Phosphorothioate nucleotides have emerged as powerful pharmacological substitutes of their native phosphodiester analogs with important translational applications in antisense oligonucleotide (ASO) therapeutics and cyclic dinucleotide (CDN) synthesis. Stereocontrolled installation of this chiral motif has long been hampered by the systemic use of phosphorus(III) [P(III)]-based reagent systems as the sole practical means of oligonucleotide assembly. A fundamentally different approach is described herein: the invention of a P(V)-based reagent platform for programmable, traceless, diastereoselective phosphorus-sulfur incorporation. The power of this reagent system is demonstrated through the robust and stereocontrolled synthesis of various nucleotidic architectures, including ASOs and CDNs, via an efficient, inexpensive, and operationally simple protocol.

Abstract. In this paper, we address issues related to flow correlation attacks and the corresponding countermeasures in mix networks. Mixes have been used in many anonymous communication systems and are supposed to provide countermeasures that can defeat various traffic analysis attacks. In this paper, we focus on a particular class of traffic analysis attack, flow correlation attacks, by which an adversary attempts to analyze the network traffic and correlate the traffic of a flow over an input link at a mix with that over an output link of the same mix. Two classes of correlation methods are considered, namely time-domain methods and frequency-domain methods. Based on our threat model and known strategies in existing mix networks, we perform extensive experiments to analyze the performance of mixes. We find that a mix with any known batching strategy may fail against flow correlation attacks in the sense that for a given flow over an input link, the adversary can correctly determine which output link is used by the same flow. We also investigated methods that can effectively counter the flow correlation attack and other timing attacks. The empirical results provided in this paper give an indication to designers of Mix networks about appropriate configurations and alternative mechanisms to be used to counter flow correlation attacks.

Acidities of iridium hydride intermediates were shown to be critical in some transformations mediated by the chiral analogues of Crabtree's catalyst, 1-3. To do this, several experiments were undertaken to investigate the acidities of hydrogenation mixtures formed using these iridium-oxazoline complexes. DFT calculations indicated that the acidity difference for Ir-H intermediates in these hydrogenations were astounding; iridium hydride from the N-heterocyclic carbene catalyst 1 was calculated to be around seven pK(a) units less acidic than those from the P-based complexes 2 and 3. Consistent with this, the carbene complex 1 was shown to be more effective for hydrogenations of acid-sensitive substrates. In deuteration experiments, less "abnormal" deuteration was observed, corresponding to fewer complications from acid-mediated alkene isomerization preceding the D(2)-addition step. Finally, simple tests with pH indicators provided visual evidence that phosphine-based catalyst precursors give significantly more acidic reaction mixtures than the corresponding N-heterocyclic carbene ones. These observations indicate carbene-for-phosphine (and similar) ligand substitutions may impact the outcome of catalytic reactions by modifying the acidities of the metal hydrides formed.

A recent proposal of data dependent similarity called Isolation Kernel/Similarity has enabled SVM to produce better classification accuracy. We identify shortcomings of using a tree method to implement Isolation Similarity; and propose a nearest neighbour method instead. We formally prove the characteristic of Isolation Similarity with the use of the proposed method. The impact of Isolation Similarity on densitybased clustering is studied here. We show for the first time that the clustering performance of the classic density-based clustering algorithm DBSCAN can be significantly uplifted to surpass that of the recent density-peak clustering algorithm DP. This is achieved by simply replacing the distance measure with the proposed nearest-neighbour-induced Isolation Similarity in DBSCAN, leaving the rest of the procedure unchanged. A new type of clusters called mass-connected clusters is formally defined. We show that DBSCAN, which detects density-connected clusters, becomes one which detects mass-connected clusters, when the distance measure is replaced with the proposed similarity. We also provide the condition under which mass-connected clusters can be detected, while density-connected clusters cannot.

Asymmetric hydrogenations of monoenes and dienes were performed to obtain terminal deoxypolyketide fragments A and the corresponding internal chirons B and C. The chiral N-heterocyclic carbene catalyst 1 was used throughout. Modest selectivities for hydrogenations of simple monoenes relayed into high selectivities for preparations of the terminal deoxypolyketide fragments in which either two hydrogenations or one and an optically pure starting material were used. Curiously, the face selectivities for hydrogenation of alpha,beta-unsaturated esters were consistently opposite to those that had been observed for styrene and stilbene derivatives in previous work, and to closely related allylic alcohol and ether derivatives in this work. Plausible mechanisms for this differing behavior were deduced by using DFT calculations. It appears that the origin of the unusual stereoselectivity for the ester derivatives is transient metal-coordination of the ester carbonyl whereas there is no evidence that the allylic alcohol or ethers coordinate. The routes developed to alpha,omega-functionalized internal deoxypolyketide fragments are extremely practical. These begin with the Roche ester being converted into alkene and, in one case, diene derivatives. Catalyst control prevails in the hydrogenations of these substrates, but there is a significant "substrate vector" (a term we used to describe the influence of the substrate on a catalyst-controlled reaction). This is determined by minimization of 1,3-allylic strain and, in some cases, syn pentane interactions. This substrate vector can be constructively paired with the (dominant) catalyst vector by use of the appropriate enantiomer of 1. In the hydrogenation of a diene derivative, two chiral centers could be formed simultaneously with overall 11:1.0 selectivity; this is the first time this has been achieved in any asymmetric synthesis of a deoxypolyketide fragment. Throughout, diastereoselectivities of the crude material in the syntheses of alpha,omega-functionalized internal deoxypolyketide fragments were in excess of 11:1.0 and chromatographically purified samples could be isolated in high yields with dr (dr=diastereomeric ratio) values consistently in excess of 40:1.0.