Ongoing main research projects

Organocatalyzed dihydroxylation of olefins as a platform for the efficient synthesis of carbocycles, metal organocatalyzed synthesis of poly-hydroxylated cyclopentenones, asymmetric synthesis of functionalised cyclopentenones via organocatalysed rearrangement and enzymatic resolution of pyranones, development and applications of new ionic liquids, preparative one-pot resolution-separation of rac-sec-alcohols based on reusable biocatalyst and temporary acylating agents, new Rh(II) chiral complexes as catalysts for the C-H insertion of carbennoid intermediates, integrated isolation, bio- and organic-synthetic transformations of the portuguese natural resources derived from Cistus ladaniferus plant and Lupinus albus seeds, design and synthesis of efficient multiphoton chromophores.


Highlights


Catalysis and Methodologies


Organocatalysis


Dihydroxylation of Olefins



The trans-dihydroxylation of olefins occurs efficiently by aqueous hydrogen peroxide catalyzed by p-toluenesulfonic acid at 50°C, allowing the catalyst reuse and an outstanding substrate functional group tolerance such as tert-butoxycarbonylamino (BocNH), benzyloxycarbonylamino (CbzNH), benzyloxy (OBn), tosyloxy (OTs), hindered ketal, (2-trimethylsilyl)ethoxymethoxy (OSEM), benzylamino (NBz), benzyloxy (OBz) and free amino acid.

Andreia A. Rosatella and Carlos A. M. Afonso, Adv. Synth. Catal. 2011, 353, 2920-2926


Asymmetric synthesis of trans-4,5-dioxygenated cyclopentenone derivatives



Dioxygenated cyclopentenones are versatile building blocks for the synthesis of several natural products. Herein we report a direct asymmetric synthesis of trans-4,5-dioxygenatedcyclopentenone derivatives through base-catalyzed rearrangement of pyranones followed by dynamic kinetic resolution. Milder conditions than previously reported for this rearrangement have been found regarding amine base catalysis, solvent and temperature effects. All data supports a mechanism involving cyclization of an intermediate formed by electrocyclic ring opening of a pyranone-derived enol. We have developed conditions for asymmetric synthesis of trans-4-tert-butoxy-5-hydroxycyclopent-2-enone, in 81% yield and 95% ee, and analogous dioxygenated cyclopentenones, via a lipase induced dynamic kinetic resolution.

J.P.M. Nunes et al., Tetrahedron 2011, 67, 2779-2787


Dehydration of tertiary alcohols



Tertiary alcohols react under mild conditions in the presence of Amberlyst®-15 (dry) (solid-supported sulfonic acid) to give predominantly the most stable alkene in very good yield. The dehydration of tertiary alcohol functionality occurs without observation of rearrangement and polymerization products, and outstanding substrate tolerance which include the NHCBz, NHBoc, OSEM, OTBDMS, OBOM and ethylene ketal functional groups. Amberlyst®-15 (dry) can be easily recovered from the reaction medium and reused for five cycles, maintaining the catalytic efficiency. In addition, the dehydration can occur under continuous operation.

Luís M. T. Frija et al., Tetrahedron 2011, 68, 7414


Efficient Tandem Morita-Baylis-Hillman/Double Cross-Aldol Reaction



The Lewis base N-methylpyrrolidine acts in water as an efficient promoter of tandem reactions between 2 cyclopenten-1-one and aqueous formaldehyde. The reaction pathway includes, as consecutive independent steps, a MBH reaction and a double cross-aldol reaction to furnish the new 2,5,5-tris(hydroxymethyl)-2-cyclopenten-1-one in excellent yield. A range of cyclic enones and 4-nitrobenzaldehyde undergo the tandem reaction similarly. The reaction mechanism was also investigated.

