Stereoselective Synthesis Of β-Lactams

β-Lactam has a long history of development starting from the discovery of penicillin in 1928, the quest for new synthetic methods and refinement of those already known remains appealing. And the research into the application of theses methods in synthesizing novel biologically active azetidinone derivatives still constitutes an active area in organic synthesis. Recent years have seen a resurgence of interest in the development of stereo- and enantioselective methodologies. The utility of β-lactams as synthons for various biologically active compounds, as well as their recognition as cholesterol absorption inhibitors and enzyme inhibitors, has given impetus to these studies. We, therefore, investigated the stereoselective syntheses of trans β-lactams, and the details are summarized below.1. Efficient and diastereoselective syntheses of trans β-lactams and anti β-aminocarbonyl compounds from carboximide and imines via the Gilman-Speeter reaction are developed. The bulky chair cyclohexane ring on the 2-position of spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one plays an important role in efficient asymmetric induction, which leads to trans β-lactams exclusively. Imines derived from anilines and aromatic or aliphatic aldehydes give good-to-satisfactory yields (50-82%). Unfortunately, N-benzylimine does not react under this condition. An enolate-imine mechanism involving the chairlike transition state has been proposed for this reaction. Formation of (Z)-enolate determines the trans configuration of the β-lactams.2. Two PEG-supported Liquid-phase syntheses of trans β-lactams are developed. Thus, using PEG-supported imines, trans β-lactams are obtained in high diastereoselectivity (tranxis > 98:2). On the other hand, using PEG-supported auxiliary, the reaction gives trans β-lactams via a "resin-capture-release" strategy. The advantage of this reaction is that it not only chemically produces β-lactams but also provokes release of the product from the resin back into the solution.3. Enantioselective synthesis of 6-lactams from chiral carboximide and imines under the Gilman-Speeter reaction is developed. The chiral substituent on the 2-position of spiro[2H-l,3-benzoxazine-2,l'-cyclohexan]-4(3H)-one induces the formation of one isomer of the trans 6-lactams. Imines derived from anilines and aromatic or a,p-unsaturated aldehydes give good to satisfactory yields (63-81%), acceptable ee value (75-86%). Unfortunately, JV-benzylimine does not react under this condition. An enolate-imine mechanism has been proposed to explain the stereoselective mechanism, which is validified by the intermediate tripped.