RESUMO
A process for the concurrent transfer of both the NHC ligand and the difluoromethyl group from [(SIPr)Ag(CF2H)] to PdX2 (X = Cl, OAc, and OPiv) for the preparation of [(SIPr)Pd(CF2H)X] complexes is described. These complexes were air-stable and easily underwent transmetalation with aryl pinacol boronate/reductive elimination to generate ArCF2H 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.
RESUMO
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. Deuterium labeling studies were conducted with a variety of aryl triflates.
Assuntos
Deutério/química , Flúor/química , Paládio/química , Catálise , Marcação por IsótopoRESUMO
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 de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.
Assuntos
Fator XIa , Fibrinolíticos , AnticoagulantesRESUMO
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 preliminary study of the reactivity of a LPd(II)(aryl)F complex based on this modified ligand is reported.
Assuntos
Hidrocarbonetos Fluorados/síntese química , Mesilatos/química , Compostos Organometálicos/química , Paládio/química , Catálise , Hidrocarbonetos Fluorados/química , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , EstereoisomerismoRESUMO
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. With this precatalyst, Suzuki-Miyaura reactions of a wide range of (hetero)aryl chlorides, bromides, and triflates with polyfluorophenyl, 2-furan, 2-thiophene, and 2-pyrroleboronic acids and their analogues proceed at room temperature or 40 °C in short reaction times to give the desired products in excellent yields.
Assuntos
Ácidos Borônicos/química , Paládio/química , CatáliseRESUMO
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. We have developed a highly diastereoselective domino multicomponent allylation reaction of a ketone and allyltrimethyl silane using the trimethylsilyl ether of a norpseudoephedrine or mandelic acid derivative as an auxiliary with a diastereoselectivity of up to 98:2. The reaction is performed at -78 degrees C in the presence of a catalytic amount of trifluoromethanesulfonic acid and leads to the corresponding tertiary ethers. The procedure can also be used for the allylation of aliphatic aldehydes with a diastereomeric ratio >99:1. Ketones give the 4,1'-syn product while the aldehydes give the reversed selectivity to yield a 4,1'-anti product. In addition, the reaction of gamma-substituted allyl silanes with ketones yields a product with two stereogenic centers and an anti diastereoselectivity of >99:1. The homoallylic ethers formed in the domino multicomponent process can be used in further synthetic transformations: the auxiliary can serve as a protecting group or can be cleaved reductively to give the corresponding homoallylic alcohols. Based on a number of both experimental and theoretical studies of the reaction mechanism, we conclude that an intermediate oxocarbenium ion is formed in the reaction of ketones. The oxocarbenium ion is attacked by the allyl silane during the stereogenic step. Using density functional theory methods, we could trace the observed stereoselectivity phenomena back to open transition states (TSs) where there is no interaction between the silane's trimethylsilyl group and the former carbonyl oxygen. On the contrary, the reaction with aldehydes forms an intermediate oxazolidinium salt, which explains the opposite selectivity. We have used the new allylation procedure in several total syntheses of natural products such as vitamin E, (+)-hydroxymyoporone, 5,6-dihydrocineromycin B, and polyoxygenated cembrenes.
RESUMO
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. Here, we present the computational rationalization for this behavior by identification of the relevant transition states (TSs), the energies of which were determined by using the B3LYP/6-31+G(d) level of theory in combination with the PCM/UAKS method to include the effects exerted by the solvent dichloromethane. To quickly narrow down the number of potentially relevant TSs from the whole set of 288 and 864 TSs for the crotylation and pentenylation, respectively, we employed a screening process based on B3LYP//AM1 energies. The predicted selectivities are in good agreement with experimentally determined ones. Furthermore, the obtained results also facilitate an explanation of the selectivities obtained in hexenylations and heptenylations. Finally, activation energies were determined that account for the significantly longer reaction times than those for the domino allylation with unsubstituted trimethylallylsilane.
RESUMO
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 transferred substituted benzyl moiety has good protecting properties in subsequent transformations and can easily be removed under reductive conditions to provide the corresponding homoallylic alcohol. The origin of the high selectivity could be elucidated by identifying the relevant transition states using quantum-chemical calculations. An excellent agreement between calculated and experimentally observed selectivities was obtained assuming an oxocarbenium ion as intermediate.
