Crystal structures of dipeptides derived from the β-amino acids (1R,2S)-2-aminocyclopentanecarboxylic acid and (1S,2R,3S)-2-amino-3- methylcyclopentanecarboxylic acid

Article abstract of DOI:10.1007/s10870-011-0164-x

Crystals of the dimeric β-peptides 13 and 20, derived from (1R,2S)-2-aminocyclopentanecarboxylic acid and (1S,2R,3S)-2-amino-3- methylcyclopentanecarboxylic acid, respectively, were synthesised and studied by X-ray diffraction in order to establish their

Full text of DOI:10.1007/s10870-011-0164-x

J Chem Crystallogr (2011) 41:1722–1728
DOI 10.1007/s10870-011-0164-x
ORIGINAL PAPER
Crystal Structures of Dipeptides Derived from the b-Amino Acids
(1R,2S)-2-Aminocyclopentanecarboxylic Acid and (1S,2R,3S)-2-Amino-
3-methylcyclopentanecarboxylic Acid
•
Elin Abraham Stephen G. Davies
•
•
•
Paul M. Roberts Amber L. Thompson
James E. Thomson
Received: 28 March 2011 / Accepted: 29 June 2011 / Published online: 19 July 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Crystals of the dimeric b-peptides 13 and 20,
derived from (1R,2S)-2-aminocyclopentanecarboxylic acid
and (1S,2R,3S)-2-amino-3-methylcyclopentanecarboxylic
acid, respectively, were synthesised and studied by X-ray
diffraction in order to establish their solid state secondary
structural characteristics. Compound 13 crystallises in the
monoclinic space group P 21 with cell parameters of
concerning the secondary structural characteristics of
b-peptides derived from (S,S)-2-aminocyclopentane-
carboxylic acid [(S,S)-ACPC or (S,S)-transpentacin] [29].
These studies indicated that hexamer 5 and pentamer 4
persist as a 12-helix in both the solid state and solution
phase. The conformational traits of a 12-helix were also
exhibited by oligomers with as few as three residues in the
solid state, although in solution trimer 2 was found to exist
as an equilibrium of many alternative conformers whilst
tetramer 3 has been shown to predominantly exist in either
a 12-helix or turn-type conformation. Furthermore, the
introduction of C(3)-alkyl substitution around the 2-ami-
nocyclopentanecarboxylic acid scaffold did not affect the
secondary structural preferences and, for example a
12-helical secondary structure was adopted in the solid
state and solution phase conformations of C(3)-substituted
hexamers 6 and 7 (Fig. 1) [30].
˚
a = 5.2682(1) A, b = 9.1211(2) A, c = 22.4467(6) A,
˚
˚
3
˚
b = 91.3855(9)°, V = 1078.29(4) A and Z = 2. Com-
pound 20 crystallizes in the orthorhombic space group P 21
˚
21 21 with cell parameters of a = 5.0968(1) A, b =
3
˚
˚
˚
11.5546(2) A, c = 43.5414(8) A, V = 2564.22(8) A and
Z = 4. In both cases adjacent molecules are linked by a
series of N–HÁÁÁO=C hydrogen bonds to form b-sheet like
structures.
Keywords b-Peptides Á b-Sheet Á Asymmetric synthesis Á
Lithium amide Á Parallel kinetic resolution
¨
Fu¨lop et al. [31] have reported that pentamer 8, derived
from (1R,2S)-ACPC [(1R,2S)-cispentacin], forms a non-
polar strand and adopts a sheet-like structure in solution.
We therefore proposed to investigate the effect of intro-
ducing C(3)-alkyl substituents around the 2-aminocyclo-
pentanecarboxylic acid scaffold on the secondary structure
of this class of b-peptides 9 and report herein our crystal-
lographic studies on both the substituted and unsubstituted
dimers (n = 2, R = Me or H) (Fig. 2).
