Ruffling-Induced Chirality:  Synthesis, Metalation, and Optical Resolution of Highly Nonplanar, Cyclic, Benzimidazole-Based Ligands

Expedient five-step syntheses of a cyclic bis(benzimidazole)-based amide <b>5 </b>and two sterically more hindered analogues <b>23</b>−<b>24</b> have been developed. These amides are chiral due to the inherent ruffling of the macrocyclic plane. Racemization of the optical antipodes of these compounds has been studied using dynamic chiral stationary phase HPLC. These studies reveal that, while the parent amide <b>5</b> racemizes rapidly, for the sterically more hindered amides <b>23</b>−<b>24</b>, the rate of racemization is significantly reduced. Bis(benzimidazole)-based amides <b>5 </b>and<b> 23</b>−<b>24</b> form stable Ni(II) complexes <b>25</b>−<b>27</b>, respectively. Like their parent ligands, complexes <b>25</b>−<b>27</b> are chiral due to their highly ruffled geometry. Studies of these complexes by chiral stationary phase HPLC reveal that metalation leads to a much lower rate of racemization. Incorporation of a strap can slow racemization even further. A series of strapped cyclic amides <b>54</b>−<b>57</b>, along with their corresponding dimers <b>58</b>−<b>61</b>, have been prepared. The rate of racemization for amides <b>54</b>−<b>57</b> is strongly dependent on the length of the strap. X-ray single-crystal structure analysis of the Ni(II) complex of strapped amide <b>54</b> reveals that the bis(benzimidazole) core retains its highly ruffled shape, with the two phenyl rings of the macrocycle located anti to the strap. Chiral separation of strapped ligands <b>54</b>−<b>57</b> and their corresponding Ni(II) complexes is shown to be facile by chiral stationary phase HPLC.