(2S,4R)-4-Ammonio-5-oxopyrrolidine-2-carboxylate

In the crystal structure of the title compound, C₅H₈N₂O₃, the mol­ecules exist in the zwitterionic form. The pyrrolidine ring adopts an envelope conformation with the unsubstituted endocyclic C atom situated at the flap. The other four endocyclic atoms are coplanar with the exocyclic carbonyl O atom, with an r.m.s. deviation from the mean plane of 0.06 Å. The carboxyl­ate substituent is located axially, while the ammonium group occupies an equatorial position. In the crystal structure, the mol­ecules are linked through N—H...O hydrogen bonds, forming a three-dimensional network.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.002 Å
• R factor = 0.027
• wR factor = 0.069
• Data-to-parameter ratio = 9.4

checkCIF/PLATON results

No syntax errors found



Alert level B
PLAT029_ALERT_3_B _diffrn_measured_fraction_theta_full Low .......       0.95

Alert level C
PLAT911_ALERT_3_C Missing # FCF Refl Between THmin & STh/L=  0.600         15
PLAT912_ALERT_4_C Missing # of FCF Reflections Above STh/L=  0.600          6

Alert level G
REFLT03_ALERT_4_G Please check that the estimate of the number of Friedel pairs is
            correct. If it is not, please give the correct count in the
            _publ_section_exptl_refinement section of the submitted CIF.
           From the CIF: _diffrn_reflns_theta_max           70.82
           From the CIF: _reflns_number_total               1169
           Count of symmetry unique reflns          742
           Completeness (_total/calc)            157.55%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured       427
           Fraction of Friedel pairs measured     0.575
           Are heavy atom types Z>Si present         no
PLAT199_ALERT_1_G Check the Reported _cell_measurement_temperature        293 K
PLAT200_ALERT_1_G Check the Reported   _diffrn_ambient_temperature        293 K
PLAT791_ALERT_4_G The Model has Chirality at C3      (Verify) ....          R
PLAT791_ALERT_4_G The Model has Chirality at C5      (Verify) ....          S

   0 ALERT level A = In general: serious problem
   1 ALERT level B = Potentially serious problem
   2 ALERT level C = Check and explain
   5 ALERT level G = General alerts; check

   2 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   0 ALERT type 2 Indicator that the structure model may be wrong or deficient
   2 ALERT type 3 Indicator that the structure quality may be low
   4 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

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S1. Comment

N-methyl amino acids and proline residues in the peptide chain may cause the cis-trans isomerisation of the amide bond and lead to conformational changes, which influence the molecular recognition (Dugave & Demange, 2003). Importance of the cis-amide bonds for the peptide bioactivity led to the construction of modified amino acids, which could lock a peptide bond in the cis-geometry (Dumy et al., 1997; Keller et al., 1998; Mutter et al., 1999; Tuchscherer & Mutter, 2001). In particular, Paul et al. (1992) designed mimetics of the cis-peptide bond based on the substitituted pyroglutamic acid residue. In contrast with a tetrazole replacement for the peptide bond, the pyroglutamic acid derivatives are more rigid (Zabrocki et al., 1988). Their carboxylic group could be either donor or acceptor of hydrogen bond without invloving the polypeptide main chain amide moieties (Kaczmarek et al., 2005).

The 4-aminopyroglutamic acid is a particularly useful residue for building the conformationally restricted peptide chains. Depending on the absolute configuration at both chiral centers it may be applied to construct the VIa or VIb β-turn mimetics.

The title compound may be obtained by two different methods elaborated by us, i.e. by electrophilic amination reaction of N-protected (S)-pyroglutamate ester, which gives separable 9:1 mixture of (2S,4R) and (2S,4S) diastereoisomers (Kaczmarek et al., 2001) or through Michael addition of dehydroalanine derivatives to sodium salt of N-benzyloxycarbonylaminomalonate ester, which gives after hydrolysis and decarboxylation mixture of all four possible stereomers. The details of the last reaction and resolution of stereoisomers will be described elsewhere (Kaczmarek, 2009).

A view of the title compound is given in Fig. 1. The molecule has two chiral centres viz. C3 and C5. Their absolute configurations follow from the synthetic procedure and are R and S, respectively.

The pyrrolidine ring adopts an envelope conformation with N1, C2, C3 and C5 almost coplanar and the C4 situated at the flap.

Additionally, the former four endocyclic atoms are coplanar with the exocyclic carbonyl oxygen, the average r.m.s. deviation from the mean plane is 0.06 Å.

The three lowest ring asymmetry parameters (Griffin et al., 1984) are: C_S(C4) = 1.26 (14), C₂(C2) = 11.92 (14), C₂(N1) = 15.46 (14)°. The carboxylate substituent is located axially in conformation stabilized by the short N1···O2 contact [2.787 (2) Å], while the ammonium group occupies equatorial position.

In the crystal each molecule is linked through N—H ···O hydrogen bonds with eight adjacent molecules, their deatils are shown in Table 2 and Fig. 2.

