Heteroaromatic alkaloids,nakijinamines, from a sponge Suberites sp.

The structures of seven new secondary metabolites isolated from an Okinawan marine sponge Suberites sp., nakijinamines A (1), B (2), and F–I (3–6) and 6-bromoconicamin (7), have been elucidated on the basis of spectroscopic analysis, chemical conversion, and conformational analysis. These analyses disclosed that 1–6 were heteroaromatic alkaloids having the hybrid structures of an aaptamine-type alkaloid and an indole alkaloid, while 7 was a bromoindole alkaloid. Nakijinamine I (6) is the first example of an aaptamine-type alkaloid possessing a 1,4-dioxane ring. Antimicrobial activities of 1–7 were evaluated.     

Chiral drugs related to guaifenesin: synthesis and phase properties of methocarbamol and mephenoxalone

The muscle relaxant methocarbamol 2 and tranquilizer mephenoxalone 3, as well as intermediate cyclic carbonate 4, have been prepared in enantiopure form by starting from enantiopure guaifenesin 1 easily available by an entrainment resolution procedure. Thermal investigations reveal that 2 is probably a conglomerate forming substance, 3 forms a stable racemic compound, and 4 occupies an intermediate position. The enantiomeric excess of a binary phase eutectic point for these substances comprises 0%, 85%, and 10%, respectively.     

Activation and transfer of oxygen—XII : Alkoxy adducts derived from 1,3,10-trimethylalloxazinium (1,3-dimethylflavinium) cations

Monoalkoxy adducts, derived from an alloxazinium cation and an alcohol in the presence of a base, are readily converted into dialkoxy adducts. Two types of dialkoxy adducts are formed. In the reaction with a monohydric alcohol C₄ is preferred for the second intermolecular nucleophilic attack to give the 4,10a-dialkoxy adduct, which rearranges into a hexahydroimidazo[4,5-b]quinoxalme derivative 5c. In the reaction with a dihydric alcohol C_4a, is the second reaction site in an intramolecular nucleophilic ringclosure to give a 4a,10a-dialkoxy adduct 6c which can be isolated as such. Both types of dialkoxy adducts can be reconverted into the alloxazinium cation.The structures of the dialkoxy adducts give every reason to reject the conclusion in the literature that C_9a is the primary addition site.Starting from 5c several reactions have been effected: (a) conversions into tetra- and di-hydroimidazo[4,5-b]quinoxalinium cations 7 and 9 and ring opening of 9 into a ureido-dihydroquinoxaline 10 (Scheme 4); (b) a rearrangement of a transient hexahydroimidazo[4,5-b]quinoxaline 5d into spirohydantoin 4 and a rearrangement of cation 7 into the alloxazinium cation 1 (Scheme 5); (c) preparation of acetylated tetra- and hexa-hydroimidazo[4,5-b]quinoxalines 11 and 12. Conversions of cation 11 into 9 and 1 and conversions of 12 into a benzimidazolinium cation 14 (Schemes 6 and 7). Degradation of 14 affords 1,2-dimethylbenzimidazole (15, Scheme 6).     

A four step synthesis of violaceic acid

The total synthesis of the biaryl ether natural product violaceic acid (1) in four steps is described. The steps included a S_NAr reaction between phenol 7 and flouroarene 12 to afford the biaryl ether 13, selective reduction of a nitro group to an amine in the presence of an aldehyde, a Cu mediated Sandmeyer reaction and final hydrolysis to afford the target compound 1. The amine 14 was also converted into the known iodide 18 which gave impure 1 on Pd mediated hydroxide cross coupling.     

