Cycloadditions, asymmetric

Ketene undergoes rapid stepwise [2+2] cycloaddition to the carbonyl group of chloral (trichloroacetaldehyde) in the presence of a catalytic amount of an amine to afford the 3-propiolactone (23)  

If this reaction is conducted under optimum conditions (toluene, -50°) in the presence of 1-2 mol % quinidine as chiral basic catalyst, the P-propiolactone is obtained with 98% e.e. as the (/ )-enantiomer (25). Useofquinineleadstothe(5)-enantiomer(24)in76%e.e. To 

However, this is a good example of the dangers which face the unwary in asymmetric synthesis, since it was later discovered that the hydrolysis step is actually accompanied by efficient inversion of absolute configuration at the stereogenic centre. Thus it is the (5)-product from quinine which gives the (/ )-malic acid and vice versa as shown. Regardless of this complication, the method allows convenient access to either enantiomer of the synthetically useful malic acid on a commercial scale. 

Electron-rich and electron-poor alkenes can react with each other in a [2 + 2] fashion to give cyclobutanes with Lewis acid catalysis. In the example below, the chiral catalyst (27) is a complex of titanium(IV) with a ligand derived from (-)-tartaric acid. In the presence of 10 mol% of this catalyst, a stepwise [2 + 2]-cycloaddition occurs to (26) affording the cyclobutane (28) with an e.e. of 98%. The product was converted in a few steps to a carbocyclic analogue of the nucleoside antibiotics oxetanocins A and 0.00 

Generation of chiral 5,6-dihydropyran-2-ones via asymmetrir t,i. i jj-tions. An applic=H , . j l [4+2 cycloaddi- 

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Cationic complexes of rran.s-chelating tridentate ligand, (/ ,/ )-4,6-dibenzo-furandiyl-2,2 -bis(4-phenyloxazoline), with transition metal(II) perchlorates as effective catalysts for asymmetric cycloaddition of nitrones 98YGK368. 

Asymmetric cycloaddition of functionalized alkenes to nitrile oxides and nitrones 98YGK11. 

Application in organic synthesis of optically active isoxazolidones obtained by asymmetric cycloaddition of nitrones with allenes 97T403. 

Silica gel [11] or alumina [11a, 12] alone, or silica and alumina together modified by Lewis-acid treatment [13] and zeolites [14], have been widely used as catalysts in Diels-Alder reactions, and these solids have also been tested as catalysts in asymmetric Diels-Alder reactions [12,13b,14]. Activated silica gel and alumina at 140 °C were used [15] to catalyze the asymmetric cycloaddition of (-)-menthyl-N-acetyl-a, S-dehydroalaninate (3) (R = NHCOMe) with cyclopentadiene in the key step for synthesizing optically active cycloaliphatic a-amino acids. When the reactions were carried out in the absence of solvent, a higher conversion was obtained. Some results are reported in Table 4.5 and compared with those obtained by using silica and alumina modified by treatment with Lewis acids. Silica gel gives a reasonable percentage of conversion after 24 h with complete diastereofacial selectivity in exo addition. 

Langlois Y. Chiral Anxiharies for Asymmetric Cycloadditions Spec. Chem. 1998 18 405... 

Krohn K. Chiral 2-Amino-1,3-Butadienes New Reagents for Asymmetric Cycloadditions Chem. Int. Ed. Engl. 1993 32 1582-1586... 

Waldmann H., Braun M. Amino Acid Esters As Chiral Auxiliaries in Asymmetric Cycloadditions Gazz. Chim. Ital. 1991 121 277-284... 

Associated to copper(II) pre-catalysts, bis(oxazolines) also allowed the asymmetric Diels-Alder and hetero Diels-Alder transformations to be achieved in nearly quantitative yield and high diastereo- and enantioselectivities. Optically active sulfoximines, with their nitrogen-coordinating site located at close proximity to the stereogenic sulfur atom, have also proven their efficiency as copper ligands for these asymmetric cycloadditions. Other precursors for this Lewis acid-catalyzed transformation have been described (e.g., zinc salts, ruthenium derivatives, or rare earth complexes) which, when associated to bis(oxazolines), pyridine-oxazolines or pyridine-bis(oxazolines), led to efficient catalysts. 

Dochnahl M, Fu GC (2009) Catalytic asymmetric cycloaddition of ketenes and nitroso compounds enantioselective synthesis of a-hydroxycarboxylic acid derivatives. Angew Chem Int Ed 48 2391-2393... 

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... 

In summary, asymmetric cycloadditions are powerful methods for the synthesis of complex chiral molecules because multiple asymmetric centers can be constructed in one-step transformations. Among them, reactions using chiral catalysts are the most effective and promising, and fruitful results have been reported in asymmetric Diels-Alder reactions. 

In recent years, much work has been done on catalyzed and asymmetric cycloaddition reactions. In the presence of 5 mol% bismuth trichloride, the simple dienes 10 (R1 = R" = H R1 = H, R2 = Me or R1 = Me, R2 = H) react with diethyl mesoxalate to afford mixtures of the cycloadducts 11 and the products 12 of an ene-reaction (equation 13)11 12. 1,3-Cyclohexadiene and ethyl glyoxylate give solely the endo adduct 13 in 50% yield (equation 14)12. 

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>. 

Similarly, Takano et al. (79) reported the intramolecular, asymmetric cycloaddition of ylides derived from thermal decomposition of aziridines 255 with the stereoselectivity rationalized by the formation of a postulated nine-membered transition state 256 in which the benzyloxymethyl group was forced into an equatorial disposition. The resultant pyrrolidine 257 contained three new stereo-genic centers, each imposed with high control (Scheme 3.87). 

Although the first attempts at asymmetric azomethine ylide cycloadditions were reported by Padwa s group (92), the acyclic azomethine ylides chosen, bearing an a-chiral alkyl substituent on the nitrogen, showed poor diastereoselectivities (93,94). When the chiral center is fixed in a cyclic structure (95) or when chirality is introduced in an intramolecular cycloaddition system (96-98), high selectivities have been accomplished. There are only a few examples known of asymmetric cycloadditions of achiral azomethine ylides to chiral dipolarophiles where cyclic azomethine ylides (99,100) or cyclic chiral dipolarophiles (94) were used. 

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. 

The enantiomeric synthesis of rranj-3,4-disubstituted tetrahydrothiophenes using a sulfur ylide cycloaddition has been reported <990L1667>. The sulfur ylide derived from the action of cesium fluoride on sulfide 111 underwent an asymmetric cycloaddition with chiral a,p-unsaturated camphorsultam amide 112 giving tetrahydrothiophene 113 (80% de). The configuration was confirmed by cleavage of the chiral auxiliary followed by reductive desulfurization with Raney-Ni which gave known carboxylic acid 114. 

Thus, (2R)-pumiliotoxin C (214) has been prepared from (R)-norvaline (212). The asymmetric center in the triene (213) controls the configuration at three carbon atoms 210). a-Kainic acid, isolated from the algae Digena simplex and Centrocerus clavulatum, was prepared by total synthesis. Its enantioselective synthesis involved a stereocon trolled intramolecular cycloaddition of a (S)-glutamic acid211). Asymmetric cycloadditions also play a decisive role in the synthesis of chiral cytochalasins. In this case 212> the primary chiral information was carried by (S)-alanine and (S)-phenylalanine, respectively. 

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