Cycloaddition Methodology

The thionation-cycloaddition sequence is accompanied by the elimination of dimethylamine from the cycloadduct to afford thiopyrans. Similarly, when the thionation-cycloaddition methodology was applied to enaminoketones 98 and 99, obtained from thiochromanones, tricyclic compounds 100 and 101 were obtained (Figure 2.12). 

Among the many recent applications to natural products, syntheses of pyrrolizidine and indolizidine alkaloids that take advantage of the 1,3-dipolar cycloaddition methodology have been reviewed [8]. The regio- and stereochemistry [9] as well as synthetic appHcations [10] of nitrile oxide cycloadditions have also been discussed. 

A solid-phase synthesis of pyrroloindolizines has been developed using this cycloaddition methodology, whereby an isoxazolopyrroloindolizine can be removed from the polymeric resin upon treatment with trifluoroacetic acid (TFA). This also results in ring opening of the isoxazole to give the isolated compound 210 (Scheme 58). A library of 96 such derivatives has been prepared in this way <1998TL5869>. 

Several novel porphyrin derivatives can then be obtained by following the mentioned cycloaddition methodologies many of the new products fulfil the requirements to be considered as potential new drugs mainly for the detection and treatment (PDT) of cancer situations and in the photo-inactivation of microorganisms. 

Phosphonated A.G-nucleosides (659) and (660), containing thymine (a), N -acetyleytosine (d) and fluorouracil (c) have been synthesized in good yields by the 1,3-dipolar cycloaddition methodology (Scheme 2.287) (152). 

The same authors extended the [2 + 2 + 2]-cycloaddition methodology to the use of highly electron-deficient tricarbonyl compounds such as ketomalonates (Equation (33)).360 In that particular case, the reaction does not stop at the initial stage of 277-pyrans 164. Instead, a thermally induced electrocyclic ring opening occurred to form the corresponding cyclopentenes 165 as final product. 

Fig. 39 Dipolar cycloaddition methodology in the synthesis of disaccharide derivatives.

Umpoled C3 fragments other than 4 have been used for the synthesis of related compounds following the [3 + 2] cycloaddition methodology [6] (Scheme 6.5). 

An elegant application of the [3 + 4] cycloaddition methodology was showcased in model studies directed toward the synthesis of the core skeleton of CP-263114 115 (Scheme 14.12) [103]. The key step is the intramolecular [3 + 4] cycloaddition of furan with the siloxy-substituted vinyldiazoacetate in 112. The oxabicychc system 113 was obtained in 68% yield and was converted in eight steps to furnish the core structure 114 [103]. 

Diels-Alder reaction of vinylindoles with dienophiles has been established as a versatile and flexible methodology for the synthesis of carbazole alkaloids. Among the two different vinylindoles, 3-vinylindoles were the first to be explored for the Diels-Alder cycloaddition methodology with a range of dienophiles to give polyfunctionalized carbazole derivatives. This reaction is catalyzed by tiifluoroacetic acid, and the yield in the absence of the acidic catalyst is very low. The reaction of substituted 3-vinylindoles 550 and 553 with ethylenic dienophiles 551 and acetylenic dienophiles 535 leads, via a tetrahydrocarbazole and a dihydrocarbazole, to the corresponding carbazoles (552 and 554), respectively (530,531) (Scheme 5.18). 

As it has been shown, there are many ways to assemble the 1,4-(oxa/thia)-2-azole ring. Most of them are performed by inter- or intramolecular cyclization of suitable acyclic precursors. Some of them are found to be suitable for the synthesis of various ring systems, by using readily available, and properly modified reactants. Of particular importance are the following (a) the cyclizations of sulfenamides leading to (oxa/thia)azolium salts (Scheme 33) (b) the cyclization of hydroxamic acids (Scheme 39) (c) the dipolar cycloaddition methodology (Scheme 40) (d) the cyclizations of chlorosulfenyl chlorides (Scheme 46) and (e) the cyclizations of chloromethane sulfonamides (Schemes 47 and 48). Other cyclizations reported are preparative ways used mainly for the synthesis of specific compounds and the scope of these reactions has not been widely studied. 

Schreiber and co-workers (436) prepared a library calculated to contain 2.18 million polycyclic compounds through the 1,3-dipolar cycloaddition of a number of nitrones with alkenes supported on TentaGel S NH2 resin (Scheme 1.83). (—)-Shikimic acid was converted into the polymer bound epoxycyclohexenol carboxylic acid 376 (or its enantiomer), coupled to the resin via a photolabile linker developed by Geysen and co-workers (437) to allow release of the products from the resin in the presence of live cells by ultraviolet (UV)-irradiation. A range of iodoaromatic nitrones (377) was then reacted with the ot,p-unsaturation of the polymer-bound amide in the presence of an organotin catalyst, using the tandem esterification/ dipolar cycloaddition methodology developed by Tamura et al. (84,85) Simultaneous cyclization by PyBrop-mediated condensation of the acid with the alcohol... 

In a very recent example, Chiu and co-workers (84-86) used the tandem ylide-cycloaddition methodology to prepare advanced intermediates directed toward the synthesis of the pseudolaric acids. Pseudolaric acids are a family of diterpenes isolated from the root bark of Pseudolarix kaempferi. These novel compounds have shown antimicrobial activity comparable to that of amphotericin B and have demonstrated cyctotoxicity against several cancer cell lines (Fig. 4.5). 

The magnesium ion-mediated nitrone cycloaddition methodology can be successfully applied to the asymmetric reactions of a chiral cyclic nitrone of the lactone type (Scheme 11.51) (169). Although (/ )-2(/f)-oxo-5-phenyl-5,6-dihydro-1,4-oxazine A-oxide is an ( )-nitrone, all of its reactions are highly diastereose-lective, producing isoxazolidine 5-alcohol cycloadducts. The chelated transition... 