Related literature

For molecular recognition in N-methyl amino acids and proline residues, see: Dugave & Demange (2003). For the construction of modified amino acids, see: Dumy et al. (1997); Keller et al. (1998); Mutter et al. (1999); Tuchscherer & Mutter (2001); Paul et al. (1992). For pyroglutamic acid derivatives, see: Zabrocki et al. (1988); Kaczmarek et al. (2005). For the preparation of the title compound, see: Kaczmarek et al. (2001); Kaczmarek (2009). For asymmetry parameters, see: Griffin et al. (1984).

S2. Experimental

An optically pure (ee>99%) N'-benzyloxycarbonyl protected precursor of the title compound was hydrogenated in methanol solution over 10% palladium on charcoal, which resulted in precipitation of the final product. After filtration of solids final product was washed out of the catalyst with the aim of water. The (2S,4R)-4-aminopyroglutamic acid crystals were grown from this water solution by slow evaporation.

S3. Refinement

All H atoms were located in difference Fourier maps and refined freely.

Computing details

Data collection: SMART (Bruker, 2003); cell refinement: SAINT-Plus (Bruker, 2003); data reduction: SAINT-Plus (Bruker, 2003); program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008) and Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008) and publCIF (Westrip, 2010).

Figures

	Fig. 1. Molecule of the title compound. Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 2. View of hydrogen bonding in the crystal of the title compound. Symmetry codes: I (x, y, z); II (x + 1/2,-y+1/2,-z+1); III (-x + 2, y + 1/2,-z+3/2); IV (-x + 1, y + 1/2,-z+3/2); V (-x + 3/2,-y, z + 1/2).

(2S,4R)-4-Ammmonio-5-oxopyrrolidine-2-carboxylate

Crystal data

C5H8N2O3	Dx = 1.502 Mg m^−3
Mr = 144.13	Melting point: 423(2) K
Orthorhombic, P212121	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2ac 2ab	Cell parameters from 7056 reflections
a = 5.9790 (3) Å	θ = 6.1–70.8°
b = 9.3665 (4) Å	µ = 1.08 mm^−1
c = 11.3809 (5) Å	T = 293 K
V = 637.36 (5) Å^3	Prism, colourless
Z = 4	0.40 × 0.40 × 0.10 mm
F(000) = 304

Data collection

Bruker SMART APEX diffractometer	1169 independent reflections
Radiation source: fine-focus sealed tube	1168 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.030
ω scans	θmax = 70.8°, θmin = 6.1°
Absorption correction: multi-scan (SADABS; Bruker, 2003)	h = −6→5
Tmin = 0.707, Tmax = 0.900	k = −11→11
7227 measured reflections	l = −13→13

Refinement

Refinement on F^2	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.027	w = 1/[σ^2(Fo^2) + (0.0468P)^2 + 0.0681P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.069	(Δ/σ)max < 0.001
S = 1.08	Δρmax = 0.13 e Å^−3
1169 reflections	Δρmin = −0.17 e Å^−3
125 parameters	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
0 restraints	Extinction coefficient: 0.047 (3)
Primary atom site location: structure-invariant direct methods	Absolute structure: Flack (1983), 461 Friedel pairs
Secondary atom site location: difference Fourier map	Absolute structure parameter: 0.1 (2)

Special details

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

	x	y	z	Uiso*/Ueq
O1	0.85679 (17)	−0.10762 (9)	0.57781 (8)	0.0373 (3)
H2	0.838 (4)	0.3509 (18)	0.9130 (15)	0.042 (4)*
O2	0.57914 (17)	0.04638 (10)	0.55325 (8)	0.0383 (3)
O3	0.6519 (2)	0.46234 (9)	0.68254 (10)	0.0469 (3)
N1	0.8566 (2)	0.27436 (11)	0.61237 (10)	0.0353 (3)
H1	0.917 (4)	0.3094 (19)	0.5549 (17)	0.054 (5)*
C1	0.7725 (2)	0.01571 (13)	0.58351 (10)	0.0283 (3)
C5	0.9163 (2)	0.12935 (13)	0.64357 (11)	0.0304 (3)
H51	1.078 (3)	0.1140 (16)	0.6258 (13)	0.032 (4)*
C4	0.8646 (3)	0.12504 (13)	0.77672 (11)	0.0340 (3)
H41	0.807 (3)	0.0354 (17)	0.8009 (15)	0.045 (5)*
H42	0.995 (4)	0.156 (2)	0.8147 (18)	0.056 (5)*
C3	0.6848 (2)	0.23810 (12)	0.79144 (11)	0.0297 (3)
H31	0.541 (3)	0.1976 (15)	0.7877 (14)	0.030 (4)*
N2	0.7038 (2)	0.31400 (11)	0.90532 (10)	0.0310 (3)
H4	0.607 (3)	0.3822 (18)	0.9140 (14)	0.036 (4)*
H3	0.695 (3)	0.249 (2)	0.9630 (14)	0.042 (4)*
C2	0.7255 (2)	0.34135 (13)	0.68928 (11)	0.0319 (3)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0425 (6)	0.0262 (4)	0.0432 (5)	0.0027 (4)	−0.0079 (4)	−0.0062 (4)
O2	0.0334 (6)	0.0347 (5)	0.0466 (5)	−0.0016 (4)	−0.0093 (4)	0.0089 (4)
O3	0.0561 (7)	0.0309 (5)	0.0536 (6)	0.0133 (5)	0.0046 (5)	0.0104 (4)
N1	0.0451 (7)	0.0234 (5)	0.0374 (6)	−0.0044 (5)	0.0072 (5)	0.0050 (4)
C1	0.0331 (7)	0.0267 (6)	0.0251 (5)	−0.0021 (4)	0.0001 (5)	0.0034 (4)
C5	0.0311 (7)	0.0241 (6)	0.0361 (6)	−0.0008 (5)	0.0004 (5)	0.0004 (5)
C4	0.0435 (8)	0.0250 (6)	0.0335 (6)	0.0040 (5)	−0.0074 (6)	0.0002 (5)
C3	0.0294 (7)	0.0257 (5)	0.0340 (6)	−0.0027 (5)	−0.0020 (4)	0.0037 (5)
N2	0.0327 (7)	0.0257 (5)	0.0345 (5)	0.0022 (5)	0.0027 (4)	0.0029 (4)
C2	0.0321 (7)	0.0270 (6)	0.0367 (6)	−0.0015 (5)	−0.0022 (5)	0.0044 (5)