Introduction
Within the field of peptidomimetics, b-peptides are known
to offer improved bioavailability and therapeutic lifetimes
when compared to the a-amino acid derived analogues [1–
5] whilst still displaying potent biological activity [6–8]; as
such they have been the subject of several investigations
[9–28]. Within this area we have recently reported studies
Experimental
Boc-[(1R,2S)-ACPC]2-OtBu 13
E. Abraham Á S. G. Davies (&) Á P. M. Roberts Á
A. L. Thompson Á J. E. Thomson
Step 1: A stirred solution of 11 [32] (2.76 g, 14.9 mmol,
97:3 dr, [98% ee) in CHCl3 (25 mL) was successively
treated with Et3N (10.4 mL, 74.5 mmol), HOBt (2.42 g,
Department of Chemistry, Chemistry Research Laboratory,
University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
e-mail: steve.davies@chem.ox.ac.uk
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J Chem Crystallogr (2011) 41:1722–1728
1723
[99:1 dr) and Boc2O (75 mg, 0.34 mmol) in MeOH
(5 mL). The resulting suspension was stirred under H2
(1 atm) for 16 h, after which time the reaction mixture was
filtered through CeliteÒ (eluent MeOH) and concentrated in
vacuo. Purification via recrystallisation (CHCl3/heptane)
gave 13 as a white crystalline solid (70 mg, 57%, [99:1
dr); mp 149–150 °C (CHCl3/heptane); [a]2D1 - 74.2 (c 0.6
in CHCl3); vmax (KBr) 3376, 3342 (N–H), 1715, 1687,
1653, 1525 (C=O); dH (400 MHz, CDCl3) 1.35–2.05 (12H,
m, 2 9 C(3)H2, 2 9 C(4)H2, 2 9 C(5)H2) overlapping
1.42 (9H, s, CMe3) and 1.43 (9H, s, CMe3), 2.64–2.75 (1H,
m, C(1)H), 2.82–2.91 (1H, m, C(1)H), 4.05–4.17 (1H, m,
C(2)H), 4.40–4.51 (1H, m, C(2)H), 5.12 (1H, d, J 7.9, NH),
6.19 (1H, d, J 8.5, NH); dC (100 MHz, CDCl3) 22.2, 22.6,
28.0, 28.2, 32.5, 32.7 (2 9 C(3), 2 9 C(4), 2 9 C(5)),
28.1, 28.4 (2 9 CMe3), 47.3, 47.8 (2 9 C(1)), 52.0, 54.1
(2 9 C(2)), 79.0, 80.8 (2 9 CMe3), 155.6 (NCO [carba-
mate]), 173.2, 173.7 (NCO [amide], COt2Bu); m/z (ESI?)
Fig. 1 b-Peptides 1-7 and the overlaid X-ray crystal structures of 5
(blue, R = Boc), 6 (purple) and 7 (green) (selected H atoms are
omitted for clarity) (Color figure online)
419 ([M ? Na]?, 100%); HRMS (ESI?) C21H36N2NaO5
?
([M ? Na]?) requires 419.2516; found 419.2515.
