ReviewMorita–Baylis–Hillman adducts: Biological activities and potentialities to the discovery of new cheaper drugs
Graphical abstract
This review aims to present by the first time the Morita–Baylis–Hillman adducts (MBHA) as a new class of bioactive compounds and highlight its potentialities to the discovery of new green efficient drugs.
Introduction
The Morita–Baylis–Hillman reaction (MBHR) is a relatively recent form to the C–C bond formation.1, 2 This reaction occurs between an sp2 electrophilic carbon (e.g., aldehydes, ketones or imines) and the α position of an alkene (or alkyne) connected to an electron-attractors groups (EAG), under tertiary amines as nucleophilic catalysis, being 1,4-diazabicyclo [2.2.2]octane (DABCO) widely used catalyst (Scheme 1).3 This reaction generates compounds called Morita–Baylis–Hillman adducts (MBHA). The MBHA have been widely used as the starting material in the natural and unnatural products synthesis.4 When the group X is N (typically NTs) this reaction is classified as Aza-MBHR and products of this reaction are the Aza-MBHA.4
This reaction has important features such as the complete atom economy, the possibility of being performed in an aqueous medium or in absence of solvents and on free-metal condition (organocatalysis). These characteristics are today receiving great attention of the synthetic organic chemists which work into academic and industries laboratories on searching on the more ecological, efficient and cheap synthetic protocols to new drug discovery.
A pivotal limitation described in several articles about this reaction is the long reaction time, for example, there are reactions that were performed in more than 65 days.3 However, due to the synthetic utility of these MBHA adducts, several protocols have been described an improvement in reaction time and yields, such as the use of ultrasound, high pressures, use of ionic liquids, change of catalyst, change of solvents, microwaves irradiation, and several other experimental protocols.4
Section snippets
Mechanistic aspects
The first mechanistic proposal for the MBHR was published by Hoffman and Rabe in 1983 following 7 years after by Hill and Isaacs. In these propositions the first step is a Michael addition of the catalyst (tertiary amine 1) to an activated alkene 2, generating a zwitterionic enolate 3 (Fig. 1). The next stage consists of an aldol addition of the aldehydes 4 and the intermediate 3 generating the new intermediate 5, which was proposed as the low step. The subsequent step involves an intramolecular
The growth and the present status
The last general review about MBHR was recently published by Basavaiah et al. in 2010 where the 1028 references cited therein shows the importance of this reaction for synthetic organic chemistry, in addition to the progress on the search for new asymmetric catalysts, intramolecular version, heterocyclic synthesis and advances in mechanistic understanding.4 A recent book published last year by Shi et al. entitled ‘The Chemistry of the Morita–Baylis–Hillman Reaction’ also demonstrates the great
The use of MBHA as starting material on the chemical synthesis
Since the work of Drewes and Emslie11 and Hoffman and Rabe,12 the MBHA have been used by chemists as synthetic intermediates on total synthesis. Various natural products and molecules of biological interest were synthesized from MBHA or using the MBH reaction as the key step for the preparation of compounds with biological interest.4 For example, in Figure 3 below we show some compounds prepared from MBHA and its biological activities.13, 14, 15, 16, 17, 18 However, it is important to detach
Conclusion
The simple MBHA have become an important class of bioactive compounds already presenting diversified biological activities as antimalarial, molluscicide, leishmanicidal, antichagasic, antitumoral, antifungal, antibacterial and herbicide. Recent applications of medicinal chemistry strategies in the design of new drug candidates for the MBHA are gaining space in literature. Now the preparation of MBHA can be performed in a single synthetic step, efficiently, with several challenges in these
Acknowledgments
This work has been supported by CNPq, CAPES and FAPESQ-PB. We are grateful for all members of the LASOM-PB’family, without which much of these presented results could not be obtained.
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