Relevant Developments in the Use of Three-Component Reactions for the Total Synthesis of Natural Products. The last 15 Years.

Multicomponent reactions (MCRs) offer a highly useful and valuable strategy that can fulfill an important role in synthesizing complex polysubstituted compounds, by simplifying otherwise long sequences and increasing their efficiency. The total synthesis of selected natural products employing three-component reactions as their common strategic MCR approach, is reviewed on a case-by-case basis with selected targets conquered during the last 15 years. The revision includes detailed descriptions of the selected successful sequences; relevant information on the isolation, and bioactivity of the different natural targets is also briefly provided.

Recent developments in the total synthesis of natural products using the Ugi multicomponent reactions as the key strategy.

The total syntheses of selected natural products using different versions of the Ugi multicomponent reaction is reviewed on a case-by-case basis. The revision covers the period 2008-2023 and includes detailed descriptions of the synthetic sequences, the use of state-of-the-art chemical reagents and strategies, as well as the advantages and limitations of the transformation and some remedial solutions. Relevant data on the isolation and bioactivity of the different natural targets are also briefly provided. The examples clearly evidence the strategic importance of this transformation and its key role in the modern natural products synthetic chemistry toolbox. This methodology proved to be a valuable means for easily building molecular complexity and efficiently delivering step-economic syntheses even of intricate structures, with a promising future.

Step-Economic Total Synthesis of Melosatin A from Eugenol.

An efficient and straightforward route toward the isatin-type natural product melosatin A is reported, employing a trisubstituted aniline as a key intermediate. The latter was synthesized in 4 steps and 60% overall yield from eugenol, through its regioselective nitration, sequentially followed by a Williamson methylation, an olefin cross-metathesis with 4-phenyl-1-butene and the simultaneous reduction of olefin and nitro groups. The final step, a Martinet cyclocondensation of the key aniline with diethyl 2-ketomalonate, provided the natural product with 68% yield.

Efficient Buchwald-Hartwig and nitrene-mediated five-membered ring closure approaches to the total synthesis of quindoline. Unexpected direct conversion of a nitro group into a phosphazene.

Two total syntheses of quindoline, which take place through the intermediacy of 3-nitroquinoline derivatives, are reported. The general synthetic sequence involves construction of the latter by mechanochemical condensation of benzaldehydes with 2-amino-nitrostyrene, followed either by reduction of the nitro group of the heterocycle and Buchwald-Hartwig cyclization or by a nitrene-mediated cyclization under solventless conditions. Use of PPh3 to generate the nitrene resulted in the unprecedented formation of a phosphazene in place of quindoline. This unexpected transformation was explained by means of DFT computations.

Total Synthesis of Aqabamycin G, a Nitrophenyl Indolylmaleimide Marine Alkaloid from Vibrio sp. WMBA.

The first total synthesis of the marine alkaloid aqabamycin G is disclosed. The synthetic sequence involved the stepwise addition to maleimide of an indole motif and a substituted diazo-benzenoid unit derived from acetaminophen. An alternative strategy using a protected phenol is also reported.

Synthesis and Biological Activity of 3-(Heteroaryl)quinolin-2(1H)-ones Bis-Heterocycles as Potential Inhibitors of the Protein Folding Machinery Hsp90.

In the context of our SAR study concerning 6BrCaQ analogues as C-terminal Hsp90 inhibitors, we designed and synthesized a novel series of 3-(heteroaryl)quinolin-2(1H), of types 3, 4, and 5, as a novel class of analogues. A Pd-catalyzed Liebeskind-Srogl cross-coupling was developed as a convenient approach for easy access to complex purine architectures. This series of analogues showed a promising biological effect against MDA-MB231 and PC-3 cancer cell lines. This study led to the identification of the best compounds, 3b (IC50 = 28 µM) and 4e, which induce a significant decrease of CDK-1 client protein and stabilize the levels of Hsp90 and Hsp70 without triggering the HSR response.

Evolution of the Synthesis of Remdesivir. Classical Approaches and Most Recent Advances.