Cbz-[(1S,2R,3S)-3-Me-ACPC]2-OtBu 20
Step 1: DDQ (8.60 g, 370 mmol) was added to a stirred
solution of 15 [34] (8.60 g, 190 mmol,[99:1 dr) in MeCN/
water (v/v 5:1, 190 mL). The resultant mixture was stirred
at rt for 32 h then satd aq K2CO3 (200 mL) was added. The
organic layer was washed sequentially with satd aq K2CO3
(2 9 100 mL) and brine (100 mL), then dried and con-
centrated in vacuo. Purification via flash column chroma-
tography (gradient elution, 2% ? 33% EtOAc in
40–60 °C petrol) gave 16 as a colourless oil (2.81 g, 49%,
[99:1 dr); [a]D18 ? 183 (c 1.0 in CHCl3); vmax (film) 3331,
2957, 1722, 1455, 1366, 1147, 761, 701; dH (400 MHz,
CDCl3) 0.94 (3H, d, J 6.1, C(3)Me), 0.96–1.08 (1H, m,
C(5)HA), 1.29 (3H, d, J 6.5, C(a)Me), 1.52 (9H, s, CMe3),
1.58 (1H, br s, NH), 1.67–1.95 (4H, m, C(3)H, C(4)H2,
C(5)HB), 2.35–2.44 (1H, m, C(1)H), 2.85–2.94 (1H, m,
C(2)H), 3.91 (1H, q, J 6.5, C(a)H), 7.81–7.46 (5H, m, Ph);
dC (100 MHz, CDCl3) 17.8 (C(3)Me), 25.3 (C(a)Me), 27.9
(CMe3), 28.3 (C(5)), 32.4 (C(4)), 42.3 (C(3)), 53.3 (C(1)),
56.2 (C(2)), 67.6 (C(a)), 79.9 (CMe3), 126.9, 126.9, 128.3
(o,m,p-Ph), 146.1 (i-Ph), 176.4 (COt2Bu); m/z (ESI?) 304
Fig. 2 Pentamer 8 [derived from (1R,2S)-ACPC] and C(3)-substi-
tuted b-peptides 9
17.9 mmol), 10 [33] (3.92 g, 14.9 mmol, [99:1 dr, [98%
ee) and EDCÁHCl (3.43 g, 17.9 mmol) under anhydrous
conditions. After 16 h, the reaction mixture was washed
sequentially with 1.0 M aq HCl (20 mL), satd aq NaHCO3
(20 mL) and brine (20 mL), then dried and concentrated in
vacuo. Purification via recrystallisation (CHCl3/heptane)
gave 12 as a white crystalline solid (3.88 g, 61%, [99:1
dr); mp 92–94 °C (CHCl3/heptane); [a]1D8 - 64.4 (c 1.1 in
CHCl3); vmax (KBr) 3335 (N–H), 1717, 1697, 1655 (C=O);
dH (400 MHz, CDCl3) 1.43 (9H, s, CMe3), 1.47–2.07 (12H,
m, 2 9 C(3)H2, 2 9 C(4)H2, 2 9 C(5)H2), 2.69–2.78 (1H,
m, C(1)H), 2.84 (1H, app q, J 7.5, C(1)H), 4.11–4.23 (1H,
m, C(2)H), 4.38–4.48 (1H, m, C(2)H), 5.04 (1H, d, J 12.5,
OCHAHBPh), 5.11 (1H, d, J 12.5, OCHAHBPh), 5.43 (1H,
d, J 7.5 NH), 6.20 (1H, d, J 8.5 NH), 7.28–7.39 (5H, m,
Ph); dC (100 MHz, CDCl3) 22.2, 22.7, 28.0, 28.3, 32.4,
32.8 (2 9 C(3), 2 9 C(4), 2 9 C(5)), 28.1 (CMe3), 47.3,
48.2 (2 9 C(1)), 52.0, 54.6 (2 9 C(2)), 66.2 (OCH2Ph),
80.8 (CMe3), 128.0, 128.0, 128.4 (o,m,p-Ph), 136.5 (i-Ph),
156.1 (NCO [carbamate]), 173.0, 173.7 (NCO [amide],
COt2Bu); m/z (ESI?) 453 ([M ? Na]?, 100%); HRMS
?
([M ? H]?, 100%); HRMS (ESI?) C19H30NO2
([M ? H]?) requires 304.2271; found 304.2276.
Step 2: Pd(OH)2/C (25% by wt., 870 mg) was added to a
stirred, degassed solution of 16 (3.48 g, 11.5 mmol,[99:1
dr) in MeOH/AcOH (v/v 40:1, 41 mL). The resulting
suspension was stirred under H2 (5 atm) for 36 h. The
reaction mixture was then filtered through CeliteÒ (eluent
MeOH) and concentrated in vacuo. The residue was
redissolved in CH2Cl2 (40 mL) and washed with satd aq
NaHCO3 (3 9 40 mL) and brine (40 mL), then dried and
(ESI?) C24H34N2NaO5 ([M ? Na]?) requires 453.2360;
?
found 453.2360.
