Application to Natural Products

Natural products have been, and remain, a rich source of leads for the pharmaceutical industry and many marketed drugs are either natural products or are modifications of such substances. Hence, considerable effort is spent in isolating and characterising chemicals from natural sources which can be tested in a variety of biological screens. Often, it is necessary to carry out laborious extraction and purification steps and the advent of directly coupled HPLC-NMR has been explored as an alternative technique for natural product identification. The use of HPLC-NMR, and other hyphenated techniques such as HPLC-MS-MS, for identification of natural products from plant sources has been reviewed by Wolfender and co-workers [40,41], 

The application of directly coupled HPLC-NMR and HPLC-CD, used separately, has been employed extensively for characteristion of natural products, as is described in more detail in another chapter in this volume [42]. 

Microbial production of secondary metabolites is also an important source of novel therapeutic agents. However, the physiological and biochemical factors that determine the onset of production of a specific secondary metabolite in a particular species are incompletely understood. Generally, a range of analytical techniques, often elaborate, time-consuming and involving extensive sample pre-treatment, have to be developed in order to monitor the details of the metabolic changes and substrate consumption that accompany secondary metabolite production. In order to provide rapid multi-parametric information about the microbial fermentation process, H HPLC-NMR has been applied to characterise microbial metabolites directly in the broth supernatants from a 

Other studies of natural products, which will be described in detail elsewhere in this book, involve the characterisation of isomeric structures, an application for which NMR spectroscopy is particularly powerful. For example, Albert et al. have used HPLC-NMR spectroscopy to determine the structures of isomers of vitamin A acetate [45]. The parent molecule has all-trans double bonds as shown below and by brief heating of this substance a number of isomers with a single cis double bond and one isomer with two cis double bonds can be formed  

By using continuous-flow 400 MHz HPLC- H NMR spectra obtained using a cyanopropyl-silica gel column with heptane as the eluent, and by examination of the spectra extracted from the pseudo-2-dimensional representation, it was possible to identify the all -trans molecule, as well as the 9-cis, 11 -cis, 13-cis and 11, 13 di-cis isomers. 

---

The Boekelheide reaction has found utility in a number of synthetic applications. A notable example of its application to natural product synthesis was described by... 

The final chapter in this volume by R. Kumar and R. Chandra (University of Delhi, India) deals with stereocontrolled additions to di- and tetrahydropyridines and particularly their application to natural product synthesis. 

Novel indole synthesis and its application to natural product synthesis 98JHC1043. 

Chemoselective reduction of a,(3-epoxy carbonyl compounds to aldols and their analogs by organoseleniums and its application to natural product synthesis 98YGK736. 

Among the many chiral Lewis acid catalysts described so far, not many practical catalysts meet these criteria. For a,/ -unsaturated aldehydes, Corey s tryptophan-derived borane catalyst 4, and Yamamoto s CBA and BLA catalysts 3, 7, and 8 are excellent. Narasaka s chiral titanium catalyst 31 and Evans s chiral copper catalyst 24 are outstanding chiral Lewis acid catalysts of the reaction of 3-alkenoyl-l,2-oxazolidin-2-one as dienophile. These chiral Lewis acid catalysts have wide scope and generality compared with the others, as shown in their application to natural product syntheses. They are, however, still not perfect catalysts. We need to continue the endeavor to seek better catalysts which are more reactive, more selective, and have wider applicability. 

Among the many recent applications to natural products, syntheses of pyrrolizidine and indolizidine alkaloids that take advantage of the 1,3-dipolar cycloaddition methodology have been reviewed [8]. The regio- and stereochemistry [9] as well as synthetic appHcations [10] of nitrile oxide cycloadditions have also been discussed. 

Bellemin-Laponnaz S, Twedel J, Ruble JC, Breitling FM, Fu GC (2000) The kinetic resolution of allylic alcohols by a non-enzymatic acylation catalyst application to natural product synthesis. Chem Conunun 1009-1010... 

Foncanlt, A.P. and Chevolot, L., Connter-cnrrent chromatography instrumentation, solvent selection and some recent applications to natural product purification, J. Chromatogr. A, 808, 3, 1998. 

The first two reactions (Table VII) date as far back as 1953, to Reppe s chemistry, and refer to processes occurring via metallacycles. An interesting application to natural products is the synthesis of muscone, which, however, has been obtained in a better way using alkylisonitriles (151) in place of carbon monoxide (example 3, Table VII). 

A large number of synthetic reactions via C-H bond activation have been reported in the last 10 years. In near future, applications to natural products and functional materials will be the next research targets, together with the development of new synthetic reactions. 

Currently, these reactions are typically conducted with Rh(l) or Ir catalysts. The Pauson-Khand-type reaction of allenynes has also witnessed important developments, especially in its applications to natural products synthesis.388 Brummond s group has been very productive in both areas. Duality in the reaction of allenynes is shown below. In the context of diversity-oriented synthesis, simply changing the reaction conditions gives versatile heterocycles in high yields (Scheme 116).389... 

In conclusion, the ene reaction has undergone a synthetic renaissance with the advent of Lewis acid and transition metal-catalyzed protocols. The carbonyl-ene, imino-ene, and Alder-ene reactions have all experienced tremendous growth due to the mild conditions in which these reactions can be performed, the high functional group compatibility and high stereoselectivity. As a confirmation of the synthetic utility of the ene reaction, there are many applications to natural product synthesis, and some of these are highlighted in Section 10.12.6. Finally, it should be mentioned that these catalyzed ene reactions are still in their infancy, so much remains to be learned. 

A relatively recent application to natural product synthesis stems from efforts to synthesize a sesquiterpene called 1-sterpurene 7 [17]. This substance is thought to be the causative agent of the so-called silver leaf disease that affects certain species of shrubs and trees. The strategy focuses on three key steps (a) electrochemical cyclization of the bis unsaturated ester 11 to produce the five-membered ring of 10, (b) a Ruhlman-modified acyloin condensation to... 

In another early application to natural product synthesis, Fleming and coworkers utilized this approach in the efficient formation of the gelsemine model (47) from 45 according to Scheme 8. The cyclization step to form the spiro-oxindole (46) proceeded in 85% yield and provided a means of generating the spiro-fused quaternary carbon without the need for carbenium ion or carbanion chemistry. 

Applications to natural product synthesis probe the limits of any synthetic method, as situations arise that would never have been considered in the course of first developing the method. Recent syntheses of valienamine 6, agelastatin 9 and tonantzitlolone 15 pressed the limits of ring-closing metathesis. 

K. Toshima and K. Tatsuta, Recent progress in O-glycosylalion methods and its application to natural products synthesis, Chem. Rev. 93 1503 (1993). 

IV-alkyl and IV-acyl derivatives has been widely used, the method of choice is that of trimethylsilylation. The procedure is widely applicable to natural products (e.g. carbohydrates, amino acids, steriods, alkaloids, polyhydroxyphenols, fatty acids, etc.), and has found great use in analytical and preparative laboratories which handle such compounds. 

Ogamino T, Ishikawa Y, Nishiyama S (2003) Electrochemical Synthesis of Spiroisoxazole Derivatives and Its Application to Natural Products. Heterocycles 61 73... 

---