Stereoselective Total Synthesis of Eburnane‐Type Alkaloids Enabled by Conformation‐Directed Cyclization and Rearrangement

Controlling the cis C20/C21 relative stereochemistry remains an unsolved issue in the synthesis of eburnane‐type indole alkaloids. Provided herein is a simple solution to this problem by developing a unified and diastereoselective synthesis of four representative members of this class of natural products, namely, eburnamonine, larutensine, terengganensine B, and melokhanine E. The synthesis features the following key steps: a) an α‐iminol rearrangement transforming the 3‐hydroxyindolenine into spiroindolin‐3‐one, b) a highly diastereoselective conformation‐directed cyclization leading to the melokhanine skeleton with the desired C20/C21 cis stereochemistry, and c) either an aza‐pinacol or an unprecedented α‐aminoketone rearrangement converting spiroindolinone back into the indole skeleton.     

Polar effects. Part 12. Inductivity and carbon participation in the solvolysis of 4-substituted 2-adamantyl arenesulfonates

The rate constants (log k) for the solvolysis of 4^e-substituted 2^e- and 2^a-adamantyl p-nitrobenzenesulfonates 14 and 15 , respectively, in 80% EtOH correlate linearly with the respective inductive substituent constants σ. Therefore, relative rates are controlled by the I effect of the substituents at C(4). The derived reaction constants, or inductivities, ρ_I of −0.80 and −0.64 for the series 14 and 15 , respectively, are far smaller than those previously determined for 6-substituted 2-norbornyl and 2-bicyclo[2.2.2]octyl sulfonates, in which the partial structure containing the substituent and the leaving group is the same. The ratio of the retained and inverted adamantanols obtained upon hydrolysis of the series 14 falls from 2.85 for R = CH₃ to ca. 1 for R = CN, i.e. as the substituent at C(4) becomes more electron-attracting. In the 2^a-series 15 this ratio is uniformly higher. These findings confirm that the 2-adamantyl cation is weakly bridged and that through-space induction in carbocations involves graded bridging of the cationic center by neighboring C-atoms.     

Cyclodextrins Initiated Ring-Opening Polymerization of Lactide Using 4-Dimethylaminopyridine (DMAP) as Catalyst: Study of DMAP/β-CD Inclusion Complex and Access to New Structures

Cyclodextrins (CDs) are cyclic oligosaccharides used in many fields. Grafting polymers onto CDs enables new structures and applications to be obtained. Polylactide (PLA) is a biobased, biocompatible aliphatic polyester that can be grafted onto CDs by -OH-initiated ring-opening polymerization. Using 4-dimethylaminopyridine (DMAP) as an organocatalyst, a quantitative functionalization is reached on native α-, β-, γ- and 2,3-dimethyl- β-cyclodextrins. Narrow molecular weight distributions are obtained with the native CDs (dispersity < 1.1). The DMAP/β-CD combination is used as a case study, and the formation of an inclusion complex (1/1) is shown for the first time in the literature, which is fully characterized by NMR. The inclusion of DMAP into the cavity occurs via the secondary rim of the β-CD and the association constant (K_a) is estimated to be 88.2 M⁻¹. Its use as an initiator for ring-opening polymerization leads to a partial functionalization efficiency, and thus a more hydrophilic β-CD-PLA conjugate than that obtained starting from native β-CD. Polymerization results including also the use of the adamantane/β-CD inclusion complex as an initiator suggest that inclusion of the DMAP catalyst into the CD may not occur during polymerization reactions. Rac-lactide does not form an inclusion complex with β-CD.     

Potential DNA bis-intercalating agents. Bridged bis-(6-chloropurines) and related compounds

Two bis-(6-chloropurines) bridged by conformationally restricted tethers were synthesized as potential DNA bis-intercalating agents. Reduction of 4,6-dichloro-5-nitropyrimidine ( 1 ) afforded 5-amino-4,6-dichloropyrimidine ( 2 ) which was then used as the starting material. Reaction of 2 with 4,4′-diaminodiphenylmethane ( 3 ) and bis-(4-aminophenyl) ether ( 4 ) yielded bis-[4-(N-5-amino-4-chloro-6-pyrimidyl)aminophenyl]methane ( 5 ) and bis-[4-(N-5-amino-4-chloro-6-pyrimidyl)aminophenyl] ether ( 6 ), respectively. Acid-catalyzed condensation of the above pyrimidines, 5 and 6 , with triethyl orthoformate in N,N-dimethylacetamide gave bis-[4-(6-chloro-9-purinyl)phenyl]methane ( 7 ) and bis-[4-(6-chloro-9-purinyl)phenyl] ether ( 8 ). The spectral data on the new compounds will be discussed.     

