Author's personal copy Enantioselective total syntheses of ropivacaine and its analogues Nagula Shankaraiah a , Ronaldo Aloise Pilli b, * , Leonardo S. Santos a, * a Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, Talca University, Talca, PO Box-747, Chile b Instituto de Química, UNICAMP, PO Box 6154, 13083-970 Campinas, SP, Brazil article info Article history: Received 15 April 2008 Revised 3 June 2008 Accepted 5 June 2008 Available online 12 June 2008 Keywords: Ropivacaine Levobupivacaine Anodic oxidation Cation pool Supramolecular complex abstract An alternative asymmetric synthesis of ropivacaine and analogues employing the ‘cation pool’ strategy and host/guest supramolecular co-catalysis approach is presented. In this study, chiral auxiliaries, several soft nucleophiles as well as one-pot conditions for anodic oxidation, followed by nucleophilic addition, have been applied. Ó 2008 Elsevier Ltd. All rights reserved. Bupivacaine is the most widely used drug in childbirth centers as the anesthetic agent given to pregnant women. It has remained the main drug for long-acting local anesthesia for many years. Bupivacaine inhibits calcium channels of central nervous system (CNS), but its systemic neurotoxic effects (e.g., convulsions, sei- zures) affect infants and mothers in childbirth. Local anesthetics bind to the ‘inner vestibule’ of the Na + channel and an interesting feature of their mechanism of action is that anesthetic drugs affin- ity to the Na + channel varies with the gating state of the channel. Finally, the search for less cardiotoxic but equally long-acting local anesthetic has led to the synthesis and development of levobupiva- caine (1) and ropivacaine (2), which was recently introduced as a new alternative for long-acting local anesthetic drug, being closely related to mepivacaine (3) and levobupivacaine (1) that were first synthesized by Ekenstam and co-workers in the mid-1950s (Fig. 1). 1 After several experimental and clinical studies, it was con- firmed that levobupivacaine (1) and ropivacaine (2) afforded lower and different toxicity profile at least 70% less compared with bupivacaine that are widely used in Europe and USA as anesthetics in childbirth. 2,3 Recently, Ramachandran and co-workers reported an asymmetric synthesis of levobupivacaine. 4 However, there are few methods available for the enantioselective construction of pip- ecolic moiety in high yields. Generally, the main process available consists of resolution of racemic mixtures containing the pipecolic ring. Thus, we disclose a novel alternative to reach this important class of compounds featuring an efficient and practical synthesis of (L)-pipecolic acid derivatives. Our approach is based on the dia- stereoselective addition of NC À to N-acyliminium ions bearing a chiral auxiliary (a-phenylmenthyl) for the introduction of asym- metry in 1–3. Our strategy allowed the use of an interesting new approach to obtain directly a N-acyliminium ion through anodic oxidation. The advantages of this technique lie in its utility for selective oxidation of cyclic N-carbamates generating highly reactive intermediates under essentially neutral conditions. 5 We also employed the ‘cat- ion pool’ technique that is useful for N-acyliminium ion generation, in which ions are accumulated in solution by low-temperature electrolysis. 6 In the next step, the reactive intermediates are allowed to react in situ with nucleophiles. The idea has been suc- cessfully applied to N-acyliminium ions. 7,8 Initially, we set up some model experiments to optimize the critical nucleophilic addition step (TMSCN, NaCN, or n-Bu 3 SnCN) to chiral N-acyliminium ion 5a. According to Table 1, when using 8-phenylmenthyl as chiral auxiliary (entry 1), isolation of the corresponding a-methoxy car- bamate, followed by TMSCN addition catalyzed by TMSOTf in CH 2 Cl 2 at À78 °C, provided 6a in 85% yield and 76% ee. The enantiomeric excess was determined after hydrolysis of 6a to 0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2008.06.028 * Corresponding authors. Tel: +56 71 201575; fax: +56 71 200448 (L.S.S.); tel.: +55 19 3788 3114 (R.A.P). E-mail addresses: pilli@iqm.unicamp.br (R. A. Pilli), lssantos@utalca.cl (L. S. Santos). N R H N O R = n-Bu, 1 R = n-Pr, 2 R = CH 3 , 3 Figure 1. Worldwide used anesthetics levobupivacaine (1), ropivacaine (2), and mepivacaine (3). Tetrahedron Letters 49 (2008) 5098–5100 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet