Cycloadditions applied

Only relatively few examples of interesting target molecules containing rings are known. These include caryophyllene (E.J. Corey, 1963 A, 1964) and cubane (J.C. Barborak, 1966). The photochemical [2 + 2]-cycloaddition applied by Corey yielded mainly the /ranr-fused isomer, but isomerization with base leads via enolate to formation of the more stable civ-fused ring system. 

Baggiolini et al.216) have succeeded in synthesizing the vitamin d-bioiin from (RR)-cystine via intramolecular [3 + 2] cycloaddition with a d.s. value of 80%. Danishefsky et al.217) synthesized pretyrosine, the biosynthetic precursor of (S)-tyrosine, by a [4 + 2]-cycloaddition applying an (S)-glutamic acid derivative as chiral auxiliary. Phenylglycine was used as the source of the chiral information in an asymmetric variation of a 1,3-dipolar cycloaddition, as reported by Grigg and Kemp et al. 218>. 

Mechanistically, the term cycloaddition applies in only a formal sense to most of the reactions in the section virtually none of these reactions involves true single-step cycloaddition of all three components that appear in the final product. More typically, cycloaddition involving a transition metal fragment and one or two other components leads to a metallacyclic intermediate whose reaction with the remaining... 

Cycloaddition involves the combination of two molecules in such a way that a new ring is formed. The principles of conservation of orbital symmetry also apply to concerted cycloaddition reactions and to the reverse, concerted fragmentation of one molecule into two or more smaller components (cycloreversion). The most important cycloaddition reaction from the point of view of synthesis is the Diels-Alder reaction. This reaction has been the object of extensive theoretical and mechanistic study, as well as synthetic application. The Diels-Alder reaction is the addition of an alkene to a diene to form a cyclohexene. It is called a [47t + 27c]-cycloaddition reaction because four tc electrons from the diene and the two n electrons from the alkene (which is called the dienophile) are directly involved in the bonding change. For most systems, the reactivity pattern, regioselectivity, and stereoselectivity are consistent with describing the reaction as a concerted process. In particular, the reaction is a stereospecific syn (suprafacial) addition with respect to both the alkene and the diene. This stereospecificity has been demonstrated with many substituted dienes and alkenes and also holds for the simplest possible example of the reaction, that of ethylene with butadiene ... 

The complementary relationship between thermal and photochemical reactions can be illustrated by considering some of the same reaction types discussed in Chapter 11 and applying orbital symmetry considerations to the photochemical mode of reaction. The case of [2ti + 2ti] cycloaddition of two alkenes can serve as an example. This reaction was classified as a forbidden thermal reaction (Section 11.3) The correlation diagram for cycloaddition of two ethylene molecules (Fig. 13.2) shows that the ground-state molecules would lead to an excited state of cyclobutane and that the cycloaddition would therefore involve a prohibitive thermal activation energy. 

A synthetically powerful method, an approach based on cycloaddition chemistry, allows one to assemble the pyridine ring in one step. Not only is this method efficient, atom economy, but also its convergency allows for the preparation for highly substituted systems in which one can, in principle, control all five positions on the pyridine ring. A versatile example of this methodology is the Boger reaction. It has been applied to the synthesis of a very diverse set of targets. 

Some of the developments of catalytic enantioselective cycloaddition reactions of carbonyl compounds have origin in Diels-Alder chemistry, where many of the catalysts have been applied. This is valid for catalysts which enable monodentate coordination of the carbonyl functionality, such as the chiral aluminum and boron complexes. New chiral catalysts for cycloaddition reactions of carbonyl compounds have, however, also been developed. 

A series of chiral boron catalysts prepared from, e.g., N-sulfonyl a-amino acids has also been developed and used in a variety of cycloaddition reactions [18]. Corey et al. have applied the chiral (S)-tryptophan-derived oxazaborolidine-boron catalyst 11 and used it for the conversion of, e.g., benzaldehyde la to the cycloaddition product 3a by reaction with Danishefsky s diene 2a [18h]. This reaction la affords mainly the Mukaiyama aldol product 10, which, after isolation, was converted to 3a by treatment with TFA (Scheme 4.11). It was observed that no cycloaddition product was produced in the initial step, providing evidence for the two-step process. 

The cycloaddition reaction between ethyl glyoxylate 4a and Danishefsky s diene 2a has been investigated by Ghosh et al. applying catalyst systems derived from Cu(OTf)2 and ligands (S)-Ph-BOX (S)-21a, (S)-t-Bu-BOX (S)-21b, and the confer-... 

In a more recent work the same research group has applied cyclic and acyclic vinyl ethers in the oxazaborolidinone-catalyzed 1,3-dipolar cycloaddition reaction with nitrones [30]. The reaction between nitrone 5 and 2,3-dihydrofuran 6 with 20 mol% of the phenyl glycine-derived catalyst 3c, gave the product 7 in 56% yield as the sole diastereomer, however, with a low ee of 38% (Scheme 6.9). 

