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Since its discovery in the late 1960s, the Morita–Baylis–Hillman (MBH) reaction has remained a powerful carbon–carbon σ-bond-forming transformation, producing small polyfunctionalized molecules. While commonly catalyzed by Lewis basic organic molecules such as tertiary amines and phosphines, several advances in functional catalysts and reaction conditions have been made in order to improve the reaction rate, substrate scope, and enantioselectivity. The goal of this Review is to give an updated summary of the main improvements made in catalytic systems for the MBH reaction over the past decade until nowadays. We hope this account will instigate further investigations in order to circumvent the remaining challenges of this fascinating transformation.

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Background: The most important cause of dementia affecting elderly people is the Alzheimer’s disease (AD). Patients affected by this progressive and neurodegenerative disease have severe memory and cognitive function impairments. Some medicines used for treating this disease in the early stages are based on inhibition of acetylcholinesterase. Population aging should contribute to increase the cases of patients suffering from Alzheimer's disease, thus requiring the development of new therapeutic entities for the treatment of this disease. Methods: The objective of this work is to identify new substances that have spatial structural similarity with donepezil, an efficient commercial drug used for the treatment of Alzheimer's disease, and to evaluate the capacity of inhibition of these new substances against the enzyme acetylcholinesterase. Results: Based on a previous results of our group, we prepared a set of 11 spirocyclohexadienones with different substitutions patterns in three steps and overall yield of up to 59%. These compounds were evaluated in vitro against acetylcholinesterase. We found that eight of them are able to inhibit the acetylcholinesterase activity, with IC50 values ranging from 0.12 to 12.67 µM. Molecular docking study indicated that the spirocyclohexadienone, 9e (IC50 = 0.12 µM), a mixedtype AChE inhibitor, showed a good interaction at active site of the enzyme, including the cationic (CAS) and the peripheral site (PAS). Conclusion: We described the first study aimed at investigating the biological properties of spirocyclohexadienones as acetylcholinesterase inhibitors. Thus, we have identified an inhibitor, which provided valuable insights for further studies aimed at the discovery of more potent acetylcholinesterase inhibitors.

We reported herein an N‐heterocyclic carbene (NHC)‐mediated intermolecular Stetter reaction between oxidized Morita‐Baylis‐Hillman (MBH) adducts and a variety of aldehydes. This protocol allows the synthesis of highly functionalized 1,4‐dicarbonyl compounds. The reaction is an alternative approach to these compounds using commercially available starting materials. This metal‐free process exhibits a wide substrate scope, excellent atom economy, compatibility with functionalized substrates and mild reaction conditions. The 1,4‐dicarbonyl compounds were prepared in two steps via MBH reactions with overall yields up to 99 %. This protocol is easily scalable. The synthetic usefulness of this method was demonstrated in a high yield synthesis of a tri‐substituted pyrrole used as an advanced intermediate in the total synthesis of kinase inhibitors as well as in the synthesis of another heterocycles.

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Background: Triple-negative BC is the most aggressive type of breast cancer and its lack of responsiveness to conventional therapies requires screening of new chemical entities. Anti-migratory compounds are promising to treat metastatic cancer since they inhibit one of the main steps of the metastatic cascade. Spirocyclic compounds are non-conventional structures used as building blocks for the synthesis of biologically active molecules and considered interesting structures in the search for exploration of new targets in cancer research. Objective: Here we evaluated the potential of eight synthetic spirocyclohexadienones as cell migration inhibitors. Methods: The anti-migratory ability of compounds was tested by wound healing and Boyden chamber approaches. Experiments in tubulin were performed by fluorescence and tubulin polymerization techniques. Finally, compounds were submitted to cell proliferation inhibition and flow cytometry assays to explore the mechanism by which they inhibit cell migration. Results: Four compounds inhibited cell migration significantly. Analogs containing the 3,4,5-trimethoxyphenil ring at R1 position were the most potent and thus selected for additional experiments. Tubulin polymerization and fluorescence assays highlighted a possible binding of spirocyclohexadienones in colchicine binding site; however, compounds did not affect cell cycle to the same extent as colchicine. Cell proliferation was affected and, notably, the most potent analogs induced apoptosis of tumor cells, suggesting a different mechanism by which they inhibit cell migration. Conclusion: We presented for the first time a series of eight synthetic spirocyclohexadienones with the ability to inhibit TNBC cell migration. These compounds represent a new category to be explored as anticancer agents.