1.3- Dipolar cycloaddition asymmetric

Various kinds of chiral acyclic nitrones have been devised, and they have been used extensively in 1,3-dipolar cycloaddition reactions, which are documented in recent reviews.63 Typical chiral acyclic nitrones that have been used in asymmetric cycloadditions are illustrated in Scheme 8.15. Several recent applications of these chiral nitrones to organic synthesis are presented here. For example, the addition of the sodium enolate of methyl acetate to IV-benzyl nitrone derived from D-glyceraldehyde affords the 3-substituted isoxazolin-5-one with a high syn selectivity. Further elaboration leads to the preparation of the isoxazolidine nucleoside analog in enantiomerically pure form (Eq. 8.52).78... 

The use of chiral 2-alkylidene-l,3-dithiane 1,3-dioxides in asymmetric cycloaddition reactions has been demonstrated. A highly enantioselective synthesis of (—)-cispentacin by an intramolecular 1,3-dipolar cycloaddition was reported (Scheme 52) <20020L1227, 20030BC684>. 

Enhanced reactivity as well as high endo-selectivity based on the rigid transition structure of N-metalated azomethine ylides is attractive for asymmetric 1,3-dipolar cycloaddition reactions. There are several reports known for the design of effective chiral nucleophiles in asymmetric cycloadditions. 

Nitrones were the first as well as the most widely used dipoles in asymmetric cycloadditions. The first report on the use of enantiomerically pure vinylsulf-oxides as dipolarophiles was due to Koizumi et al. [153], who described in 1982 the reaction of (-R)-vinyl p-tolyl sulfoxide 1 with acyclic nitrones 191. The reactions required 20 h in refluxing benzene to be completed, yielding a mixture of only two compounds, 192 and 193 (Scheme 91). They exhibited identical endo or exo stereochemistry (which was not unequivocally assigned), deduced from the fact that their reduction yielded enantiomeric thioethers. The major component, 192, exhibits (S) configuration at C-3, determined by chemical correlation. The authors claim this paper [153] to be the first example of 1,3-dipolar cycloaddition using chiral dipolarophiles. 

These results indicate that the sulfinyl group seems to be much more efficient in the control of the stereoselectivity of 1,3-dipolar cycloadditions (endo or exo adducts are exclusively obtained in de> 80%) than in Diels-Alder processes (mixtures of all four possible adducts were formed). Additionally, complete control of the regioselectivity of the reaction was observed. Despite these clearly excellent results, the following paper concerning asymmetric cycloaddition of cyclic nitrones and optically pure vinyl sulfoxides was reported nine years later [154]. (Meanwhile, only one paper [155], related to the synthesis of /1-nicotyri-nes, described the use of reaction of nitrones with racemic vinyl sulfoxides, but these substrates were merely used as a masked equivalent of acetylene dipolaro-phile). In 1991, Koizumi et al. described the reaction of one of the best dipolarophiles, the sulfinyl maleimide 109, with 3,4,5,6-tetrahydropyridine 1-oxide 194 [154]. It proceeded in CH2C12 at -78 °C to afford a 60 20 10 6 mixture of four products in ca. 90 % yield (Scheme 92). 

The first volume begins with a comprehensive review by Prof. Jose Luis Garcia Ruano and Dr. Belen Cid de la Plata of asymmetric cycloaddition mediated by sulfoxides, including dipolar and other processes in addition to Diels-Alder chemistry. It is followed by a discussion of the synthetic uses of thiocarbonyl compounds by Prof. Patrick Metzner. 

Copper(I) catalysis has demonstrated its long-held reputation in asymmetric synthesis over the past decade. The moderate Lewis acidity and coordination property of Cu(l) salts make it a versatile metal center in various metal-ligand complex systems and thereby have broad applications in the area of organic chemistry, especially in the asymmetric catalysis field. This chapter summarizes the recent developments of Cu(l)-catalyzed asymmetric cycloaddition and cascade addition-cyclization reactions since 2010. A wide range of asymmetric transformations catalyzed by chiral Cu(l) complexes are discussed, such as the 1,3-dipolar cycloadditions, including [3+2], [3+3], and [3+6] cycloadditions. Other cycloadditions and cascade addition-cyclization reactions are also discussed. 

Asymmetric dipolar cycloaddition of azomethine imines derived from diazoal-kane-pyridazine cycloadducts 98JHC1187. 

Asymmetric Metal-catalyzed 1,3-Dipolar Cycloaddition Reactions... 

The 1,3-dipoles consist of elements from main groups IV, V, and VI. The parent 1,3-dipoles consist of elements from the second row and the central atom of the dipole is limited to N or O [10]. Thus, a limited number of structures can be formed by permutations of N, C, and O. If higher row elements are excluded twelve allyl anion type and six propargyl/allenyl anion type 1,3-dipoles can be obtained. However, metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions have only been explored for the five types of dipole shown in Scheme 6.2. 

Finally, there is the enantioselectivity of the 1,3-dipolar cycloaddition reactions. This chapter is limited to describing only the metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions that involve non-chiral starting materials. The only fac-... 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

The first, and so far only, metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes was reported by Ukaji et al. [76, 77]. Upon treatment of allyl alcohol 45 with diethylzinc and (l ,J )-diisopropyltartrate, followed by the addition of diethylzinc and substituted hydroximoyl chlorides 46, the isoxazolidines 47 are formed with impressive enantioselectivities of up to 96% ee (Scheme 6.33) [76]. 

The above described approach was extended to include the 1,3-dipolar cycloaddition reaction of nitrones with allyl alcohol (Scheme 6.35) [78]. The zinc catalyst which is used in a stoichiometric amount is generated from allyl alcohol 45, Et2Zn, (R,J )-diisopropyltartrate (DIPT) and EtZnCl. Addition of the nitrone 52a leads to primarily tmns-53a which is obtained in a moderate yield, however, with high ee of up to 95%. Application of 52b as the nitrone in the reaction leads to higher yields of 53b (47-68%), high trans selectivities and up to 93% ee. Compared to other metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions of... 

Whereas there are numerous examples of the application of the products from diastereoselective 1,3-dipolar cycloaddition reaction in synthesis [7, 8], there are only very few examples on the application of the products from metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction in the synthesis of potential target molecules. The reason for this may be due to the fact that most metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction have been carried out on model systems that have not been optimized for further derivatization. One exception of this is the synthesis of a / -lactam by Kobayashi and Kawamura [84]. The isoxazoli-dine endo-21h, which was obtained in 96% ee from the Yb(OTf)3-BINOL-catalyzed... 

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