Assuntos
Compostos Alílicos/química , Álcoois Benzílicos/química , Hexanonas/química , Álcoois/química , Estrutura Molecular , EstereoisomerismoRESUMO
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. A screening process has been devised to select 61 potentially relevant TSs from a total of almost 300 theoretically possible TSs. Final results were obtained from gas-phase calculations employing the B3LYP/6-31+G(d) level of theory as well as in dichloromethane solution using the B3LYP/6-311++G(2d,p)//B3LYP/6-31+G(d) level of theory in combination with polarizable continuum model and the UAKS set of radii. The agreement of theoretically predicted and experimentally observed selectivities is very good in both cases. However, the relative energy differences for several relevant TSs differ significantly when going from gas phase to solution, thus illustrating the necessity of performing calculations in solution to draw correct conclusions.
Assuntos
Simulação por Computador , Cetonas/química , Modelos Químicos , Propanóis/síntese química , Alquilação , Estrutura Molecular , Propanóis/química , Teoria Quântica , Reprodutibilidade dos Testes , EstereoisomerismoRESUMO
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. Here we report the palladium-catalyzed trifluoromethylation of aryl chlorides under mild conditions, allowing the transformation of a wide range of substrates, including heterocycles, in excellent yields. The process tolerates functional groups such as esters, amides, ethers, acetals, nitriles, and tertiary amines and, therefore, should be applicable to late-stage modifications of advanced intermediates. We have also prepared all the putative intermediates in the catalytic cycle and demonstrated their viability in the process.
Assuntos
Hidrocarbonetos Clorados/química , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/síntese química , Paládio/química , Catálise , Fluorbenzenos/química , Ligantes , Metilação , Estrutura Molecular , OxirreduçãoRESUMO
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. We have prepared [LPd(II)Ar(F)] complexes, where L is a biaryl monophosphine ligand and Ar is an aryl group, and identified conditions under which reductive elimination occurs to form an Ar-F bond. On the basis of these results, we have developed a catalytic process that converts aryl bromides and aryl triflates into the corresponding fluorinated arenes by using simple fluoride salts. We expect this method to allow the introduction of fluorine atoms into advanced, highly functionalized intermediates.
Assuntos
Fluoretos/química , Fluoretos/síntese química , Flúor/química , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/síntese química , Mesilatos/química , Paládio/química , Catálise , Fenômenos Químicos , Meios de Contraste , Radioisótopos de Flúor , Isomerismo , Ligantes , Estrutura Molecular , Oxirredução , Tomografia por Emissão de PósitronsRESUMO
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. Using butanone as substrate, the anti product is found as main product in both cases. By computational investigation employing the B3LYP/6-31+G(d) level of theory in dichloromethane solution (PCM/UAKS), we found that the attack of O-methyl-substituted carboxenium ions by crotyl silane explains the experimentally observed selectivities, indicating that these crotylations in fact proceed in an S(N)1-type reaction via this ionic intermediate. Comparison of relevant open transition-state structures leads to a rationalization of the observed selectivities. For all systems studied, three transition-state conformations are necessary and sufficient to determine the selectivity. This has been confirmed by studying the MCC reactions of isobutyraldehyde. Activation energies for the stereogenic step have been determined by calculation of the transition state and substrate structures in dichloromethane solution at the B3LYP/6-311+G(2d,p)//B3LYP/6-31+G(d) level of theory in dichloromethane solution. The possibility to predict simple diastereoselectivity in general Lewis acid-mediated crotylations of aldehydes and ketones is discussed.
Assuntos
Aldeídos/química , Cetonas/química , Modelos Químicos , Silanos/química , Compostos de Trimetilsilil/química , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
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. Global and local harmonic frequency shift calculations at MP2 level indicate that this transition is due to a gauche-gauche dimer, but the predictions are sensitive to basis set and correlation level. Energetically, the homochiral gauche-gauche dimer is predicted to be the most stable ethanol dimer conformation. The harmonic MP2 predictions are corroborated by perturbative anharmonicity contributions and CCSD(T) energies. Thus, a consistent picture of the subtle hydrogen bond energetics and vibrational dynamics of the ethanol dimer is starting to emerge for the first time.