K.P. Guerra, C. A. M. Afonso, Eur. J. Org. Chem. 2011, 2372-2379




Biocatalysis


Enzymatic Resolution and Separation of sec-Alcohols with ILs



Going their different ways: A simple, robust, efficient, and reusable system for the one-pot preparative resolution and separation of sec-alcohols is described. The system is based on the combination of sequential enzymatic kinetic resolution (lipase B from Candida Antarctica, CALB) and transesterification in ionic liquids (ILs) with an ionic acylating agent 1 and removal of each enantiomer by extraction with an organic solvent.

N. M. T. Lourenço, C.A.M. Afonso, Angew. Chem. Int. Ed. 2007, 46, 8178 –8181


Enzymatic Resolution and Separation of sec-Alcohols with fatty esters



A two consecutive step procedure for the resolution-separation of secondary alcohols employing ethyl tetradecanoate in the presence of lipase allowed the enzymatic kinetic resolution of two target molecules, 1-phenylethanol and 6-methylhept-5-en-2-ol. (S)-1-Phenylethanol was isolated in a yield of 47% with an ee of 94% and (R)-1-phenylethanol in a yield of 51% with an ee of 95%. (S)-6-Methylhept-5-en-2-ol was isolated in a yield 47% and an ee of 87% and (R)-6-methylhept-5-en-2-ol in a yield 49% and an ee of 90%.

C. M. Monteiro et al., Tetrahedron: Asymmetry 2010, 21, 952–956




Rhodium catalysis


Selective arylation of aldehydes with di-rhodium(II)/NHC catalysts



Here is described the preparation of four new rhodium(II) complexes bearing axial NHC ligands. The presence of electron-withdrawing bridging ligands resulted in an enhanced reactivity in the arylation of aldehydes with boronic acids when compared with the tetraacetate counterparts. Complex 15 (Rh2tfa4(IPr)2) proved to be the most active catalyst for this transformation allowing the selective conversion of aromatic, aliphatic and vinyl aldehydes into the respective alcohols in excellent yields. It was demonstrated that the good group tolerance could be further extended to aromatic and conjugated ketones. DFT calculations carried out on this system showed the complementarily of the bridging ligands and axial ligand in these dinuclear complexes. It was also disclosed that Rh(II)/NHC catalytic system can promote the racemization of 1-phenyl ethanol.

A.F. Trindade et al., Tetrahedron 2010, 66, 8494-850


C-H Carbene Insertion of a-Diazo Acetamides by Photolysis in Non-Conventional Media



Light from a mercury vapor high-pressure lamp was used to induce the photolytic decomposition of alfa-diazo acetamides in hexane and in nonconventional media such as water or a film. The corresponding beta- and/or gama-lactams were obtained in reasonable yields and in some cases with good diastereoselectivities with no need to use a metallic catalyst. Experimental studies on chiral substrates demonstrated the occurrence of insertion with retention of configuration.

Candeias et al., J. Org. Chem. 2008, 73, 15




Metal Organocatalysis

An efficient and simple Morita-Baylis-Hillman reaction



By using of precise catalytic amount of N-methylpyrrolidine (5 mol %) and Ba(OH)2 (1.5 mol %) in H2O/CH3OH 5/1 or CH3OH/CH2Cl2 3/1 solvent mixtures at T=0 °C a Morita–Baylis–Hillman derivatives could be obtained in good to excellent yield from 2-cyclopenten-1-one, 2-cyclohexen-1-one and formaldehyde and diverse aryl aldehydes after suitable reaction time.

