Fuyuhiko Inagaki

Rhodium(I)‐Catalyzed Intramolecular [5+2] Cycloaddition Reactions of Alkynes and Allenylcyclopropanes: Construction of Bicyclo[5.4.0]undecatrienes and Bicyclo[5.5.0]dodecatrienes

Highly strained cyclopropane derivatives have served as useful and powerful C3 building blocks [1] for the construction of various ring systems, and the metal-catalyzed cleavage of the activated carbon-carbon s bond of the cyclopropane ring 3] must be one of the most attractive methods from a synthetic point of view. Of particular interest is the Rhcatalyzed [5+2] cycloaddition of vinylcyclopropanes with carbon–carbon p-components for the efficient formation of seven-membered compounds. In 1995, Wender et al. reported the first example of the Rh-catalyzed [5+2] cycloaddition reaction of vinylcyclopropanes with alkynes to provide bicyclo[5.3.0]decadienes. This method was successfully applied to the [5+2] cycloaddition reactions of allenes as well as alkenes 4a] as an alternative carbon–carbon p-counterpart. In sharp contrast to the extensive investigation of vinylcyclopropanes, 3–5] very few examples of the ringclosing reaction of allenylcyclopropane, which is regarded as an alkylidene homologue of vinylcyclopropane, have been reported. Two representative examples are shown in Scheme 1; one involves the Rh-catalyzed cycloisomeriza-

Total syntheses of (-)- and (+)-goniomitine.

The Stille coupling reaction of 3-(benzyloxymethyl)-1-(tert-butyldiphenylsiloxy)ethyl-1-(tributylstannyl)allene with N-(tert-butoxycarbonyl)-2-iodoaniline directly produced the corresponding 2-vinylindole derivative, which was independently transformed into natural (-)-goniomitine and unnatural (+)-goniomitine via the cross-metathesis with chiral oxazolopiperidone lactams. The antiproliferative activity of the synthesized natural (-)-goniomitine in Mock and MDCK/MDR1 cells showed them to be more potent to retard cell growth than unnatural (+)-goniomitine.

Total Synthesis of (±)-Meloscine

The total synthesis of (±)-meloscine was completed in a highly stereoselective manner starting from the known 4-(2-aminophenyl)-2,3-dihydro-N-methoxycarbonylpyrrole. The crucial step in this total synthesis involves the efficient construction of the tetracyclic framework of the target natural product by the intramolecular Pauson-Khand reaction.

Rhodium(I)‐Catalyzed Intramolecular Carbonylative [2+2+1] Cycloaddition of Bis(allene)s: Bicyclo[6.3.0]undecadienones and Bicyclo[5.3.0]decadienones

No templates needed: The title reaction makes it easy to construct the bicyclo[6.3.0]undecadienone framework in high yields (see scheme). A template effect is not required to achieve this ring-closing reaction efficiently. The present method can be applied to the construction of bicyclo[5.3.0] and bicyclo[4.3.0] ring systems. Ts = p-toluenesulfonyl.

Csp3–Csp3 and Csp3–H Bond Activation of 1,1-Disubstituted Cyclopentane

The unprecedented C(sp(3))-C(sp(3)) bond cleavage of unactivated cyclopentane has been achieved. Rh(I)-catalyzed cycloaddition of allenylcyclopentane-alkynes produced in situ the 9-cyclopentyl-8-rhodabicyclo[4.3.0]nona-1,6-diene intermediates, which subsequently underwent [7+2] cycloaddition via β-C elimination, affording bicyclo[7.4.0]tridecatriene derivatives in good yields. Changing the Rh(I) catalyst effected the Cγ-H bond activation of the common 9-cyclopentyl-8-rhodabicyclo[4.3.0]nona-1,6-diene intermediate to produce the novel spiro[2.4]heptane skeleton in a site-selective manner.

Formal synthesis of (+)-nakadomarin A.

The formal synthesis of (+)-nakadomarin A was completed. The significant points of this synthesis are the highly stereoselective formation of the diazatricyclo[6.4.0.0(1,5)]dodecane skeleton (A, B, and D rings) based on the Pauson-Khand reaction and novel furan ring (C ring) formation, using the vinyl residue of the Pauson-Khand product.

Structural complexity through multicomponent cycloaddition cascades enabled by dual-purpose, reactivity regenerating 1,2,3-triene equivalents

Multicomponent reactions allow for more bond-forming events per synthetic operation, enabling more step and time economical conversion of simple starting materials to complex and thus value-added targets. These processes invariably require that reactivity be relayed from intermediate to intermediate over several mechanistic steps until a termination event produces the final product. Here we report a multicomponent process in which a novel 1,2,3-butatriene equivalent (TMSBO: TMSCH2C≡CCH2OH) engages chemospecifically as a two-carbon alkyne component in a metal-catalyzed [5+2] cycloaddition with a vinylcyclopropane to produce an intermediate cycloadduct. Under the reaction conditions, this intermediate undergoes a remarkably rapid 1,4-Peterson elimination, producing a reactive four-carbon diene intermediate that is readily intercepted in either a metal-catalyzed or thermal [4+2] cycloaddition. TMSBO thus serves as an yne-to-diene transmissive reagent coupling two powerful and convergent cycloadditions - the homologous Diels-Alder and Diels-Alder cycloadditions - through a vinylogous Peterson elimination, and enabling flexible access to diverse polycycles.

Total syntheses of (+)-fawcettimine and (+)-lycoposerramine-B.

The total synthesis of (+)-fawcettimine was completed in a highly stereoselective manner starting from the oxatricyclo[7.3.0.0(1,5)]dodecanedione derivative. The crucial step in this total synthesis involves the efficient construction of the azonane framework by the intramolecular Mitsunobu reaction. Furthermore, the first total synthesis of (+)-lycoposerramine-B was also accomplished via the common synthetic intermediate.

Rhodium(I)-Catalyzed Intramolecular Carbonylative [2+2+1] Cycloadditions and Cycloisomerizations of Bis(sulfonylallene)s

Novel [{RhCl(CO)dppp}(2)]-catalyzed intramolecular carbonylative [2+2+1] cycloadditions of bis(phenylsulfonylallene) derivatives under CO, leading to the facile formation of bis(phenylsulfonyl)bicyclo[n.3.0] frameworks (n=4-6), have been developed. The terminal double bonds of both allenyl moieties served exclusively as the two pi-components. In particular, this newly developed method was shown to be a powerful tool for the construction of bicyclo[6.3.0]undecadienones, which have hardly been prepared by the known Pauson-Khand (-type) reactions. The bicyclo[7.3.0]dodecadienone homologue (one extra carbon) could be formed in rather low yields. Alternatively, novel cycloisomerizations of bis(phenylsulfonylallene) derivatives with catalysis by the same Rh(I) complex under N(2) readily produced the 3,4-dimethylene-2,5-bis(phenylsulfonyl)cyclononene and the corresponding cyclooctene and cycloheptene frameworks.

Histidine augments the suppression of hepatic glucose production by central insulin action

Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes.