Prevalence of Eight-membered hydrogen-bonded rings in some bis(cyclobutane) β-dipeptides including residues with trans stereochemistry

Article abstract of DOI:10.1021/ol900636w

Three new bis(cyclobutane) β-dipeptides have been synthesized from appropriate derivatives of cis- and trans-2-aminocyclobutane-1-carboxylic acid, respectively. The predominance of eight-membered hydrogen-bonded rings has been manifested for (trans,trans)- and (trans,cis)-β- dipeptides while the formation of six-membered rings is preferred for the (cis,trans)- β-dipeptide similarly to the previously described (cis,cis)-diastereomer.

Full text of DOI:10.1021/ol900636w

ORGANIC
LETTERS
2
009
Vol. 11, No. 11
301-2304
Prevalence of Eight-Membered
2
Hydrogen-Bonded Rings in Some
Bis(cyclobutane) ꢀ-Dipeptides Including
Residues with Trans Stereochemistry
†
‡
‡
‡
Elisabeth Torres, Esther Gorrea, Eric Da Silva, Pau Nolis,
§
‡
Vicen c¸ Branchadell, and Rosa M. Ortu n˜ o*
,‡
Departament de Qu ´ı mica and SerVei de Resson a` ncia Magn e` tica Nuclear, UniVersitat
Aut o` noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
rosa.ortuno@uab.es
Received March 26, 2009
ABSTRACT
Three new bis(cyclobutane) ꢀ-dipeptides have been synthesized from appropriate derivatives of cis- and trans-2-aminocyclobutane-1-carboxylic
acid, respectively. The predominance of eight-membered hydrogen-bonded rings has been manifested for (trans,trans)- and (trans,cis)-ꢀ-
dipeptides while the formation of six-membered rings is preferred for the (cis,trans)- ꢀ-dipeptide similarly to the previously described
(cis,cis)-diastereomer.
ꢀ
-Peptides offer unique possibilities to fold, prompted by
the investigation of hydrogen-bonding in small peptides is
crucial to understand complex conformations in larger
oligomers.
Carbocycle and heterocycle ꢀ -disubstituted ꢀ-peptides
are particularly prone to adopt well-defined conformations
the formation of intramolecular hydrogen bonds leading to
helices, strands, or sheets as the most usual conformations.
These defined secondary structures are often responsible for
the biological activities found in oligomers containing
ꢀ
coexist with substructures resulting from interresidual hy-
drogen-bonds between NH(i) and CO(i + 1), (i) and (i + 1)
being two consecutive residues in the peptide backbone. This
1
2
2,3
1
-amino acid residues. Sometimes, secondary structures
in solution. However, besides several examples on 12- and
1,3
1
4-helical-foldings, there are only a few instances on eight-
4-7
helices.
An eight-membered ring with hydrogen-bonding
between next neighbors has been described as the charac-
teristic secondary structural motif in ꢀ-oligopeptides consist-
ing of 1-(aminomethyl)-cyclopropanecarboxylic acid. These
hydrogen-bonded rings arrange in a ribbon-type secondary
1
confers high rigidity on these oligomers. For this reason,
†
Dedicated to Professor Josep Font on the occasion of his 70th birthday.
Departament de Qu ´ı mica.
Servei de Resson a` ncia Magn e` tica Nuclear.
‡
§
5
(
1) For recent reviews, see: (a) Seebach, D.; Beck, A. K.; Bierbaum,
structure in solution. Moreover, the formation of consecutive
D. J. Chemistry & BiodiVersity 2004, 1, 1111. (b) Gelman, M. A.; Gellman,
S. H. In EnantioselectiVe Synthesis of ꢀ-Amino Acids, 2nd ed.; Juaristi, E.,
Soloshonok, V. A., Eds.; John Wiley and Sons: New York, 2005; pp
eight-membered hydrogen-bonded ring helices (8-helix) has
5
3
2
27-585. (c) F u¨ l o¨ p, F.; Martinek, T. A.; T o´ th, G. K. Chem. Soc. ReV. 2006,
5, 323. (d) Seebach, D.; Hook, D. F.; Glattli, A. Biopolymers 2006, 84,
3. (e) Le Grel, P.; Guichard, P. In Foldamers: Structure, Properties, and
(2) See, for instance: Claridge, T. D. W.; Goodman, J. M.; Moreno, A.;
Angus, D.; Barker, S. F.; Taillefumier, C.; Watterson, M. P.; Fleet, G. W.
Tetrahedron Lett. 2001, 42, 4251.
Applications; Hecht, S., Huc, I., Eds.; Wiley-VCH: New York, 2007; pp
5-74. (f) Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008, 41, 1366. (g)
Horne, W. S.; Gellman, S. H. Acc. Chem. Res. 2008, 41, 1399.
3
(3) Izquierdo, S.; Kogan, M. J.; Parella, T.; Moglioni, A.; Branchadell,
V.; Giralt, E.; Ortu n˜ o, R. M. J. Org. Chem. 2004, 69, 5093
.
1
0.1021/ol900636w CCC: $40.75  2009 American Chemical Society
Published on Web 05/06/2009

