Natural products asymmetric synthesis

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. 

Enantiomerically pure cyclopropanes are a frequent motif in the structure of natural products. Their synthesis is often demanding and many approaches have been made [50, 51]. Porcine pancreatic lipase (PPL) was used for the stereoselective desymmetrization of a cyclopropane dibutanoate (Fig. 2). The asymmetric hydrolysis of the meso compound yielded the corresponding enantiopure alcohol almost quantitatively. The intermediate obtained was successfully applied in the total synthesis of dictyopterenes A and C, sexual pheromones of brown algae [52], and constanolactones (see below) [53]. 

B. Dounay, L. E. Overman, The Asymmetric Intramolecular Heck Reaction in Natural Product Total Synthesis, Chem. Rev. 2003, 103, 2945-2963. 

Dounay AB, Overman LE. The asymmetric intramolecular Heck reaction in natural product total synthesis. Chem. Rev. 2003 103 2945-2963. 

The Asymmetric Intramolecular Heck Reaction in Natural Product Total Synthesis ... 

Abstract This chapter provides an overview of emerging strategies for the selective introduction of functionality at oxindole C3. Specific emphasis has been devoted toward asymmetric methods for the introduction of C3 quaternary centers and spirocyclic ring systems. The chapter has been divided into two sections oti general methodology for the stereoselective synthesis of oxindoles and spirooxin-doles, respectively. A third section is devoted toward efforts in natural product total synthesis involving oxindole or spirocyclic variants as targets or key intermediates. 

Metal-Catalyzed Cross-Coupling Reactions, Vol. 1,2nd edn (eds A. de Meijere and F. Diederich), Wiley-VCH Verlag GmbH, Weinheim, Germany, pp. 217-315 (c) Dounay, A.B. and Overman, L.E. (2003) The asymmetric intramolecular Heck reaction in natural product total synthesis. Chem. Rev., 103, 2945-63 (d) Link, J.T. (2002) The intramolecular Heck reaction. Org. React., 60, 157-534 (e) Shibasaki, M. and Miyazaki, F. (2002) Asymmetric Heck reactions, in... 

The synthesis of carbocycles via a two-component cascade reaction in an asymmetric fashion has attracted much attention from the chemical community. Due to his importance in natural products, the synthesis of cyclopropanes, cyclopentanes, and cyclohexanes has been one of the common goals for organocatalytic methodologies. The high stereoselectivity achieved, green procedures, and soft conditions make this organocatalytic approximation one of the most attractive ones to build complex cyclic scaffolds. 

Asymmetric phase-transfer catalysis is a method that has for almost three decades proven its high utility. Although its typical application is for (non-natural) amino acid synthesis, over the years other types of applications have been reported. The unique capability of quaternary ammonium salts to form chiral ion pairs with anionic intermediates gives access to stereoselective transformations that are otherwise very difficult to conduct using metal catalysts or other organocatalysts. Thus, this catalytic principle has created its own very powerful niche within the field of asymmetric catalysis. As can be seen in Table 5 below, the privileged catalyst structures are mostly Cinchona alkaloid-based, whereas the highly potent Maruoka-type catalysts have so far not been applied routinely to complex natural product total synthesis. 

The intramolecular Diels-Alder reaction is most frequently used in natural product total synthesis, and numerous examples will be described in the synthetic utility section. As with the intermolecular variant, intramolecular reactions are highly regioselective and stereoselective and participate in hetero, inverse electron demand, and asymmetric Diels-Alder reactions. One report from 2008 describes the investigation of an intramolecular hetero Diels-Alder reaction in ionic liquids. ... 

Although (—)-palau amine is an architecturally daunting natural product, its synthesis was finally accomplished by the Baran group in 2010. In the publication describing this work, Baran et al. also described the asymmetric syntheses of other... 

Allylation of carbonyl compounds is another very useful carbon-carbon bond forming asymmetric transformation in organic synthesis. This transformation yields the homoallylic alcohols that have proven to be valuable reagents and intermediates that have found numerous applications in natural product total synthesis. In particular, asymmetric allyl-boration of aldehydes employing tartrate- and pinane-derived reagents has been widely exploited. Although the asymmetric allylation reaction is well documented and widely used in solution phase, the asymmetric variant of the allylation of carbonyl compounds on the solid support has remained largely unexplored. ... 

Monoterpenes and iridoids are very important natural products, and the biosynthetic pathways toward these compounds are nowadays well understood. We choose this class of secondary metabolites to highlight the potential of asymmetric organocatalysis for the total synthesis of complex natural products. Asymmetric organocatalysis has been one of the most exciting fields in organic chemistry over the last decades, and we hope that we have been able to illustrate how diverse and powerful this methodology can be with respect to different activation modes that are possible and different substance classes that can be easily accessed thereby. 

To date, several different catalysts, both organocatalysts and metal-based catalysts, are available for the asymmetric Michael-type addition reactions. Indeed, a high level of achievement has been reached in terms of enanatioselectiv-ity and product yield. However, specihc windows for particular substrates, especially in natural product motif synthesis, are stdl in great demand. Thus, the exploration of more gen-eraL as well as more operationally simple (e.g., moisture stable and air stable), catalysts is attainable. Through the further in-depth structural investigation of catalyst-substrate interaction in Michael addition, a more sophisticated, yet more efficient, catalyst can be developed, and thus, the Turn Over Number (TON) can be expected to be increased. These future developments certainly will be fmitfiil to pharmaceutically and industrially related processes. 

Clearly, there is a need for techniques which provide access to enantiomerically pure compounds. There are a number of methods by which this goal can be achieved . One can start from naturally occurring enantiomerically pure compounds (the chiral pool). Alternatively, racemic mixtures can be separated via kinetic resolutions or via conversion into diastereomers which can be separated by crystallisation. Finally, enantiomerically pure compounds can be obtained through asymmetric synthesis. One possibility is the use of chiral auxiliaries derived from the chiral pool. The most elegant metliod, however, is enantioselective catalysis. In this method only a catalytic quantity of enantiomerically pure material suffices to convert achiral starting materials into, ideally, enantiomerically pure products. This approach has found application in a large number of organic... 

Chiral oxazoline-based synthetic methods have been employed in the asymmetric synthesis of a large number of natural products. A few representative examples of these applications are shown below. 

Asymmetric Birch reduction and reduction-alkylation in synthesis of natural products 99CC1263. 

For excellent discussions of the use of optically active starting materials in synthesis, see (a) Hanes-sian, S. The Total Synthesis of Natural Products. The Chiron Approach, Pergamon Press New York, 1983 (b) Scott, J.W. In Asymmetric Synthesis, Morrison, J.D. Scott, J. W., Eds., Academic Press San Diego, 1984, Vol. 4, p. 1. 

This highly convergent synthesis amply demonstrates the utility of Evans s asymmetric aldol and alkylation methodology for the synthesis of polypropionate-derived natural products. By virtue of the molecular complexity and pronounced lability of cytovaricin, this synthesis ranks among the most outstanding synthetic achievements in the macrolide field. 

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