K.P. Guerra, C.A.M. Afonso, Tetrahedron 2011, 67, 2562-2569










Biological Activity



Toxicological evaluation on human colon carcinoma cell line (CaCo-2) of ionic liquids



Toxicological evaluation of a new group of ionic liquids was performed on human colon cancerous cells—CaCo-2. They belong to different classes of cations: imidazolium (IM), dimethyl-guanidinium (dmg) and tetramethyl-guanidinium (tmg), methyl-pyrrolidinium (MPyr), 2-methyl-1-ethyl-pyridinium (2-MEPy), quaternary ammonium (benzyltriethyl-ammonium–BzTEA; phenyltrimethyl-ammonium–PhTMA; tri-n-octyl-methylammonium-Aliquat) and tri-n-hexyl-tetra-n-decylphosphonium (P6,6,6,14). The new results were compared with data obtained in previous reported studies performed in our lab, and we clearly saw that toxicity can vary significantly with the type of anion. Dicyanoamide-[DCA] and bis(trifluoromethanesulfonyl)amide-[NTf2] were seen to visibly change the impact of some cations. Some were considerably less harmful for CaCo-2 monolayer when the anion was [DCA] or [NTf2], while others induced an abnormal increase of cellular metabolism when [NTf2] was present and therefore, they were considered toxic. However, some cations induced similar responses in the presence of a broad number of anions as (1-butyl-3-methylimidazolium)-[C4MIM] (with the exception of [FeCl4]), (1-(2-hydroxyethyl)-3-methylimidazolium)-[C4OHMIM] and [C4MPyr] and did not cause toxicity. Consequently, they are considered promising cations for building human friendlier solvents. But, a reasonable number of other combinations involving different classes of cations were also seen to not significantly affect viability of the CaCo-2 monolayer.

R. F. M. Frade et al., Green Chem., 2009, 11, 1660-1665


New dirhodium complex with activity towards colorectal cancer



A novel dirhodium complex (Rh2(L-PheAla)2(OAc)2 is reported with strong activity towards human colon adenocarcinoma cells. Its effect was not accompanied by generation of reactive oxygen species (ROS) neither by activation of caspase-3.

R. F. M. Frade et al., Bioorg. Med. Chem. Lett. 2010, 20, 3413–3415







Materials


Spectroscopic probes


Two-photon absorption properties of push–pull oxazolones derivatives



New fluorescent oxazolone derivatives with high two-photon absorption cross-section were synthesized. Electron donor (phenyl, dimethylaniline and furanyl) and acceptor (nitrobenzene and ethenyl-phenyl-benzimidazol) groups have been appended to the methylene end of 4-(methylidene)-2-phenyl-1,3-oxazol-5(4H)-one in order to produce an highly conjugated p-system with push–pull geometry. The linear and nonlinear optical properties of the oxazolones have been determined. The compounds with a high charge transfer from the substituent group to the oxazolone ring have relatively high two-photon absorption cross-sections (80–100 GM). The best performing nonlinear fluorophore being the benzimidazol derivative with a two-photon absorption cross-section of 80 GM and a relatively high emission quantum yield 0.31.

C. A. B. Rodrigues et al., Dyes and Pigments 2012, 95, 713-722


Two-Photon absorbing cromophores



Two-Photon Absorbing (TPA) chromophores are molecules that absorb simultaneously two photons, accompanied by the transition of an electron from a lower energy level to a higher level, and release half of the absorbed photons with twice of energy. This type of compounds have attracted high interest in the last few years due to their photochemical properties and subsequent wide range of applications such as microfabrication, data storage, photodynamic therapy, optical power limiting and sensors.

He et al., Chem. Rev. 2008, 108, 1245-1330
Pawlicki et al., Angew. Chem. Int. Ed. 2009, 48, 3244-3266


Photochromic switches



Photochromic switches are molecules that suffer light-induced reversible change of color. A converts to B upon absorption of electromagnetic radiation that induces a chemical transformation resulting in diferent absorption spectra of these two species. Compounds having this property have a wide range of applications in optical data storage and optical switching for optoelectronic devices.

