Catalytic Enantioselective -Dipolar Cycloadditions

In more recent years, chiral catalysts that promote a number of enantioselective [l,3]-dipolar cycloadditions have been developed [23, 31-34]. It had long been recognized that there were some significant obstacles to be overcome in order to develop such transformations successfully the often moderate endojexo selectivity observed in [l,3]-dipolar cycloadditions, as well as the propensity of the Lewis basic dipoles and products to inactivate the chiral catalysts. 

Catalytic enantioselective nitrone cycloadditions were first published in 1994, by Scheeren [84] and by Jorgensen [85, 86]. Jorgensen reported that the TADDOL-derived titanium catalyst 92 [87] promoted the cycloaddition re- 

Kanemasa has reported that chiral ligand 106 [91] in combination with Zn(II) or Mg(II) promotes catalytic, enantioselective cycloadditions of nitrones [92] and trimethylsilyldiazomethane [93]. In cycloadditions with the latter reagent, intriguing results were observed when oxazolidinones 96 and 108 were employed (Equations 3 and 4, respectively). The cycloaddition of 96 mediated by the Zn complex of ligand 106 afforded 107 in 99% ee. In contrast, oxazolidinone 108 in combination with the Mg complex of 106 resulted in opposite facial selectivity to give 109 in 97% ee. Under the employed reaction conditions, desilylation of the initially formed cycloadducts is followed by in situ acylation to give the corresponding N-acetylated products. 

Using a related cycloaddition protocol, Schreiber found that the chiral P,N-ligand QUINAP (121) exhibited comparable high enantioselectivity in silver-catalyzed dipolar cycloadditions (Equation 6) [98], The highest asymmetric induction was observed for tert-hutyl acrylate (119) with aromatic imino esters such as 118. The process shows a wide substrate scope, as the transformation was tolerant both of a-substitution in 118 and of /3-substitution of the acrylate dipolarophile 119. Carreira has crafted and studied the use of a family of atropisomeric P,N-ligands, as exemplified by 122 [99]. 

The silver complex prepared from 122 promotes dipolar cycloaddition reactions of azomethine ylides to give products such as 120 with excellent en-antioselectivity (95% ee). This class of ligands has been shown to be more conveniently prepared and, importantly, it is possible to gain access to a wide range of structural variants of the parent scaffold, permitting facile ligand optimization. 

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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-... 

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. 

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

Catalytic enantioselective 1,3-dipolar cycloaddition between nitrones with alkenes using a novel heterochiral ytterbium(III) catalyst is reported (Eq. 8.58).91 The desired isoxazolidine derivatives are obtained in excellent yields with excellent diastereo- and enantioselectivities. 

Finally, the catalytic enantioselective 1,3-dipolar cycloaddition reaction has recently been developed to be a highly selective reaction of nitrones with electron-deficient alkenes activated by chiral Lewis acids. High levels of regio-, diastereo-, and enantioselectivities can now be reached using catalysts 89 <2000JOC9080>, 90 <2002JA4968>, or 91 <2005JA13386> (Scheme 29). 

The enantioselective catalytic 1,3-dipolar cycloaddition of linear or cyclic nitrones to enals was accomplished using the half-sandwich rhodium(III) complex S, Rc)-[(ri -C5Me5)Rh (/ )-Prophos (H20)](SbF6)2 as catalyst precursor [33, 34]. At —25°C, quantitative conversions to the cycloadducts, with up to 95% ee, were achieved (Scheme 10). The intermediate with the dipolarophile coordinated to the rhodium has been isolated and completely characterized, including the X-ray determination of its molecular structure [33, 34]. 

The development and application of catalytic enantioselective 1,3-dipolar cycloadditions is a relatively new area. Compared to the broad application of asymmetric catalysis in carbo- and hetero-Diels-Alder reactions (337,338), which has evolved since the mid-1980s, the use of enantioselective metal catalysts in asymmetric 1,3-dipolar cycloadditions remained almost unexplored until 1993 (5). In particular, the asymmetric metal-catalyzed reactions of nitrones with alkenes has received considerable attention during the past 5 years. 

Kobayashi and Kawamura (374) used the catalytic enantioselective 1,3-dipolar cycloaddition for the synthesis of an optically active p-lactam (Scheme 12.85). The... 

In the area of [3 + 2]-cycloadditions (1,3-dipolar cycloadditions), chiral silver catalysts have been utilized extensively for the enantioselective formation of five-membered rings from prochiral substrates. For example, Zhang and co-workers360 have reported the highly enantioselective Ag(i)-catalyzed [3 + 2]-cycloaddition of azomethine ylides to electron-deficient alkenes. Thus, reaction of ct-imino esters 442 with dimethyl maleate in the presence of catalytic amounts of silver(i) acetate and the chiral bisferrocenyl amide phosphine 443 provided the chiral pyrrolidines 444 with high stereoselectivities and chemical yields (Scheme 131). Only the endo-products were isolated in all cases. 

The enantioselectivity of the chiral oxaborolidine-catalyzed asymmetric 1,3-dipolar cycloaddition can be controlled by the a-side-chain substituent in this catalyst and the solvent (Tables 4 and 5) [59b]. A remarkable reversal of enantioselectivity is achieved with catalysts with aryl substituents in the a-side-chain and by adding ligand-like solvents. Both enantiomers of a chiral /i-amino ester have been prepared in two catalytic steps. 

Table 4. Reversal of enantioselectivity in catalytic asymmetric 1,3-dipolar cycloaddition.

