Cycloaddition, 1,3-dipolar 163, Hetero-Diels-Alder

Cycloadditions. Both hetero-Diels-Alder reactions of polymer-bound aldimines with Danishefsky s diene to afford 2-aryl-2,3-dihydro-4-pyridones and 1,3-dipolar cycloadditions of nitrones with a, 3-unsaturated amides are catalyzed by YbfOTflj. Remarkable switch in diastereoselectivity by solvent is observed in the latter reactions. 

While catalyst 22/23 has been known to be valuable in other C-C bond-forming strategies, for example, 1,3-dipolar cycloaddition [149], hetero-Diels-Alder reaction [150], Friedel-Crafts-type alkylation [151], double-Michael reaction [152], [2,3]-Wittig rearrangement [153], and Claisen-Schmidt condensation [154], only references are given here. 

This chapter will try to cover some developments in the theoretical understanding of metal-catalyzed cycloaddition reactions. The reactions to be discussed below are related to the other chapters in this book in an attempt to obtain a coherent picture of the metal-catalyzed reactions discussed. The intention with this chapter is not to go into details of the theoretical methods used for the calculations - the reader must go to the original literature to obtain this information. The examples chosen are related to the different chapters, i.e. this chapter will cover carbo-Diels-Alder, hetero-Diels-Alder and 1,3-dipolar cycloaddition reactions. Each section will start with a description of the reactions considered, based on the frontier molecular orbital approach, in an attempt for the reader to understand the basis molecular orbital concepts for the reaction. 

The theoretical investigations of Lewis acid-catalyzed 1,3-dipolar cycloaddition reactions are also very limited and only papers dealing with cycloaddition reactions of nitrones with alkenes have been investigated. The Influence of the Lewis acid catalyst on these reactions are very similar to what has been calculated for the carbo- and hetero-Diels-Alder reactions. The FMOs are perturbed by the coordination of the substrate to the Lewis acid giving a more favorable reaction with a lower transition-state energy. Furthermore, a more asynchronous transition-structure for the cycloaddition step, compared to the uncatalyzed reaction, has also been found for this class of reactions. 

The combination of pericyclic transformations as cycloadditions, sigmatropic rearrangements, electrocydic reactions and ene reactions with each other, and also with non-pericyclic transformations, allows a very rapid increase in the complexity of products. As most of the pericyclic reactions run quite well under neutral or mild Lewis acid acidic conditions, many different set-ups are possible. The majority of the published pericyclic domino reactions deals with two successive cycloadditions, mostly as [4+2]/[4+2] combinations, but there are also [2+2], [2+5], [4+3] (Nazarov), [5+2], and [6+2] cycloadditions. Although there are many examples of the combination of hetero-Diels-Alder reactions with 1,3-dipolar cycloadditions (see Section 4.1), no examples could be found of a domino all-carbon-[4+2]/[3+2] cycloaddition. Co-catalyzed [2+2+2] cycloadditions will be discussed in Chapter 6. 

As with all-carbon Diels-Alder reactions, the hetero-Diels-Alder reaction [41] can also be used as the first step in many combinations with other transformations. In contrast to the normal Diels-Alder reaction, several examples are known where the first step is followed by a 1,3-dipolar cycloaddition. This type of domino reaction has been especially investigated by Denmark and coworkers, and used for the synthesis of several complex natural products. Since Denmark has reviewed his studies in... 

Alkyl and silyl nitronates are, in principle, /V-alkoxy and /V-silyloxynitrones, and they can react with alkenes in 1,3-dipolar cycloadditions to form /V-alkoxy- or /V-silyloxyisoxaz.olidine (see Scheme 8.25). The alkoxy and silyloxy groups can be eliminated from the adduct on heating or by acid treatment to form 2-isoxazolines. It should be noticed that isoxazolines are also obtained by the reaction of nitrile oxides with alkenes thus, nitronates can be considered as synthetic equivalents of nitrile oxides. Since the pioneering work by Torssell et al. on the development of silyl nitronates, this type of reaction has become a useful synthetic tool. Recent development for generation of cyclic nitronates by hetero Diels-Alder reactions of nitroalkenes is discussed in Section 8.3. 

Hetero Diels-Alder reactions using nitroalkenes followed by 1,3-dipolar cycloadditions provide a useful strategy for the construction of polycyclic heterocycles, which are found in natural products. Denmark has coined the term tandem [4+2]/[3+2] cycloaddition of nitroalkenes for this type of reaction. The tandem [4+2]/[3+2] cycloaddition can be classified into four families as shown in Scheme 8.31, where A and D mean an electron acceptor and electron donor, respectively.149 In general, electron-rich alkenes are favored as dienophiles in [4+2] cycloadditions, whereas electron-deficient alkenes are preferred as dipolarophiles in [3+2] cycloadditions. 

Many examples of asymmetric reactions catalyzed by copper complexes with chiral ligand systems have been reported. In particular, various copper-bis(oxazoline) catalysts (e.g., complexes (H) to (L), Scheme 48) are effective for carbon-carbon bond-forming reactions such as aldol,204 Mukaiyama-Michael, Diels-Alder,206 hetero Diels-Alder,207,208 dipolar cycloaddition,209,210... 

Such a conclusion is, nevertheless, connected with the synchronous character of the mechanism. If a stepwise process is involved (nonsimultaneous formation of the two new bonds), as for unsymmetric dienes and/or dienophiles or in hetero Diels-Alder reactions, a specific microwave effect could intervene, because charges are developed in the transition state. This could certainly be so for several cycloadditions [47, 48] and particularly for 1,3-dipolar cycloadditions [49]. Such an assumption has... 

