By a hybrid design of naturally derived excitatory amino acids, dysiherbaines and kainic acid, we have successfully developed a series of artificial glutamate analogs with sp3-rich scaffold via domino Ugi/Diels-Alder reaction, and domino metathesis reaction of oxanorbornenes as key steps. All of the first-generation analogs were found to be neuronally active upon mice intracerebroventricular injection. As the second-generation analogs, we then synthetically modified the heterotricyclic structure, and found that analogs with a carbonyl group on the A-ring still keep the original activity of the first-generation analogs. Structural modification of the second-generation analogs by diversity-oriented reactions such as multicomponent Prins-Ritter reaction was furthermore studied to improve the activity profiles. Electrophysiological studies have identified IKM-159 of the second-generation analogs as an antagonist selective to AMPA-type ionotropic glutamate receptor. The molecular interactions were clarified from crystallographic studies of IKM-159 in complex with GluA2 ligand-binding domain (LBD). From the structure-activity relationships and the structural insights of the complex, a new structural design is proposed herein for neuronally active agents with improved potency and selectivity. We also propose here that generation of sp3-rich scaffold by hybrid strategy of known bioactive molecules would be of use for discovery of artificial bioactive agents with novel activity profiles.
In the course of our studies on the total synthesis of natural products, serious problems frequently arose due to the particular reactivity of synthetic intermediates. However, we attempted to exploit such potential reactivities, for developing new synthetic methods to achieve the total synthesis. An example in this context is the total synthesis of (−)-spiroxin C that was achieved by using a stereospecific photoredox reaction of naphthoquinone, which had been discovered during our synthetic effort toward bis-C-glycoside natural products. Dibenzobicyclo [3.2.1] octadienone structure is often embedded in the dimeric polyketide natural products. Although the intriguing motif has fascinated the synthetic community, no synthetic access had been established. By using bisnaphthoquinone acetal as the precursor to the bicyclic motif, we developed a reductive cyclization, in which thiolate worked as both a nucleophile and a reductant. Use of the asymmetric 1,4-addition of aryl pinacol borane and the reductive cyclization enabled the first total synthesis of (+)-engelharquinone and its epoxide.
The polycyclic ether marine toxin “yessotoxin” was isolated from the digestive glands of the scallop Patinopecten yessoensis, which shows diarrhetic shellfish poisoning. This toxin is produced by dinoflagellates, and consisted of the unique structures, which involves the ladder-shaped and trans-fused polycyclic ethers. Thus several groups have been reported the synthetic studies of this toxin. In recent years, we have been studying the Pd(II)-catalyzed cyclization and its application to the synthesis of natural products, especially aza sugars and alkaloids. Herein we describe the Pd(II)-catalyzed cyclization to ether and its application to the synthetic studies of yessotoxin. This reviews the activation of the allyl alcohol and the stereoselective construction of cyclic ethers by using Pd(II)catalyst. We attained the AB, CD and JK ring systems of yessotoxin, respectively. And the medium-size ether construction is also involved.
The reactivity of transition metal clusters has been of special interest in these days in the area of organometallic chemistry, owing to their capability of activating substrates through the cooperative effects of multiple metal centers. Although the multiple coordination to the metal centers enables facile bond activation of the substrates, the formed multiple M-C bond are an obstacle to the elimination of the substrates from the multinuclear site. However, we found that electrostatic repulsion of the substrate with the electron-rich multinuclear site comprised of (C5Me5)Ru fragments and stabilization by the recovery of aromaticity could be a driving force for the elimination from the multinuclear site. Thus, we attempted the reaction of polyhydrido clusters with pyridines to design a novel cluster catalysis. We report herein dehydrogenative coupling of 4-picoline and dehydrogenative oxidation of cyclic amines catalyzed by diruthenium complexes, [(CpsRu)(µ-H)2]2 (Cps=C5Me5 and C5tBu3H2), which involve unique chemical transformations at a diruthenium site.
Since discovering the first stable nucleophilic carbene, the application of N-heterocyclic carbenes (NHCs) has dramatically drawn attention in organic chemistry. Recently, NHCs have become popular ligands in organometallic chemistry and many complexes incorporating NHCs have been used in organic synthesis. NHCs act as not only ligands for metal, but also as organocatalysts. The nucleophilic carbene attacks onto carbonyl groups to afford the key intermediate, so called the Breslow intermediate, which attacks to the other carbonyl compounds to afford the products. In addition, catalytic asymmetric reactions using chiral NHCs have been reported with good to excellent stereoselectivities. Here, amino acid-derived chiral triazolium and imidazolium salts, each bearing a pyridine ring, were developed as N-heterocyclic carbene organocatalysts and chiral ligands toward catalytic asymmetric reactions.
Cinchona alkaloids have so far been one of the most explored and utilized classes of natural products and their plentiful applications have seen in various fields such as medicine and catalysis. In this review, three total syntheses of cinchona alkaloids reported in 2018 are described.
Two first total syntheses of calyciphylline A-type alkaloids with highly condensed polycyclic structures are described. One is total synthesis of daphniyunnine C established by Li and co-workers. The other is total synthesis of himalensine A achieved by Dixon and co-workers.
Lignin, the second largest biomass next to cellulose, is potentially the richest renewable resources of aromatic compounds in nature. Although controlled depolymerization of lignin is an intense focus of research, its complex and diversely linked structure hampers the development of a reliable process for the production of fine aromatic chemicals. Arguably, disconnection of β-O-4 linkages by C-O bond cleavage is the key reaction to produce low-molecular-weight valuable aromatics from lignin. This short review describes recent advances of C-O bond cleavage reactions in dimeric lignin model compounds, as well as isolated natural lignin polymers.
Strychnine is an indole alkaloid consisted of highly conjugated seven rings, which is known as a target molecule for many organic chemists from its isolation. In this review, four recent synthetic studies of strychnine were described, which were reported after the review by Overmann et al. in 2012.