Stereochemical studies—LVII: Synthesis of optically active compounds by the novel use of meso-compounds—1. Efficient synthesis of two structural types of optically pure prostaglandin intermediates

With an aim to overcome several inefficient aspects of ordinary methods of preparing optically active compounds, we have developed a new method which recommends utilization of symmetrically functionalized meso-compounds in place of racemic compounds.As shown in Scheme 1, when the mesa-compound (I) is monofunctionalized by an optically active functional group (A) and each of the formed diastereomers (II and III) is subjected to further chemical elaborations including protective group transposition, it is theoretically possible to convert the total amount of the starting material (I) into the requisite optically pure product (VI or VII) by selecting synthetic schemes.By employing this novel concept, two structural types of the prostaglandin intermediates ((?)- and ( + )-2a,b) have been prepared from the meso-diols (1a, b) by way of the two diastereomeric monoesters (13a, b and 14a, b) which are produced by the reactions of 1a, b with N-mesyl- and N-phthaloyl-(S)-phenylalanyl chloride (3a, b).     

Selective conformational changes of cyclic systems—XII: Enhanced reactivity of ten membered ring ketones due to transanular steric compression: hydrates and hemiketals from oxo-[2.2]metacyclophanes

The rigid, 10-membered ring Ketones incorporated in [2.2]metacyclophanes exhibit a pronounced tendency towards adduct formation with nucleophiles. [2.2]Metacyclophane-1,10-dione (1) readily adds water and alcohols, e.g. in dioxane solution containing 20$\text{n}\text{n}$ water an equilibrium is attained between 1 (9%) and the mono- and dihydrates 1' (55%) and 1″ (36%) respectively. In pure water the equilibrium is further shifted towards the adducts, as revealed by an extrapolation. Equilibration of the dihydrate 1″ which can be isolated in crystalline form gives corresponding results. In methanol the equilibrium mixture consists mostly of the diastereomeric bishemiketals 1aa, 1ee and 1ae. A similar behaviour is found for the monoketone 2, 1-propylenethioketal of [2.2]1metacyclophane-l,10-dione. The reactions studied are fully reversible on evaporation of the solvents and subsequent warming under reduced pressure.The results are gained from a combinatory evaluation of ¹H NMR and absorption spectra of 1 and 2 in solution. The enhanced reactivity of the CO groups in 1 and 2 can be accounted for by a relief of steric strain on rehybridization sp²→sp³ due to a simultaneous conformational change. In dodecahydro-[2.2]metacyclophane-1,10-dione (3), where a similar relief of strain is not operative an anomalous carbonyl reactivity is not observed.     

Electrochemical oxidation of 6-hydroxy-1,2,3,4-tetrahydro-β-carboline in aqueous solution

The electrochemical oxidation of 6-hydroxy-1,2,3,4-tetrahydro-β-carboline (1), an alkaloid which occurs naturally in the mammalian brain, has been studied in aqueous solution particularly at physiological pH. The first voltammetric oxidation peak of 1 observed at the pyrolytic graphite electrode generates a radical intermediate which dimerizes to give 5,5′-bi-(6-hydroxy-1,2,3,4-tetrahydro-β-carboline) (3). However, the putative radical intermediate can also be further oxidized (1e) to give a C(5)-centered carbocation which can either dimerize in an ion-substrate reaction to give 3 or be attacked by water to give 5,6-dihydroxy-1,2,3,4-tetrahydro-β-carboline (8) which is rapidly oxidized further to 1,2,3,4-tetrahydro-β-carboline-5,6-dione (9). In the presence of glutathione dione 9 forms the 8-S-glutathionyl conjugate of 8 which is easily oxidized to the 8-S-glutathionyl conjugate of 9. It is suggested that 1 might be an alkaloid which is elevated in the brain as a result of chronic alcoholism, and the roles of the oxidative transformations of this compound in some of the addictive and neurophathological consequences of ethanol consumption are discussed.     

Preparation of the cde-ring system of pleurotin and geogenine via a stereoselective free radical cyclization

A synthesis of lactone 3, a projected intermediate in an approach to pleurotin (1) and geogenine (2), is described. The trans-perhydroindan nucleus is constructed using a stereoselective free radical cyclization (5 → 9).     

