Synthetic scope and DFT analysis of the chiral binap-gold (I) complex-catalyzed 1,3-dipolar cycloaddition of azlactones with alkenes

The 1,3-dipolar cycloaddition between glycine-derived azlactones with maleimides is efficiently catalyzed by the dimeric chiral complex [(Sa)-Binap·AuTFA]2. The alanine-derived oxazolone only reacts with tert-butyl acrylate giving anomalous regiochemistry, which is explained and supported by Natural Resonance Theory and Nucleus Independent Chemical Shifts calculations. The origin of the high enantiodiscrimination observed with maleimides and tert-butyl acrylate is analyzed using DFT computed at M06/Lanl2dz//ONIOM(b3lyp/Lanl2dz:UFF) level. Several applications of these cycloadducts in the synthesis of new proline derivatives with a 2,5-trans-arrangement and in the preparation of complex fused polycyclic molecules are described.

Multicomponent Azide-Alkyne Cycloaddition Catalyzed by Impregnated Bimetallic Nickel and Copper on Magnetite

A new bimetallic catalyst derived from nickel and copper has been used successfully for the first time in the multicomponent reaction of terminal alkynes, sodium azide, and benzyl bromide derivatives. The presence of both metallic species on the surface of magnetite seems to have a positive and synergetic effect. The catalyst loading is the lowest ever published for a catalyst of copper anchored on any type of iron support. The catalyst could be easily removed from the reaction media just by magnetic decantation and it could be reused up to ten times without any negative effect on the initial results.

Binap-silver-catalyzed enantioselective multicomponent 1,3-dipolar cycloaddition of azomethines ylides derived from ethyl glyoxylate

The enantioselective binap–silver catalyzed multicomponent 1,3-dipolar cycloaddition using ethyl glyoxylate, phenylalanine ethyl ester, and maleimides is described. The employment of basic silver carbonate allows the reaction to take place in the absence of an extra base giving high yields and ee. In addition, low-level calculations regarding the importance of the benzyl substituent at the α-position of the amino ester justify the expected absolute configuration of the final cycloadducts and the observed high enantiodiscrimination.

Silver-catalysed multicomponent 1,3-dipolar cycloaddition of 2-oxoaldehydes-derived azomethine ylides

The silver-catalysed multicomponent reaction between ethyl glyoxylate, 2,2-dimethoxyacetaldehyde, or phenylglyoxal as aldehyde components with a α-amino ester hydrochloride and a dipolarophile in the presence of triethylamine is described. This domino process takes place at room temperature by in situ liberation of the α-amino ester followed by the formation of the imino ester, which is the precursor of a metalloazomethine ylide. The cycloaddition of this species and the corresponding dipolarophile affords polysubstituted proline derivatives. Ethyl glyoxylate reacts with glycinate, alaninate, phenylalaninate and phenylglycinate at room temperature in the presence of representative dipolarophiles affording endo-2,5-cis-cycloadducts in good yields and high diastereoselection. In addition, 2,2-dimethoxyacetaldehyde is evaluated with the same amino esters and dipolarophiles, under the same mild conditions, generating the corresponding endo-2,5-cis-cycloadducts with higher diastereoselections than the obtained in the same reactions using ethyl glyoxylate. In the case of phenylglyoxal the corresponding 5-benzoyl-endo-2,5-cis cycloadducts are obtained in short reaction times and similar diasteroselection.

Enantioselective Synthesis of Polysubstituted Spiro-nitroprolinates Mediated by a (R,R)-Me-DuPhos·AgF-Catalyzed 1,3-Dipolar Cycloaddition

The synthesis of constrained spirocycles is achieved effectively by means of 1,3-dipolar cyclodditions employing α-imino γ-lactones as azomethine ylide precursors and nitroalkenes as dipolarophiles. The complex formed by (R,R)-Me-DuPhos 18 and AgF is the most efficient bifunctional catalyst. Final spiro-nitroprolinates cycloadducts are obtained in good to moderate yields and both high diastereo- and enantioselectivities. Density functional theory (DFT) calculations supported the expected absolute configuration as well as other stereochemical parameters.

Synthesis of thioenol ether functionalized cyclooctyne and its orthogonal cycloaddition sequence

In this work, the synthesis of a new bifunctionalized cyclooctyne for a possible layer by layer surface functionalization is presented. The main objective is to find a more stable molecule than the literature known methyl enol ether substituted cyclooctyne. Accordingly, the two target functionalities are an internal alkyne group and a vinyl methyl sulfide group. The synthesis was achieved in 9 steps and consists first of all in the preparation of an aldehyde starting from 1,5-cyclooctadiene with a cyclopropanation reaction followed by a reduction and the SWERN oxidation to an aldehyde. The new functionality was introduced by exploiting the WITTIG reaction. For the alkyne group a bromination followed by a double elimination gave good results. The reactivity of the new molecule was tested using a sequential application of SPAAC and iEDDA reactions, comparing it with the cyclooctyne functionalized with a methyl enol ether. Concerning the comparison of both compounds the sulfur ether is significantly slower and therefore more stable. It will be tested in the future for surface functionalization from the KOERT group.

Synthesis And Antiproliferative Activity Of 8-hydroxyquinoline Derivatives Containing A 1,2,3-triazole Moiety.

Twelve novel 8-hydroxyquinoline derivatives were synthesized with good yields by performing copper-catalyzed Huisgen 1,3-dipolar cycloaddition (click reaction) between an 8-O-alkylated-quinoline containing a terminal alkyne and various aromatic or protected sugar azides. These compounds were evaluated in vitro for their antiproliferative activity on various cancer cell types. Protected sugar derivative 16 was the most active compound in the series, exhibiting potent antiproliferative activity and high selectivity toward ovarian cancer cells (OVCAR-03, GI50 < 0.25 μg mL(-1)); this derivative was more active than the reference drug doxorubicin (OVCAR-03, GI50 = 0.43 μg mL(-1)). In structure-activity relationship (SAR) studies, the physico-chemical parameters of the compounds were evaluated and docking calculations were performed for the α-glucosidase active site to predict the possible mechanism of action of this series of compounds.

Cyclooligomerisation of azido-alkyne-functionalised sugars: synthesis of 1,6-linked cyclic pseudo-galactooligosaccharides and assessment of their sialylation by Trypanosoma cruzi trans-sialidase

Cyclic pseudo-galactooligosaccharides were synthesized by cyclooligomerisation of isomeric azido-alkyne derivatives of beta-D-galactopyranose under Cu(I)-catalysed azide-alkyne 1,3-dipolar cycloaddition reaction conditions. The principal products isolated were cyclic dimers and trimers, with lower amounts of cyclic tetramer and pentamer also evident in some cases. Molecular mechanics calculations suggest very compact but flexible structures for the cyclic trimers, with secondary OH groups exposed outside the macrocycle and available for enzymatic glycosylation. The cyclic dimers and trimers represent a new type of acceptor substrate for Trypanosoma cruzi trans-sialidase, giving rise to doubly and triply sialylated glycomacrocycles, respectively.

Expanding cyclitol structural diversity by biocatalysis and metalocatalysis. A click chemistry approach

The palladium catalyzed cross-coupling reaction of phenyltrifluoroborate with a chemoenzymatically derived bromoazidoconduritol, combined with 1,3-dipolar cycloaddition, with a variety of alkynes is described. Fourteen new compounds were synthesized in moderate to good yields. The click chemistry reaction can be effected by using sodium ascorbate and CuSO(4) center dot 5H(2)O as catalyst in toluene-H(2)O at room temperature.

