Publications

Human Adenovirus (HAdV) infections in immunocompromised patients can result in
disseminated diseases with high morbidity and mortality rates due to the absence of
available treatments for these infections. Ircinia felix sponge was selected for the
significant anti-HAdV activity displayed by its organic extracts. Its chemical analysis
yielded three novel sesterterpene lactams, ircinialactams J-L, along with three known
sesterterpene furans which structures were established by a deep spectrometric
analysis. Ircinialactam J displayed significant antiviral activity against HAdV without
significant cytotoxicity, showing an effectiveness 11 times greater than that of the
standard treatment, cidofovir®. Some structure-activity relationships were deduced.
Mechanistic assays suggest that ircinialactam J targets an early step of the HAdV
replicative cycle before HAdV genome reaches the nucleus of the host cell. The first
total synthesis of ircinialactam J was also accomplished to prove the structure and to
provide access to analogues. Key steps are a regio- and stereoselective construction
of the trisubstituted Z-olefin at Δ7 by iron-catalyzed carbometallation of a
homopropargylic alcohol, a stereoselective methylation to generate the stereogenic
center at C18, and the formation of the (Z)-Δ20 by stereoselective aldol condensation
to introduce the tetronic acid unit. Ircinialactam J is a promising antiviral drug against
HAdV infections.

A new atom-economical synthesis of β-alkenyl-substituted BODIPYs via indium(III)-catalyzed intermolecular alkyne
hydroarylation with meso-substituted BODIPYs is described. While catalysis with InI3 allows the double β-functionalization of
BODIPY, resulting in regioselectively branched β,β′-disubstituted alkenyl BODIPYs, catalytic InCl3 enables the formation of linear
β-substituted alkenyl BODIPYs. Subsequent In(III)-catalyzed intermolecular alkyne hydroarylation allows the synthesis of
unsymmetrical push−pull BODIPY derivatives. Therefore, indium catalysis offers complementary regioselectivity in good chemical
yields and functional group tolerance. The resulting BODIPY dyes displayed bathochromically shifted absorption and emission
according to the electron-nature of the substituents in the alkenyl moiety with high molar extinction coefficients (ε up to 88,200 M−1
cm−1) and quantum yields (0.14−0.96).

Tandem cycloisomerization reactions of functionalized 1,6-enynes under indium(III) catalysis are described. This atom-economic transformation proceeds smoothly with 5-exo-dig regioselectivity using commercial In(III) halides and 1,6-enynes furnished with alcohol, carboxylic acid or amine functional groups to give bicyclic structures in good yields and diastereoselectivities. The reaction with enynals involves a three–step mechanism to give an oxatricycle and a conjugated 1,3-diene. In the absence of the internal nucleophile the enyne cycloisomerization evolves through a skeletal rearrangement or a cyclopropanation reaction after the regioselective 5-exo-dig cyclization. The 1,6-enyne cycloisomerization is stereospecific and the stereoselectivity appears to be independent of the internal nucleophile. Experimental data support a common reaction mechanism involving an initial alkyne electrophilic p-coordination of In(III) followed by Markovnikov electrophilic alkene addition and ring-closure by nucleophilic attack. DFT studies hold up a stepwise mechanism involving the formation of a chiral non-classical carbocation intermediate that determines the diastereoselectivity of this tandem cycloisomerization reaction.

In this chapter the metal-catalyzed cross-coupling reactions of indium organometallics are reviewed. First, the various methods for the preparation of organoindium (transmetalation, direct insertion and indation of alkynes) are described and their structure are analyzed. Then, the reactivity in metal-catalyzed reactions is reviewed according to an organization based on the metal catalyst. The main section is the cross-coupling reaction under palladium catalysis which includes a general introduction, synthetic scope analysis, versatility and applications of the different indium organometallics and the reactive organic electrophiles (aryl, alkenyl, alkyl halides, triflates and others). Finally, other metal-catalyzed cross-coupling reactions are included along with general conclusions.

Overall, indium organometallics are shown as useful reagents for cross-coupling reactions with a variety of organic electrophiles. Their main features are the readily transmetalation to different transition metal complexes (palladium, nickel, rhodium, copper or iron) to transfer the organic groups attached to indium, and the high versatility and chemoselectivity as well.

1H-Isochromenes and 1,2-dihydroisoquinolines are synthesized
by regioselective indium(III)-catalyzed intramolecular hydrofunctionalization
of o-(alkynyl)benzyl derivatives. The reaction with o-
(alkynyl)benzyl alcohols and amines proceeds using indium triiodide
(5–10 mol%) in toluene at 80–100 °C via regioselective 6-endo-dig intramolecular
alkyne hydroalkoxylation or hydroamination in good yields.
Alternatively, the cycloisomerization reaction of o-(alkynyl)benzaldehydes
and imine derivatives using InI3 (5 mol%) and the Hantzsch ester
(120 mol%) takes place, under milder reaction conditions, to give a variety
of functionalized 1H-isochromenes and 1,2-dihydroisoquinolines
through a domino cycloisomerization/reduction approach.

