Buy article online - an online subscription or single-article purchase is required to access this article.
Download citation
Download citation
link to html
The pseudodipeptide, (S)-N-iso­propyl {[N-(pivaloyl)­pyrrol­idin-2-yl]­methyl­amino­oxy}acet­amide, C15H29N3O3, adopts a global extended conformation with the hydroxy­l­amine group in the g+/g structure. The C-terminal amide NH interacts intramolecularly with the hydroxy­lamine O atom. Both NH bonds of each mol­ecule are hydrogen bonded to the C-­terminal amide carbonyl of a neighbouring mol­ecule.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270100006478/gs1085sup1.cif
Contains datablocks I, aero

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S0108270100006478/gs1085Isup2.hkl
Contains datablock I

CCDC reference: 150342

Comment top

The so-called reduced peptide group Cα-CH2—NH—Cα is often used to mimic the transient state Cα-C(OH)2—NH—Cα of the peptide group during enzymatic cleavage of the amide bond (Epps et al., 1988; Sawyer, Pals, Mao, Maggiora et al., 1988; Sawyer, Pals, Mao, Staples et al., 1988; Kaltenbronn et al., 1990; Gante, 1994). However, the pKa of this amide surrogate is about neutrality and may depend on the environment, so that at least a part of the molecules may be protonated into Cα-CH2—N+H2—Cα at the physiological pH (Aumelas et al., 1987; Vanderesse et al., 1998). Contrary to the neutral form, the ionic form is a proton donor capable of strong hydrogen bonds with nucleophiles, that may induce particular folded structures (Vanderesse et al., 1998) or interaction modes in intermolecular interactions. We have recently proposed two reduced amide surrogates having the N—N or N—O fragment that decreases the pKa to such a value that it is not protonated at the physiological pH (Vanderesse et al., 1998; Thévenet et al., 2000). Here we report the crystal molecular structure of a pseudodipeptide containing the methyleneaminoxy link, (I). \sch

The three-dimensional structure (Table 1) shows that the C6—C10—N2—O2—C11 hydroxylamine fragment assumes a skew conformation, so that the C6···C11 (Cα···Cα) distance of 3.682 (4) Å is a little bit shorter than the corresponding distance of 3.81 Å for a peptide group (Benedetti, 1977). The molecule assumes a globally extended conformation (Fig. 1) in which the C-terminal NH is intramolecularly hydrogen-like bonded to the hydroxylamine oxygen (Table 2), exactly as in chloroform solution (Thévenet et al., 2000). Although it is out of the usual criteria defining hydrogen bonds (Baker & Hubbard, 1984), such a bent interaction has already been encountered in various crystal molecular structures of modified peptides (Toniolo et al., 1989; Aubry et al., 1994; Crisma et al., 1999). Molecules are held in files along the x axis by a double interaction involving both NH groups of a given molecule and the C-terminal amide carbonyl of another molecule (Table 2).