Step 2: Pd(OH2)/C (25% by wt., 34 mg) was added to a
stirred, degassed solution of 12 (134 mg, 0.31 mmol,
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J Chem Crystallogr (2011) 41:1722–1728
˚
concentrated in vacuo to give 17 as a colourless oil (1.88 g,
82%, [99:1 dr) [34]; [a]2D1 - 46.4 (c 1.2 in CHCl3); {lit.
[34] for enantiomer [a]2D2 ? 51.8 (c 1.0 in CHCl3)}; dH
(400 MHz, CDCl3) 1.20 (3H, d, J 6.5, C(3)Me), 1.08–1.21
(1H, m, C(4)HA), 1.44 (2H, br s, NH2), 1.47 (9H, s, CMe3),
1.72–2.00 (4H, m, C(3)H, C(4)HB, C(5)H2), 2.80–2.88
(1H, m, C(1)H), 2.92 (1H, app t, J 7.5, C(2)H).
k = 0.71073 A) at 150(2) K with an Oxford Cryosystems
Cryostream N2 open-flow cooling device [35] and pro-
cessed using the DENZO-SMN package [36], including
unit cell parameter refinement and inter-frame scaling
(which were carried out using SCALEPACK within
DENZO-SMN).
The structures were solved using SIR92 [37]. Refine-
ment was carried out using full-matrix least-squares within
the CRYSTALS suite [38], on F2. All non-hydrogen atoms
were refined with anisotropic displacement parameters.
Hydrogen atoms on nitrogen atoms were generally visible
in the difference map and their positions and isotropic
displacement parameters were refined using restraints prior
to inclusion into the model with riding constraints [39].
The Flack x parameters [40, 41] for 13 and 20 were
determined to be 0.5(17) and -1.4(14), and analysis [42,
43] of the Bijvoet pairs gave Hooft y parameters [44] of -
0.3(7) and 0.01(5), respectively. The Bayesian analysis
gave the probability that the structure of 13 is the correct
enantiomer as 77% assuming enantiopurity and 49%
allowing for the possibility of racemic twinning; the cor-
responding values of 82 and 53% were obtained for 20. In
the absence of a significant anomalous signal, the Friedel
pairs were merged for the final refinement for both
structures.
Step 3: Et3N (1.04 mL, 7.48 mmol) and CbzCl
(1.07 mL, 7.48 mol) were added sequentially to a stirred
solution of 17 (1.36 g, 6.80 mmol,[99:1 dr) in anhydrous
THF (200 mL) at 0 °C. The resultant mixture was then
allowed to warm to rt and stirred for 16 h before the addi-
tion of brine (200 mL). The aqueous layer was extracted
with CH2Cl2 (2 9 200 mL) and the combined organic
extracts were then dried and concentrated in vacuo. Purifi-
cation via flash column chromatography (gradient elution,
2% ? 18% EtOAc in 40–60 °C petrol) gave 18 as a col-
ourless oil (2.09 g, 92%, [99:1 dr); [a]2D1 ? 74.2 (c 1.1 in
CHCl3); vmax (film) 3337 (N–H), 1725 (br), 1512 (C=O); dH
(400 MHz, CDCl3)1.02 (3H, d, J 6.3, C(3)Me), 1.11–1.27
(1H, m, C(4)HA), 1.40 (9H, s, CMe3), 1.80–2.02 (4H, m,
C(3)H, C(4)HB, C(5)H2), 2.96–3.06 (1H, m, C(1)H), 3.76
(1H, app q, J 9.4, C(2)H), 5.10 (2H, s, OCH2Ph), 5.21 (1H,
d, J 9.4, NH), 7.26-7.42 (5H, m, Ph); dC (100 MHz, CDCl3)
17.8 (C(3)Me), 26.8, 39.7 (C(4), C(5)), 28.0 (CMe3), 31.1
(C(3)), 46.9 (C(1)), 60.2 (C(2)), 66.6 (OCH2Ph), 80.7
(CMe3), 128.0, 128.1, 128.5 (o,m,p-Ph), 136.6 (i-Ph), 156.2
(NCO), 174.2 (CO2t Bu); m/z (ESI?) 334 ([M ? H]?,
Selected structural details for 13 and 20 are included in
Table 1 and full crystallographic data have been deposited
with the Cambridge Crystallographic Data Centre as sup-
plementary publication numbers CCDC 815399 and
815400, respectively. Copies of these data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
?
