research communications\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890

A cyclic carbo-isosteric penta-depsipeptide: cyclo(Phe1D-Ala2–Gly3–Phe4–APO5)

aGlobal Discovery Chemistry, Novartis Institutes for Biomedical Research, Novartis International AG, CH-4002 Basel, Switzerland
*Correspondence e-mail: stephanie.gueret@novartis.com

Edited by A. J. Lough, University of Toronto, Canada (Received 4 December 2014; accepted 15 December 2014; online 1 January 2015)

The title compound, cyclo(Phe1D-Ala2–Gly3–Phe4–APO5), C26H32N4O5, is the minor diastereoisomer of a cyclic penta-peptidomimetic analogue containing a novel 2-amino­propyl lactone (APO) motif, which displays the same number of atoms as the native amino acid glycine and has a methyl group in place of the carbonyl O atom. The crystal structure presented here allows the analysis of the secondary structure of this unprecedented cyclic carbo-isosteric depsipeptide. The conformation of the central ring is stabilized by an intra­molecular N—H⋯O hydrogen bond between the carbonyl O atom of the first residue (Phe1) and the amide group H atom of the fourth residue (Phe4). Based on the previously reported hydrogen bond and on the values of the torsion angles φ and ψ, the loop formed by the first, second, third and fourth residues (Phe1, D-Ala2, Gly3 and Phe4) can be classified as a type II′ β-turn. The loop around the new peptidomimetic motif, on the other hand, resembles an open γ-turn containing a weak N—H⋯O hydrogen bond between the carbonyl group O atom of the fourth residue (Phe4) and the amide unit H atom of the first residue (Phe1). In the crystal, the peptidomimetic mol­ecules are arranged in chains along the b-axis direction. Within such a chain, the mol­ecules of the structure are linked via N—H⋯O hydrogen bonds between the amide group H atom of the secondary residue (D-Ala2) and the carb­oxy unit O atom of the fourth residue (Phe4) in a neighboring mol­ecule. The newly formed methyl stereocentre of the APO peptidomimetic motif (APO5) was obtained as the minor diastereoisomer in a ring-closing reductive amination reaction and adopts an R configuration.

1. Chemical context

Cyclic peptidomimetics, with their ability to mimic the secondary structure of peptides, represent a very attractive class of macrocycles. While still being modular and promising a strong affinity for a broad range of biological targets, they have improved pharmacological properties and bioavailability compared to linear peptides.

[Scheme 1]

During our research, we have developed a highly selective cyclization method to access a new class of cyclic carbo-isosteric depsipeptides (Guéret et al., 2014[Guéret, S. M., Meier, P. & Roth, H. J. (2014). Org. Lett. 16, 1502-1505.]). Our strategy allowed the formation of a novel APO motif which is believed to mimic the glycine amino-acid structure. In order to study the secondary structure of our peptidomimetic motifs, we have started crystallization trials for various analogues. The first compound for which we obtained crystals suitable for single crystal structure determination was the title compound cyclo(Phe1D-Ala2–Gly3–Phe4–APO5).

2. Structural commentary

The cyclic carbo-isosteric depsipeptide cyclo(Phe1D-Ala2–Gly3–Phe4–APO5) was obtained as the minor diastereoisomer in a ring-closing reductive amination reaction between the C-terminal methyl ketone and the N-terminal amine of phenyl­alanine 1 of the linear precursor H2N–Phe1D-Ala2–Gly3–Phe4–CO2CH2COCH3. The two natural amino acids, Phe1 and Phe4 are in an L-configuration, whereas the unnatural alanine unit, Ala2 is in a D-configuration, following the Cahn–Ingold–Prelog priority rules or CORN rules (Cahn et al., 1966[Cahn, R. S., Ingold, C. K. & Prelog, V. (1966). Angew. Chem. Int. Ed. Engl. 5, 385-415.]). Based on the known stereochemistry of the backbone amino acids, the absolute configuration of the newly formed methyl stereocentre α to the secondary amine (N9) of the minor diastereoisomer could be unambiguously assigned as C19R. The result is supported by a Flack x parameter of 0.10 (11), calculated using the quotient method (Parsons & Flack, 2004[Parsons, S. & Flack, H. (2004). Acta Cryst. A60, s61.]) as implemented in the 2013 version of SHELXL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]). The structure of the title compound in the crystal, including the residue-labelling scheme, is shown in Fig. 1[link].

[Figure 1]
Figure 1
The structure of the title compound in the crystal, including the residue-labelling scheme. Non-H atoms are represented by displacement ellipsoids drawn at the 50% probability level. H atoms are represented as small spheres of arbitrary radius. The atom labelling has been omitted for clarity but is displayed in Fig. 2[link].

