Synthesis of N‐Aryl Formyl Pyrrole from γ‐Lactam Derivatives: A Highlight

Pyrrole containing analogs are considered as a potential source of biologically active compounds and have significant set of advantageous properties and are found in many natural products. A number of methods have been reported till now to synthesize pyrrole and pyrrole containing analogs. This review article outlines highlight the recent progresses in pyrrole synthesis from γ‐lactam derivatives.     

Platinum‐Catalyzed Domino Reaction with Benziodoxole Reagents for Accessing Benzene‐Alkynylated Indoles

Indoles are omnipresent in natural products, bioactive molecules, and organic materials. Consequently, their synthesis or functionalization are important fields of research in organic chemistry. Most works focus on installation or modification of the pyrrole ring. To access benzene‐ring‐functionalized indoles with an unsubstituted pyrrole ring remains more challenging. Reported herein is a platinum‐catalyzed cyclization/alkynylation domino process to selectively obtain C5‐ or C6‐functionalized indoles starting from easily available pyrroles. The work combines, for the first time, a platinum catalyst with ethynylbenziodoxole hypervalent iodine reagents in a domino process for the synthesis of polyfunctionalized arene rings and gives access to important building blocks for the synthesis of bioactive compounds and organic materials.     

Formyl group activation of a bromopyrrole ester in Suzuki cross-coupling reactions: application to a formal synthesis of Polycitone A and B and Polycitrin A

A new pyrrole building block is described, which allows for the regiospecific synthesis of 2,3,5-trisubstituted pyrroles and 2,3,4,5-tetrasubstituted pyrroles. Optimization studies are presented for the preparation of the pyrrole building block along with the evaluation of various cross-coupling conditions and cross-coupling agents. A short, formal synthesis of the natural products Polycitone A, Polycitone B, and Polycitrin A from the pyrrole building block is also described.     

4-alkoxy- and 4-amino-2,2'-bipyrrole synthesis

[Structure: see text] 4-alkoxy-2,2'-bipyrroles and the first examples of 4-amino-2,2'-bipyrroles have been synthesized by a diversity-oriented strategy from 4-hydroxyproline. The bipyrrole products offer interesting potential as building blocks for making pyrrole products, as demonstrated by the first synthesis of an amino prodigiosin analogue.     

The Application of Vinylogous Iminium Salt Derivatives and Microwave Accelerated Vilsmeier-Haack Reactions to Efficient Relay Syntheses of the Polycitone and Storniamide Natural Products

Studies directed at the synthesis of polycitone and storniamide natural products via vinylogous iminium salts and microwave accelerated Vilsmeier-Haack formylations are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole or a 2,3,4-trisubstituted pyrrole from a vinamidinium salt or vinamidinium salt derivative followed by formylation at the 5-position of the pyrrole. Subsequent transformations of the selectively formylated pyrroles lead to efficient and regiocontrolled relay syntheses of the respective pyrrole containing natural products.     

含氟内酯化合物的合成方法研究进展

内酯化合物广泛存在于天然产物和具有生理活性的物质中, 因此, 内酯化合物的合成一直是人们非常关心的一个研究领域, 不仅作为天然产物的重要合成砌块, 也用来合成一些精细化工产品和医药中间体. 将氟原子或含氟基团引入到内酯化合物分子中, 可使其生理活性发生改变. 就含氟内酯化合物合成方法的研究进展进行了综述.     

Recent development in preparation reactivity and biological activity of enaminoketones and enaminothiones and their utilization to prepare heterocyclic compounds

Enaminoketones and esters are gaining increased interest, particularly cyclic‐β‐enaminoesters, which are known as important intermediates for the synthesis of heterocycles and natural products, because the enantioselective preparation of highly functionalized compounds is of central importance in synthetic chemistry. Enaminones are versatile synthetic intermediates that combine the ambident nucleophilicity of enamines with the ambident eletrophilicity of enones. Enaminoketones and enaminonitriles have proven to be versatile building blocks for the synthesis of various heterocycles such as pyridine, pyrimidine and pyrrole deriva tives. Enaminones systems have “enone” character, and may act as acceptors in both 1,2 and 1,4‐additions. In this way the enaminone serves as a scaffold for annulation, and can gain access to systems such as pyrroles indolizidines, quinolizidines and perhydroindoles, all of which are common motifs in alkaloid structures. Enaminones are frequently employed as building blocks for the preparation of a variety of bicyclic compounds of biological interest and have been recently recognized as potential anticonvulsant compounds. Since a large number of developments in the use of enaminones in heterocyclic synthesis have occurred, a review of the recent developments in the synthetic approaches, covering the literature since 1995 until 2004, to these interesting molecules and their useful chemical transformations and biological activity can be considered of considerable value.     

