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.     

Electrophilic Vinylation of Thiols under Mild and Transition Metal‐Free Conditions

The iodine(III) reagents vinylbenziodoxolones (VBX) were employed to vinylate a series of aliphatic and aromatic thiols, providing E‐alkenyl sulfides with complete chemo‐ and regioselectivity, as well as excellent stereoselectivity. The methodology displays high functional group tolerance and proceeds under mild and transition metal‐free conditions without the need for excess substrate or reagents. Mercaptothiazoles could be vinylated under modified conditions, resulting in opposite stereoselectivity compared to previous reactions with vinyliodonium salts. Novel VBX reagents with substituted benziodoxolone cores were prepared, and improved reactivity was discovered with a dimethyl‐substituted core.     

Multinuclear NMR spectra and GIAO/DFT calculations of N-benzylazoles and N-benzylbenzazoles

The ¹H, ¹³C, and ¹⁵N chemical shifts of almost the whole series of N-benzyl azoles and benzazoles, with the exception of the unknown 1-benzyl-1H-pentazole (10) and the very unstable 2-benzyl-2H-isoindole (12), have been measured. In addition, the X-ray crystal structure of 1-benzyl-1H-indazole (14) was solved (monoclinic, space group P2₁/n), its geometry being very close to that used for the calculations. The absolute chemical shieldings were calculated at the gauge-independent atomic orbital (GIAO)/Becke, 3-parameter, Lee-Yang-Parr (B3LYP)/6-311++G(d,p) level and then transformed with very robust empirical equations into chemical shifts of the three nuclei showing an excellent agreement with the 313 experimental values.

     

Polarization observable measurements for γp → K+Λ and γp → K+Σfor energies up to 1.5 GeV

Beam asymmetries and hyperon recoil polarizations for the reactions γp → K ⁺Λ and γp → K ⁺Σ⁰ have been measured from the threshold production to 1500MeV with the GRAAL facility located at the ESRF in Grenoble. These results complement the database for the beam asymmetry, covering for the first time the production threshold region. Recent theoretical analyses are presented for which the beam asymmetry data bring interesting new information and allow to better determine some resonance parameters. Most importantly, these results strengthen the need of a new D₁₃ state around 1900MeV.     

Measurement of πphotoproduction on the proton from 550 to 1500 MeV at GRAAL

Neutral pion photoproduction has been measured from 550 to 1500 MeV with the GRAAL facility, located at the ESRF in Grenoble. Differential cross-section and beam asymmetry have been measured over a wide angular range. These high-precision data improve significantly the database for the beam asymmetry in the second and third resonance regions covering for the first time the energy domain 1100-1500 MeV. New partial-wave analyses including these data are presented for which the beam asymmetry brings crucial constraints.     

Experimental and theoretical studies on glucose hydrogenation to produce sorbitol

Quantum chemical calculations were performed to obtain information on the molecular properties of relevant species involved in catalytic glucose hydrogenation for the production of sorbitol.