Cusido et al., Eur. J. Org. Chem. 2009, 2031-2045,
Tian et al., J. Mater. Chem. 2008, 18, 1617-1622,
Bouas-Laurent et al., Pure Appl. Chem. 2001, 73, 639-665




Ionic liquids (ILs)


Synthesis and properties of new functionalized guanidinium based ionic liquids as non-toxic versatile organic materials



Functionalized guanidinium ionic liquids as a new class of versatile organic materials have been developed. Guanidinium salts containing olefinic functionalities have been prepared and completely characterized. In order to illustrate the versatility of olefinic units, they were brominated and some bromine-containing ionic liquids have been obtained. Relevant physico-chemical properties of the new synthesized salts were evaluated including their melting points, glass transition temperatures, miscibilities, densities, surface tensions and contact angles with glass and Teflon surfaces. Additionally toxicity studies were performed using the human colon carcinoma CaCo-2 cell line. Several new functionalized guanidinium based ILs showed high densities, low contact angles with Teflon, low surface tensions as well as a non-toxic behaviour.

G.V.S.M. Carrera et al., Tetrahedron 2010, 66, 8785-8794


Dissolution and Transformation of Carbohydrates in Ionic Liquids


Carbohydrates have a high number of hydroxyl groups, which makes them preferentially soluble in water, although this solvent is not always the most suitable. Polar organic solvents, such as pyridine, dimethylsulfoxide and dimethyformamide, are the few solvents able to dissolve carbohydrates however they have a higher impact in the environment and provide a less efficient solvent media due to deactivation in biocatalysis, for instance. A way to overcome these problems is to use Ionic Liquids (ILs). Data suggest that ILs can be acceptable solvents for carbohydrate dissolution and that they lead to higher yield and more selective reactions. In this review, we will focus mainly on monosaccharide dissolution and functional transformation, despite some references to polysaccharides, as an attempt to demonstrate ILs can be a suitable media for carbohydrate chemistry.

Andreia A. Rosatella et al., Curr. Org. Synt. 2011, 8, 840-860




Valorization of natural resources



Short synthesis of the natural product 3β-hydroxy-labd-8(17)-en-15-oic acid via microbial transformation of labdanolic acid



Starting from labdanolic acid, extracted from Cistus ladaniferus plant, the first synthesis of the natural product 3β-hydroxy-labd-8(17)-en-15-oic acid was achieved, via microbial transformation mediated by Penicillium janczewskii followed by dehydration. The structure of a new labdane diterpene, namely 3β-hydroxy-labdanolic acid, was elucidated by X-ray crystallography and spectroscopic data.

Luís M.T. Frija et al., Phytochemistry Letters, 2013, 6, 165


5-Hydroxymethylfurfural (HMF) as a building block platform



We provide a combined overview of 5-hydroxymethylfurfural (HMF) as an important renewable building block, and include discussion of the effects of HMF on microorganisms and humans, HMF production and functional group transformations.

A. A. Rosatella et al., Green Chem., 2011, 13, 754-793


An Integrated Approach for the Production and Isolation of 5-Hydroxymethylfurfural from Carbohydrates



An integrated, simple, efficient, reusable, and scalable methodology for the dehydration of fructose to HMF offers outstanding yields and high purities. The method uses wet tetraethylammonium bromide as reaction medium, allowing the isolation of HMF by crystallization from the reaction medium. The process is also feasible starting from other carbohydrates, such as glucose, sucrose, or inulin.

S. P. Simeonov et al., ChemSusChem., 2012, 5, 1388-1391


Synthetic transformations of Portuguese natural resources derived from Cistus ladaniferus



Cistus ladaniferus (rock rose), called "esteva" in Portugal is a wild, persistent shrub, which is widespread in the center of the Country. From the extract of this plant have been identified 186 compounds, including flagrancies such as Ambrox and diterpenes like labdane derivatives. However, labdanolic acid is one major compound which has been easily isolated in high quantities. Due to the rich structural features of this molecule and the structural similarity to several relevant target bioactive molecules, this investigation focuses on developing efficient methodologies for the chemical and bio-manipulation of labdanolic acid into biological active compounds.

L. M. T. Frija et al., Chem. Rev., 2011, 111, 4418–4452

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