The Synthesis Of 3-Aryl-β-lactams Via Suzuki Cross Coupling Reaction

β-Lactams have recently attracted medical chemists'attention as cholesterol absorption inhibitors. The momocyclicβ-lactam Ezetimibe has been on the market as an anti-cholesterolemia drug. The previous research of our laboratory shows that 3-aryl-β- lactams have good activity on inhibiting cholesterol absorption. In this thesis, we explored a rapid and efficient method to synthesize 3-aryl-β-lactam containing various aryl groups on the C3 position via the Suzuki reaction between 3-halo-β-lactams and aryl boric acid.In Chapter One, the progress of monocyclicβ-lactams as cholesterol absorption inhibitors was reviewed. In the pervious we discovered the 3-aryl-β-lactams of backbone re-organized ezetimibe analogs showed activity in inhibiting the absorption of cholesterol. These compounds were synthesized via Staudinger reaction as the key step. However, only limited munber of C3 aryl analogs could be readily prepared dur to the inavailability of the starting aryl acetic acid. In recent years, Suzuki reactions are widely used, due to attractive attributes such as the commercial availability, the air and water stability, and the nontoxic nature of boric acids. But no reports on reactions betweenα-halo-β-lactams and aryl boric acid was found in the literature.In Chapter Two, Suzuki cross coupling betweenα-halo-β-lactams and aryl boric acid was investigated. Starting from 2-chloro-2-oxoethyl acetate and imine, 3- halo-β-lactams were prepared via a sequence of Staudinger reaction, hydrolyzation and halogen substitute reaction. The reaction of 3-bromo-β-lactams and phenyl boric acid under Pd(OAc)2/PPh3 catalyst system and 3 eq K3PO4 could give desired product with 83% yield. Under the above conditions, thirteen 3-aryl-β-lactams were synthesized in good to excellent yields(79%-91%). The reaction results were summarized as follows: (1) Many substituted groups on 3-bromo-β-lactam and aryl boric acids were tolerated; for the bromo substituted, yield was lower compare to the others; for the 3-halo-β-lactam without a protecting group on the nitrogen, no desired product was obtained; (2) Aryl boric acids also react with 3-iodo and 3-chroloβ-lactams and the latter gives lower yield; (3)The reactions give trans lactam as major product and no Biphenyl byproduct found, the dehalogen byproduct was formed occasionally sometimes.This thesis described a new method to synthesize 3-aryl-β-lactams through Suzuki Cross Coupling between aryl bronic acids and 3- halo-β-lactams. This is the first time to apply Suzuki cross couplings on theα-arylation of lactam.