The amide rotation of cis-trans lactams is fundamentally important, but has rarely been studied, with the exception of reports on peptide-based lactams. Here, we find a consistent relationship between the trans/cis ratio of the lactam amide and the trans/cis-amide rotation rate upon elongation of the stapling side chain of two 7-azabicyclo[2.2.1]heptane bicyclic units linked via a non-planar amide bond. That is, as the chain length increases, the spinning rate from trans-to cis-lactam amide decreases, resulting in an increase in the trans ratio. This chain length dependence of lactam amide isomerization and our simulation studies support the idea that the current lactam amide can rotate 360 degrees due to the occurrence of nitrogen pyramidalization of lactam. The direction of tilting of the pyramidalization of nitrogen atoms in the bicyclic system is synchronous with the direction of the semicircular rotation of the amide.
Helicenes, a class of non-planar polyaromatic hydrocarbons whose characteristic is helicity, are fascinating functional molecules with unique optical and electronic properties. In recent years, “multiple helicenes” having plural helicities in a single molecule have developed rapidly into an attractive research field due to their highly distorted structure, with the partially delocalized π-systems reflecting the assembly of plural helicities. In this account, we describe our recent work covering the synthesis, structures, properties, and theoretical study of multiple helicenes, DH-1, HH-2, and TH-3. Our strategy for the synthesis of multiple helicenes includes the assembly of helicene subunits by palladium-catalyzed reactions.
The attachment of oligosaccharides is one of the most abundant post-translational modification of proteins. The resultant glycoproteins play central roles in many biological processes. However, the intrinsic heterogeneity of native glycoproteins regarding to the structures of oligosaccharides has hampered the detailed functional studies of the oligosaccharides attached to the proteins. To address this issue, we have been developing chemical methodologies for the synthesis of homogeneous glycoproteins. The chemical approach for the glycoprotein synthesis consists of the preparation of oligosaccharide and glycopeptide building blocks, the assembly of the full length glycopeptides of the target glycoproteins, and folding. This synthetic strategy allowed us to synthesize a variety of structurally defined forms of glycoproteins.
The synthesis of organic compounds containing all-carbon quaternary stereocenters through the addition of allylmetals to aldehydes is still a challenge. In this account we describe two methods to achieve this transformation stereoselectively: one involves the zinc-mediated Barbier-type allylation and the other allylboration of a sugar-derived aldehyde. These methods were applied to the total synthesis of (+)-vibsanin A, and the synthesis of the tricyclic core of (−)-callophycoic acid A.
Nitric oxide (NO) is a signaling molecule that mediates vasodilation, neurotransmission, and immune response. Due to its instability in biological environments, NO-releasing small-molecular compounds have been developed for biological experiments and also as therapeutic reagents for vascular diseases. Although photocontrollable NO releasers are very useful chemical tools because of their precise operability in response to light irradiation, their biological applications have been limited, mainly because they require UV light irradiation or contain metal ions with the potential to cause cytotoxicity. In order to overcome these problems, our group has developed visible-light-responsive NO releasers based on photoreodox reaction. These compounds are composed of two moieties, an NO-releasing moiety and a light-harvesting antenna moiety. After photoirradiation, photoinduced electron transfer from the NO releasing moiety to the antenna takes place, followed by NO release. Based on this system, we developed a blue-light-controllable NO releaser and a yellowish-green-light-controllable one, which are applicable for cellular and ex vivo experiments. This account focuses on recent developments in photoredox-driven NO releasers and their applications for spatiotemporally controlled NO release in cells and ex vivo.
Peptides provide a unique platform for creation of biofunctional molecules. Peptide design can be motivated by natural protein structures or attained de novo. For designed peptides to exert expected functions, a specific structure is needed whereby membranes can be employed to obtain stabilized helical structures. In biological systems, membranes are not limited to simple barriers between the extracellular and intracellular spaces or barriers that delineate intracellular compartments; they also stabilize the structures of peptides and proteins. Here, we review our approaches to the creation of membrane-interacting amphiphilic peptides as artificial ligand-gated ion channels, enhancers of cellular uptake of bioactive materials, and modulators of membrane lipid packing.
