Dipolarophiles asymmetric cycloaddition reactions, chiral

To control the stereochemistry of 1,3-dipolar cycloaddition reactions, chiral auxiliaries are introduced into either the dipole-part or dipolarophile. A recent monograph covers this topic extensively 70 therefore, only typical examples are presented here. Alkenes employed in asymmetric 1,3-cycloaddition can be divided into three main groups (1) chiral allylic alcohols, (2) chiral amines, and (3) chiral vinyl sulfoxides or vinylphosphine oxides.63c... 

S.2.2 Inverse Electron Demand Cycloaddition Chiral Lewis acid-catalyzed asymmetric cycloaddition reactions of carbonyl yhdes with electron-dehcient dipolarophiles described up to this point could be clas sified by the reaction controlled by the strongest interaction between highest occupied molecular orbital (HOMO) of the carbonyl ylides and LUMO of the dipolarophiles. It is known that inverse electron demand type cycloadditions of carbonyl ylides, which are controlled by the strongest interaction between the dipolarophile HOMO and the carbonyl ylide LUMO, also occur. In 2007, Suga et al. also reported that high enantioselectivities were obtained for the inverse electron... 

Nitrones were the first as well as the most widely used dipoles in asymmetric cycloadditions. The first report on the use of enantiomerically pure vinylsulf-oxides as dipolarophiles was due to Koizumi et al. [153], who described in 1982 the reaction of (-R)-vinyl p-tolyl sulfoxide 1 with acyclic nitrones 191. The reactions required 20 h in refluxing benzene to be completed, yielding a mixture of only two compounds, 192 and 193 (Scheme 91). They exhibited identical endo or exo stereochemistry (which was not unequivocally assigned), deduced from the fact that their reduction yielded enantiomeric thioethers. The major component, 192, exhibits (S) configuration at C-3, determined by chemical correlation. The authors claim this paper [153] to be the first example of 1,3-dipolar cycloaddition using chiral dipolarophiles. 

Cooper, D.M., Grigg, R., Hargreaves, S. ef a/. (1995) X = Y-ZH compounds as potential 1,3-dipoles. Part 44. Asymmetric 1,3-dipolar cycloaddition reaction of imines and chiral cyclic dipolarophiles. Tetrahedron, 51, 7791-7808. 

Recent advances have been made in the enantioselective cycloaddition of nitrones and alkenes. By using a chiral auxiliary attached to the nitrone or the alkene, moderate to good levels of asymmetric induction have been reported. A number of metal complexes with chiral ligands catalyse the cycloaddition reaction of nitrones, particularly for dipolarophiles containing two carbonyl groups for biden-tate co-ordination to the metal. An alternative approach, using a,p-unsaturated aldehydes and chiral secondary amines has been successful (3.138). The endo product is the major stereoisomer in these cycloaddition reactions and the catalysis is thought to proceed via the reactive intermediate iminium ion 210, with addition of the nitrone to the face of the alkene opposite the benzyl substituent. 

Dipolar cycloaddition reactions are not restricted to the use of alkene or alkyne dipolarophiles. Many hetero-dipolarophiles, particularly aldehydes and imines, undergo successful 1,3-dipolar cycloaddition with a range of 1,3-dipoles. The chemistry therefore provides access to a variety of five-membered heterocyclic compounds and compounds derived therefrom. Recent developments have focused on asymmetric dipolar cycloaddition reactions in the presence of a chiral catalyst, or the application of the chemistry to the preparation of biologically active compounds. 

The asymmetric induction on the 1,3-dipolar cycloaddition reaction of carbonyl ylides has also been studied using chiral dipolarophile. The Rh2(OAc)4-catalyzed reactions of o-(methoxycarbonyl)diazoacetophenone 89 with enantiomerically pure vinyl sulfoxides 103 afforded 4,10-epoxybenzo-[4,5]cyclohepta[l,2-c]furan-3,9-dione 105, in good or moderate yield with complete regioselectivity [113]. The endo stereoisomer 105a is favored with respect to the exo isomer 105b and interestingly, high diastereoselectivity and complete enantioselectivity have been achieved (Scheme 32). 