The secondary structure of the cyclic peptidomimetic, in which all peptidic bonds adopt a trans conformation, is stabilized by a β-turn containing an intra­molecular hydrogen bond (Table 1[link], Fig. 2[link]) between the carbonyl oxygen O23 of the first residue (Phe1) and the amide hydrogen N15—H15 of the residue located three residues after the first residue (Phe4). The related torsion angle values fall into the corresponding type II′ β-turn Ramachandran plot area (Ramachandran et al., 1963[Ramachandran, G. N., Ramakrishnan, C. & Sasisekharan, V. (1963). J. Mol. Biol. 7, 95-99.]). The APO peptidomimetic motif adopts an open γ-turn with a loose hydrogen bond between the carbonyl oxygen of the lactone unit (O25) of the first residue (Phe4) and the secondary amine (N9) of the residue located two residues after the first (Phe1). Selected backbone torsion angles are given in Table 2[link] and a review on the secondary structure of peptides and proteins is given by Smith et al. (1980[Smith, J. A., Pease, L. G. & Kopple, K. D. (1980). Crit. Rev. Biochem. Mol. Biol. 8, 315-399.]).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
N9—H9⋯O25 0.95 (3) 2.49 (3) 3.338 (3) 149 (2)
N15—H15⋯O23 0.83 (3) 2.08 (3) 2.853 (3) 155 (2)
N18—H18⋯O34i 0.87 (3) 2.29 (3) 3.163 (4) 177 (3)
N21—H21⋯O25ii 0.80 (3) 2.18 (3) 2.949 (3) 161 (3)
Symmetry codes: (i) [x-{\script{1\over 2}}, -y+{\script{3\over 2}}, -z+2]; (ii) [-x+2, y+{\script{1\over 2}}, -z+{\script{3\over 2}}].

Table 2
Selected backbone torsion angles (°)

Phe1 C10—N9—C8—C22 φ1 −61.6 (2)
Phe1 N9—C8—C22—N21 ψ1 131.8 (2)
D-Ala2 C22—N21—C20—C19 φ2 55.4 (2)
D-Ala2 N21—C20—C19—N18 ψ2 −134.2 (2)
Gly3 C19—N18—C17—C16 φ3 −79.0 (3)
Gly3 N18—C17—C16—N15 ψ3 −4.0 (3)
Phe4 C16—N15—C14—C13 φ4 −121.6 (2)
Phe4 N15—C14—C13—O12 ψ4 40.3 (2)
APO5 C13—O12—C11—C10 φ5 103.6 (2)
APO5 O12—C11—C10—N9 ψ5 −77.0 (2)
[Figure 2]
Figure 2
The atom- and residue-labelling scheme of the title compound, showing the intra­molecular hydrogen bond. All atoms are represented as small spheres of arbitrary radius.

3. Supra­molecular features

The cyclo(Phe1D-Ala2–Gly3–Phe4–APO5) mol­ecules align in the crystal in infinite chains parallel to the b axis (Fig. 3[link]). Within each chain, the peptide mol­ecules are linked via hydrogen bonds between O25 and N21—H21 (blue). The individual chains are loosely connected via hydrogen bonds between O34 and N18—H18 (orange).

[Figure 3]
Figure 3
Packing diagram along the face diagonal of the plane defined by the a and c axes, showing the hydrogen-bonded chains parallel to b. Hydrogen bonds are indicated as green (intra­molecular), blue (inter­molecular within the chains) and orange (inter­molecular between chains) dotted lines. H atoms have been omitted for clarity.

