Enantioselectivity 1,3-dipolar cycloadditions

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... 

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. 

In enantioselective, 1,3-dipolar cycloadditions of nitrones to methacrolein the catalysts used were (r 5-C5Me5)MR-Prophoscontaining complexes (M = Rh, Ir and (R)-Prophos = l,2-bis(diphenylphosphino)propane) (754b). 

The 1,3-dipolar cycloaddition of nitrones to vinyl ethers is accelerated by Ti(IV) species. The efficiency of the catalyst depends on its complexation capacity. The use of Ti( PrO)2Cl2 favors the formation of trans cycloadducts, presumably, via an endo bidentate complex, in which the metal atom is simultaneously coordinated to the vinyl ether and to the cyclic nitrone or to the Z-isomer of the acyclic nitrones (800a). Highly diastereo- and enantioselective 1,3-dipolar cycloaddition reactions of nitrones with alkenes, catalyzed by chiral polybi-naphtyl Lewis acids, have been developed. Isoxazolidines with up to 99% ee were obtained. The chiral polymer ligand influences the stereoselectivity to the same extent as its monomeric version, but has the advantage of easy recovery and reuse (800b). 

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 first effective enantioselective 1,3-dipolar cycloaddition of diazoalkanes catalyzed by chiral Lewis acids was reported in the year 20(X) (139). Under catalysis using zinc or magnesium complexes and the chiral ligand (R,/ )-DBFOX/Ph, the reaction of diazo(trimethylsilyl)methane with 3-alkenoyl-2-oxazolidin-2-one 75 (R = H) gave the desilylated A -pyrazolines (4S,5R)-76 (R =Me 87% yield, 99% ee at 40 °C) (Scheme 8.18). Simple replacement of the oxazohdinone with the 4,4-dimethyloxazolidinone ring resulted in the formation of (4R,5S)-77 (R = Me 75% yield, 97% ee at -78 °C). 

Nitrones are the most widely studied of the 1,3-dipoles in the field of catalyzed enantioselective 1,3-dipolar cycloaddition reactions. Effective catalysis using a variety of chiral Lewis acid catalysts has been reported for the nitrone cycloaddition... 

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... 

TABLE 9.22. ENANTIOSELECTIVE 1,3-DIPOLAR CYCLOADDITION OF a,p-UNSATURATED OXAZOLIDINONES AND NITRONES... 

BINOL-catalysed enantioselective 1,3-dipolar cycloaddition between a-substituted acroleins and alkyl diazoacetates yielded chiral 2-pyrazolines with 95% ee. This methodology has been used to synthesise manzacidin A.86... 

The silver acetate-promoted 1,3-dipolar cycloaddition of nitrilimines with 3(/f )-pheny]-4(A )-cinnamoyl-2-azetidinone produced the major adduct, 4-(4,5-dihydro- (g) pyrazol-5-yl)carbonyl-2-azetidinones, with high stereoselectivity.70 The 1,3-dipolar cycloadditions of substituted 2,7-dime(liyl-3-thioxo-3,4,5,6-ici.rahydro-2//- 1,2,41 triazepin-5-one with iV-aryl-C-ethoxycarbonylnitrilimines are highly chemoselective, where the sulfur atom of the dipolarophile interacts with the carbon atom of the dipole.71 The enantioselective 1,3-dipolar cycloaddition of nitrile imines with electron deficient acceptors produces dihydropyrazoles in the presence of 10 mol% of chiral Lewis acid catalyst.72... 

Puglisi A, Benaglia M, Celentano G, Cinquini M, Cozzi F (2004) Enantioselective 1,3-dipolar cycloadditions of unsaturated aldehydes promoted by a poly(ethylene glycol)-supported organic catalyst. Eur J Qrg Chem 567-573... 

An example of enantioselective 1,3-dipolar cycloaddition of ethyl diazopyruvate to 2,3-dihydrofuran, catalyzed by a chiral ruthenium-PyBox complex, to provide a tetrahydrofurofuran was reported (Equation 125). However, the adduct 240 was only obtained in 74% ee, and its absolute configuration not determined <2004SL2573, 2005HCA1010>. As shown in Equation (126), 2,3-dihydrofuran also participated in 1,3-dipolar cycloaddition with dipoles derived from aziridines under Sc(OTf)3-catalyzed conditions, forming rfr-fused furopyrrolidines <2001TL9089>. 

When, on the other hand, organocatalyst 133 (possessing a bulky 2,5-diaryl-pyrrole moiety) is applied, product 134 was selectively formed by a highly diastereo- and enantioselective 1,3-dipolar cycloaddition (11 examples, 56-90%, 60-91% ee). This reaction most likely involves activation of the nitroalkene by the thiourea, via the earlier mentioned doubly hydrogen-bonded interaction, followed by a concerted attack of the in situ formed azomethine ylide (this ylide is not activated by nor coordinated to the organocatalyst, because of the bulky, nonbasic pyrrole group, but is most likely formed via a 1,2-prototropic rearrangement [92]). 

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>. 

Kasahara, K, lida, H, Kibayashi, Ch., Asyimnetric total synthesis of (+)-negamycin and (—)-3-epinegamycin via enantioselective 1,3-dipolar cycloaddition, J. Org. Chem., 54, 2225-2233, 1989. 

Kanemasa et al. reported that the enantioselective 1,3-dipolar cycloaddition of the 3-(alkenoyl)-2-oxazo-lidinones 417 and trimethylsilyldiazomethane in the presence of Zn(C104)2-i, i -DBF0X/Ph complex gave the 2-pyrazoline cycloadducts 418 in high yields with good to excellent ee values (Scheme 132).194... 

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

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... 

Scheme 7. Enantioselective 1,3-dipolar cycloaddition of nitrones with ketene acetals catalyzed by oxazaborolidines.

---