Concurrent induction of two chiral centers from symmetrical 3, 4-disubstituted and 3,3,4-trisubstituted 4-pentenals using Rh-catalyzed asymmetric cyclizations

Asymmetric cyclization of symmetrical 3,4-disubstituted and 3,3, 4-trisubstituted 4-pentenals was studied using Rh-complexes with chiral ligands. The cyclization of symmetrical 4-pentenals 4a,b by a neutral Rh[(R)-BINAP]Cl afforded cis-3,4-disubstituted (4R)-cyclopentanones 9a,b of >95% ee in 25-31% yields; on the other hand, the cyclization of 4a-c by a cationic Rh[(R)-BINAP]ClO(4) afforded trans-3,4-disubstituted (4S)-cyclopentanones 10a-c of >95% ee in 70-81% yields. All stereoisomers could be stereoselectively made by the selection of a neutral or cationic Rh-complex, and (R)- or (S)-BINAP ligand. The Rh-catalyzed cyclization could be applied to the construction of cyclopentanones 17 and 18 bearing a chiral quaternary carbon. The cyclization by the cationic Rh[(R)-BINAP]ClO(4) afforded the optically active trans-3,3, 4-trisubstituted cyclopentanones 18a-c of 92-95% ee in 75-83% yields. The catalytic cycle was also studied by using deuterium aldehyde, and the tentative mechanisms of the enantio- and diastereoselection were proposed.

[Molecular mechanics study on Conformation of a homooligopeptide constituted by isovalin].

Conformational energy computations on a homo-hexapeptide of (S)-isovaline were performed using molecular mechanics on MacroModel. Conformational search calculations were carried out by Monte Carlo method. AMBER* was used as the force field. The global minimum energy conformation was found to be a 3(10)-helix coordinated by four hydrogen bonds. The results of the theoretical analysis of the conformation of the peptide are in agreement with its reported conformational properties in the solid state determined by X-ray crystallographic analysis.

Aldol condensation versus conjugate addition: intramolecular cyclization using a combination of Lewis acid and 1,2-diol.

The reactivity of 3-substituted 4-methyl-4-(3-oxobutyl)-2-cyclohexen-1-ones (1) in the presence of a combination of a Lewis acid and a 1,2-diol was studied. The results suggest several factors that influence 6-membered ring formation, including two types of intramolecular aldol reaction and intramolecular 1,4-addition, due to the C3-substituent, Lewis acid, and the presence of diol. In this study, novel methodology to prepare two types of decalin skeleton could be developed.

alpha-Oxyalkylation and alpha-amidoalkylation of nebularine tri-O-benzoate via homolytic processes.

A series of new purine ribonucleoside derivatives having oxyalkyl or amidoalkyl functionality at the 6-position have been synthesized from nebularine tri-O-benzoate by Miniscitype homolytic processes using ammonium persulfate as the radical initiator.

Preparation of chiral, highly functionalized cyclopentanes and its application to the synthesis of prostaglandin E1.

This paper describes the preparation of the polyfunctionalized cyclopentane ((+/-)-5) by silica gel-catalyzed air-oxidation, and its kinetic resolution by means of microbial reduction with Rhodotorula rubra to afford optically pure (-)-5 (greater than 99% ee). Starting with (-)-5, a new route to prostaglandin E1 was established.

A novel method of preparing amine-modifying C-4' oxidized nucleotide.

A novel method of preparing C-4' oxidized nucleotide, a monomeric model of an alkali labile lesion (1) has been studied. The C-4' selenated 4a and 4b were found to be effective in preparing 3, a monomeric model of 1, by the reaction with NBS (N-bromosuccinimide). The successive reaction of 3 with amine at room temperature afforded the alpha,beta-unsaturated gamma-methylene-gamma-lactam (2) in good yield.

Solid-state conformation of a hybrid tripeptide between beta-amino acid; 8-aminocyclooct-4-enecarboxylic acid and 2-aminoisobutyric acid.

An eight-membered cyclic beta-amino acid, 8-aminocyclooct-4-enecarboxylic acid, was designed as a conformationally restricted non-proteinogenic amino acid. A hybrid tripeptide containing this eight-membered cyclic beta-amino acid and 2-aminoisobutyric acids was synthesized by conventional solution methods. The conformation of the tripeptide was studied using X-ray analysis and was shown to form an eleven-membered hydrogen-bonded turn (3(11)-helical structure) in the solid state.

Asymmetric synthesis of alpha,alpha-disubstituted alpha-amino acids using (S,S)-cyclohexane-1,2-diol as a chiral auxiliary.

