An unexpected bicyclic pyrrolidinedione formed by rearrangement of the β-lactam ring under basic conditions

During synthetic studies on anti-elastase polycyclic β-lactams from conveniently substituted monolactams, we attempted to obtain an N-(1´-methoxycarbonyalkylidene)-β-lactam by α-selenoxide elimination. Although the desired alkenes 5 were obtained, the main products were the N-unsubstituted 2-azetidinone 2 and the bridged bicyclic pyrrolidinedione 7 . The structure of compound 7 was established by spectroscopic methods and confirmed by X-ray crystallography


Introduction
As a part of our studies on the synthesis 1 and anti-elastase activity 2 of β-lactam compounds, we have recently prepared the compounds 3 and 4 (Scheme 1).These substances were active in vitro against Human Leukocyte Elastase (HLE), showing the epoxide (-)4bα the best inhibition with an IC50 = 7M. 3Throughout the synthetic process we noticed that the epoxides 4 should be prepared by epoxidation of 1 [b)] and then β-elimination [a)].When the β-elimination reaction was carried out before the epoxidation, a 3:2 mixture of the N-unsubstituted compound 2 and the monolactam 3 was obtained, and further epoxidation was not possible.Scheme 1

Results and Discussion
In order to increase the anti-elastase activity of these β-lactams, we planned the introduction of an alkyl substituent at the C-2' position.The preparation of the N-1-ethenyl monolactams 5 were carried out from the precursor monolactam 6 according to the protocol reported by Alcaide and coworkers 4 (Scheme 2).

Scheme 2
The Staudinger reaction between methoxyacetyl chloride and the imine obtained from cinnamaldehyde with D/L-norvaline methyl ester in the presence of TEA afforded a 1:1 mixture of two diastereomers 6 + 6' in 90% yield after column chromatography.When this mixture was reacted sequentially with LiHMDS, PhSeBr and m-CPBA it afforded a 1:3:2 mixture of 5, 2 and 7 in 75% yield.
Compounds 6, 5 and 2 2 displayed IR spectra absorption bands of β-lactam ring (1760 cm -1 ) and the NMR data were in agreement with the proposed structures.The C-3, C-4 configuration shown for these compounds, was clearly established on the basis of their 1 H NMR coupling constants between the hydrogen atoms H-3 and H-4 (Jcis ≥ 4.0 Hz, Jtras ≤ 2.0 Hz) but the Z/E geometry at C1' in compounds 5 we were not able to assign from the available spectroscopic data.
Compound 7 shows spectral data very different from those expected for a β-lactam compound.The IR spectrum of 7 does not show the characteristic β-lactam ring absorption band but other bands at 3200, 1787 and 1722 cm -1 were presented.These data together with the signals displayed in 13 C-NMR at 204.0 and 169.9 ppm, suggest the presence of ketone and amide functional groups.In addition, the 13 C-NMR spectrum agreed with the presence of the phenyl, methoxyl and propyl groups, two quaternary Csp3 as well as three methynes (two vinylic and one aliphatic), which were reflected in the 1 H-NMR spectrum as an ABX system with coupling constants JAB = 9.6 Hz, JAX = 2.6 Hz and JBX = 2.5 Hz.All these data and those provided by the HMQC and the HMBC spectra prompted us to propose the structure shown in Scheme 2 for the compound ()7, which was confirmed by X-ray crystallography.A view of the crystal structure of this compound is shown in Figure 1 and the most relevant crystallographic data and the hydrogen bond interactions are summarized in Table 1 and Table 2, respectively.There is one molecule in the asymmetric unit and the N-O distances found are on the same order as those reported for other compounds with similar fragments. 5,6In fact, the N( 1   The evolution of the diastereomers 6 on reaction with LiHMDS, PhSeCl and m-CPBA could be explained as summarized in Scheme 3. The carbanion A', in equilibrium with the enolate A or directly formed from 6, can progress by -elimination and protonation to the N-unsubstituted 3,4-cis-2-azetidinone 2 (pathway 1).An excess of base can drive the reaction to the dianion B which after attack by the PhSeCl followed by oxidation with m-CPBA and -elimination of the phenylselenyl-oxo moiety gave the 3,4trans alkenes 5 (pathway 2).Finally, the dianion B can also rearrange to the ketal C that will afford after acid work-up, the bicyclic compound 7 (pathway 3).
Mass spectra (MS), were recorded on a APPLIED BIOSYSTEMS QSTAR XL (HRMS, 5 kV) spectrometer.IR spectra were recorded as neat film on a NICOLET IR-100 instrument. 1 H and 13 C NMR spectra were obtained on Bruker instruments WP-200-SY and Avance 400-DRX (200 and 400 MHz respectively) in CDCl3 solutions with tetramethylsilane as internal standard.Solvents and reagents were purified according to standard techniques.

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9oncentrated under reduced pressure.Column chromatography of the crude product (700 mg) with hexanes/ethyl acetate mixtures as eluent afforded 118 mg (12.5%) of a 2:1 mixture of 1'-Z/E-monolactams 5, 228 mg (37.5%) of 2 and 214 mg (25.0%) of bicyclic compound 7.The compound 7 was dissolved in hexane-dichloromethane at room temperature and suitable crystals for X-ray diffraction studies grew over a period of one week when the solution was exposed to the air.A single crystal was mounted on glass fibre for data collection on a Bruker KAPPA APEX II CCD diffractometer.Data were collected at 293 K using Cu Kα radiation (λ = 1.54178Å) and ω scan technique, and were corrected for Lorentz and polarization effects.A semiempirical absorption correction was applied using SADABS7, and the program SAINT8was used for integration of the diffraction profiles.Structure solution, refinement and data output were carried out with the SHELXTL ® program package9.The structure was solved by direct methods combined with difference Fourier synthesis and refined by full-matrix least-squares procedures, with anisotropic thermal parameters in the last cycles of refinement for all non-hydrogen atoms.The position of the hydrogen atoms was determined by difference Fourier synthesis and refined, together their isotropic thermal parameter, by least squares procedures.Weighted R factors (ωR) and all goodness-of-fit (S) are based on F 2 , conventional R factors (R) are based on F. Crystallographic data (excluding structure factors) for the structure reported in this paper has been deposited at the Cambridge Crystallographic Data Centre as supplementary material (nº.CCDC-730530).

Table 1 .
Crystal and experiment data for compound 7  ARKAT USA, Inc.