In this manuscript, our synthetic study and antibacterial investigation of plusbacin A3(1), which is an antibacterial depsipeptide, and its dideoxy derivative are described. To establish an efficient total synthesis of 1, a solvent-dependent diastereodivergent Joullié-Ugi three-component reaction (JU-3CR) was optimized to construct trans-3-hydroxyl prolines [Pro(3-OH)]. Firstly, the effect of solvent on diastereoselectivity of the JU-3CR was investigated by an α-substituted five-membered cyclic imine as a substrate. The cis and trans isomers were selectively generated in toluene and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), respectively. The Hammett analysis of the JU-3CR suggests the presence of two reaction mechanisms in the JU-3CR. With the diastreoselective JU-3CR in hand, we applied the reaction to the synthesis of plusbacin A3. Two strategies were investigated toward the total synthesis of 1. In the first synthetic strategy, the key steps were the trans-selective JU-3CR and a late stage macrolactonization. The JU-3CR provided the desired trans products, and the coupling of the fragments to prepare the precursor to the cyclization proceeded smoothly. However, all the attempts toward the macrolactonization were unsuccessful to provide the desired cyclic peptide. Then, the second synthetic strategy that included an esterification in an initial stage was investigated. Two Pro(3-OH) residues were constructed by the JU-3CR with a convertible isocyanide strategy. Subsequent peptide coupling and macrolactamization successfully afforded plusbacin A3. Investigating the antibacterial activity of 1 compared with that of its dideoxy analogue revealed that the threo-β-hydroxyaspartic acid residues are essential for antibacterial activity. Notably, there was a low potential for the development of resistance in S. aureus against plusbacin A3.
(−)-L-755,807, which was isolated from an endophytic fungus, Microsphaeropsis sp., consists of a characteristic epoxy-γ-lactam ring and a tetraene-containing side chain, and exhibits bradykinin B2 receptor antagonist activity. The first total synthesis of (−)-L-755,807 was accomplished through a convergent approach, employing a late-stage coupling between the ring and side-chain segments. The ring segment was efficiently synthesized by a novel syn-selective Darzens reaction between di-tert-butyl bromomalonate and α-alkoxy aldehyde, and the side-chain segment was prepared by a highly stereoselective Horner-Wadsworth-Emmons reaction as a key step to construct the tetraene part. This synthesis enabled us to assign the relative and absolute configurations of (−)-L-755,807. Furthermore, we discovered an additional biological activity of this compound, namely, potent amyloid β aggregation inhibitory activity, which could be useful in the treatment of Alzheimer’s disease. The epoxy-γ-lactam moiety was identified as a likely pharmacophore for this activity. In this article, we describe the total synthesis, stereochemical assignment, and biological evaluation of (−)-L-755,807.
Solid-state magnetic switches are of increasing interest for future application to sensing, memory, display, etc. The authors and co-workers have developed unconventional spin transition/crossover materials, where the sense of organic chemistry has competently been adopted. The first example is a supramolecular chemistry of genuine organic nitroxide biradicals with a triplet ground state, which undergo stepwise polymerization/depolymerization in a crystal. The second example belongs to 2p-3d heterospin systems where the nitroxide-nickel(II) or -copper(II) bond rotates and switches exchange coupling. The third example is an iron(II) spin crossover material carrying a stearyl group and displaying an order-disorder-type structural transition. As these examples show, single-crystal-to-single-crystal structural transitions are often recorded, thanks to small atomic dislocation. Molecular motion in crystalline solids is observed more frequently than expected. Attentive crystallographic study affords sure proof for the spin transition phenomenon.
Molecular oxygen is recognized as an ideal oxidant, because it is abundantly available, inexpensive, and environmentally benign. Despite the recent remarkable progress of catalytic oxidative dehydrogen reactions such as a transformation of hydroxy group into the corresponding carbonyl group using molecular oxygen as a terminal oxidant, catalytic methodologies for directly incorporating molecular oxygen into organic substrate remain a significant challenge in synthetic chemistry. In this article, we have summarized our recent efforts to use manganese complex as a catalyst for directly incorporating molecular oxygen in air (pure oxygen is not required) under ambient conditions into unactivated carbon-carbon double bond.
Among porous molecular crystals that are formed via self-assembly of organic molecules, those constructed through preorganized hydrogen bonds, named hydrogen-bonded organic frameworks (HOFs), recently attract much attention as new porous organic materials because of their high crystallinity, potential designability, and facile construction process. HOFs, however, are relatively fragile and their current designing strategy is still insufficient compared with other porous materials such as metal-organic frameworks (MOFs) and covalent organic frameworks (COFs) because of weakness of H-bonds. Stable HOFs with permanent porosity have been required. In connection with this, we have demonstrated that various C3-symmetric π-conjugated molecules possessing o-bis(4-carboxyphenyl)aryl groups in their periphery successfully gave H-bonding low-density networked structures, which effectively gave stable HOFs with permanent porosity by activation (removal of included solvent molecules). The obtained HOFs show significant thermal stability over 300 °C and permanent porosity with the Brunauer-Emmett-Teller (BET) surface area values up to 1288 m2g−1. The frameworks also can work as a platform to achieve very unique alignment of functional molecules such as C60. Moreover, optelectronic properties of π-conjugated systems applied for the building blocks enabled to provide multifunctional HOFs such as acid-responsive HOFs with permanent porosity. Our strategy for constructing functional HOFs contribute to developing a new field of porous organic materials.
Self-assembly of low molecular weight peptide into nanofibers offers biomaterials that mimic structures and functions of extracellular matrices in nature. This review summarizes design and synthesis strategies of self-assembling peptides and their applications in regenerative medicine.
Diarylsulfides are an important class of natural products, pharmaceutical, and functionalized molecules in various research fields such as biology, pharmacy, and material science. However, C-S bond formation reaction is often required high-temperature condition using transition metal catalysts. The appropriate substrate scope is also limited. Therefore, the development of sustainable and efficient procedures for the C-S bond formation is essential in synthetic chemistry. Herein, novel methods for the C-S coupling reaction of diarylsulfides are introduced.
In drug discovery, peptides are significantly useful and important in the drug discovery process. In analogy to nonpeptidic small-molecule counterparts, they can sometimes suffer from disadvantages such as their low bioavailability and poor metabolic stability. This review describes a synthetic method of an oxetanyl type peptidomimetic and its application.
Since the Carbon-Carbon bond (C-C bond) is a fundamental bond constituting organic molecules, if the C-C bond can be directly functionalized, complex organic molecules can be synthesized in shorter process compared to the conventional methods. Therefore, the C-C bond activation reactions have been attracted a lot of attention in recent years. The present review focused on the recent advances in the late transition metal catalyzed C-C bond activation reactions via β-carbon elimination.
Earned a chance to study chemical biology of nucleic acid at Stanford University. I show why did I decide to study abroad, how did I choose a labolatory to join, and what did I feel and acquire in the lab, Silicon Valley and the US. As for the research project at Stanford, I focused on DNA repair, its enzyme and inhibitors. The interface of chemistry and biology using chemistry-based tools and strategies is quite effective to provide potentially useful materials and new technologies for next generation science. In particular, biochemical applications/material sciences with synthetic nucleic acids, DNA and RNA have growth potential, and they are one of the most attactive fields. This article describes the chemical biology tool with fluorescent DNA probe for detection of 8-oxoguanine DNA glycosylase activity, and the structure-activity relationships of the inhibitors by synthesizing a broad range of analogues. The best inhibitor SU0268 was synthesized by straightforward process from commercially available starting materials and shown to be selective for inhibiting the enzyme, and displayed no toxicity in human cell lines.