Dipolar enantioselectivity

Separation of enantiomers by physical or chemical methods requires the use of a chiral material, reagent, or catalyst. Both natural materials, such as polysaccharides and proteins, and solids that have been synthetically modified to incorporate chiral structures have been developed for use in separation of enantiomers by HPLC. The use of a chiral stationary phase makes the interactions between the two enantiomers with the adsorbent nonidentical and thus establishes a different rate of elution through the column. The interactions typically include hydrogen bonding, dipolar interactions, and n-n interactions. These attractive interactions may be disturbed by steric repulsions, and frequently the basis of enantioselectivity is a better steric fit for one of the two enantiomers. ... 

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. 

In an analogous study by Meske, the impact of various oxazaborolidinone catalysts for the 1,3-dipolar cycloaddition reactions between acyclic nitrones and vinyl ethers was studied [31]. Both the diastereo- and the enantioselectivities obtained in this work were low. The highest enantioselectivity was obtained by the application of 100 mol% of the tert-butyl-substituted oxazaborolidinone catalyst 3d [27, 32] in the 1,3-dipolar cycloaddition reaction between nitrone la and ethyl vinyl ether 8a giving endo-9a and exo-9a in 42% and 27% isolated yield, respectively, with up to 20% ee for endo-9a as the best result (Scheme 6.10). 

A model for the mechanism of the highly enantioselective AlMe-BINOL-cata-lyzed 1,3-dipolar cycloaddition reaction was proposed as illustrated in Scheme 6.13. In the first step nitrone la coordinates to the catalyst 11b to form intermediate 12. In intermediate 13, which is proposed to account for the absolute stereoselectivity of this reaction, it is apparent that one of the faces of the nitrone, the si face, is shielded by the ligand whereas the re face remains available... 

The high enantioselectivity of the exo product opens up a new and readily accessible route to an enantioselective synthesis of interesting isoquinoline alkaloids (Scheme 6.15) [35]. The tricyclic isoxazolidine exo-15b was obtained from the 1,3-dipolar cydoaddition reaction as the pure exo isomer and with 58% ee [34]. As shown in Scheme 6.15 the exo product from the 1,3-dipolar cydoaddition was converted into 17 in two steps without racemization at the chiral center. In addition to the illustrated synthesis, the 6,7-dimethoxy-derived isoxazolidine exo-15b is a very useful precursor for the synthesis of naturally occurring isoquinoline alkaloids [36-40]. 

A rather unexpected discovery was made in connection to these investigations [49]. When the 1,3-dipolar cycloaddition reaction of la with 19b mediated by catalyst 20 (X=I) was performed in the absence of MS 4 A a remarkable reversal of enantioselectivity was observed as the opposite enantiomer of ench-21 was obtained (Table 6.1, entries 1 and 2). This had not been observed for enantioselective catalytic reactions before and the role of molecular sieves cannot simply be ascribed to the removal of water by the MS, since the application of MS 4 A that were presaturated with water, also induced the reversal of enantioselectivity (Table 6.1, entries 3 and 4). Recently, Desimoni et al. also found that in addition to the presence of MS in the MgX2-Ph-BOX-catalyzed 1,3-dipolar addition shown in Scheme 6.17, the counter-ion for the magnesium catalyst also strongly affect the absolute stereoselectivity of the reac-... 

In a more recent study on 1,3-dipolar cycloaddition reactions the use of succi-nimide instead of the oxazolidinone auxiliary was introduced (Scheme 6.19) [58]. The succinimide derivatives 24a,b are more reactive towards the 1,3-dipolar cycloaddition reaction with nitrone la and the reaction proceeds in the absence of a catalyst. In the presence of TiCl2-TADDOLate catalyst 23a (5 mol%) the reaction of la with 24a proceeds at -20 to -10 °C, and after conversion of the unstable succinimide adduct into the amide derivative, the corresponding product 25 was obtained in an endojexo ratio of <5 >95. Additionally, the enantioselectivity of the reaction of 72% ee is also an improvement compared to the analogous reaction of the oxazolidinone derivative 19. Similar improvements were obtained in reactions of other related nitrones with 24a and b. 

The enantioselective inverse electron-demand 1,3-dipolar cycloaddition reactions of nitrones with alkenes described so far were catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminum complexes. However, the glyoxylate-derived nitrone 36 favors a bidentate coordination to the catalyst. This nitrone is a very interesting substrate, since the products that are obtained from the reaction with alkenes are masked a-amino acids. One of the characteristics of nitrones such as 36, having an ester moiety in the a position, is the swift E/Z equilibrium at room temperature (Scheme 6.28). In the crystalline form nitrone 36 exists as the pure Z isomer, however, in solution nitrone 36 have been shown to exists as a mixture of the E and Z isomers. This equilibrium could however be shifted to the Z isomer in the presence of a Lewis acid [74]. 

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]. 

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. 

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... 

