Strategies for the stereocontrolled formation of oxygen analogues of penicillins and cephalosporins.

The synthesis of oxacephalotin and oxacephamandol, which are more active than natural, sulfur-containing congeners, and the isolation of clavulanic acid, a potent inhibitor of beta-lactamase enzymes, directed attention of many academic and industrial laboratories the synthesis of oxygen analogues of penicillins and cephalosporins. The present review focuses attention on the problem of stereocontrol in the formation of a desired configuration of the bridgehead carbon atom in the title compounds. Five feasible synthetic methods leading to the basic skeletons of clavams and 5-oxacephams are discussed. Three of them involve the nucleophilic substitution at C-4 of the azetidin- 2-ones performed as inter- or intramolecular process and the remaining two involve cycloaddition reactions between ketenes and iminoethers, or between vinyl ethers and isocyanates. Owing to the general application, stereospecificity and high asymmetric induction, the last method seems to be most advantageous. The weak point of the nucleophilic substitution methodology is that a nucleophile approaches the 3-substituted azetidin-2-one ring preferentially anti to the existing substituent and in the case where there is no substituent at C-3, that the stereoselectivity of formation of the new chirality center at C-4 is low. All discussed methods are illustrated by the examples taken from the literature.

Stereoselectivity in formation of oxacephams from 1,3-alkylidene-threitols.

The [2+2]cycloaddition of CSI to the (Z)-propenyl ethers derived from respective 1,3-methylidene- and 1,3-ethylidene-threitols, contrary to the corresponding erythritol derivatives, is characterized by a low stereoselectivity and a lack of stereospecificity. On the other hand, the alternative method of the oxacepham formation, based on the 4-vinyloxy-azetidinone, proceeds with an excellent stereoselectivity. The CD-spectroscopy offers an attractive tool for determination of the absolute configuration of the bridgehead carbon atom at the 5-oxacepham skeleton.

Stereocontrolled formation of oxacephams from carbohydrates.

The [2 + 2] cycloaddition of chlorosulfonyl isocyanate to (Z)-4-O-propenyl ethers 16, 17, 29 and 30 proceeds with an excellent stereoselectivity in the case of ether 16 and with moderate stereoselectivity in remaining cases. Adducts were transformed into corresponding oxacephams: 37 in the first case, a mixture of 37/40 in the second and third case, and a mixture of 50/51 in the last case. In all instances addition to the si-re side of the olefin dominates. Oxacephams 41 and 52 with opposite R-configuration at the bridgehead carbon C-5a can be obtained by the alternate methodology based on the alkylation of nitrogen in 4-vinyloxyazetidin-2-one by protected 6-O-triflate 24 or 25, followed by cyclization via intramolecular displacement of the vinyloxy group. Compounds 37, 40, 41, 50, 51 and 52 constitute a convenient entry leading to polyfunctionalized oxacephams.

Structure-chiroptical properties relationship in oxabicyclic beta-lactam derivatives.

The relationship between molecular structure of 5-dethia-5-oxacephams and clavams and their chiroptical properties was investigated by means of X-ray diffraction analysis, molecular modeling calculations and circular dichroism spectroscopy. It was found that the amide chromophore of the beta-lactam unit in these compounds is nonplanar with nitrogen atom having a pyramidal configuration. It was also found that the helicity of the lactam moiety in investigated oxacephams and clavams is controlled by the absolute configuration at the C-6 and C-5 carbon atom, respectively. Thus, the applicability of helicity rule correlating a positive (negative) torsional angle of the beta-lactam subunit O=C-N-C with a negative (positive) sign of the n-->pi* CE, previously applied to oxacephams, is now extended to clavams.

5-Dethia-5-oxacephams: toward correlation of absolute configuration and chiroptical properties.

The relationship between chiroptical properties of differently substituted 5-dethia-5-oxacephams and their respective molecular structures was investigated. The amide chromophore of the beta-lactam unit in these compounds was found to be nonplanar with a shallow pyramidal configuration at the nitrogen atom. Due to the nonplanarity, the beta-lactam system becomes inherently dissymmetric, which is supported by a high magnitude of the n --> pi* CD band. It was also found that the helicity of the lactam moiety in investigated oxacephams is controlled by the absolute configuration at the C(6) carbon atom. On this basis, a helicity rule correlating a positive (negative) sign of the n right arrow pi Cotton effect with a negative (positive) O [double bond] C [bond] N [bond] C(6) torsional angle for policyclic beta-lactam derivatives possessing a nonplanar amide chromophore was formulated.