The [3+2] cycloaddition strategy provides an effective method to access valuable intermediates for the construction of biologically important alkaloids, amino acids, amino carbohydrates and P-lactams [58-62]. The reaction involves the concerted pericyclic addition of a dipole and a dipolarophile and considerable efforts have been made to render these reactions asymmetric nsing Lewis acid catalysis and chiral anxiliaries [63]. 

Koizumi and co-workers (38) reported the first asymmetric synthesis of (15)-(—)-a-tropanol (149) via a 1,3-dipolar cycloaddition protocol. Treatment of the chiral dipolarophile 150 with 151 in tetrahydrofuron (THF) delivered cycloadducts exo-152 and endo-153. Although the reaction proceeded with low facial selectivity,... 

The azomethine ylide was generated by treatment of A -benzyl-Af-(methoxy-methyl)-trimethylsilylmethylamine (155) with TFA and underwent the required cycloaddition step with chiral dipolarophile 156, stereocontrol being induced by Evan s auxiliary. The ot, p-unsaturated acid dipolarophile was tethered to a chiral oxazoladine in two easy, high-yielding steps. The auxiliary served three purposes to give asymmetric control to the reaction, to allow for separation of the reaction products by generating column separable diastereoisomers, and hnally to activate the olefin in the cycloaddition step (Scheme 3.45). 

By attachment of a chiral controlling unit, the reaction could also be carried out asymmetrically (100). Subjecting 352 (R = 2-naphthyl, R = H) to cycloaddition with 353 in the presence of AgOAc (1.5 M equiv) and EtaN (1.0 M equiv) furnished the enantiopure adduct 354 in 50%, with no other reaction products being observed. The reaction could be improved by alteration of the metal salt. Treatment of 352 (R = R = Ph) with dipolarophile 353 in the presence of LiBr and EtsN delivered the expected, enantiomerically pure adduct 354 in >90% yield, while 352 (R = 2-naphthyl, R = H) gave rise to 354 in quantitative yield with TINO3 and EtaN (Scheme 3.119). 

Yamamoto and co-workers (135,135-137) recently reported a new method for stereocontrol in nitrile oxide cycloadditions. Metal ion-catalyzed diastereoselective asymmetric reactions using chiral electron-deficient dipolarophiles have remained unreported except for reactions using a-methylene-p-hydroxy esters, which were described in Section 11.2.2.6. Although synthetically very useful and, hence, attractive as an entry to the asymmetric synthesis of 2-isoxazohnes, the application of Lewis acid catalysis to nitrile oxide cycloadditions with 4-chiral 3-(2-aIkenoyl)-2-oxazolidinones has been unsuccessful, even when > 1 equiv of Lewis acids are employed. However, as shown in the Scheme 11.37, diastereoselectivities in favor of the ffc-cycloadducts are improved (diastereomer ratio = 96 4) when the reactions are performed in dichloromethane in the presence of 1 equiv of MgBr2 at higher than normal concentrations (0.25 vs 0.083 M) (140). The Lewis acid... 

An alternative approach in the asymmetric catalysis in 1,3-dipole cycloaddition has been developed by Suga and coworkers. The achiral 1,3-dipole 106 was generated by intramolecular reaction of an Rh(ii) carbene complex with an ester carbonyl oxygen in the Rh2(OAc)4-catalyzed diazo decomposition of <9-methoxycarbonyl-o -diazoacetophenone 105 (Scheme 12). The asymmetric induction in the subsequent cycloaddition to G=G and G=N bond was achieved by chiral Lewis acid Sc(iii)-Pybox-/-Pr or Yb(iii)-Pybox-Ph, which can activate the dipolarophile through complexation. With this approach, up to 95% ee for G=0 bond addition and 96% ee for G=G bond addition have been obtained, respectively. ... 

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