As for boron catalysts, the aluminum catalysts have exclusively been applied for the inverse electron-demand 1,3-dipolar cycloaddition between alkenes and nitrones. The first contribution to this field was published by j0rgensen et al. in... 

Several titanium(IV) complexes are efficient and reliable Lewis acid catalysts and they have been applied to numerous reactions, especially in combination with the so-called TADDOL (a, a,a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol) (22) ligands [53-55]. In the first study on normal electron-demand 1,3-dipolar cycloaddition reactions between nitrones and alkenes, which appeared in 1994, the catalytic reaction of a series of chiral TiCl2-TADDOLates on the reaction of nitrones 1 with al-kenoyloxazolidinones 19 was developed (Scheme 6.18) [56]. These substrates have turned out be the model system of choice for most studies on metal-catalyzed normal electron-demand 1,3-dipolar cycloaddition reactions of nitrones as it will appear from this chapter. When 10 mol% of the catalyst 23a was applied in the reaction depicted in Scheme 6.18 the reaction proceeded to give a yield of up to 94% ee after 20 h. The reaction led primarily to exo-21 and in the best case an endo/ exo ratio of 10 90 was obtained. The chiral information of the catalyst was transferred with a fair efficiency to the substrates as up to 60% ee of one of the isomers of exo3 was obtained [56]. 

In most TiCl2-TADDOLate-catalyzed Diels-Alder and 1,3-dipolar cycloaddition reactions oxazolidinone derivatives are applied as auxiliaries for the alkenoyl moiety in order to obtain the favorable bidentate coordination of the substrate to the catalyst... 

A quite different type of titanium catalyst has been used in an inverse electron-demand 1,3-dipolar cycloaddition. Bosnich et al. applied the chiral titanocene-(OTf)2 complex 32 for the 1,3-dipolar cycloaddition between the cyclic nitrone 14a and the ketene acetal 2c (Scheme 6.25). The reaction only proceeded in the presence of the catalyst and a good cis/trans ratio of 8 92 was obtained using catalyst 32, however, only 14% ee was observed for the major isomer [70]. 

For the activation of a substrate such as 19a via coordination of the two carbonyl oxygen atoms to the metal, one should expect that a hard Lewis acid would be more suitable, since the carbonyl oxygens are hard Lewis bases. Nevertheless, Fu-rukawa et al. succeeded in applying the relative soft metal palladium as catalyst for the 1,3-dipolar cycloaddition reaction between 1 and 19a (Scheme 6.36) [79, 80]. They applied the dicationic Pd-BINAP 54 as the catalyst, and whereas this type of catalytic reactions is often carried out at rt or at 0°C, the reactions catalyzed by 54 required heating at 40 °C in order to proceed. In most cases mixtures of endo-21 and exo-21 were obtained, however, high enantioselectivity of up to 93% were obtained for reactions of some derivatives of 1. 

Furukawa et al. also applied the above described palladium catalyst to the inverse electron-demand 1,3-dipolar cycloaddition of nitrones with vinyl ethers. However, all products obtained in this manner were racemic [81]. 

In 1997 the application of two different chiral ytterbium catalysts, 55 and 56 for the 1,3-dipolar cycloaddition reaction was reported almost simultaneously by two independent research groups [82, 83], In both works it was observed that the achiral Yb(OTf)3 and Sc(OTf)3 salts catalyze the 1,3-dipolar cycloaddition between nitrones 1 and alkenoyloxazolidinones 19 with endo selectivity. In the first study 20 mol% of the Yb(OTf)2-pyridine-bisoxazoline complex 55 was applied as the catalyst for reactions of a number of derivatives of 1 and 19. The reactions led to endo-selective 1,3-dipolar cycloadditions giving products with enantioselectivities of up to 73% ee (Scheme 6.38) [82]. In the other report Kobayashi et al. described a... 

Zinc-tartrate complexes were applied for reactions of both nitrones and nitrile oxides with allyl alcohol and for both reaction types selectivities of more than 90% ee were obtained. Whereas the reactions of nitrones required a stoichiometric amount of the catalyst the nitrile oxide reactions could be performed in the presence of 20 mol% of the catalyst. This is the only example on a metal-catalyzed asymmetric 1,3-dipolar cycloaddition of nitrile oxides. It should however be no-... 

By selection of conditions and catalyst, the intermediate hydroxyimine (11) can be directed to either (he hydroxy ketone (10) or amino alcohol (12), Over platinum oxide in methanol-acetic acid-water the amino alcohol forms, whereas over alkali-free Ra-Ni in methanol-water or over 10% Pd-on-C in methanol-water containing boric acid, the hydroxy ketones form in excellent yield. Nitrile oxide cycloadditions have been applied to five-membered ring syntheses (.50). 

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