Highly complex molecules synthesis

Few known and thermodynamically feasible molecular structures are presently seen as impossible goals for synthesis. New transformations and effective strategies permit chemists to synthesize highly complex molecules, such as new natural compounds discovered in the continued chemical exploration of the natural world. Again, the point of such work is to develop new chemistry that permits an approach to structures of the type found in nature. This expands the power of chemistry and allows medicinal chemists to synthesize complex structures. 

A diastereoselective ewrfo-cyclization into an oxidatively generated oxocarbenium ion was a key step in a formal synthesis of leucascandrolide A. Exposing 56 to CAN provided cw-tetrahydropyran 57 in high yield and with excellent stereocontrol (Scheme 3.20). This transformation provides further evidence that oxidative electrophile formation is tolerant of several functional groups and can be applied to complex molecule synthesis. The synthetic sequence also utilized a Lewis acid mediated ionization reaction to form an oxocarbenium ion in the presence of the homobenzylic ether (58, 59), illustrating that two carbocation precursors that ionize through chemically orthogonal conditions can be incorporated into the same structure. 

Although the classical Nef reaction has proved quite useful for the conversion of nitroalkenes to carbonyl derivatives, the conditions originally developed for this transformation are quite harsh, and side reactions of functionalized molecules are frequently observed. In order to address this limitation, a considerable amount of effort has been dedicated toward the development of mild conditions that could be used in reactions of highly functionalized substrates that often serve as intermediates in complex molecule synthesis. 

An example of the use of an intermolecular carbopalladation in complex molecule synthesis is the preparation of a PAF (platelet activating factor) antagonist (Scheme 11). In the key step, an intermolecular Heck reaction of 2-naphthyl triflate with 2,3-dihydrofuran 71 yields 2-naphthyl-2,3-dihydrofuran 72 in 52% yield with excellent enantioselectivity. The reaction presumably occurs via the cationic manifold and the alkene is isomerized by a hy-dropalladation/dehydropalladation reaction. The minor product 2,5-dihydrofuran 73 is obtained in 26% yield with modest enantioselectivity favoring the opposite absolute configuration at the key center. Critical to the reaction is the use of the sterically demanding and highly basic proton sponge [l,8-bis(dimethylamino)naphthalene] as the base. It is... 

At least for aryl iodides, the application of phosphine complexes of palladium still continues to be practised in complex preparations where mild conditions are desirable to secure high selectivity. In these cases, halide scavenger additives are often used to enable the polar pathway, because phosphine ligands under mild conditions block the coordination places need for alkene binding. Owing to the low reactivity of those systems, high loadings of precatalyst are only tolerable in complex molecule synthesis. For example, this approach enabled clean vinylation of vinylic boronate 63 to afford complex diene 64 (62 64, Scheme 2.13) [62]. 

This enzyme-like reactivity enables the synthesis of highly complex molecules from substrates containing carboxylic acids, such as picrotoxinin derivatives which, when exposed to the same oxidizing conditions, yield lactone and hydroxylactone products (Scheme 38). 

This chapter deals with three important classes of biotransformations. Firstly, those enzymes that catalyse the stereoselective formation of carbon-carbon bonds will be examined. These enzymes, whose natural functions often are to degrade carbohydrate-like molecules, have proved to be versatile catalysts for C—C bond synthesis. Secondly, we shall look at those enzymes that mediate the formation of C—X bonds, where X = O, N, S, Hal (halogen). These enzymes are termed lyases (see Table 2.1) and often carry out very simple reactions (e.g. the addition of water to a double bond) with very high stereoselectivity and regioselectivity. Finally, the application of a range of enzymes (including C—C bond formation) to carbohydrate synthesis will be examined. This chapter will conclude with some examples of the ways in which multienzyme reactions can be constructed to enable highly complex molecules to be assembled in an efficient manner. 

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