Toshiro Konoike

Concise allene synthesis from propargylic alcohols by hydrostannation and deoxystannylation: A new route to chiral allenes

Abstract Propargylic alcohols were converted to allenes in a two-step one-pot process comprised of hydrostannation of propargylic alcohols and subsequent deoxystannylation. Chiral ( S )-2,3-decadiene of high enantiomeric excess (ee) can be prepared in a similar way.

Synthesis and structure–activity relationships of potent and orally active sulfonamide ETB selective antagonists

The synthesis and structure activity relationships of a series of N-pyrimidinyl benzenesulfonamides as ETB selective antagonists are described. N-Isoxazolyl benzenesulfonamide 1a, previously reported, (1) was selected as a lead compound, and isosteric replacement of the isoxazole ring of 1a with a pyrimidine ring led to the discovery of the highly potent ETB selective antagonist 6e with oral bioavailability. Modification of the terminal aldehyde group at the 6-position of the pyrimidine ring was investigated, and malonate 15b and acylhydrazone 16f were found to be equipotent to aldehyde 6e. Compound 6e showed ETB antagonistic activity on in vivo evaluation.

A novel allylic hydroxylation of sterically hindered olefins by Fe-porphyrin-catalyzed mCPBA oxidation

A novel allylic hydroxylation by mCPBA of triterpenes bearing sterically hindered olefin is catalyzed by Fe(PFPP)Cl. Oleanolic acid, ursolic acid, dihydrolanosterol and their derivatives are converted to the corresponding allylic alcohols by mCPBAFe(PFPP)Cl under mild conditions. In contrast, for common or electron-deficient olefins, mCPBAFe(PFPP)Cl is an efficient epoxidation system. The intermediacy of an Fe-oxo-porphyrin and subsequent hydrogen abstraction and recombination are proposed for the selective α-hydroxylation of triterpenes.

Synthesis and pharmacological properties of ureidomethylcarbamoylphenylketone derivatives. A new potent and subtype-selective nonpeptide CCK-B/gastrin receptor antagonist, S-0509.

A novel series of CCK-B/gastrin receptor antagonists-ureidomethylcarbamoylphenylketone derivatives-were designed, synthesized, and evaluated for activity. Structure-activity relationship studies revealed the importance of a carboxylic acid at substituent R2 and tert-butoxycarbonyl group at R1 in structure A. Compound 7a (S-0509) showed remarkable affinity for the CCK-B/gastrin receptor and a subtype selectivity profile in vitro. Administration (id) of 7a led to excellent inhibition of gastric acid secretion induced by pentagastrin in anesthetized rats with an ED50 value of 0.014 mg/kg. Furthermore, 7a proved to have poor blood-brain permeability by its small effect on enhancement of morphine analgesia. Thus, S-0509 has an increase in selectivity for the peripheral effects of gastrin antagonism from the central effects of CCK-B antagonism.

SYNTHESIS OF 2-13C-OLEANOLIC ACID AND 2-13C-MYRICERONE

Abstract Synthetic way for 13C-labeled oleanolic acid 1 and myricerone 2 has been developed, starting from the parent 1 and 2. The procedure involves ring opening and closure of the A rings of these oleanane triterpenes. 13C was introduced into the 2-position by 13C-MeLi as an isotope source. Chelation controlled addition of methyllithium to α-hydoxypentanone 11 is a common crucial step for labeling of 1 and 2, and judicious choice of protecting groups is essential for 2.

New route to 3-(substituted) methyl 1-oxa- and (1-thia)cephems from 3-exomethylene intermediates via sulfenyl chloride adducts

Abstract Addition of methane- and benzenesulfenyl chlorides to 3-exomethylene-1-oxacephams 10 and 14 gave 3β-sulfenyl-3α-chloromethyl adducts 11 and 15. Nucleophilic substitution of the adducts proceeded facilely to afford compounds 18–23, which were converted into Δ3-derivatives 26 and 27 by oxidative elimination. This new route, as illustrated by the sequence 6→7→8→3, has an essential advantage in using the saturated intermediates 7 and 8 with a stabler β-lactam ring which is compatible in nucleophilic substitution, alkaline ester hydrolysis and further manipulations. These synthetic features are well demonstrated by successful synthesis of 1-oxacefamandol 35 and 7β-(2-thienylacetyl-amino)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3- acid (45)

Oxidative Coupling of Carbon Acid Compounds by Means of Ag2O

Abstract Transition-metal catalyzed coupling of carbanions by means of transition metal compounds has constituted a convenient method of the carbon-carbon bond formation in organic synthesis.1 Recently, CuCl2-promoted coupling of lithium enolates of ketones2 and esters3 has been reported, which provides new routes to 1,4-diketones and succinate derivatives, respectively. Now we found that some carbon acids, such as acylacetate and monosubstituted malonate, were readily oxidatively dimerized by Ag2O without intervention of their carbanions in dimethyl sulfoxide (DMSO) according to eq. 1.

Directed lithiation of N-(tert-butoxycarbonyl)aminoisoxazole: synthesis of 4-substituted aminoisoxazoles

Abstract Directed lithiation of 3-(Boc-amino)isoxazole 4 and 5-(Boc-amino)isoxazole 9 is described. Dilithioisoxazoles reacted with a variety of electrophiles to give the corresponding 4-substituted isoxazoles.

(S)-(−)-2-tert-butyl-3-methylene-oxirane: Synthesis and hydroboration of a chiral allene oxide

Abstract The chiral allene oxide, ( S )-(−)-2- tert -butyl-3-methylene-oxirane 12 (( S )-(−)-1- tert -butylallene oxide) was prepared in a moderate yield and in high enantiomeric excess by a three-step conversion starting from 4,4-dimethyl-2-pentyn-1-ol 6 . The procedure was comprised of hydrostannylation, Sharpless epoxidation and deoxystannylation. The chiral allene oxide 12 has moderate stability for identification and characterization and undergoes hydroboration to afford a chiral diol, ( R )-4,4-dimethylpentane-1,3-diol 15 .

Practical procedure for epimerization of 7α-amino-1-oxacephems to 7β-amino epimers

Abstract 7α-Amino-1-oxacephems can be epimerized to their 7β-amino epimers by treatment with chloral to give Schiff bases, followed by dehydrochlorination with Hunig base, borohydride reduction, and hydrolysis.