Reaction of (S)-homoserine lactone with Grignard reagents: synthesis of amino-keto-alcohols and b-amino acid derivatives Özlem Gündog ˘du, Pınar Turhan, Aytekin Köse, Ramazan Altundas ß, Yunus Kara ⇑ Department of Chemistry, Faculty of Sciences, Ataturk University, 25240 Erzurum, Turkey article info Article history: Received 14 July 2017 Accepted 8 August 2017 Available online xxxx abstract The ring-opening reaction of homoserine lactone with phenylmagnesium bromides was systematically examined. A reliable method to achieve b-amino acid precursors was developed by tuning the reaction conditions to favor mono-addition to the carbonyl moiety of the lactone. Ó 2017 Published by Elsevier Ltd. 1. Introduction b-Amino acids are important compounds in Nature and syn- thetic chemistry because they present a broad range of biological properties. Several approaches for the efficient synthesis of these compounds have been developed. 1 One of these approaches involves aspartic acid and methionine. (S)-Homoserine lactone can be readily obtained from (S)-methionine, 2,3 and the reaction of this lactone with a variety of Grignard reagents yields the corre- sponding amino alcohols, 3,4 which can then be easily oxidized into b-amino acids. However, treatment of lactone 1 with Grignard reagents yields bis-addition, not mono-addition, of the reagent to the carbonyl group, furnishing tertiary alcohols 2 (Scheme 1). To avoid bis-addition, several methodologies have been devel- oped. 5 Seki et al. also reported the synthesis of c-aryl or alkyl-sub- stituted homochiral b-amino acids from N-Cbz-(S)-homoserine lactone. 3 The literature reports two main methods for synthesizing amino-keto acids from such compounds: Friedel–Crafts acylation and organometallic reaction with the corresponding anhydride or acyl chloride. 6 Although amino-keto acids are accessible via the Friedel–Crafts reaction with anhydrides or acyl chlorides, the con- trol of regioselectivity is strictly reagent-dependent. In addition, nucleophilic groups containing aryl and alkyl compounds are usually unable to undergo Friedel–Crafts reactions. These are the major drawbacks in the synthesis of aryl amino-keto acids when using the Friedel–Crafts reaction. Although the reaction of organo- metallics with lactones is well known in the literature, bis- homoserine has not been studied in detail, and its potential in developing easy access to b-amino acid precursors has not been evaluated. Herein we report a straightforward and efficient synthe- sis of c-keto-b-amino acids via the ring-opening reaction of homoserine lactone. 2. Results and discussion We commenced with the synthesis of N-Boc-(S)-homoserine lactone 1a from (S)-methionine using a known method as described in the literature. 3 (S)-Methionine was subjected to S- alkylation and nucleophilic displacement of a dialkyl sulfide, and the L-homoserine obtained was then converted into lactone 1 with HCl (Scheme 2). Two equivalents of PhMgBr prepared 7 in situ from PhBr and Mg turnings in the presence of 1,2-dibromoethane were treated with one equivalent of lactone 1a at room temperature (Scheme 3). After purification of the crude material, keto-alcohols 6 and 7 were obtained in yields of 70% and 20%, respectively. For this reaction, at least a twofold excess of PhMgBr was necessary: one equivalent for the acidic proton (–NHBoc) and one equivalent to achieve the addi- tion to the carbonyl group of the lactone. In our attempts to improve the synthesis of keto-alcohol 6, 2.3 equiv of PhMgBr were used and the desired keto-alcohol was obtained in good yield. It should be noted that depending on the reaction temperature used, an increased ratio of bis-addition product 7 was found. Thus, to eliminate 7, the reaction was repeated at 0 and 78 °C, however these reactions failed. Despite our failure to eliminate bis-addition product 7, the synthesis of 6 in good yield encouraged us to expand this simple methodology to a series of in situ prepared Grignard http://dx.doi.org/10.1016/j.tetasy.2017.08.009 0957-4166/Ó 2017 Published by Elsevier Ltd. ⇑ Corresponding author. E-mail address: yukara@atauni.edu.tr (Y. Kara). O O NH 2 PhMgBr (4.4 equiv.) 1 2 OH NH 2 Ph OH Ph Scheme 1. Bis-addition of PhMgBr to homoserine lactone. Tetrahedron: Asymmetry xxx (2017) xxx–xxx Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy Please cite this article in press as: Gündog ˘du, Ö. ; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.08.009