De novo development of molecular catalyst (MC) for a targeted ideal reaction is challenging and requires deep understanding of chemistry. Irrespective of the how and why for the finding of high performance MC realizing high reactivity, turnover frequency, selectivity, and productivity, the mechanism should be pursued because it offers a great source of creativity. A detailed mechanistic study of Oguni asymmetric reaction catalyzed by DAIB-Zn complex (DAIB: 3-exo-dimethylaminoisoborneol) has established a new leading concept, that is “Donor-Acceptor Bifunctional Catalyst (DACat),” for the design of a MC. The concept has been categorized into four by two parameters: i) intramolecular (Intramol) or intermolecular (Intermol) and ii) metathesis (M)- or redox (R)-type reaction. The four concepts have realized a new type of MCs including asymmetric hydrogenation of ketones, allyloxy bond cleaving reaction, and asymmetric dehydrative allylation. This account overviews the results obtained in our group.
Highly stereoselective synthesis of multi-substituted cyclopropane is important owing to their distribution in nature, and significant biological activities of their analogs. We report here the highly stereoselective synthesis of multi-functionalized cyclopropanes using the SmI2-promoted Reformatsky-type reaction, acylation, silylation of 1-chlorocyclopropanecarboxylic esters, and the fundamental Reformatsky reaction of 1-bromocyclopropanecarboxylic esters. As the stereo inductive transformation of synthesized highly substituted cyclopropanes, we describe Lewis acid-mediated ring-expansion of methyl (arylhydroxymethyl)-cyclopropanecarboxylates to afford 1,2-dihydronaphthalene-3-carboxylic acid esters. In addition, total syntheses of (+/−)-cyclogalgravin, its dicarboxyl analog, and three kinds of (+)-podophyllic aldehydes have been achieved. Key steps include highly stereoselective constructions of tetra-substituted cyclopropanes and the Lewis acid-mediated chiral transfer ring expansion with excellent level of stereoinductions.
The construction of various nanometer-sized cyclophanes has been carried out by the use of reversible formation of spiroborate linkages. Bis(2,3-dihydroxynaphthalene)s were converted into the corresponding cyclic spiroborate trimers in the presence of equimolar amount of boric acid in N,N-dimethylformamide. The cyclic trimer of 2,2’,3,3’-tetrahydroxy-1,1’-binaphthyl possessed a crown-ether-like cavity and exhibited selective recognition toward potassium or barium cations. This cyclic trimer also had bowl-shaped cavities at both sides of its symmetry plane, and acted as a ditopic host that iteratively recognized spherical cationic complex to form a supramolecular polymer structure. Multicomponent construction of cyclic spiroborates was also realized by the combination of oligo(2,3-dihydroxynaphthalene)s and 2,3,6,7-tetrahydroxy-9,10-anthraquinone. It was found that the rectangular-shaped spiroborate nanocycles were constructed in a self-organization manner and exhibited characteristic molecular recognition behavior toward cationic aromatic guests.
Renieramycin marine natural products have been attracting many synthetic organic chemists and natural product researchers due to their promising biological activities along with unique skeletal characteristics. This paper described our recent synthetic studies on total syntheses of renieramycin G and cribrostatin 4 along with powerful contribution for isolation and structure determination of several stabilized renieramycin derivatives via KCN pretreated Thai blue sponge, Xestospongia sp. Several chemical transformations of natural products also presented.
Neuromedin U (NMU) displays various physiological activities including an anorexigenic effect, and the C-terminal heptapeptide-amide sequence is necessary to activate two NMU receptors (NMUR1 and NMUR2). Based on this heptapeptide, we recently developed highly active NMUR1 hexapeptide agonist 4d and NMUR2-selective hexapeptide agonist 8c. Moreover, we identified two major biodegradation sites (Phe2-Arg3 and Arg5-Asn6) by the stability analysis of 4d in serum. On the other hand, myostatin is an endogenous negative regulator of skeletal muscle mass, which is recognized as a therapeutic target for muscle atrophic disorders. Recently, we successfully identified myostatin inhibitory peptides 9 and 16 (24 and 23 amino acids, respectively) with minimum sequence derived from mouse myostatin prodomain. These peptides directly bind to myostatin with KD values of 30-36 nM. Moreover, peptide 9 significantly increased tibialis anterior muscle mass in Duchenne muscular dystrophy model mice. Therefore, these synthesized peptides would be promising mid-sized molecules for peptide-based medicinal chemistry.
Addition of boronic acids to ynamides can be a useful method to obtain enamides, which have been considered as good prochiral precursors for the synthesis of optically active compounds bearing quaternary stereogenic centers. Although the regioselectivity for carbometalation should be required, recently, highly regio- and stereocontrolled addition reactions have been developed by using transition metal catalysts. In this review, three types of regio- and stereocontrolled synthesis of multisubstituted enamides are discussed.
Organofluorine compounds are utilized for pharmaceuticals, agrochemicals, materials, and polymers. On the other hand, they play significant roles in organic synthesis, such as solvents, additives, and catalysts. Recently, it is reported that fluorine atoms can stabilize the conformers of organic molecules and even change the parent compounds’ conformations by stereoelectronic effects. Therefore directing groups or catalysts in regio- or enantioselective reactions have been improved by fluorine atoms incorporated in the molecular designs.
2-Pyridones are now in great interest as promising drug candidates, because of its nucleobase-like structure and various directions of hydrogen bonds. Among numerous reports of its synthesis, direct installation of substituents into already-made 2-pyridone “platform” through C-H bond activation is arguably one of the most efficient methods to access to its derivatives. In this review, several elegant methods on the C-H functionalization of 2-pyridones are discussed.
Thanks to the development of automation systems and programs for single crystal X-ray diffraction analysis, X-ray structure analysis have become a familiar technic for organic chemists to obtain structural information. However, determination of the absolute configuration of organic compounds only including light-atom (C, H, N, O) by X-ray diffraction have been a difficult topic due to the weak resonant scattering from light atoms. The main purpose of this review is to introduce recent developments of absolute structure determination method by X-ray structure analysis. New algorisms, such as Hooft parameter and Parsons parameter, make it possible to determine the absolute configuration of organic compound by typical X-ray diffractometer without any special equipment.