Geometric parameters (Å, º)

O1—C1	1.2621 (16)	C4—C3	1.5187 (19)
O2—C1	1.2399 (17)	C4—H41	0.949 (17)
O3—C2	1.2179 (16)	C4—H42	0.94 (2)
N1—C2	1.3321 (17)	C3—N2	1.4826 (16)
N1—C5	1.4485 (15)	C3—C2	1.5318 (16)
N1—H1	0.82 (2)	C3—H31	0.939 (17)
C1—C5	1.5295 (17)	N2—H2	0.88 (2)
C5—C4	1.5470 (17)	N2—H4	0.867 (18)
C5—H51	0.997 (17)	N2—H3	0.898 (18)
C2—N1—C5	115.19 (10)	C3—C4—H41	109.0 (11)
O3—C2—N1	127.55 (12)	C5—C4—H41	112.3 (10)
O3—C2—C3	125.30 (12)	C3—C4—H42	108.7 (13)
N1—C2—C3	107.15 (11)	C5—C4—H42	106.1 (13)
N1—C5—C1	113.86 (10)	H41—C4—H42	116.4 (17)
N1—C5—C4	102.44 (10)	N2—C3—C4	112.11 (10)
C1—C5—C4	107.90 (10)	N2—C3—C2	110.40 (10)
C3—C4—C5	103.37 (10)	N2—C3—H31	107.7 (9)
C4—C3—C2	104.12 (10)	C4—C3—H31	111.1 (9)
C2—N1—H1	126.6 (13)	C2—C3—H31	111.5 (9)
C5—N1—H1	117.8 (13)	C3—N2—H2	110.3 (11)
O2—C1—O1	124.76 (12)	C3—N2—H4	113.6 (11)
O2—C1—C5	119.14 (11)	H2—N2—H4	107.9 (16)
O1—C1—C5	115.82 (11)	C3—N2—H3	108.0 (11)
N1—C5—H51	108.9 (9)	H2—N2—H3	104.4 (16)
C1—C5—H51	110.7 (9)	H4—N2—H3	112.3 (15)
C4—C5—H51	112.9 (8)
N1—C5—C4—C3	26.38 (13)	O2—C1—C5—N1	−26.96 (16)
C5—C4—C3—C2	−25.98 (13)	O1—C1—C5—N1	158.87 (11)
C5—N1—C2—O3	−179.48 (14)	O2—C1—C5—C4	86.02 (13)
C5—N1—C2—C3	1.41 (16)	O1—C1—C5—C4	−88.15 (13)
C4—C3—C2—N1	16.23 (14)	C1—C5—C4—C3	−94.06 (11)
C4—C3—C2—O3	−162.91 (14)	C5—C4—C3—N2	−145.33 (10)
C2—N1—C5—C4	−17.99 (15)	N2—C3—C2—O3	−42.41 (18)
C2—N1—C5—C1	98.23 (14)	N2—C3—C2—N1	136.73 (12)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O2^i	0.82 (2)	2.07 (2)	2.8535 (15)	161.2 (18)
N2—H2···O1^ii	0.88 (2)	1.87 (2)	2.7346 (16)	168.5 (17)
N2—H3···O1^iii	0.897 (17)	1.886 (17)	2.7788 (14)	173.4 (17)
N2—H4···O2^iv	0.868 (17)	1.935 (17)	2.7967 (15)	172.3 (17)

Symmetry codes: (i) x+1/2, −y+1/2, −z+1; (ii) −x+2, y+1/2, −z+3/2; (iii) −x+3/2, −y, z+1/2; (iv) −x+1, y+1/2, −z+3/2.