Lithiation of 4-membered heterocycles as useful strategy for the preparation of new molecular scaffolds: addressing the regioselectivity in azetidines and thietanes

Four-membered heterocycles (4-MH) with one or two heteroatoms are of great importance in medicinal chemistry and synthetic organic chemistry. This kind of scaffolds show peculiar structural features, related to the ring “puckering”, and biological properties. Our recent research efforts have been focused on the stereoselective synthesis and functionalization of some 4-MH such as azetidines, thietanes and oxazetidines

Imaging of Inflammation in Spinal Cord Injury: Novel Insights on the Usage of PFC-Based Contrast Agents

Labeling of macrophages with perfluorocarbon (PFC)-based compounds allows the visualization of inflammatory processes by 19F-magnetic resonance imaging (19F-MRI), due to the absence of endogenous background. Even if PFC-labeling of monocytes/macrophages has been largely investigated and used, information is lacking about the impact of these agents over the polarization towards one of their cell subsets and on the best way to image them. In the present work, a PFC-based nanoemulsion was developed to monitor the course of inflammation in a model of spinal cord injury (SCI), a pathology in which the understanding of immunological events is of utmost importance to select the optimal therapeutic strategies. The effects of PFC over macrophage polarization were studied in vitro, on cultured macrophages, and in vivo, in a mouse SCI model, by testing and comparing various cell tracking protocols, including single and multiple administrations, the use of MRI or Point Resolved Spectroscopy (PRESS), and application of pre-saturation of Kupffer cells. The blood half-life of nanoemulsion was also investigated by 19F Magnetic Resonance Spectroscopy (MRS). In vitro and in vivo results indicate the occurrence of a switch towards the M2 (anti-inflammatory) phenotype, suggesting a possible theranostic function of these nanoparticles. The comparative work presented here allows the reader to select the most appropriate protocol according to the research objectives (quantitative data acquisition, visual monitoring of macrophage recruitment, theranostic purpose, rapid MRI acquisition, etc.). Finally, the method developed here to determine the blood half-life of the PFC nanoemulsion can be extended to other fluorinated compounds

Synthesis of NH-sulfoximines from sulfides by chemoselective one-pot N- and O-transfers

Direct synthesis of NH-sulfoximines from sulfides has been achieved through O and NH transfer in the same reaction, occurring with complete selectivity. The reaction is mediated by bisacetoxyiodobenzene under simple conditions and employs inexpensive N-sources. Preliminary studies indicate that NH-transfer is likely to be first, followed by oxidation, but the reaction proceeds successfully in either order. A wide range of functional groups and biologically relevant compounds are tolerated. The use of AcO15NH4 affords 15N-labeled compounds

Synthesis of Sulfoximine Carbamates by Rhodium-Catalyzed Nitrene Transfer of Carbamates to Sulfoxides

Sulfoximines are of considerable interest for incorporation into medicinal compounds. A convenient synthesis of <i>N</i>-protected sulfoximines is achieved, under mild conditions, by rhodium-catalyzed transfer of carbamates to sulfoxides. The first examples of 4-membered thietane-oximines are prepared. Sulfoximines bearing Boc and Cbz groups are stable to further cross coupling reactions, and readily deprotected. This method may facilitate the preparation of <i>NH</i>-sulfoximines providing improved (global) deprotection strategies, which is illustrated in the synthesis of methionine sulfoxide (MSO)

Regioselective functionalization of 2-arylazetidines: evaluating the ortho-directing ability of the azetidinyl ring and the a-directing ability of the N-substituent

The regioselective lithiation–functionalization of 2-arylazetidines has been explored. The nature of the N-substituent is mainly responsible for a regioselectivity switch. ortho-Lithiation occurred, using hexyllithium as a greener base, in N-alkylazetidines, while abenzylic lithiation has been observed with N-Boc azetidines

Exploiting structural and conformational effects for a site-selective lithiation of azetidines

Interest in molecular structures bearing four-membered heterocycles (FMHs) is growing due to the possibility to explore new regions of the chemical space and get new lead molecules. Our interest in the development of divergent synthesis of functionalized FMHs, prompted us to disclose factors affecting the reactivity of nitrogen-bearing FMHs towards metalating agents. Our investigations demonstrated that structural factors and conformational preferences need to be considered in planning a site-selective functionalization of azetidines. It will be showed how such factors could have pivotal importance in the reactivity of FMHs

Regio- and Stereoselective Synthesis of Sulfur-Bearing Four-Membered Heterocycles: Direct Access to 2,4-Disubstituted Thietane 1-Oxides

Starting from readily available C2-substituted thietane 1-oxides, a straightforward synthesis of new C2,C4-disubstituted thietane 1-oxides has been developed by using a lithiation/electrophilic trapping sequence. The chemical and configurational stability of lithiated C2-substituted thietane 1-oxides has been investigated as well as the stereochemical implications for this process. The results demonstrate that a stereoselective functionalization at the C2, C4 positions of a thietane is feasible, leaving intact the four-membered ring

2-Arylazetidines as ligands for nicotinic acetylcholine receptors

Alternative and complementary procedures were adopted for preparing 2-arylazetidine derivatives in moderate to good yields. Preliminary biological evaluation of 2-arylazetidines as ligands of nicotinic acetylcholine receptors allowed to identify chloro-substituted analogs as the most interesting congeners. The title compounds may be considered as suitable hit compounds for developing new nicotinic acetylcholine receptor ligands that may be safer than the currently available drugs targeting nicotinic acetylcholine receptors. Our described synthetic approaches enable facile access to a large number of diversely decorated azetidines for studying the structure–activity relationships and for refining the toxico-pharmacological profile of these agents

Harnessing the <i>ortho</i>-directing ability of the azetidine ring for the regioselective and exhaustive functionalization of arenes

This work demonstrates how the directing ability of the azetidine ring could be useful for regioselective ortho-C-H functionalization of aryl compounds. Robust polar organometallic (lithiated) intermediates are involved in this synthetic strategy. The reagent n-hexyllithium emerged as a safer, yet still effective, basic reagent for the hydrogen/lithium permutation relative to the widely used reagent nBuLi. Two different reaction protocols were discovered for regioselective lithiation at the ortho positions adjacent to the azetidine ring, which served as a toolbox when other competing directing groups were installed on the aromatic ring. The coordinating ability of the azetidine nitrogen atom, as well as the involvement of dynamic phenomena related to the preferential conformations of 2-arylazetidine derivatives, were recognized to be responsible for the observed reactivity and regioselectivity. A site-selective functionalization of the aromatic ring was achieved for aryl azetidines with either coordinatively competent groups (e.g. methoxy) or inductively electron-withdrawing substituents (e.g. chlorine and fluorine). By fine-tuning the reaction conditions, regioselective introduction of several substituents on the aromatic ring could be realized. Several substitution patterns were accomplished, which included 1,2,3-trisubstitution, 1,2,3,4-tetrasubstitution, and 1,2,3,4,5-pentasubstitution, up to the exhaustive substitution of the aromatic ring