Grigg et al. have found that chiral cobalt and manganese complexes are capable of inducing enantioselectivity in 1,3-dipolar cycloaddition reactions of azomethine... 

The reactions of nitrones constitute the absolute majority of metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions. Boron, aluminum, titanium, copper and palladium catalysts have been tested for the inverse electron-demand 1,3-dipolar cycloaddition reaction of nitrones with electron-rich alkenes. Fair enantioselectivities of up to 79% ee were obtained with oxazaborolidinone catalysts. However, the AlMe-3,3 -Ar-BINOL complexes proved to be superior for reactions of both acyclic and cyclic nitrones and more than >99% ee was obtained in some reactions. The Cu(OTf)2-BOX catalyst was efficient for reactions of the glyoxylate-derived nitrones with vinyl ethers and enantioselectivities of up to 93% ee were obtained. 

Dipolar cydoadditions are one of the most useful synthetic methods to make stereochemically defined five-membered heterocydes. Although a variety of dia-stereoselective 1,3-dipolar cydoadditions have been well developed, enantioselec-tive versions are still limited [29]. Nitrones are important 1,3-dipoles that have been the target of catalyzed enantioselective reactions [66]. Three different approaches to catalyzed enantioselective reactions have been taken (1) activation of electron-defident alkenes by a chiral Lewis acid [23-26, 32-34, 67], (2) activation of nitrones in the reaction with ketene acetals [30, 31], and (3) coordination of both nitrones and allylic alcohols on a chiral catalyst [20]. Among these approaches, the dipole/HOMO-controlled reactions of electron-deficient alkenes are especially promising because a variety of combinations between chiral Lewis acids and electron-deficient alkenes have been well investigated in the study of catalyzed enantioselective Diels-Alder reactions. Enantioselectivities in catalyzed nitrone cydoadditions sometimes exceed 90% ee, but the efficiency of catalytic loading remains insufficient. 

We are the first group to succeed with the highly enantioselective 1,3-dipolar cycloadditions of nitronates [75]. Thus, the reaction of 5,6-dihydro-4H-l,2-oxazine N-oxide as a cyclic nitronate to 3-acryloyl-2-oxazilidinone, at -40 °C in dichloro-methane in the presence of MS 4 A and l ,J -DBFOX/Ph-Ni(II) complexes, gave a diastereomeric mixture of perhydroisoxazolo[2,3-fe][l,2]oxazines as the ring-fused isoxazolidines in high yields. The J ,J -DBFOX/Ph aqua complex prepared from... 

Schemes 16-19 present the details of the enantioselective synthesis of key intermediate 9. The retrosynthetic analysis outlined in Scheme 5 identified aldoxime 32 as a potential synthetic intermediate the construction of this compound would mark the achievement of the first synthetic objective, for it would permit an evaluation of the crucial 1,3-dipolar cycloaddition reaction. As it turns out, an enantioselective synthesis of aldoxime 32 can be achieved in a straightforward manner by a route employing commercially available tetronic acid (36) and the MEM ether of allyl alcohol (74) as starting materials (see Scheme 16).

Carbonyl ylides continue to be targets of opportunity because of their suitability for trapping by dipolar addition. High enantiocontrol has been achieved in the process described by Eq. 16 [109], but such high enantioselectivity is not general [110] and is dependent on those factors suggested by Scheme 11. Using achiral dirhodium(II) catalysts, Padwa and coworkers have developed a broad selection of tandem reactions of which that in Eq. 17 is illustrative [111] these... 

In 2007, a novel C2-symmetric diphenylthiophosphoramide ligand was found to be a fairly efficient chiral ligand for the Cu(I)-promoted 1,3-dipolar cycloaddition of imines and pyrrole-2,5-dione derivatives to give the corresponding adducts in moderate to good enantioselectivities and good yields (Scheme 10.14). ... 

Scheme 6.7. Catalytic Enantioselective 1,3-Dipolar Cycloaddition Reactions...

The domino process can be catalyzed by a Cu-complex with (S.S)-tBu-bis(oxazo-line) to give 2-616 with excellent enantioselectivity (97-98% ee) [320b,c]. The use of 5 A molecular sieves turned out to be obligatory. Wada and coworkers also reported on a related transetherification/l,3-dipolar cycloaddition procedure to give access to trans-fused bicyclic y-lactones [321]. 

Scheme 6/2.6. Enantioselective domino carbene-formation/1,3-dipolar cycloaddition.

Diastereoselective intramolecular cycloaddition of nitrones is useful for constructing nitrogen- containing cyclic structures. The reaction serves as a key step in a number of natural product syntheses.63 Tufarriello and coworkers have used this strategy for preparing cocaine and other alkaloids.74 As a classical example, enantioselective total synthesis of (+)-luciduline is presented in Scheme 8.13, in which a useful feature of the 1,3-dipolar addition of nitrones is nicely illustrated.75... 

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