Experimental top

The pseudodipeptide was obtained by coupling NH2—O—CH2—CO—NHiPr to the Boc-L-Pro-H aldehyde, with subsequent tBuCO (Piv) for tert-butyloxycarbonyl (Boc) substitution, and reduction of the oxime by NaBH3CN. The commercially available Boc-NH—O—CH2—COOH (382 mg, 2 mmol) and N-methylmorpholine (NMM) (0.22 ml, 2 mmol) in tetrahydrofuran (THF) (20 ml) were treated dropwise under stirring with isobutylchloroformate (0.26 ml, 2 mmol) diluted in THF (2 ml) at 255 K, and stirring was maintained for 15 min. Isopropylamine (0.17 ml, 2 mmol) in THF (2 ml) was added dropwise, and the temperature was allowed to reach room temperature. The mixture was stirred overnight. NMM hydrochloride was filtered off and the solvent was evaporated. Boc-NH—O—CH2—CO—NHiPr was purified by silica gel chromatography with ethyl acetate/petroleum ether (60/40, v/v) as eluent (Rf = 0.58, 348 mg, 1.5 mmol, yield = 75%). The Boc group was quantitatively eliminated with trifluoroacetic acid (TFA) in dichloromethane (DCM) (40/60), and TFA·NH2—O—CH2—CO—NHiPr was recovered by lyophilization from an aqueous solution. TFA·NH2—O—CH2—CO—NHiPr (369 mg, 1.5 mmol) in ethanol (20 ml) was treated with NMM (0.16 ml, 1.5 mmol) and coupled to Boc-L-Pro-H (597 mg, 3 mmol), obtained from Boc-L-Pro-OH (Fehrentz & Castro, 1983), in the presence of sodium acetate (492 mg, 6 mmol) and molecular sieves. The mixture was stirred at room temperature overnight to give Boc-Proψ[CH=N—O]Gly-NHiPr which was purified by silica gel chromatography with ethyl acetate/petroleum ether (70/30, v/v) (Rf = 0.53, 385 mg, 1.23 mmol, yield = 82%). The Boc group was quantitatively eliminated with TFA in DCM (40/60), and the resulting TFA·H-Proψ[CHN—O]Gly-NHiPr was obtained by lyophilization from an aqueous solution. TFA·H-Proψ[CHN—O]Gly-NHiPr (402 mg, 1.23 mmol) was dissolved in chloroform (20 ml), the solution was cooled to 273 K, and diisopropylethylamine (0.42 ml, 2.46 mmol) and pivaloyl chloride (0.23 ml, 1.85 mmol) were successively added dropwise. The mixture was stirred at 273 K for 2 h to give Piv-Proψ[CHN—O]Gly-NHiPr which was purified by silica gel chromatography with ethanol/ethyl acetate/petroleum ether (10/60/30, v/v/v) (Rf = 0.67, 245 mg, 0.82 mmol, yield = 67%). Piv-Proψ[CHN—O]Gly-NHiPr (245 mg, 0.82 mmol) was dissolved in methanol (10 ml) and NaBH3CN (515 mg, 8.2 mmol) was added under stirring at room temperature in 8 portions over 96 h while the pH was adjusted to 3 with acetic acid (acid-base indicator: methyl orange). The solution was poured into 5 ml of water saturated with K2CO3. The solution was repeatedly extracted with DCM (5 x 5 ml). The organic phases were combined and washed three times with 5% aqueous NaHCO3 and three times with brine. Piv-Proψ[CH2—NH—O]Gly-NHiPr was purified by silica gel chromatography with ethanol/ethyl acetate/petroleum ether (10/60/30, v/v/v) as eluent (Rf = 0.45, 125 mg, 0.42 mmol, yield = 51%). Single crystals were obtained by slow evaporation of a DCM solution.

Refinement top

The absolute stereochemistry of the title compound was assumed from Boc-L-Pro-OH purchased from Neosystem corporation (Strasbourg, France). The position of H atoms attached to N atoms were located from a difference map and the N—H bond distance was restrained to 1.03 (1) Å (Taylor & Kennard, 1983). H atoms connected to carbon were placed at calculated positions using a riding model. All hydrogen atoms have isotropic displacement displacement parameters fixed at 1.3 times that of the parent atom.

Computing details top

Data collection: CAD-4 Software (Enraf-Nonius, 1989); cell refinement: CAD-4 Software; data reduction: maXus (Mackay et al., 1999); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: maXus.