4. Synthesis and crystallization

Step 1 The linear precursor H2N-Phe1D-Ala2–Gly3–Phe4–CO2CH2COCH3 (90.7 mg, 152 µmol) was stirred in hydrogen chloride (4 M in 1,4-dioxane, 20.0 ml) at 0° C for 1 h, then at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting amine was used in the following step without further purification. Step 2 The previously obtained crude amine was dissolved in DMF (15.2 ml) and acetic acid (152 µl, 2.66 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h. Step 3 To the imine reaction mixture, sodium cyano­borohydride (11.5 mg, 182 µmol) was added followed by methanol (3.80 ml), leading to a final concentration of 8 mM with a 1:4 ratio of MeOH/DMF. The resulting reaction mixture was stirred at room temperature for 16 h and then concentrated under vacuum. The crude residue was directly purified by preparative RP-HPLC on an Atlantis Prep T3 OBD (30 × 150 mm; 5 µm) column at a flow rate of 60 ml/min with a step gradient of 5 to 15% for 2.5 min, 15 to 35% for 12 min, 35 to 45% for 2 min, then 45 to 95% for 0.1 min of MeCN in H2O + 0.1% TFA. Selected fractions were combined and lyophilized to yield the desired cyclic peptidomimetic (65.0 mg, 85%) as a white fluffy solid, TFA salt and a 81:19 mixture of two diastereoisomers. A fraction of the purified mixture of diastereoisomers (29 mg) was re-purified by preparative chiral-HPLC using a Chiralpak (20 × 250 mm; 5 µm) column at a flow rate of 12 ml/min with an optimized n-hepta­ne/i-PrOH/MeOH/DEA (80:18:2:0.03) isocratic gradient to afford the major diastereoisomer (16.0 mg, d.e. = 98.9%) as a desalted white fluffy solid and the minor diastereoisomer (3.2 mg, d.e. = 99.4%) as desalted white fluffy solid.

Crystallization of minor diastereoisomer Crystals of the title compound were obtained by dissolving the minor diastereo­isomer in a minimum amount of ethyl acetate and n-heptane (1:1) from which the solvents were allowed to slowly evapor­ate at room temperature.

Analytical data of the crystalline minor diastereoisomer HRMS (ESI) calculated for C26H33N4O5 [M + H]+: 481.2541, found 481.2448. IR (neat) νmax/cm−1 3335 (br), 3065, 3035, 2940, 1730, 1675 (br), 1545, 1480, 1455, 1205, 1135, 750, 725, 700. 1H NMR (600 MHz, (CD3)2SO) 8.81 (1H, dd, J = 7.2 and 5.2 Hz, NH), 8.59 (1H, d, J = 4.6 Hz, NH), 7.85 (1H, d, J = 9.7 Hz, NH), 7.33–7.16 (10H, m, 2 × Phe-5ArH), 4.77 (1H, td, J = 9.3 and 6.0 Hz, Phe-Hα), 3.97 (1H, dd, J = 7.1 and 4.6 Hz, Ala-Hα), 3.86–3.73 (3H, m, OCH2 and Gly-Hα), 3.41 (1H, t, J = 7.3 Hz, Phe-Hα), 3.36–3.34 (2H, m, Gly-Hα), 3.18 (1H, dd, J = 13.9 and 6.0 Hz, Phe-Hβ), 2.94 (1H, dd, J = 13.9 and 9.0 Hz, Phe-Hβ), 2.68 (1H, dd, J = 13.6 and 6.5 Hz, Phe-Hβ), 2.62 (1H, dd, J = 13.6 and 8.0 Hz, Phe-Hβ), 2.59–2.53 (1H, m, CHCH3), 2.18 (1H, s, NHamine), 1.12 (3H, d, J = 7.0 Hz, Ala-3Hβ), 0.78 (3H, d, J = 6.4 Hz, CHCH3). 13C NMR (150 MHz, (CD3)2SO) 176.5, 173.9, 170.2, 168.5, 138.6, 137.3, 129.2 (4 × CH), 128.4 (2 × CH), 127.9 (2 × CH), 126.6, 126.1, 67.5, 60.2, 52.8, 51.3, 50.1, 42.5, 39.5, 37.6, 17.4, 15.9.

5. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3[link]. The C-bound H atoms were calculated in idealized positions (C–H = 0.98–1.00 Å) and refined using a riding model with Uiso(H) = 1.2Ueq(parent atom). The hydrogen atoms of the amide groups and the hy­droxy group were located in a difference Fourier map and allowed to refine freely.

Table 3
Experimental details

Crystal data
Chemical formula C26H32N4O5
Mr 480.56
Crystal system, space group Orthorhombic, P212121
Temperature (K) 100
a, b, c (Å) 10.126 (9), 15.096 (14), 15.355 (13)
V3) 2347 (4)
Z 4
Radiation type Cu Kα
μ (mm−1) 0.78
Crystal size (mm) 0.12 × 0.07 × 0.05
 
Data collection
Diffractometer Bruker SMART 6000 CCD
Absorption correction Multi-scan (SADABS; Sheldrick, 1999[Sheldrick, G. M. (1999). SADABS. University of Göttingen, Germany.])
Tmin, Tmax 0.486, 0.753
No. of measured, independent and observed [I > 2σ(I)] reflections 23011, 4133, 3847
Rint 0.075
(sin θ/λ)max−1) 0.595
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.047, 0.112, 1.09
No. of reflections 4133
No. of parameters 330
H-atom treatment H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3) 0.31, −0.43
Absolute structure Flack x determined using 1590 quotients [(I+)−(I)]/[(I+)+(I)] (Parsons & Flack, 2004[Parsons, S. & Flack, H. (2004). Acta Cryst. A60, s61.])
Absolute structure parameter 0.10 (11)
Computer programs: SMART (Bruker, 2003[Bruker (2003). SMART. Bruker AXS Inc., Madison, Wisconsin, USA.]), SAINT (Bruker, 2004[Bruker (2004). SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]), SHELXS97 and SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]), PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]) and publCIF (Westrip, 2010[Westrip, S. P. (2010). J. Appl. Cryst. 43, 920-925.]).

