The direct transformation of C-H bonds has attracted much interest in recent years, because it avoids prior functional group manipulations for the synthesis of a pre-activated precursor and thus greatly streamlines synthetic sequences. Among such reactions, functionalization of unreactive C(sp3)-H bonds is particularly advantageous for construction of highly complex natural products, which generally contain a high ratio of sp3-hybridized carbon centers. However, this extremely useful reaction remains challenging mainly due to the lack of general strategies for activating inert C(sp3)-H bonds. We developed four reagent systems for direct C-H oxidation, and established three carbon-chain elongations via straightforward installation of carbon unit to C-H bonds. Highly reactive chemical species acting like oxygen radical are utilized as a key C-H activator.
Solifenacin succinate (Vesicare®), a novel muscarinic receptor antagonist for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency, has been approved in more than 60 countries. In the course of continuing efforts to develop potent and bladder-selective muscarinic M3 receptor antagonists, solifenacin was designed as one of conformationally restricted analogues of quinuclidin-3-yl benzhydrylcarbamate with little selectivity among muscarinic receptor subtypes. In preclinical studies, solifenacin exhibited a highly bladder-selective profile compared with other antimuscarinic agents. Clinically, solifenacin ameliorates all symptoms in OAB patients; and, in particular, it produces a significant decrease in urgency episodes, which is the principal symptom of OAB with good tolerability. In this article, the drug discovery and the process development of solifenacin succinate are described.
Chemiluminescence is a phenomenon in which an electronically excited fluorescent molecule is generated during the chemical reaction and emits light as a visual output. Although there have been numerous investigations of chemiluminescence so far, a lot of problems unsettled are remaining, for example, a question of what is the high-energy intermediates that interact with fluorophores. In this review, our investigations on chemiluminescence from the viewpoint of organic chemistry are described, emphasizing the mechanistic studies and the application of peroxyoxalate chemiluminescence. Employing various reactive oxalate derivatives, the kinetic studies allowed us to suggest the structures of the high-energy intermediates in the peroxyoxalate chemiluminescence. The chemiluminescence of the suitable phosphonate carbanions during the oxy-Wittig type reaction was also mentioned, in which the phospha-1,2-dioxetane is the most likely high-energy intermediate. Some chemiluminescence reactions were connected with ligand-metal ion host-guest chemistry to get a useful hint for further application of chemiluminescence to chemical detection.
Polythiophenes have so far been in the best class of balanced high-performance materials as a p-type semiconductor among all π-conjugated polymers in terms of solubility, chemical stability, charge mobility, and commercial availability. Therefore, very much attention has been paid to these materials for prompt application to polymer electronic devices, such as organic field-effect transistors and photovoltaic cells. Recently the controlled polymerization has been achieved via Grignard metathesis polymerization in a chain-growth manner to synthesize well-defined poly(3-alkylthiophene)s with predictable molecular weight, narrow molecular weight distribution, and high regioregularity. This strategy allows synthesizing a variety of block copolymers and they show unique phase separation, induced by block conformation as well as crystalline structure of polythiophene segments. This review article describes synthesis, morphology, and organic photovoltaic characteristics of polythiophene-based block copolymers in detail. Especially, the utility of block copolymers as compatibilizers in organic photovoltaics has been discussed.
In recent years, polar solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) have received a considerable attention as a promoter of organic reactions. We have developed several catalyst-free reactions using DMSO and molecular sieves (MS) 4A. Very fundamental and significant reactions in organic synthesis, such as Henry reaction, Michael addition reaction, Knoevenagel reaction and so on, proceed smoothly at room temperature in DMSO with MS 4A to afford the corresponding adduct in high yields. By this method, neither a base nor an acid catalyst is necessary to complete the reaction. These reactions shown here are attractive from the standpoints of environmentally friendly organic synthesis because of high atom economy and mild reaction conditions.
Functional analyses of endogenous proteins represent indispensable steps for development of drugs for the protein targets. Here, informative-function-incorporated artificial proteins corresponding to the targets should serve as a useful molecular device for evaluating the naturally occurring proteins as a potential drug target. Chemical synthesis and chemical manipulation of proteins allow such artificial proteins to be prepared. We therefore developed a facile synthetic protocol for proteins and a chemical device for functional change of proteins. In this review are addressed both N-sulfanylethylanilide (SEAlide) peptides for protein synthesis and stimulus-responsive amino acids for the functional conversion. SEAlide peptides were initially developed as peptide thioester precursors obtainable by 9-fluorenylmethyloxycarbonyl (Fmoc) solid-phase peptide synthesis. Investigation on the SEAlide peptides uncovered that a one-pot/multi-fragment sequential native chemical ligation (NCL) is achieved efficiently using the SEAlide unit to give proteins. For functional change of proteins, stimulus-responsive amino acids were developed. Upon responding to various stimuli, the newly developed amino acid-containing peptides are spliced into two peptide parts. Combination of the splicing reaction and an acyl-transfer chemistry allows the function of peptide to be changed.
Kinamycins and lomaiviticins are potent antiproliferative antimicrobial natural products possessing a unique diazotetrahydrobenzo[b]fluorene moiety. Biological and structural features of these compounds have attracted much attention from synthetic chemists. In this review, recent synthetic efforts toward lomaiviticins reported by Shair’s group and Herzon’s group are described.
Propargylic esters are transformed into vinylcarbenoids via 1,2-rearrangement of acyloxy groups by transition metal catalysts. This review describes new reactions proceeding via the 1,2-acyloxy rearrangement using rhodium catalysts.