Natural Products and Biologically Active Compounds

Since the aromatic Claisen rearrangement is a useful synthetic tool for the regio-selective introduction of carbon functional group at the ortho position of phenol derivatives, a number of applications of this reaction to the synthesis of natural products and biologically active compounds have been reported. 

The Eli Lilly group reported the synthesis of zatosetron, a potent, selective, and long-acting SHTj receptor antagonist, through the thermal aromatic Claisen rearrangement and the following acid-catalyzed cyclization to form a coumaran skeleton 106 as a key step [80]. 

Very recently, the enantioselective total synthesis of hexahydropyrrolo[2,3-h]-indole alkaloids, (-)-pseudophynaminol, through tandem olefination, isomerization and asymmetric Claisen rearrangement was reported [81]. Using a 3-ketodi-hydroindole derivative 107, the reaction smoothly proceeded under extremely 

Biichi et al. reported the total synthesis of atrovenetin via a base-promoted site-selective Claisen rearrangement followed by the formation of a benzofuran framework 111 [83]. 

Danishefsky et al. developed a stereospedfic route for the synthesis of deoxy analog of mitomycin via an aromatic Claisen rearrangement [84]. The aUyl aryl ether 112 was prepared from allylic alcohols and phenol derivative via the Mitsu-nobu reaction. The aromatic Claisen rearrangement of 1,3-disubstituted aUyhc ether 112 proceeded under thermal conditions (N,N-dimethylaniline reflux) to afford the ortho rearrangement product 113 in 80% yield. 

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Aziridines are important compounds due to their versatility as synthetic intermediates. In addition, aziridine rings are present in innumerable natural products and biologically active compounds. Nitrene addition to alkenes is one of the most well established methods for the synthesis of aziridines. Photolysis or thermolysis of azides are good ways to generate nitrenes. Nitrenes can also be prepared in situ from iodosobenzene diacetate and sulfonamides or the ethoxycarbonylnitrene from the A-sulfonyloxy precursor. 

Hydroxylated six-membered ring nitrogen containing heterocycles is a common feature of many natural products and biologically active compounds.127 Willis and coworkers have... 

The addition of doubly deprotonated HYTRA to achiral4 5 as well as to enantiomerically pure aldehydes enables one to obtain non-racemic (3-hydroxycarboxylic acids. Thus, the method provides a practical solution for the stereoselective aldoi addition of a-unsubstituted enolates, a long-standing synthetic problem.7 As opposed to some other chiral acetate reagents,7 both enantiomers of HYTRA are readily available. Furthermore, the chiral auxiliary reagent, 1,1,2-triphenyl-1,2-ethanediol, can be recovered easily. Aldol additions of HYTRA have been used in syntheses of natural products and biological active compounds, and some of those applications are given in Table I. (The chiral center, introduced by a stereoselective aldol addition with HYTRA, is marked by an asterisk.)... 

Optically active epoxides are important building blocks in asymmetric synthesis of natural products and biologically active compounds. Therefore, enantio-selective epoxidation of olefins has been a subject of intensive research in the last years. The Sharpless [56] and Jacobsen [129] epoxidations are, to date, the most efficient metal-catalyzed asymmetric oxidation of olefins with broad synthetic scope. Oxidative enzymes have also been successfully utilized for the synthesis of optically active epoxides. Among the peroxidases, only CPO accepts a broad spectrum of olefinic substrates for enantioselective epoxidation (Eq. 6), as shown in Table 8. 

Superelectrophilic reactions have been shown to be particularly useful in various synthetic conversions particularly of unactivated er and 7r-bonds, such as in alkanes and electron deficient arenes. Superelectrophiles have also been used in the synthesis of natural products and biologically active compounds. Superelectrophilic chemistiy has also... 

Heteroatom transfer reactions to carbon-carbon double bonds using catalytic or stoichiometric amounts of transition-metal complexes have recently attracted considerable interest in the convenient synthesis of three-membered heterocycles (Eq. (1)). The latter are versatile building blocks for the construction of complex organic compounds, such as natural products and biologically active compounds (Eq. (1)) [11. 

Many natural products and biologically active compounds contain cyclopropane rings we shall feature j ist a few. First, a most important natural insecticide, a pyrethrin from the East African pyrethrum daisy, and its synthetic analogue decamethrin, now the most important insecticide in agriculture (see Chapter 1). Very low doses of this highly active and nonpersistent insecticide are needed. 

