COMMUNICATION Making Easier the β-Lactam Fragmentation via Metal-Assistance: Mechanistic Insight

The OsH6(PPr3)2-mediated fragmentation of a 4-(2 pyridyl)-2-azedidinone has been achieved and its mechanism has been investigated by DFT calculations. The addition of the C4-H bond of the substrate to OsH2(PPr3)2 allows the active participation of an osmium lone pair in the B-type β-lactam fragmentation process. This new mechanism makes the N1-C4/C2-C3 fragmentation of the lactamic core thermally accessible through a stepwise process. The β-lactam ring is part of the core structure of several antibiotic families. The enzymatic hydrolysis of the N1-C2 bond results in their irreversible inactivation as a consequence of the acylation of the active sites. Additionally, the N1-C2 rupture has been used in the preparation of β-amino acids. Cleavages of the less polar N1-C4, C4-C3, and C3-C2 bonds are also known and have important applications in organic synthesis as part of the so-called β-lactam synthon method. Scheme 1. Possible fragmentation pathways of the four-member lactamic core. The concerted or sequential breakage of parallel N-C and C-C bonds is less usual. The rupture of N1-C2 and C3-C4 (A in Scheme 1) is the inverse process to the Staudinger reaction and gives rise to a ketene and an imine, whereas the breakage of N1-C4 and C2-C3 (B in Scheme 1) leads to an olefin and an isocyanate. Both types of fragmentation have been observed by EI-Mass spectrometry. The A-type fragmentation occurs under irradiation. However, although the B-type fragmentation of N(arylidenamino)and N-(alkylidenamino)-2-azetidinones occurs at room temperature, under ozonolysis, the thermal B-type fragmentation of the β-lactam ring is generally a difficult reaction, which should entail a high energy barrier. Previous calculations have reported activation energies of more than 40 kcal mol for such process. It appears to be a concerted asynchronous [2+2] cycloreversion, since it takes place with complete retention of the stereochemistry. Metal-promoted degradation of β-lactams remains unknown. Here, we report a much easier osmiummediated fragmentation which shows a different reaction mechanism rather than the concerted [2+2] cycloreversion. The hexahydride complex OsH6(PPr3)2 (1) has proven to activate σ-bonds of a wide range of organic molecules, including the N-H bond of 4-(2-pyridyl)-2-azetidinones. The replacement of the hydrogen atom of this group by aryl protects the nitrogen atom against the metal center, which is directed towards the C3-H bond of the four membered ring. The addition of this bond to the osmium atom activates the rupture of the N1C4 and C2-C3 bonds. Thus, the treatment of toluene solutions of 1 with 1.0 equiv of cis-1-(4-methoxiphenyl)-3-methoxi-4(pyridin-2-yl)azetidin-2-one (I), for 6 h, under reflux affords the trihydride-osmium(IV) derivative OsH3{κ-C,N-[py-2CH=COMe]}(PPr3)2 (2) which was isolated as a yellow solid in 60% yield (eq 1). Complex 2 was characterized by X-ray diffraction analysis. The structure (Figure 1) proves the N1-C4 and C2-C3 bond cleavage of the β-lactam ring. The geometry around the osmium atom can be rationalized as a distorted pentagonal bipyramid with the phosphine ligands occupying axial positions (P(1)-Os-P(1A) = 167.32(5)o). The metal coordination sphere is completed by the chelated group, which acts with a N(1)-Os-C(7) bite angle of 75.98(18)o and the hydrides. The metallabicycle is planar and shows a significant electron delocalization which is translated into bond lengths between those expected for single and double bonds. This is clearly evident in the C(7)-C(6) and C(6)-C(5) distances of 1.401(7) and 1.434(7) Å, which are similar. As expected for three inequivalent hydride ligands, the H NMR spectrum, in toluene-d8, at 203 K shows three hydride resonances at -6.16, -10.82, and -11.55 ppm. In the C{H} NMR spectrum, the most noticeable feature is the resonance [a] Dr. L. Casarrubios, Dr. J. G. Muntaner, Prof. Dr. M. A. Sierra Departamento de Química Orgánica, Facultad de Ciencias Químicas, Centro de Innovación en Química Avanzada (ORFEOCINQA), Universidad Complutense, 28040 Madrid, Spain email: [email protected] [b] Prof. Dr. M. A. Esteruelas, C. Larramona, Dr. E. Oñate Departamento de Química Inorgánica, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Centro de Innovación en Química Avanzada (ORFEO-CINQA), Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain email: [email protected] [c] Prof. Dr. A. Lledós, Dr. M. A. Ortuño Departament de Química, Centro de Innovación en Química Avanzada (ORFEO-CINQA), Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain. email: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.2011xxxxxx.