Masaru Hashimoto

Total synthesis of natural (+)-FR900482. 2. Efficient syntheses of the aromatic and the optically active aliphatic fragments

Abstract The synthesis of the aromatic fragment 4 was achieved starting from commercially available 5-hydroxy-isophthalic acid (6) by utilizing Claisen rearrangement of 9, bromolactonization of 12, and modified Curtius rearrangement of 16 as key steps. Furthermore, the optically active aliphatic fragment 5 was synthesized in an optically pure form starting with l -diethyl tartrate (7) by featuring epoxide formation of 26, nucleophilic epoxide opening of 27 with an azide anion, reduction of the azide function in 33 to an amine, and formation of the N-protected 1,3-oxazolidine 35.

A Novel Bisretinoid of Retina Is an Adduct on Glycerophosphoethanolamine

PURPOSE Fluorescent bisretinoid compounds accumulate in retinal pigment epithelial (RPE) cells as a consequence of two processes: random reactions of vitamin A aldehyde in photoreceptor cell outer segments, and phagocytosis of discarded photoreceptor outer segment discs by RPE. The formation of bisretinoid is accentuated in some forms of retinal degeneration. The detection of a novel bisretinoid fluorophore that is a conjugate of all-trans-retinal and glycerophosphoethanolamine is reported. METHODS Human RPE/choroid, eyes harvested from Abca4 (ATP-binding cassette transporter 4) null mutant mice, and biosynthetic reaction mixtures were analyzed by ultra performance liquid chromatography coupled to mass spectrometry and by nuclear magnetic resonance spectra and spectrofluorometry. RESULTS A fluorescent compound in mouse eyes and in human RPE/choroid corresponded to the product of the reaction between all-trans-retinal and glycerophosphoethanolamine (A2-GPE), as determined on the basis of molecular weight (m/z 746), absorbance (approximately 338,443 nm), and retention time. Nuclear magnetic resonance spectra were consistent with a pyridinium molecule with a glycerophosphate moiety. The emission maximum of A2-GPE was approximately 610 nm. A2-GPE accumulated with age in mouse eyes and was more abundant in Abca4(-/-) mice, a model of recessive Stargardt disease. CONCLUSIONS To date, several bisretinoids of RPE lipofuscin have been isolated and characterized, and for all of these, formation involves the membrane phospholipid phosphatidylethanolamine. Conversely, the bisretinoid A2-GPE is detected as sn-glycero-3-phosphoethanolamine (GPE) derivatized by two all-trans-retinal. The pathways by which A2-GPE may form under conditions of increased availability of all-trans-retinal, for instance in the Abca4(-/-) mouse, are discussed.

Asymmetric synthesis of (1R,2S)-2-fluorocyclopropylamine, the key intermediate of the new generation of quinolonecarboxylic acid, DU-6859

Abstract The title synthesis was achieved by featuring diastereoface selective cyclopropanation of (4R,5S)-4,5-diphenyl-3-vinyl-2-oxazolidinone, the chiral and conformationally rigid N-vinylcarbamate, with zinc-monofluorocarbenoid followed by hydrogenolysis of formed (4R,5S)-3-[(1R-2S)-2-fluorocyclopropyl]-4,5-diphenyl-2-oxalidinone.

Stereochemical Investigations of Isochromenones and Isobenzofuranones Isolated from Leptosphaeria sp. KTC 727

Two new metabolites, (R)-3,4-dihydro-4,6,8-trihydroxy-4,5-dimethyl-3-methyleneisochromen-1-one (1) and (R)-7-hydroxy-3-((S)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one (2), were isolated along with two structurally known related compounds (3 and 4) from the culture broth of Leptosphaeria sp. KTC 727 (JCM 13076 = MAFF 239586). These structures were disclosed mainly with (1)H and (13)C NMR spectroscopic analyses. The relative configuration of 2 was established by NOE studies. The absolute configuration of this molecule was determined by a combination of the modified Moshers method and CD spectra after derivatizations. The theoretical CD profiles also supported these assignments. Structural correlations enabled us to establish the absolute configurations of metabolites 1, 3, and 4, in which configurations of the latter two had not been established. Compound 2 exhibited the strongest antifungal activity among them, inhibiting the hyphal growth of Cochliobolus miyabeanus at about 0.5 μg/mL.