In general, cyclization is the most crucial step in the synthesis of macrocyclic compounds formed out of repeated units of a π-system. However, a particular combination of aromatic wall unit and appropriate angular linkage can efficiently give cyclic compounds such as calix[n]arene and its analogues. This straightforward method allows material chemists to supply these compounds on multi-gram scale. Nevertheless, a more resourceful strategy is also required, because this simple approach is less feasible outside of specific combinations. Recently, we have newly developed a straightforward one-pot synthetic approach using a palladium coupling for a series of thiacalix[n]thiophene, thiacalix[n]dithieno[3,2-b:2’,3’-d]thiophene (thiacalix[n]DTT), and selenacalix[n]selenophenes, which are cyclic homologues of divalent chalcogen-bridged (S or Se) cyclic oligothiophene derivatives. A palladium-catalyzed reaction of (Bu3Sn)2S or (Bu3Sn)2Se with dibromothiophene, dibromoselenophene, or diboromo-DTT derivatives led to effective cyclization in good yield. In the presence of appropriate substituents, this method seems to kinetically favor the formation of macrocycles. The molecular and physical properties, including X-ray analysis, absorption spectra and redox properties, of the resultant macrocycles were also described. Unlike conventional calixarenes, they possess electron-donating ability, exhibiting multielectron redox processes due to electron delocalization. Thiacalix[n]DTT derivatives (n=4-6) acted as a cavitand for C60 molecules; the cyclic 4-mer formed a 1:2 complex in the solid state, while the 5- and 6-mer formed 1:1 complexes in solution. Furthermore, thiacalixthiophene and selenacalix[n]-selenophene having tert-butylphenyl groups exhibit gelling behavior in toluene, despite the absence of any hydrogen binding sites. Intermolecular chalcogen (S or Se) interactions facilitate the self-assembly that results in this gel formation.
Oligo(N-substituted glycine) (oligo-NSG), also known as peptoid, is a synthetic oligomer with high proteolytic stability and membrane permeability due to the N-substituted structures. These beneficial pharmacokinetic properties make the oligomer attractive for biological applications. However, its conformational flexibility limits its utilization as protein ligands. Recently, the introduction of backbone substituents to oligo-NSG has been demonstrated to restrict its own backbone bond rotations via steric interactions, and the resulting oligo(N-substituted alanine) (oligo-NSA) has been demonstrated to be a conformationally constrained oligomer. Here, we review the concept, history, synthetic methodologies, conformational analysis, and biological applications of the new synthetic oligomer. We also conducted overview research on N-substituted peptides consisting of non-α-amino acid residues to facilitate the plausible future expansion of the conformationally constrained peptoids of diverse three-dimensional structures.
Brasilicardins A-D, isolated from the culture broth of the actinomycete Nocardia brasiliensis IFM 0406, constitute a class of natural products with a unique structure consisting of a highly strained tricyclic terpenoid core with the central ring in the boat conformation, an amino acid, and a mono- or disaccharide. These molecules display potent immunosuppressive activities and their intriguing biological and structural aspects make brasilicardins attractive synthetic targets. In 2018, we achieved the total synthesis of all brasilicardins A-D. In this account, our efforts toward the completion of a unified total synthesis of brasilicardins are described, focusing on the development of methodologies directed towards construction of the characteristic tricyclic terpenoid core, which represents the most critical and challenging task of the chemical synthesis.
Polycyclic aromatic hydrocarbons (PAHs) with zigzag edges have attracted increasing attention for their unique optical and electronic properties. This account describes our synthetic approaches to dibenzo[hi,st]ovalene (DBOV) as a novel PAH with a combination of armchair and zigzag edges and the elucidation of its unique optoelectronic and photophysical properties, such as strong red emission with a fluorescence quantum yield of up to 0.89 and stimulated emission. Furthermore, DBOV demonstrated the so-called fluorescence blinking that enables its application as a fluorophore in single-molecule localization microscopy, which is one of the modern superresolution fluorescence microscopy methods. The self-assembly of a DBOV derivative bearing two 3,4,5-tris(dodecyloxy)phenyl groups was also investigated, showing the formation of helical columnar stacks. On the other hand, the regioselective bromination of DBOV was achieved, allowing the postsynthetic functionalization and modulation of the optoelectronic properties. Moreover, π-extension of the DBOV at the bay regions led to circumpyrene, the largest circumarene synthesized to date.