Influence of the C-terminal substituent on the crystal-state conformation of Adm peptides

Article abstract of DOI:10.1002/pep2.24121

The bis-functionalized diamondoid α-amino acid 2-aminoadamantane-2-carboxylic acid (Adm) has been used as the building block of four N^α-formyl homo-dipeptide alkylamide sequences via a solution-phase Ugi multicomponent reaction approach. The conformers of these peptides have been determined in the crystalline state by X-ray diffraction to distinguish the influences of the C-terminal substituent. One of the Adm peptides folds into an open and a hydrogen-bonded γ-turn geometry. Moreover, 3D-structures have been observed featuring two consecutive γ-turns in an incipient γ-helical structure, a significantly distorted nonhelical β-turn, as well as an S-shaped conformation with opposite helical screw senses. A significant topological variety is thus exhibited by the -Adm-Adm- sequences contingent on their C-terminal substituents, illustrating both the broad conformational potential and the need for further characterization of this sterically bulky residue in explorations of its ?, ψ space.

Full text of DOI:10.1002/pep2.24121

Received: 4 March 2019
DOI: 10.1002/pep2.24121
Revised: 24 April 2019
Accepted: 6 May 2019
F U L L P A P E R
Influence of the C-terminal substituent on the crystal-state
conformation of Adm peptides
Fatemeh M. Mir1
| Marco Crisma2
| Claudio Toniolo2,3
| William D. Lubell1
1Département de Chimie, Université de
Montréal, Montréal, Québec, Canada
Abstract
2Institute of Biomolecular Chemistry, Padova
Unit, Padova, Italy
The bis-functionalized diamondoid α-amino acid 2-aminoadamantane-2-carboxylic
acid (Adm) has been used as the building block of four Nα-formyl homo-dipeptide
alkylamide sequences via a solution-phase Ugi multicomponent reaction approach.
The conformers of these peptides have been determined in the crystalline state by
X-ray diffraction to distinguish the influences of the C-terminal substituent. One of
the Adm peptides folds into an open and a hydrogen-bonded γ-turn geometry. More-
over, 3D-structures have been observed featuring two consecutive γ-turns in an
incipient γ-helical structure, a significantly distorted nonhelical β-turn, as well as an
S-shaped conformation with opposite helical screw senses. A significant topological
variety is thus exhibited by the -Adm-Adm- sequences contingent on their C-terminal
substituents, illustrating both the broad conformational potential and the need for
further characterization of this sterically bulky residue in explorations of its ϕ, ψ
space.
3Department of Chemistry, University of
Padova, Padova, Italy
Correspondence
Claudio Toniolo, Department of Chemistry,
University of Padova, via Marzolo 1, 35131
Padova, Italy.
Email: claudio.toniolo@unipd.it
William D. Lubell, Département de Chimie,
Université de Montréal, C. P. 6128, Succursale
Centre-Ville, Montréal, Québec,
Canada H3C 3J7.
Email: william.lubell@umontreal.ca
Funding information
FRQNT Centre in Green Chemistry and
Catalysis (CGCC), Grant/Award Number:
Strategic Cluster RS-171310; Natural Sciences
and Engineering Research Council of Canada
(NSERC), Grant/Award Number: Discovery
Grant RGPIN-06647; Université de Montréal
K E Y W O R D S
2-aminoadamantane-2-carboxylic acid peptides, crystal-state conformation, β-turn,
γ-helix, γ-turn
solution,[32] Adm derivatives and dipeptides, such as Ac-Adm-NHMe
(Ac, acetyl; NHMe, methylamino) and Ac-Adm-Gly-NHMe, have
been suggested to fold in γ-turn conformations based on NMR and
1
| INTRODUCTION
Cα,α-Dialkylglycines have the potential for restricting backbone confor-
mation within peptide chains. For example, numerous 3D-structural
analyses of α-aminoisobutyric acid (Aib) residues[1–6] in different pep-
tides in solution and in the crystal state have demonstrated the strong
tendency for this achiral amino acid to induce type-III (III0) β-turn[7–12]
and 310−/α-helical conformations.[1–4,13,14] Although Cα,α-cycloalkyl
α-amino acid residues (e.g., 1-aminocyclopentane-1-carboxylic acid,
Ac5c, and 1-aminocyclohexane-1-carboxylic acid, Ac6c)[15] exhibit simi-
lar propensity, as the bulkiness of both Cα,α-substituents increases in
acyclic α-amino acids of this class (e.g., Cα,α-diethylglycine, Deg), the
fully extended conformation becomes more stable.[16–18]
IR absorption spectroscopic studies. Moreover, certain Adm homo-
peptides[30,31] have been observed by X-ray diffraction to exhibit
two consecutive, regular γ-turns, indicating the possibility to form
the still uncharacterized γ-helix.[33]
The influences of the C-terminal substituent on the tendency of the
-Adm-Adm- dipeptide sequence to adopt the γ-turn conformation have
now been investigated by the synthesis and X-ray diffraction analysis of
a series of di- and tripeptides N-terminating in a common formyl group.
The sequences listed below feature different C-terminal substituents to
specifically examine the role of size and hydrogen-bond donor and
acceptor units: HCO-(Adm)2-Gly-OEt (4a), HCO-(Adm)2-NHiPr (4b),
HCO-(Adm)2-NHtBu (4c), and HCO-(Adm)2-Aib-OMe (4d). In addition,
the X-ray diffraction structure of a strictly related dipeptide, HCO-Adm-
Aib-OMe (2d), has been also solved and studied.
The diamondoid[19–22] 2-aminoadamantane-2-carboxylic acid
(Adm) residue has shown intriguing potential for adopting the rela-
tively uncommon γ-turn conformation[23–29] in X-ray diffraction
studies of short Adm-rich peptides and homo-peptides.[30,31] In
Peptide Science. 2019;e24121.
wileyonlinelibrary.com/peptidesci
© 2019 Wiley Periodicals, Inc.
1 of 9
https://doi.org/10.1002/pep2.24121

2 of 9
MIR ET AL.
previously reported. 1H NMR (300 MHz, CDCl3): δ 1.58 (s, 6H), 3.74
(s, 3H), 6.68 (s, 1H), 8.10 (s, 1H) ppm.
2
| EXPERIMENTAL
Ethyl isocyanoacetate (1a). HCO-Gly-OEt (5.7 g, 43.5 mmol) in
DCM (43 mL) was treated with triethylamine (TEA) (13.2 g,
130.5 mmol, 3 eq), cooled to −5 ꢀC and treated dropwise with POCl3
(8 g, 52.2 mmol, 1.2 eq). After stirring at −5 ꢀC for 1 hour, the
resulting reddish mixture was treated with a solution of sat. NaHCO3
(30 mL) and agitated thoroughly. The organic phase was separated,
washed with brine, dried over Na2SO4, filtered, and evaporated under
reduced pressure to afford a reddish liquid, which was purified by col-
umn chromatography using an eluent of hexane:EtOAc (7:3). Evapora-
tion of the collected fractions gave isocyanide 1a as pale-yellow oil
(3.6 g, 31.8 mmol,73%). Rf 0.48 (7:3 hexane:EtOAc). 1H NMR
(500 MHz, CDCl3): δ 1.28 (t, J = 7.0 Hz, 3H), 4.20 (s, 2H), 4.24 (q,
J = 7.0 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ 14.0, 43.5, 62.7,
161.0, 164.0 ppm. IR absorption (ATR): ν 2162, 1750; HRMS (ESI): m/
z calcd for C5H8NO2 114.0555; found [M + H]+ 114.0551.
