Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders.

Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based design approach, we identified a novel micromolar hit with attractive physicochemical properties.

Two Ligands Transfer from Ag to Pd: En Route to (SIPr)Pd(CFH)(X) and Its Application in One-Pot C-H Borylation/Difluoromethylation.

A process for the concurrent transfer of both the NHC ligand and the difluoromethyl group from [(SIPr)Ag(CFH)] to PdX (X = Cl, OAc, and OPiv) for the preparation of [(SIPr)Pd(CFH)X] complexes is described. These complexes were air-stable and easily underwent transmetalation with aryl pinacol boronate/reductive elimination to generate ArCFH in high yields. Based on this discovery, the first one-pot C-H borylation and difluoromethylation process for the preparation of difluoromethylated (hetero)arenes was developed.

Studying regioisomer formation in the Pd-catalyzed fluorination of aryl triflates by deuterium labeling.

Isotopic labeling has been used to determine that a portion of the desired product in the Pd-catalyzed fluorination of electron-rich, non-ortho-substituted aryl triflates results from direct C-F cross-coupling. In some cases, formation of a Pd-aryne intermediate is responsible for producing undesired regioisomers. The generation of the Pd-aryne intermediate occurs primarily via ortho-deprotonation of a L·Pd(Ar)OTf (L = biaryl monophosphine) species by CsF and thus competes directly with the transmetalation step of the catalytic cycle.

Evidence for in situ catalyst modification during the Pd-catalyzed conversion of aryl triflates to aryl fluorides.

A mechanistic investigation of the Pd-catalyzed conversion of aryl triflates to fluorides is presented. Studies reveal that C-F reductive elimination from a LPd(II)(aryl)F complex (L = t-BuBrettPhos or RockPhos) does not occur when the aryl group is electron rich. Evidence is presented that a modified phosphine, generated in situ, serves as the actual supporting ligand during catalysis with such substrates.

A new palladium precatalyst allows for the fast Suzuki-Miyaura coupling reactions of unstable polyfluorophenyl and 2-heteroaryl boronic acids.

Boronic acids which quickly deboronate under basic conditions, such as polyfluorophenylboronic acid and five-membered 2-heteroaromatic boronic acids, are especially challenging coupling partners for Suzuki-Miyaura reactions. Nevertheless, being able to use these substrates is highly desirable for a number of applications. Having found that monodentate biarylphosphine ligands can promote these coupling processes, we developed a precatalyst that forms the catalytically active species under conditions where boronic acid decomposition is slow.

The palladium-catalyzed trifluoromethylation of aryl chlorides.

The trifluoromethyl group can dramatically influence the properties of organic molecules, thereby increasing their applicability as pharmaceuticals, agrochemicals, or building blocks for organic materials. Despite the importance of this substituent, no general method exists for its installment onto functionalized aromatic substrates. Current methods either require the use of harsh reaction conditions or suffer from a limited substrate scope.

Formation of ArF from LPdAr(F): catalytic conversion of aryl triflates to aryl fluorides.

Despite increasing pharmaceutical importance, fluorinated aromatic organic molecules remain difficult to synthesize. Present methods require either harsh reaction conditions or highly specialized reagents, making the preparation of complex fluoroarenes challenging. Thus, the development of general methods for their preparation that overcome the limitations of those techniques currently in use is of great interest.

Asymmetric allylation of methyl ketones by using chiral phenyl carbinols.

Novel chiral auxiliaries for the stereoselective allylation of aliphatic methyl ketones with allyltrimethylsilane and their use in the synthesis of homoallylic ethers are described. In a multicomponent domino process catalyzed by trifluoromethanesulfonic acid, the allyl moiety and the auxiliary are transferred onto the substrate to yield tertiary homoallylic ethers. The most useful auxiliary for a general application turned out to be the trimethylsilyl ether of phenyl benzyl carbinol with an induced diastereoselectivity of 90:10 using ethyl methyl ketone and 94:6 using isopropyl methyl ketone as substrates.

The domino multicomponent allylation reaction for the stereoselective synthesis of homoallylic alcohols.

Stereoselective allylations of carbonyl compounds such as aldehydes and ketones are useful but challenging reactions in organic chemistry. The resulting chiral secondary and tertiary homoallylic alcohols or ethers are valuable building blocks in the synthesis of biologically active natural compounds and pharmaceuticals. Although researchers have developed several methods for the facially selective allylation of aldehydes, the stereoselective allylation of ketones still poses a severe problem.

Stereoselective allylation of ketones: explanation for the unusual inversion of the induced stereochemistry in the auxiliary-mediated crotylation and pentenylation of butanone by DFT calculations.

Auxiliary-mediated domino crotylations and pentenylations of butanone yield homoallylic ethers with two newly formed stereogenic centers. With our norpseudoephedrine-derived auxiliary, we observed the formation of anti isomers exclusively, and the nature of the major isomer was independent of the substrate double bond geometry. Interestingly, there is a switch in induced selectivity when going from crotylation to pentenylation.

Determination of the origin of stereoselectivity in multiple-transition-state reactions using DFT calculations: enantioselective synthesis of homoallylic alcohols from aliphatic methyl ketones via an auxiliary-mediated allylation.

Computational investigations on the highly stereoselective allylation of butanone in the presence of a chiral norpseudoephedrine-derived auxiliary have been performed. They suggest an SN1-type mechanism via the attack of allyltrimethylsilane to an intermediately formed oxocarbenium ion. The identification of preferred transition states (TSs) leads to a straightforward rationalization of the observed selectivity which can be extended to analogues of the auxiliary.

Origin of syn/anti diastereoselectivity in aldehyde and ketone crotylation reactions: a combined theoretical and experimental study.

We report on experimentally determined and computationally predicted diastereoselectivities of (a) multicomponent crotylation (MCC) reactions of simple aliphatic aldehydes and ketones and (b) of acetal substitution (AS) reactions of aldehyde dimethyl acetals with E- and Z-configurated crotyl trimethylsilane to give homoallylic methyl ethers bearing two newly formed stereogenic centers. We found that corresponding MCC and AS reactions give nearly equal syn/anti ratios. While the crotylations of acetaldehyde and propionaldehyde mainly result in the syn product for E-configurated silane and in the anti product for Z-configurated silane, the syn product is found as main product for the crotylation of pivaldehyde regardless of substrate double bond geometry.

Combined jet relaxation and quantum chemical study of the pairing preferences of ethanol.

The subtle trans-gauche equilibrium in the ethanol molecule is affected by hydrogen bonding. The resulting conformational complexity in ethanol dimer manifests itself in three hydrogen-bonded OH stretching bands of comparable infrared intensity in supersonic helium expansions. Admixture of argon or nitrogen promotes collisional relaxation and is shown to enhance the lowest frequency transition.