An efficient synthetic route to functionalized d-lactams Ali Samarat, Jihe `ne Ben Kraı¨em, Taı¨cir Ben Ayed, Hassen Amri * Laboratoire de Chimie Organique & Organome ´tallique, Faculte ´ des Sciences, Campus Universitaire, 2092-Tunis, Tunisia article info Article history: Received 13 May 2008 Received in revised form 7 July 2008 Accepted 17 July 2008 Available online 22 July 2008 Keywords: Aza-Michael addition Primary amines 2-Alkylidene glutarates d-Lactams abstract This paper describes a convenient synthesis of disubstituted functionalized d-lactams based on Michael addition of primary amines to dimethyl-E-2-alkylidene glutarates 2 followed by an intramolecular cyclisation. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Six-membered nitrogen-containing heterocycles are common skeletons in many natural products and exhibit diverse and im- portant biological properties. 1,2 Alkaloids that contain the piperi- dine ring are targets for medicinal chemistry. 3–7 Accordingly, functionalized d-lactams have been generally used as precursors of the corresponding piperidines. 8–10 Functionalized d-lactams and structurally related compounds have attracted considerable at- tention because of various biological activities, including anti-tu- mour compounds, 11 enzyme inhibitors 12–14 and anti-HIV agents. 15 Over the last few years, there is an increasing interest in the de- velopment of general methods for their preparation and several syntheses of these heterocycles, using different approaches, have been reported. 16–24 Our interest in the synthesis of poly- functionalized heterocyclic compounds 25–30 has led us to the de- sign of a rapid access to these functionalized d-lactams using dimethyl (E)-2-alkylidene glutarates 2 as key intermediates. 2. Results and discussion We have previously described a highly stereoselective synthesis of dimethyl (E)-2-alkylidene glutarates 2 by nucleophilic sub- stitution of the vinylic bromine atom in the diester 1 , by using cuprates as nucleophilic reagents generated in situ at low tem- perature (Scheme 1). 31 The dimethyl (E)-2-bromomethylene glu- tarate 1 was prepared through a simple tandem-process: bromination–dehydrobromination of dimethyl-2-methylene glu- tarate 2a. 32 As summarized in Scheme 2, we have recently demonstrated that glutarates 2 represent a useful building block for the enan- tioselective synthesis of functionalized g-butyrolactones by the utilisation of the Sharpless asymmetric dihydroxylation (AD) and aminohydroxylation (AA) processes, 33 while the silylcupration of the same Michael acceptors 2, followed by oxidation of the carbon– silicon bond and cyclisation provide the corresponding function- alized d-lactones. 34 We now report the use of dimethyl (E)-2-alkylidene glutarates 2 as intermediates in the synthesis of functionalized d-lactams. In our approach, the construction of the nitrogen-containing heterocycle is based on an efficient coupling of primary amines to Michael ac- ceptors 2. In fact, the condensation of glutarates 2 with primary amines in methanol, as solvent, at reflux proceeds via a two-step sequence: a nucleophilic conjugate addition of amine to the acti- vate ethylenic carbon leading to the b-amino-ester intermediate, which spontaneously undergoes an intramolecular cyclisation through a 6-exo-trig process 35 to provide the corresponding functionalized d-lactam 3 (Scheme 3). It is interesting to notice that spontaneous lactamization of the resulting b-aminoester intermediate was completely regioselective in the examined cases; only d-lactams were obtained in moderate and good yields. The disubstituted d-lactams 3e–g were obtained as a mixture of two isomers with good diatereoselectivity and satis- factory yields (Table 1). A small coupling constant (4–5 Hz) for the two protons at C-2 (d 4.2–3.9) and C-3 (d 2.9–3.1) suggested a cis configuration for the major isomer of the disubstituted lactams 3e–g. This result allowed us to establish the configuration of the b-amino-ester precursor. The major isomer was found to possess * Corresponding author. E-mail address: hassen.amri@fst.rnu.tn (H. Amri). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.07.057 Tetrahedron 64 (2008) 9540–9543