The azetidin-2-one (β-lactam) ring is widely recognized as a key structural motif in several families of antibiotics.¹ Ezetimibe (1), has recently been commercialized as an effective acyl-CoA cholesterol acyltransferase inhibitor for lowering cholesterol levels. The drug is absorbed into the intestinal epithelial cell and remains associated in great part with the epithelial cell membrane where it is believed to interfere with the putative sterol transporter system.² This apparently prevents both free cholesterol and plant sterols (phytosterols) from being transported into the cell from the intestinal lumen.

 The novel structure and potent biological activity of ezetimibe has prompted intense synthetic interest in the synthetic community which led to the development of several syntheses for this molecule. Many of these routes have utilized chiral auxiliary based synthesis and used chiral HPLC for the purification of the intermediates.³

In connection with our interest for the synthesis of azetidin-2-one ring⁴, we wish to report a facile and efficient method for the preparation of Ezetimibe precursor 4 via a copper (I)-mediated reaction between diaryl nitrone 3 and chiral terminal acetylene 2

1. Veinberg, G.; Vorona, M.; Shestakova, I.; Kanepe, I.; Lukevics, E. Curr. Med. Chem. 2003, 10, 1741.

2. Bays,H. Expert Opin. Investig. Drugs 2002, 11, 1587.

3. Castaner, R. M.; Sorbera, L. A.; Castaner, J. Drugs Future 2000, 25, 679.

4. Stecko, S.;Mames, A.; Furman, B.; Chmielewski, M. J. Org. Chem.  2008, 73, 7402.

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1. Diastereoselective Synthesis of β-Lactams via Kinugasa Reaction
2. From unsaturated sugar α,β-lactones to β-lactams. The synthesis. Od α,β-nienasyconych laktonów cukrowych do syntezy β-laktamów.
3. An asymmetric synthesis of 4-aryloxyazetidin-2-ones and 3,4-benzo-2-hydroxycephams
4. Cyclic Enaminones as Building Blocks in the Synthesis of Piperidine-Containing Natural Products and Biolo- gically Active Compounds
5.  Straightforward Methodology for the Stereoselective Synthesis of Benzo[a]- and Indolo[2,3-a]quinolizidines
6.  An entry to carbapenams via asymmetric Kinugasa reaction involving cyclic nitrones and terminal acetylenes
7. Reactions of diastereomeric sugar derived sulfites with sterically demanding organometallics
8. Polyhydroxylated indolizidine and pyrrolizidine alkaloids. Synthesis and bioactivity.
9. Strategies of the synthesis of oxa- and carba-penams and cephams