γ- and β-Peptide Foldamers from Common Multifaceted Building Blocks: Synthesis and Structural Characterization

Article abstract of DOI:10.1021/acs.orglett.5b02263

Structural characterization of 3,4-disubstituted γ-peptide and 2,3-disubstituted β-peptide foldamers derived from common multifaceted β-nitromethyl γ-amino acids and the chemical transformation of the β-nitromethyl group in γ-peptides into various functio

Full text of DOI:10.1021/acs.orglett.5b02263

Letter
pubs.acs.org/OrgLett
γ- and β‑Peptide Foldamers from Common Multifaceted Building
Blocks: Synthesis and Structural Characterization
Mothukuri Ganesh Kumar and Hosahudya N. Gopi*
Department of Chemistry, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pune 411008, India
S
* Supporting Information
ABSTRACT: Structural characterization of 3,4-disubstituted γ-peptide and 2,3-
disubstituted β-peptide foldamers derived from common multifaceted β-nitromethyl
γ-amino acids and the chemical transformation of the β-nitromethyl group in γ-
peptides into various functional derivatives are reported. The γ3,4-oligomers and α,γ-
hybrid peptides showed characteristic C14-and C12-helical conformations in single
crystals. Further, the new 2,3-disubstituted acyclic β-peptide showed the C6-helical
conformation despite the poor geometry of H-bonds.
he relationship between a well-defined structure and
Tfunction of proteins inspire the creation of foldamers
from non-natural building blocks.1 Among them, the most widely
studied foldamers are constructed from β- and γ-amino acid
subunits.2 The oligomers of β- and γ-amino acids displayed a
variety of helical structures with different H-bond pseudocycles.
The remarkable helical structures and side-chain projections of
β- and α,β-hybrid peptides have been exploited in designing
inhibitors for various protein−protein interactions,3 antimicro-
bials,4 and biomaterials.5 Despite the excellent biological
activities of γ-amino acids such as pregabalin6 and gabapentin,7
the biological activities of γ- and hybrid γ-peptides have yet to be
explored. Nevertheless, several bacteria are reported to produce
poly-γ-glutamate, which allowed bacteria to survive at high salt
concentrations and was also suspected of playing a role in
virulence.8 In the course of our investigation on structure and
reactivity of α,β-unsaturated γ-amino acids, we recently reported
the synthesis of β-nitromethyl γ-amino acids through highly
diastereoselective Michael addition of nitromethane.9 The
literature search revealed that the alkyl nitro group can be
transformed into a variety of functional groups including amines,
carboxylic acids, aldehydes, ketones, alkenes, oximes, hydroxyl
amines, 1,3-dipolar addition products, etc. under mild con-
ditions.10 With these multifaceted properties of alkyl nitro
groups, we anticipated that the β-nitromethyl γ-amino acids may
serve as excellent building blocks to construct 3,4-disubstituted γ-
peptide foldamers, 2,3-disubstituted β-peptide foldamers, as well
as intermediates to introduce various chemical modifications on
foldamers. Moreover, to the best of our knowledge, peptides with
alkyl nitro group functionality have not been systematically
investigated to date. The notable properties of alkyl nitro groups
encouraged us to investigate their structural and functional
properties in peptides. Herein, we report the synthesis and
structural characterization of homooligomers (P1−P3), hetero-
oligomers (P4 and P5) of β-nitromethyl γ3,4-peptide foldamers,
mild transformation of the β-nitromethyl group in γ3,4-peptides
into the corresponding peptide acid (P6), amine (P7), and 1,3-
diploar cycloaddition product (P8), transformation of β-
nitromethyl γ-amino acids into 2,3-disubstituted β-amino acids,
and the crystal conformation of the 2,3-disubstituted β-peptide
foldamer (P9). The structural characterization, chemical
diversity, and mild chemistry reported here can be further
explored to build novel functional foldamers.
