Search

Valuable synthetic routes to the Lycopodium alkaloid lycodine ( 1) and its unsymmetric dimers, complanadines A ( 4) and B ( 5), have been developed. Regioselective construction of the bicyclo[3.3.1]nonane core structure of lycodine was achieved by a remote functionality-controlled Diels-Alder reaction and subsequent intramolecular Mizoroki-Heck reaction. A key coupling reaction of the lycodine units, pyridine N-oxide ( 66) and aryl bromide ( 65), through C−H arylation at the C1 position of 66 provided the unsymmetric dimer structure at a late stage of the synthesis. This strategy greatly simplified the construction of the dimeric architecture and functionalization. Complanadines A ( 4) and B ( 5) were synthesized by adjusting the oxidation level of the bipyridine mono- N-oxide ( 67). The diverse utility of this common intermediate ( 67) suggests a possible biosynthetic pathway of complanadines in Nature. Both enantiomers of lycodine ( 1) and complanadines A ( 4) and B ( 5) were prepared in sufficient quantities for biological evaluation. The effect on neuron differentiation of PC-12 cells upon treatment with culture medium, in which human astrocytoma cells had been cultured in the presence of 1, 4, or 5 was evaluated. [ABSTRACT FROM AUTHOR]

Limonoids are highly oxygenated C13α-triterpenes and common secondary metabolites. Several hundred congeners have been isolated to date. The first total synthesis of (±)-limonin, the flagship congener of the limonoids, is now reported and features 1) a tandem radical cyclization generating the BCD ring system with the C13α configuration that is essential to the limonoids and a Robinson annulation to construct the limonoid androstane framework, 2) a singlet-oxygen cycloaddition and a Baeyer-Villiger oxidation to synthesize the highly oxidized D ring, and 3) a Suárez reaction to construct the unique AA′ ring system. [ABSTRACT FROM AUTHOR]

Ciguatoxins, the principal causative agents of ciguatera seafood poisoning, are extremely large polycyclic ethers. We report herein a reliable route for constructing the left wing of CTX1B, which possesses the acid/base/oxidant-sensitive bisallylic ether moiety, by a 6- exo radical cyclization/ring-closing metathesis strategy. This new route enabled us to achieve the second-generation total synthesis of CTX1B and the first synthesis of 54-deoxyCTX1B. [ABSTRACT FROM AUTHOR]

The cyanosporasides A-F are a collection of monochlorinated benzenoid derivatives isolated from the marine actinomycetes Salinispora and Streptomyces sp. All derivatives feature one of two types of cyanocyclopenta[ a]indene frameworks, which are regioisomeric in the position of a single chlorine atom. It is proposed that these chloro-substituted benzenoids are formed biosynthetically through the cycloaromatization of a bicyclic nine-membered enediyne precursor. Herein, we report the synthesis of such a bicyclic precursor, its spontaneous transannulation into a p-benzyne, and its differential 1,4 hydrochlorination reactivity under either organochlorine or chloride-salt conditions. Our bioinspired approach culminated in the first regiodivergent total synthesis of the aglycons A/F and B/C, as well as cyanosporasides D and E. In addition, empirical insights into the site selectivity of a natural-like p-benzyne, calculated to be a ground-state triplet diradical, to hydrogen, chlorine, and chloride sources are revealed. [ABSTRACT FROM AUTHOR]

Doppelte Freude: Totalsynthesen der dimeren Alkaloide (−) ‐ Complanadin A (1) und B (2) gelangen ausgehend von (−) ‐ Lycodin. Die unsymmetrische Struktur wurde durch direkte Arylierung eines Pyridin ‐ N ‐ oxids aufgebaut. Die absoluten Konfigurationen und spezifischen Drehwerte der Complanadine wurden ermittelt. Cbz=Benzyloxycarbonyl. [ABSTRACT FROM AUTHOR]

1: Ciguatoxins (CTXs) are known to bind to receptor site 5 of the voltage-dependent Na channel, but the toxin's physiological effects are poorly understood. In this study, we investigated the effects of a ciguatoxin congener (CTX3C) on three different Na-channel isoforms, rNav1.2, rNav1.4, and rNav1.5, which were transiently expressed in HEK293 cells. 2: The toxin (1.0?µmol?l-1) shifted the activation potential (V1/2 of activation curve) in the negative direction by 4-9?mV and increased the slope factor (k) from 8?mV to between 9 and 12?mV (indicative of decreased steepness of the activation curve), thereby resulting in a hyperpolarizing shift of the threshold potential by 30?mV for all Na channel isoforms. 3: The toxin (1.0?µmol?l-1) significantly accelerated the time-to-peak current from 0.62 to 0.52?ms in isoform rNav1.2. Higher doses of the toxin (3-10?µmol?l-1) additionally decreased time-to-peak current in rNav1.4 and rNav1.5. 4: A toxin effect on decay of INa at -20?mV was either absent or marginal even at relatively high doses of CTX3C. 5: The toxin (1?µmol?l-1) shifted the inactivation potential (V1/2 of inactivation curve) in the negative direction by 15-18?mV in all isoforms. 6: INa maxima of the I-V curve (at -20?mV) were suppressed by application of 1.0?µmol?l-1 CTX3C to a similar extent (80-85% of the control) in all the three isoforms. Higher doses of CTX3C up to 10?µmol?l-1 further suppressed INa to 61-72% of the control. 7: Recovery from slow inactivation induced by a depolarizing prepulse of intermediate duration (500?ms) was dramatically delayed in the presence of 1.0?µmol?l-1 CTX3C, as time constants describing the monoexponential recovery were increased from 38±8 to 588±151?ms (n=5), 53±6 to 338±85?ms (n=4), and 23±3 to 232±117?ms (n=3) in rNav1.2, rNav1.4, and rNav1.5, respectively. 8: CTX3C exerted multimodal effects on sodium channels, with simultaneous stimulatory and inhibitory aspects, probably due to the large molecular size (3?nm in length) and lipophilicity of this membrane-spanning toxin.British Journal of Pharmacology (2004) 142, 879-889. doi:10.1038/sj.bjp.0705852 [ABSTRACT FROM AUTHOR]

1. Desmosine and isodesmosine were detected in an invertebrate molluscan species, i.e. in an insoluble protein in the hinge ligament of a bivalve species, Sakhalin surf clam (Pseudocardium sachalinensis, in family Mactridae). The protein is rich in glycine and methionine S-oxide but devoid of hydroxyproline and hydroxylysine. 2. 3,3′-Methylenebistyrosine was also detected in the HCl hydrolysate of the hinge-ligament protein, but it was found to be an artefact produced from tyrosine and formaldehyde derived from methionine S-oxide during the HCl hydrolysis of the protein. [ABSTRACT FROM AUTHOR]

Alkaloid Synthesis Structurally complex Lycopodium alkaloid complanadines A and B, both with unsymmetrical dimer architectures, were effectively synthesized by designing an appropriate intermediate based on C−H arylation. Our result suggests the intermediacy of a mono ‐ N ‐ oxide in the biosynthesis of dimeric alkaloids. This competent route enabled the evaluation of neuronal differentiation effects of both natural ‐ type enantiomers and antipodes. More information can be found in the Full Paper by C. Tsukano et al. on page 802 ff. [ABSTRACT FROM AUTHOR]