Phenyl Silicates with Substituted Catecholate Ligands: Synthesis,Structural Studies and Reactivity

While the generation of aryl radicals by photoredox catalysis under reductive conditions is well documented, it has remained challenging under an oxidative pathway. Because of the easy photo-oxidation of alkyl bis-catecholato silicates, a general study of phenyl silicates bearing substituted catecholate ligands has been achieved. The newly synthesized phenyl silicates have been fully characterized, and their reactivity has been explored. It was found that, thanks to the substitution of the catecholate moiety, notably with the 4-cyanocatecholato ligand, the phenyl radical could be generated and trapped. Computational studies provided a rationale for these findings.     

Design,Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents

Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of Asclepiadaceas. They are characterized by interesting biological activities, such as pronounced cytotoxicity against different human cancerous cell lines, including multidrug-resistant examples. Nonetheless, these derivatives are associated with severe neurotoxicity and loss of in vivo activity due to the highly lipophilic nature of the alkaloids. Here, we describe the development of highly polar prodrugs of antofine and tylophorine as hypoxia-targeted prodrugs. The developed quaternary ammonium salts of phenanthroindolizidines showed high chemical and metabolic stability and are predicted to have no penetration through the blood–brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions.     

A Subthreshold PMOS Analog Cortex Decoder for the (8, 4, 4) Hamming Code

This paper presents a method for decoding high minimal distance (d_min) short codes, termed Cortex codes. These codes are systematic block codes of rate 1/2 and can have higher d_min than turbo codes. Despite this characteristic, these codes have been impossible to decode with good performance because, to reach high d_min, several encoding stages are connected through interleavers. This generates a large number of hidden variables and increases the complexity of the scheduling and initialization. However, the structure of the encoder is well suited for analog decoding. A proof‐of‐concept Cortex decoder for the (8, 4, 4) Hamming code is implemented in subthreshold 0.25‐μm CMOS. It outperforms an equivalent LDPC‐like decoder by 1 dB at BER=10^?5 and is 44 percent smaller and consumes 28 percent less energy per decoded bit.     

Supercycled SW(f)-TPPM sequence for heteronuclear dipolar decoupling in solid-state nuclear magnetic resonance

The performance of a supercycled SW(f)-TPPM sequence for heteronuclear dipolar decoupling in solid-state NMR is analyzed here. The decoupling performance of this sequence with respect to experimental parameters, such as, the phase angle, proton offset and MAS frequency is studied. A comparison is made with two other commonly used decoupling schemes in solid-state NMR namely, SPINAL-64 and SW(f)-TPPM, on a sample of U-13C-labeled tyrosine. Our results show that supercycled SW(f)-TPPM performs better than the former sequences. Also, numerical spin dynamics studies are presented which support the experimentally observed efficiency in the decoupling.     

A tele-operated mobile ultrasound scanner using a light-weight robot.

This paper presents a new tele-operated robotic chain for real-time ultrasound image acquisition and medical diagnosis. This system has been developed in the frame of the Mobile Tele-Echography Using an Ultralight Robot European Project. A light-weight six degrees-of-freedom serial robot, with a remote center of motion, has been specially designed for this application. It holds and moves a real probe on a distant patient according to the expert gesture and permits an image acquisition using a standard ultrasound device. The combination of mechanical structure choice for the robot and dedicated control law, particularly nearby the singular configuration allows a good path following and a robotized gesture accuracy. The choice of compression techniques for image transmission enables a compromise between flow and quality. These combined approaches, for robotics and image processing, enable the medical specialist to better control the remote ultrasound probe holder system and to receive stable and good quality ultrasound images to make a diagnosis via any type of communication link from terrestrial to satellite. Clinical tests have been performed since April 2003. They used both satellite or Integrated Services Digital Network lines with a theoretical bandwidth of 384 Kb/s. They showed the tele-echography system helped to identify 66% of lesions and 83% of symptomatic pathologies.