Figures top
[Figure 1] Fig. 1. The molecular structure of the pseudodipeptide with the atom-numbering scheme and 25% probability displacement ellipsoids. H atoms except those of the NH groups are omitted for clarity.
(S)—N-(tert-butylcarbonyl)-2-[[O-(N-isopropylacetamidyl)] -hydroxylaminomethylene]-pyrrolidine top
Crystal data top
C15H29N3O3Dx = 1.169 Mg m3
Mr = 299.41Cu Kα radiation, λ = 1.54060 Å
Orthorhombic, P212121Cell parameters from 25 reflections
a = 5.3860 (5) Åθ = 9.7–26.2°
b = 11.470 (2) ŵ = 0.66 mm1
c = 27.539 (3) ÅT = 293 K
V = 1701.3 (4) Å3Prismatic, colorless
Z = 40.6 × 0.1 × 0.1 mm
F(000) = 656
Data collection top
Nonius Mach3
diffractometer
Rint = 0.000
Radiation source: Nonius FR591 rotating Cu anodeθmax = 69.7°, θmin = 3.2°
Graphite monochromatorh = 06
ω/2θ scansk = 013
1877 measured reflectionsl = 033
1877 independent reflections2 standard reflections every 60 min
1702 reflections with I > 2σ(I) intensity decay: 3.7%
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)] = 0.054H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.157 w = 1/[σ2(Fo2) + (0.112P)2 + 0.304P]
where P = (Fo2 + 2Fc2)/3
S = 1.06(Δ/σ)max = 0.019
1877 reflectionsΔρmax = 0.28 e Å3
197 parametersΔρmin = 0.33 e Å3
2 restraintsExtinction correction: SHELXL97 (Sheldrick, 1997), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.0125 (16)
Crystal data top
C15H29N3O3V = 1701.3 (4) Å3
Mr = 299.41Z = 4
Orthorhombic, P212121Cu Kα radiation
a = 5.3860 (5) ŵ = 0.66 mm1
b = 11.470 (2) ÅT = 293 K
c = 27.539 (3) Å0.6 × 0.1 × 0.1 mm
Data collection top
Nonius Mach3
diffractometer
Rint = 0.000
1877 measured reflections2 standard reflections every 60 min
1877 independent reflections intensity decay: 3.7%
1702 reflections with I > 2σ(I)
Refinement top
R[F2 > 2σ(F2)] = 0.0542 restraints
wR(F2) = 0.157H atoms treated by a mixture of independent and constrained refinement
S = 1.06Δρmax = 0.28 e Å3
1877 reflectionsΔρmin = 0.33 e Å3
197 parameters
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
O20.3926 (4)0.23774 (17)0.07053 (7)0.0442 (5)
O30.9164 (4)0.4192 (2)0.04322 (9)0.0580 (6)
O10.2749 (5)0.25799 (18)0.25725 (7)0.0562 (6)
N10.2908 (4)0.08643 (17)0.21961 (8)0.0383 (5)
N30.5056 (5)0.4479 (2)0.02998 (10)0.0468 (6)
H30.328 (3)0.416 (3)0.0294 (14)0.061*
N20.3164 (5)0.29575 (19)0.11501 (8)0.0453 (6)
H20.178 (5)0.348 (3)0.1018 (12)0.059*
C120.7006 (5)0.3856 (2)0.04434 (10)0.0431 (6)
C60.4081 (5)0.1432 (2)0.17694 (10)0.0397 (6)
H60.53770.19740.18760.052*
C50.2316 (5)0.1526 (2)0.25858 (9)0.0389 (6)
C100.2102 (6)0.2081 (2)0.14761 (10)0.0431 (6)
H10A0.11620.15230.12860.056*
H10B0.09610.24610.16980.056*
C130.5235 (6)0.5661 (3)0.01026 (12)0.0530 (8)
H130.69780.59040.00900.069*
C10.1008 (5)0.1012 (3)0.30359 (11)0.0475 (7)
C90.2741 (7)0.0412 (2)0.21346 (11)0.0506 (7)
H9A0.10700.06890.21980.066*
H9B0.38890.08130.23490.066*
C110.6451 (6)0.2631 (3)0.06192 (13)0.0534 (8)
H11A0.70750.20830.03800.069*
H11B0.73660.24990.09180.069*
C70.5233 (7)0.0403 (3)0.15064 (12)0.0575 (8)
H7A0.53680.05560.11610.075*
H7B0.68700.02290.16340.075*
C40.1954 (8)0.0178 (3)0.32134 (14)0.0700 (10)
H4A0.36670.01130.33050.091*
H4B0.17920.07410.29570.091*
H4C0.09920.04240.34880.091*
C80.3446 (8)0.0588 (3)0.16046 (13)0.0613 (9)
H8A0.42420.13380.15560.080*
H8B0.19990.05370.13960.080*
C30.1355 (9)0.1880 (4)0.34519 (13)0.0760 (12)
H3A0.30880.19440.35290.099*
H3B0.04630.16130.37320.099*
H3C0.07310.26290.33560.099*
C140.3775 (11)0.6485 (3)0.04224 (18)0.0863 (13)
H14A0.45400.65270.07370.112*
