81%)
Scheme 4. Preparation of monoprotected diamines derived from Phe,
Ala and Leu.
amino alcohols protected with CbzCl in THF/Na2CO3.
The OH was treated with MsCl/Et3N in the presence of
NaN3 to give the azides 21–23 in good yields.12 Reduc-
tion with PPh3/HCl/H2O in THF gave amines 25–27 in
Scheme 5. Reagents and conditions: (a) (i) LiAlH4, THF, reflux, 12 h, (ii) CbzCl, THF, Na2CO3, (iii) MsCl, NaN3, TBAI, toluene, 80 °C, 6 h; (b)
PPh3, THF, followed by HCl 1 M; (c) (i) Et2Zn, CH2I2, DCM, R2CHO, rt, 2 h, (ii) PCC, DCM, rt, 12 h; (d) 24–27, AcOH, MW, 130 °C, 5–12 m,
200 psi.
COOMe
O
COOMe
c, d
a, b
NH
O
COOMe
O
NHCbz
N
NH
NHCbz
N
NHBoc
17
N
N
H
38
Ph
39
COOMe
NHCbz
COOH
c, d, a
N
N
Ph
NHBoc
35
40
HN
O
Scheme 6. Reagents and conditions: (a) LiOH, THF/H2O, rt 24 h; (b) HAlaOH, DMTMM, NMM, THF, rt 12 h; (c) HCOONH4, i-PrOH, MW,
120 °C, 6 min; (d) BocPheOH, DMTMM, NMM, THF, rt 12 h.

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M. Alongi et al. / Tetrahedron Letters 46 (2005) 7069–7072
dissolved into dry dichloromethane (60 mL) under nitro-
gen and the mixture cooled to 0 °C. Diiodo methane
(2,4 mL, 30 mmol) was slowly added and the mixture
stirred for 10 min. After the formation of a white
precipitate, 4,4-dimethyl 3-oxopentanoate (1.3 mL,
7.3 mmol) was added and the reaction was stirred for
Scaffolds 39 and 40 show a high level of diversity with
variations in positions 1, 2 and 5 around the pyrrole
related to the original synthetic scheme. One additional
level of diversification at positions 1, 2 and 3 is possible
using traditional combinatorial peptide chemistry.
Moreover, this system can be used to achieve rigidity
inside a peptide strand or to mimic a potentially active
turn.
30 min.
A solution of 3-Cbz-aminopropanal (1.51 g,
7.3 mmol) in DCM (8 mL) containing diethyl zinc (8 ml
of a 1.0 M solution in hexane, 8 mmol) was slowly added
and the mixture stirred at 0 °C for 1 h. Silica gel (20.0 g)
was added and the mixture stirred at room temperature
for additional 30 min. The mixture was filtered under
vacuum and the solvent evaporated. The crude (2.16 g)
was dissolved in dry dichloromethane, PCC (3.3 g,
15.3 mmol) was added and the mixture stirred at room
temperature until TLC analysis (eluent hexane/AcOEt 1:1)
showed disappearance of the starting material. Eventually,
additional PCC could be added. The mixture was passed
through a short path of silica gel and eluted with
dichloromethane. The solvent was collected and evapo-
rated under vacuum to give product 12 (1.65 g, 66% yield).
An analytical sample was purified by column chromato-
In summary, we have explored the possibility to use the
Paal–Knorr reaction to prepare pyrrole-based amino
acids and developed a convenient route to new highly
functionalised scaffolds for parallel synthesis. The syn-
thesis of new cyclic peptides incorporating these pyr-
role-based building blocks and the structural studies
are currently under investigation.
Acknowledgment
1
graphy on silica gel (eluent hexane/AcOEt 1:1). H NMR
This work was financially supported by Nikem-
Research srl (Milan).
(200 MHz, CDCl3) d 1.11 (s, 9H, t-Bu), 3.00–3.10 (m, 4H,
2CH2CO), 3.36 (t-like, 2H, COCH2), 3.55 (s, 3H,
COOMe), 3.99 (m, 2H, CH2N), 4.34 (m, 1H, CH), 5.10
(s, 2H, Cbz), 6.00 (s, 1H, NH), 7.28 (m, 5H, Ar). 13C
NMR (75 MHz, CDCl3) d 10.8, 32.4, 33.5, 38.5, 44.9, 49.0,
51.0, 56.8, 126.5, 128.0, 129.3, 138.5, 165.8, 171.2, 202.5,
211.7. MS (ES/MS), 378 (M++1). Product 12 (1 g,
2,63 mmol) was dissolved into acetic acid (3 mL) into a
50 mL round-bottom flask equipped with a stir bar and a
reflux condenser. Benzyl amine (1.84 g, 17.2 mmol) was
added and the flask inserted into the cavity of a Discover
Microwave System apparatus (from CEM) and heated at
150 W for 12 min (internal temperature 170 °C). The
mixture was diluted with AcOEt and the solvent washed
several times with a saturated solution of NaHCO3. The
organic layer was dried over anhydrous Na2SO4 and the
References and notes
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1
solvent evaporated. The H NMR spectrum of the crude
showed the presence of compound 16 together with
benzylamine acetate. The required pyrrole was purified
by flash chromatography (eluent hexane/AcOEt 8:1,
Rf = 0.37) that gave product 16 as a solid, mp90–91 °C.
(0.79 g, 67% yield). 1H NMR (200 MHz, CDCl3) d 1.10 (s,
9H, t-Bu), 3.13 (t, J = 7 Hz, 2H, CH2-pyrrole), 3.60 (s, 3H,
COOMe), 4.30 (t, J = 8 Hz, 2H, CH2NHCbz) 4.86 (s, 2H,
CH2–N), 5.16 (s, 2H, OCH2Ph), 6.11 (br s, 1H, NH), 6.32
(d, 1H, H-4), 7.30 (m, 10H, Ar). 13C NMR (75 MHz,
CDCl3) d 11.2, 15.3, 29.5, 31.2, 31.9, 33.4, 40.7, 44.6, 52.7,
70.9, 103.4, 111.8, 126.3, 127.4, 127.6, 128.6, 128.7, 131.6,
133.6, 134.6, 137.4, 138.7, 155.7, 165.4. ES/MS 449
(M++1). Anal. Calcd for C27H32N2O4: C, 72.30; H,
7.19; N, 6.25. Found C, 72.20; H, 7.12; N, 6.29.
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15. 1H NMR (300 MHz) spectra of 39 and 40 showed the
presence of
a single diastereoisomer, proving that
11. (Benzyloxycarbonylaminoethyl)-1-benzyl-5-tert-butyl-3-carb-
oxymethyl-pyrrole 16 General procedure. Diethyl zinc
(30 mL of a 1.0 M solution in hexane, 30 mmol) was
no racemisation (at least < 5%) occurred during the
synthesis.