Methyl 2,2-dimethyl-isocyanoacetate (1d).[35] This compound
was synthesized according to the procedure described above for 1a
using HCO-Aib-OMe (7.5 g, 49.2 mmol), TEA (24.3 mL, 246 mmol,
5 eq), and POCl3 (6.9 mL, 73.8 mmol, 1.5 eq) at −20 ꢀC. Evaporation
of the volatiles gave an orange liquid that was purified by column
chromatography using hexane:EtOAc (7:3) as eluent to furnish
isocyanide 1d (3.75 g, 29.5 mmol, 60%) as a pale-yellow liquid that
exhibited the same characteristics as previously reported. Rf 0.72 (3:7
hexane:EtOAc); 1H NMR (300 MHz, CDCl3): δ 1.64 (s, 6H), 3.80
(s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 27.5, 53.6, 59.5, 157.9,
170.1 ppm.
2.1 | Synthesis and characterization
Dichloromethane (DCM) and methanol (MeOH) were used after dry-
ing by passage through solvent filtration systems (GlassContour,
Irvine, CA). Reagents from commercial sources were used as received.
Purification by silica gel chromatography was performed on 230-400
mesh silica gel. Analytical thin-layer chromatography was carried out on
silica gel 60 F254 (Aluminum Sheet) and visualized by UV absorbance or
by staining with iodine. Melting points were obtained on sample in capil-
lary tubes using a Mel-Temp melting point apparatus and reported in
degree Celsius (ꢀC). Infrared absorption spectra were recorded on a
Bruker Alpha P FT-IR spectrophotometer equipped with a single reflec-
tion ATR sampling module that allows spectral acquisition from neat solid
and liquid samples. The frequency of absorption is reported in reciprocal
centimeters (cm−1). 1H and 13C NMR spectra were recorded at room
temperature (rt) in CDCl3 (7.26 ppm/77.16 ppm) or in deuterated
dimethylsulfoxide (DMSO, d6) (2.50 ppm/39.52 ppm) on Bruker AV
(300/75 and 500/125 MHz) instruments and referenced to internal sol-
vent. Chemicals shifts are reported in parts per million (ppm); coupling
constants (J values) in Hertz; abbreviations for peak multiplicities are s
(singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet) and br (broad).
High-resolution mass spectrometry (HRMS) was performed by the Cen-
tre Régional de Spectroscopie de Masse de l'Université de Montréal,
using protonated molecular ions [M + H]+, [M + 2H]/2+ or sodium
adducts [M + Na]+ for empirical formula confirmation.
HCO-Gly-OEt. A mixture of HCl ꢁ H-Gly-OEt (10.0 g, 70 mmol)
and ammonium formate (9.20 g, 146 mmol, 2.1 eq) in CH3CN (75 mL)
was heated at reflux and stirred for 16 hours. The volatiles were
removed under reduced pressure. The residue was partitioned
between water (30 mL) and DCM (30 mL). The layers were separated.
The aqueous phase was extracted with DCM (2 × 30 mL). The com-
bined organic layer was dried over Na2SO4 and filtered. The filtrate was
concentrated to provide HCO-Gly-OEt as a pale-yellow liquid (6.98 g,
53.2 mmol, 76%) that was used without further purification. Rf 0.33 (1:4
hexane: ethyl acetate, EtOAc). 1H NMR (500 MHz, CDCl3): δ 1.21 (t,
J = 7.0 Hz, 3H); 3.98 (d, J = 6.0 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 6.85 (br,
1H), 8.17 (s, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ 14,0, 39.9, 61.6,
161.6, 169.6 ppm. HRMS (ESI): m/z calcd for C5H10NO3 132.0655;
found [M + H]+ 132.0657.
HCO-Aib-OMe.[34–36] A solution of H-Aib-OH (5.0 g, 48.5 mmol)
in MeOH (25 mL) was cooled to 0 ꢀC, treated with SOCl2 (7.0 mL,
97 mmol, 2 eq) and left to stir for 16 hours with warming to rt. The
volatiles were removed under reduced pressure to give HClꢁH-Aib-
OMe as a white solid in quantitative yield. The salt was dissolved in
formic acid (15 mL), treated with a solution of sodium formate (3.21 g,
50.9 mmol, 1.05 eq) in a minimum amount of formic acid, and left to
stir at 40 ꢀC. After 2 hours, the mixture was filtered, and the filtrate
was treated with 1:1 formic acid: acetic anhydride (4 mL/15 mL),
heated to 80 ꢀC and stirred for 20 hours. The mixture was filtered and
the filtrate was concentrated under vacuum to give HCO-Aib-OMe as
HCO-Adm-Gly-OEt (2a). A solution of isocyanoacetate 1a (3 g,
26.5 mmol) in MeOH (2 M) was treated with adamantan-2-one
(3.98 g, 26.5 mmol, 1 eq) followed by a solution of ammonium for-
mate (2.0 g, 31.8 mmol, 1.2 eq) in the minimum amount of water, and
stirred for 24 hours. The volatiles were evaporated. The residue was
dissolved in CHCl3, washed with water and brine, dried over Na2SO4,
and evaporated to a residue that was purified on column chromatog-
raphy using hexane:EtOAc (1:1) as eluent to provide dipeptide 2a
(1.52 g, 4.92 mmol, 56%) as a powder: Rf 0.34 (1:1 hexane:EtOAc); m.
p. 165.2-167.2ꢀC; 1H NMR (300 MHz, CDCl3): δ 1.26 (t, J = 7.2 Hz,
3H); 1.67 (m, 1H), 1.71 (m, 3H), 1.76 (m, 2H), 1.83-1.84 (m, 2H),
1.94-2.04 (m, 4H), 2.68 (m, 2H), 3.99 (d, J = 5.8 Hz, 2H), 4.17 (q,
J = 7.1 Hz, 2H), 5.82 (s, 1H), 7.59 (t, J = 5.7 Hz, 1H), 8.13 (d,
J = 2.0 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ 14.3, 26.5, 26.6,
32.2, 32.5, 33.9, 37.4, 41.5, 61.4, 64.9, 161.9, 169.9, 172.8 ppm. IR
absorption (ATR): ν 3254, 1746, 1682, 1641, 1531; HRMS (ESI): m/z
calcd for C16H25N2O4 309.1809; found [M + H]+ 309.1818.
HCO-Adm-NHiPr (2b). This compound was synthesized from iso-
propyl isocyanide (1b, 1.0 g, 14.5 mmol) according to the procedure
described above for the synthesis of dipeptide 2a and purified by col-
umn chromatography using hexanes:EtOAc (3:2) as eluent. The col-
lected fractions were evaporated to give 2b as a powder (2.4 g,
9.1 mmol, 63%): Rf 0.33 (3:97 MeOH:DCM); m.p. 181-185 ꢀC; 1H NMR
(500 MHz, CDCl3): δ 1.13 (d, J = 6.5 Hz, 6H), 1.65-1.74 (m, 6H),
1.80-1.82 (m, 2H), 1.92-1.96 (m, 4H), 2.64 (br, 2H), 4.01-4.07 (m, 1H),
a
pale-yellow oil, which exhibited the same characteristics as

MIR ET AL.
3 of 9
6.07 (s, 1H), 6.96 (d, J = 7.5 Hz, 1H), 8.12 (d, J = 2.5 Hz, 1H) ppm. 13C
NMR (125 MHz, CDCl3): δ 22.6, 26.5, 26.6, 32.1, 32.6, 34.0, 37.4, 41.4,
64.9, 161.7, 171.2 ppm. IR absorption (ATR): ν 3320, 3286, 1652, 1518;
HRMS (ESI): m/z calcd for C15H25N2O2 265.1911; found [M + H]+
265.1916.
