Lewis acid catalysis cycloaddition

Perfluoropolyenes also can rearrange to four-membered ring products upon fluoride ron or Lewis acid catalysis [112, II3, 114] (equations 46 and 47) These intramolecular cycloadditions are multistep processes involving carbanion or carbocation intermediates... 

The author has been involved for quite a long time in the study of Lewis acid catalysis of 1,3-dipolar cycloaddition reactions. From his research group, a series of methodologies directed to the Lewis acid-mediated stereochemical and regiochem-ical control of 1,3-dipolar cycloaddition reactions has been reported this includes ... 

The final class of reactions to be considered will be the [4 + 2]-cycloaddition reaction of nitroalkenes with alkenes which in principle can be considered as an inverse electron-demand hetero-Diels-Alder reaction. Domingo et al. have studied the influence of reactant polarity on the reaction course of this type of reactions using DFT calculation in order to understand the regio- and stereoselectivity for the reaction, and the role of Lewis acid catalysis [29]. The reaction of e.g. ni-troethene 15 with an electron-rich alkene 16 can take place in four different ways and the four different transition-state structures are depicted in Fig. 8.16. 

The most frequently encountered, and most useful, cycloaddition reactions of silyl enol ethers are Diels-Alder reactions involving silyloxybutadicncs (Chapter 18). Danishefsky (30) has reviewed his pioneering work in this area, and has extended his studies to include heterodienophiles, particularly aldehydes. Lewis acid catalysis is required in such cases, and substantial asymmetric induction can be achieved using either a chiral lanthanide catalyst or an a-chiral aldehyde. 

Recently, Akiyama et al. reported an enantiocontrolled [3+2] cycloaddition of chirally modified Fischer alkenylcarbene complexes 180 with aldimines 181 under Lewis-acid catalysis (Sn(OTf)2) to afford enantiomerically pure 1,2,5-trisubstituted 3-alkoxypyrrolines 182 (Scheme 40) [121]. The mode of formation of these products 182 was proposed to be a [4+2] cycloaddition, with the complexes 180 acting as a 1-metalla- 1,3-diene with subsequent reductive elimination. Upon hydrolysis under acidic conditions, the enol ethers give the enantiomerically pure 3-pyrrolidinones 183 (Table 9). 

The cycloaddition of chiral, racemic and non-racemic alkoxybutadienes 109 with phenyltriazolinedione led to aza compounds [110] in high yield, with good facial selectivity (diastereomeric excess 87-92%) (Equation 2.31). The cycloadditions of the same dienes with N-phenylmaleimide require Lewis acid catalysis. 

Dihydrothiopyrans have also been prepared by cycloaddition between a,jS-unsaturated thioketones and carbonyl-activated dienophiles under Lewis-acid catalysis [78]. A marked dependence of the reaction yield on the catalyst was observed. The results of the cycloaddition reaction of thioketone 77 with methyl metacrylate, catalyzed by different catalysts, are illustrated in Equation 3.24. 

Lewis-acid catalysis is effective in intermolecular as well as intramolecular /zomo-Diels-Alder reactions. Thus, complex polycyclic compounds 93 have been obtained in good yield by the cycloaddition of norbornadiene-derived dienynes 92 by using cobalt catalyst, whereas no reaction occurred under thermal conditions [91] (Scheme 3.18). 

The complex obtained from commercially available chiral a-amino acids (AA) with Cu + ion induces asymmetry in the Diels-Alder reaction of 31 (R = H) with 32. By using 10% Cu(II)-AA (AA = L-abrine) the cycloaddition occurs e/iJo-stereoselectively in 48 h at 0°C with high yield and with acceptable enantioselectivity ee = 1A%). This is the first example of enantioselective Lewis-acid catalysis of an organic reaction in water [9b]. 

As with D-A reactions, it is possible to achieve enantioselective cycloaddition in the presence of chiral catalysts.156 Many of the catalysts are similar to those used in enantioselective D-A reactions. The catalysis usually results from a lowering of the LUMO energy of the dipolarophile, which is analogous to the Lewis acid catalysis of D-A reactions. The more organized TS, incorporating a metal ion and associated... 

Lewis acid catalysis has been used to promote stepwise [2 + 2] cycloaddition of silyl enol ethers and unsaturated esters.178 The best catalyst is (C2H5)2A1C1 and polyfluoroalkyl esters give the highest stereoselectivity. The reactions give the more stable trans products. 

While doubly activated dienophiles gave moderate to good yields under thermal conditions (Table 11), mono activated alkenes such as cyclohexenone (123) failed to react at temperatures up to 150 °C but underwent cycloaddition under Lewis-acid catalysis even if with poor yields (Table 12, entries 1-3) [32],... 

Cycloaddition of the nitrone 161 to the lactone 160 in boiling benzene for 6 h gave a 53 37 10 mixture of the three optically active adducts 162-164 in 66% combined yield (Scheme 9.50). Formation of the diastereoisomers 162-164 can be rationalized in terms of a highly preferred anti approach of the nitrone to the hydroxymethyl group in the transition state. The isomer ratio in the adducts was found to be dependent upon the solvent used in the reaction. Optimization of the reaction or the dia-stereoselectivity by Lewis acid catalysis failed. However, attempts to accelerate the cycloadditions by microwave irradiation, using 1,4-dioxane as the solvent, were successful and the reaction time decreased from hours to less than 10 min with only a... 

In the cycloaddition of vinylallenes 217 and 218, both Lewis acid catalysis and thermal conditions gave analogous results in terms of stereoselectivities [178],... 