100%); HRMS (ESI?) C19H28NO4 ([M ? H]?) requires
334.2013; found 334.2022.
Step 4: TFA (3 mL) was added to a stirred solution of 18
(1.73 g, 5.20 mmol, [99:1 dr) in CH2Cl2 (9 mL) at 0 °C.
The reaction mixture was allowed to warm to rt and stirred
for 3 h before being concentrated in vacuo and dried under
high vacuum to give 19 as a colourless oil (1.19 g, 83%,
[99:1 dr); [a]D23 ? 44.3 (c 0.9 in CHCl3); vmax (film) 3290
(br, N–H, O–H), 1714, 1517 (C=O); dH (400 MHz, MeOH-
d4) 0.99 (3H, d, J 6.5, C(3)Me), 1.09–1.24 (1H, m, C(4)HA),
1.83–2.13 (4H, m, C(3)H, C(4)HB, C(5)H2), 2.90 (1H, app
q, J 7.6, C(1)H), 3.70 (1H, app t, J 7.6, C(2)H) 5.02 (1H, d,
J 12.3, OCHAHBPh), 5.12 (1H, d, J 12.3, OCHAHBPh),
7.26–7.40 (5H, m, Ph); dC (100 MHz, MeOH-d4) 17.1
(C(3)Me), 26.4 (C(5)), 31.3 (C(4)), 38.8 (C(3)), 46.8 (C(1)),
61.0 (C(2)), 66.4 (OCH2Ph), 127.7, 127.9, 128.4 (o,m,p-
Ph), 137.4 (i-Ph), 157.8 (NCO), 176.9 (CO2H); m/z (ESI-)
276 ([M - H]-, 100%); HRMS (ESI-) C15H18NO4- ([M–
H]-) requires 276.1241; found 276.1240.
Results and Discussion
b-Peptides 13 and 20 were prepared in accordance with our
previously optimised coupling procedures [29, 30].1 Thus,
coupling of the monomer acid 10 [33] and monomer amine
11 [34]2 was achieved with HOBt/EDCÁHCl to give dimer
12 in [97:3 dr. Purification of the reaction mixture via
recrystallisation (CHCl3/heptane) gave dimer 12 in 61%
1
It was found that 2,6-di-tert-butylphenol (2,6-DTBP) was not
compatible with preparing large quantities ([10 g) of the prerequisite
b-amino ester in the lithium amide conjugate addition step. Thus, an
alternative, scalable procedure was developed using 2-pyridone to
quench the lithium b-amino enolate which produced a 97:3 mixture of
C(2)-epimeric b-amino esters. For other diastereoselective protona-
tions of lithium b-amino enolates with 2-pyridone from our labora-
tory, see Refs. [45–47].
Single Crystal X-ray Diffraction
2
b-Amino ester (1R,2S)-11 was converted to the corresponding (R)-
and (RS)-MTPA derivatives (Mosher’s amides) and was determined
to be[98% ee by both H and 19F NMR spectroscopic analyses. See
Refs. [48–50].