5.74 (br, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ 22.4, 26.2, 26.4, 33.3
(2C), 35.0, 37.3, 42.1, 68.6, 158.2, 166.7 ppm. IR absorption (ATR):
ν = 3315, 2122, 1647, 1533; HRMS (ESI): m/z calcd for C15H23N2O
247.1805; found [M + H]+ 247.1810.
“CN-Adm”-NHtBu (3c) was synthesized from HCO-Adm-NHtBu
2c (6.75 g, 24.24 mmol) according the procedure described above for
the preparation of isocyanoacetate 1a at −5 ꢀC. The resulting yellow
powder was purified by column chromatography using hexane:EtOAc
(9:1) as eluent to afford isocyanide 3c as a white powder (6.0 g,
23.0 mmol, 94%): Rf 0.36 (9:1 hexane:EtOAc); m.p. 116-120 ꢀC; 1H
NMR (500 MHz, CHCl3): δ 1.37 (s, 9H), 1.71 (m, 2H), 1.75-1.77 (m,
4H), 1.81 (m, 1H), 1.89 (m, 1H), 1.94-1.97 (m, 2H), 2.22-2.24 (m, 2H),
2.28 (m, 2H), 5.69 (s, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ 26.2,
26.3, 28.5, 33.3, 35.1, 37.2, 39.4, 51.8, 68.9, 158.0, 166.6 ppm. IR
absorption (ATR): ν 3363, 2120, 1660, 1527; HRMS (ESI): m/z calcd
for C16H25N2O 261.19614; found [M + H]+ 261.19712.
HCO-Adm-NHtBu (2c). This compound was synthesized from
tert-butyl isocyanide (1c, 3.0 g, 41.6 mmol) according to the procedure
described above for the synthesis of dipeptide 2a and purified by col-
umn chromatography using hexane:EtOAc (7:3) as eluent. The col-
lected fractions were evaporated to give 2c as a powder (8.3 g,
29.8 mmol, 72%): Rf 0.2 (7:3 hexane:EtOAc); m.p. 197-200 ꢀC; 1H
NMR (500 MHz, CDCl3): δ 1.32 (s, 9H), 1.63-1.72 (m, 6H), 1.79-1.84
(m, 2H), 1.92-2.00 (m, 4H), 2.60 (br, 2H), 6.16 (s, 1H), 6.95 (s, 1H),
8.11 (d, J = 2.0 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ 26.4,
26.6, 28.6, 32.1, 32.6, 34.1, 37.3, 51.0, 65.4, 161.7, 171.0 ppm. IR
absorption (ATR): ν 3264, 1674, 1649, 1540; HRMS (ESI): m/z calcd
for C16H27N2O2 279.2067; found [M + H]+ 279.2066.
“CN-Adm”-Aib-OMe (3d) was synthesized from dipeptide 2d
(1.51 g, 4.68 mmol) according to the procedure described above for
the synthesis of isocyanoacetate 1a and purified by column chroma-
tography using hexane:EtOAc (7:3) as eluent to afford isocyanide 3d
as a powder (1.31 g, 4.3 mmol, 92%): Rf 0.56 (7:3 hexane:EtOAc); m.
p. 115.9-117.4ꢀC; 1H NMR (300 MHz, CDCl3): δ 1.58 (s, 6H), 1.72 (m,
2H), 1.75-1.81 (m, 5H), 1.89-1.90 (m, 1H), 1.94-1.97 (m, 2H),
2.22-2.25 (m, 2H), 2.33 (m, 2H), 3.74 (s, 3H), 6.55 (s, 1H) ppm. 13C
NMR (75 MHz, CDCl3): δ 24.4, 26.2, 26.3, 33.1, 33.2, 34.9, 37.2, 52.9,
56.9, 68.6, 158.4, 166.6, 174.8 ppm. IR absorption (ATR): ν 3372,
2126, 1726, 1675, 1529; HRMS (ESI): m/z calcd for C17H25N2O3
305.1860; found [M + H]+ 305.1869.
HCO-Adm-Aib-OMe (2d). This compound was synthesized
according to the procedure described above for the synthesis of
dipeptide 2a using methyl 2,2-dimethyl-isocyanoacetate 1d (1.27 g,
10.0 mmol), adamantan-2-one (1.5 g, 10.0 mmol, 1 eq), and ammonium
formate (0.95 g, 15.0 mmol, 1.5 eq). The residue was purified on column
chromatography using hexanes:EtOAc (7:3) as eluent to give dipeptide
2d as a powder (1.98 g, 6.1 mmol, 62%): Rf 0.50 (1:9 MeOH:EtOAc); m.
p. 185.8-189.5 ꢀC; 1H NMR (300 MHz, CDCl3): δ 1.48 (s, 6H), 1.66 (m,
1H), 1.70 (m, 4H), 1.75 (m, 1H), 1.82 (m 2H), 1.92-2.01 (m, 4H), 2.65 (m,
2H), 3.68 (s, 3H), 5.70 (s, 1H), 7.57 (s, 1H), 8.15 (d, J = 2.0 Hz, 1H) ppm.
13C NMR (75 MHz, CDCl3): δ 25.0, 26.5, 26.7, 32.1, 32.5, 33.9, 37.3,
52.4, 56.0, 64.9, 161.9, 171.2, 174.9 ppm. HRMS (ESI): m/z calcd for
HCO-(Adm)2-Gly-OEt (4a) was synthesized from isocyanide 3a
(1.0 g, 3.43 mmol) according to the procedure described above for the
synthesis of dipeptide 2a and purified by column chromatography
using hexane:EtOAc (3:7) as eluent to give tripeptide 4a as a powder
(1.1 g, 2.3 mmol, 67%): Rf 0.35 (3:7 hexane:EtOAc); m.p. 197-200 ꢀC; 1H
NMR (500 MHz, DMSO): δ 1.17 (t, J = 7.1 Hz, 3H), 1.52-1.54 (m, 4H),
1.57-1.64 (m, 8H), 1.72-1.83 (m, 5H), 1.88-1.95 (m, 6H), 2.01-2.08
(m, 2H), 2.56-2.58 (m, 3H), 3.75 (d, J = 2.5 Hz, 2H), 4.06 (q, J = 7.1 Hz,
2H), 7.25 (s, 1H), 7.77 (t, J = 5.7 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 8.08
(d, J = 1.8 Hz, 1H) ppm. 13C NMR (125 MHz, DMSO): δ 14.0, 25.9, 26.0,
26.2, 26.4, 31.3, 31.7, 32.2, 32.3, 33.3 (2C), 37.1, 37.3, 41.0, 60.2, 62.8,
64.1, 161.5, 170.0, 171.4, 172.1 ppm. IR absorption (ATR): ν 3275, 1761,
1650, 1513; HRMS (ESI): m/z calcd for C27H39N3O5Na 508.2782; found
[M + Na]+ 508.2774.
C
17H27N2O4 323.1965, found [M + H]+ 323.1976.
“CN-Adm”-Gly-OEt (3a) was synthesized from dipeptide 2a
(1.51 g, 4.68 mmol) according to procedure described above for the
synthesis of isocyanoacetate 1a. The volatiles were removed and the
orange residue was purified by column chromatography using hex-
ane:EtOAc (7:3) as eluent to afford isocyanide 3a as a white
powder (1.03 g, 3.5 mmol, 72%). Rf 0.35 (7:3 hexane:EtOAc); m.p.