Supporting information


Computing details top

Data collection: SMART (Bruker, 2003); cell refinement: SAINT (Bruker, 2004); data reduction: SAINT (Bruker, 2004; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009); software used to prepare material for publication: publCIF (Westrip, 2010).

3,12-Dibenzyl-9,14-dimethyl-1-oxa-4,7,10,13-tetraazacyclopentadecane-2,5,8,11-tetrone top
Crystal data top
C26H32N4O5Dx = 1.360 Mg m3
Mr = 480.56Cu Kα radiation, λ = 1.54178 Å
Orthorhombic, P212121Cell parameters from 9940 reflections
a = 10.126 (9) Åθ = 4.1–68.8°
b = 15.096 (14) ŵ = 0.78 mm1
c = 15.355 (13) ÅT = 100 K
V = 2347 (4) Å3Block, colourless
Z = 40.12 × 0.07 × 0.05 mm
F(000) = 1024
Data collection top
Bruker SMART 6000 CCD
diffractometer
4133 independent reflections
Radiation source: Microstar rotating anode generator3847 reflections with I > 2σ(I)
Incoatec multilayer mirrors monochromatorRint = 0.075
Detector resolution: 5.6 pixels mm-1θmax = 66.6°, θmin = 4.1°
ω scansh = 1212
Absorption correction: multi-scan
(SADABS; Sheldrick, 1999)
k = 1717
Tmin = 0.486, Tmax = 0.753l = 1818
23011 measured reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.047H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.112 w = 1/[σ2(Fo2) + (0.0764P)2]
where P = (Fo2 + 2Fc2)/3
S = 1.09(Δ/σ)max = 0.011
4133 reflectionsΔρmax = 0.31 e Å3
330 parametersΔρmin = 0.43 e Å3
0 restraintsAbsolute structure: Flack x determined using 1590 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons & Flack, 2004)
0 constraintsAbsolute structure parameter: 0.10 (11)
Primary atom site location: structure-invariant direct methods
Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
C10.6916 (2)0.75967 (14)0.68262 (14)0.0209 (4)
H10.68940.73330.73880.025*
C20.6031 (2)0.82691 (14)0.66282 (14)0.0227 (4)
H20.54310.84750.70580.027*
C30.6026 (2)0.86397 (14)0.58022 (15)0.0223 (4)
H30.54130.90950.56630.027*
C40.6915 (2)0.83465 (15)0.51801 (14)0.0231 (4)
H40.69040.85940.46110.028*
C50.7827 (2)0.76883 (14)0.53901 (13)0.0206 (4)
H50.84500.75010.49660.025*
C60.7835 (2)0.73002 (14)0.62175 (13)0.0191 (4)
C70.8833 (2)0.65948 (13)0.64407 (13)0.0191 (4)
H7A0.92030.63540.58930.023*
H7B0.83740.61050.67440.023*
C80.9979 (2)0.69186 (13)0.70179 (13)0.0178 (4)
H81.03990.74480.67410.021*
N91.09594 (18)0.62140 (11)0.70982 (11)0.0188 (4)
H91.056 (2)0.5716 (19)0.7369 (18)0.023*
C101.2144 (2)0.64565 (14)0.76043 (13)0.0196 (4)
H101.19090.69410.80210.024*
C111.2647 (2)0.56634 (14)0.81143 (14)0.0213 (4)
H11A1.26320.51300.77390.026*
H11B1.35710.57700.82970.026*
O121.18248 (15)0.55144 (9)0.88820 (9)0.0204 (3)
C131.0956 (2)0.48517 (13)0.88625 (14)0.0196 (4)
C141.0182 (2)0.48060 (14)0.97123 (13)0.0198 (4)
H141.07800.45361.01580.024*
N150.98462 (18)0.56809 (12)1.00179 (11)0.0191 (4)
H150.949 (3)0.6021 (18)0.9664 (19)0.023*
C161.0227 (2)0.59836 (14)1.08029 (13)0.0184 (4)
C170.9816 (2)0.69272 (14)1.10269 (13)0.0212 (4)
H17A0.92360.69041.15450.025*
H17B1.06190.72611.11940.025*
N180.9139 (2)0.74228 (11)1.03547 (11)0.0197 (4)
