Highly functionalised organolithium and organoboron reagents for the preparation of enantiomerically pure a-amino acids Christopher W. Barfoot, a Joanne E. Harvey, a Martin N. Kenworthy, a John Paul Kilburn, a Mahmood Ahmed b and Richard J. K. Taylor a, * a Department of Chemistry, University of York, Heslington, York YO10 5DD, UK b GlaxoSmithKline, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, UK Received 27 July 2004; accepted 15 October 2004 Available online 10 December 2004 Abstract—Homochiral, highly functionalised organolithium reagents derived from L-serine have been generated and reacted with electrophiles. The novel enantiomerically pure adducts thus obtained were then converted, through b-amino alcohols, into novel non- proteinogenic a-amino acids. The methodology also made available a novel boronic acid which was then employed as a Suzuki cross- coupling partner, elaborating a new pathway to phenylalanine analogues. q 2004 Elsevier Ltd. All rights reserved. Nucleophilic alanine equivalents have attracted a great deal of attention in recent years. 1–6 These reagents are particu- larly useful for the preparation of enantiopure proteinogenic and non-proteinogenic a-amino acids, 1 as well as enantio- pure a-amino alcohols, and other related ‘chiral building blocks’ used in natural product synthesis. Prominent examples of these reagents include aspartate-derived anion 1, 2 related sulfonyl reagent 2, 3 Wittig reagents 3 4 and 4, 5 and the organonickel reagent 5. 6 Although ground-breaking and potentially valuable, these reagents have not been widely employed in organic synthesis, possibly due to the difficulty of preparation, the additional steps needed to remove the anion-stabilising/activating group or to readjust the oxidation level and, in the case of reagent 5, its low reactivity. The organozinc reagent 6 designed and prepared by Jackson and his group, 7 has proved particularly versatile and has been successfully adopted by other researchers for prepa- ration of a number of natural products and medicinally active compounds. 8 This reagent can be employed in a variety of coupling procedures (e.g., to aryl halides and acyl halides 7a ), and its copper derivative also undergoes allyla- tion or conjugate additions. 7b Unfortunately, due to its low nucleophilicity, reaction with simple aldehydes/ketones is not possible (Fig. 1). During synthetic efforts towards the synthesis of scyphos- tatin 9a and aranorosin, 9b we required a highly reactive organometallic reagent, i.e. 7, capable of 1,2-addition to cyclic ketones. In this paper we describe the successful 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.10.097 Tetrahedron 61 (2005) 3403–3417 Figure 1. Alanine anion equivalents. Keywords: Cross-coupling; a-Amino acids; Organolithium; Suzuki; Alanine anions. * Corresponding author. Tel.: C44 1904 432606; fax: C44 1904 434523; e-mail: rjkt1@york.ac.uk