The synthetic utility of this procedure was illustrated by the practical synthesis of the versatile intermediate y-lactone (i )-5-methyltetrahydrofuran-2-one (Fransson et al, 2005). Chiral y-lactones are important structural syn-thons for the synthesis of natural products and biologically active compounds (Benincori et al, 2004). 

Table 3-9 Syntheses of important natural products and biologically active compounds involving the Heck reaction (HR) (Figures 3.2 and 3.3)...

Syntheses of Natural Products and Biologically Active Compounds... 

Chiral molecules are characterized by three-dimensional handedness and can exist in two enantiomeric forms of opposite absolute configuration (AC). Most natural products and biologically active compounds are chiral and their biological and molecular functions are closely related to their chirality, that is, AC and conformation. Furthermore, many drugs derived from natural products or of purely synthetic origin are currently used in enantiopure form. Therefore, the unambiguous determination of the AC of chiral compounds is critical for the studies of natural products and biomolecular systems.1... 

In nature, the intramolecular condensation of a 1,3-dicarbonyl moiety with a keto group in polyketides is an important step in the biosynthesis of aromatic compounds. Biomimetic transformations of this type have been intensively investigated by Harris. (For a discussion, see Chapter 1.5, this volume.) In the following, the synthesis of some natural products and biologically active compounds using the Knoevenagel reaction will be described. 

Modem acetylene chemistry plays a critical role in the current world-wide efforts to synthesize new molecular and polymeric carbon allotropes as well as carbon-rich nanomaterials. It is rapidly becoming clear that the preparative challenges in this interdisciplinary research area at the interface between materials science and chemistry are formidable and rival those in the more established synthesis of natural products and biologically active compounds. Modern materials research strongly relies on advanced synthetic methodology, and it is hoped that the field will attract many synthetically oriented chemists into its ranks their efforts will be rewarded by the development of materials with unique properties and unprecedented applications. 

In this chapter, applications of amidine, guanidine and phosphazene superbases to the synthesis of natural products have been discussed. Many structurally complex natural products have been synthesized efficiently and elegantly by making use of the reactions described. Currently, much attention is focussed on the development of chiral superbases and their application to asymmetric reactions. Such catalytic asymmetric reactions are expected to offer exciting and efficient new approaches to the synthesis of natural products and biologically active compounds. 

Reductions of aromatic nitro compounds provide a simple and general access to various heterocyclic compounds through the domino process (Scheme 9.23). Quinolines are important skeletal moieties present in various natural products and biologically active compounds [58]. Most common methods of their preparation involve condensation of o-amino benzaldehydes with an enolizable carbonyl compound (Friedlander synthesis) [59]. Miller et al. [60] reported an efficient synthesis of quinolines 109, in which a reduction of o-nitroaryl carbaldehyde by SnCl2 followed by condensation with an enolizable carbonyl compound in the presence of ZnCl2 yielded 109 through a domino process. In 2001, Bunce et al. [61] reported a domino nitroarene reduction/reductive amination sequence for the preparation of tetrahydroquinoline-4-carboxylic ester 110 with excellent yields. 

Pyrazole nucleus constitutes a number of sub-structures of natural products and biologically active compounds. Several derivatives of these systems find use in medicine described as follows ... 

The asymmetric synthesis of cyclopropanes has attracted continual efforts in organic synthesis, due to their relevance in natural products and biologically active compounds. The prevalent methods employed include halomethylmetal mediated processes in the presence of chiral auxiliaries/catalysts (Simmons-Smith-type reactions), transition-metal-catalyzed decomposition of diazoalkanes, Michael-induced ring closures, or asymmetric metalations [8-10,46], However, the asymmetric preparation of unfunctionahzed cyclopropanes remains relatively undisclosed. The enantioselective activation of unactivated C-H bonds via transition-metal catalysis is an area of active research in organic chemistry [47-49]. Recently, a few groups investigated the enantioselective synthesis of cyclopropanes by direct functionalization reactions. 

In conclusion, the recent developments towards more practical reagents and catalysts to perform C—H amination reactions have provided a variety of new synthetic tools to prepare various nitrogen derivatives. Furthermore, a number of stereoselective methods have been recently disclosed. All this progress should promote the use of C—H amination reactions in total synthesis of natural products and biologically active compounds. 

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