New chiral phosphine-phosphite ligands in the enantioselective palladium-catalyzed allylic alkylation

A series of chiral phosphine-phosphite ligands 1-6 have been synthesized and used in the enantioselective palladium-catalyzed reaction of rac-1,3-diphenyl-2-propenyl acetate with dimethyl malonate as nucleophile. Ligands 1a, 2, 3, 5a, 6a, and 6b have been synthesized starting from racemic tert-butylphenylphosphinoborane. The use of dynamically resolved Li phosphide (-)-sparteine provided the optically pure ligands. Crystals of the allylpalladium (6a) complex were obtained, suitable for X-ray crystal structure determination. The X-ray crystal structure of the allylpalladium (6a) complex revealed a longer palladium-carbon bond distance trans to the phosphine moiety indicating that the attack of the nucleophile takes place at the carbon trans to the phosphine moiety. This was confirmed by the fact that the phosphine moiety did not affect the enantioselectivity directly. Under mild reaction conditions, enantioselectivities up to 83% were obtained (25 degrees C) with ligand 1e. Systematic variation of the ligand bridge and the phosphite moiety showed that the configuration of the product is controlled by the atropisomerism of the biphenyl substituent at the phosphite moiety. The conformation of the biphenyl group, in turn, is controlled by the substituent at the chiral carbon in the bridge. Ligands with large bite angles yielded higher enantioselectivities.     

Aminosulf(ox)ides as ligands for Iridium(I)-catalyzed asymmetric transfer hydrogenation

A new class of efficient catalysts was developed for the asymmetric transfer hydrogenation of unsymmetrical ketones. A series of chiral N,S-chelates (6-22) was synthesized to serve as ligands in the iridium(I)-catalyzed reduction of ketones. Both formic acid and 2-propanol proved to be suitable as hydrogen donors. Sulfoxidation of an (R)-cysteine-based aminosulfide provided a diastereomeric ligand family containing a chiral sulfur atom. The two chiral centers of these ligands showed a clear effect of chiral cooperativity. In addition, aminosulfides containing two asymmetric carbon atoms in the backbone were synthesized. Both the sulfoxide-containing beta-amino alcohols and the aminosulfides derived from 1,2-disubstituted amino alcohols gave rise to high reaction rates and moderate to excellent enantioselectivities in the reduction of various ketones. The enantioselective outcome of the reaction was favorably affected by selecting the most appropriate hydrogen donor. Enantioselectivities of up to 97% were reached in the reduction of aryl-alkyl ketones.     

An improved synthesis of haloacetamidine-based inactivators of protein arginine deiminase 4 (PAD4)

Protein arginine deiminase 4 (PAD4) is an enzyme that hydrolyzes peptidyl arginine residues to form citrulline and ammonia. This enzyme has been implicated in several disease states, for example, rheumatoid arthritis, and therefore represents a unique target for the development of a novel therapeutic. A solution-phase synthesis of Cl-amidine, the most potent PAD4 inactivator described to date, has been developed. This synthesis proceeds in 80% yield over four steps at a significantly (12-fold) lower cost.     

A note on the relationship between the Szlenk and $$w^*$$-dentability indices of arbitrary $$w^*$$-compact sets

We prove the optimal estimate between the Szlenk and \(w^*\)-dentability indices of an arbitrary \(w^*\)-compact subset of the dual of a Banach space. For a given \(w^*\)-compact, convex subset K of the dual of a Banach space, we introduce a two player game the winning strategies of which determine the Szlenk index of K. We give applications to the \(w^*\)-dentability index of a Banach space and of an operator.     

Technical considerations for the use of 15N-DNA stable-isotope probing for functional microbial activity in soils

Stable-isotope DNA probing is a culture-independent technique that may provide a link between function and phylogeny of active microorganisms. The technique has been used in association with 13C substrates while here we evaluate feasibility and limitations of 15N-DNA stable-isotope probing (SIP) using labelled and unlabelled pure microbial cultures or soil extracts. Our results showed that (15)N-DNA probing is feasible for cultures as well as soil samples. Limitations of 15N-DNA-SIP are (a) the need for relatively large quantities of DNA to visualise bands (although molecular resolution is much higher) and (b) 15N-DNA enrichment needed to ideally be >50 at%; however, this requirement can be lowered to approx. 40 atom% 15N with pure cultures using a modified CsCl centrifugation method (140K g for 69 h). These advances in 15N-DNA-SIP methodology open new opportunities to trace active microbial populations utilising specific N substrates in situ.     

On the univalence of functions defined by certain integral transforms

The integral transform $\text{F(z) = ∝}{}_0{}^{\mathrm{z}}\text{(f′(t))}{}^{\mathrm{\alpha }}\text{(}\text{g(t)}\text{t}\text{)}{}^{\mathrm{\beta }}\text{dt}$, where α and β are real, of pairs of special analytic functions f(z) = z + ···, g(z) = z + ···, univalent in the open unit disc Δ is studied. The transform and our results extend some recent results due to Shirakova.     

Synthesis and Evaluation of a Macrocyclic Actinium-225 Chelator,Quality Control and In Vivo Evaluation of 225Ac-crown-αMSH Peptide

Targeted alpha-therapy (TAT) has great potential for treating a broad range of late-stage cancers by delivering a focused and lethal radiation dose to tumors. Actinium-225 (²²⁵Ac) is an emerging alpha emitter suitable for TAT; however, the availability of chelators for Ac remains limited to a small number of examples (DOTA and macropa). Herein, we report a new Ac macrocyclic chelator named ‘ crown’ , which binds quantitatively and rapidly (<10 min) to Ac at ambient temperature. We synthesized ²²⁵Ac- crown -αMSH, a peptide targeting the melanocortin 1 receptor (MC1R), specifically expressed in primary and metastatic melanoma. Biodistribution of ²²⁵Ac- crown -αMSH showed favorable tumor-to-background ratios at 2 h post injection in a preclinical model. In addition, we demonstrated dramatically different biodistrubution patterns of ²²⁵Ac- crown -αMSH when subjected to different latency times before injection. A combined quality control methodology involving HPLC, gamma spectroscopy and radioTLC is recommended.