1
Single crystal diffraction data for 13 and 20 were collected
using a Nonius j-CCD diffractometer (Mo-Ka radiation,
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J Chem Crystallogr (2011) 41:1722–1728
1725
Table 1 Crystallographic data and refinement details for compounds
13 and 20
Compound
13
20
Empirical formula
Formula weight
Crystal habit, colour
Crystal system
C21H36N2O5
396.53
C26H38N2O5
458.60
Plate, colourless
Monoclinic
P21
Plate, colourless
Orthorhombic
P212121
5.0968(1)
11.5546(2)
43.5414(8)
90
Space group
˚
a (A)
5.2682(1)
9.1211(2)
22.4467(6)
90
˚
b (A)
˚
c (A)
a (°)
b (°)
c (°)
91.3855(9)
90
90
90
3
˚
Volume (A )
1078.29(4)
2
2564.22(8)
4
Z
Density (calc. g cm-3
)
1.221
1.188
Temperature (K)
190
190
˚
Radiation type/k (A)
Mo Ka/0.71073
0.086
Mo Ka/0.71073
0.082
Absorption coeff.
(mm-1
)
F(000)
432
992
Crystal size (mm)
0.05 9 0.10 9 0.10 0.20 9 0.30 9 0.30
Reflections measured
4833
5334
3272
2%
Scheme 1 Reagents and conditions: (i) EDCÁHCl, HOBt, NEt3,
CHCl3, rt, 16 h; (ii) Pd(OH)2/C, Boc2O, H2 (1 atm), MeOH, rt, 16 h;
(iii) lithium (S)-N-benzyl-N-(a-methylbenzyl)amide and lithium (R)-
N-3,4-dimethoxybenzyl-N-(a-methylbenzyl)amide (50:50 mixture),
THF, -78 °C, 3 h, then NH4Cl (satd, aq); (iv) DDQ, CH2Cl2/H2O
(5:1 v/v), rt, 32 h; (v) Pd(OH)2/C, H2 (5 atm), MeOH/AcOH (40:1
v/v), 36 h; (vi) CbzCl, NEt3, THF, 0 °C to rt, 16 h; (vii) TFA/CH2Cl2
(1:3 v/v), 0 °C to rt, 3 h. [Ar = 3,4-dimethoxyphenyl]
Independent reflections 2596
Rint
2.5%
1595
Observed reflns.
2001
[I [ 2.0r(I)]
Number of parameters 253
Goodness-of-fit on F2
298
1.112
1.103
Final R indices
[I [ 2.0r(I)]
R indices [all data]
R1 = 0.038,
wR2 = 0.067
R1 = 0.042,
wR2 = 0.091
purification via flash column chromatography. Subsequent
removal of the N-a-methylbenzyl group via hydrogenolysis
gave 17 in 82% yield,[99:1 dr and[98% ee.3 Treatment of
17 with CbzCl gave 18 in 92% yield followed by TFA
promoted ester hydrolysis to give N-Cbz protected b-amino
acid 19 in 83% yield,[99:1 dr and[98% ee. Utilising the
HOBt/EDCÁHCl/CHCl3 mediated protocol, monomer acid
19 and monomer amine 17 were coupled to give Cbz-
[(1S,2R,3S)-3-Me-ACPC]2-OtBu 20 in 68% yield and
[99:1 dr (Scheme 1). Recrystallisation of 20 from CH2Cl2/
pentane gave colourless prisms which were subjected to
X-ray diffraction analysis. Unfortunately, all attempts at the
recrystallisation of the corresponding trimers, tetramers and
pentamers (which were all prepared using our standard
coupling methodology) [29, 30] were unsuccessful.
R1 = 0.083,
wR2 = 0.076
R1 = 0.082,
wR2 = 0.103
-3
˚
Dqmax, Dqmin (e A
)
0.18, -0.16
0.19, -0.18
CCDC deposition no.
815399
815400
isolated yield as a single diastereoisomer ([99:1 dr).
Subsequent treatment of dimer 12 with Boc2O and
Pd(OH)2/C under an atmosphere of H2 gave Boc-[(1R,2S)-
ACPC]2-OtBu 13 in 57% yield and [99:1 dr. Recrystalli-
sation of 13 from CHCl3/heptane gave colourless prisms
which were subjected to X-ray diffraction analysis.