H180.828 (3)0.7378 (18)1.0336 (17)0.024*
C190.9831 (2)0.77969 (13)0.96966 (13)0.0175 (4)
C200.8968 (2)0.82801 (14)0.90145 (13)0.0197 (4)
H200.80260.80970.90900.024*
N210.94164 (18)0.80253 (12)0.81497 (12)0.0188 (4)
H210.953 (3)0.8414 (19)0.7802 (19)0.023*
C220.94722 (18)0.71732 (13)0.79294 (13)0.0165 (4)
O230.91694 (15)0.65798 (9)0.84460 (9)0.0196 (3)
C241.3230 (2)0.67838 (15)0.69969 (15)0.0236 (5)
H24A1.35040.63010.66100.035*
H24B1.39880.69820.73420.035*
H24C1.28960.72790.66470.035*
O251.08111 (16)0.43461 (10)0.82577 (10)0.0245 (3)
C260.8961 (2)0.42006 (14)0.96385 (15)0.0238 (5)
H26A0.92450.36090.94340.029*
H26B0.85630.41281.02230.029*
C270.7928 (2)0.45570 (14)0.90239 (15)0.0222 (5)
C280.7071 (2)0.52271 (15)0.92819 (15)0.0244 (5)
H280.70780.54260.98690.029*
C290.6201 (2)0.56087 (15)0.86874 (17)0.0275 (5)
H290.56310.60720.88720.033*
C300.6156 (2)0.53217 (15)0.78319 (16)0.0271 (5)
H300.55680.55900.74280.033*
C310.6983 (2)0.46364 (15)0.75708 (15)0.0254 (5)
H310.69500.44260.69880.030*
C320.7853 (2)0.42612 (15)0.81573 (15)0.0245 (5)
H320.84130.37930.79710.029*
O331.08418 (17)0.55439 (10)1.13399 (10)0.0268 (4)
O341.10326 (14)0.77972 (10)0.96627 (9)0.0220 (3)
C350.9080 (3)0.92754 (14)0.91424 (15)0.0258 (5)
H35A1.00020.94580.90670.039*
H35B0.87830.94310.97300.039*
H35C0.85270.95790.87120.039*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0215 (10)0.0231 (10)0.0180 (10)0.0008 (9)0.0012 (8)0.0021 (8)
C20.0219 (10)0.0258 (10)0.0206 (11)0.0004 (9)0.0018 (8)0.0027 (8)
C30.0211 (10)0.0214 (10)0.0244 (11)0.0019 (9)0.0031 (9)0.0020 (8)
C40.0258 (11)0.0238 (10)0.0197 (10)0.0018 (9)0.0035 (9)0.0019 (9)
C50.0214 (11)0.0239 (11)0.0163 (10)0.0001 (8)0.0017 (8)0.0022 (8)
C60.0191 (10)0.0199 (10)0.0183 (10)0.0038 (8)0.0030 (8)0.0015 (8)
C70.0221 (10)0.0192 (10)0.0160 (9)0.0009 (8)0.0005 (8)0.0017 (8)
C80.0202 (10)0.0172 (9)0.0161 (9)0.0002 (8)0.0009 (8)0.0029 (7)
N90.0199 (9)0.0186 (9)0.0180 (9)0.0007 (7)0.0003 (7)0.0003 (7)
C100.0206 (11)0.0209 (10)0.0174 (10)0.0004 (8)0.0006 (8)0.0028 (8)
C110.0191 (10)0.0262 (11)0.0186 (10)0.0001 (8)0.0023 (8)0.0007 (9)
O120.0213 (7)0.0245 (8)0.0153 (7)0.0021 (6)0.0003 (6)0.0002 (6)
C130.0207 (10)0.0161 (9)0.0221 (10)0.0023 (8)0.0013 (8)0.0006 (8)
C140.0248 (11)0.0190 (10)0.0157 (9)0.0008 (9)0.0005 (8)0.0021 (8)
N150.0253 (9)0.0165 (8)0.0155 (9)0.0030 (7)0.0023 (7)0.0015 (7)
C160.0187 (10)0.0229 (10)0.0137 (9)0.0011 (8)0.0009 (8)0.0029 (8)
C170.0284 (11)0.0204 (10)0.0148 (10)0.0001 (9)0.0004 (9)0.0001 (7)
N180.0205 (9)0.0203 (9)0.0183 (9)0.0002 (7)0.0008 (7)0.0006 (7)
C190.0228 (11)0.0151 (9)0.0145 (9)0.0016 (8)0.0000 (8)0.0030 (7)
C200.0217 (10)0.0193 (10)0.0182 (10)0.0019 (9)0.0007 (8)0.0003 (8)
N210.0260 (9)0.0169 (9)0.0134 (8)0.0004 (7)0.0001 (7)0.0023 (7)
C220.0154 (9)0.0188 (10)0.0153 (10)0.0001 (7)0.0038 (7)0.0012 (8)
O230.0240 (7)0.0194 (7)0.0153 (7)0.0010 (6)0.0002 (6)0.0011 (5)
C240.0233 (10)0.0239 (10)0.0237 (11)0.0002 (9)0.0006 (9)0.0003 (8)
O250.0272 (8)0.0244 (7)0.0219 (8)0.0005 (7)0.0011 (6)0.0057 (6)
