Natural Products and Medicinal Agents

The azirine ring has also been found in several natural products. The first azirine-containing natural product isolated was Azirinomycin (140) 71JAN48 . More recently, the similar azirine-containing antibiotic Dysidazirine (141) was isolated and shown to possess cytotoxic and antibacterial activity 88JOC2103 . The synthesis of an aminoazirine-containing peptide (142) has been reported 93T467l . 

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Marazano and co-workers have used the Zincke reaction extensively to prepare chiral templates for elaboration to substituted piperidine and tetrahydropyridine natural products and medicinal agents. For example, 3-picoline was converted to Zincke salt 40 by reaction with 2,4-dinitrochlorobenzene in refluxing acetone, and treatment with R- -)-phenylglycinol in refluxing n-butanol generated the chiral pyridinium 77. Reduction to... 

Because vicinal diamines and 2-aminoalcohols are important components of natural products and medicinal agents, and used as ligands for metal-catalyzed reactions, especially in asymmetric synthesis, efficient methods for the compounds have been extensively investigated over the past decade. " ... 

The indole nucleus is a common and important feature of a variety of natural products and medicinal agents.2 The traditional approach for preparing the indole nucleus is the Fischer indole reaction.3 As this reaction has shortcomings, the palladium-catalyzed coupling of ortho-haloanilines is becoming an excellent alternative.4 Recently, the submitters disclosed a new and efficient method for indole synthesis using a palladium-catalyzed annulation between o-iodoanilines and ketones (Scheme I).5... 

Abstract This review details recent developments in the Pd-catalyzed C-H bond arylation and alkenylation of indoles and pyrroles, aromatic heterocycles that are frequently displayed in natural products and medicinal agents. 

Biaryl C-C bond formation, via metal-catalyzed cross-coupling tactics, is a widely used transformation in the synthesis of both complex natural products and medicinal agents. Efficient catalytic methods have emerged for the union of complex... 

The indole and pyrrole nucleus are common structural motifs in a range of natural products and medicinal agents (Fig. 1). Therefore, methods for their selective and efficient functionalization are important targets for chemical synthesis. The inherent reactivity of these heteroarenes has attracted widespread interest as ideal substrates for direct metal-catalyzed C-H bond functionalization reactions. However, related to their intrinsic reactivity is their sensitivity to harsh aerobic reaction conditions, and so methods to enable direct transformations on these heteroarenes must take this into account. 

A common strategy employed to effect selectivity is exploitation of inherent substrate reactivity and utilization of activated C-H bonds. Heteroaromatic compounds represent common motifs in both natural products and medicinal agents and contain certain C-H bonds that are intrinsically more reactive than others. By using heteroaromatic motifs as the Ar-H unit, the inherent differences in reactivity of C-H bonds around the motif can be exploited to achieve selectivity. 

The abundance of oxygenated cyclohexanes in natural products and medicinal agents suggests the use of furans through a Diels-Alder reaction followed by cleavage of the C-O bond. There are an abundance of such applications, some of which are shown (Scheme 26). 

RECENTLY ISOLATED NATURAL PRODUCTS AND MEDICINAL AGENTS... 

Pyrrolo[3,2-df pyridazines are a class of interesting and useful A -heterocycles [40—42]. However, synthetic methods for such heterocyclic compounds have been very much limited such as condensation of pyrrole-2,3-diones with hydrazine. There are no reports on one-pot multi-component synthesis of pyrrolo[3,2-(f py-ridazines [43]. Moreover, synthetic methods for pyrrole-2,3-diones are also very limited [43]. On the other hand, transition-metal-mediated reactions of azides are of great importance and versatility in organic synthesis, because azides could be readily transformed into a wide variety of valuable A -containing natural products and medicinal agents [44-50]. 

Wagner, H. In Natural Products as Medicinal Agents Beal JL and Reinhard Ed, Hippoktrates Stuttgart 1989, pp 217-239. 

In retrospect, neither of these important antimicrobial agents could have been developed if Lilly did not have a fully integrated natural products discovery group that included scientists dedicated to bioconversions of natural products and medicinal chemists dedicated to modifying complex cyclic peptides and other secondary metabolites. This may be a lesson learned to help guide antibiotic discovery and development in the 21st century. 

Baker, J. T. and Wells, R. J. (1982) Biologically active substances from Australian marine organisms. In Beal J. L. and Rernbard E. (Eds.) Natural Products as Medicinal Agents, Hippokrates, Stuttgard, 281—318. 

W. Kohl, H. Vogelmann and G. Hfifle, Pianta Med., (1980) 283, Abstracts International congress on Natural Products as Medicinal Agents, Strassbourg, 1980. 

Barz, W. and B. E. Ellis, Potential of plant cell cultures for pharmaceutical production, in Natural Products as Medicinal Agents (J. L. Beal and E. Reinhard, eds.), 471-507, Hippocrates Verlag, Stuttgart, 1981. 

Thiophene-containing molecules can be found in both natural products and synthetic chemotherapeutics. Bithiophene 1, a naturally occurring nematocide, is isolated from the roots of Echinops spaerocephalus, whereas tiaprofenic acid, an anti-inflammatory agent, is a synthetic thiophene derivative. Moreover, thiophene is a useful template for four-carbon homologation via reduction [1], as well as a bioisostere of the benzene ring and other heterocycles in medicinal chemistry. 

Lee K-H. (2010) Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach. J Nat Prod 73 500-516. 

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