The monomeric units 19 and 17 were prepared from
(RS)-14 using our previously reported parallel kinetic res-
olution (PKR) methodology [30, 34, 51, 52]. Oxidative
removal of the N-(3,4-dimethoxybenzyl) group within 15
was achieved upon treatment with DDQ [34]. Thus, under
the optimised conditions for this transformation treatment
of b-amino ester 15 (89% diastereoisomeric purity) [34]
with DDQ gave 16 in 49% isolated yield and[99:1 dr after
The molecular structures of 13 and 20 are illustrated in
(Fig. 3). In both cases the adjacent molecules are linked by
3
b-Amino ester (1S,2R,3S)-17 was converted to the corresponding
(R)- and (RS)-MTPA derivatives (Mosher’s amides) and was deter-
mined to be [98% ee by both 1H and 19F NMR spectroscopic
analyses. See Refs. [48–50].
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Fig. 3 Molecular structure of 13 (left) and 20 (right), showing the displacement ellipsoids drawn at the 50% probability level
Fig. 4 H-bonding within the
crystal structures of 13 (left) and
20 (right), selected H atoms are
omitted for clarity. Hydrogen
bonding interactions are shown
as a dotted line forming
R2,2(14) rings that connect
together to give C2,2(14) chains
[for 13: N–HÁÁÁO=3.141(4),
˚
3.106(4) A; for 20: N–
HÁÁÁO=3.062(4), 2.994(4) A]
˚
a series of intermolecular N–HÁÁÁO=C hydrogen bonds to
form tape-like arrangements in the crystal structure
formed from R2,2(14) rings (Fig. 4) [53]. There is
excellent parity between the two structures despite them
possessing different N-protecting groups and differing by
virtue of the additional C(3)-methyl group in each of the
monomeric units within 20. As the two peptides were
synthesised in the opposite enantiomeric series (with
respect to the parent 2-aminocyclopentanecarboxylic acid
scaffold), 20 has been represented as its antipode so that
the two structures can be overlaid4 for comparison
(Fig. 5). The C(3)-methyl groups within 20 do not,
therefore, disrupt the hydrogen bonding in the solid state.
This finding is consistent with our observations that C(3)-
methyl substitution does not disrupt the helical secondary
structure of b-peptides derived from the epimeric b-amino
acid (1S,2S,3R)-2-amino-3-methylcyclopentanecarboxylic
acid [30].
Whilst it was not possible to produce crystals of the
corresponding trimers, tetramers or pentamers which were
suitable for X-ray crystallographic analyses, a combination
1
of IR, H NMR and CD spectroscopic analyses confirmed
that these oligomers display traits indicative of intermo-
lecular hydrogen bonding and are therefore consistent with
a similar conformation in solution.
4
The structures of 13 and ent-20 were overlaid using the Chem-3D
structure mapping function.
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J Chem Crystallogr (2011) 41:1722–1728
1727
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Fig. 5 Overlaid molecular structures of 13 (green) and ent-20
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Conclusion
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In conclusion, the crystal structures of the b-peptides Boc-[(1R,
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20, derived from (1R,2S)-2-aminocyclopentanecarboxylic
acid and (1S,2R,3S)-2-amino-3-methylcyclopentanecarboxylic
acid respectively, were studied by X-ray diffraction.
In both cases adjacent molecules are linked by a series of
N–HÁÁÁO=C hydrogen bonds to form sheet like structures.
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Supporting Information
´
´
´
¨
28. Martinek TA, Mandity IM, Fu¨lop L, Toth GK, Vaas E, Hollosi
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M, Forro E, Fu¨lop F (2006) J Am Chem Soc 128:13539
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Full crystallographic data for 13 and 20 have been depos-
ited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 815399 and
815400, respectively. Copies of these data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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