Severe acute respiratory syndrome (SARS) is a contagious respiratory disease in humans which is caused by the SARS-CoV. The key enzyme in the processing of polyproteins pp1a and pp1ab, translated by the viral RNA genome of SARS-CoV is called a 3CL protease. Due to its functional importance in the viral life cycle, SARS-CoV 3CL protease is considered to be an attractive target for a drug for SARS therapy. In a research program on SARS 3CL protease, we found for the first time that mature SARS 3CL protease is subject to degradation at the 188Arg/189Gln site, and prepared R188I mutant protease with high activity and stability. Next, practical synthetic routes for the preparation of peptide aldehydes on a solid support were investigated. Efficient transformation of acetal/thioacetal structures as a key step was employed. For the application of the methodology, we designed and synthesized the tetrapeptide aldehyde Ac-Thr-Val-Cha-His-H with an IC50 value of 98 nM against SARS 3CL protease. In addition, we found new scaffolds, phenylisoserine and decaisoquinoline derivatives connected with the essential functional groups to show the potent inhibitory activities against SARS 3CL protease.
Transition metal-catalyzed cross-coupling between aryl halides and nucleophiles is one of the most reliable C-C and C-heteroatom bond forming reactions. However, preparation of haloarenes usually requires multi-step operation, making the whole cross-coupling process inefficient. Nitroarenes, synthesized by a single-step nitration of arenes, can be attractive alternatives as electrophiles in cross-coupling methodology, but inherent inertness of C(sp2)-NO2 bonds toward metal catalysts has been a bottleneck of general denitrative transformations. Recently, we have overcome this obstacle and achieved direct activation of Ar-NO2 bonds by using Pd/BrettPhos catalysis. Herein, we describe the development of denitrative couplings by Pd/BrettPhos catalyst and its unique suitability from a mechanistic point of view. Deep understanding of reaction mechanism also enabled us to design more active Pd/NHC system.
Cyclization reactions between two multiple bonds have been fascinating processes that allow the discovery of new reactions and the construction of carbo- and/or heterocycles. Among multiple bonds, heteroatom-substituted olefins have different reactivity from those having heteroatom on the allylic or homoallylic position, but the reactions have been reported few cases until the 2000s. Lately, the reactions between multiple bonds and heteroatom-substituted olefins have been reported, and this review explains them by the reaction class.
The yeast-reduction products of (±)-methyl (2-oxocyclohexyl)acetate and (±)-methyl (2-oxocyclopentyl)acetate were applied to the syntheses of natural compounds with high enantiomeric excess. In this experiment, both enantiomers or all stereoisomers of lipoic acid, dihydropi-nidine, epidihydropinidine, (6-methyltetrahydropyran-2-yl)acetic acid, 6,7-dihydro-5-HETE, goniodiol, boronolide, cryptocarya diacetate, 1,3-polyol/α-pyrone, and 6-(2-hydroxy-6-phenylhex-1-yl)-5,6-dihydro-2H-pyran-2-one were synthesized from these yeast-reduction products. In the study of goniodiol, antibacterial activities of all stereoisomers were shown and the more effective stereochemistries were clarified. In the research of boronolide, plant growth regulatory activities of both enantiomers were compared. The success of syntheses of all stereoisomers of 1,3-polyol/α-pyrone enabled us to compare the antifungal activity against plant pathogenic fungi. The stereospecific phytotoxicity was observed among the stereoisomers of 6-(2-hydroxy-6-phenylhex-1-yl)-5,6-dihydro-2H-pyran-2-one.
This review deals with our synthetic efforts for guanidine alkaloid of saxitoxin (STX), a paralytic shellfish toxin. STX shows potent inhibitory activity against voltage-gated sodium channels (NaVs), which are membrane proteins that involve in the generation and propagation of action potentials in neurons. More than 50 analogs of STX have been isolated from nature, and these analogs commonly possess characteristic tricyclic core skeleton including two kinds of 5-memberd and 6-memberd cyclic guanidine. For the synthesis of the core structure, we have developed a neighboring acyl group assisted cyclization strategy to give tricycle with a fully protected form of saxitoxinol under quite mild conditions. This key intermediate allows us total synthesis of (＋)-decarbamoyl saxitoxin (dcSTX), (＋)-gonyautoxin 3 (GTX3) including and STX. Besides, we have achieved the synthesis of 11-saxitoxinethanoic acid (SEA), which is an unusual STX derivative bearing carbon-carbon bond at the C11 position by applying Mukaiyama aldol condensation reaction with silyl enolether derived from the key intermediate of fully protected saxitoxinol. NaV inhibitory activities of some synthetic derivatives with C11-substituents in STX were also described.
Birch reduction is one of the most fundamental and popular organic chemical reactions. Although this reaction enables the unique transformation such as the direct reduction of benzene rings to 1,4-dienes, the use of liquid NH3 and alkali metal, which are hazardous and risky, is required for the original reaction condition. This short review describes the new alternative methods without liquid NH3 and alkali metal.