Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors hold great potential as disease modifying anti-Alzheimer's drugs. This digest provides an overview of the amidine containing class of BACE1 inhibitors, of which multiple examples are now progressing through clinical trials. The various structural modifications highlight the struggle to combine potency with the optimal properties for a brain penetrant BACE1 inhibitor, and illustrate the crowded competitive landscape. This overview concludes with a summary of potential issues including substrate and target selectivity and a synopsis of the status of the current and past clinical assets.

All you need is an open vial! The direct α arylation of cyclic alkylamines (see scheme) requires an open vial, as the hydrogen atom involved in the C(sp3)H‐activation process is ultimately released as hydrogen gas. Reports on the formation of hydrogen gas in direct transition‐metal‐catalyzed functionalizations are still rare. Open‐vial reactions proved crucial to this direct arylation procedure as, upon sealing, catalyst deactivation occurs.

1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.

Although a plethora of highly selective and reliable methods for the construction of C-C bonds are known to organic chemists, there is growing interest in the development of new protocols that offer different or orthogonal reactivity to that of existing methods. In 2000, Liebeskind and Srogl described a mechanistically unprecedented transition-metal-catalyzed cross-coupling of thioesters with boronic acids to produce ketones under neutral conditions. This desulfitative cross-coupling process is catalytic in palladium(0), stoichiometric in copper(I), and applicable to a range of organosulfur derivatives and nucleophilic organometallic reagents. In this Minireview, we highlight recent applications of this intriguing cross-coupling reaction in modern organic synthesis, with an emphasis on cases in which traditional methods for C-C bond formation have failed.

Human kinesin Eg5, which plays an essential role in mitosis by establishing the bipolar spindle, has proven to be an interesting drug target for the development of cancer chemotherapeutics. Here, we report the crystal structures of the Eg5 motor domain complexed with enastron, dimethylenastron, and fluorastrol. By comparing these structures to that of monastrol and mon-97, we identified the main reasons for increased potency of these new inhibitors, namely the better fit of the ligand to the allosteric binding site and the addition of fluorine atoms. We also noticed preferential binding of the S-enantiomer of enastron and dimethylenastron to Eg5, while the R-enantiomer of fluorastrol binds preferentially to Eg5. In addition, we performed a multidrug resistance (MDR) study in cell lines overexpressing P-glycoprotein (Pgp). We showed that one of these inhibitors may have the potential to overcome susceptibility to this efflux pump and hence overcome common resistance associated with tubulin-targeting drugs.

Highly fluorescent and stable 6,7-dimethoxy-2-oxoquinoline-4-carbonitriles (11) were synthesized starting from appropriate 4-hydroxyquinolones 3 via reactive 4-chloroquinolones 8 by using toluenesulfinates as catalysts. In contrast to the well-described 4-trifluoromethyl-substituted analogues 18, N-substituted derivatives 11 fluoresce in water, polar, and apolar solvents in a narrow 430-440-nm window with almost constant quantum yield of 0.5. Equal excitation is possible in the broad double maximum between 385 and 410 nm yield-

Über Schwefel zum Erfolg: Die Kreuzkupplung von organischen Schwefelverbindungen mit Boronsäuren unter neutralen Bedingungen in Gegenwart eines Palladium(0)‐Katalysators und einer stöchiometrischen Menge eines Kupfer(I)‐Cofaktors hat sich als wertvolle C‐C‐Verknüpfungsmethode etabliert (siehe Schema). Diese basenfreie Kupplung verläuft nach einem beispiellosen Mechanismus und hat deutliche Vorteile, wenn andere Pd0‐katalysierte Verfahren versagen. Um die Fülle an bereits bekannten hoch selektiven und zuverlässigen Methoden zur C‐C‐Bindungsknüpfung zu ergänzen, besteht ein wachsendes Interesse an der Entwicklung neuer Verfahren mit einer veränderten oder orthogonalen Reaktivität. Liebeskind und Srogl beschrieben 2000 eine übergangsmetallkatalysierte Kreuzkupplung von Thioestern mit Boronsäuren zur Synthese von Ketonen unter neutralen Bedingungen. Diese desulfurierende Kreuzkupplung verläuft unter Palladium(0)‐Katalyse mit stöchiometrischem Kupfer(I)‐Zusatz, folgt einem beispiellosen Mechanismus und ist auf eine Reihe von Organoschwefelderivaten und nucleophilen Organometallreagentien anwendbar. Hier betrachten wir neuere Anwendungen dieser faszinierenden Reaktion in der organischen Synthese. Besondere Berücksichtigung finden Fälle, bei denen herkömmliche Methoden der C‐C‐Bindungsbildung versagt haben.

An efficient two-step synthetic pathway toward the preparation of diversely substituted 5-aroyl-3,4-dihydropyrimidin-2-ones is realized. The protocol involves an initial trimethylsilyl chloride-mediated Biginelli multicomponent reaction involving S-ethyl acetothioacetate, aromatic aldehydes, and ureas as building blocks to generate a set of 3,4-dihydropyrimidine-5-carboxylic acid thiol esters. These thiol esters serve as starting materials for a subsequent Pd-catalyzed Cu-mediated Liebeskind-Srogl cross-coupling reaction with boronic acids to provide the desired 5-aroyl-3,4-dihydropyrimidin-2-one derivatives. Both steps were performed using microwave heating in sealed vessels, either in an automated sequential or parallel format using dedicated microwave reactor instrumentation. A diverse library of 30 5-aroyl-3,4-dihydropyrimidin-2-ones was prepared with commercially available aldehyde, urea, and boronic acid building blocks as starting materials.