The development of chiral hypervalent iodine-catalyzed oxidative transformations is one of the most challenging areas in asymmetric organocatalysis. Although several elegant chiral hypervalent iodine(III and V) reagents or catalysts had been developed for various asymmetric oxidation reactions, the enantioselectivities had been moderate before our paper was published in 2010. We have had a great interest in the development of organocatalysis based on hypervalent chemistry since 2007. In this account, we describe our design concept of conformationally-flexible chiral hypervalent organoiodine(III), and the results obtained for catalytic use of our chiral iodines(III) for enantioselective Kita oxidative spirolactonization. Additionally, other chiral hypervalent iodine-mediated asymmetric oxidation reactions reported after our publications are also highlighted briefly.
The silyl- and boryl-directed regiocontrol of benzyne reactions and their theoretical analyses using density functional theory (DFT) are described herein. The Diels-Alder reactions of both 3-silyl- and 3-borylbenzynes with substituted furans and the [3+2] cycloadditions of 3-silylbenzynes with 1,3-dipoles predominantly produced distal cycloadducts, whereas the [3+2] cycloadditions of the borylbenzynes exclusively produced proximal cycloadducts. Moreover, primary amines selectively underwent nucleophilic addition reactions at the more hindered ortho-position of the silyl group of the benzynes. The origin of these anomalous regiochemistries was theoretically evaluated using the natural bond orbital and reaction pathway analyses including the transition states of these reactions. On the basis of DFT calculations, it is proposed that the reactions of the borylbenzynes were controlled by the electrostatic effect of the boryl group, whereas those of the silylbenzynes were primarily governed by the steric effect of the silyl group.
2-Alkynylbenzaldehydes are attractive substrates for organic reactions, because they possess two reactive functional groups, the formyl and alkynyl groups. It is well known that cationic rhodium(I) complexes are able to activate the aldehyde C-H bond through oxidative addition, and the alkyne triple bond through π-complexation. In this account, I describe the rhodium(I)-catalyzed [4+2] annulation reactions of 2-alkynylbenzaldehydes with unsaturated compounds which proceed via benzo-fused five-membered acylrhodacycles, generated through aldehyde C-H bond activation followed by intramolecular cis addition of rhodium acyl hydrides to the alkyne triple bond. Analogous [4+2] annulation reactions of 2-vinylbenzaldehyde with unsaturated compounds are also described. Furthermore, the asymmetric annulation of 2-alkynylbenzaldehydes with cyclic dicarbonyl compounds catalyzed cooperatively by rhodium(I) and silver(I) complexes is also described. This unique annulation presumably proceeds via formation of benzopyrilium intermediates after alkyne activation and subsequent ketone hydroacylation through aldehyde C-H bond activation.
Transition metal-catalyzed amination of allylic compounds via a π-allylmetal intermediate is a powerful and useful method for synthesizing allylamines. Direct catalytic substitution of allylic alcohols with amines, which forms water as the sole coproduct, has recently attracted attention in terms of its environmental and economical advantages. Here, we describe the development of a direct catalytic amination of both aryl- and alkyl-substituted allylic alcohols with various amines including the smallest nitrogen nucleophile ammonia using Pt-Xantphos and Pt-DPEphos catalyst systems, which allow the selective synthesis of various monoallylamines including the biologically active compounds naftifine and flunarizine, in good to high yield without requiring any activator.
Conjugated giant macrocyclic oligothiophenes 2Tn (n=2-4), 5Tn (n=2-6), and 6Tn (n=2-5) composed of 2,5-thienylenes, ethynylenes, and vinylenes with 24π to 180π electron systems have been synthesized using a modified McMurry coupling reaction as the key step. For the synthesis of cyclo[n](2,5-thienylene-ethynylene)s nCTE (n=10 and 12) composed of 2,5-thienylenes and ethynylenes, a bromination-dehydrobromination then double elimination procedure was employed. X-ray analyses of 2T2 (24π), 5T2 (60π), and 6T2 (72π) revealed unique molecular and packing structures, reflecting their planar cyclic frameworks having medium to large inner cavities. Interestingly, giant macrocycles self-aggregate in the solid state to form various nanostructures reflecting their nanophase separation, and the two-photon absorption properties of 6Tn (n=2-5) show that increasing π-conjugation leads to an increase in the two-photon absorption cross section with magnitudes as high as 100,000 GM being realized. Furthermore, the giant macrocycle 6T5 behaves as a synthetic cyclic pigment comparable to the natural light-harvesting system.