The broad-spectrum antiviral Remdesivir, a monophosphate nucleoside analogue prodrug (ProTide), was repurposed. In May 2020, it received emergency approval by the FDA, being the first drug approved to fight the new coronavirus (COVID-19) disease which targets the virus directly. The main synthetic strategies toward Remdesivir, and their relevant modifications, are presented and discussed, to provide a panoramic view of the state-of-the-art and the more important advances in this field. Recent progress, proposed improvements, and uses of novel technologies for the synthetic sequence are also detailed.

Langmuir-Blodgett monolayers holding a wound healing active compound and its effect in cell culture. A model for the study of surface mediated drug delivery systems.

Langmuir and Langmuir-Blodgett films holding a synthetic bioinspired wound healing active compound were used as drug-delivery platforms. Palmitic acid Langmuir monolayers were able to incorporate 2-methyltriclisine, a synthetic Triclisine derivative that showed wound healing activity. The layers proved to be stable and the nanocomposites were transferred to solid substrates. Normal human lung cells (Medical Research Council cell strain 5, MRC-5) were grown over the monomolecular Langmuir-Blodgett films that acted as a drug reservoir and delivery system. The proliferation and migration of the cells were clearly affected by the presence of 2-methyltriclisine in the amphiphilic layers. The methodology is proposed as a simple and reliable model for the study of the effects of bioactive compounds over cellular cultures.

Isolation and synthesis of cryptosanguinolentine (isocryptolepine), a naturally-occurring bioactive indoloquinoline alkaloid.

Cryptosanguinolentine (isocryptolepine) is one of the minor naturally-occurring monomeric indoloquinoline alkaloids, isolated from the West African climbing shrub Cryptolepis sanguinolenta. The natural product displays such a simple and unique skeleton, which chemists became interested in well before it was found in Nature. Because of its structure and biological activity, the natural product has been targeted for synthesis on numerous occasions, employing a wide range of different strategies. Hence, discussed here are aspects related to the isolation of isocryptolepine, as well as the various approaches toward its total synthesis.

The 6π-azaelectrocyclization of azatrienes. Synthetic applications in natural products, bioactive heterocycles, and related fields.

Covering: 2006 to 2018 The application of the 6π-azaelectrocyclization of azatrienes as a key strategy for the synthesis of natural products, their analogs and related bioactive or biomedically-relevant compounds (from 2006 to date) is comprehensively reviewed. Details about reaction optimization studies, relevant reaction mechanisms and conditions are also discussed.

First total synthesis of ampullosine, a unique isoquinoline alkaloid isolated from Sepedonium ampullosporum, and of the related permethylampullosine.

A straightforward and convenient approach toward the first total synthesis of ampullosine, a structurally unique 3-methylisoquinoline alkaloid isolated from Sepedonium ampullosporum, is reported. Access to the related O-methyl ampullosine methyl ester from a common intermediate is also disclosed. The synthetic sequence toward the natural product comprised a Kolbe-type carboxylation of 3,5-dihydroxybenzoic acid and further esterification of the diacid, followed by masking of one of the phenols through selective ester reduction and subsequent acetonide formation. Installation of the three-carbon atom required for the 3-methylpyridine ring was performed by triflation of the remaining free phenol and a Pd-catalyzed Suzuki-Miyaura reaction with potassium E-propenyltrifluoroborate. Deprotection of the acetonide, followed by partial oxidation of the benzylic alcohol to the salicylaldehyde, O-methylation of the free phenol and hydrazonation of the resulting ortho-anisaldehyde derivative gave a hydrazone-based 1-azatriene. This was further subjected to 6π-azaelectrocyclization to afford permethylampullosine (11 steps, 14% overall yield), whereas exhaustive demethylation with AlI3 generated in situ gave ampullosine (12 steps, 3.2% global yield).

Total Synthesis of Waltherione F, a Nonrutaceous 3-Methoxy-4-quinolone, Isolated from Waltheria indica L. F.