Diels-Alder reactions [31] and 1,3-dipolar cycloadditions [32, 33] have been performed by use of this methodology. For example, Diaz-Ortiz described the hetero-Diels-Alder and 1,3-dipolar cycloaddition reactions of ketene acetals. The reactions were improved and products were isolated directly from the crude reaction mixture without polymerization of the ketene acetals [34],... 

Bis(oxazoline)-type complexes, which have been found useful for asymmetric aldol reactions, Diels-Alder, and hetero Diels-Alder reactions can also be used for inducing 1,3-dipolar reactions. Chiral nickel complex 180, which can be prepared by reacting equimolar amounts of Ni(C10)4 6H20 and the corresponding (J ,J )-4,6-dibenzofurandiyl-2,2 -bis(4-phenyloxazoline) (DBFOX/Ph) in dichloromethane, can be used for highly endo-selective and enantioselective asymmetric nitrone cycloaddition. The presence of 4 A molecular sieves is essential to attain high selectivities.88 In the absence of molecular sieves, both the diastereoselectivity and enantioselectivity will be lower. Representative results are shown in Scheme 5-55. 

A previous review has highlighted the following methods of ring synthesis intramolecular cyclization of oximes, nitro alkenes, and nitrones, and [4+2] cycloaddition reactions <1996CHEC-II(6)279>. In addition to that, this review includes the intramolecular cyclization of hydroxylamines, hydroxamates, hetero-Diels-Alder [4+2], 1,3-dipolar cycloaddition of nitrile oxides to alkenes, and [3+3] cycloaddition reactions. This review does not cover cycloaddition reactions of the [4+2] [3+2] and [4+2] [3+2] [3+2] types which primarily led to heterocycle-fused oxazine ring systems. 

The carbo- and hetero-Diels-Alder reactions are excellent for the constmction of six-membered ring systems and are probably the most commonly applied cycloaddition. The 1,3-dipolar cycloaddition complements the Diels-Alder reaction in a number of ways. 1,3-Dipolar cycloadditions are more efficient for the introduction of heteroatoms and are the preferred method for the stereocontrolled constmction of five-membered heterocycles (1 ). The asymmetric reactions of 1,3-dipoles has been reviewed extensively by us in 1998 (5), and recently, Karlsson and Hogberg reviewed the progress in the area from 1997 and until now (6). Asymmetric metal-catalyzed 1,3-dipolar cycloadditions have also been separately reviewed by us (7-9). Other recent reviews on special topics in asymmetric 1,3-dipolar cycloadditions have appeared. These include reactions of nitrones (10), reactions of cyclic nitrones (11), the progress in 1996-1997 (12), 1,3-dipolar cycloadditions with chiral allyl alcohol derivatives (13) and others (14,15). 

The development and application of catalytic enantioselective 1,3-dipolar cycloadditions is a relatively new area. Compared to the broad application of asymmetric catalysis in carbo- and hetero-Diels-Alder reactions (337,338), which has evolved since the mid-1980s, the use of enantioselective metal catalysts in asymmetric 1,3-dipolar cycloadditions remained almost unexplored until 1993 (5). In particular, the asymmetric metal-catalyzed reactions of nitrones with alkenes has received considerable attention during the past 5 years. 

Examples of asymmetric amplification in Diels-Alder or hetero-Diels-Alder reactions are listed in Table 6 (see page 281), together with an example of amplification during a 1,3-dipolar cycloaddition. 

If nitroalkenes are employed as heterodienes in hetero Diels-Alder reactions instead of nitrosoalkenes, cyclic nitrones are formed. These cycloadducts undergo numerous subsequent reactions, and especially the combination of this hetero Diels-Alder reaction with a 1,3-dipolar cycloaddition is an extremely powerful tool for the synthesis of polycyclic alkaloids. This domino [4+ 2]/[3+ 2] cycloaddition chemistry has been comprehensively reviewed by Denmark and Thorarensen very recently, and this review also covers many hetero Diels-Alder reactions of nitroalkenes being not part of this sequential transformation [5]. Therefore the present article will focus on some selected examples which might highlight the advanced state of the art concerning stereocontrol of these reactions. On the other hand, an insight shall be given into the multitude of polycyclic structures accessible by means of nitroalkene cycloaddition chemistry. 

However, far the most powerful synthetical methodology involving cycloaddition chemistry of nitroalkenes is the combination of a hetero Diels-Alder reaction with a 1,3-dipolar cycloaddition of the resulting nitrone. Up to six stereo-genic centers may be constructed in the course of this protocol, and a multitude of preparative options results from applying either intra- or intermolecular varieties of the single steps and from the different modes to connect the resulting cyclic entities (Fig. 4-13). 

Both Diels-Alder and hetero-Diels-Alder reactions can be rendered stereoselective using l copper(II) salts, but inferior levels of stereoselection were observed relative to other pybox derivatives. Lanthanide-catalyzed 1,3-dipolar cycloaddition also exhibited moderate (61%) enantioselection. ... 

Electrocyclic reactions Diels-Alder reactions Hetero-Diels-Alder reactions 1,3-Dipolar cycloadditions... 

Theoretical calculations of metal-catalyzed hetero Diels-Alder and 1,3-dipolar cycloaddition reactions 02MI12. 

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