RESUMO
Computational reaction prediction has become a ubiquitous task in chemistry due to the potential value accurate predictions can bring to chemists. Boronic acids are widely used in industry; however, understanding how to avoid the protodeboronation side reaction remains a challenge. We have developed an algorithm for in silico prediction of the rate of protodeboronation of boronic acids. A general mechanistic model devised through kinetic studies of protodeboronation was found in the literature and forms the foundation on which the algorithm presented in this work is built. Protodeboronation proceeds through 7 distinct pathways, though for any particular boronic acid, only a subset of mechanistic pathways are active. The rate of each active mechanistic pathway is linearly correlated with its characteristic energy difference, which in turn can be determined using Density Functional Theory. We validated the algorithm using leave-one-out cross-validation on a data set of 50 boronic acids and made a further 50 rate predictions on academically and industrially important boronic acids out of sample. We believe this work will provide great assistance to chemists performing reactions that feature boronic acids, such as Suzuki-Miyaura and Chan-Evans-Lam couplings.
RESUMO
A catalytic enantioselective and regiodivergent arylation of alkenes is described. Chiral copper(II)bisoxazoline complexes catalyze the addition of diaryliodonium salts to allylic amides in excellent ee. Moreover, the arylation can be controlled by the electronic nature of the diaryliodonium salt enabling the preparation of nonracemic diaryloxazines or ß,ß'-diaryl enamides.
Assuntos
Compostos Alílicos/química , Amidas/química , Cobre/química , Hidrocarbonetos Aromáticos/química , Oniocompostos/química , Oxazóis/química , Catálise , Hidrocarbonetos Aromáticos/síntese química , Oxazinas/síntese química , Oxazinas/química , EstereoisomerismoRESUMO
A gram-scale catalytic enantioselective formal synthesis of morphine is described. The key steps of the synthesis involve an ortho-para oxidative phenolic coupling and a highly diastereoselective "desymmetrization" of the resulting cyclohexadienone that generates three of the four morphinan ring junction stereocenters in one step. The stereochemistry is controlled from a single carbinol center installed through catalytic enantioselective hydrogenation. These transformations enabled the preparation of large quantities of key intermediates and could support a practical and scalable synthesis of morphine and related derivatives.
Assuntos
Analgésicos Opioides/síntese química , Morfina/síntese química , Acoplamento Oxidativo , Fenóis/química , EstereoisomerismoRESUMO
The copper-catalysed conjugate addition of trialkylaluminium and dialkylzinc reagents to polyconjugated nitroolefins (nitrodiene and nitroenyne derivatives) is reported. A reversed Josiphos ligand L7 allows for the selective 1,4- or 1,6-addition with high enantioselectivities.
RESUMO
The copper-catalyzed conjugate addition of various Grignard reagents to polyconjugated enones (dienone and enynone derivatives) is reported. The catalyst system, composed of copper triflate and an NHC ligand, led to the unusual selective formation of the 1,4-addition products. This reaction allows for the creation of all-carbon chiral quaternary centers with enantiomeric excesses up to 99%. The remaining unsaturation on the 1,4 adducts give access to valuable synthetic transformations.
RESUMO
Synthesis of 1,3-substituted cyclobutyls enabled by zinc insertion into functionalized iodocyclobutyl derivatives followed by Negishi coupling with halo-heteroaromatics is reported. Two distinct sets of conditions were developed; the first involved a two-step batch protocol using activated Rieke zinc, and the second involved a multistep continuous flow process. Both methods showed complementarity and allowed for rapid access to these medicinally relevant motifs, the possibility of scaling up, and automation for library synthesis.
RESUMO
Chiral amines catalyze the enantioselective conjugate addition of aldehydes to vinyl phosphonates in high yields and with enantioselectivities up to 97% ee. This novel process provides synthetically useful chiral gamma-geminal phosphonate aldehydes which can be easily converted in a few steps into chiral beta-substituted vinyl phosphonates with conservation of the optical purity.
Assuntos
Aldeídos/química , Organofosfonatos/química , Compostos de Vinila/química , Catálise , Imidazolidinas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Estereoisomerismo , Compostos de Vinila/síntese químicaRESUMO
The formation of chiral and sterically congested cyclohexanone derivatives has been achieved through a multistep sequence with one single purification step. (n-Butoxymethyl)-diethylamine was identified as a highly efficient reagent for the direct trapping of aluminum enolates. The Lewis acidic character of aluminum suffices to activate the α-aminoether to form in situ an electrophilic iminium species. In return the aluminum enolate is rendered more nucleophilic by coordination of the butoxy group and formation of an aluminate.
RESUMO
Readily available alkenylalanes, arising from hydroalumination of unprotected terminal alkynes, have been directly employed for the copper-catalyzed asymmetric conjugate addition (ACA) to ß-substituted cyclic enones. The desired products, containing a quaternary stereogenic center, are generally obtained in good yields and enantioselectivities.
RESUMO
In this letter we describe an unusual result in terms of regioselectivity with respect to copper-catalyzed conjugate additions of various Grignard reagents to cyclic enynones. The use of Cu(OTf)(2) and NHC ligand L1 as the catalyst combination in CH(2)Cl(2) led to the unique formation of the 1,4 adduct. This selectivity does not follow the general trend previously observed in the literature using extended Michael acceptors. Moreover these reactions allowed for the creation of a quarternary stereogenic center with enantioselectivities up to 97% ee.
RESUMO
The first highly enantioselective and regiodivergent conjugate addition of trialkylaluminium reagents to nitrodienes and nitroenynes is described. By a design of the substrate and a fine-tuning of the reaction conditions, it is possible to selectively form the 1,4- or 1,6-adduct. The same combination of catalyst, copper source, and a ferrocene-based phosphine ligand afforded enantioselectivities up to 95% and 91%, respectively.