C260.0273 (11)0.0189 (10)0.0251 (11)0.0004 (9)0.0024 (9)0.0027 (8)
C270.0200 (10)0.0173 (10)0.0294 (11)0.0052 (8)0.0027 (9)0.0024 (8)
C280.0225 (11)0.0234 (10)0.0273 (11)0.0047 (9)0.0041 (9)0.0040 (9)
C290.0189 (11)0.0236 (11)0.0399 (14)0.0003 (9)0.0004 (9)0.0027 (10)
C300.0207 (10)0.0233 (11)0.0374 (13)0.0024 (9)0.0028 (9)0.0022 (10)
C310.0220 (11)0.0266 (11)0.0275 (12)0.0054 (9)0.0004 (9)0.0038 (9)
C320.0220 (11)0.0205 (10)0.0309 (11)0.0016 (9)0.0025 (9)0.0034 (9)
O330.0357 (9)0.0265 (8)0.0183 (7)0.0055 (7)0.0044 (7)0.0016 (6)
O340.0221 (8)0.0232 (7)0.0206 (7)0.0003 (6)0.0016 (6)0.0003 (6)
C350.0357 (12)0.0195 (10)0.0221 (10)0.0034 (10)0.0016 (9)0.0014 (8)
Geometric parameters (Å, º) top
C1—C21.387 (3)C16—C171.523 (3)
C1—C61.393 (3)C17—N181.447 (3)
C1—H10.9500C17—H17A0.9900
C2—C31.386 (3)C17—H17B0.9900
C2—H20.9500N18—C191.353 (3)
C3—C41.385 (3)N18—H180.87 (3)
C3—H30.9500C19—O341.218 (3)
C4—C51.394 (3)C19—C201.546 (3)
C4—H40.9500C20—N211.455 (3)
C5—C61.399 (3)C20—C351.519 (3)
C5—H50.9500C20—H201.0000
C6—C71.507 (3)N21—C221.331 (3)
C7—C81.540 (3)N21—H210.80 (3)
C7—H7A0.9900C22—O231.235 (3)
C7—H7B0.9900C24—H24A0.9800
C8—N91.460 (3)C24—H24B0.9800
C8—C221.539 (3)C24—H24C0.9800
C8—H81.0000C26—C271.508 (3)
N9—C101.475 (3)C26—H26A0.9900
N9—H90.95 (3)C26—H26B0.9900
C10—C111.519 (3)C27—C281.391 (3)
C10—C241.524 (3)C27—C321.406 (4)
C10—H101.0000C28—C291.393 (4)
C11—O121.461 (3)C28—H280.9500
C11—H11A0.9900C29—C301.384 (4)
C11—H11B0.9900C29—H290.9500
O12—C131.333 (3)C30—C311.390 (4)
C13—O251.211 (3)C30—H300.9500
C13—C141.523 (3)C31—C321.381 (4)
C14—N151.442 (3)C31—H310.9500
C14—C261.542 (3)C32—H320.9500
C14—H141.0000C35—H35A0.9800
N15—C161.345 (3)C35—H35B0.9800
N15—H150.83 (3)C35—H35C0.9800
C16—O331.228 (3)
C2—C1—C6121.3 (2)N18—C17—C16116.85 (18)
C2—C1—H1119.4N18—C17—H17A108.1
C6—C1—H1119.4C16—C17—H17A108.1
C3—C2—C1119.9 (2)N18—C17—H17B108.1
C3—C2—H2120.1C16—C17—H17B108.1
C1—C2—H2120.1H17A—C17—H17B107.3
C4—C3—C2120.0 (2)C19—N18—C17120.2 (2)
C4—C3—H3120.0C19—N18—H18121.6 (18)
C2—C3—H3120.0C17—N18—H18117.1 (18)
C3—C4—C5119.9 (2)O34—C19—N18123.31 (19)
C3—C4—H4120.0O34—C19—C20122.35 (19)
C5—C4—H4120.0N18—C19—C20114.24 (19)
C4—C5—C6120.81 (19)N21—C20—C35110.87 (18)
C4—C5—H5119.6N21—C20—C19108.49 (17)
C6—C5—H5119.6C35—C20—C19109.68 (18)
C1—C6—C5118.1 (2)N21—C20—H20109.3
C1—C6—C7121.49 (19)C35—C20—H20109.3
C5—C6—C7120.40 (18)C19—C20—H20109.3
C6—C7—C8114.32 (17)C22—N21—C20120.04 (18)
C6—C7—H7A108.7C22—N21—H21122.1 (19)
C8—C7—H7A108.7C20—N21—H21117.4 (19)
C6—C7—H7B108.7O23—C22—N21121.80 (19)
C8—C7—H7B108.7O23—C22—C8119.05 (18)
H7A—C7—H7B107.6N21—C22—C8119.11 (18)
N9—C8—C22109.38 (16)C10—C24—H24A109.5
N9—C8—C7109.26 (17)C10—C24—H24B109.5
C22—C8—C7110.56 (17)H24A—C24—H24B109.5
N9—C8—H8109.2C10—C24—H24C109.5
C22—C8—H8109.2H24A—C24—H24C109.5
C7—C8—H8109.2H24B—C24—H24C109.5
C8—N9—C10114.60 (16)C27—C26—C14113.00 (18)
C8—N9—H9109.2 (15)C27—C26—H26A109.0
C10—N9—H9107.9 (15)C14—C26—H26A109.0
N9—C10—C11110.42 (17)C27—C26—H26B109.0