To begin with, the β-nitromethyl-substituted γ-amino acids
(2a and 2b) were synthesized starting from (E)-α,β-unsaturated
γ-amino esters (1a and 1b) through highly diastereoselective
Michael addition of nitromethane in the presence of DBU as
shown in Scheme 1. The major anti addition products were
isolated in excellent yields after the column chromatography and
subjected for the construction of peptides and chemical
transformations. In order to understand the conformations of
β-nitromethyl γ3,4- peptides, we synthesized homooligomers
(P1−P3) and heterooligomers (P4 and P5) in solution-phase
Scheme 1. Synthesis of N-Boc-β-Nitromethyl-Substituted γ-
Amino Esters
Received: August 4, 2015
© XXXX American Chemical Society
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synthesis using standard DCC/HOBt coupling conditions. The
sequences of the peptides are shown in Scheme 2. The
Cγ−Cβ and Cβ−Cα bonds. Intriguingly, the extension of
dipeptide to tri (P2) and tetrapeptide (P3) leads to (P)-14-
helical conformations similar to those of the γ4-peptides.11a The
helical conformation in P2 and P3 is stabilized by one and two
intramolecular H-bonds between the i and i+3 residues,
respectively. The H-bond parameters are tabulated in the
Supporting Information (Tables S4−S6 and S8). The helical
structure in P2 is stabilized by the 14-membered H-bond
between the Boc amide CO (i) and the NH of the C-terminal γ-
residue (i+3), while P3 structure is stabilized by two intra-
molecular 14-membered H-bonds between Boc amide CO (i)
and NH of γ3,4 Val3 (i+3) and between the Val1 CO (i) and γ3,4
Val4 NH (i+3). Though there is a possibility to attain C9-helices
similar to the P1, both P2 and P3 attained the C14-helix
conformation. Crystal structure analysis of P2 and P3 reveal that
except the C-terminal γ3,4-residue, the other γ3,4-residues adopted
g+, g+ conformations. The directionality and the pattern of H-
bonding (i → i+3) observed in the γ3,4- tri and tetrapeptides
resemble the 310-helix in α-peptides as well as 14-helix of γ4-
peptides.15,11a The torsional angles of P2 and P3 are given in
Tables S3 and S7, respectively. Careful analysis of the
intramolecular H-bonds in P1−P3 revealed that the H-bond
distance is relatively larger in the 14-helix compared to the C9-
helix. Overall, these novel γ3,4-disubstituted amino acids favor the
helical conformation even in simple dipeptides.
These results motivated us to design P4 and P5 to understand
the conformations of γ3,4-amino acids in 1:1 α,γ-hybrid peptides.
The sequences of the peptides are shown in Scheme 2. Peptide
P4 consists of both γ3,4 and γ4-amino acids along with Aib, while
P5 composed of alternating γ3,4 amino acids. Peptides were
synthesized in solution-phase chemistry and pure peptides were
subjected to crystallization. Single crystals of P4 obtained from
the methanol solution gave the X-ray structure as shown in the
Figure 2A. The 12-helical structure of P4 is stabilized by three
intramolecular H-bonds between i and i+3 residues similar to the
other α,γ-hybrid peptides.16 Both γ4-Phe and γ3,4-Phe adopted
required g+, g+ conformations along Cγ−Cβ and Cβ−Cα bonds to
accommodate into the 12-helix. The H-bond parameters and
torsion angles are tabulated in the Supporting Information
(Tables S9−S12). Enormous efforts have been made to
crystallize P5 in various solvent combinations; however, it gave
single crystals only in 2-propanol solution. The X-ray structure of
P5 is shown in Figure 2A. The 12-helical conformation of P5 is
stabilized by two 12-membered H-bonds. Analysis reveals that
instead of participating into the canonical intramolecular H-
bonding the terminal amide NH is involved in strong
intermolecular H-bonding with the solvent 2-propanol. In
contrast to P4, the nitro and the CO groups of γ3,4Phe2 in P5
are involved in intermolecular H-bonding with NH of the γ3,4
Phe2 and Boc-amide NH of the other helix. These intermolecular
interactions lead to the arrangement of 12-helices into a
spectacular right-handed superhelix with the pore diameter of
7.3 Å. Solvent 2-propanol occupied the helical groove of the
super helix in the crystal packing, suggesting its important role in
peptide crystallization. A well-organized helical assembly of P5 is
shown in Figures 2B. The tubular arrangement of the hybrid 12-
helix, P5, resembles the arrangement of β-sheets in β-helix,
however, through noncovalent interactions.17 Recently, the
tubular porous organic and peptide structures have attracted
considerable attention due to their applications in the separation
science, catalysis, and nanobiotechnology.18 We hypothesize that
the tubular architecture of P5 may serve as a new template to
design soft biomaterials. In contrast, the P4 12- helix with single
Scheme 2. Sequences of γ3,4-Peptides and α, γ3,4-Hybrid
Peptides Derived from the Major Anti-Isomers
deprotection of N-Boc and ethyl esters was carried out using
TFA and NaOH, respectively. We adopted stepwise couplings
from the C- to N-terminus to avoid unexpected impurities during
the hydrolysis of peptide esters. All pure peptides were subjected
to growth of X-ray quality crystals in various solvent
combinations to understand their unambiguous conformations.
