Design and Synthesis of Chiral Molecular Receptors for the Chiral Discrimination of Amino Acids and Amines

Abstract

Section I. Highly Enantioselective Chiral Discrimination of ┒-Amino Acids with C2 Symmetric Homoditopic ReceptorsMost of the ┒-amino acid chiral receptors developed hitherto, contain different binding moieties for the recognition of the amine and the carboxylate groups. One major consequence of using different binding moieties is that the chiral receptor so designed, loses its symmetry. The importance of symmetry in a chiral receptor or catalyst, is well documented. Molecular symmetry can reduce the number of possible intermediates or transition states and hence dramatically increase the probability of success in chiral recognition or in asymmetric reaction catalysis, as the case may be. One way of retaining symmetry in the design of chiral receptors for ┒-amino acids is the use of the same binding element for both the carboxylate and amine groups. To achieve this end we decided to use the recently developed (o carboxamido)-trifluoroacetophenone (o-CATFA) moiety for both amine and carboxylate recognition. The o-CATFA group forms hydrogen bond stabilized adducts with both carboxylates and amines with a binding constant in the range of ~106 for the carboxylate and ~104 for amine groups respectively. We chose a 1, 1▽ binaphthyl scaffold for the generation of chiral orientation between the two o-CATFA binding elements. The two o-CATFA groups were attached to the 3, 3’ position of 1,1▽ binaphthyl for utilization of the chiral cleft between the two naphthyl rings of 1,1▽ binaphthyl. To modulate the dihedral angle between the two naphthyl rings, we introduced alkoxy groups in the 2, and 2’ positions of the binaphthyl scaffold. We synthesized two receptors (S)-1 and (S)-2 each containing isopropoxy or methoxy groups respectively in the 2 and 2’positions. The choice of the isopropxy group was also dictated by an intention of introducing steric congestion in the receptor. 19F NMR binding studies of both receptors (S)-1 and (S)-2 with ┒-amino acid tetrabutylammonium carboxylates revealed that receptor (S)-1 binds with L-amino acids with high enantioselectivity. The enantioselectivities achieved by receptor (S)-1 were in the range of 78:22 to 96:4 (L-AA:D-AA) for various racemic amino acids. However, the corresponding ratios for receptor (S)-2 were only in the range of 50:50 to 62:38. A very high chiral discrimination of ┒-amino acids has been realized by a C2-symmetric homoditopic receptor (S)-2, which is based on a binaphthyl chiral skeleton with 2,2▽-diisopropoxy substituents and a common binding side arm, (o carboxamido)-trifluoroacetophenone moiety, in the 3,3▽-positions. The importance of having appropriately sized substituents in the 2, 2▽ positions of the 1, 1▽- binaphthyl scaffold was also delineated.Section IIPart A. Development of C3 Symmetric Cage-like Receptors for the Chiral Recognition of ┒-Chiral Primary Organoammonium IonsEnantioselective recognition of ┒-chiral primary organoammonium ions by receptors of various symmetries, C1, C2 and C3 has been previously reported. However most of the ┒-chiral primary organoammonium ions used as guests have sterically bulky groups like phenyl or naphthyl at the ┒-chiral center. The recognition of organoammonium ions with sterically undemanding substituents appeared to be a worthwhile endeavour. As a starting point to our design, we used an “open type” C3 symmetric benzene-based tripodal tris(oxazoline) receptors (S,S,S)-1, developed by our group. We envisaged that the macrobicyclization of this receptor would yield C3 symmetric cage-like receptors 2a and 2b. These cage-like receptors are expected to enclose a confined chiral space in their cavities. The nitrogen atoms of the three oxazoline rings, which bind to the ammonium ion through three hydrogen bonds, are expected to be oriented into the interior of the cavity. Binding studies of the receptors 2a and 2b with two ┒-chiral primary organoammonium ions, ┒-phenylethylammonium and alanine methyl ester indicated that both receptors exhibit enantioselective recognition. The enantioselectivities achieved towards sterically undemanding guest alanine methyl ester ranged from 72(R):28(S) for receptor 2a to 64(R):36(S) for receptor 2b. For the same guest, the open type receptor did not display any enantioselective recognition. In the case of an organoammonium guest with sterically bulky ┒-substituent like ┒-phenylethylammonium ion, the enantioselectivities ranged from 72(R):28(S) for 2b to 61(R):39(S) for 2a. This is comparable to the 71(R):29(S) enantioselectivity obtained for the same guest with the open type receptor. One reason for the enantioselectivity being at the same level could be that the chiral cavity could be too tight a fit for guests with bulky substituents. Cage-like receptors that have internal binding sites and a C3-symmetric chiral bias have been synthesised, and their chiral discrimination behavior towards ┒-chiral organoammonium ions compared with their open structures.Part B. Development of pseudo-C3 Symmetric Receptors for the Chiral Recognition of ┒-Chiral Organoammonium Ions Pseudo C3-symmetric receptor 2a and 2b with three hydrogen bond donor oxazolines for the enantioselective recognition of ┒-chiral organoammonium ions was designed. Though the design of these two receptors lacks an element of symmetry, it was hoped that the absence of steric interactions between the three arms would facilitate the inward orientation of the three hydrogen bond donor nitrogen atoms of the three oxazoline moieties. While receptor 2a was successfully synthesized, the synthesis of receptor 2b could not be realized. Binding studies of receptor 2a towards ┒-phenylethylammonium ion indicated very poor affinity and total absence of enantioselectivity.The lack of an enantioselective recognition capability by receptor 2a can be directly attributed to its extremely low binding affinity towards ┒-chiral organoammonium ions. One possible reason for the lack of binding affinity for organoammonium ions by receptor 2a could be absence of the hydrophobic pocket provided by the three oxazoline phenyl rings as in the case of the previous C3 symmetric receptors: the hydrophobic pocket seems to enhance the binding affinity. Another possible reason for the lack of binding affinity could be the improper orientation of the nitrogen atom of the oxazoline ring which is directly attached to the central benzene scaffold, unlike the other two oxazolines which are attached through methylene spacers. Effective recognition of the ammonium ion requires a minimum of three interactions, usually through hydrogen bonding. It appears that hydrogen bond donation by the oxazoline moeity attached directly to the benzene core is ineffective and hence a tripodal three point interaction with the ammonium ion is not realized.