87.6-90.8 ꢀC; 1H NMR (500 MHz, CDCl3): δ 1.28 (t, J = 7.2 Hz, 3H),
1.72 (m, 2H), 1.77-1.82 (m, 5H), 1.90-1.91 (m, 1H), 1.98-2.01 (m,
2H), 2.23-2.26 (m, 2H), 2.38 (m, 2H), 4.06 (d, J = 5.3 Hz, 2H), 4.22 (q,
J = 7.2 Hz, 2H), 6.56 (br, 1H) ppm. 13C NMR (125 MHz, CDCl3):
δ 14.2, 26.1, 26.3, 33.2 (2C), 34.9, 37.2, 41.7, 61.8, 68.5, 158.7,
167.8, 169.5 ppm. IR absorption (ATR): ν 3377, 2120, 1744, 1659,
1525; HRMS (ESI): m/z calcd for C16H23N2O3 291.1703; found
[M + H]+ 291.1709.
HCO-(Adm)2-NHiPr (4b) was synthesized from isocyanide 3b
(1.6 g, 6.47 mmol) according to the procedure described above for the
synthesis of dipeptide 2a and purified by column chromatography using
hexane:EtOAc (2:3) as eluent to afford dipeptide 4b as a powder (2.5 g,
5.7 mmol, 87%): Rf 0.25 (2:3 hexane:EtOAc); m.p. 192-198 ꢀC; 1H
NMR (500 MHz, CHCl3): δ 1.10 (d, J = 6.6 Hz, 6H), 1.62 (m, 1H), 1.65
(m, 1H), 1.69-1.70 (m, 9H), 1.76 (m, 1H), 1.79-1.83 (m, 4H), 1.93-1.95
(m, 6H), 2.00 (m, 1H), 2.03 (m, 1H), 2.64-2.66 (m, 4H), 3.99-4.07 (m,
1H), 5.74 (s, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.92 (s, 1H), 8.13 (d,
J = 1.9 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ 22.8, 26.4, 26.6
“CN-Adm”-NHiPr (3b) was synthesized from HCO-Adm-NHiPr 2b
(2 g, 7.6 mmol) according the procedure described above for the synthe-
sis of isocyanoacetate 1a at −5 ꢀC. The resulting orange solid was puri-
fied by column chromatography using hexane:EtOAc (7:3) as eluent. The
collected fractions were evaporated to give isocyanide 3b as a white
powder (1.70 g, 6.9 mmol, 90%): Rf 0.53 (7:3 hexane:EtOAc);
m.p. 130-133 ꢀC; 1H NMR (500 MHz, CHCl3): δ 1.18 (d, J = 7.0 Hz, 6H),
1.72 (m, 2H), 1.76-1.78 (m, 4H), 1.81 (m, 1H), 1.89-1.91 (m, 1H),
1.96-1.99 (m, 2H), 2.23-2.26 (m, 2H), 2.31 (m, 2H), 4.07-4.14 (m, 1H),

4 of 9
MIR ET AL.
(2C), 26.9, 32.2, 32.6, 32.7, 32.8, 34.0, 34.2, 37.3, 37.7, 41.1, 64.7,
65.3, 161.3, 171.2, 172.1 ppm. IR absorption (ATR): ν 3360, 1677,
1511; HRMS (ESI): m/z calcd for C26H40N3O3 442.3060; found
[M + H]+ 442.3073.
and SADABS (or TWINABS where appropriate) software packages
(Bruker AXS).
The structures were solved by ab initio procedures of the SIR
2014[37] or SHELXT[38] programs, and refined by full-matrix least-squares
procedures on F2, using all data, by application of the SHELXL-2014[39]
or OLEX2[40] programs, with anisotropic displacement parameters for all
of the nonhydrogen atoms. Hydrogen atoms were calculated at idealized
positions and refined using a riding model.
HCO-(Adm)2-NHtBu (4c) was synthesized from isocyanide 3c
(2.0 g, 7.65 mmol) according to the procedure described above for
the synthesis of dipeptide 2a and purified by column chromatography
using hexane:EtOAc (7:3) as eluent to give dipeptide 4c as a powder
(2.96 g, 6.5 mmol, 85%): Rf 0.21 (7:3 hexane:EtOAc); m.p. 228-
230 ꢀC; 1H NMR (500 MHz, CDCl3): δ 1.30 (s, 9H), 1.62 (m, 1H), 1.64
(m, 1H), 1.68-1.72 (m, 8H), 1.75 (m, 1H), 1.78-1.82 (m, 5H), 1.94-1.96
(m, 6H), 2.00 (m, 1H), 2.03 (m, 1H), 2.63 (m, 2H), 2.68 (m, 2H), 5.55
(s, 1H), 6.83 (s, 1H), 6.93 (s, 1H), 8.13 (d, J = 1.9 Hz, 1H) ppm. 13C
NMR (125 MHz, CDCl3): δ 26.3, 26.5, 26.6, 26.9, 28.8, 32.3, 32.6,
32.7, 32.8, 34.1, 34.2, 37.3, 37.6, 50.7, 65.3, 65.4, 161.0, 170.9,
171.9 ppm. IR absorption (ATR): ν 3256, 1684, 1655, 1538; HRMS
(ESI): m/z calcd for C27H42N3O3 456.3221; found [M + H]+ 456.3242.
HCO-(Adm)2-Aib-OMe (4d) was synthesized from isocyanide
3d (1.0 g, 3.3 mmol) according to the procedure described above
for the synthesis of dipeptide 2a and purified by column chroma-
tography using hexane:EtOAc (7:3) as eluent to give tripeptide 4d
as a powder (1.03 g, 2.1 mmol, 62%): Rf 0.34 (1:9 MeOH:EtOAc);
m.p. 198-203 ꢀC; 1H NMR (500 MHz, CDCl3): δ 1.44 (s, 6H),
1.61-1.64 (m, 2H), 1.68-1.70 (m, 8H), 1.74-1.83 (m, 6H), 1.93-1.98
(m, 6H), 2.02-2.05 (m, 2H), 2.64 (m, 2H), 2.68 (m, 2H), 3.66 (s, 3H),
5.66 (s, 1H), 6.94 (s, 1H), 7.55 (s, 1H), 8.12 (d, J = 1.9 Hz, 1H) ppm.
13C NMR (125 MHz, CDCl3): δ 25.1, 26.3, 26.5, 26.6, 26.9, 32.3,
32.5, 32.6, 32.7, 34.0 (2C), 37.3, 37.6, 52.3, 55.7, 64.6, 65.5, 161.6,
171.2, 172.4, 175.0 ppm. IR absorption (ATR): ν 3285, 1739, 1677,
1650, 1524; HRMS (ESI): m/z calcd for C28H42N3O5 500.3119;
found [M + H]+ 500.3133.
Relevant crystal data and structure refinement parameters are
reported in Tables S1-S5. CCDC 1880257-1880261 contain the supple-
mentary crystallographic data for this article. The data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/structures.
3
| RESULTS
3.1 | Peptide synthesis
Cα,α-Disubstituted glycines are generally recalcitrant to peptide bond
formation because of their remarkable steric hindrance. This phenom-
enon becomes particularly significant in coupling reactions to their
α-amino functionality.[41,42] These unfavorable properties are magni-
fied in couplings to Adm residues due to the increased bulkiness of
this diamondoid residue.[19–22]
Among the different methods examined for coupling Cα,α-disubstituted
glycines, the Ugi multicomponent reaction[35,43] employing the com-
mercially available 2-adamantanone, ammonium formate, and different
isonitriles (CN-R) was found to furnish Adm derivatives and peptides in
relatively high yields (Scheme 1). Four isonitriles 1a-d were investigated
to begin the synthesis of a series of Adm dipeptides possessing various
C-terminal residues: iso-propyl and tert-butyl isonitriles 1b and 1c were
obtained from commercial sources; α-amino ester-derived isonitriles 1a
and 1d were respectively synthesized by formylation using ammonium
formate and acetic anhydride, followed by isonitrile formation using
POCl3 and TEA. Adamantan-2-one was respectively reacted with
isonitriles 1a-d and ammonium formate in MeOH to afford Nα-formyl
Adm-containing C-alkylamides and dipeptides 2a-d. Formamides 2a-d
were converted into the corresponding isonitriles 3a-d in excellent
yields using POCl3 and TEA, and elongated by the Ugi procedure to the
corresponding Nα-formyl Adm di- and tripeptides 4a-d.
2.2 | X-Ray diffraction
Single crystals, suitable for X-ray diffraction analysis, of di- and
tripeptides 2d and 4a-d were obtained from ethyl acetate (2d), ace-
tone (4a and 4c), DCM (4b), and DCM/hexane (4d).
X-Ray diffraction data for peptide 2d were collected with a Gemini
E four-circle kappa diffractometer (Agilent Technologies) equipped
with a 92-mm EOS CCD detector, using graphite monochromated Cu
Kα radiation (λ = 1.54178 Å). Data collection and reduction were per-
formed with the CrysAlisPro software (Agilent Technologies). A semi-
empirical absorption correction based on the multi-scan technique
using spherical harmonics was implemented in the SCALE3 ABSPACK
scaling algorithm.
3.2 | Crystal-state conformational analysis
The 3D-structures of the Adm-containing di- and tripeptides 2d and
4a-d were solved by X-ray diffraction (Figures 1–5). The C-terminal
substituent effects on peptide conformation with specific attention to
γ-turn formation were assessed by evaluation of ϕ and ψ backbone
torsion angles (Table 1) and intramolecular hydrogen-bond distances
between amide (peptide) carbonyl and N-H groups (Table 2). Com-
posed of achiral Adm, Gly and Aib residues, the five peptides were
expected to crystallize in two enantiomeric conformers. For example,
peptides 2d, 4a and 4b crystallized in centrosymmetric space groups.
On the other hand, peptides 4c and 4d crystallized in one of the
X-Ray diffraction data collection for the remaining four structures
(4a-d) was performed at the Laboratoire de Diffraction des Rayons X
de l'Université de Montréal with a Bruker Venture Metaljet diffrac-
tometer, equipped with a Gallium Liquid Metal Jet Source (Ga Kα radi-
ation, λ = 1.34139 Å), Helios MX Mirror Optics, a kappa goniometer,
and a Photon 100 CMOS detector. Data collection, data reduction,
and absorption correction were achieved by use of the APEX 2, SAINT,

MIR ET AL.
5 of 9
SCHEME 1 Solution-phase syntheses
of Nα-formyl Adm-containing di- and
tripeptides
O
HCO2NH4,
adamantan-2-one,
POCl3,TEA,
CH2Cl2
H
N
H
NHR
CN
R
MeOH,
H2O(minimum)
O
2a: 56%
2b: 63%
2c: 72%
2d: 62%
1a: R = CH2CO2Et
1b: R = iPr
1c: R = tBu
1d: R = C(CH3)2CO2Me
O
HCO2NH4,
adamantan-2-one,
O
O
H
N
CN
NHR
H
N
NHR
MeOH,
H2O(minimum)
H
O
4a: 67%
4b: 87%
4c: 85%
4d: 62%
3a: 72%
3b: 90%
3c: 94%
3d: 92%
Sohncke space groups in which molecules of only one handedness
occur,[44] due to the rather uncommon phenomenon termed spontane-
ous resolution.[45] Crystals of peptides 4c and 4d were affected by
twinning through inversion.
residue is also helical, but of opposite screw sense with respect to
the preceding residue [ϕ2, ψ2 = −48.05(16)ꢀ, −47.20(15)ꢀ]. The overall
backbone of 2d can be described as S-shaped.[46,47] Without intramo-
lecular hydrogen bonds, the amide N-H of the Adm and Aib residues
form respectively intermolecular hydrogen bonds with the carbonyl
oxygens of the Adm and formyl groups in a (−x + 1/2, y + 1/2,
−z + 1/2) symmetry-related molecule (Table 2), the packing mode
In the five structures, the amide, peptide, and ester bonds, all
adopt the usual trans isomer (ω = 180ꢀ) without significant deviation
(|Δω | ≤ 7.9ꢀ) from the ideal planarity.
In the molecule arbitrarily selected as the asymmetric unit in the
centrosymmetric structure of the dipeptide HCO-Adm-Aib-OMe com-
posed of two achiral, Cα-tetrasubstituted α-amino acids (2d; Figure 1),
the Adm residue adopts a left-handed, highly distorted helical confor-
mation [ϕ1, ψ1 = 72.41(16)ꢀ, 75.06(13)ꢀ] (Table 1). The C-terminal Aib
FIGURE 2 X-Ray diffraction structure of HCO-(Adm)2-Gly-OEt
(4a). Displacement ellipsoids are drawn at the 30% probability level.
Most hydrogen atoms are omitted for clarity. The single C O…H─N
intramolecular hydrogen bond is indicated by a dashed line
FIGURE 1 X-Ray diffraction structure of HCO-Adm-Aib-OMe
(2d). Displacement ellipsoids are drawn at the 30% probability level.
Most hydrogen atoms are omitted for clarity

6 of 9
MIR ET AL.
FIGURE 5 X-Ray diffraction structure of HCO-(Adm)2-Aib-
OMe (4d). Displacement ellipsoids are drawn at the 30% probability
FIGURE 3 X-Ray diffraction structure of HCO-(Adm)2-NHiPr
(4b). Displacement ellipsoids are drawn at the 30% probability level.
Most hydrogen atoms are omitted for clarity. The two C O…H─N
intramolecular hydrogen bonds are indicated by dashed lines
level. Most hydrogen atoms are omitted for clarity. The single
C
O…H─N intramolecular hydrogen bond is indicated by a
dashed line
regular γ-turn. Specifically, the ϕ2 value [−69.2(3)ꢀ] is appropriate for
a γ-turn conformation, but the ψ2 value [96.8(3)ꢀ] is slightly too large,
suggesting formation of an “open” γ-turn. In corroboration, the intra-
molecular H…O distance (2.60 Å) between the N-terminal Adm(1) car-
bonyl oxygen and the Gly(3) N-H exceeds slightly the commonly
accepted limit for the onset of a hydrogen bond (≤ 2.50 Å).[48–50] The
C-terminal Gly(3) residue is semi-extended [ϕ3, ψ3 = 84.5(3)ꢀ, −158.4
(2)ꢀ]. Two intermolecular hydrogen bonds between the N-terminal
Adm(1) amide N-H and the Adm(2) carbonyl of a translationally
equivalent molecule (x-1, y, z) generate molecular rows along the
featuring rows of molecules, related through a 2-fold axis, along the
b direction. Packing is favored by van der Waals interactions.
