Marco Blangetti

Suzuki-Miyaura Cross-Coupling in Acylation Reactions, Scope and Recent Developments

Since the first report and due to its handiness and wide scope, the Suzuki-Miyaura (SM) cross coupling reaction has become a routine methodology in many laboratories worldwide. With respect to other common transition metal catalyzed cross couplings, the SM reaction has been so far less exploited as a tool to introduce an acyl function into a specific substrate. In this review, the various approaches found in the literature will be considered, starting from the direct SM acylative coupling to the recent developments of cross coupling between boronates and acyl chlorides or anhydrides. Special attention will be dedicated to the use of masked acyl boronates, alkoxy styryl and alkoxy dienyl boronates as coupling partners. A final section will be then focused on the acyl SM reaction as key synthetic step in the framework of natural products synthesis.

Strigolactone Analogs as Molecular Probes in Chasing the (SLs) Receptor/s: Design and Synthesis of Fluorescent Labeled Molecules

Originally identified as allelochemicals involved in plant-parasite interactions, more recently, Strigolactones (SLs) have been shown to play multiple key roles in the rhizosphere communication between plants and mycorrhizal fungi. Even more recent is the hormonal role ascribed to SLs which broadens the biological impact of these relatively simple molecules. In spite of the crucial and multifaceted biological role of SLs, there are no data on the receptor(s) which bind(s) such active molecules, neither in the producing plants nor in parasitic weeds or AM fungi. Information about the putative receptor of SLs can be gathered by means of structural, molecular, and genetic approaches. Our contribution on this topic is the design and synthesis of fluorescent labeled SL analogs to be used as probes for the detection in vivo of the receptor(s). Knowledge of the putative receptor structure will boost the research on analogs of the natural substrates as required for agricultural applications.

Homo- and Hetero-oxidative Coupling of Benzyl Anions

The regioselective benzylic metalation of substituted toluenes using BuLi/KO-t-Bu/TMP(H) (LiNK metalation conditions) with subsequent in situ oxidative C-C coupling has been developed for the facile generation of 1,2-diarylethanes. A range of oxidants can be used for the oxidative coupling step, with 1,2-dibromoethane proving optimal. Heterocouplings can be achieved starting from a mixture of two different toluenes with a bias toward cross coupling achievable by using a 2-fold excess of one toluene starting material. The utility of this approach is illustrated by the synthesis of several biologically active natural products. A distinct advantage is that the synthetic steps typically required to preactivate the coupling substrates are eliminated and no transition metal is required to facilitate the C-C bond formation.

Furazan and furoxan sulfonamides are strong α-carbonic anhydrase inhibitors and potential antiglaucoma agents

A series of furazan and furoxan sulfonamides were prepared and studied for their ability to inhibit human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, hCA II, hCA IX, and hCA XII. The simple methyl substituted products 3-5 were potent inhibitors. Differing structural modifications of these leads had differing effects on potency and selectivity. In particular, products in which the sulfonamide group is separated from the hetero ring by a phenylene bridge retained high potency only on the hCA XII isoform. The sulfonamides 3-5 exerted intraocular pressure (IOP) lowering effects in vivo in hypertensive rabbits more efficiently than dorzolamide. Some other products (39-42), although less effective in vitro hCA II/XII inhibitors, also effectively lowered IOP in two different animal models of glaucoma.

LIC-KOR-promoted synthesis of alkoxydienyl amines: an entry to 2,3,4,5-tetrasubstituted pyrroles.

A stereoselective approach to the synthesis of (E)-alkoxydienylamines (2) is described, starting from alpha,beta-unsaturated acetals (1) and aryl imines, under superbasic conditions. These can be readily converted into alpha-arylglycine derivatives (3) by mild acidic hydrolysis or, in turn, cyclized under oxidative conditions in the presence of a Pd catalyst to 2,3,4,5-tetrasubstituted pyrroles (4).

Light-Tunable Generation of Singlet Oxygen and Nitric Oxide with a Bichromophoric Molecular Hybrid: a Bimodal Approach to Killing Cancer Cells.

