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

Krzysztof Kaczmarek; Jakub Wojciechowski; Wojciech M Wolf

doi:10.1107/S1600536810004277

. 2010 Mar 13;66(Pt 4):o831–o832. doi: 10.1107/S1600536810004277

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

Krzysztof Kaczmarek ^a, Jakub Wojciechowski ^b, Wojciech M Wolf ^b,^*

PMCID: PMC2984054 PMID: 21580659

Abstract

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.

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 ▶).

Experimental

Crystal data

C₅H₈N₂O₃
M _r = 144.13
Orthorhombic,
a = 5.9790 (3) Å
b = 9.3665 (4) Å
c = 11.3809 (5) Å
V = 637.36 (5) Å³
Z = 4
Cu Kα radiation
μ = 1.08 mm⁻¹
T = 293 K
0.40 × 0.40 × 0.10 mm

Data collection

Bruker SMART APEX diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2003 ▶) T _min = 0.707, T _max = 0.900
7227 measured reflections
1169 independent reflections
1168 reflections with I > 2σ(I)
R _int = 0.030

Refinement

R[F ² > 2σ(F ²)] = 0.027
wR(F ²) = 0.069
S = 1.08
1169 reflections
125 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.13 e Å⁻³
Δρ_min = −0.17 e Å⁻³
Absolute structure: Flack (1983 ▶), 461 Friedel pairs
Flack parameter: 0.1 (2)

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

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810004277/bt5187sup1.cif

e-66-0o831-sup1.cif^{(14.8KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810004277/bt5187Isup2.hkl

e-66-0o831-Isup2.hkl^{(57.8KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯O2ⁱ	0.82 (2)	2.07 (2)	2.8535 (15)	161.2 (18)
N2—H2⋯O1ⁱⁱ	0.88 (2)	1.87 (2)	2.7346 (16)	168.5 (17)
N2—H3⋯O1ⁱⁱⁱ	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)

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) .

Acknowledgments

Financial support from the Ministry of Science and Higher Education, Poland (project No. 2P05F00129) is gratefully acknowledged.

supplementary crystallographic information

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.

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.