Scheme 1
.
Synthesis of ꢀ-Dipeptides 4, 7, and 8. Structure of Peptide 9
6
been described for oxanorbornene ꢀ-peptides, and for
Compounds 4, 7, and 8 were synthesized as described in
Scheme 1. Trans-derivative 1 was prepared by epimerization
of the cis-isomer as previously described in the literature.
7
peptides derived from nucleoside ꢀ-amino acids. In the last
2,3
10
two cases, a conformationally constrained ring and ꢀ -trans-
stereochemistry is a common structural feature which ac-
counts for the propensity to fold into a 8-helix.
Monoprotected cis-intermediates 3 and 6 had been already
8
,11
prepared in our laboratory.
Removal of the N-Boc
We have recently described the formation of intraresidue
hydrogen bonds affording cis-fused [4.2.0]octane structural
units in ꢀ-dipeptides made up by monomers derived from
cis-2-aminocyclobutane-1-carboxylic acid. One example of
these ꢀ-dipeptides is compound (cis,cis)-9 in Scheme 1. This
protection in 1 under treatment with TFA and triethylsilane
afforded amine 5 in 89% yield. Amine 5 was coupled with
acid 6 in the presence of N-(3-dimethylaminopropyl)-N′-
ethylcarbodiimide (EDAC) as a dehydrating agent and
hydroxybenzotriazole (HOBt) as a catalyst providing 7 in
8
substructure is retained in a related tetramer, which adopts
4
4% yield. Similarly, acid 2 was reacted with amine 5 to
9
a strand-mimicking secondary structure in solution.
give 8 in 42% yield. Alternatively, saponification of the
methyl ester in 1 with diluted NaOH provided acid 2 in 95%
yield. Subsequent coupling of acid 2 with amine 3 in the
presence of pentafluorophenyl diphenylphosphinate (FDPP)
afforded 4 in 90% yield showing the efficiency of FDPP in
peptide coupling reactions.
In this Letter we report on our preliminary results on the
synthesis and structural study of a new family of cyclobutane
ꢀ
-dipeptides. They consist of two monomers of trans
stereochemistry, (trans,trans)-8, or one cis- and one trans-
monomer, (cis,trans)-7 and (trans,cis)-4 (Scheme 1). The
secondary structures of these compounds in solution have
8
The three new ꢀ-dipeptides 4, 7, and 8 were fully
characterized and their secondary structures in solution were
investigated by using experimental techniques and molecular
modeling (see the Supporting Information). The most
relevant features are listed in Table 1 where one can observe
that the same trends are followed by 4 and 8. Thus, a
complete set of standard 1D and 2D NMR experiments was
been investigated and compared with (cis,cis)-9. The
combined results from NMR experiments and theoretical
calculations show the predominance of an 8- over a
6-membered hydrogen-bonded structure for diastereomers 4
and 8.
(
4) (a) Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. 1994, 116, 1054.
(
b) Winkler, J. D.; Piatnitski, E. L.; Mehlmann, J.; Kasparec, J.; Axelsen,
1
done for each ꢀ-dipeptide. The high-resolution H NMR
P. H. Angew. Chem. Int. Ed 2001, 40, 743. (c) Gademann, K.; H a¨ ne, A.;
Rueping, M.; Jaun, B.; Seebach, D. Angew. Chem., Int. Ed. 2003, 42, 1534.
3
spectra in CDCl for 4 and 8 exhibit a high deshielded
chemical shift (8.28-8.47 ppm) for the NH10 proton (com-
pare with the 5.90 ppm value found for 7). That suggests
(
d) Li, X.; Yang, D. Chem. Commun. 2006, 3367, and references therein.
(
(
5) Abele, S.; Seiler, P.; Seebach, D. HelV. Chim. Acta 1999, 82, 1559.
6) Doerksen, R. J.; Chen, B.; Yuan, J.; Winkler, J. D.; Klein, M. L.
Chem. Commun. 2003, 2534.
7) Threlfall, R.; Davies, A.; Howartz, N. M.; Fisher, J.; Cosstick, R.
Chem. Commun. 2008, 585.
8) Izquierdo, S.; R u´ a, F.; Sbai, A.; Parella, T.; Alvarez-Larena, A.;
Branchadell, V.; Ortu n˜ o, R. M J. Org. Chem. 2005, 70, 7963.
9) R u´ a, F.; Boussert, S.; Parella, T.; D ´ı ez-P e´ rez, I.; Branchadell, V.;
Giralt, E.; Ortu n˜ o, R. M. Org. Lett. 2007, 9, 3643.
(
(10) Fernandes, C.; Gauzy, C.; Yang, Y.; Roy, O.; Pereira, E.; Faure,
´
´
(
S.; Aitken, D. J. Synthesis, 2007, 2222.
´
´
(11) Mart ´ı n-Vil a` , M.; Muray, E.; Aguado, G. P.; Alvarez-Larena, A.;
(
Branchadell, V.; Minguill o´ n, C.; Giralt, E.; Ortu n˜ o, R. M. Tetrahedron:
Asymmetry 2000, 11, 3569
.
2302
Org. Lett., Vol. 11, No. 11, 2009