Key building blocks of natural product biosynthesis and their significance in chemistry and medicine.

The principle features of the biosynthesis of natural products have been elucidated during the past thirty years by the use of isotopic methods. It was discovered that large groups of natural products originate from the same biosynthetic precursor—the key building block. The conversion of key building blocks into biologically active natural products serves as a model for the development of more efficient syntheses in chemistry. In medicine, information about key building blocks permits the elucidation and therapy of metabolic diseases.     

Stereoselective Synthesis of Tropanes via a 6π‐Electrocyclic Ring‐Opening/ Huisgen [3+2]‐Cycloaddition Cascade of Monocyclopropanated Heterocycles

The synthesis of tropanes via a microwave‐assisted, stereoselective 6π‐electrocyclic ring‐opening/ Huisgen [3+2]‐cycloaddition cascade of cyclopropanated pyrrole and furan derivatives with electron‐deficient dipolarophiles is demonstrated. Starting from furans or pyrroles, 8‐aza‐ and 8‐oxabicyclo[3.2.1]octanes are accessible in two steps in dia‐ and enantioselective pure form, being versatile building blocks for the synthesis of pharmaceutically relevant targets, especially for new cocaine analogues bearing various substituents at the C‐6/C‐7 positions of the tropane ring system. Moreover, the 2‐azabicyclo[2.2.2]octane core (isoquinuclidines), being prominently represented in many natural and pharmaceutical products, is accessible via this approach.     

Synthesis of N-benzyl-des-D-ring lamellarin K via an acyl-Claisen/Paal-Knorr approach

Lamellarin K is a complex pyrrole natural product and member of the lamellarin family – a group of natural products known for their potent biological activities, such as, antiproliferative activity and inhibition of P-gp mediated drug efflux pumps. We herein describe the synthesis of the N-benzyl-des-D ring analogue of lamellarin K using a route that centres on an acyl-Claisen reaction to eventually prepare a highly-functionalised 1-aryl-4-methyl-1,4-diketone. Paal-Knorr pyrrole formation using this diketone undergoes auto-oxidation to give a fully-substituted 5-formyl pyrrole which was converted into the natural lactone B ring. Antiproliferative testing of the N-benzyl-des-D ring analogue gave an IC₅₀ of 2.63 μM against the MDA-MB-231 breast cancer cell line.     

Furan-containing conjugated polymers for organic solar cells

Development of organic semiconductors is one of the most intriguing and productive topics in material science and engineering. Many efforts have been made on the synthesis of aromatic building blocks such as benzene, thiophene and pyrrole due to the facile preparation accompanied by the intrinsic environmental stability and relatively efficient properties of the resulting polymers. In the past, furan has been less explored in this field because of its high oxidation potential. Recently, furan has attracted obsession due to its weaker aromaticity, the greater solubilities of furan-containing π-conjugated polymers relative to other benzenoid systems and the accessibility of furan-based starting materials from renewable resources. This review elaborates the advancements of organic photovoltaic polymers containing furan building blocks. The uniqueness and advantages of furan-containing building blocks in semiconducting materials are also discussed.     

Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries

Natural products were analyzed to determine whether they contain appealing novel scaffold architectures for potential use in combinatorial chemistry. Ring systems were extracted and clustered on the basis of structural similarity. Several such potential scaffolds for combinatorial chemistry were identified that are not present in current trade drugs. For one of these scaffolds a virtual combinatorial library was generated. Pharmacophoric properties of natural products, trade drugs, and the virtual combinatorial library were assessed using a self-organizing map. Obviously, current trade drugs and natural products have several topological pharmacophore patterns in common. These features can be systematically explored with selected combinatorial libraries based on a combination of natural product-derived and synthetic molecular building blocks.     

Oxidation properties of β-substituted pyrroles

Pyrroles represent building blocks of conjugated poly(heterocycles) which, as organic conductors, are potential materials for organic electronics. Oxidation of β-substituted pyrroles constitutes an important first step in the process of electropolymerization. Ionization energy and the electron spin density distribution are two the most important properties regarding monomers. These properties are studied as a function of electron-withdrawing and electron-donating substituents of pyrrole ring. Evolution of molecular structure, nature of bonding, and electronic density are studied as an effect of ionization process.     

