Structure natural product-inspired compounds

A number of examples such as 1,3-dioxanes, macrolactones, °° ring-containing biaryls, ° spirooxindoles, alkaloid-like compounds, and polycyclic compounds from the Schreiber group illustrate this approach to natural product-like libraries (see Chapter 11). An early example converted shikimic acid into intermediate tetracyclic y-butyrolactones, which were then functionalized around the core structure (see Chapter 11, Subsection 11.10.2). y-Butyrolactones, found in about 10% of all natural products and which exhibit a broad range of biological activities, are a key element in a number of recent natural product-like compounds. A more recent example, inspired by the rich skeletal diversity of indole alkaloids, utilized the rhodium(II)-catalyzed consecutive cyclization-cycloaddition reactions developed by Padwa and coworkers (Scheme 1.4). A stereocontrolled tandem reaction utilizing the versatile scaffold allowed for multiple modes of intramolecular reactions. 

Solid-phase techniques are also used for synthesis of compounds with trans-decalin motif where the Robinson annulation is used for synthesis of some natural product inspired structures such as that of 75. The protocol uses an immobilized solid phase bound Nazarov reagent that reacts with the enamine of the starting ketone under basic conditions. After cyclization the product is released from the solid phase by using TBAF at room temperature overnight. For the products 75a-c only one stereoisomer was formed (de > 98%) with modest 22-38% yields. 

The term biology-oriented synthesis (BIOS) [45] has been used to describe the design of compound libraries based on biologically relevant chemical space [46]. The areas in protein structures that participate in productive protein-ligand interactions have been, for the most part, already defined by natural products and drugs. Thus libraries inspired by natural products and other bioactive molecules are expected to have a higher probability of biologically activity than randomly synthesized molecules [47,48]. 

Natural Product Scaffolds and Protein Structure Similarity Clustering (PSSC) as Inspiration Sources for Compound Library Design in Chemogenomics and Drug Development... 

In Chapter 3, the group of Prof. Herbert Waldmann at the Max Plank Institute for Molecular Physiology provides a rationale on how natural products which play historically a predominant role in drug discovery are efficiently used in combination with protein structure similarity clustering to inspire directed compound library design and target identification. 

In addition, there are many important nonantibiotic uses of 2-azetidinones in fields ranging from enzyme inhibition [15-21] to gene activation [22], Systems containing one carbon atom common to two rings, spirocyclic compounds, represent an important structural organization. Spirocyclic p-lactams (Fig. 3) behave as p-tum mimetics [23-26] as well as enzyme inhibitors [27, 28], they are precursors of a,a-disubstituted p-amino acids [29-32], and the spiranic p-lactam moiety is present in chartellines and chartelamides [33-38], a family of marine natural products. Synthetic studies and biosynthetic speculation inspired by an unexpected reaction on the marine alkaloid chartelline C have been described [38],... 

The Aspidosperma family of indole alkaloids has inspired many synthetic strategies for the construction of their pentacyclic framework of the parent compound aspidospermidine (366), since the initial clinical success of two derivatives, vinblastine (10) and vincristine, as anticancer agents. The alkaloids such as (-)-rhazinal (369) and (-)-rhazinilam (6) have been identified as novel leads for the development of new generation anticancer agents [10,11]. Bis-lactams (-)-leucunolam (370) and (-t-)-epi-leucunolam (371) have bio-genetic and structural relationships with these compounds [236]. Recently, enantioselective or racemic total syntheses of some of the these natural product were achieved. One successful synthesis was the preparation of the tricyclic ketone 365, an advanced intermediate in the synthesis of aspidospermidine (366), from pyrrole (1) (Scheme 76) [14]. The key step is the construction of the indolizidine 360, which represents the first example of the equivalent intramolecular Michael addition process [14,237,238]. The DIBAL-H mediated reduction product was subject to mesylation under the Crossland-... 

Naturally occurring thyrsiferol analogues continue to be an inspiration for many synthetic, biosynthetic, and structure-activity relationship investigations. An overview of the efforts directed toward the biosynthesis of these natural products along with the biological activity displayed by each of the aforementioned compounds is addressed in the next section. 

Dekker, F. J., Wetzel, S., Waldmann, H. Natural product scaffolds and protein structure similarity clustering (PSSC) as inspiration sources for compound library design in chemogenomics and drug development. Chemogenomics 2006, 59-84. 

Programmes of synthesis based on natural product leads often advance only slowly and are uncertain to deliver commercial products for crop protection. Many man-years of work may be invested without finding the single compound in which all the required properties are combined. Nevertheless, when successful, these projects lead to highly profitable products, and natural products remain an inspiration to chemists as an important source of novel structures and modes of action. 

This phase saw continuous advances in chemistry and medicine. Organic chemistry was now capable of the synthesis of relatively complex targets by multistep sequences. The concept of systematically preparing a compound series and testing it for a biological effect became common, as exemplified in Ehrlich s quest for antisyphilitic agents. More and more pure natural products were identified and their structures elucidated. Synthetic mimics became a reahty. For example, amphetamines were inspired by the natnral prodnct lead, ephedrine. 

---