Synthetic studies on the key component of the new generation of quinolonecarboxylic acid, DU-6859. 2.: Asymmetric synthesis of (1R,2S)-2-fluorocyclopropylamine

Abstract The title synthesis was achieved by featuring diastereoface-selective cyclopropanation of (4R,5S)-4,5-diphenyl-3-vinyl-2-oxazolidinone and its related compounds, the chiral conformationally rigid N-vinylcarbamates, with zinc-monofluorocarbenoid, followed by hydrogenolysis of the major addition products. The diastereoface-selectivity of the cyclopropanation could be explained by the most stable conformation of 3-vinyl-2-oxazolidinone derivatives and attack from the less hindered face of the conformer.

Synthesis, chemical property, and cytotoxicity of the carzinophilin congeners carrying a 2-(1-acylamino-1-alkoxycarbonyl)methylidene-1-azabicyclo[3.1.0]hexane system

Abstract Synthesis of the title compounds was achieved by employing condensation of the 2-methoxy-1-pyrroline with ethyl nitroacetate and construction of 1-azabicyclo[3.1.0]hexane systems from 5-mesyloxymethylpyrrolidines as key steps. Some of these congeners which carry a C 6 C 11 unit involving the naphthalene part, were found to exhibit prominent cytotoxicity and effectively alkylate nucleophiles at both the aziridine and epoxide moieties.

Synthetic studies on the key component of the new generation of quinolonecarboxylic acid, DU-6859. 1. Synthesis of (1R,2S)-2-fluorocyclopropylamine by the use of optical resolution

Abstract The title synthesis was achieved by employing highly cis-selective cyclopropanation of N-benzyl-N-vinylcarbamates with zinc-monofluorocarbenoid, deprotection of the formed N-benzyl-N-(cis-2-fluorocyclopropyl)carbamates, and optical resolution of the resulting dl-cis-2-fluorocyclopropylamine by the use of l-menthyl chloroformate as a resolving agent. The cis-selectivity observed for the key cyclopropanation could be explained by the bent transition state model.

Isolation and Absolute Stereochemistry of Optically Active Sydonic Acid from Glonium sp. (Hysteriales, Ascomycota)

Optically active sydonic acid (1) was isolated for the first time from a culture broth of Glonium sp. The absolute stereochemistry was established to be (S) by comparing the circular dichroism (CD) spectrum with that of (+)-curcutetraol after conversion into (+)-sydonol (2).

Total synthesis of an enantiomeric pair of FR900482. 2. Syntheses of the aromatic and the optically active aliphatic segments

Abstract The synthesis of the aromatic segment 4 was achieved starting from commercially available 5-hydroxyisophthalic acid (6) by utilizing Claisen rearrangement of 9, bromolactonization of 12, and modified Curtius rearrangement of 16 as the key steps. Furthermore, the optically active aliphatic segments 5 and ent-5 were synthesized in enantiomerically pure forms starting with natural (2R,3R)- and unnatural (2S,3S)-diethyl tartrate (7 and ent-7), respectively: The synthetic scheme features epoxide formation of 26, nucleophilic epoxide opening of 27 with an azide anion, reduction of the azide function in 33 to an amine, and formation of the N-protected 1,3-oxazolidine 35.

Novel synthesis of (+)-hydantocidin based on the plausible biosynthetic pathway

Abstract The title synthesis was examined by employing two synthetic schemes which feature N,O-spiroketal formation as a key step. Although the stepwise synthesis starting with D-fructose and proceeding through the D-psicose derivatives successfully produced a mixture of (+)-hydantocidin (1) and its C5-epimer [(−)-5-epihydantocidin (2)] the one-step synthesis utilizing D-isoascorbic acid and urea as starting materials was found to give 2 more selectively than 1. Studies on the key N,O-spiroketal formation and epimerization between 1 and 2 were also carried out to explore some novel aspects of the obtained results.