The design, synthesis, photochemical properties, and biological evaluation of a novel photoactivatable bichromophoric conjugate are reported. The compound 1, [4‐(4,4‐difluoro‐2,6‐diiodo‐1,3,5,7‐tetramethyl‐4‐bora‐3a,4a‐diaza‐s‐indacen‐8‐yl)‐N‐(3‐((4‐nitro‐3‐(trifluoromethyl)phenyl)amino)propyl)butanamide] combines a 2,6‐diiodo‐1,3,5,7‐tetramethyl BODIPY derivative as singlet oxygen (1O2) photosensitizer and 4‐nitro‐3‐(trifluoromethyl)aniline (NOPD) as nitric oxide (NO) photodonor, joined by an alkyl spacer. These two chromogenic units absorb in distinct regions of the visible spectrum, and their individual photochemical properties are conserved in the molecular conjugate. Irradiation of the bichromophoric conjugate with green light afforded 1O2 in high quantum yields, whereas 1O2 production was negligible with the use of blue light; under this latter condition, NO was released. Photogeneration of NO and cytotoxic 1O2 can therefore be regulated by appropriately tuning the excitation light wavelength and intensity. Tested on melanoma cancer cells, this resulted in amplified photomortality relative to that of a structurally correlated model compound 2 [4‐(4,4‐difluoro‐2,6‐diiodo‐1,3,5,7‐tetramethyl‐4‐bora‐3a,4a‐diaza‐s‐indacen‐8‐yl)‐N‐(3‐(p‐tolylamino)propyl)butanamide] deprived of the NO‐release capacity. The cellular uptake of 1, evaluated by confocal fluorescence microscopy, showed that the product is localized in the cytoplasm.

Overcoming multidrug resistance by targeting mitochondria with NO-donating doxorubicins

A library of nitric oxide-donor doxorubicins (NO-DOXOs) was synthesized by linking appropriate NO-donor moieties at C-14 position through an ester bridge. Their hydrolytic stability was evaluated. The intracellular accumulation and cytotoxicity of these novel NO-DOXOs were studied in DOXO-sensitive (HT29) and DOXO-resistant (HT29/dx) tumor-cells. Hydrolytically-stable compounds accumulated in HT29 and HT29/dx cells, thanks to the nitration of plasma-membrane efflux transporters. Surprisingly, no close correlation was found between intracellular accumulation and cytotoxicity. Only compounds with high mitochondria retention (due to nitration of mitochondrial efflux transporter) exert high cytotoxicity, through the activation of a mitochondrial-dependent apoptosis.

N-Metalated imines by reaction of 1,1-diethoxybut-2-ene with aromatic nitriles, as useful intermediates for the synthesis of substituted pyrimidines and cyclopentenones

A new approach to the synthesis of pyrimidines and cyclopentenones is described. The method exploits the reactivity of alpha,beta-unsaturated acetals with aromatic nitriles in the presence of the Schlossers superbase LIC-KOR.

Light-Regulated NO Release as a Novel Strategy To Overcome Doxorubicin Multidrug Resistance.

Nitric oxide (NO) release from a suitable NO photodonor (NOP) can be fine-tuned by visible light stimuli at doses that are not toxic to cells but that inhibit several efflux pumps; these are mainly responsible for the multidrug resistance of the anticancer agent doxorubicin (DOX). The strategy may thus increase DOX toxicity against resistant cancer cells. Moreover, a novel molecular hybrid covalently joining DOX and NOP showed similar increased toxicity toward resistant cancer cells and, in addition, lower cardiotoxicity than DOX. This opens new and underexplored approaches to overcoming the main therapeutic drawbacks of this chemotherapeutic based on light-controlled release of NO.

Use of mixed Li/K metal TMP amide (LiNK chemistry) for the synthesis of [2.2]metacyclophanes

Summary A new two-step general approach to [2.2]metacyclophane synthesis from substituted m-xylenes is described. The strategy employs a selective benzylic metalation and oxidative C–C bond formation for both synthetic operations. Regioselective benzylic metalation is achieved using the BuLi, KOt-Bu, TMP(H) (2,2,6,6-tetramethylpiperidine) combination (LiNK metalation conditions) and oxidative coupling with 1,2-dibromoethane. The synthetic ease of this approach compares favourably with previously reported methods and allows for ready access to potentially useful planar chiral derivatives.