Multicomponent reactions (MCRs) are important transformations, which allow the attainment of structurally complex derivatives in a single step, starting from three or more compounds with relatively simple structures. These reactions are generally associated with the principles of green chemistry, allowing the incorporation of most (or all) atoms of the starting materials in the products (atom economy) and reducing purification steps (and, consequently, the need for solvents and waste production). For a long time, asymmetric methodologies (in special enantioselective protocols) for most multicomponent transformations remained a gap in the literature, limiting the use of these reactions to produce derivatives only as racemates or in low diastereoselectivities. Over the last two decades, a better comprehension of the mechanisms associated with these transformations allowed the development of efficient enantio- and diastereoselective procedures, attracting the interest of both academia and industry. In this review, selected examples of four important multicomponent reactions (Strecker, Mannich, Passerini and Ugi) will be discussed, presenting a general overview of the development of this field and pointing out possible advantages and limitations of the above mentioned methodologies. In some cases, discussions around mechanisms, proposed transition states and activation modes will be detailed disclosed.

Transformations involving structurally complex molecules, natural products and representative molecules are extremely important to obtain key reaction intermediates, in addition to accessing molecules with bioactive properties. The development of cyanation methodologies in those molecules becomes important, because nitriles are versatile and important building blocks in organic synthesis. They can be converted into other organic functions, including amines, alcohols, α-amino acids and various carbonyl compounds and can therefore become relevant synthetic intermediates. Recent studies show new and intriguing asymmetric cyanation protocols or reagents as those that use electrophilic cyanide source, metal- and oxidant-free or avoid the use of toxic cyanide reagents. Photoredox catalysis emerges as a relevant approach from the point of view of green and sustainable chemistry; usually provides access to the versatile skeleton of α-aminonitriles that among their various modes of reactivity and provide access to reactive iminium ion. Thus, this perspective aims to highlight these impressive advances as well as to show their main advantages and applications.

RECENT ADVANCES IN THE SYNTHESIS OF REMDESIVIR, MOLNUPIRAVIR (EIDD-2801) AND TENOFOVIR: PROMISING MOLECULES IN THE TREATMENT OF COVID-19. The search for new treatments to contain the Covid-19 pandemic has highlighted the importance of nucleoside antivirals, such as Remdesivir, Tenofovir and Molnupiravir. Over the last two years, these molecules have been intensely investigated as promising alternatives against SARS-CoV-2 virus. Considering the increasingly demand for those substances, several research groups are intensely investigating synthetic developments in order to obtain these nucleoside derivatives and their intermediates in a fast, efficient and accessible manner. In this context, this review aims to in-depth present the recent advances concerning the preparation of Remdesivir, Tenofovir and Molnupiravir. Aspects involving differences in the starting materials and reagents, as well as the advantages and limitations of each protocol would be carefully disclosed. Moreover, the use of synthetic tools, such as flow chemistry, organocatalysis and biocatalysis, would also be detailed. Finally, this review also presents aspects involving the scale-up of these transformations, including discussions about stereo- and diastereoselectivity, as well as product isolation details. In summary, an overview of the existing synthetic strategies for these active pharmaceutical ingredients (APIs) are presented.

4-Aminopyrrolo[2,1-f][1,2,4]triazine is a fundamental raw material in the synthesis of remdesivir, which demand has increased due to the tests and potential repositioning of this drug against Coronavirus disease 2019 (COVID-19). Here, three chemical steps route for the preparation of remdesivir’s nucleobase is described. Particularly, a highly chemoselective cyanation of Klein’s route and successful application of monochloramine prepared from commercial bleach as an N-amination reagent are presented.

Cancer is a chronic degenerative disease considered one of the most important causes of death worldwide. In this context, a series of dual-protected amino acid derivatives was synthesized and evaluated as potential novel anticancer agents. The 40 derivatives were prepared in up to three reaction steps. The cytotoxic activities were screened in vitro against a panel of tumor and non-tumor cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among the synthesized derivatives, three of them showed promising activity against cancer cells with half-maximal inhibitory concentration (IC50) ranging between 1.7-6.1 µM. The most promising derivative, bearing both a lipophilic N-alkyl diamine moiety and a protected amino acid scaffold showed a selectivity index of 3.4 towards tumor cells. The N-alkyl diamine moiety seems to play a crucial role in the enhancement of the anticancer activity. On the other hand, the incorporation of an amino acid scaffold resulted in increase in the selectivity towards cancer cell lines.

New insights into the formation of azlactone heterocycles bearing different substituents are hereby presented. The sum of both kinetic and thermodynamic factors contributes for the formation of 2-alkyl or 2-aryl substituted azlactones, while the cyclization of 2-alcoxy azlactones is less favored. These results are in perfect accordance with experimental observations obtained by infrared (IR) and electrospray ionization mass spectrometry (ESI(+)-MS) of the crude reaction mixture.

Nickel complexes have been widely used as catalysts in organic reactions. Their low price compared to Pd and Pt complexes, in addition to their high reactivity and affinity to ϖ systems; the possibility to access different oxidation states and the difficulty to undergo beta-hydride elimination are important features that have attracted the attention of chemists in recent decades. Furthermore, some drawbacks observed with Pd catalysis have been solved by Ni catalysis. These Ni based-catalysts have been used in different reaction manifolds to promote challenging transformations. Herein, recent work using nickel catalysts in different types of reactions, such as carbonylations, carboxylations, C-H activations and dual catalytic systems are described. Critical mechanistic investigations, as well as synthetic applications are also covered.

Azlactones are useful building blocks in the synthesis of functional amino acid derivatives, heterocycles and bioactive molecules. In this work, a protocol for the organocatalytic functionalization of dipeptides has been presented. 2-Alkyl-substituted azlactone intermediates in the presence of different amines and alcohols were combined in a ring opening reaction approach. The products were synthesized in moderate to excellent isolated yields, providing new insights in peptide transformations involving carbodiimide activation.

In the past few years, photoredox catalysis has become a powerful tool in the field of organic synthesis. Using this efficient method, it is possible to excite organic compounds from visible light and attain alternative mechanistic pathways for the formation of chemical bonds, a result which is not obtainable by classical methods. The rapid growth of work in the area of photoredox catalysis is due to its low cost, broad chemical utility protocols, and, especially, its relevancy from the green and sustainable chemistry viewpoints. Thus, this study proposes a brief theoretical discussion of and highlights recent advances in visible-light-induced photoredox catalysis through the analysis of catalytic cycles and intermediates.

The philosophy of organocatalysis is based on the utilization of organic compounds to catalyze organic transformations without the intervention of metals. This area has attracted much attention of the synthetic chemistry community on the last years, which can be confirmed by the explosion of published papers dealing with this subject. Phosphorus compounds, urea and thiourea derivatives, alkaloids, guanidine derivatives, for example, have already been used as organocatalysts. In this review we have focused on the use of chiral amines as organocatalyst. We have also chosen some outstanding examples to demonstrate the potentiality of this strategy in the synthesis of natural products and biologically active compounds.