Synthesis of 5-alkynyl-2,2,6-trimethyl-1,3-dioxin-4-ones and 1,4-disubstituted-1,2,3-triazoles

Herein we report an approach to the formation of 5-alkynyl-1,3-dioxin-4-ones using Suzuki-Miyaura cross-coupling reaction of potassium alkynyltrifluoroborate salts with 2,2,6-trimethy1-5-iodo-1,3-dioxin-4-one. The resulting 5-ethynyltrimethylsilyl-1,3-dioxin-4-ones obtained through the Sonogashira reaction were further reacted in a Cu(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition to form functionalized 1,4-disubstituted-1,2,3-triazoles in good yields, using mild conditions and ultrasonic radiation to expedite the reaction. (C) 2011 Elsevier Ltd. All rights reserved.

Recognition of cyclic, acyclic, exocyclic, and spiro Acetals via structurally diagnostic ion/molecule reactions with the (CH3)(2)N-C+=O acylium ion

Reactions of the model acylium ion (CH3)(2)N-C+=O with acyclic, exocyclic, and Spiro acetals of the general formula (RO)-O-1-(CRR4)-R-3-OR2-upole mass spectrometry. Characteristic intrinsic reactivities were observed for each of these classes of acetals. The two most Characteristic intrinsic reactivities were observed for each of these classes of acetals. The two most common reactions observed were hydride and alkoxy anion [(RO-)-O-1 and (RO-)-O-2] abstraction. Other specific reactions were also observed: (a) a secondary polar [4(+) + 2] cycloaddition for acetals bearing alpha,beta-unsaturated R-3 or R-4 substituents and (b) OH- abstraction for exocyclic and spiro acetals. These structurally diagnostic reactions, in conjunction with others observed previously for cyclic acetals, are shown to reveal the class of the acetal molecule and its ring type and substituents and to permit their recognition and distinction from other classes of isomeric molecules.

Copper-organic frameworks assembled from in situ generated 5-(4-pyridyl) tetrazole building blocks: synthesis, structural features, topological analysis and catalytic oxidation of alcohols

Two new metal- organic compounds {[Cu-3(mu(3)-4-(p)tz)(4)(mu(2)-N-3)(2)(DMF)(2)](DMF)(2)}(n) (1) and {[Cu(4ptz) (2)(H2O)(2)]}(n) (2) {4-ptz = 5-(4-pyridyl)tetrazolate} with 3D and 2D coordination networks, respectively, have been synthesized while studying the effect of reaction conditions on the coordination modes of 4-pytz by employing the [2 + 3] cycloaddition as a tool for generating in situ the 5-substituted tetrazole ligands from 4-pyridinecarbonitrile and NaN3 in the presence of a copper(II) salt. The obtained compounds have been structurally characterized and the topological analysis of 1 discloses a topologically unique trinodal 3,5,6-connected 3D network which, upon further simplification, results in a uninodal 8-connected underlying net with the bcu (body centred cubic) topology driven by the [Cu-3(mu(2)-N-3)(2)] cluster nodes and mu(3)-4-ptz linkers. In contrast, the 2D metal-organic network in 2 has been classified as a uninodal 4-connected underlying net with the sql [Shubnikov tetragonal plane net] topology assembled from the Cu nodes and mu(2)-4-ptz linkers. The catalytic investigations disclosed that 1 and 2 act as active catalyst precursors towards the microwave-assisted homogeneous oxidation of secondary alcohols (1-phenylethanol, cyclohexanol, 2-hexanol, 3-hexanol, 2-octanol and 3-octanol) with tert-butylhydroperoxide, leading to the yields of the corresponding ketones up to 86% (TOF = 430 h(-1)) and 58% (TOF = 290 h(-1)) in the oxidation of 1-phenylethanol and cyclohexanol, respectively, after 1 h under low power ( 10 W) microwave irradiation, and in the absence of any added solvent or additive.

HOMO-raising strategies in aminocatalysis, from Enamine to Tetraenamine

Dissertação para obtenção do Grau de Mestre em Bioorgânica