Photoirradiation of an appropriately designed caged compound enables the control and manipulation of biological processes in living cells with high spatial and temporal resolution. Brominated (coumarin-4-yl)methyl groups were designed to have favorable photochemical and physical properties as photoremovable protecting groups of caged compounds. Caged compounds of various types of biologically related molecules including neurotransmitters, second messengers, inhibitors of some proteins and mRNAs have been synthesized. A membrane-permeable caged cGMP, Bhc-cGMP/Ac, controlled a cGMP-dependent signaling pathway in a freely swimming sperm cell. Spot illumination of Bhcmoc-diC8 produced localized accumulation of diacylglycerol in a single T-cell.
Ladder-shaped polyether (LSP) toxins attract considerable attention among synthetic organic chemists due to their potent biological activities coupled with their unique molecular structures. Although a number of methods for synthesizing LSPs have been reported, developments of convergent and practical methods are necessary for efficient synthesis of LSPs in order to reveal their biological function at the molecular level and because of their limited availability from natural sources. During the course of our synthetic studies of LSPs, we developed a convergent method via α-cyano ethers (α-cyano ether method). An additional two rings can be constructed through the coupling of fragments, which is an advantage of this strategy for the construction of polycyclic systems. Medium-sized cyclic ethers are formed by ring-closing metathesis, and tetrahydropyran rings are stereoselectively constructed by reductive etherification or thioacetal formation followed by alkylation. The α-cyano ether method was successfully applied to the synthesis of the partial structure corresponding to the ABCDEFGHIJ ring system of yessotoxin, where utilization of a microflow reactor was found to be effective for reductive etherification. The α-cyano ether method was also applicable for synthesizing the WXYZA'B'C' ring system of maitotoxin, and designed artificial tetra-, hepta-, and decacyclic LSPs.
Saxitoxin is as potent and specific blocker of voltage-gated sodium channels as tetrodotoxin. This unique biological activity has established the importance of these two small natural products in neurophysiological experiments. In order to find new blockers of the voltage-gated sodium channels, an efficient synthetic route to the skeleton of saxitoxin was developed. This new synthetic route is based on two key reactions (i) cascade cyclization of a guanidino-acetylene initiated by the bromocation (Br+) and (ii) transformation of the geminal-dibromomethylene moiety to enol acetate, and culminated in the total synthesis of decarbamoyl-α-saxitoxinol, a naturally-occurring analog of saxitoxin.
The development of novel designed chemical agents, which can selectively degrade target proteins or carbohydrates by irradiation with a specific wavelength of light under mild conditions without any additives, is introduced.
In this account, full details of our total synthetic studies on aspergillides A, B and C, which have been isolated from the marine-derived fungus Aspergillus ostianus strain 01F313, are presented. The highly diastereoselective constructions of tri- and tetra-substituted tetrahydropyrans employing intramolecular oxy-Michael (IMOM) reactions have been developed and successfully applied to the first generation total syntheses of aspergillides A and C. However, the longer reaction steps and lower overall yields prompted us to try and devise a general methodology that would be useful for a highly efficient synthesis of all the aspergillides. To this end, a biomimetic [6-exo-trig] transannular oxy-Michael (TAOM) strategy was invented and successfully and efficiently applied to the second generation total syntheses of aspergillides A, B and C. Ultimately, the cycloaddition was controlled by using more suitable conditions, and aspergillide A/B and aspergillide C/3-epi-aspergillide C were able to be synthesized from a common precursor. In addition, successful conversions of aspergillide A to aspergillide B and 3-epi-aspergillide C to aspergillide C were demonstrated for the first time during these synthetic studies.