Conformationally restricted analogues of both (S)-b-homoserine and (S)-aspartic acid from chiral 3-acylamino pyrrolidin-2-ones Roberta Galeazzi, a Gianluca Martelli, a Mario Orena, a, * Samuele Rinaldi a and Piera Sabatino b a Dipartimento di Scienze dei Materiali e della Terra, Universita ` Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy b Dipartimento di Chimica “G. Ciamician”, Universita ` di Bologna, Via Selmi 2, 40126 Bologna, Italy Received 19 January 2005; revised 16 March 2005; accepted 31 March 2005 Available online 29 April 2005 Abstract—Starting from chiral 3,4-trans-disubstituted pyrrolidin-2-ones 11a and 11b, obtained from a Baylis–Hillman adduct, conformationally restricted analogues of both (S)-b-homoserine, 17, and (S)-aspartic acid, 21, were synthesized, respectively, and these compounds are suitable either for introduction in peptidomimetics or for synthesis of novel b-foldamers. q 2005 Elsevier Ltd. All rights reserved. 1. Introduction Properly substituted pyrrolidin-2-ones (g-lactams) can be isosteres of natural amino acids. Thus, they can give rise to conformational constrictions useful to both restrict the flexibility of the peptide molecules and to provide informations on the topographical requirements of recep- tors, 1 when they are introduced in bioactive peptides. Moreover, the incorporation of these units in a peptide lead to analogues that display a lot of advantages such as increased biostability and bioselectivity against the natural biological target of the parent peptide. Therefore, they are interesting target compounds, 2 useful for the synthesis of both terminally constrained or internally constrained peptidomimetics 3 and their availability in an enantiomeri- cally pure form is important for applications in medicinal chemistry. 4 In this field, our attention was focused to the pyrrolidin-2-ones 3 and 4, that are constrained analogues of (S)-b-homoserine 1 and (S)-aspartic acid, 2, respectively (Scheme 1). 2. Results and discussion We already demonstrated the viability of the approach involving (C-3)–(C-4) bond formation for construction of the pyrrolidin-2-one ring, leading to conformationally restricted amino acids in the enantiomerically pure form. 5 As a further development, we recently, devised a conjugate addition/ring closure sequence starting from the Baylis– Hillman adduct 5 and (S)-phenylethylamine, leading to formation of both (N-1)–(C-5) and (N-1)–(C-2) bonds of the g-lactam ring, and this synthetic approach was directed toward the synthesis of chiral 3-hydroxypyrrolidin-2-ones, intermediates for the preparation of an inhibitor of glycosidases. 6 Our previous investigations concerning the chemistry of Baylis–Hillman adducts disclosed a straight- forward general procedure for the preparation of 3- acylamino-2-methylene alkanoates, by exploiting the cor- responding acyl carbamates. 7 In this report, the acyl carbamates 7a,b were prepared in quantitative yield by reaction of the adduct 5 and the appropriate acyl isocyanate 6a,b (Scheme 2). 8 However, whereas treating the 1- naphthoyl carbamate 7b with DABCO in DCM gave the corresponding 1-naphthoylamino derivative 8b in good yield, the trichloroacetylamino derivative 8a was obtained only in a disappointing 20% yield from 7a under the same reaction conditions. The other products of this reaction were a complex, inseparable mixture of polar products. To overcome this problem, an alternative approach to com- pound 8a was devised, starting from the trichloroacetimi- date 9. The preparation of this compound, however, turned 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.03.129 Tetrahedron 61 (2005) 5465–5473 Scheme 1. Keywords: Amino acids; Analogues; Baylis–Hillman; Peptidomimetics; Conformational constrictions. * Corresponding author. Tel.: C39 071 2204720; fax: C39 071 2204714; e-mail: m.orena@univpm.it