Diastereoselective alkylation of ethyl 2-methyl- and/or 2-ethylacetoacetates using the (S,S)-cyclohexane-1,2-diol as an acetal chiral auxiliary afforded enol ethers (2a-f and 5a-f) of 92->95% de in 31-70% yields. Removal of the cyclohexane-1,2-diol with BF(3)-OEt(2) afforded beta-keto esters (3 and 6) bearing a chiral quaternary carbon. The beta-keto esters could be easily converted into optically active alpha-methylated and/or alpha-ethylated alpha,alpha-disubstituted amino acids (12 and 13) in 21-99% yields using Schmidt rearrangement.

Insight into acid-mediated asymmetric spirocyclization in the presence of a chiral diol.

Asymmetric spirocyclization based on intramolecular conjugate addition using a combination of a Lewis acid and an optically active cyclohexane-1,2-diol has been studied in connection with 1) the effect of substituents on the cyclohexane-1,2-diol and 2) the effect of substituents on the substrate. This reaction was found to be both thermodynamically and kinetically controlled under restricted conditions.

Molecular design of a new class of spin-labeled ribonucleosides with N-tert-butylaminoxyl radicals.

We designed a new type of spin-labeled nucleosides with an N-tert-butylaminoxyl radical which is introduced to the nucleobase directly. Purine and pyrimidine ribonucleosides containing the aminoxyl radical such as 1a-d, 2, 3, and 4 were synthesized to investigate the stability and behavior of the N-tert-butylaminoxyl radical on a nucleobase. Lithiation of tri-O-silylated 6-chloropurine ribonucleoside (5) followed by reaction with 2-methyl-2-nitrosopropane (MNP) gave the key compound 6a, which was further converted to 6b-d. Oxidation of the obtained 6a-d and their triols (7a-d) with Ag(2)O led to formation of the corresponding stable spin-labeled nucleosides (8a-d and 1a-d), which were confirmed by EPR spectroscopy. Similarly, the precursors of spin-labeled pyrimidines (13, 20, and 23) were synthesized by site-selective lithiation of tri-O-protected pyrimidine derivatives (9, 18, and 21) followed by the reaction with MNP and deprotection. An EPR study showed that the aminoxyl radicals (2, 3, and 4) were stable and that their hyperfine structures were dependent on the position of the radical. Electron densities of pyrimidine also affected hyperfine structures.

Application of Rh-catalyzed cyclization to the formation of a chiral quaternary carbon.

Rh-Catalyzed cyclization was applied to the formation of a chiral quaternary carbon. It has become clear that the Rh-complex can discriminate between isopropenyl and 2-isopentenyl (or isopentyl) substituents, and the cyclization afforded 3,3,4-trisubstituted cyclopentanones with a chiral quaternary carbon in a stereoselective manner. The cyclization of 4-pentenals 6a, b by an achiral neutral Rh(PPh3)3Cl afforded 3,3,4-cis-trisubstituted cyclopentanones (+/-)-7a,b in 86-96%, and the cyclization by a cationic Rh[(R)-BINAP]CIO4 afforded 3,3,4-trans-trisubstituted cyclopentanones (-)-8a, b of 82-86% ee in 88-98% yields. The mechanism of stereoselection by Rh-complexes is also discussed.

Synthesis and properties of a new class of nucleosides with spin source.

Novel spin-labeled ribonucleosides 1-5 were synthesized to investigate stability and behavior of N-tert-butyl aminoxyl radical on nucleobase. Site selective lithiation of tri-O-protected ribonucleosides followed by the reaction with 2-methyl-2-nitrosopropane (MNP) resulted in introduction of N-tert-butylhydroxylamino group into various positions of purine or pyrimidine nucleus. Oxidation of the obtained hydroxylamines with Ag2O led to formation of 1-5. EPR study showed that the unpaired electron of the aminoxyl radical was delocalized into the nucleobase and hyperfine structures were dependent on the position of the radical.

Morphine metabolism in the opium poppy and its possible physiological function. Biochemical characterization of the morphine metabolite, bismorphine.

We identified a novel metabolic system of morphine in the opium poppy (Papaver somniferum L.). In response to stress, morphine is quickly metabolized to bismorphine consisting of two morphine units, followed by accumulation in the cell wall. This bismorphine binds predominantly to pectins, which possess high galacturonic acid residue contents, through ionical bonds. Our newly developed method using artificial polysaccharides demonstrated that bismorphine bridges are formed between the two amino groups of bismorphine and the carboxyl groups of galacturonic acid residues, resulting in cross-linking of galacturonic acid-containing polysaccharides to each other. The ability of bismorphine to cross-link pectins is much higher than that of Ca2+, which also acts as a cross-linker of these polysaccharides. Furthermore, we confirmed that cross-linking of pectins through bismorphine bridges leads to resistance against hydrolysis by pectinases. These results indicated that production of bismorphine is a defense response of the opium poppy. Bismorphine formation is catalyzed by anionic peroxidase that pre-exists in the capsules and leaves of opium poppies. The constitutive presence of morphine, together with bismorphine-forming peroxidase, enables the opium poppy to rapidly induce the defense system.