Table 1. Significant Experimental NMR and Calculated Parameters for ꢀ-Dipeptides 4, 7-9
b
qualitative interresidue NOEs calcd distance
a
a
δ
δ
exptl δ
calcd δ
b
dipeptide
NH10 NH
4
NH10-δ NH
4
NH10-δ NH
4
H10-H
5
/
H10-H
8
H10-H
5
H10-H
8
calcd hydrogen-bond length
(
(
(
(
trans,cis)-4
8.28 4.88
3.40
3.55
0.65
3.81
3.84
0.69
--
strong
strong
weakc
weak
/
/
/
/
weak
2.53
2.47
4.51c
4.51
2.96
3.02
2.23c
2.23
CO
CO
CO
CO
3
3
9
9
-
-
-
-
NH10
NH10
1.93
1.93
2.24
2.22
trans,trans)-8 8.47 4.92
weak
cis,trans)-7
cis,cis)-9
a
5.90 5.25
strongc
NH
NH
4
c
c
c
c
6.41 5.44
0.97
strong
4
b
c
In ppm, from CDCl
3
solutions. In angstroms. Reference 8.
that the NH10 proton is implied in a strong hydrogen-bond
in those ꢀ-dipeptides.
Some additional NMR experiments were performed to rule
out the possibility of N-H hydrogen-bonds to solvent and
to exclude the existence of intermolecular aggregates Thus,
the chemical shift of NH10 was not concentration dependent
Theoretical calculations at the B3LYP/6-31G (d) level of
theory nicely support these experimental data. Figure 2 shows
the calculated structures for the most stable conformers of 7
and 8.
For these structures, the calculated difference between the
4
H NMR shifts of NH and NH10 compares fairly with the
1
experimental data as observed in Table 1. Moreover, the
electronic CD spectra calculated for these compounds (gas
phase) predict bands that are in qualitative agreement with
the experimental spectra in methanol (see the Supporting
Information).
Table 1 shows the interatomic distances between NH10
5 8
proton and H /H calculated for the most stable conformers
of the four ꢀ-dipeptides considered, which are in very good
accordance with the observed NOE contacts (Figure 2).
in a range of 60-5 mM in CDCl
methanol-d was added to both concentrate and dilute
respective solutions of 4 and 8, in the concentrate sample,
the NH signal rapidly disappeared while the NH10 signal
remained. Analogous behaviors were found in the dilute
sample. These results pointed out the involvement of NH10
in an intramolecular hydrogen bonding. 1D selective NOE-
SY(EXSY) experiments also led to the same conclusion (see
Figures S21-S24 in the Supporting Information for details).
3
. Moreover, when
4
4
Furthermore, the calculated CO -NH10 distance for 4 and
3
IR spectroscopy reinforces these findings. Two bands of
-
1
9 4
8 (1.9 Å) is shorter than the calculated CO -NH distance
comparable intensity at about 3447 and 3280 cm corre-
sponding to free and associated N-H stretching, respectively,
were observed in the spectra of 4 and 8 in dilute chloroform
5
solutions (ca. 5 mM).
Analogously, the same reasoning applies to explain the
NH
4
chemical-shift behavior. Thus, a more deshielded
8
position is found for the NH
4
proton of 7 and 9 (5.25-5.44
ppm) with respect to the same proton in 4 and 8 (4.88-4.92
ppm). That indicates that the formation of the hydrogen bond
through NH is only present in ꢀ-dipeptides with 5,8-cis
4
stereochemistry.
Moreover, by means of 1D selective TOCSY experiments,
the isolated selection of NH10 and NH protons and posterior
4
magnetization transfer to the whole spin system permits the
1
editing of the H NMR spectrum of each residue into two
separated subspectra. Furthermore, the spatial disposition
between residues was disclosed by performing a 1D selective
NOE experiment on H10 in every case. Figure 1 shows, as
an example, the experiments performed on 8.
Interestingly, for all ꢀ-dipeptides herein studied, two
interresidue NOE contacts are observed between the NH10
5 8
proton and H /H protons (Table 1). However, the strength
of the NOE observed clearly depends upon the adopted
spatial arrangement. In 4 and 8, strong interresidue NOE
1
Figure 1
.
(A) H NMR spectrum of 8 recorded at 500 MHz in
contacts are observed between NH10 and H
are detected between NH10 and H (Table 1).
Opposite results are obtained for 7, showing a weak
interresidue NOE contact between NH10 and H while a
. A similar
5
and weak ones
3 10
CDCl . (B) Selective 1D TOCSY experiment selecting NH proton.
Magnetization is transferred to the whole spin system by using 60
ms mixing time. (C) Selective 1D TOCSY experiment selecting
NH proton. Magnetization is transferred to the whole spin system
4
by using 60 ms mixing time. (D) Selective 1D NOE experiment
8
5
stronger one is observed between NH10 and H
result had been obtained for 9.
8
on NH10 proton (NOE mixing time was set to 500 ms).
8
Org. Lett., Vol. 11, No. 11, 2009
2303

