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.

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.

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.

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.