N9—C10—C24110.16 (18)C14—C26—H26B109.0
C11—C10—C24109.20 (18)H26A—C26—H26B107.8
N9—C10—H10109.0C28—C27—C32117.8 (2)
C11—C10—H10109.0C28—C27—C26120.9 (2)
C24—C10—H10109.0C32—C27—C26121.1 (2)
O12—C11—C10110.26 (17)C27—C28—C29120.6 (2)
O12—C11—H11A109.6C27—C28—H28119.7
C10—C11—H11A109.6C29—C28—H28119.7
O12—C11—H11B109.6C30—C29—C28120.9 (2)
C10—C11—H11B109.6C30—C29—H29119.6
H11A—C11—H11B108.1C28—C29—H29119.6
C13—O12—C11118.28 (16)C29—C30—C31119.2 (2)
O25—C13—O12124.8 (2)C29—C30—H30120.4
O25—C13—C14124.47 (19)C31—C30—H30120.4
O12—C13—C14110.74 (17)C32—C31—C30120.1 (2)
N15—C14—C13111.01 (17)C32—C31—H31120.0
N15—C14—C26112.16 (19)C30—C31—H31120.0
C13—C14—C26112.10 (18)C31—C32—C27121.4 (2)
N15—C14—H14107.1C31—C32—H32119.3
C13—C14—H14107.1C27—C32—H32119.3
C26—C14—H14107.1C20—C35—H35A109.5
C16—N15—C14122.33 (19)C20—C35—H35B109.5
C16—N15—H15120.0 (18)H35A—C35—H35B109.5
C14—N15—H15117.2 (18)C20—C35—H35C109.5
O33—C16—N15124.3 (2)H35A—C35—H35C109.5
O33—C16—C17119.49 (19)H35B—C35—H35C109.5
N15—C16—C17116.21 (18)
C6—C1—C2—C32.0 (3)O33—C16—C17—N18177.65 (19)
C1—C2—C3—C40.9 (3)N15—C16—C17—N184.0 (3)
C2—C3—C4—C51.0 (3)C16—C17—N18—C1979.0 (3)
C3—C4—C5—C61.7 (3)C17—N18—C19—O345.5 (3)
C2—C1—C6—C51.2 (3)C17—N18—C19—C20178.25 (17)
C2—C1—C6—C7177.58 (19)O34—C19—C20—N2149.5 (3)
C4—C5—C6—C10.6 (3)N18—C19—C20—N21134.16 (19)
C4—C5—C6—C7179.45 (19)O34—C19—C20—C3571.7 (3)
C1—C6—C7—C875.1 (3)N18—C19—C20—C35104.6 (2)
C5—C6—C7—C8103.7 (2)C35—C20—N21—C22175.89 (19)
C6—C7—C8—N9172.90 (16)C19—C20—N21—C2255.4 (2)
C6—C7—C8—C2266.7 (2)C20—N21—C22—O231.1 (3)
C22—C8—N9—C1061.6 (2)C20—N21—C22—C8178.64 (17)
C7—C8—N9—C10177.27 (17)N9—C8—C22—O2345.8 (2)
C8—N9—C10—C11145.33 (18)C7—C8—C22—O2374.5 (2)
C8—N9—C10—C2494.0 (2)N9—C8—C22—N21131.84 (19)
N9—C10—C11—O1277.0 (2)C7—C8—C22—N21107.8 (2)
C24—C10—C11—O12161.69 (17)N15—C14—C26—C2759.4 (2)
C10—C11—O12—C13103.6 (2)C13—C14—C26—C2766.3 (2)
C11—O12—C13—O251.6 (3)C14—C26—C27—C2878.9 (3)
C11—O12—C13—C14179.37 (16)C14—C26—C27—C3297.2 (2)
O25—C13—C14—N15140.7 (2)C32—C27—C28—C292.1 (3)
O12—C13—C14—N1540.3 (2)C26—C27—C28—C29174.1 (2)
O25—C13—C14—C2614.4 (3)C27—C28—C29—C301.0 (3)
O12—C13—C14—C26166.61 (17)C28—C29—C30—C310.7 (3)
C13—C14—N15—C16121.6 (2)C29—C30—C31—C321.2 (3)
C26—C14—N15—C16112.1 (2)C30—C31—C32—C270.0 (3)
C14—N15—C16—O332.8 (3)C28—C27—C32—C311.7 (3)
C14—N15—C16—C17178.95 (19)C26—C27—C32—C31174.6 (2)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N9—H9···O250.95 (3)2.49 (3)3.338 (3)149 (2)
N15—H15···O230.83 (3)2.08 (3)2.853 (3)155 (2)
N18—H18···O34i0.87 (3)2.29 (3)3.163 (4)177 (3)
N21—H21···O25ii0.80 (3)2.18 (3)2.949 (3)161 (3)
Symmetry codes: (i) x1/2, y+3/2, z+2; (ii) x+2, y+1/2, z+3/2.
Selected backbone torsion angles (°) top
Phe1C10—N9—C8—C22φ1-61.6 (2)
Phe1N9—C8—C22—N21ψ1131.8 (2)
D-Ala2C22—N21—C20—C19φ255.4 (2)
D-Ala2N21—C20—C19—N18ψ2-134.2 (2)
Gly3C19—N18—C17—C16φ3-79.0 (3)
Gly3N18—C17—C16—N15ψ3-4.0 (3)
Phe4C16—N15—C14—C13φ4-121.6 (2)
Phe4N15—C14—C13—O12ψ440.3 (2)
APO5C13—O12—C11—C10φ5103.6 (2)
APO5O12—C11—C10—N9ψ5-77.0 (2)
 

