1,3-Dipolar cycloadditions diastereoselectivity

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... 

Padwa and Prein (105,106) applied chiral, but racemic, isomiinchnone dipoles in diastereoselective 1,3-dipolar cycloadditions. The carbonyl ylide related isomiinch-none derivative rac-70 was obtained from the rhodium-catalyzed cyclization of diazo-derivative rac-69 (Scheme 12.24) (105). The reactions of the in situ formed dipole with a series of alkenes was described and in particular the reaction with maleic acid derivatives 71a-c gave rise to reaction with high selectivities. The tetracyclic products 72a-c were all obtained in good yield with high endo/ exo and diastereofacial selectivities. In another paper by the same authors, the reactions of racemic isomilnchnones having an exo-cyclic chirality was described (106). 

One of the classical ways to perform diastereoselective 1,3-dipolar cycloaddition is by the addition of a 1,3-dipole to an allyl alcohol derivative (65, 107-120). Very recently, a short review article was devoted to this area (13). Among the most commonly applied acyclic allyl alcohol derivatives are alkenes 73-75 (Scheme 12.25). These alkenes have been used in reactions with nitrones. 

The chiral acrylate 164 was used in a 1,3-dipolar cycloaddition with a nitrile imine. Bis(trityl)nitrile imine was found to undergo a diastereoselective 1,3-dipolar cycloaddition with (f )-a-(acyloxy)-p,p-dimethyl-y-butyrolactone 164 to give the 2-pyrazoline product with a de of 50% (Scheme 12.51) (275). 

Karlsson and Hogberg (291,292) applied the thiocarbonyl ylide 175 in a diastereoselective 1,3-dipolar cycloaddition with 165. The thiocarbonyl yhde was generated in situ by an elimination reaction. The reaction with 165 gave 176 (R = Bu, BnO, Ph) with selectivities of up to 64—80% de. Furthermore, the cycloaddition of a chiral galactose-derived nitrile imine with 165 has been reported (104). 

The amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

Semiempirical AMI and DFT (B3LYP/6-31G ) calculations were used to investigate the highly diastereoselective 1,3-dipolar cycloaddition of 1,4-dihydropyridine- (g) containing azomethine ylides to [60]fullerene (Prato s reaction). The activation energy for the four calculated transition state structures favours the formation of SSaS and... 

A highly diastereoselective 1,3-dipolar cycloaddition of a nitrone employing the sultam auxiliary has been used in the synthesis of 215, a major metabolite of nicotine <04T9997>. i-gulose-derived nitrone 212, upon treatment with a, P-unsaturated sultam (25)-213, undergoes 1,3-dipolar cyeloaddition to afford the isoxazolidine 214 with high endo stereoselectivity, which is further elaborated to hydroxycotinine (-i-)-215. 

A highly regio- and diastereoselective 1,3-dipolar cycloaddition of nitrile oxides to the imine groups in 2,4-dimethyl-3//-l,5-benzodiazepines to afford bis[l,2,4-oxadiazolo[l,5]benzodiazepine] adducts has been reported by Baouid and co-workers stereochemical features were confirmed by single crystal X-ray crystallography on one of the adducts <04SC3565>. 

Muthusamy and co-workers have demonstrated [82] the reactions of the bicyclic ylide 57, generated from the diazocarbonyl compoimd 56, with symmetrical and unsymmetrical dipolarophiles. Thus, exposure of the cyclohexanone-substituted a-diazocarbonyl compound 56 to DMAD in the presence of Rh2(OAc)4 as the catalyst has furnished the cycloadduct 58 (Scheme 16). This cycloaddition was diastereoselective and, in the case of unsymmetrical dipolarophiles such as methyl methacrylate and propargyl bromide, they were regioselective and afforded oxygen heterocycles 59 and 60, respectively. The same research group has reported the 1,3-dipolar cycloaddition of the bicyclic carbonyl yUde 57 with other dipolarophiles, namely fulvenes [83]. In these tandem cycUzation-cycloaddition reactions involving fulvenes, four stereocenters and two new C-C bonds are formed in a single step. Symmetrical dipolarophiles such as macrocycHc olefins were also used for diastereoselective 1,3-dipolar cycloaddition reaction with 56 [84]. 

Diastereoselective 1,3-Dipolar Cycloadditions. Several examples of high diastereofacial selectivity with homochiral dipolarophiles have been reported. Cycloaddition of (1) with the cyclic dipolarophile (3) occurs with complete r-facial selectivity as a result of addition from the side opposite the bulky sUyloxymethyl group (eq 4). The key step in an asymmetric synthesis of (S)-(—)-cucurbitine involves cycloaddition of (1) with the a,p dehydrolactone (4) to give the pyrrolidine (5) as a single diastere-omer (eq 5). ... 

Suga, H., Funyu, A., Kakehi, A. (2007). Highly enantioselective and diastereoselective 1,3-dipolar cycloaddition reactions between azomethine imines and 3-acryloyl-2-oxazolidinone catalyzed by binaphthyldiimine-Ni(II) Complexes. Organic Letters, 9, 97-100. 

Cinchona alkaloid thiourea catalyst 17 (Figure 37.2) was later employed by Gong el al. to induce the enantio- and diastereoselective 1,3-dipolar cycloaddition of azomethine ylides generated from Schiffbases and nitroalkenes [31]. This process provided straightforward access to chiral highly substituted pyrrolidines with good yields, moderate enantioselectivities (<63% ee), and excellent diastereoselectivities... 

Luft JAR, Meleson K, Houk KH. Transition structures of diastereoselective 1,3-dipolar cycloadditions of nitrile oxides to chiral homoallylic alcohols. Org. Lett. 2007 9 555-558. 

Moon M-E, Park JY, Jeong E-H, Vajpayee V, Kim H, Chi K-W. Regio- and diastereoselective 1,3-dipolar cycloaddition between perfluoro-2-methyl-2-pentene and nitrones a facile approach to partially-fluorinated isoxazoli-dines. Bull. Korean Chem. Soc. 2010 31(6) 1515-1518. 

Diastereoselective [1,3]-Dipolar Cycloadditions Using Chiral Auxiliaries... 

---