Waltherione F was totally synthesized in seven steps and 31% overall yield from 2-nitro-3-methylanisole without the use of protecting groups. Key steps in the sequence were a Suzuki-Miyaura coupling to attach the n-octyl chain and a microwave-promoted cyclization of an acetonyl anthranilate to give the heterocyclic core whose 3-OH was O-methylated.

Photophysical and Photochemical Properties of 3-methylpterin as a New and More Stable Pterin-type Photosensitizer.

Pterin derivatives are heterocyclic compounds which are present in different biological systems. Neutral aqueous solutions of pterins present acid-base and keto-enol equilibria. These compounds, under UV-A radiation fluoresce, undergo photooxidation, generate reactive oxygen species and photoinduce the oxidation of biological substrates. As photosensitizers, they may act through different mechanisms, mainly through an electron transfer-initiated process (type-I mechanism), but they also produce singlet molecular oxygen (1 O2 ) upon irradiation (type-II mechanism). In general, upon UV-A excitation two triplet states, corresponding to the lactim and lactam tautomers, are formed, but only the last one is the responsible for the photosensitized reactions of biomolecules. We present a study of the photochemical properties of 3-methylpterin (3-Mep) which, in contrast to most pterin derivatives, exists only in the lactam form. Also an improvement in the synthesis of 3-Mep is reported. The spectroscopic properties 3-Mep in aqueous solution were similar to those of the unsubstituted pterin derivative (Ptr) in its acid form, such as absorption, fluorescent and phosphorescent emission spectra. Experiments using 2'-deoxyguanosine 5'-monophosphate (dGMP) as oxidizable target demonstrated that methylation at C-3 position of the pterin moiety does not affect significantly the efficiency of photosensitization, but results in a more photostable sensitizer.

The 3,4-dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-one alkaloids. Results of 20 years of research, uncovering a new family of natural products.

Covering: up to April 2016Aspergillus and Penicillium are fungal species known to produce a high diversity of secondary metabolites, many of them endowed with interesting bioactivity. The small but steadily growing family of the naturally occurring 5-hydroxy-4-aryl-quinolin-2(1H)-one alkaloids and closely related compounds, which represent the results of various research projects that spanned over 20 years and involved scientists from different continents, are covered here. Emphasis is placed on the isolation and chemical structures of the different compounds, together with their source microorganisms, environmental conditions, country or region of origin, and relevant biological activities. In addition, stereochemical aspects, as well as the proposed biosynthetic pathways for the different members, and the incipient synthetic efforts towards some of the compounds or their key intermediates, are discussed in detail.

A convenient approach to an advanced intermediate toward the naturally occurring, bioactive 6-substituted 5-hydroxy-4-aryl-1H-quinolin-2-ones.

5-Hydroxy-4-aryl-3,4-dihydro-1H-quinolin-2-ones are a small family of natural products isolated from fungal strains of Penicillium and Aspergillus. Most of its members, which are insecticides and anthelmintics, carry an isoprenoid C-6 side chain. The synthesis of a 6-propenyl-substituted advanced intermediate for the total synthesis of these natural products is presented in this paper. This was achieved through the stereoselective construction of a ß,ß-diarylacrylate derivative from 6-nitrosalicylaldehyde, using a Wittig olefination and a Heck-Matsuda arylation, followed by a selective Fe(0)-mediated reductive cyclization. Installation of the 6-propenyl side chain was performed by 5-O-allylation of the heterocycle, followed by Claisen rearrangement and conjugative migration of the allyl double bond, as the key steps. The Grubbs II-catalyzed olefin cross metathesis of the 6-allyl moiety with 2-methylbut-2-ene to afford a precursor of peniprequinolone is also reported.

Neocryptolepine: A Promising Indoloisoquinoline Alkaloid with Interesting Biological Activity. Evaluation of the Drug and its Most Relevant Analogs.

