Synthesis of Axially Chiral Binaphthothiophene δ-Amino Acid Derivatives Bearing Chalcogen Bonds

Axially chiral binaphthothiophene amino acid was synthesized as a stable artificial δ-amino acid. Nand C-protected derivatives of this unnatural amino acid were also prepared and applied for derivatization to the dipeptide. The crystal structure of the dipeptide revealed that the carbonyl groups of both the amide and the ester moieties were fixed with naphthothiophene rings in coplanar geometry via intramolecular chalcogen bonds. Unnatural amino acids have played significant roles as key building blocks for bioactive compounds in the production of small-molecule drugs and artificial peptides in peptide mimetics. In catalytic asymmetric synthesis, asymmetric unnatural amino acids possessing central chirality have also been employed as chiral organocatalysts. Unnatural amino acids bearing axial chirality have unique structural features, as their chiral environments are different from that of amino acids with central chirality. Although unnatural amino acids have been well developed, the synthesis and application of axially chiral amino acids have not yet been fully exploited. Therefore, the development of axially chiral amino acids possessing novel structural features would have a significant impact in the field of medicinal chemistry, peptide mimetics, and catalytic asymmetric synthesis. We have synthesized axially chiral binaphthyl δ-amino acid (S)-1 and its N-protected derivatives bearing aniline-type amines as well as carboxy groups at 2,2’-positions (Figure 1a). Furthermore, the N-protected derivative of (S)-1 was found to be applicable as a chiral building block for artificial peptides, and a chiral ligand for dirhodium(II) carboxylate catalyst. The structure of 1 was characterized by its axial chirality, which leads the amino and the carboxy groups to locate in perpendicular geometry. Unfortunately, however, the stability of 1 itself was greatly affected by spontaneous lactamization to 2, and therefore 1 was not stable enough for storage. On the other hand, we have also reported the synthesis of axially chiral binaphthothiophene dicarboxylic acid (S)-3, which has the distinct feature of sulfur atoms incorporated into its fused tricyclic π-systems (Figure 1b). The crystal structure of 3 revealed that the carboxy groups were aligned in coplanar geometry with the naphthothiophene rings due to conformational lock via intramolecular chalcogen bonds (S•••O interactions). From both of these studies of axially chiral compounds, we envisaged that binaphthothiophene δ-amino acid (S)-4, and its derivatives may have characteristic structures due to their axial chirality as well as intramolecular chalcogen bonds (Figure 1b). Herein, we describe the synthesis of (S)-4 and its Cand N-protected derivatives from (S)-3, stability of (S)-4, as well as the structural features of artificial dipeptide composed of 4. Figure 1. (a) Spontaneous lactarmization of (S)-1. (b) Structure of axially chiral binaphthothiophene δ-amino acid (S)-4 and dicarboxylic acid (S)-3. We began the synthesis of (S)-4 and its C-protected derivative (S)-6 from O-benzylation of (S)-3 (Scheme 1). This monobenzylation was carried out under previously developed conditions for the selective monoesterification of biphenyl as well as binaphthyl dicarboxylic acids. In this case however, the yield obtained was not sufficient (34%) to yield (S)-5. Curtius rearrangement of (S)-5 in the presence of diphenylphosphoryl azide (DPPA), and subsequent hydrolysis of the isocyanate intermediate with water yielded amino acid benzyl ester (S)-6. HPLC analysis with chiral stationary phase indicated that (S)-4 stable (S)-3 chalcogen bond