Precursor of a β-lactamase inhibitor: allyl (4S,8S,9R)-10-[(E)-ethylidene]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0^3,8]undec-2-ene-2-carboxylate

Abstract

The molecular structure of the title tricyclic compound, C(17)H(21)NO(4), which is the immediate precursor of a potent synthetic inhibitor [Lek157: sodium (8S,9R)-10-[(E)-ethylidene]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylate] with remarkable potency, provides experimental evidence for the previously modelled relative position of the fused cyclohexyl ring and the carbonyl group of the beta-lactam ring, which takes part in the formation of the initial tetrahedral acyl-enzyme complex. In this hydrophobic molecule, the overall geometry is influenced by C[bond]H...O intramolecular hydrogen bonds [3.046 (4) and 3.538 (6) A, with corresponding normalized H.O distances of 2.30 and 2.46 A], whereas the molecules are interconnected through intermolecular C[bond]H...O hydrogen bonds [3.335 (4)-3.575 (5) A].

Chelated Assisted Metal-Mediated N–H Bond Activation of β-Lactams: Preparation of Irida-, Rhoda-, Osma-, and Ruthenatrinems

“…Both bond lengths are consistent with those reported for N -arylpicolinamidate iridium(III) derivatives . The lactamic N(1)–C(1) and C(1)–O(1) distances of 1.428(14) and 1.222(13) Å, respectively, agree with those found in the scarce pure organic trinems characterized by X-ray diffraction analysis. , …”

“…Figure 1 gives a drawing of the molecule. The structure proves the formation of the tricyclic skeleton with a dihedral angle between the five-membered metallacycle and the fourmembered lactamic ring of 55.55°, which compares well with the related angle in allyl (4S,8S,9R)-10-[(E)-ethylidene]-4methoxy-11-oxo-1-azatricyclo[7.2.0.0 3,8 ]undec-2-ene-2-carboxylate (53.74°), 16 the immediate synthetic precursor of the βlactamase inhibitor sodium (8R,9R)-10-[(E)-ethylidene]-4methoxy-11-oxo-1-azatricyclo[7.2.0.0 3,8 ]undec-2-ene-2-carboxylate (Lek157). The geometry around the metal center is close to octahedral, with the pentamethylcyclopentadienyl ligand occupying three sites of a face, whereas the pyridylamidate moiety lies in the opposite site with a bite angle of 75.0(3)°.…”

“…17 The lactamic N(1)−C(1) and C(1)−O(1) distances of 1.428( 14) and 1.222(13) Å, respectively, agree with those found in the scarce pure organic trinems characterized by X-ray diffraction analysis. 16,18 Metallatrinems 1a,b exist in solution as 5/1 mixtures of the two pairs of diastereoisomers resulting from the chirality of the metal center and both CH carbon atoms of the lactamic fourmembered ring. The most noticeable spectroscopic feature of these compounds is the presence of a singlet at 175.8 ppm for 1a and 177.1 ppm for 1b in the 13 C{ 1 H} NMR spectra, in chloroform-d, corresponding to the lactamic carbonyl group of the major diastereoisomer, which appears shifted by about 9 ppm toward lower field with regard to that of 2a (167.2 ppm).…”

Acyclic Twisted Amides

“…In general, the amide bond geometry of structurally characterized β-lactams presented in Figures and − can be characterized as N-pyramidalized (average χ N of 54.4°), while twist is less significant (average τ of 19.2°), as expected from the geometry of the fused four-membered ring system. There is only a very scattered correlation between N-pyramidalization and twist of the amide bond, with the general trend of higher twist with increased nitrogen pyramidalization ( R 2 = 0.30).…”

“…The most common are [ 2 .4.0] and [ 2 .3.0] ring systems with the six-membered ring such as 1,3-oxazinane (e.g., 4.30 ), and more common five-membered ring, such as thiazolidine 1,1-dioxide (e.g., 4.32 ), thiazolidine 1-oxide (e.g., 4.33 ), thiazolidine (e.g., 4.34 ), 1,3-selenazolidine (e.g., 4.36 ), pyrrolidine (e.g., 4.81 ), imidazolidine (e.g., 4.94 ), or oxazolidine (e.g., 4.101 ) . In general, more dense substitution of the fused ring, in particular at the α-positions to the nitrogen atom and the carbonyl group and ring unsaturation, result in higher N-pyramidalization. − These N-pyramidalized amides are well-known to be highly reactive as acylating reagents and are important pharmacophores in medicinal chemistry research.…”