Plants are one of the most important resources for the discovery of new drugs. The potential of natural compounds as new drug leads is clearly illustrated by the discovery and development of many modern medicines. This is an encouraging factor that drives natural products research in the vegetable kingdom. Neocryptolepine is a tetracyclic nitrogen heterocycle isolated from the African climber Cryptolepis sanguinolenta, which is widely used in traditional African medicine in many countries of Central and West Africa. The natural product is one of the representative examples of the small family of indolo[2,3-b]quinoline alkaloids, being endowed of multiple biological activities, including DNA-binding and inhibition of the enzyme topoisomerase II. It is also cytotoxic, antibacterial, antifungal and molluscicidal, also displaying antiprotozoal activity, particularly as antitrypanosomal, antileishmanial, antischistosomal and antiplasmodial. Some of these activities have been related to the product's ability to bind to DNA and to inhibit topoisomerase II; however, the exact mechanisms behind all of the observed bioactivities have not been comprehensively clarified. Major research activities regarding neocryptolepine have been focused into two seemingly opposite fields, related to its cytotoxic and antimalarial properties. Optimization of the natural product as a cytotoxic agent implied improvements in its bioavailability and activity, while the need of non-cytotoxic compounds guided the design and optimization of antimalarial agents. Therefore, the aim of the present article is to systematically review the current knowledge about the diversity of the biological activities related to neocryptolepine, its analogs and derivatives.

A facile and convenient sequential homobimetallic catalytic approach towards ß-methylstyrenes. A one-pot Stille cross-coupling/isomerization strategy.

An efficient one-pot synthetic approach towards ß-methylstyrenes is reported. The transformation, based on sequential homobimetallic catalysis, involves a Stille cross-coupling reaction between aryl halides and allyltributylstannane, followed by an in situ palladium-catalyzed conjugative isomerization. The reaction was optimized, and the best results were obtained with 10 mol% Pd(PPh3)2Cl2, 8.0 equiv. LiCl, and 0.5 equiv. PPh3 in diglyme at 130 °C for 12 h. It was demonstrated that the reaction tolerates a wide variety of functional groups.

Synthesis of symmetrically substituted 3,3-dibenzyl-4-hydroxy-3,4-dihydro-1H-quinolin-2-ones, as novel quinoline derivatives with antibacterial activity.

A novel series of symmetrically substituted 3,3-dibenzyl-4-hydroxy-3,4-dihydro-1H-quinolin-2-ones was synthesized and tested as antimicrobials. The minimum inhibitory concentration (MIC) values of the most active heterocycles were slightly higher than those exhibited by levofloxacin, employed as comparator. Structural factors affecting the activity were explored along three diversification points, including the substituents of the aromatic rings of the 3-benzyl moieties, as well as the functionalization of both, the homocyclic ring of the heterocycle and the quinolonic nitrogen atom. 6-Chloro and 3,3-bis(4'-chlorobenzyl) derivatives showed the lower MIC values. Optimally substituted heterocycles were synthesized, which exhibited enhanced activity.

Modulators of complement activation: a patent review (2008 - 2013).

INTRODUCTION: The architecture of the complement system has evolved during the last 600 - 700 million years to become an amazingly efficient and highly versatile alerting and cell killing device. Under physiological conditions, this system acts as a well-regulated cascade, protecting the organism against pathogens and participating during the initial defensive steps of humoral and cellular response. The unregulated activation of this system may cause or even aggravate diseases; therefore, its modulation is currently considered of high importance. AREAS COVERED: This review is a critical examination on patent literature published between 2008 and 2013. An insight is provided about the discovery and development of novel therapeutic agents. These include macromolecules, polysaccharides and proteins, specific antibodies, and hybrid or chimeric products. Peptides and low molecular weight organic compounds (natural products, their derivatives and fully synthetic molecules) are covered as well. EXPERT OPINION: The search of specific inhibitors of the complement cascade has become one of the Holy Grails of Medicinal Chemistry for the last 30 - 40 years, with very few cases of success. Some highly specific macromolecules are currently available as modulators of the complement. However, there is still a marked need to find new, more specific, efficient and convenient alternatives, especially suited for chronic administration, including novel inexpensive small molecule inhibitors. Analogously, despite the initial success with specific monoclonal antibodies, a vast territory is awaiting to be explored and conquered, regarding the regulation of complement activation by antibody-mediated blockage of specific polypeptides or receptor sites.