Esther Lete

Brønsted Acid Catalyzed Enantioselective α-Amidoalkylation in the Synthesis of Isoindoloisoquinolines

The Parham cyclization-intermolecular α-amidoalkylation sequence results in the facile enantioselective synthesis of 12b-substituted isoindoloisoquinolines (ee up to 95%) using BINOL-derived Brønsted acids. α-Amidoalkylation of indole occurs through the formation of a chiral conjugate base/bicyclic quaternary N-acyliminium ion pair.

Synthesis of enantiomerically enriched amines by chiral ligand mediated addition of organolithium reagents to imines

Abstract The effect of the imine and ligand structure on the enantioselective addition of organolithiums to imines has been studied. Thus, (−)-sparteine-mediated additions of MeLi and/or n -BuLi to p -anisidine derived phenylimine 1a afforded the corresponding amines with modest e.e.s. The use of bulkier or more reactive imines (naphthyl or tosyl imines) resulted in loss of enantioselectivity. The best enantioinduction with this ligand was obtained with enolizable imines 8 and 10 . When bis(oxazolidines) were used as chiral ligands, a strong influence of their structure in the enantioselectivity of the addition of MeLi and n -BuLi to phenylimine 1a was observed.

Enantioselective synthesis of pyrrolo[2,1-a]isoquinolones via stereocontrolled N-acyliminium ion cyclisations

Abstract Stereocontrolled N -acyliminium ion cyclisation of L-DOPA derived succinimide 5 has been investigated. Addition of organolithiums to chiral non-racemic 5 yields oxoamides, which are cyclised diastereoselectively upon treatment with BF 3 ·OEt 2 , to afford 5,10b- trans pyrroloisoquinolones in moderate yields and high ee (99%).

Functionalized organolithium compounds: Generation via reductive lithiation and nucleophilic addition to N-phenethylimides. Access to functionalized dihydropyrrolo[2,1-a]isoquinolinones

Abstract A procedure for producing 1,4-dianion equivalents consists of reductive lithiation, induced by 4,4.-di-tert-butylbiphenylide, of functionalized phenyl sulfides. Nucleophilic addition of 4-lithio-2-(trimethylsilylmethyl)but-1-ene 1 and 2-(3-lithiopropyl)-2-trimethylsilyl-1,3-dithiane 2 thus prepared to N-phenethyl-cis-norbor-5-en-2,3-dicarboximide 9 afforded the corresponding α-hydroxy lactams in good yields. Besides, access to C-10b substituted α,β-unsaturated pyrroloisoquinolinones 3 was efficiently achieved via a tandem organolithium nucleophilic addition — N-acyliminium ion cyclization sequence and subsequent retro Diels-Alder reaction. The methodology can be extended to functionalized organolithiums, but the N-acyliminium cyclization fails if the allylsilane moiety is present.

A simple direct approach to 1-substituted 3-arylisoquinolines from deoxybenzoins and nitriles

Abstract A new one-pot synthesis of 3-arylisoquinolines was accomplished by reaction of deoxybenzoins with an excess of nitriles and phosphorus pentoxide at room temperature. The usefulness of this synthesis was demonstrated by the facile preparation of 1-alkyl, 1-alkenyl, and 1-aryl substituted 3-aryl-isoquinolines 3 and 4 on a preparative scale. The effect of nitrile type and deoxybenzoin substitution pattern on the feasibility of ring construction were studied. In most cases, naphtalene 6 and pyrimidines 7 or 8 were isolated as side products. When the reaction was similarly carried out with phosphorus oxychloride, instead of phosphorus pentoxide, the major product was the chlorostilbene derivative 5 .

Tandem carbophilic addition-N-acyliminium ion cyclization for the synthesis of functionalized pyrrolo[2,1-a]isoquinolones: Key intermediates for the preparation of Erythrina-type alkaloids

Abstract Sequential carbophilic addition of organolithium reagents- N -acyliminium ion cyclization of N -phenenethylsuccinimide 3 yields pyrrolo[2,1-a]isoquinolones 1 in high yields, with the possibility of varying the substituent at C-10b by changing the organolithium. Application of this methodology to the cis -norbor-5-en-2,3-dicarboximide 7 using a functionalized organolithium reagent, the 3-(2-trimethylsilyl-1,3-dithian-2-yl)propyllithium 11 , followed by desilylation and subsequent retro-Diels-Alder reaction affords the α,β-unsaturated pyrroloisoquinolone 9b , immediate precursor of Erythrina -type alkaloids.