In contrast to the γ4-, γ2,4-, γ3,3, γ4,4-, and γ2,3,4-peptides,11 the
conformations of γ3,4-peptides have not been systematically
investigated. We speculated greater helical propensity from γ3,4-
peptides due to the favorable gauche interactions of side chains
similar to the tetrasubstituted ethanes.12
Single-crystal structures of P1, P2, and P3 are shown in Figure
1. Analysis of the crystal structure of P1 reveals that it adopted a
Figure 1. Single-crystal conformations of P1, P2, and P3.
helical type of conformation with a single nine-membered H-
bond between Boc-amide CO and the NH of C-terminal residue
(i → i+2), resembling the γ-turn in α-peptides.13 Similar types of
9-helices have also been observed in the homooligomers of
gabapentin, however, with mirror image torsional values.14 The
torsional variables of γ-amino acid derivatives were analyzed by
introducing two new additional variables θ1(N−Cγ−Cβ−Cα) and
θ2(Cγ−Cβ−Cα−C′) along with ϕ (C′−N−Cγ−Cβ) and ψ (Cα−
Cβ−C′−N).14 The torsional values are tabulated in the
Supporting Information (Table S1). Inspection of the crystal
structure reveals that the β-nitromethyl γ-amino acids adopted
the g+, g+ (θ1 ≈ θ2≈ ∼ 60°) backbone conformations along the
B
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hydrogenation20 in the presence of 20% Pd/C under hydrogen
atmosphere and the free amine was subsequently protected with
Cbz-group (P7). The 1,3-dipolar cycloaddition product P8 from
P4 was achieved by the treatment of phenylacetylene in the
presence of phenyl isocyanate and triethylamine under mild
conditions.21 All hybrid peptide derivatives were isolated in good
yields after purification and characterized (see the Supporting
Information). These results suggested that the nitro group on
peptides can be transformed into various functional derivatives.
The transformation of β-nitromethyl to the corresponding
carboxylic acid was further explored in simple amino acids to
derive new 2,3-disubstituted β-amino acids (Scheme 4).19 The
Scheme 4. Transformation of β-Nitromethyl γ-Amino Esters
into 2,3-Disubstituted β-Amino Acids and Sequence of β2,3-
Peptide P9
Figure 2. (A) X-ray structures of α, γ3,4-hybrid tetrapeptide 12-helices
P4 and P5. (B) Hierarchical assembly of α,γ3,4-hybrid 12-helix P5 into
right-handed superhelix along the b-axis and top view of the ordered self-
organization of P5 (along the c-axis).
2,3-disubstituted β-amino acids were isolated in excellent yields
and directly subjected to the synthesis of β-peptide P9. The
peptide was synthesized in the solution phase, and pure peptide
was subjected to crystallization. The single-crystal conformation
of P9 is shown in Figure 3. Instructively, the 2,3-disubstituted β-
nitro amino acid did not show helical pores in single crystals,
suggesting the requirement of two nitro groups for the
hierarchical tubular assembly. Overall the structural analysis of
homo- and heterooligomers of β-nitromethyl-substituted γ-
amino acids suggested that they readily adopt helical
conformations and follow the trend of other γ-peptides. In
addition, helical pores observed in P5 offer the glimpse of
potential of β-nitromethyl γ-amino acids and laid the foundation
for further investigation.
Figure 3. X-ray structure of β-peptide P9 C6-helix (side chains omitted
for clarity).
To verify whether these nitropeptides can undergo organic
transformations similar to the alkyl nitro groups,10 we subjected
P4 to various organic transformations (Scheme 3).The nitro
group in P4 was transformed to corresponding peptide
carboxylic acid (P6) using simple oxidation mediated by the
mixture of NaNO2 and acetic acid in DMSO.19 Further, the nitro
group of P4 was reduced to corresponding amine using catalytic
peptide adopted a helical screwtype conformation with 6-
memberd H-bonds. Even though extensive theoretical calcu-
lations suggested stable C6-helical conformation in β-peptides,22
they are scarcely studied in single crystals. However, C6-helical
conformations of β-peptides have been reported using cyclic β-
amino acids in solution.23 The torsion angles and H-bond
parameters of P9 are tabulated in the Supporting Information. It
is worth mentioning that β-nitromethyl γ-amino acids can be
transformed into novel 2,3-disubstituted β-amino acids.
Scheme 3. Organic Transformations of Hybrid Peptide P4 to
P6, P7, and P8
In conclusion, we have presented the synthesis, conforma-
tional analysis, and chemical diversity of novel β-nitromethane-
substituted γ-amino acid homo-oligomers and α,γ-hybrid
peptides. In addition, β-nitromethyl-substituted γ-amino acids
were used to construct 2,3-disubstituted β-peptide foldamers.
Both γ3,4 and α,γ3,4-hybrid peptides showed characteristic C14-
and C12-helical conformations, respectively. Additionally, the
2,3-disubstiuted β-peptide derived from the nitro amino acids
showed a notable C6-helix signature. Overall, the single-crystal
conformations of the γ3,4-peptides, the self-organized helical pore
from the α,γ3,4-hybrid 12-helix, and the transformation of alkyl
nitro group into a variety of functional groups reported here can
be utilized further for the construction of functional foldamers
and peptidomimetics.
C
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B.; Gellman, S. H.; Rapaport, H. Chem. - Eur. J. 2011, 17, 14857.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02263.
■
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Experimental procedures, 1H and 13C NMR, mass spectra,
and CCDC numbers (PDF)
Crystallographic data for P1−P5 and P9 (CIF)
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hn.gopi@iiserpune.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
M.G.K. is thankful to CSIR-India for research fellowship.
■
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