Target-oriented syntheses

The total synthesis of palytoxin (1) is a landmark scientific achievement. It not only extended the frontiers of target-oriented synthesis in terms of the size and complexity of the molecules, but also led to new discoveries and developments in the areas of synthetic methodology and conformational analysis. Among the most useful synthetic developments to emerge from this synthesis include the refinement of the NiCh/CrC -mediated coupling reaction between iodoolefins and aldehydes, the improvements and modifications of Suzuki s palladium-catalyzed diene synthesis, and the synthesis of A-acyl vinylogous ureas. 

In this review, an attempt is made to exhaustively catalog the rapidly growing subset of metal-catalyzed reductive C-C bond formations comprising the hydrometallative and hydrogenative carbocyclization of 7t-unsaturated substrates, and application of these methods in target-oriented synthesis. Content is organized on the basis of reaction... 

For a review on asymmetric catalysis in target-oriented synthesis, see A. H. Hoveyda, Stimulating Topics in Organic Chemistry (Eds. F. Vogtle, J. F. Stoddart, M. Shibasaki), Wiley-... 

Hoveyda in his essay on asymmetric catalysis in target-oriented synthesis (p 145). The concept of catalysis-based total synthesis, in which a series of catalytic enantioselective reactions are employed in combination with other catalytic reactions, is emerging as the desirable way to make complex natural products and medidnally-important target compounds. 

There are few transformations that can, in a single stroke, provide the structural and stereochemical complexities that are attained through a Diels-Alder cydoaddition. It is little surprise then that numerous studies have appeared in the past decade that aim to develop a catalytic asymmetric Diels-Alder process. It is only in a few instances, however, that these catalytic asymmetric protocols have been applied to target-oriented synthesis. Several impres-... 

Furthermore, the copper-mediated SN2 substitution reaction is not restricted to carbon-carbon bond formation, as can be seen form the synthesis of silylallenes [15], stannylallenes [16] and bromoallenes [17] using propargylic electrophiles and the corresponding heterocuprates. The resulting allenes are often used as intermediates in target-oriented synthesis, e.g. in cyclization and reduction reactions [15-17]. 

In conjunction with the chiral anion TRIP (156) (10 mol%), diamine 157 (10 mol%) can be used in the catalytic asymmetric epoxidation of a,p-unsaturated ketones (>90% ee) [196], while the secondary amine 158 (10 mol%) can be used for the epoxidation of both di- and trisubstituted a,P-unsaturated aldehydes (92-98% ee) (Fig. 15) [211], The facile nature of these reactions, using commercially available peroxides as the stoichiometric oxidant, together with the synthetic utility of the epoxide products suggests application in target oriented synthesis. 

Based on this precedent, Nelson et al. used an intramolecular reaction in the total synthesis of (-)-rhazinilam. In this context, trisubstituted allenes are excellent precursors for a diastereoselective heterocyclic annulation that highlights the usefulness of this reaction in target-oriented synthesis [49]. In this case, the aforementioned catalyst that yielded the best results was [AuPPh3OTf], affording a higher yield and diastereoselectivity than Pd(II). 

For an excellent account of this concept and its conceptual difference to target-oriented synthesis, see a) S. L. Schreiber, Science 2000, 287, 1964-1969. For some notable examples of this approach, see b)... 

The development of synthetic methods is a very important branch of natural product synthesis, and complex target-oriented synthesis. The new chemical methods that are developed by chemists simplify the process of synthesis. This simplification generally leads to a shorter number of steps in the synthesis and therefore a more efficient synthesis. New synthetic methods are usually developed with simple substrates which highlight the main functional group transformation. These methods can be difficult to be transferred to a more complex molecule therefore, it is important that a new synthetic method demonstrates the scope and limitation of the method. 

Catalytic alcoholysis of silanes by a variety of transition metal based catalysts is a useful method to form silyl ethers under mild conditions (Scheme 19). The process is atom-economical hydrogen gas is the only byproduct. This mild method has not been fully exploited for the preparation of unsymmetrical bis-alkoxysilanes. A catalytic synthesis using silicon alcoholysis would circumvent the need of bases (and the attendant formation of protic byproducts), and eliminate the need for excess silicon dichlorides in the first silyl ether formation. We sought catalytic methods that would ultimately allow formation of chiral tethers that are asymmetric at the silicon center (Scheme 20). Our method, once developed, should be easily transferable for use with high-value synthetic intermediates in a complex target-oriented synthesis therefore, it will be necessary to evaluate the scope and limitation of our new method. 

Thus far we have been using (+)-ethyl lactate as the alcohol in the first step in the synthesis of silyl ketals. As we mentioned in the introduction, in order for our method to be transferred for use with high-value synthetic intermediates in a complex target-oriented synthesis, we must explore the scope and limitation of our method. We began by evaluating the synthesis of silyl ketals by reversing the order of the alcohol addition (Scheme 30). 

Oxidative nucleophilic substitution is, however, a more versatile technique and a much better choice for target-oriented synthesis (Sections 15.1.1 and 15.1.2.2). In 1950, Wessely and co-workers examined the use of lead tetraacetate (LTA) in acetic acid to determine the structure of phenols and, in doing so, they developed their oxidative acetoxylation reaction, referred to herein as Wessely oxidation (Figure 13) [68-76]. If both an ortho- and a para-position are available to accommodate the entry of the acetoxy nucleophile, ortho products often predominate even when the ortho position is already occupied by a resident alkyl (e.g. 40 —> 41a/b) or allcoxy group (Figure 13) [69, 74]. 

Among various recent applications of diastereoselective cuprate addition reactions to cyclic enones in target-oriented synthesis,81,81a 81c,83 87 the synthesis of (—)-dihydrocodeinone and (—)-morphine by Mulzer and co-work-... 

The previous examples have amply demonstrated the high levels of //-stereoselectivity that are usually encountered in copper-mediated S -substitution reactions.3 5,16,16a,8° Several new approaches to influence the stereochemical course of these transformations and to utilize them for target-oriented synthesis have been reported in the... 

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