Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT).

Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the Trypanosoma genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound 7 that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an in silico model to predict the brain-to-plasma partition coefficient Kp as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios (Kp,uu) to cure a CNS disease such as HAT.

Ruthenium-Catalyzed Multicomponent Reactions: Access to α-Silyl-ß-Hydroxy Vinylsilanes, Stereodefined 1,3-Dienes, and Cyclohexenes.

The synthesis of densly functionized α-silyl-ß-hydroxyl vinylsilanes via ruthenium-catalyzed multicomponent reaction (MCR) is reported herein. Exceptionally high regio- and diastereoselectivity was achieved by employing an unprecedented hydrosilylation of bifunctional silyl-propargyl boronates. The simple protocol, mild reaction conditions, and unique tolerability of this method make it a valuable tool for the synthesis of highly elaborated building blocks. The one-pot synthesis of stereodefined olefins, the generation of a valuable cyclohexene building block through a four-component MCR, and further functionalization in an abundance of diastereoselective reactions is disclosed herein.

Stereocontrolled Synthesis of Vinyl Boronates and Vinyl Silanes via Atom-Economical Ruthenium-Catalyzed Alkene-Alkyne Coupling.

The synthesis of vinyl boronates and vinyl silanes was achieved by employing a Ru-catalyzed alkene-alkyne coupling reaction of allyl boronates or allyl silanes with various alkynes. The double bond geometry in the generated vinyl boronates can be remotely controlled by the juxtaposing boron- and silicon groups on the alkyne substrate. The synthetic utility of the coupling products has been demonstrated in a variety of synthetic transformations, including iterative cross-coupling reactions, and a Chan-Lam-type allyloxylation followed by a Claisen rearrangement. A sequential one-pot alkene-alkyne-coupling/allylation-sequence with an aldehyde to deliver a highly complex α-silyl-ß-hydroxy olefin with a handle for further functionalization was also realized.

Development of Non-C2-symmetric ProPhenol Ligands. The Asymmetric Vinylation of N-Boc Imines.

The development and application of a new generation of non-C2-symmetric ProPhenol ligands is reported herein. Rational design of the ProPhenol ligand paved the way to the first catalytic and asymmetric vinylation of N-Boc imines via hydrozirconation giving rise to valuable allylic amines in excellent yields and enantioselectivities. The utility of this method was demonstrated by developing the shortest reported asymmetric synthesis of the selective serotonine reuptake inhibitor (SSRI) (-)-dapoxetine.

Rh(III)-catalyzed intramolecular redox-neutral cyclization of alkenes via C-H activation.

Biologically interesting fused oligocyclic lactams have been prepared via an intramolecular redox-neutral cyclization process. By the proper choice of the substrates with a wide variety of tethered olefins, the less favored C-H bond can be activated and functionalized. This C-H activation proceeds under mild conditions, obviates the need for external oxidants, and displays a broad scope with respect to the substituents.

Rh(III)-catalyzed synthesis of multisubstituted isoquinoline and pyridine N-oxides from oximes and diazo compounds.

Multisubstituted isoquinoline and pyridine N-oxides have been prepared by Rh(III)-catalyzed cyclization of oximes and diazo compounds via aryl and vinylic C-H activation. This intermolecular annulation involving tandem C-H activation, cyclization, and condensation steps proceeds under mild conditions, obviates the need for oxidants, releases N2 and H2O as the byproducts, and displays a broad substituent scope.

Sonogashira-Hagihara reactions of halogenated glycals.

Herein, we report on our findings of the Sonogashira-Hagihara reaction with 1-iodinated and 2-brominated glycals using several aromatic and aliphatic alkynes. This Pd-catalyzed cross-coupling reaction presents a facile access to alkynyl C-glycosides and sets the stage for a reductive/oxidative refunctionalization of the enyne moiety to regenerate either C-glycosidic structures or pyran derivatives with a substituent in position 2.

Intramolecular oxycyanation of alkenes by cooperative Pd/BPh3 catalysis.

The cooperative catalysis by palladium and triphenylborane effects the intramolecular oxycyanation of alkenes through the cleavage of O-CN bonds and the subsequent insertion of double bonds. The use of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) as a ligand for palladium is essential for allowing the transformation to proceed with high chemo- and regioselectivity. Variously substituted dihydrobenzofurans with both a tetra-substituted carbon and cyano functionality are accessed by the newly developed methodology.

A Pd-catalyzed approach to (1-->6)-linked C-glycosides.

A flexible and robust method for the assembly of (1-->6)-linked C-glycosidic disaccharides is presented. The key reaction is a Pd-catalyzed coupling of 1-iodo- or 1-triflato-glycals with alkynyl glycosides. Reinstallation of the native hydroxyl group pattern is achieved after selective hydrogenation of the triple bond using Raney-nickel. Epoxidation with DMDO and reductive epoxide opening gives access to either the alpha- or the beta-derivative, depending on the hydride source.

Hybrids of sugars and aromatics: A Pd-catalyzed modular approach to chromans and isochromans.

Herein we describe the synthesis of highly substituted chromans and isochromans using carbohydrates as starting materials. The key step of our synthetic approach is the annelation of the benzene moiety via a highly efficient Pd-catalyzed domino reaction. This powerful approach led to a small library of highly substituted chromans and isochromans by making use of a variety of different diynes and bromoglycals. We investigated several Pd-catalysts in order to improve the yields and to enlarge the scope of the domino reaction. Furthermore, we elucidated the mechanistic picture of the reaction with isotope-labelling experiments. Most probably the reaction proceeds via an oxidative addition followed by two carbopalladation steps and a final cyclization reaction.

Domino access to highly substituted chromans and isochromans from carbohydrates.

Herein we describe the synthesis of highly substituted chromans and isochromans using carbohydrates as starting materials. Our approach makes use of a Pd-catalyzed domino reaction consisting of oxidative addition, followed by two carbopalladation steps and completed by a cyclization to annelate the benzene moiety. The versatility of this route has been demonstrated by a small library of highly substituted chromans and isochromans.