We carried out systematic studies on the preferential and diastereomeric crystallizations with the aid of X-ray crystallographic analyses and found that there is high correlation in molecular length between a target racemate and a derivatizing/resolving agent. On the basis of the results, we proposed relative molecular length and CH/π rules. The rules were applied to the development of non-natural enantiopure compounds, which were highly useful in asymmetric syntheses, chiral polyamide synthesis, and so on. Recent results concerned with the enantioseparation by phosphonothioic and phosphinothioic acids and with the asymmetric synthesis of phosphorothioates are also described.
Hippopotamus produces colorless sweat over its entire body. The color of the sweat turns red within a few minutes and then becomes brown during a few hours by producing polymers. We isolated the unstable red and orange pigments, called hipposudoric acid and norhipposudoric acid, respectively, responsible to the red coloration of the sweat. Syntheses of these pigments were performed using the Pschorr reaction for the formation of the fluorenone core and the oxidation in the last step producing the unstable diquinone as the key steps. The tautomeric structures of the common chromophore of these pigments in a protic solvent and in an aprotic solvent were also discussed.
New practical catalysts have been developed for asymmetric cyclopropanation of 2, 5-dimethyl-2, 4-hexadiene with tert-butyl diazoacetate. First, the effects of the substituents on the salicylaldehyde moiety in the copper Schiff-base complex on the catalytic activity and the stereoselectivities were investigated. As a result, a substitution at the 5-position of hydrogen with the nitro-group on the salicylaldehyde moiety was found to enhance the catalytic efficiency. In addition, a combination catalyst of the copper Schiff-base complex with a Lewis acid was found to enhance the catalytic efficiency and achieved 90% chemical yield and 91% ee at 20°C with 0.1 mol% catalyst loading. Then, new cationic bisoxazoline-copper complex catalysts with PF6-as the counter ion were demonstrated to achieve the highest stereoselectivities (trans/cis = 88/12, 96% ee at 0°C) with tert-butyl diazoacetate. Furthermore, the asymmetric induction mechanism of the cyclopropanation reaction catalyzed by each complex was studied with density functional calculations.
Aplyronine A 1 is a potent antitumor macrolide isolated from the sea hare Aplysia kurodai. Aplyronine A interacts with actin, one of the major proteins in cytoskeleton. We achieved total synthesis of aplyronine A and its 18 analogs and investigated structure-activity relationships. Analysis of the interaction of aplyronine analogs with actin by a photoaffinity labeling method and X-ray crystal structure analysis of actin complex with aplyronine A have been carried out. These results revealed that aplyronine A binds to actin at the hydrophobic cleft between subdomains 1 and 3 of actin. The binding mode of the macrolactone part of aplyronine A was different from previously reported macrolides. In addition, the trimethylserine moiety of aplyronine A, the essential functional group for cytotoxicity against HeLa S3 cells, was sticking out from a surface of actin-aplyro-nine A complex.
We have developed a new and efficient synthetic method for functionalized indoles and benzofurans via the route involving [3, 3] -sigmatropic rearrangement of N-trifluoroacetyl enamine. N-Trifluoroacetyl enehydrazine carrying a cyclopentene ring smoothly underwent [3, 3] -sigmat-ropic rearrangement followed by cyclization to give indoline in excellent yield. Cyclohexenyl or acyclic N-trifluoroacetyl enehydrazines gave indoles in good yields. The rearrangement of N-trifluoroacetyl enehydrazines proceeded smoothly even under either aqueous or solvent-free conditions. The acylation of cyclic or acyclic oxime ethers with TFAA proceeded under mild conditions to give the dihydrobenzofurans in excellent yields without the isolation of N-trifluoroacetyl enehydoxylamine. On the other hand, the reaction of oxime ethers with trifluoroacetyl triflate (TFAT) in the presence of DMAP gave the benzofurans in good yields. It is noteworthy that dihydrobenzofurans or benzofurans can be formed selectively from the same substrate by changing only the reagent. This successive method was successfully applied to the synthesis of natural products.
The manufacturing process of Micafungin (1) which is a novel candin antifungal agent discovered and developed by Astellas Pharma Inc. was studied. A new asymmetric isoxazole ring formation which is key reaction for synthesis of side chain active ester 2 was developed via β-keto enamine intermediate. And also a reaction condition of selective acylation with FUN intermediate 3 and purification of Micafungin drug substance was investigated from the viewpoints of high quality and productivity.
This mini review focuses on the developments of Ir-catalyzed direct borylation of arenes via C-H activation. The regioselectivity of the borylation is mainly controlled by the steric factors. The regioselective C-H bond activation/functionalization can provide the borylated arenes which are otherwise difficult to synthesize. Recent applications of the borylation to polycyclic aromatic hydrocarbons and porphyrins are briefly described.
Some strategies to modify a certain amino acid residue of a native protein in a chemo-selective fashion have been developed. In this review, the modifications of proteins, which can change their functionalities, such as solubility or retargeting of adenoviral gene transfer, are discussed.