TETRAHEDRON LETTERS Tetrahedron Letters 44 (2003) 1927–1930 Pergamon On the C-2 epimerisation of kainoids Philippe Klotz* and Andre ´ Mann Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081, Faculte ´ de Pharmacie, 74 route du Rhin, BP 24, F -67401 Illkirch, France Received 19 December 2002; revised 3 January 2003; accepted 5 January 2003 Abstract—The conditions for the epimerisation at carbon C-2 of phenyl kainic acid esters 6 and 7 and cis -3-prolinoglutamic esters 10 were systematically addressed. We found that the use of KHMDS in THF gave improved results over the existing procedures. Some mechanistic aspects of this peculiar epimerisation are discussed. © 2003 Elsevier Science Ltd. All rights reserved. afforded compounds 6a endo with a cis relationship at carbon C-2 and C-3, and, therefore an additional epimerisation step was required at the carbon C-2 to reach the precursor 8a (Scheme 1) of the desired bio- active stereomer. This epimerisation step is crucial and has been used in several synthesis of kainoids. 9d,e,g,10b,12 However, in our hands when we tried the reported epimerisation procedures on compound 6a as well as on 7a exo (to get 9a, the corresponding allo analogue) 10c no convincing results were obtained. In this letter, we present a systematic study which led to the proposal of new reaction conditions and relevant mechanistic considerations. It must be emphasised that other teams encountered similar difficulties for the C-2 epimerisation: Rubio, 12a in a synthesis of KA; Ogasawara, in his synthesis of acromelic acid; 10h and more recently, Karoyan, 13 faced difficulties for the epimerisation at carbon C-2 of cis -3-prolinoglutamic acid diester 10a. Probably the presence of the acetate appendage at carbon C-3 induces new steric and elec- tronic constraints, which render the C-2 epimerisation much more complex than it is in proline itself (see below). We focussed our study towards the phenyl Kainic acid 2 (KA) is a naturally constrained analogue of glutamic acid 1, the major excitatory amino acid in the mammalian central nervous system (Fig. 1). 1 KA 2 shows high affinity for specific subtypes of glutamate receptors—the KA receptors—and is widely used as a reference tool 2 to mimic the symptoms of neuronal injuries in animal brains such as epilepsy, Alzheimer’s disease 3 and Huntington’s chorea. 4 KA is the parent member of the large kainoid family 5 including aryl kainoids 3, acromelic acid (for ex. acromelic acid A 4) or domoic acid 5, which are all powerful neuroexcita- tory agents. 6 The pyrrolidine skeleton, in all these molecules (2–5), embedded three contiguous stereocenters in a typical trans (C2–C3), cis (C3–C4) arrangement which is a crucial feature for binding to the KA receptor. 7 Recently, a shortage of kainic acid 8 has prompted several groups to search for new efficient synthetic routes towards KA 9 and the corresponding analogues 3, 4 and 5. 10 As we are involved in the kainoid area, we proposed a very short synthesis (only six steps) of phenylkainic acid (Ar=Ph in 3). 11 Our synthetic route Figure 1. Glutamic acid and kainoid family. * Corresponding author. Fax: (33) 03 90 24 43 10; e-mail: ph.klotz@pharma.u-strasbg.fr 0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved. PII:S0040-4039(03)00077-7