Acknowledgements

We thank Philippe Piechon for crystallizing the title compound.

References

First citationBruker (2003). SMART. Bruker AXS Inc., Madison, Wisconsin, USA.  Google Scholar
First citationBruker (2004). SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.  Google Scholar
First citationCahn, R. S., Ingold, C. K. & Prelog, V. (1966). Angew. Chem. Int. Ed. Engl. 5, 385–415.  CrossRef CAS Web of Science Google Scholar
First citationGuéret, S. M., Meier, P. & Roth, H. J. (2014). Org. Lett. 16, 1502–1505.  PubMed Google Scholar
First citationParsons, S. & Flack, H. (2004). Acta Cryst. A60, s61.  CrossRef IUCr Journals Google Scholar
First citationRamachandran, G. N., Ramakrishnan, C. & Sasisekharan, V. (1963). J. Mol. Biol. 7, 95–99.  CrossRef PubMed CAS Web of Science Google Scholar
First citationSheldrick, G. M. (1999). SADABS. University of Göttingen, Germany.  Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationSmith, J. A., Pease, L. G. & Kopple, K. D. (1980). Crit. Rev. Biochem. Mol. Biol. 8, 315–399.  CrossRef CAS Google Scholar
First citationSpek, A. L. (2009). Acta Cryst. D65, 148–155.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationWestrip, S. P. (2010). J. Appl. Cryst. 43, 920–925.  Web of Science CrossRef CAS IUCr Journals Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Follow Acta Cryst. E
Sign up for e-alerts
Follow Acta Cryst. on Twitter
Follow us on facebook
Sign up for RSS feeds