The X-ray diffraction structure of the less bulky of the two
tripeptides studied, HCO-(Adm)2-Gly-OEt (4a, Figure 2), is stabilized
by a single i + 2 to i intramolecular hydrogen bond between the for-
myl carbonyl oxygen and the Adm(2) amide N-H (Table 2) in a
7-membered γ-turn conformation possessing characteristic backbone
ϕ1, ψ1 torsion angles [−75.9(3)ꢀ, 79.2(3)ꢀ] for the N-terminal Adm
(1) residue (Table 1).[23,24,29] Moreover, the values for the Adm
(2) backbone torsion angles are rather close to those expected for a
a
direction. Another intermolecular hydrogen bond is observed
between opposing Gly(3) amide N-H and Gly(3) ester C=O groups,
forming a (1-x, 1-y, 1-z) centrosymmetric pair (Table 2).
Peptides exhibiting two consecutive γ-turns are characteristic of
incipient γ-helices and relatively rare.[29] The crystal-state conformers
of dipeptide alkyl amides HCO-(Adm)2-NHR 4b and 4c (R = iPr and
tBu, Figures 3 and 4) illustrate the potential for the Adm residue to
favor such geometry. Both 4b and 4c feature a classical 7-membered
ring γ-turn structure with an i + 2 to i intramolecular hydrogen bond
between the formyl C O and the Adm(2) peptide N-H groups
(Table 2). In both 4b and 4c, the N-terminal Adm(1) residue adopts
characteristic ϕ1 and ψ1 torsion angles [76.49(12)ꢀ, −79.37(10)ꢀ for
4b, and −77.5(5)ꢀ, 84.8(4)ꢀ for 4c (Table 1)]. Moreover, the C-terminal
Adm(2) residue adopts γ-turn geometry in both dipeptides, which
exhibit i + 2 to i intramolecular hydrogen-bond distances between the
N-terminal Adm(1) carbonyl oxygen and the alkyl amide N-H (2.40 Å
and 2.10 Å, respectively, for 4b and 4c, Table 2). Although the ϕ2 tor-
sion angle matches ideal γ-turn geometry in both dipeptides, and the
ψ2 torsion angle is regular for 4c [70.5(4)ꢀ], ψ2 deviates significantly
[−88.12(10)ꢀ] from the ideal in 4b (Table 1). In both structures, an
intermolecular hydrogen bond is observed between the Adm(1) amide
FIGURE 4 X-Ray diffraction structure of HCO-(Adm)2-NHtBu
(4c). Displacement ellipsoids are drawn at the 30% probability level.
Most hydrogen atoms are omitted for clarity. The two C O…H─N
intramolecular hydrogen bonds are indicated by dashed lines
N-H and Adm(2)
C O groups in symmetry-related molecules

MIR ET AL.
7 of 9
TABLE 1 Backbone ϕ and ψ torsion angles (ꢀ) observed for the X-ray diffraction structures of Nα-formyl Adm-containing di- and tripeptides
Entry
2d
Peptide sequence
ϕ1
ψ1
75.06 (13)
ϕ2
ψ2
ϕ3
ψ3
Type of turn
HCO-Adm-Aib-OMe
HCO-(Adm)2-Gly-OEt
HCO-(Adm)2-NHiPr
HCO-(Adm)2-NHtBu
HCO-(Adm)2-Aib-OMe
72.41 (16)
−75.9 (3)
76.49 (12)
−77.5 (5)
63.1 (5)
−48.05 (16)
−69.2 (3)
69.79 (11)
−74.3 (4)
−51.4 (5)
−47.20 (15)
96.8 (3)
—
4a
79.2 (3)
−79.37 (10)
84.8 (4)
84.5 (3)
−158.4 (2)
One γ-turn, one “open” γ-turn
Two consecutive γ-turns
Two consecutive γ-turns
Distorted type-II0 β-turn
4b
−88.12 (10)
70.5 (4)
4c
4d
−96.9 (4)
−49.6 (5)
56.2 (5)
43.9 (5)
Abbreviations: Aib, α-aminoisobutyric acid; OMe, methoxy; OEt, ethoxy; NHiPr, iso-propylamino; NHtBu, tert-butylamino.
(Table 2), which pack respectively along the a direction and around
the 31 screw axis in the crystals of 4b and 4c.
consecutive γ-turn conformer, Ac-(Adm)2-NHMe could adopt a distorted
type-II (II0) β-turn with backbone torsion angles differing less than 10ꢀ
from those found for tripeptide 4d.[30] This nonhelical type of turn had
however not been previously reported experimentally for N-acyl Adm
dipeptide amide sequences. Overall, the crystal structures of 4b-d con-
firm that the double γ-turn and type-II (II0) β-turn conformations are
energetically accessible for -Adm-Adm- dipeptide sequences. Although
the ϕ and ψ torsion angles of the N-terminal Adm(1) residue in 4d are
rather close to those of a regular γ-turn, the distance (2.67 Å) between
the formyl C O oxygen and the Adm(2) peptide N-H is too long for an
intramolecular hydrogen bond.
In the crystal structure of the bulkier tripeptide HCO-(Adm)2-Aib-
OMe 4d (Figure 5), the -Adm-Adm- dipeptide adopts ϕ and ψ torsion
angles [63.1(5)ꢀ, −96.9(4)ꢀ; −51.4(5)ꢀ, −49.6(5)ꢀ (Table 1)] which are
reminiscent of the i + 1 and i + 2 residues of an ideal 10-membered ring
type-II0 β-turn structure (60ꢀ, −120ꢀ; −90ꢀ, 0ꢀ).[7–12] In spite of signifi-
cant distortion, an i + 3 to i intramolecular hydrogen bond (2.20 Å) is
observed between the formyl C O and Aib(3) peptide N─H groups
(Table 2). The conformation adopted by the C-terminal Aib(3) residue is
helical [ϕ3, ψ3 = 56.2(5)ꢀ, 43.9(5)ꢀ] with a screw-sense reversal with
respect to the preceding Adm(2) residue. As a result, the C-terminal
-Adm(2)-Aib(3)- sequence adopts an S-shaped folding[46,47] similar to
that observed for dipeptide 2d. However, in the case of 4d the torsion
angles of the two residues are closer to the values typical, respectively,
for a right-handed and a left-handed regular α-helical conformation
than those of 2d. Tripeptide 4d packs with an intermolecular hydrogen
bond between the N-terminal Adm(1) N-H and the central Adm(2) C=O
oxygen group of a (−x, ½ + y, ½-z) symmetry-related molecule (Table 2).
Previously, conformational energy calculations using density func-
tional theory [performed using the B3LYP functional combined with the
6-31 + G(d,p) basis set] had predicted that after the most stable
An overlay of the four structures containing the -(Adm)2- sequence,
namely HCO-(Adm)2-Gly-OEt (4a), HCO-(Adm)2-NHiPr (4b), HCO-
(Adm)2-NHtBu (4c), and HCO-(Adm)2-Aib-OMe (4d) is illustrated in
Figure 6. For 4b and 4d, the (−x, −y, −z) counterparts are shown for the
molecules to which torsion angles reported in Table 1 refer. In all four
structures, the ϕ torsion angle of the N-terminal Adm residue is negative
and ψ is positive, to enable a clear visual comparison. The maximum
overlap of the N-terminal Adm residue (positioned at the top) was used
to superimpose the four structures. Three of them, 4a, 4b, and 4c, show
close proximity also for their N-terminal formyl group and the second
Adm residue. The outlier is 4d, owing to its (distorted) β-turn fold,
TABLE 2 Intramolecular and intermolecular hydrogen-bond parameters for the X-ray diffraction structures of Nα-formyl Adm-containing
di- and tripeptides
Distance
Distance Angle
(Å) H…A
(ꢀ) D-H…A Symmetry equivalence of A
Entry Peptide sequence
Type
Donor D-H Acceptor A (Å) D…A
2d
HCO-Adm-Aib-OMe
Intermolecular N1-H1
Intermolecular N2-H2
Intramolecular N2-H2
Intermolecular N1-H1
Intermolecular N3-H3
Intramolecular N2-H2
Intramolecular NT-HT
Intermolecular N1-H1
Intramolecular N2-H2
Intramolecular NT-HT
Intermolecular N1-H1
O1
O0
O0
O2
O3
O0
O1
O2
O0
O1
O2
O0
O2
2.8448 (14) 2.02
3.0822 (16) 2.23
159.9
168.4
128.1
172.9
147.1
137.4
120.0
163.0
122.3
131.0
153.0
163
−x + 1/2, y + 1/2, −z + 1/2
−x + 1/2, y + 1/2, −z + 1/2z
4a
HCO-(Adm)2-Gly-OEt
2.935 (3)
2.851 (3)
3.163 (3)
2.31
1.98
2.39
x, y, z
x − 1, y, z
1 − x, 1 − y, 1 − z
x, y, z
4b
4c
4d
HCO-(Adm)2-NHiPr
HCO-(Adm)2-NHtBu
2.9167 (11) 2.22
2.9214 (11) 2.40
2.9026 (12) 2.03
x, y, z
x − 1, y, z
x, y, z
3.118 (5)
2.756 (5)
2.833 (5)
3.038 (5)
2.859 (5)
2.56
2.10
2.02
2.20
2.05
x, y, z
y − x, 1 − x, −1/3 + z
x, y, z
HCO-(Adm)2-Aib-OMe Intramolecular N3-H3
Intermolecular N1-H1
156
−x, 1/2 + y, 1/2 − z

8 of 9
MIR ET AL.
positions of type-III (III0)/I (I0) β-turns, and all types of extended struc-
tures, including the semi-extended, type-II poly-(Pro)n helix and the
fully extended structure.[16–18]
The observed backbone topologies concur with those previously
reported in X-ray diffraction analyses of Adm peptides, including Adm
homo-tripeptides,[30,31] in which incipient γ-helices as well as a rare
isolated α-turn with average ϕ and ψ torsion angle values of the same
sign [57.1ꢀ, 51.7ꢀ] were observed.[51–55] The two achiral amino acid
components in the -CO-Adm-Aib-OR sequences analyzed in the pre-
sent study, peptides 2d and 4d, both exhibit S-shaped helical conforma-
tions with opposite screw senses. The bias for this conformation may in
part be due to the extremely strong propensity for the Aib residue to
adopt helical geometry.[1–6] Whether this 3D-structural disposition is
restricted to isolated Nα-acyl dipeptide esters or may propagate to longer
sequences (e.g., −[Adm-Aib]n−, n > 1) remains to be investigated.
The steric bulk of the C-terminal amino substituent (-NHR)
appears to play a role on the conformation of the -Adm-Adm- dipep-
tide sequence. In contrast to the influences of Aib residues observed
in dipeptide 2d and tripeptide 4d discussed above, those of an addi-
tional Adm residue (in homo-tripeptides)[31] and tBu in dipeptide 4c
tend to favor a regular γ-turn conformation. On the other hand, less
bulky di- and trisubstituted carbons [e.g., in Cbz-Adm-Gly-OEt,[30]
and Gly in tripeptide 4a; iPr in dipeptide 4b, in HCO-(Adm)3-NHi-
Pr,[31] and in “N3”-(Adm)3-NHi-Pr[30]; and Ala in Cbz-Adm-L-Ala-
OMe,[28]] distort the ideal γ-turn torsion angle values by rotating the
Adm C-terminal amide away from serving as a correctly positioned
N-H hydrogen-bond donor. This 3D-structural change may generate
an open γ-turn and even an α-helical conformation. In addition to
steric bulk, the dipole interaction of ester moieties may likely dictate
rotation about the Adm C-terminal amide to influence potential for
adopting ideal γ-turn backbone torsion angles. In this context, this
study offers light on design elements for favoring specific peptide
FIGURE 6 Overlay of the X-ray diffraction structures of HCO-
(Adm)2-Gly-OEt (4a) (red), HCO-(Adm)2-NHiPr (4b) (orange), HCO-
(Adm)2-NHtBu (4c) (green), and HCO-(Adm)2-Aib-OMe (4d) (blue).
See text for details
characterized inter alia by the helical backbone torsion angles adopted
by Adm(2).
4
| DISCUSSION
The backbone conformations of four Nα-formyl Adm homo-dipeptide
sequences possessing various C-terminal secondary amide compo-
nents were determined in the crystal state using X-ray diffraction.
Moreover, the corresponding -Adm-Aib- hetero-dipeptide sequence
with a C-terminal ester group was also investigated. Although the
results of the present study are limited to similar sequences that may
largely depend on the crystallization solvent and crystal packing
forces, certain trends do emerge from examination of the influences
exerted by the nature of the C-terminal groups.
secondary structures using Adm as
residue.
a
novel Cα,α-dialkylglycine
ACKNOWLEDGMENTS
This research was supported by the Natural Sciences and Engineering
Research Council of Canada (NSERC) Discovery Grant RGPIN-06647,
the FRQNT Centre in Green Chemistry and Catalysis (CGCC) Strategic
Cluster RS-171310, and the Université de Montréal. We thank
Mr. T. Maris (X-ray diffraction), C. Malveau, Dr. P. Aguiar and S. Bilodeau
(NMR spectroscopy), Dr. A. Fürtös, K. Gilbert, and M.-C. Tang (mass
spectrometry) from Université de Montréal Laboratories for their assis-
tance in analyses.
Two ϕ and ψ regions of the Ramachandran map were predomi-
nantly found to be explored by the Adm residues. In the most exten-
sively populated region, the two backbone torsion angles ( 60ꢀ < ϕ <
80ꢀ and 70ꢀ < ψ < 95ꢀ) are characterized by opposite sign. Within
this region, ϕ and ψ values of comparable magnitude (up to 80ꢀ) are
typical of the central residue of an intramolecularly hydrogen-bonded
γ-turn and are also observed in consecutive γ-turns of incipient γ-heli-
ces, whereas ψ values larger than 80ꢀ are associated with slightly dis-
torted (open) γ-turns and may be as well tolerated at position i + 1 of
a type-II (II0) β-turn. The second region, characterized by ϕ and ψ tor-
sion angles with the same sign and ψ > 50ꢀ, may host the i + 2 posi-
tion of a distorted type-II (II0) β-turn. The steric bulk of the Adm
residue apparently restricts the ϕ and ψ values from adopting confor-
mations common to homo-peptides based on Cα,α-disubstituted gly-
cines with smaller substituents, including the 310-helix, both corner
ORCID
Fatemeh M. Mir
Marco Crisma
https://orcid.org/0000-0002-0653-9010
https://orcid.org/0000-0003-3552-4106
https://orcid.org/0000-0002-2327-1423
https://orcid.org/0000-0002-3080-2712
Claudio Toniolo
William D. Lubell

MIR ET AL.
9 of 9
[34] T. Yamada, Y. Omote, Y. Yamanaka, T. Miyadawa, S. Kuwata, Synthe-
sis 1998, 1998, 991.
REFERENCES
[1] N. Shamala, R. Nagaraj, P. Balaram, Chem. Commun. 1978, 996.
[2] E. Benedetti, A. Bavoso, B. Di Blasio, V. Pavone, C. Pedone, M. Crisma,
G. M. Bonora, C. Toniolo, J. Am. Chem. Soc. 1982, 104, 2437.
[3] C. Toniolo, E. Benedetti, Macromolecules 1991, 24, 4004.
[4] I. L. Karle, Biopolymers 2001, 60, 351.
[35] T. Pirali, G. C. Tron, G. Masson, J. Zhu, Org. Lett. 2007, 9, 5275.
[36] S. Kotha, M. Behera, P. Khedkar, Tetrahedron Lett. 2004, 45, 7589.
[37] M. C. Burla, R. Caliandro, B. Carrozzini, G. L. Cascarano, C. Cuocci,
C. Giacovazzo, M. Mallamo, A. Mazzone, G. Polidori, J. Appl.
Crystallogr. 2015, 48, 306.
[5] R. Gessmann, H. Brückner, K. Petratos, J. Pept. Sci. 2016, 22, 76.
[6] J. Solá, M. Helliwell, J. Clayden, Biopolymers 2011, 95, 62.
[7] C. M. Venkatachalam, Biopolymers 1968, 6, 1425.
[8] J. A. Geddes, K. B. Parker, E. D. T. Atkins, E. Beighton, J. Mol. Biol.
1968, 32, 343.
[38] G. M. Sheldrick, Acta Crystallogr. A 2015, 71, 3.
[39] G. M. Sheldrick, Acta Crystallogr. C 2015, 71, 3.
[40] L. J. Bourhis, O. V. Dolomanov, R. J. Gildea, J. A. K. Howard,
H. Puschmann, Acta Crystallogr. A 2015, 71, 59.
[41] F. Formaggio, Q. B. Broxterman, C. Toniolo, in Houben-Weyl,
Methods of Organic Chemistry, Vol. E22c, Synthesis of Peptides and
Peptidomimetics (Eds: M. Goodman, A. Felix, L. Moroder, C. Toniolo),
Thieme, Stuttgart, Germany 2003, p. 292.
[9] P. N. Lewis, F. A. Momany, H. A. Scheraga, Biochim. Biophys. Acta
1973, 303, 211.
[10] C. Toniolo, CRC Crit. Rev. Biochem. 1980, 9, 1.
[11] J. A. Smith, L. G. Pease, CRC Crit. Rev. Biochem. 1980, 8, 315.
[12] G. D. Rose, L. M. Gierasch, J. A. Smith, Adv. Protein Chem. 1985,
37, 1.
[42] H. Brückner, M. Currle, in Second Forum on Peptides, Vol. 174 (Eds:
A. Aubry, M. Marraud, B. Vitoux), Libbey Eurotext, Paris 1989, p. 251.
[43] S. Samsoniya, D. Zurabishvili, T. Bukia, G. Buzaladze, M. Lomidze,
E. Elizbarashvili, U. Kazmaier, Bull. Georgian Natl. Acad. Sci. 2014, 8, 85.
[44] M. Nespolo, M. I. Aroyo, B. Souvignier, J. Appl. Crystallogr. 2018, 51,
1481.
[13] L. Pauling, R. B. Corey, H. R. Branson, Proc. Natl. Acad. Sci. USA 1951,
37, 205.
[14] C. Toniolo, E. Benedetti, Trends Biochem. Sci. 1991, 16, 350.
[15] C. Toniolo, M. Crisma, F. Formaggio, C. Peggion, Biopolymers 2001,
60, 396.
[45] L. Pérez-Garcia, D. B. Amabilino, Chem. Soc. Rev. 2002, 31, 342.
[46] V. K. Goel, M. Guha, A. P. Baxia, S. Dey, T. P. Singh, J. Mol. Struct.
2003, 658, 135.
[16] E. Benedetti, V. Barone, A. Bavoso, B. Di Blasio, F. Lelj, V. Pavone,
C. Pedone, G. M. Bonora, C. Toniolo, M. Leplawy, Biopolymers 1988,
27, 357.
[47] E. Vijayaraghavan, V. K. Goel, S. Dey, T. P. Singh, Struct. Chem. 2005,
16, 445.
[17] M. Tanaka, Chem. Pharm. Bull. (Tokyo) 2007, 55, 349.
[18] C. Peggion, A. Moretto, F. Formaggio, M. Crisma, C. Toniolo, Biopoly-
mers 2013, 100, 621.
[48] R. Taylor, O. Kennard, W. Versichel, Acta Crystallogr. B 1984, 40, 280.
[49] C.-H. Görbitz, Acta Crystallogr. B 1989, 45, 390.
[50] I. Y. Torshin, I. T. Weber, R. W. Harrosin, Protein Eng. 2002, 15, 359.
[51] V. Pavone, G. Gaeta, A. Lombardi, F. Nastri, O. Maglio, C. Isernia,
M. Saviano, Biopolymers 1996, 38, 705.
[19] A. P. Marchand, Science 2003, 299, 52.
[20] H. Schwertfeger, A. A. Fokin, P. R. Schreiner, Angew. Chem. Int. Ed.
2008, 47, 1022.
[52] K.-C. Chou, Biopolymers 1997, 42, 837.
[21] L. Wanka, K. Iqbal, P. R. Schreiner, Chem. Rev. 2013, 113, 3516.
[22] M. A. Gunawan, J.-C. Hierso, D. Poinsot, A. A. Fokin, N. A. Fokina,
B. A. Tkachenko, P. R. Schreiner, New J. Chem. 2014, 38, 28.
[23] G. Némethy, M. P. Printz, Macromolecules 1972, 5, 755.
[24] B. W. Matthews, Macromolecules 1972, 5, 818.
[25] J. L. Flippen-Anderson, I. L. Karle, Biopolymers 1976, 15, 1081.
[26] E. J. Milner-White, B. M. Ross, R. Ismail, K. Belhadj-Mostefa, R. Poet,
J. Mol. Biol. 1988, 204, 777.
[53] C. Ramakrishnan, D. V. Nataraj, J. Pept. Sci. 1998, 4, 239.
[54] M. Narita, K. Sode, S. Ohuchi, Bull. Chem. Soc. Jpn 1999, 72, 1807.
[55] B. Dasgupta, L. Pal, G. Basu, P. Chakrabarti, Proteins: Struct. Funct.
Bioinform. 2004, 55, 305.
SUPPORTING INFORMATION
[27] A. I. Jiménez, G. Ballano, C. Cativiela, Angew. Chem. Int. Ed. 2005,
44, 396.
Additional supporting information may be found online in the
Supporting Information section at the end of this article.
[28] R. Kishore, P. Balaram, Biopolymers 1985, 24, 2041.
[29] M. Crisma, M. De Zotti, A. Moretto, C. Peggion, B. Drouillat, K. Wright,
F. Couty, C. Toniolo, F. Formaggio, New J. Chem. 2015, 39, 3208.
[30] D. Mazzier, L. Grassi, A. Moretto, C. Alemán, F. Formaggio,
C. Toniolo, M. Crisma, J. Pept. Sci. 2017, 23, 346.
[31] F. M. Mir, M. Crisma, C. Toniolo, W. D. Lubell, unpublished.
[32] Y. Kuroda, H. Ueda, H. Nozawa, H. Ogoshi, Tetrahedron Lett. 1997,
38, 7901.
How to cite this article: Mir FM, Crisma M, Toniolo C,
Lubell WD. Influence of the C-terminal substituent on the
crystal-state conformation of Adm peptides. Pept Sci. 2019;
e24121. https://doi.org/10.1002/pep2.24121
[33] J. Donohue, Proc. Natl. Acad. Sci. USA 1953, 39, 470.