The novel indium-catalyzed synthesis of benzannulated spiroketals by a double intramolecular hydroalkoxylation reaction of o-(hydroxyalkynyl)benzyl alcohols is reported. The reaction proceeds under mild reaction conditions using a low catalyst loading of indium triiodide (2–5 mol%) with a variety of benzyl
and homobenzyl alcohols, allowing the regioselective synthesis of a set of naturally occurring and new benzannulated spiroketals (5,5-, 5,6-, 5,7-, 6,6- and 6,7-) in good yields. The synthetic transformationinvolves the indium(III)-catalyzed electrophilic alkyne activation followed by the regioselective intramolecular hydroalkoxylation reaction. The method is the first example of spiroketal synthesis using main group catalysis representing an economical alternative to precious transition metals. In addition, it provides a complementary strategy for the regioselective synthesis of spiroketals and spiroaminals

A microwave-assisted one-pot synthesis of BODIPY dyes from pyrroles and acyl chlorides is reported. This protocol features short reaction times, low temperatures, minimum amount of solvent, scalability, versatility, and good yields of the products. These simple, efficient and sustainable conditions can be also
applied to the synthesis of derivatives such as BOPHY, BOAHY and BOPAHY.

Fluorescent imidazole-triazole based ligands L1 and L2 have been designed as chemical push-pull chemosensors for divalent metal ions and synthesized through palladium-catalyzed cross-coupling reactions using indium organometallics and click chemistry. The novel ligands exhibit intense absorption in the ultraviolet region with high molar extinction coefficients, and strong fluorescence emission with large Stokes displacements.
On the basis of UV–Vis absorption spectroscopy and fluorescence emission data in acetonitrile, L1 is shown as a bifuncional chemosensor with differential response for Fe2+ and Cu2+ over a range of selected 3d divalent and other metal ions. The binding site of the ligand was established by single-crystal X-ray diffraction and 1H NMR
spectroscopy studies. The association constants, determined by spectrofluorimetric titrations, show a steady binding affinity of L1 for Cu2+ and Fe2+ in comparison with other previously reported fluorescent bidentate chemosensors, offering the lowest limit of detection (LOD) with Cu2+. DFT calculations provide a rationale properly understanding and interpreting the experimentally observed results. Indeed, a mechanism of the different optical responses of L1 towards 3d divalent metal ions is proposed.

Boron-dipyrromethene complexes (BODIPYs) are attracting a growing interest for their notable photophysical properties.
Specifically, their application in organic photocatalysis is receiving particular attention thanks to their ability to undergo both electron and energy transfer processes, thus acting as promising photoredox catalysts and photosensitizers.
Although the number of examples employing these organic dyes is constantly increasing, there are not so many studies that correlate their chemical composition to their photocatalytic activity.
In this work, a rationally designed structure-activity relationship study was performed by selecting a synthetically relevant atom transfer radical addition (ATRA) reaction as a benchmark. We demonstrated how the presence of heavy atoms in the chromophore’s core turned out to be essential for achieving high reactivity levels. On the contrary, electronwithdrawing groups in position 8 (meso) undermined the catalytic performances, in agreement with the proposed reaction mechanism.

A versatile and efficient method to prepare borylated arenes furnished with alkyl, alkenyl, alkynyl, aryl and heteroaryl functional groups is developed by merging Ir-catalyzed C–H borylations (CHB) with a chemoselective palladium-catalyzed cross-coupling of triorganoindium reagents (Sarandeses-Sestelo coupling) with aryl halides bearing a boronic ester substituent. Using triorganoindium cross-coupling reactions to introduce unsaturated moieties enables the synthesis of borylated arenes that would be difficult to access through the direct application of the CHB methodology. The sequential double catalyzed procedure can be also performed in one vessel.

The indium(III)-catalyzed cascade cycloisomerization reaction of 1,5-enynes with pendant aryl nucleophiles is reported. The reaction proceeds in cascade, under mild reaction conditions, using InI₃ (5 mol%) as catalyst with a range of 1,5-enynes furnished with aryl groups (phenyl and phenol) at the alkene (E and Z isomers) and with terminal and internal alkynes. Using 1-bromo-1,5-enynes a one-pot sequential indium-catalyzed cycloisomerization and palladium-catalyzed cross-coupling with triorganoindium reagents was developed. The double cyclization is stereospecific and operates via a biomimetic cascade cation-olefin through a 1,5-enyne cyclization (6-endo–dig) and subsequent C–C hydroarylation or a C–O phenoxycyclization. DFT computational studies on 1,5-enynyl aryl ethers support a two-step mechanism where the first stereoselective 1,5-enyne cyclization produce a non-classical carbocation intermediate that evolves to the tricyclic reaction product through a S_EAr mechanism. Using this approach, a variety of tricyclic heterocycles such as benzo[b]chromenes, phenanthridines, xanthenes, and spiroheterocyclic compounds are efficiently synthesized with high atom economy.