Synthesis of novel, simplified, C-7 substituted eleutheside analogues with potent microtubule-stabilizing activity

The synthesis of a number of novel, simplified, C-7 substituted eleutheside analogues with potent tubulin-assembling and microtubule-stabilizing properties is described, using ring closing metathesis as the key-step for obtaining the 6-10 fused bicyclic ring system. The RCM precursors were synthesized starting from aldehyde 3 [prepared in six steps on a multigram scale from R-(−)-carvone in 30% overall yield] via multiple stereoselective Hafner-Duthaler allyltitanations and/or Brown allylborations. ‘Second generation’ RCM-catalyst 15 gave the desired ring closed ten-membered carbocycles as single Z stereoisomers in good yields. The RCM stereochemical course (100% Z) is likely to reflect thermodynamic control. Molecular mechanics and semi-empirical calculations also show that the Z stereoisomers of these ten-membered carbocycles are consistently more stable than the E. The crucial role of the homoallylic and allylic substituents and of their protecting groups for the efficiency of the RCM reactions is discussed. In particular, we have found that p-methoxyphenyl (PMP) protected allylic alcohols, the products of a stereoselective oxyallylation, are compatible with the RCM reaction and give better yields than the corresponding free allylic alcohols. One of the simplified analogues of the natural product (44, lacking inter alia the C-4/C-7 ether bridge) retains potent microtubule-stabilizing activity. However, the cytotoxicity tests did not parallel the potent tubulin-assembling and microtubule-stabilizing properties: limited cytotoxicity was observed against three common tumor cell lines (human ovarian carcinoma, human colon carcinoma and human leukemia cell lines, IC₅₀ in the μM range), approximately two orders of magnitude less than paclitaxel (IC₅₀ in the nM range). The mechanism of cell cycle arrest induced by compound 44 is similar to that obtained with paclitaxel.     

Meson photoproduction on the nucleon with polarized photons

Meson photoproduction with polarized photons has proved to be a powerful tool to identify contributions of baryon resonances that are not evident in the differential cross-sections. It provides information that are complementary to those extracted using pion-nucleon scattering data. Extensive results have been produced in the past on beam asymmetries by the Graal collaboration for η and π ⁰ on the proton. New results are now available for the same reactions on the quasi-free neutron and for the K⁺ photoproduction on the proton. Contributions from hitherto undetected baryon resonances may be important to understand the results.     

Strong coupling limit of gφ4 theory: General formalism and applications

A method, independently proposed by Kaiser and by us, to study the strong coupling limit of the Green functions is described and discussed. Although its quantum mechanical version exhibits unusual features, an application to the anharmonic oscillator indicates that the method is able to reproduce correctly known numerical results. In spite of difficulties in the setting up of a renormalization program for the theory, a preliminary study of the CS β function for the gφ⁴ interaction shows that $\text{β(g}{}_{\mathrm{<mtext>r</mtext>}}$ is asymptotically linear in the renormalization coupling constant. Evidence is given for the compatibility of this behaviour with the information that can be drawn from the known perturbative expansion.     

Highly regioselective control of 1,2-addition of organolithiums to α,β-unsaturated compounds promoted by lithium bromide in 2-methyltetrahydrofuran: a facile and eco-friendly access to allylic alcohols and amines

Very high regioselective 1,2-addition of organolithiums to α,β-unsaturated carbonyl-like compounds (ketones, aldehydes, and imines) in the presence of LiBr was achieved by carrying out reactions in the sustainable solvent 2-methyltetrahydrofuran. Excellent yields (in isolated product) of allylic alcohols and allylic amines were recovered under a simple experimental procedure at 0 °C.     

Simultaneous photoproduction of eta and pi0 mesons on the proton

The analysis of the gammap-->etapi(0)p reaction has been performed using data from the GRAAL experiment. The total and differential cross sections and the beam asymmetry have been obtained from threshold up to 1.5 GeV of beam energy. The two resonances S11(1535) and Delta(1700) are expected to be excited in the intermediate states of this reaction. The results are used to test predictions based on the assumption that both resonances are dynamically generated from the meson-baryon interaction provided by chiral Lagrangians. The term involving the Delta(1700) excitation, followed by the decay into etaDelta(1232), is found to be dominant.     

Halogen-Imparted Reactivity in Lithium Carbenoid Mediated Homologations of Imine Surrogates: Direct Assembly of bis-Trifluoromethyl-β-Diketiminates and the Dual Role of LiCH2I

The selective formal insertion (homologation) of a carbon unit bridging the two trifluoroacetamidoyl chlorides (TFAICs) units is reported. The tactic is levered on a highly chemoselective homologation–metalation–acyl nucleophilic substitution sequence which precisely enables to assemble novel trifluoromethylated β-diketiminates within a single synthetic operation. Unlike previous homologations conducted with LiCH₂Cl furnishing aziridines, herein we exploit the unique capability of iodomethyllithium to act contemporaneously as a C1 source (homologating effect) and metalating agent. The mechanistic rationale grounded on experimental evidences supports the hypothesized proposal and, the structural analysis gathers key aspects of this class of valuable ligands in catalysis.     

A formal total synthesis of eleutherobin using the ring-closing metathesis (RCM) reaction of a densely functionalized diene as the key step: investigation of the unusual kinetically controlled RCM stereochemistry

Asymmetric oxyallylation reactions and ring-closing metathesis have been used to synthesize compound 3, a key advanced intermediate used in the total synthesis of eleutherobin reported by Danishefsky and co-workers. The aldehyde 6, which is readily prepared from commercially available R-(-)-carvone in six steps in 30 % overall yield on multigram quantities, was converted into the diene 5 utilizing two stereoselective titanium-mediated Hafner-Duthaler oxyallylation reactions. The reactions gave the desired products (8 and 12) in high yields (73 and 83 %, respectively) as single diastereoisomers, with the allylic alcohol already protected as the p-methoxyphenyl (PMP) ether, which previous work has demonstrated actually aids ring-closing metathesis compared to other protective groups and the corresponding free alcohol. Cyclization under forcing conditions, using Grubbs' second-generation catalyst 13, gave the ten-membered carbocycle (E)-14 in 64 % yield. This result is in sharp contrast to similar, but less functionalized, dienes, which have all undergone cyclization to give the Z stereoisomers exclusively. A detailed investigation of this unusual cyclization stereochemistry by computational methods has shown that the E isomer of the ten-membered carbocycle is indeed less thermodynamically stable than the corresponding Z isomer. In fact, the selectivity is believed to be due to the dense functionality around the ruthenacyclobutane intermediate that favors the trans-ruthenacycle, which ultimately leads to the less stable E isomer of the ten-membered carbocycle under kinetic control. During the final synthetic manipulations the double bond of enedione (E)-16 isomerized to the more thermodynamically stable enedione (Z)-4, giving access to the advanced key-intermediate 3, which was spectroscopically and analytically identical to the data reported by Danishefsky and co-workers, and thereby completing the formal synthesis of eleutherobin.