H14B0.21040.62040.04560.112*
H14C0.37530.72460.02780.112*
C20.1714 (6)0.0938 (6)0.29024 (17)0.0955 (18)
H2A0.19280.03840.26440.124*
H2B0.22860.16890.27980.124*
H2C0.26530.06920.31800.124*
C150.416 (2)0.5665 (4)0.03952 (14)0.132 (3)
H15A0.51360.51740.06030.171*
H15B0.41600.64460.05200.171*
H15C0.24860.53780.03830.171*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O20.0472 (11)0.0398 (9)0.0454 (10)0.0002 (9)0.0024 (9)0.0028 (8)
O30.0357 (10)0.0630 (13)0.0752 (14)0.0026 (11)0.0017 (10)0.0116 (12)
O10.0694 (15)0.0398 (10)0.0594 (11)0.0068 (12)0.0066 (11)0.0005 (8)
N10.0369 (11)0.0300 (9)0.0482 (11)0.0010 (10)0.0008 (10)0.0092 (8)
N30.0353 (12)0.0434 (12)0.0618 (14)0.0006 (11)0.0025 (11)0.0166 (11)
N20.0566 (14)0.0330 (10)0.0465 (12)0.0043 (12)0.0063 (11)0.0051 (9)
C120.0388 (13)0.0448 (14)0.0458 (13)0.0017 (13)0.0065 (12)0.0052 (11)
C60.0325 (12)0.0371 (12)0.0494 (14)0.0023 (12)0.0012 (11)0.0086 (11)
C50.0298 (12)0.0390 (13)0.0479 (13)0.0029 (12)0.0021 (11)0.0077 (10)
C100.0400 (13)0.0396 (13)0.0496 (14)0.0069 (13)0.0042 (12)0.0109 (11)
C130.0462 (15)0.0431 (15)0.0696 (18)0.0064 (15)0.0037 (14)0.0191 (13)
C10.0316 (13)0.0607 (17)0.0501 (14)0.0036 (14)0.0017 (11)0.0094 (13)
C90.0568 (18)0.0307 (12)0.0643 (16)0.0012 (13)0.0017 (15)0.0071 (11)
C110.0420 (15)0.0473 (16)0.0711 (18)0.0086 (14)0.0122 (14)0.0144 (14)
C70.0558 (18)0.0535 (17)0.0630 (17)0.0232 (16)0.0121 (15)0.0089 (14)
C40.068 (2)0.070 (2)0.072 (2)0.009 (2)0.0076 (19)0.0344 (18)
C80.077 (2)0.0377 (14)0.0690 (18)0.0118 (16)0.0012 (19)0.0010 (13)
C30.085 (3)0.090 (3)0.0534 (17)0.006 (3)0.0084 (19)0.0026 (17)
C140.105 (4)0.0549 (19)0.099 (3)0.008 (3)0.004 (3)0.005 (2)
C20.0302 (16)0.177 (6)0.080 (2)0.011 (3)0.0022 (16)0.015 (3)
C150.267 (9)0.074 (2)0.054 (2)0.014 (5)0.008 (4)0.0246 (19)
Geometric parameters (Å, º) top
O2—C111.411 (4)C6—C71.518 (4)
O2—N21.453 (3)C6—C101.531 (4)
O3—C121.225 (4)C5—C11.543 (4)
O1—C51.232 (4)C13—C151.489 (6)
N1—C51.353 (4)C13—C141.513 (6)
N1—C91.477 (3)C1—C21.514 (4)
N1—C61.485 (3)C1—C31.530 (5)
N3—C121.330 (4)C1—C41.536 (5)
N3—C131.464 (4)C9—C81.522 (5)
N2—C101.464 (3)C7—C81.514 (5)
C12—C111.516 (4)
C11—O2—N2108.6 (2)N2—C10—C6112.7 (2)
C5—N1—C9129.3 (2)N3—C13—C15108.6 (3)
C5—N1—C6118.8 (2)N3—C13—C14109.2 (3)
C9—N1—C6111.7 (2)C15—C13—C14109.4 (4)
C12—N3—C13123.7 (3)C2—C1—C3109.7 (4)
O2—N2—C10108.2 (2)C2—C1—C4110.4 (4)
O3—C12—N3124.9 (3)C3—C1—C4107.4 (3)
O3—C12—C11119.1 (3)C2—C1—C5105.6 (3)
N3—C12—C11115.9 (3)C3—C1—C5107.3 (3)
N1—C6—C7102.2 (2)C4—C1—C5116.3 (3)
N1—C6—C10109.6 (2)N1—C9—C8103.1 (2)
C7—C6—C10114.3 (3)O2—C11—C12115.7 (2)
O1—C5—N1118.9 (2)C8—C7—C6103.8 (2)
O1—C5—C1119.1 (3)C7—C8—C9103.3 (3)
N1—C5—C1122.0 (2)
C13—N3—C12—O30.6 (5)C12—N3—C13—C15121.0 (5)
C5—N1—C6—C7161.1 (3)C12—N3—C13—C14119.8 (4)
C9—N1—C6—C714.6 (3)O1—C5—C1—C296.9 (4)
C1—C5—N1—C6177.8 (2)N1—C5—C1—C280.3 (4)
C5—N1—C6—C1077.4 (3)O1—C5—C1—C320.0 (4)
N1—C6—C10—N2161.3 (2)N1—C5—C1—C3162.8 (3)
C6—C10—N2—O283.8 (3)O1—C5—C1—C4140.3 (3)
C10—N2—O2—C11125.4 (2)N1—C5—C1—C442.6 (4)
N2—O2—C11—C1273.8 (3)C5—N1—C9—C8174.9 (3)
O2—C11—C12—N312.6 (4)C6—N1—C9—C810.0 (4)
C11—C12—N3—C13177.7 (3)O3—C12—C11—O2169.0 (3)
C9—N1—C6—C10107.0 (3)N1—C6—C7—C833.5 (3)
C9—N1—C5—O1175.4 (3)C10—C6—C7—C884.7 (3)
C6—N1—C5—O10.6 (4)C6—C7—C8—C940.5 (3)
C9—N1—C5—C17.5 (5)N1—C9—C8—C730.7 (3)
C7—C6—C10—N284.7 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N3—H3···O21.02 (1)2.37 (4)2.725 (3)99 (2)
N3—H3···O3i1.02 (1)2.25 (2)3.211 (3)156 (3)
N2—H2···O3i1.02 (1)2.29 (2)3.249 (3)155 (3)
Symmetry code: (i) x1, y, z.

Experimental details

Crystal data
Chemical formulaC15H29N3O3
Mr299.41
Crystal system, space groupOrthorhombic, P212121
Temperature (K)293
a, b, c (Å)5.3860 (5), 11.470 (2), 27.539 (3)
V3)1701.3 (4)
Z4
Radiation typeCu Kα
µ (mm1)0.66
Crystal size (mm)0.6 × 0.1 × 0.1
Data collection
DiffractometerNonius Mach3
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
1877, 1877, 1702
Rint0.000
(sin θ/λ)max1)0.609
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.054, 0.157, 1.06
No. of reflections1877
No. of parameters197
No. of restraints2
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.28, 0.33

Computer programs: CAD-4 Software (Enraf-Nonius, 1989), CAD-4 Software, maXus (Mackay et al., 1999), SIR92 (Altomare et al., 1994), SHELXL97 (Sheldrick, 1997), maXus.

Selected torsion angles (º) top
C1—C5—N1—C6177.8 (2)C10—N2—O2—C11125.4 (2)
C5—N1—C6—C1077.4 (3)N2—O2—C11—C1273.8 (3)
N1—C6—C10—N2161.3 (2)O2—C11—C12—N312.6 (4)
C6—C10—N2—O283.8 (3)C11—C12—N3—C13177.7 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N3—H3···O21.022 (10)2.37 (4)2.725 (3)99 (2)
N3—H3···O3i1.022 (10)2.250 (18)3.211 (3)156 (3)
N2—H2···O3i1.022 (10)2.293 (18)3.249 (3)155 (3)
Symmetry code: (i) x1, y, z.
 

Subscribe to Acta Crystallographica Section C: Structural Chemistry

The full text of this article is available to subscribers to the journal.

If you have already registered and are using a computer listed in your registration details, please email support@iucr.org for assistance.

Buy online

You may purchase this article in PDF and/or HTML formats. For purchasers in the European Community who do not have a VAT number, VAT will be added at the local rate. Payments to the IUCr are handled by WorldPay, who will accept payment by credit card in several currencies. To purchase the article, please complete the form below (fields marked * are required), and then click on `Continue'.
E-mail address* 
Repeat e-mail address* 
(for error checking) 

Format*   PDF (US $40)
   HTML (US $40)
   PDF+HTML (US $50)
In order for VAT to be shown for your country javascript needs to be enabled.

VAT number 
(non-UK EC countries only) 
Country* 
 

Terms and conditions of use
Contact us

Follow Acta Cryst. C
Sign up for e-alerts
Follow Acta Cryst. on Twitter
Follow us on facebook
Sign up for RSS feeds