Bioactive natural products chiral synthesis

Chiral aryl acetic acids constitute a privileged class of target structures due to their prevalence in bioactive natural products and pharmaceuticals and so, unsurprisingly, they constitute attractive targets for asymmetric synthesis [198]. The face-selective addition of a nucleophile to an aryl alkyl ketene provides a very direct entry for the preparation of such compounds. Although this can be achieved by the use of a chiral nucleophile or acid (cf. Scheme 8.1) [199], catalysis of the addition of an achiral nucleophile is clearly attractive from the standpoint of efficiency. 

O-Benzylglycidol as a chiral building block in the synthesis of bioactive natural products 91YZ647. 

Microbial or enzymatic preparations of the chiral building blocks useful in organic synthesis are reviewed. Conversions of these chiral building blocks to important bioactive natural products are also illustrated. 

With the enantioselective intramolecular benzoin reaction established as a synthetic tool, and in combination with our efforts in the synthesis of bioactive natural products bearing a quaternary a-hydroxy ketone unit (Davis and Weismiller 1990 Heller and Tamm 1981), such as the 4-chromanone derivative (S)-eucomol (Bohler and Tamm 1967 Crouch et al. 1999), a catalytic asymmetric synthesis of various 3-hydroxy-4-chromanones brought about by the chiral triazolium salts 127, 123b and 102 as pre-catalysts was investigated (Enders et al. 2006d). The sterically different pre-catalysts were chosen in order to adjust the catalyst system to the steric and electronic properties of the substrates 128. A screening of the reaction conditions indicated 10 mol% of the... 

Optically purified hydrogenation products listed in Table 7 and 10 are promising compounds as a chiral synthetic block for the synthesis of various natural products as well as a chiral auxiliary for diastereo-differentiating reactions. Using available optically purified reaction products, we have carried out several application studies. Among them, two major works, in the field of bioactive natural products and stereo controlled synthetic organic chemistry, will briefly be mentioned. 

In this chapter we have highlighted several practical approaches for the synthesis of chiral propargyl alcohols by various methods, the most practical ones being the asymmetric alkynation of carbonyl compounds in the presence of chiral auxiliaries and the p-eUmination of stereochemically well-defined a,p-dioxyhalides. These two approaches have been utilized efficiently in the synthesis of several bioactive natural products. 

Optically active a- and p-hydroxyaldehydes are useful chiral building blocks for the synthesis of bioactive natural products such as grahamimycin Ai [459] and amino sugars [460]. PSL-catalyzed resolution of the corresponding dithioacetal esters gave both enantiomers in excellent optical purity (Scheme 2.65) [461]. A significant selectivity enhancement caused by the bulky sulfur atoms was... 

In an effort to further evaluate the generality of this concept, we were particularly attracted to evaluate novel methods for the synthesis of chiral 1,3-diamine motifs and of 1,3-aminoalcohol functionahties, both of which constitute particularly important structural elements in various bioactive natural products and medicinal compounds. Because of their prevalence, a number of strategies for the construction of such systems have been reported. Inspired by our domino concept in combination with certain hmitations of existing methods, in particular, with respect to modularity and convergence, a more direct and flexible procedure for 1,3-diamine and 1,3-amino alcohol synthesis based on stereoselective intramolecular allylic substitution reaction seemed desirable. 

Enzymes and microorganisms help synthetic chemists to prepare nonracemic chiral building blocks. At present lipases are most useful enzymes. Additional new building blocks will be designed and prepared to facilitate enantioselective synthesis. Combination of organic synthesis with biotransformation will continue to provide efficient routes for the enantioselective synthesis of bioactive natural products. 

Both chiral lactones and ketones have been utilized in asymmetric synthesis of bioactive compounds like lipoic acid [175[ and natural products like various insect pheromones [176[. 

Scheme 7 summarizes the synthesis of (7JR,llS)-7,ll-dimethylheptadecane (1), the female sex pheromone of the spring hemlock looper (Lambdina athasaria) by Mori [ 18]. Enantiopure alkanes are usually synthesized by coupling enantio-pure building blocks derived from natural products or compounds prepared by asymmetric synthesis. Even among hydrocarbons, chirality is very important for pheromone activity, and in this particular case meso-1 was bioactive, while neither (7R,11R)-1 nor (7S,11S)-1 showed bio activity. 

The previous section discussed chelation enforced intra-annular chirality transfer in the asymmetric synthesis of substituted carbonyl compounds. These compounds can be used as building blocks in the asymmetric synthesis of important chiral ligands or biologically active natural compounds. Asymmetric synthesis of chiral quaternary carbon centers has been of significant interest because several types of natural products with bioactivity possess a quaternary stereocenter, so the synthesis of such compounds raises the challenge of enantiomer construction. This applies especially to the asymmetric synthesis of amino group-substituted carboxylic acids with quaternary chiral centers. 

Amines bearing a stereocenter a to the nitrogen atom are among the most commonly found subunits in bioactive molecules, natural products, and chiral ligands. As such, there has been much interest in developing methods for their synthesis. Of these methods, the addition of nonstabilized carbanions to activated imines con stitutes one of the most reliable ways for synthesizing this important dass of compounds [1, 2],... 

In conclusion, q -arene transition metal complexes have demonstrated their unique potential for organic synthesis. In particular, planar-chiral q -arene-Cr(CO)3 complexes are valuable building blocks for the diastereo- and enanti-oselective synthesis of complex natural products and related bioactive compounds. Highly original and competitive overall syntheses of various classes of natural products have been developed. The expenditure spent for the introduction of the metal fragment pays off especially in those cases, where the various chemical and stereochemical effects of the metal unit can be exploited in several subsequent transformations. Besides arene-Cr(CO)3 complexes, cationic arene-RuCp complexes have also been applied in synthesis, especially as they allow for efficient arylether formation under mild conditions. 

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