Catalytic asymmetric 1,3-dipolar cycloaddition of a nitrone with a dipolarophile has been performed using a chiral scandium catalyst [31]. The chiral catalyst, which was effective in asymmetric Diels-Alder reactions, was readily prepared from Sc(OTf)3, (7 )-(-i-)-BINOL, and d5 -l,2,6-trimethylpiperidine. The reaction of benzylbenzylide-neamine A-oxide with 3-(2-butenoyl)-l,3-oxazolidin-2-one was performed in the presence of the chiral catalyst to yield the desired isoxazolidine in 69 % ee with perfect diastereoselectivity (endolexo = > 99 1) (Sch. 8) [31,46], It was found that reverse enantioselectivity was observed when a chiral Yb catalyst, prepared from Yb(OTf)3, the same (i )-(-i-)-BINOL, and cd-l,2,6-trimethylpiperidine, was used instead of the Sc catalyst under the same reaction conditions. 

CsMes)M (i )-l,2-bis(diphenylphosphino)propane (H20)] were found to catalyze the 1,3-dipolar cycloaddition of some acyclic and cyclic nitrones with methacrolein with complete diastereoselectivity and good enantioselec-tivity. Some intermediates involved in the process were isolated and characterized and a catalytic cycle involving [M]-aldehyde, [M]-nitrone, and [M]-adduct species was proposed <2005JA13386>. The reactions of A -phenyl C-aryl nitrones with the electron-poor a-bromoacrolein were effectively catalyzed by Zn(ll) complexes such as 534 and afforded isoxazolidine-4-carboxaldehydes, with high diastereo- and enantioselectivity, that were reduced to the corresponding alcohols (Scheme 123) <2004TL4061>. 

The first enantioselective organocatalytic 1,3-dipolar cycloaddition of acyclic nitrones with acrolein and crotonal-dehyde has been reported <2000JA9874>. In particular, the reversible formation of iminium ions from a,/3-unsatu-rated aldehydes and the enantiopure imidazolidinone 535 provided ( A-4-formylisoxazolidines in high yields and ees (Equation 86). A polymer-supported version of catalyst 535 was also prepared <2004EJ0567>. The catalytic performance of various chiral pyrrolidinium salts in the cycloaddition of 1-cycloalkene-l-carboxaldehydes was also evaluated <2003EJO2782>. 

Zhang et al. investigated the asymmetric 1,3-dipolar cycloaddition of tert-butyl 2-(diphenylmethyleneamino)acetate and nitroalkenes promoted by bifunctional thiourea compounds derived from cinchona alkaloids, affording chiral pyrrolidine derivatives 13 with multisubstitutions. Catalyst lm delivered the best results in terms of catalytic activity, diastereoselectivity and enantioselectivity. Nevertheless, only moderate ee values could be obtained while the diastereoselectivities were generally good (Scheme 10.18) [22]. 

Exo- and enantioselective 1,3-dipolar cycloaddition of nitrones 161 with 3-(2-alkenoyl)-2-thiazolidinethiones 162 is carried out in the presence of a catalytic amount of binaphthyldiimine-Ni(II) complex, readily prepared in situ from dirmine 160 and Ni(C104)2 6H20 <050L1431>. 

However, at this stage relatively little progress has been made in research on asymmetric catalytic carbene transfer to imines. In 1995, Jacobsen and Jorgensen reported independently that reaction of ethyl diazoacetate with selected imines can be catalyzed by copper salts [27,28]. In the former case [27], moderate levels of enantioselection were found to be imparted by bisoxazoline ligands associated with the copper catalyst (Scheme 11). The observation of racemic pyrrolidine byproducts in the reaction was taken to support a mechanism of catalysis involving initial formation of a copper-bound azomethine yhde intermediate (Scheme 12 ). Collapse of this intermediate to the optically active aziridine apparently competes with dissociation of the copper to a free azomethine ylide. The latter can react with fumarate formed by diazoester decomposition in a dipolar cycloaddition to afford racemic pyrrolidine. 

Catalytic enantioselective 1,3-dipolar cycloaddition reactions of nitrones 00CC1449. 

Mish, M.R., Gnerra, E.M., and Carreira, E.M., Asymmetric dipolar cycloadditions of Me3SiCHN2. Synthesis of a novel class of amino acids azaprolines, J. Am. Chem. Soc. 119 (35), 8379, 1997. Kim, Y., Singer, R.A., and Carreira, E.M., Total synthesis of macrolactin A with versatile catalytic, enantioselective dienolate aldol addition reactions, Angewandte Chemie-Intemational Edition 37 (9), 1261, 1998. 

Dipolar cycloadditions between nitrones and alkenes are most useful and convenient for the preparation of isoxazolidine derivatives, which are readily converted to 1,3-amino alcohol equivalents under mild reducing conditions (Tufariello 1984, Torssell 1988). In spite of the importance of chiral amino alcohol units for the synthesis of biologically important alkaloids, amino acids, 3-lactams, and amino sugars, etc. (for a review see Frederickson 1997), catalytic enantioselective 1,3-dipolar cycloadditions remain relatively unexplored (Seerden et al. 1994, 1995, Gothelf and Jorgensen 1994, Gothelf et al. 1996, Hori et al. 1996, Seebach et al. 1996, Jensen et al. 1997). Catalytic enantioselective... 

Hydroxyethyl (3-lactam derivative was synthesized using the present reactions (scheme 17). Isoxazolidine derivative 37, prepared via the catalytic enantioselective 1,3-dipolar cycloaddition, was treated with methoxymagnesium iodide (Evans et al. 1985) to give methyl ester 38. Reductive N-O bond cleavage and deprotection of... 

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