Type III polyketide synthase beta-ketoacyl-ACP starter unit and ethylmalonyl-CoA extender unit selectivity discovered by Streptomyces coelicolor genome mining

Polyketide synthases (PKSs) are involved in the biosynthesis of many important natural products. In bacteria, type III PKSs typically catalyze iterative decarboxylation and condensation reactions of malonyl-CoA building blocks in the biosynthesis of polyhydroxyaromatic products. Here it is shown that Gcs, a type III PKS encoded by the sco7221 ORF of the bacterium Streptomyces coelicolor, is required for biosynthesis of the germicidin family of 3,6-dialkyl-4-hydroxypyran-2-one natural products. Evidence consistent with Gcs-catalyzed elongation of specific beta-ketoacyl-ACP products of the fatty acid synthase FabH with ethyl- or methylmalonyl-CoA in the biosynthesis of germicidins is presented. Selectivity for beta-ketoacyl-ACP starter units and ethylmalonyl-CoA as an extender unit is unprecedented for type III PKSs, suggesting these enzymes may be capable of utilizing a far wider range of starter and extender units for natural product assembly than believed until now.     

Synthesis of 5-aryl-2-oxopyrrole derivatives as synthons for highly substituted pyrroles

A small library of 2-oxo-5-(hetero)arylpyrroles was prepared starting from 2,3-dioxo-5-(hetero)arylpyrrolidines. The large synthetic possibilities of these 2-oxopyrroles were investigated. The 2-oxopyrroles offer a large number of possible derivatizations including reactions with electrophiles. The chloroformylation of 2-oxo-5-(hetero)arylpyrroles provides pyrrole carbaldehydes. Some pyrrole carbaldehydes were used to synthesize polycyclic compounds like pyrrolo[3,4-d]pyridazinones, a thienopyrrole, a pyrrolobenz[1,4]oxazepine, a pyrrolobenzo[1,4]thiazepine, and a pyrrolobenzo[1,4]diazepine. Hereby we showed through a short exploration that the oxopyrroles and analogues are interesting and versatile synthetic building blocks.     

Stereoselective synthesis of cyercene A and the placidenes

Members of a family of alpha-methoxy-gamma-pyrone-containing polypropionate natural products have been stereoselectively synthesized. Two key iodovinyl pyrone building blocks were coupled to appropriately selected vinyl stannanes to assemble the highly substituted polyene side chains of the natural products. [structure: see text]     

Regio- and stereoselective synthesis of Nor-nonactinic acid derivatives--kinetic reaction control in the Lewis acid mediated domino reaction of 1,3-dicarbonyl dianions with 1-bromo-2,3-epoxypropanes

Reaction of 1,3-dicarbonyl dianions with epibromohydrin derivatives results in formation of functionalized 2-alkylidene-5-hydroxymethyltetrahydrofurans. These reactions proceed by chemoselective attack of the dianion onto the carbon attached to the bromine atom and subsequent nucleophilic attack of the resultant monoanion onto the epoxide. The cyclization products, which were formed with very good regio- and stereoselectivities, are of pharmacological relevance and represent versatile building blocks for the synthesis of natural products.     

Directed evolution of a gatekeeper domain in nonribosomal peptide synthesis

Modular natural products are biosynthesized by series of enzymes that activate, assemble, and process a nascent chain of building blocks. Adenylation domains are gatekeepers in nonribosomal peptide biosynthesis, providing the entry point for assembly of typical peptide-based natural products. We report the directed evolution of an adenylation domain based on a strategy of using a weak, promiscuous activity as a springboard for reprogramming the biosynthetic assembly line. Randomization of residues invoked in a "specificity-conferring code" and selection for a non-native substrate lead to mutant G2.1, favoring smaller amino acids with a specificity change of 10(5): a 170-fold improvement for L-alanine corresponds to a 10(3)-fold decrease for its original substrate (L-phenylalanine). These results establish directed evolution as a method to change gatekeeper domain specificity and suggest that adaptation of modules in combinatorial biosynthesis is achievable with few mutations during evolution.     

The parallel and convergent universes of polyketide synthases and nonribosomal peptide synthetases

Polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs) catalyze chain elongation from simple building blocks to create a diverse array of natural products. PKS and NRPS proteins share striking architectural and organizational similarities that can be exploited to generate entirely new natural products.     

The application of vinylogous iminium salt derivatives to an efficient synthesis of the pyrrole containing alkaloids Rigidin and Rigidin E

Studies directed on the synthesis of the pyrrole containing marine natural products Rigidin and Rigidin E via vinylogous iminium salts are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole from a vinamidinium salt followed by acylation at the 5-position of pyrrole. Halogenation and aminocarbonylation at the 3-position of pyrrole followed by hydrolysis of the ester group at C-2 and subsequent Curtius rearrangement generates the pyrrolopyrimidine skeleton. A final deprotection step completes the synthesis of Rigidin and Rigidin E.