The tandem transesterification/[3 + 2]-cycloaddition methodology is be a powerful synthetic tool, since it guarantees high diastereoselectivity even under thermal conditions. It has been successfully apphed to synthetic work of the N-terminal amino acid component of Nikkomycin Bz (Scheme 11.53) (173). Thus, the sugar-based oxime is condensed with a glyoxylate hemiacetal to produce a chiral nitrone ester, which is then reacted with ( )-p-niethoxycinnamyl alcohol in the presence of a catalytic amount of TiCU at 100 °C. After the intramolecular cycloaddition, the... 

However, this intramolecular cycloaddition methodology has found more widespread use in the preparation of cis-fused heterobicyclic rather than carbobicyclic products, by insertion of a heteroatom into the hydrocarbon tail of the alkenyl nitrone. Particular attention has been given to the synthesis of THF adducts (326, X = 0) (202,317,354,358-365), and to a lesser extent the N (82,361,366-368) S (202,203,369), or silyloxy analogues (54,55,370). Aurich and Biesemeier (359) prepared ether dipoles (327), which slowly cyclized at ambient temperature to afford the cis-fused bicyclic adducts 328 (Scheme 1.70). Reductive cleavage of the... 

Muthusamy et al. (82) prepared a number of oxacyclic ether compounds from the tandem ylide formation-dipolar cycloaddition methodology. Their approach provides a synthetic tactic to compounds such as ambrosic acid, smitopsin, and linearol. Starting with either cyclopentane or cyclohexane templates, they prepared ylide sizes of five or six, which are trapped in an intermolecular cycloaddition reaction by the addition of DMAD. The products are isolated in good overall yield. In a second system, 2,5-disubstituted cyclohexenyl derivatives are utilized to generate the pendent ylide, then, A-phenylmaleimide is added in an intermolecular reaction, accessing highly substituted oxatricyclic derivatives such as 182 (Scheme 4.43). 

Likewise, benzyldihydroisoquinolinium derivatives can be used in a photochemical synthesis of tetrahydroisoquinolines. Thus, 2-(2-trimethyl-silylmethylphenylmethyl)-3,4-dihydroisoquinoliniun perchlorates have been successfully cyclized, as in the synthesis of the protoberbine alkaloids (+)xylopinine and (+)stylopine. The reaction proceeds via SET from the xylyl donor to the iminium moiety, fragmentation of the benzylsilane radical cation and carbon-carbon bond formation in the intermediate diradical. The synthesis is rather general and the yields compare favorably with those obtained from related substrates via a dipolar cycloaddition methodology [298] (Sch. 27). 

As the key precursor towards the realization of 1,7-epoxy cyclononanes and 1,8-epoxycyclodecanes, an 1 l-oxatricyclo[6.2.1.02,6]decane skeleton was constructed by using the Hoffmann [4+3] cycloaddition methodology <07EJO4383>. In Majetich s total synthesis of (-)-salviasperanol, the key step was the trifluoroacetic acid-promoted isomerization of a vinyl epoxide to 2,5-dihydrofuran, whose O-thiocarbamate was removed by radical reaction to produce salviasperanol dimethyl ether <07OL85>. The synthetic route is depicted below. 

A one-step synthesis of di- and trisubstituted furans from acyl isocyanates adds to the scope of the cycloaddition methodology <2004S1359>. The reaction proceeded via an intermediate 4-trimethylsilyloxyoxazole 71, generated in situ from an acyl isocyanate and TMS-diazomethane, which reacted with dimethyl acetylenedicarboxylate... 

A cycloaddition methodology has been exploited in the cation radical-mediated reactions between electron-rich chalcone epoxides 287 and A -aryl imines 286 using tris(4-bromophenyl)aminium hexachloroantimonate (TBPA -SbCle ) as the radical initiator to generate substituted 1,3-oxazolidines 288a and 288b in good yields (Equation 21) <2005SL161>. 

Dipolar cycloaddition methodology has also been utilized in a one-pot three-component system to generate oxazolidines 292 <2005T6088>. Reactions between sulfonyl azides and vinyl ethers, for example 289, generated aziridine intermediates 290, which then reacted via ring-opened zwitterionic intermediate 291 with aldehydes to generate the oxazolidines in good yields (Scheme 82). 

This cycloaddition methodology utilizing N-lithiated azomethine ylides has some advantages. (1) The ylides can be generated in situ concurrently with or prior to cycloaddition. (2) The ylides are highly reactive toward a number of carbonyl-activated olefins. (3) Wide structural modification of ylides is possible. (4) The cycloadditions are perfectly diastereoselective. (5) No demetallation procedure is necessary. (6) No critical epimerization occurs even in the reactions of cyano-stabilized ylides 144. 

A unique approach to the synthesis of fused-ring thiiranes and thiirenes involves the utilization of cycloaddition methodology. The use of diphenylthiirene oxide and the corresponding dioxide as dieneophiles in [2 + 2], [4 + 2], and 1,3-dipolar cycloadditions is well established. Often the initial... 

With Ni(0) catalysts they can react by two different reaction mechanism which give the possibility of synthesizing methylene-cyclopentanes with different substituent patterns (see Eqs. 81, 86 and 87). In Table 11 some of the most interesting results obtained in the preparation of methylenecyclopentanes from [(2-acetoxymethyl)-3-allyl]trimethylsilan or methylenecyclopropanes and electron deficient olefins by this new [3+2]-cycloaddition methodology are summarized. 

---