Enantioselective Ir-Catalyzed Hydrogenation of Terminal Homoallyl Sulfones: Total Synthesis of (-)-Curcumene.

A novel methodology for the preparation of chiral methyl benzylic compounds is reported. Terminal homoallyl sulfones were prepared from homoallyl alcohols, which are easily accessible through the recently reported Lewis acid isomerization of oxetanes. The iridium-catalyzed asymmetric hydrogenation of homoallylic sulfones afforded γ-chiral sulfones with excellent enantioselectivities (up to 98% ee). The synthetic potential of this novel methodology was demonstrated by the total synthesis of (R)-(-)-curcumene.

Amino acids with fluorescent tetrazine ethers as bioorthogonal handles for peptide modification.

A set of 3-bromo-1,2,4,5-tetrazines with three distinct substitutions have been used as reagents for late-stage functionalization of small molecules through nucleophilic aromatic substitution. Spectroscopic studies of the products obtained proved that tetrazine ethers are intrinsically fluorescent. This fluorescence is lost upon inverse Electron-Demand Diels-Alder (iEDDA) cycloaddition with strained alkenes. Tetrazine-phenol ethers are rather interesting because they can undergo rapid iEDDA reactions with a second order rate constant (k 2) compatible with bioorthogonal ligations. As a showcase, l-tyrosine was derivatized with 3-bromo-6-methyl-1,2,4,5-tetrazine and coupled to the peptide drug octreotide. This peptide was detected in cellular flow cytometry, and its fluorescence turned off through a bioorthogonal iEDDA cycloaddition with a strained alkene, showing for the first time the detection and reactivity of intrinsically fluorescent tetrazines in a biologically relevant context. The synthesis and characterization of fluorescent tetrazine ethers with bioorthogonal applicability pave the way for the generation of useful compounds for both detection and bioconjugation in vivo.

Direct and Enantioselective Aldol Reactions Catalyzed by Chiral Nickel(II) Complexes.

A direct and asymmetric aldol reaction of N-acyl thiazinanethiones with aromatic aldehydes catalyzed by chiral nickel(II) complexes is reported. The reaction gives the corresponding O-TIPS-protected anti-aldol adducts in high yields and with remarkable stereocontrol and atom economy. Furthermore, the straightforward removal of the achiral scaffold provides enantiomerically pure intermediates of synthetic interest, which involve precursors for anti-α-amino-ß-hydroxy and α,ß-dihydroxy carboxylic derivatives. Theoretical calculations explain the observed high stereocontrol.

Synthesis and Application of 3-Bromo-1,2,4,5-Tetrazine for Protein Labeling to Trigger Click-to-Release Biorthogonal Reactions.

3-Bromo-1,2,4,5-tetrazine has been synthesized in an oxidant- and metal-free method. The synthesis is scalable and relies on inexpensive starting materials. 3-Bromo-1,2,4,5-tetrazine can undergo nucleophilic aromatic substitutions with differently substituted heteroatoms under mild conditions. In particular, its excellent reactivity has been used to attain chemoselective protein labeling. The resulting labeled lysines can react with strained dienophiles to trigger fast click-to-release (CtR) biorthogonal reactions. The characterization of the CtR reaction in physiological conditions and a therapeutically relevant example with the monoclonal antibody Trastuzumab to showcase its application is presented. Finally, 3-bromo-1,2,4,5-tetrazine has been used to achieve site-selective protein labeling through the genetic incorporation of the first unnatural amino acid bearing an unsubstituted 1,2,4,5-tetrazin-3-yl functionality, which can also undergo CtR reactions.

Assisted attenuation of a soil contaminated by diuron using hydroxypropyl-ß-cyclodextrin and organic amendments.

Diuron desorption and mineralisation were studied on an amended and artificially contaminated soil. The amendments used comprised two different composted organic residues i.e., sewage sludge (SS) mixed with pruning wastes, and urban solid residues (USR), and two different solutions (with inorganic salts as the micronutrients and hydroxypropyl-ß-cyclodextrin (HPBCD)). After applying micronutrients to activate the soil flora, 15.5% mineralisation could be reached after 150 days, indicating that the soil has a potential capacity to mineralise the herbicide through biostimulation-assisted attenuation. Diuron mineralisation was also improved when HPBCD solutions were applied. Indeed, the extent of herbicide mineralisation reached 29.7% with this application. Moreover, both the lag phase and the half-life time (DT50) were reduced to 33 and 1,778 days, respectively, relative to the application of just micronutrients (i.e., 39 and 6297 days, respectively). Organic amendments were also applied (i.e., USR and SS) on the contaminated soil: it was found that the diuron mineralisation rate was improved as the amendment concentration increased. The joint application of all treatments investigated at the best conditions tested was conducted to obtain the best diuron mineralisation results. The micronutrient amendment plus 4% USR or SS amendment plus HPBCD solution (10-fold diuron initially spiked) caused an extent of diuron mineralisation 33.2 or 46.5%, respectively.

Enhanced mineralization of diuron using a cyclodextrin-based bioremediation technology.

The phenylurea herbicide diuron [N-(3,4-dichlorophenyl)-N,N-dimethylurea] is widely used in a broad range of herbicide formulations and, consequently, it is frequently detected as a major soil and water contaminant in areas where there is extensive use. Diuron has the unfortunate combination of being strongly adsorbed by soil organic matter particles and, hence, slowly degraded in the environment due to its reduced bioavailability. N-Phenylurea herbicides seem to be biodegraded in soil, but it must be kept in mind that this biotic or abiotic degradation could lead to accumulation of very toxic derived compounds, such as 3,4-dichloroaniline. Research was conducted to find procedures that might result in an increase in the bioavailability of diuron in contaminated soils, through solubility enhancement. For this purpose a double system composed of hydroxypropyl-ß-cyclodextrin (HPBCD), which is capable of forming inclusion complexes in solution, and a two-member bacterial consortium formed by the diuron-degrading Arthrobacter sulfonivorans (Arthrobacter sp. N2) and the linuron-degrading Variovorax soli (Variovorax sp. SRS16) was used. This consortium can achieve a complete biodegradation of diuron to CO2 with regard to that observed in the absence of the CD solution, where only a 45% biodegradation was observed. The cyclodextrin-based bioremediation technology here described shows for the first time an almost complete mineralization of diuron in a soil system, in contrast to previous incomplete mineralization based on single or consortium bacterial degradation.