Diels-Alder Reaction structurally complex natural product

The Diels-Alder reaction occupies a cherished place in the hearts of organic synthetic chemists, not only in the synthesis of steroids [45] but far and wide in the synthesis of structurally complex natural products [46]. The Diels-Alder... 

The composition of the reaction mixture depends, to a considerable extent on the nature of the corresponding substituents. If, for example, one of the substituents is of the donor and the other of the acceptor nature, then the preferred outcome of the Diels-Alder reaction is the "ortho" product.The rationalization of the observed differences in the regioselectivity can be again very simply given in terms of the Fukui s theory of frontier orbitals [43-46]. In contrast to previous examples where the discrimination between the allowed and foibidden reactions was based on the mere comparison of the nodal structure of frontier orbitals of individual components, the situation in this case is more complex. 

It is well recognized that the Diels-Alder reaction is a powerful method for constructing functionalized, six-membered carbocyclic compounds, especially in the synthesis of structurally complex natural products. Organocatalytic versions of enantioselective Diels-Alder reactions have also been explored for the synthesis of natural products. 

Application to both Type I and Type II intramolecular Diels-Alder cycloaddition has also met with appreciable success, the most efficient catalyst for these reactions being imidazolidinone 21 (Scheme 7) [51, 52]. The power of the inttamolecular Diels-Alder reaction to produce complex carbocyclic ring structures from achiral precursors has frequently been exploited in synthesis to prepare a number of natural products via biomimetic routes. It is likely that the ability to accelerate these reactions using iminium ion catalysis will see significant application in the future. 

Recently, the first examples of catalytic enantioselective preparations of chiral a-substituted allylic boronates have appeared. Cyclic dihydropyranylboronate 76 (Fig. 6) is prepared in very high enantiomeric purity by an inverse electron-demand hetero-Diels-Alder reaction between 3-boronoacrolein pinacolate (87) and ethyl vinyl ether catalyzed by chiral Cr(lll) complex 88 (Eq. 64). The resulting boronate 76 adds stereoselectively to aldehydes to give 2-hydroxyalkyl dihydropyran products 90 in a one-pot process.The diastereoselectiv-ity of the addition is explained by invoking transition structure 89. Key to this process is the fact that the possible self-allylboration between 76 and 87 does not take place at room temperature. Several applications of this three-component reaction to the synthesis of complex natural products have been described (see section on Applications to the Synthesis of Natural Products ). 

The reverse reactions of Diels-Alder reactions for thermal dissociations of cycloadducts in to dienes and dienophiles at higher temperatures or in the presence of Lewis acid or base are known as the retro-Diels-Alder (rDA) reactions. These reactions in most cases proceed in a concerted process. These reactions are often used for separation of diene or dienophile from their mixture with other compounds. Proper selection of conditions of these reactions provides new dienes and dienophiles, which are important synthons for synthesis of several bioactive natural products and organic molecules of complex structures. For example, the D-A adduct of 4-phenyl oxazole 110 with methyl acetylene dicarboxylate, on retro-D-A reaction gives new compounds, benzonitrile, and furan 3,4-dicarboxylic acid methyl ester 111 [65]. 

The Diels-Alder reaction is a powerful transformation that can generate structural and stereochemical complexity in a single chemical operation. This is amply demonstrated by some of its ingenuous applications in total syntheses of natural products. The first example of an intramolecular Diels-Alder reaction seems only to have been reported, by Alder, in 1953 [29, 30, 46). After this surprisingly slow start in comparison with its intermo-lecular counterpart, countless applications of intramolecular Diels-Alder reactions have since appeared [28-31]. 

The Pauson-Khand reaction (PKR) is among the most powerful transformations in terms of molecular complexity increment [1]. Only a few of other reactions like the Diels-Alder, or the cyclotrimerization of alkynes can compete with the PKR, which consists formally of a [2 + 2 + 1] cycloaddition in which a triple bond, a double bond and carbon monoxide form a cy-clopentenone [2-12], This constitutes one of the best ways to construct cyclopentenones, which upon further transformations can be converted into structures present in numerous natural products (Scheme 1). 

The venerable Diels-Alder cycloaddition reaction is rapidly approaching its centennial. Much has transpired since its early days, when it was commonly perceived only as an approach to dienes. The initial predictions of Diels and Alder proved all too conservative, as this cycloaddition reaction has impacted the synthesis of all classes of natural and anthropogenic products. Importantly, the design, synthesis, and study of catalysts continue to provide a wealth of fundamental insight into the process. Moreover, the evolution of this area enables opportunities for the preparation of complex structures, whose syntheses are significantly simplified upon application of the Diels-Alder transform. 

---