Readily obtainable primary α- and β-amino acid lithium salts were found to be efficient catalysts for iminium-enamine-type asymmetric organocatalyses. By using L-phenylalanine lithium salt as a catalyst, asymmetric Michael addition of α-branched aldehydes to nitroalkenes was achieved via the formation of enamines to obtain synthetically useful γ-nitroaldehydes possessing a quaternary carbon stereogenic center in high yields with high enantioselectivity. On the other hand, highly enantioselective Michael addition of malonates to enones was successfully carried out by the iminium catalysis using a mixed catalyst consisting of a primary β-amino acid, O-tert-butyldiphenylsilyl (S)-β-homoserine, and its lithium salt. Details of the studies regarding to the organocatalyses using primary α- and β-amino acid lithium salt-catalysts including substrate scopes and mechanistic studies are described.
Utilization of ab initio and DFT calculations for the development of organic synthesis is described here. The first topic is the base-mediated intramolecular amination of bromoallens having an axial chirality. The treatment of both (4S,aR)- and (4S,aS)-bromoallenes with NaH in DMF affords cis-ethynylaziridines in 92:8-99:1 and 79:21-91:9 selectivity, respectively. These experimental results were rationalized by DFT calculations with Onsager solvation model. The calculations also predicted that a less polar solvent gives higher cis selectivity for the (4S,aS) isomers. In fact, improvement of the cis selectivity to >99:1 has been realized by using a less polar THF solvent. The second topic is the intramolecular in-plane SN2 reaction of haloalkenes with inversion of configuration at the sp2 carbon, which was predicted to be a facile process for the first time by DFT calculations (ΔG=14.4 kcal/mol). This prediction was confirmed experimentally and the intramolecular in-plane SN2 reaction was utilized for the preparations of various four- and five-membered cyclic compounds. The third topic is the origin of π-facial stereoselectivity in the alkylation of enolates derived from 4-substituted γ-butyrolactones. The main source of the anti-selectivity is eclipsing strain in the syn-transition structures. The fourth topic is the mechanistic study on the gold catalyzed C-S bond formation of α-thioallenes to form 2,5-dihydrothiophenes. The proton transfer is the rate-limiting step with very high activation energy in a gas phase. In the presence of one water molecule, activation energy was lowered by as much as 19.9 kcal/mol. This prediction was also confirmed experimentally.
Development of effective methods for the synthesis of modified oligonucleotides having various functional groups is highly desirable today. Recently, we developed O-selective phosphorylation named the proton-block method and the activated phosphite method to synthesize modified DNA oligonucleotide having alkaline-labile functional groups. In RNA synthesis without base protection, it was found that O-selectivity of the phosphorylation with P-N bond cleavage using 6-nitro-HOBt was more than 99%. Additionally, development of new protecting groups, which can be removed under mild conditions, such as AzMB, PSC and amidine-type groups was carried out. Furthermore, we developed the effective pyrophosphorylation using O-N phosphoryl rearrangement of phosphoramidite compound mediated by HOBt derivative. This new pyrophosphorylation could be applied to the synthesis of adenylpyrophosphoryl capped and 5’-terminal m32,2,7Gppp capped oligonucleotides.
Recently, from materials science viewpoint, development of chalcogen-containing π-conjugated systems is much attractive because of their unique photochemical and electronic properties. We have studied new methods for the highly regio- and stereoselective introduction of group 16 heteroatom moieties into unsaturated bonds, i.e., photoinduced radical reactions and transition-metal-catalyzed reactions. Therefore, applications of these methods to construction of chalcogen-containing π-conjugated systems are of great importance because these approaches may lead to discover of new functional materials. This review deals with the introduction of chalcogeno groups into acetylene derivatives bearing redox or photochemical properties such as ferrocene, porphyrin, and diethynylbenzene derivatives.
A novel and efficient method for the kinetic resolution of racemic alcohols with achiral carboxylic acids or racemic carboxylic acids with achiral alcohols using dehydration condensation is accounted in this paper. The first kinetic resolution of racemic alcohols with achiral carboxylic acids was accomplished by asymmetric esterification via the in situ formation of a mixed anhydride using carboxylic anhydrides as coupling reagents in the presence of chiral acyl-transfer catalysts. Because this protocol utilized the transacylation process to generate the mixed-anhydride, not only racemic secondary alcohols but also racemic carboxylic acids are applicable to the asymmetric esterification in the same manner. The variety of optically active carboxylic esters are also produced by the kinetic resolution of racemic 2-arylalkanoic acids, including non-steroidal anti-inflammatory drugs (NSAIDs), with achiral alcohols, using carboxylic anhydrides in the presence of chiral acyl-transfer catalysts.
The Michael/Mannich cascade reaction between acrylate and chiral sulfinimines progressed smoothly by the presence of magnesium thiolate to give optically active β-amino-α-methylthio esters in good yields. The enantioselectivity at the adjacent carbon to the amino group was almost perfect. This procedure was useful for not only aromatic imines but also aliphatic imines. The following oxidation of the phenylthio group and thermal treatment afforded chiral β-amino-α-methylene esters, which were regarded as a potentially useful synthetic building block. Thus, the present method provides a practically useful alternative reaction to the asymmetric aza-Morita-Baylis-Hillman reaction. N-allylated or N-propargylated adducts were examined to the RCM reaction, the Pauson-Khand reaction, and gold(I) catalyzed cyclization. An asymmetric synthesis of (−)-trachelanthamidine was demonstrated. The N-propargylated adducts underwent a cascade radical reaction by treatment with Bu3SnH, Me2S2 and (Me3Si)3SiH, with which radical addition-cyclization-substitution reaction occurred in one step in a highly stereoselective manner. The bicyclic stannolanes, which was prepared by the radical cascade triggered by tin radical, underwent a regioselective double Stille coupling reaction to give multicyclic heterocyclic compounds in good yields.
The development of synthetic method of nitrile without metal cyanide is attracting much attention in synthetic organic chemistry because classical cyanation normally requires toxic metal cyanides and careful handling to prevent the generation of HCN gas. Recently, direct nitrogenation of hydrocarbons has been accomplished as a new approach to synthesize nitriles without metal cyanide. These approaches enable the straightforward utilization of hydrocarbons in organic synthesis. This short review focuses on the direct transformation of methyl arenes, alkynes, and alkenes by using appropriate oxidant and nitrogen sources.