MIANN models in medicinal, physical and organic chemistry.

Reducing costs in terms of time, animal sacrifice, and material resources with computational methods has become a promising goal in Medicinal, Biological, Physical and Organic Chemistry. There are many computational techniques that can be used in this sense. In any case, almost all these methods focus on few fundamental aspects including: type (1) methods to quantify the molecular structure, type (2) methods to link the structure with the biological activity, and others. In particular, MARCH-INSIDE (MI), acronym for Markov Chain Invariants for Networks Simulation and Design, is a well-known method for QSAR analysis useful in step (1). In addition, the bio-inspired Artificial-Intelligence (AI) algorithms called Artificial Neural Networks (ANNs) are among the most powerful type (2) methods. We can combine MI with ANNs in order to seek QSAR models, a strategy which is called herein MIANN (MI & ANN models). One of the first applications of the MIANN strategy was in the development of new QSAR models for drug discovery. MIANN strategy has been expanded to the QSAR study of proteins, protein-drug interactions, and protein-protein interaction networks. In this paper, we review for the first time many interesting aspects of the MIANN strategy including theoretical basis, implementation in web servers, and examples of applications in Medicinal and Biological chemistry. We also report new applications of the MIANN strategy in Medicinal chemistry and the first examples in Physical and Organic Chemistry, as well. In so doing, we developed new MIANN models for several self-assembly physicochemical properties of surfactants and large reaction networks in organic synthesis. In some of the new examples we also present experimental results which were not published up to date.

Oxidation Reactions of 2′-Functionalized 3-Aryltetrahydro and 3,4-Dihydroisoquinolines

Abstract Several 2′-functionalized 3-arylisoquinolines in different oxidation stages have been prepared. Fremys salt or I 2 /NaAcO oxidation of 2′-functionalized 3-aryltetrahydroisociuinolines always stops at the 3,4-dihydroisquinoline stage; however, better yields and shorter reaction times are obtained with iodine. Air/KOH/DMSO oxidation of 3,4-dihydroisoquinolines furnished the aromatic derivatives with concomitant cleavage of the TBDPS group. While 3-arylisoquinolin-1-(2H)-ones are obtained by air oxidation of 3,4-dihydroisquinolinium salts, the use of DDQ in dioxane resulted in a selective dehydrogenation to the corresponding N -substituted isoquinolinium salts.

Intramolecular carbolithiation reactions for the synthesis of 2,4-disubstituted tetrahydro-quinolines: evaluation of TMEDA and (-)-sparteine as ligands in the stereoselectivity.

The preparation of 4-substituted 2-phenyltetrahydroquinolines from N-alkenylsubstituted 2-iodoanilines via intramolecular carbolithiation reactions has been investigated. The stereochemical outcome of the carbolithiation reactions depends on the nature of organolithium employed to perform the lithium-halogen exchange, the solvent, or the use of additives, for example, TMEDA or chiral bidentated ligands such as (-)-sparteine. Thus, the 2,4-disubstituted tetrahydroquinolines are obtained with moderate diastereoselectivities (up to 77:23) and with ee up to 94% when Weinreb amide derivatives are used (R = CONMe(OMe)).

Determination of the stereochemistry of 1-substituted 3-aryltetrahydroisoquinolines by1H NMR spectroscopy

Abstract The cis -1,3-disubstituted tetrahydroisoquinolines 2 can be obtained in a highly diastereoselective fashion through Pictet-Spengler cyclization of the 1,2-bis(3,4-dimethoxyphenyl)-ethylamine with aliphatic and aromatic aldehydes under acidic conditions. However, the epimeric trans -1,3-disubstituted tetrahydroisoquinolines 3 are also isolated as minor products. The stereochemistry of the tetrahydroisoquinolines was unambiguously assigned on the basis of the 1 H NMR data, and are supported by difference NOE measurements.