Visible-Light Mediated Bioactive Molecules Synthesis

The electron-deficient azaarenes organic compounds are a ubiquitous theme in natural products with interesting biological properties and widely used in drug discovery. The functionalization of azaarenes (quinoxaline, pyrazine, quinoline or isoquinoline) types of organic compounds is of considerable interest, affording new procedures to introduce new skeleton of bioactive molecules such as Timapiprant (an anti-asthmatic and anti-inflammatory agent), Papaverine (a smooth muscle relaxant), Emetine (an anti-protozoan) and it opens the door to the development of new libraries of bioactive compounds.

In this case of the [2+2] photocycloaddition of double bonds to generate cyclobutanes is one of the most employed reactions in photochemical synthesis. In particular, the [2+2] cycloaddition followed by retroaldol condensation reaction was used for the synthesis of 1,5-dicarbonyl compounds.  

In this new regards, the [2+2] photocycloaddition followed by a ring-opening rearomatization reaction between electron-deficient 2-methylene-azaarenes and double bonds, taking advantage of the ability of these heterocyclic derivatives to form the corresponding pseudo-enamine intermediate described by Prof. José Alemán from Universidad Autónoma de Madrid, 28049 Madrid, Spain and his research team, which was reported in Nature Communications Chemistry on 4^th September 2020.

 In their study, a custom-made photoreactor setup at 455 nm was used for the photocatalytic reactions (Figure 1). The vial is placed inside the fitted well in which irradiation takes place at the desired wavelengths (365, 385, 420, 450 or 540 nm) using 380 mW single LEDs. The reaction temperature is kept at 20-25 ºC using a recirculating chiller.

Figure 1. Experimental setup was employed during photocatalytic reactions and the reaction of quinoline derivative (1a) and styrene (2a) to derived product (4a). [1].

The research team delivered the following interesting concept:

(i) The procedure shows a high functional group tolerance either on the double bond or the heteroarene side and allows the presence of different electron-withdrawing groups. 

(ii) the wide applicability of this reaction has been demonstrated through the late-stage derivatization of several natural products.

(iii) photochemical studies, together with theoretical calculations, support a mechanism involving the photosensitization of the pseudo-enamine intermediate.

Figure 2.  [2+2] cycloaddition & ring-opening rearomatization [1].

They envisioned that pseudo-enamine species with a heteroarene core in the structure could undergo a [2+2] cycloaddition in the presence of an olefin, thus giving access to the derivatization of compounds with pharmacological or biological interest (see imine-enamine equilibrium, Figure 2).

Therefore, in this work they present the [2+2] cycloaddition reaction between β-electron withdrawing substituted azaarene derivatives and different double bonds followed by a ring-opening rearomatization of the cyclobutane intermediate. In addition, DFT calculations together with fluorescence quenching studies provide pieces of evidence of which species play a key role in the mechanistic proposal.

It should be highlighted that the reaction proceeded in a regioselective manner, this is a very important factor for the synthesis of these types of biological active compounds, since the other plausible product coming from the enolization of the ester [CH₂CO₂Me→CH=C(OH)OMe] was not observed. In addition, they proved that the photocatalytic nature of the reaction was confirmed when the experiment was performed without light or a photocatalyst, without conversion for both cases.

The late-stage functionalization (LSF) has an important tool for the development of libraries of bioactive compounds in the field of drug discovery, starting from lead structures and avoiding the de novo synthesis. LSF has improved the structure activity relationships, the optimization of on-target potency and the physical properties of the lead compounds. This is evidenced by a large number of methods for the functionalization of peptides or complex bioactive molecules.

Figure 3. Late-stage functionalization using this methodology [1].

In this regard, Prof. José Alemán’s team has introduced electron-deficient azaarenes in the structure of complex natural products in a simple steps (Figure 3).

In particularly, following three main nature products were obtained by this method:

(i) The hormone estrone was derivatized to methyl 4-((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6Hcyclopenta[a]phenanthren-3-yl)-4-(quinolin-2-yl)butanoate (5a) with an 85% yield.

(ii) The amino acid Tyrosine derivatized to methyl 4-(4-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)-4(quinolin-2-yl)butanoate (5b) with an excellent 89% yield.

(iii) Finally, δ-Tocopherol (vitamin E), which is employed as a food preservative for its antioxidant properties, was transformed to Methyl 4-((R)-2,8-dimethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl)-4-(quinolin-2yl)butanoate (5c) with an excellent 92% yield.

This research team summarized that the reaction gives good results with quinolines, isoquinolines, quinoxalines and pyrazines bearing different electron-withdrawing substituents in the β-position. The process is highly functional group tolerant, and it was performed efficiently with a variety of styrenes, bearing electron donating or withdrawing groups, as well as heteroaryl or alkyl-substituted double bonds.

Our SNB team is interested in this research work because of its applicability could be demonstrated by the late-stage functionalization of different natural products.

Reference

1. N. Salaverri et al., Nature Communications Chemistry, 3, 132 (2020) https://doi.org/10.1038/s42004-020-00378-x.

Blog Written By

Dr. A. S. Ganeshraja

Assistant Professor

National College, Tiruchirappalli

Tamil Nadu, India

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