In the last two decades, enantioselective organocatalysis has established itself as one of the three pillars of asymmetric catalysis. The rapid growth in the area is due to the rationalization of organocatalysis based on the generic modes of catalyst activation, being applied to several types of reactions, in a rather generic and predictable way and providing high enantioselectivities. This tutorial review presents the evolution of this area through a brief discussion on all generic modes of activation previously systematized in the literature: activation via enamine, iminium ion, hydrogen-bonding, counterion, SOMO, photoredox, carbene and phase-transfer, and the recent advances in the area.

Abstract Background: Despite the development of new therapies for leishmaniasis, among the 200 countries or territories reporting to the WHO, 87 were identified as endemic for Tegumentary Leishmaniasis and 75 as endemic for Visceral Leishmaniasis. The identification of antileishmanial drug candidates is essential to fill the drug discovery pipeline for leishmaniasis. In the hit molecule LQB-118 selected, the first generation of pterocarpanquinones was effective and safe against experimental visceral and cutaneous leishmaniasis via oral delivery. In this paper, we report the synthesis and antileishmanial activity of the second generation of pterocarpanoquinones. Methods: The second generation of pterocarpanquinones 2a-f was prepared through a palladium-catalyzed oxyarylation of dihydronaphtalen and chromens with iodolawsone, easily prepared by iodination of lawsone. The spectrum of antileishmanial activity was evaluated in promastigotes and intracellular amastigotes of L. amazonensis, L. braziliensis, and L. infantum. Toxicity was assessed in peritoneal macrophages and selective index calculated by CC50/IC50. Oxidative stress was measured by intracellular ROS levels and mitochondrial membrane potential in treated cells. Results: In this work, we answered two pertinent questions about the structure of the first-generation pterocarpanquinones: the configuration and positions of rings B (pyran) and C (furan) and the presence of oxygen in the B ring. When rings B and C are exchanged, we noted an improvement of the activity against promastigotes and amastigotes of L. amazonensis and promastigotes of L. infantum. As to the oxygen in ring B of the new generation, we observed that the oxygenated compound 2b is approximately twice as active against L. braziliensis promastigotes than its deoxy derivative 2a. Another modification that improved the activity was the addition of the methylenedioxy group. A variation in the susceptibility among species was evident in the clinically relevant form of the parasite, the intracellular amastigote. L. amazonensis was the species most susceptible to novel derivatives, whilst L. infantum was resistant to most of them. The pterocarpanoquinones (2b and 2c) that possess the oxygen atom in ring B showed induction of increased ROS production. Conclusions: The data presented indicate that the pterocarpanoquinones are promising compounds for the development of new leishmanicidal agents.

A reação entre o iodo e a N-metil-piperazina ou a tiomorfolina em água, na presença de KI, levou a formação de complexos amina-iodo estáveis e de fácil manipulação, tal qual o complexo morfolina-iodo, previamente descrito na literatura. Entretanto, o complexo formado entre o iodo e a N,N-tetrametiletilenodiamina mostrou-se pouco estável, enquanto que nenhum complexo foi isolado quando a piperidina foi usada como base. Estes resultados mostram que a presença do segundo heteroátomo na estrutura das aminas é fundamental para a formação e estabilidade desses complexos. Neste trabalho descrevemos, pela primeira vez, o emprego dos complexos morfolina-iodo, N-metil-piperazina-iodo e tiomorfolina-iodo como agentes de iodação de vários fenóis substituídos, conduzindo a uma série de produtos iodados em rendimentos variando de bons a excelentes.

The reaction between iodo and N-methyl-piperazine or thiomorpholine in water, in the presence of KI, led to the formation of stable and easy to handle amine-iodine complexes, as the complex morpholine-iodo previously reported in the literature. However, the complex obtained using N,N-tetrametylethylenediamine proved less stable, while no complex was formed when piperidine was used as base. These results show that the presence of a second heteroatom in the structure of amines is of fundamental importance for the formation and stability of these complexes. In this work we describe, for the first time, the use of complexes morpholine-iodo, N-methyl-piperazine-iodo and thiomorpholine-iodo as iodinating reagents of several substituted phenols, leading to iodinated products in good to excellent yields.