Elimination of the nitrile group from o-aminonitriles—IV: A new and efficient synthesis of 3,5-diarylaminobenzenes from arylidenemalonodinitriles and 1-arylethylidenemalonodinitriles

A synthesis of a variety of 5'-amino-m-terphenyls (6) and 3,5-diarylaminobenzenes through an efficient elimination of cyano groups from 5'-amino-4',6'-dicyano-m-terphenyls (4) using sodium hydroxide in ethanol at 220°, is described, The starting o-aminonitriles (4) are conveniently prepared from arylidenemalonodinitriles (1) and 1-arylethylidenemalonodinitriles (2). This strategy is applied for the synthesis of an aminoquaterphenyl (13) and a diaminoquinquephenyl (16).     

Carbonylation in benzyl alcohol. A new and easy method for the preparation of aromatic benzyl esters

The carbonylation of the iodides 2a-c and 12a-b in benzyl alcohol with carbon monoxide affords the corresponding benzyl esters 3a-c and 13a-b in good yields. It is shown that 3a can be easily and selectively cleaved to the acid 4a by catalytic hydrogenation. The acid is converted to an ester, 7a, and an amide, 6a.     

Beobachtungen zum mechanismus der nenitzescu-reaktion—II

The pyrrolo-indoles 9, 10 and 12 have been isolated as by-products. The structure of carbinolamine 13, a potential precurser of pyrrolo [2,3-f] indoles, was examined by chemical and spectroscopic methods. Under Nenitzescu-conditions 13 could not be reduced to the pyrroloindole 11, but the furano-indolenin 16 was isolated. The origin of the pyrrolo [3,2-e] indole 12 from carbinolamin 17 was proved by a corresponding reaction. The course of the reaction via the ring-opening of the indole 19 can be excluded and thus a direct ring-closure of F is made probable. Attempts to reduct 17 show that the carbinolamine can not be considered as a precursor of hydroxyindoles in an apolar, aprotic medium. Thus a reaction corresponding to an oxidation-reduction mechanism is not possible under these conditions. The experiments indicate that another mechanism, namely the direct cyclisation of H in this case leads to indole formation.     

Pyrroloquinoline derivatives from a Tongan specimen of the marine sponge Strongylodesma tongaensis

Pyrroloquinoline alkaloids are well known bioactive metabolites commonly found from latrunculiid sponges. Two new pyrroloquinoline alkaloids, 6-bromodamirone B (1) and makaluvamine W (2), were isolated from the Tongan sponge Strongylodesma tongaensis. Makaluvamine W (2) contains an oxazole moiety, which is rare in this large group of natural products, and is the first example of a pyrroloquinoline with nitrogen substitution at C-8. Both 1 and 2 lacked activity against a human promyelocytic leukemia cell line (HL-60), supporting the premise that an intact iminoquinone moiety plays a key role in the cytotoxicity of this compound class. The chemotaxonomic impact of these makaluvamine-type compounds is also discussed.     

Novel secoeunicellins produced by an octocoral Cladiella sp

Two novel 6,7-secoeunicellins, cladieunicellins W (1) and X (2), along with a known eunicellin, klymollin Y (3), were isolated from an octocoral identified as Cladiella sp. The structures of secoeunicellins 1 and 2 were elucidated by spectroscopic methods. 1 is the first secoeunicellin possessing a γ-lactone ring and 2 represents the first secoeunicellin possessing two tetrahydrofuran moieties. Secoeunicellin 2 displayed significant inhibitory effects on the generation of superoxide anions and the release of elastase. These results implied that the methoxy group at C-6 in 2 plays an important role in determining the activity of these compounds.     

A C6, C7 Oxygen Functionalized Intermediate for the Synthesis of Forskolin: Stereochemical Control in an Intramolecular Diels-Alder Reaction

Stereospecific intramolecular Diels-Alder reactions of aldehydes 3a and 3b afford lactones 4 and 5, respectively. The mechanism of the reactions is considered. Lactone 4 is elaborated further to provide acetonide 14b, an important intermediate in an approach to the synthesis of forskolin (1).     

