Natural products structural complexity

Dehydrogenation (the conversion of alicycllc or hydroaroraatic compounds into their aromatic counterparts by removal of hydrogen and also, in some cases, of other atoms or groups) finds wide appUcation in the determination of structure of natural products of complex hydroaroraatic structure. Dehydrogenation is employed also for the synthesis of polycyclic hydrocarbons and their derivatives from the readily accessible synthetic hydroaroraatic compounds. A very simple example is the formation of p-raethylnaphthalene from a-tetra-lone (which is itself prepared from benzene—see Section IV,143) ... 

Many classes of natural product possess heterocyclic components (e.g. alkaloids, carbohydrates). However, their structures are often complex, and although structure-based names derived by using the principles outlined in the foregoing sections can be devised, such names tend to be impossibly cumbersome. Furthermore, the properties of complex natural product structures are often closely bound up with their stereochemistry, and for a molecule containing a number of asymmetric elements the specification of a particular stereoisomer by using the fundamental descriptors (R/S, EjZ) is a job few chemists relish. 

The Pictet-Spengler condensation has been of vital importance in the synthesis of numerous P-carboline and isoquinoline compounds in addition to its use in the formation of alkaloid natural products of complex structure. A tandem retro-aldol and Pictet-Spengler sequence was utilized in a concise and enantioselective synthesis of 18-pseudoyohimbone. Amine 49 cyclized under acidic conditions to give the condensation product 50 in good yield. Deprotection of the ketone produced the indole alkaloid 51. 

The development of highly efficient asymmetric catalysts is one of the most intensively investigated research fields today.1 Catalytic asymmetric reactions are extremely powerful in terms of the practicality and atom economy.2 The power of asymmetric catalysis is rapidly growing, so as to be applicable to syntheses of natural products with complex structures. We call total syntheses using catalytic asymmetric reactions in key steps catalytic asymmetric total syntheses . In this chapter, we describe our recent success in catalytic asymmetric total syntheses of (-)-strychnine and fostriecin. Both of the total syntheses involve catalytic asymmetric carbon-carbon bond forming reactions using bifunctional catalysts developed in our group3 as key steps. 

Despite this limitation, in vitro biosynthesis using purified biocatalysts promises to be a simple and inexpensive means to access a wealth of complex natural product structures under clean and controlled conditions. The versatility of this technology can be significantly enhanced by the application of genetic engineering to create novel proteins. 

Inventing new candidate structures is surprisingly difficult because we tend to think only of structural types that we already know well. Many complex natural product structures have supposedly been elucidated in recent years but a significant proportion of them are wrong. The proposed structures are all apparently compatible with the available spectroscopic data and are usually reasonable. But they are by no means the only structures that are compatible with the data. Usually the authors had failed to think of the correct structure even as a possibility. In most cases we still do not know which are right and which are are... 

It was during the 1970 s and early 80 s that advances in technology transformed natural product discovery programmes. The advent of HPLC, and later coupling to UV diode-array detectors and then mass spectrometers, improved the efficiency of dereplication procedures. The ability to rapidly separate complex mixtures reduced the time from lead identification to natural product structure. The discovery of doramectin is a fine example of the use of such technology. 

Vinblastine (Fig. 7.1), an alkaloid used against advanced teratomas and lymphomas, is an example of how complex the structures of natural products can be. However, analytical skills and instruments have advanced to such an extent that even this structure is relatively simple compared to some of the natural product structures being studied today. 

In 1818 strychnine (1), which in larger amounts occurs in the poison nut Strychnos nux vomica L.) and the St. Ignatius bean (Strychnos ignatii Bergius), was isolated by Pelletier and Caventou [3] and was one of the first alkaloids obtained in pure form. Tbe structure determination by chemical degradation of the natural product, a complex structure with seven rings and six stereogenic centres, proved to be difficult and tedious. Many... 

In an interesting departure from the otherwise exclusive applications of the D-HMBC experiment in natural product structure elucidation that have been cited above, Carbajo etal. used the D-HMBC experiment in a study of alkenylcarbyne- and alkenylvinylidene-tungsten complexes. Using both H- - W and inverse detection methods, the authors demonstrated an approxi-... 

MS, however, offers a series of obvious advantages over NMR spectroscopy. They include superior resolution (if high-resolution MS detectors are employed), superior sensitivity, more facile and economical coupling to online separation techniques (LC and GC), analysis of samples in aU three states of matter (gas, liquid, and solid), no molecular weight restrictions, and finally the ability to trap selected ions in the gas phase prior to characterization, thereby allowing a second dimension of separation. For complex samples containing natural products as minor constituents, especially, structure elucidation by MS constitutes the only practical access to natural product structures. 

Many enzymes are involved in the synthesis of secondary metabolites. The modular biosynthetic enzymes polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) are responsible for the generation of a multitude of structurally diverse and biologically important small-molecule natural products. A complex carbon structure is assembled sequentially from simple carbon building blocks (acyl-CoA and amino acids). The elongation of each carbon unit is catalyzed by... 

Site-selective molecular transformations can be performed in either a substrate-controlled or a catalyst-controlled manner, at least in principle. More arbitrary and diverse molecular transformation is expected, especially by such catalyst-controlled transformations. The molecular recognition process with its dynamic nature seems to be responsible for the performance of catalyst-controlled site-selective molecular transformation. Various examples of catalyst-controUed site-selective functionalization and its application to biological active natural products with complex structures are described. We know, however, that we are still at the preliminary stage in this emerging scientific field of site-selective catalysis. 1 believe that publication of this book can stimulate extensive development of methods for these future-oriented molecular transformations. 

The first case study was selected to showcase the complexity associated with the correct stereochemistry assignment of cyclic peptide natural products. Structure of cyclocinamide A underwent several modifications after its first appearance in 1997 [127]. Konopelski reported a synthetic design that utiHzed the potential of turn-inducing capability of (cyclo)Asn (Scheme 8.1) that led to the cyclocinamide derivatives, particularly aU-S isomer, without racemization [128]. The retrosynthetic strategy rehed on the use of (cyclo)Asn, as internal conformational element was... 

The thesis results have already inspired further work in progress on efficient synthesis of indoles and isoquinolines, and his findings would contribute to the diversity-oriented synthesis for the drug discovery and facUe synthesis of biologically active natural products containing complex structure. 1 hope his outstanding thesis will contribute to synthetic research of many readers. 

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