2-aminocyclobutanecarboxylic acid residues. In these ꢀ-dipep-
tides, the presence of rigid cyclobutane rings together with
2,3
5
,8-trans stereochemistry (ꢀ -trans), through the constraints
it imposes on the torsions around C -C , accounts for the
5
8
formation of eight-membered hydrogen-bonded rings. This
structural motif prevails over six-membered rings, a char-
8
,9
acteristic of the cis series.
It is noteworthy that the cis/trans stereochemistry in the
N-Boc cyclobutane residue (5,8-relative configuration) gov-
erns the conformational bias of these ꢀ-dipeptides. Therefore,
the combined or alternative use of cyclobutane residues with
cis and trans stereochemistry, respectively, can be a good
tool for the design of secondary structures in small ꢀ-pep-
tides. In larger oligomers, this would give rise to helical
structures not accessible from carbocyclic cyclopentane and
Figure 2
. Structures of 7 (A) and 8 (B) optimized at the B3LYP/
6
-31G(d) level of calculation. Methyl hydrogen atoms have been
omitted for clarity.
for 7 and 9 (2.2 Å). These data suggest an eight-membered
hydrogen-bonding for ꢀ-dipeptides 4 and 8. The existence
of a six-membered hydrogen-bonded structure is predicted
1
cyclohexane derivatives. Active investigations are in progress
to confirm this hypothesis.
8
for 7, similarly to the previously described 9.
To summarize, from the combined results obtained by
means of experimental techniques and theoretical calcula-
tions, we can state the prevalent secondary structures for the
Acknowledgment. Financial support from Ministerio de
Ciencia e Innovaci o´ n (CTQ2007-61704/BQU) and Gener-
alitat de Catalunya (2009SGR) is gratefully acknowledged.
ꢀ
-dipeptides studied. For 4 and 8, an eight-membered cycle
through a hydrogen bond between the NH10 proton and CO
3
Supporting Information Available: Synthetic procedures
and full characterization of 4, 7, and 8, detailed NMR
experiments, and theoretical studies. This material is available
free of charge via the Internet at http://pubs.acs.org.
is established. Differently, in the 5,8-cis-ꢀ-dipetide 7, as well
8
as in 9, a six-membered hydrogen-bonded ring conformation
4 9
involving the NH proton and CO is favored.
Thus, in conclusion, we have reported herein on a novel
family of ꢀ-oligomers made, totally or in part, of (trans)-
OL900636W
2304
Org. Lett., Vol. 11, No. 11, 2009