Naturally-occurring novel bioactive microbial metabolites (so called Omura natural products) have been discovered by a variety of customised screening methods in The Kitasato Institute, which have been promising to subsequently develop into novel and extremely useful pharmaceutical products. This review provides an overview of this research, encompassing the isolation, and efficient total synthesis, mode of action, and the analogues synthesis as well as the determination of the absolute stereochemistry of Omura natural products, such as 1) meroterpenoids, pyripyropenes (cholesterol lowering agents), arisugacins (acetylcholinesterase inhibitors), 2) indole alkaloids, madindolines (IL-6 modulators), and neoxaline (cell proliferation inhibitor), 3) macrolides, macrosphelides (cell-cell adhesion inhibitors), and luminamicin (anti-anaerobic antibiotic), and 4) cyclic peptides, beuveriolides (ACAT inhibitors) and verticilide (ryanodine inhibitor) and also argifin (chitinase inhibitor).
This account describes the synthesis of all members of the strophasterol family of natural products (strophasterols A-F and glaucoposterol A) isolated from mushrooms. They share a common rearranged steroidal skeleton named “straphastane” [15(14→22)-abeoergostane] which was first identified in 2012. Strophasterol A, an inducer of fruiting body formation in mushrooms, and its epimer strophasterol B have been synthesized from ergosterol in 18 steps that features a completely diastereoselective acyl radical cyclization to construct an isolated cyclopentanone ring and hydrogenation of a common cyclopentene intermediate using two types of catalysts to stereodivergently obtain two epimeric cyclopentane derivatives, one of which has been elaborated into strophasterol A and the other into strophasterol B. In the synthesis of strophasterols C, E, and F, which have an oxo or hydroxy group at C23 on the side chain moiety, a 1,3-dipolar cycloaddition of a nitrile oxide intermediate has been employed to simultaneously install the isolated cyclopentanone ring and a C23 oxygen functionality as the key transformation. The proposed structure of glaucoposterol A has also been synthesized, and its NMR analysis has revealed that the proposed stereochemistry of glaucopostrerol A is incorrect and suggested that glaucoposterol A has the same structure as strophasterol F. In addition, the stereochemistry of strophasterol D has been determined through synthesis of two candidate stereoisomers.
In recent years, as the immunomodulatory mechanisms have been greatly elucidated, examples of selective immunomodulatory actions have been found for a wide variety of small-molecule compounds, including natural products. In particular, with regard to immune activation through inhibition of immunosuppressive molecules, which has been the focus of recent attention, research on inhibitors of enzymatic immunosuppressive molecules has focused on small molecules. On the other hand, it is important to understand the molecules derived from microorganisms that activate or suppress the immune system, for understanding the mechanisms of infection or the protection against the microbes. This group of molecules is also a treasure trove of diverse immunomodulatory structures. In this article, we introduce the development of synthetic methods for immunomodulatory molecules based on natural compounds and their related compounds. Firstly, the development of IDO1 inhibitors, which are attracting attention as targets for anti-tumor agents by inhibiting immunosuppressive molecules, based on longamide B, a natural product derived from marine sponges, was introduced. In the latter half, the synthesis and development of the selective immune modulatory compounds, based on microbial innate immune receptor ligands. are introduced. The compounds include 1,7-bisphosphate heptose (HBP) as a novel factor involved in innate immune activation via TIFA, and also inositol phospholipids (EhPIb from Entamoeba histolytica and Ac1PIM1 from Mycobacterium tuberculosis) involved in regulating immune mechanisms were described with the characteristic methods of phosphate introduction.
Carbon dioxide, a greenhouse gas, is among the most important challenges in reducing carbon emissions to reduce global warming. Using carbon dioxide as a carbon resource efficiently requires effective and straightforward synthetic methods for C-C bond transformations. Recently, transition-metal catalyzed coupling reactions of carbon dioxide with soft nucleophiles such as alkynes, conjugated dienes, and a variety of unsaturated hydrocarbons have been studied to provide the corresponding unsaturated carboxylic acids. This article describes the Ni-catalyzed fixation reactions of carbon dioxide with unsaturated hydrocarbons and the highly regio- and stereoselective C-C bond formations promoted by carbon dioxide through nickel carbonate key intermediates.
Pyrylium salt represents one of the most fundamental classes of molecules in the field of organic chemistry. The chemistry of pyrylium salts in particular has received much attention, as they not only represent fascinating synthetic building blocks for new compounds, but potentially also offer promise in functional devices, such as organic electronic devices, dyes or sensors. On the other hand, several papers have been published on the synthesis of thio- or selenopyrylium salts, and some of these compounds have known to be present among bioimaging molecules. In contrast to the chemistry of pyrylium salts, study on the synthetic investigations of thiopyrylium salts as well as its selenium congeners still remain limited. As far as superior properties of organic devices based on pyrylium salts are concerned, thio- and selenopyrylium salts are promising candidates for molecular electronics. Disclosing their properties is extremely fascinating from the viewpoint of not only fundamental chemistry but also developing molecular electronics or new building blocks containing sulfur or selenium heterocycles. Herein, we present studies on (i) the synthesis of benzo[c]thio- or benzo[c]selenopyrylium salts, (ii) the synthesis of dicationic heteroacenes containing thio- or selenopyrylium moieties, (iii) the construction of thiopyrylium scaffold by Lewis or Brønsted acid-promoted cyclization of thioethers, and (iv) the synthesis of thiopyrylium salts fused thiophene moieties. In this work, we have demonstrated that thioethers, which contain a formyl group at the 2´-position, undergo a Lewis- or Brønsted-acid-promoted cyclization reaction to afford thiopyrylium salts in good yield. This new and highly versatile cyclization not only extends the scope of the synthetic methods that can be used to synthesize thiopyrylium-fused cationic frameworks, but will potentially also expand the use of thiopyrylium molecules in materials chemistry.
The Barton-McCombie type reaction usually requires prefunctionalization of the hydroxy group of alcohols to induce deoxygenative generation of alkyl radicals. In recent years, synthetic reactions, wherein reactive intermediates generated in situ induce homolytic C-O bond cleavage of alcohols, have been reported. The present short review will discuss recent progress in radical alkylation using alcohols as alkyl radical sources.