Alcaloides steroidiques—CLXIV : Isomerisation en presence d'une base ou d'un acide d'oxazirannes steroidiques derives de la conanine

Isomerisation into an imino-carbinol or a nitrone is the first step in the hydrolysis of an oxazirane. This isomerisation, studied on three steroidal compounds lead to the following results: compound 6, bearing cis-oriented 18H and oxazirane ring, gives rise only to the nitrone 13. Compound 1 which bears trans 18H may isomerise either into the imino-carbinol 5 or into the nitrone 11 (11 is quantitatively obtained in acidic conditions with minimum basic catalysis). The case of compound 7 which isomerises whatever the conditions into the α hydroxylated imino-ether 8 shows the influence of structural factors which enhance the mobility of the 18H.     

Alkylation d'enamines par les halogeno-5 ene-3 ynes-1

The alkylation of several enamines of cyclanones with 5-halogeno 3-ene 1-ynes 1 gives a mixture of isomeric ketones 3 and 4. The composition of this mixture is independent of the enamine but is related to the nature of the halide 1. The primary halides lead essentially to ketones 3 and the secondary halides give predominantly 4. Both ketones are always formed via an initial C-alkylation; a mechanism taking account of the experimental results is proposed.     

Synthetic studies toward verrucosidin: Determination of the absolute configuration

The tetrahydrofuran portion 3 of verrucosidin 1, a potent neurotoxin, is synthesized in an enantiomerically pure form via the stereoselective osmylation of the chiral hydroxy diene ester 5 as a key step.     

Etude de la reaction chlorocarbene-acetals de cetenes : II. Stereoselectivite de la reaction

We have studied the stereoselectivity of the addition reaction of chloro and chloromethyl carbenoids with ketene alkylsilyl acetals. The best stereoselectivity was generally observed with the dimethyl tertiobutylsilyloxy group. With the chlorocarbenoid, using an E ketene acetal we obtained in majority (8?0%) an E α,β-ethylenic ester and using a Z ketene acetal we obtained in majority (7?0%) a Z α,β-ethylenic ester. In the case of the chloromethyl carbenoid the two ketene acetal isomers led to the same E α-substituted α,β-ethylenic ester (8?8% of selectivity). With the chlorophenylcarbenoid, formation of 9?0% of E α phenyl α,β-ethylenic ester is observed.     

Enantiomeric synthesis of carbocyclic d-4′-C-methylribonucleosides as potential antiviral agents

An efficient synthetic approach for the preparation of enantiomerically pure carbocyclic d-4′-C-methylribonucleosides 3a–f is reported. The key intermediate, d-2,3-O-cyclohexylidene-4-methylcyclopentenone 8, was prepared starting from d-ribose in eight steps via an oxidative rearrangement. Conjugate addition of a catalytic vinylcopper(I) reagent to the α,β-unsaturated ketone 8 yielded cyclopentyl alcohol 10, which bears a quaternary stereogenic carbon at the C4-position. The cyclopentyl alcohol 10 was subsequently coupled with 6-chloropurine or 2-amino-6-chloropurine via an S_N2 reaction, followed by a series of functional group transformations and deprotections to furnish purine ribonucleosides 3a–c. Pyrimidine bases were constructed on cyclopentylamine 29 using a linear approach, which furnished the pyrimidine nucleosides 3d–f.     

Acyclic stereoselection. 21. Synthesis of an ionophore synthon having four asymmetric carbons by sequential aldol addition,claisen rearrangement and hydroboration

Allylic alcohol 7, obtained by a synthesis involving stereoselective aldol addition to an unsaturated aldehyde, is transformed by the Ireland variant of the Claisen rearrangement into unsaturated acid 9. Subsequent elaboration of this material gives homoallylic alcohols 13 and 14, which are hydroborated to obtain primarily 3 and 4. It is shown that the hydroboration is intermolecular, rather than intramolecular.