Uncatalysed Diels-Alder reactions usually have to be carried out at relatively high temperatures (normally around 100 °C)73, often leading to undesired side reactions and retro-Diels-Alder reactions which are entropically favoured. The Diels-Alder reaction became applicable to sensitive substrates only after it was realized that Lewis acids (e.g. A Clg) are catalytically active56. As a consequence, Diels-Alder reactions can now be carried out at temperatures down to — 100°C85. The use of Lewis acid catalysts made the [4 + 2]-cycloaddition applicable to the enantioselective synthesis of many natural compounds51,86. Nowadays, Lewis acid catalysis is the most effective way to accelerate and to stereochemically control Diels-Alder reactions. Rate accelerations of ten-thousand to a million-fold were observed (Table 7, entries A and B). 

The mechanistic interpretation involves the interaction of a hydrophobic substituent in the ligand bound to Cu(II) with an aromatic ring in the dienophile exerting a favorable effect on the dienophile-Cu(II) interaction. Both the catalytic efficiency of Lewis-acid catalysis and the stereochemistry of the cycloaddition benefit from this water- induced interaction (Figure 7.9). 

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]. 

The class of 3-silyl-substituted reagents provides, upon addition with aldehydes, allylic silanes that offer many options for further derivatization. Oxidative processes are described in previous sections (see the sections on Preparation of 1,2-Diols and 1,4-Diols). If the appropriate silicon substituents are chosen, formal [3+2] cycloadditions with aldehydes can be promoted under Lewis acid catalysis. For example, the mismatched addition of the Z-3-propyl-3-benzhydryldimethyl allylsilane 183 to an a-benzyloxy aldehyde proceeds with low diastereofacial selectivity in favor of product 184 however, after protection of the secondary alcohol, an efficient [3+2] annulation provides the polysubsubstituted furan 185 in good yield and acceptable stereoselectivity (Scheme 24). ° The latter is brought forward to a tricyclic unit found in the antitumor natural product angelmicin B. 

When 2-aza-3-silyloxy-l,3-diene 336 was heated with aliphatic or aromatic aldehydes in toluene, stereoisomeric tetrahydro-l,3-oxazin-4-one derivatives 200 and 337 were obtained without Lewis acid catalysis (Equation 34). The cycloaddition proved to be highly diastereoselective in favor of the OTr/o-adducts, leading to the >-isomers 200 as the main products <1999TL7079, 2002S2043>. 

Grigg and co-workers (310) recently examined the 1,3-APT reaction of various aldoximes (270) (R or R = H) with divinyl ketone (Scheme 1.56). While ketoximes 270 (R = R) form a mixture of adducts, 271 and 272 via nitrone 273, the aldoximes selectively afford 272 (as a mixture of endo and exo diastereoisomers). Under the thermal reaction conditions, the oxime starting materials can undergo ( /Z) isomerization, while the nitrone intermediate was expected to be unaffected and the isolated cycloadducts showed no interconversion via cycloreversion. Thus, the increasing selectivity for endo-212 [via ( )-273, R = H] over exo-212 [via (Z)-273, R = H] with the increasing size of the aldoxime substituent was attributed primarily to the inhibition of oxime isomerization by steric clash between R or R and the oxime OH. In contrast, Lewis acid catalysis, in particular by hafnium (iv) chloride, of the cycloaddition of various aldoximes with this dipolarophile gave exo-271 exclusively (216). 

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... 

Indole (2) undergoes electrophilic substitution preferentially at the b(C3)-position whereas pyrrole (1) reacts predominantly at the a(C2)-position [15]. The positional selectivity in these five-membered ring systems is well explained by the stability of the Wheland intermediates for electrophilic substitution. The intermediate cations from 3 (for indole, 2) and a (for pyrrole, 1) are the more stabilized. Pyrrole compounds can also participate in cycloaddition (Diels-Alder) reactions under certain conditions, such as Lewis acid catalysis, heating, or high pressure [15]. However, calculations of the frontier electron population for indole and pyrrole show that the HOMO of indole exhibits high electron density at the C3 while the HOMO of pyrrole is high at the C2 position [25-28] (Scheme 3). 

Lewis, F.D. and Barancyk, S.V. (1989) Lewis Acid catalysis of photochemical reactions. 8. Photodimerization and cross-cycloaddition of coumarin. Journal of the American Chemical Society, 111, 8653-8661. 

A major problem in the reaction of a,/3-unsaturated carbonyl compounds and alkenes proves to be the competition between hetero Diels-Alder and ene reactions. Intramolecular cycloadditions of 1,6- and 1,7-dienes with ester and cyano groups at the double bond yield the ene product nearly exclusively, but with alkylidene- and benzylidene-ketoesters and 1,3-diketones the Diels-Alder reaction is preferred under thermal conditions, however under Lewis acid catalysis also ene reactions occur [12]. 

However, activation with suitable substituents is not the only method to make 1-aza-1,3-butadienes react in aza Diels-Alder reactions. Nevertheless, Lewis acid catalysis has not yielded good results in this area of hetero Diels-Alder chemistry. Interestingly, Lewis and Bronsted acids promote a [3 + 2] cycloaddition process instead of the aza Diels-Alder reaction upon addition of a,/ -unsatura-ted hydrazones to quinones [249],... 

Lewis acid catalysis, apparently dispensible due to the very high reactivity of nitroso dienophiles, has not yet been investigated although such a study has been suggested by Streith and Defoin [8]. Thus, examples of asymmetric catalysis lack completely in this area of hetero Diels-Alder chemistry. Nevertheless, cycloadditions involving nitroso dienophiles have reached an advanced level concerning stereoselectivity and therefore much attention has been paid towards the preparation and application of chiral, enantiopure dienophiles and dienes for these reactions. 

The cycloaddition of ketenes to carbonyl compounds also shows the expected regioselectivity. Both HOMO,keI() c/LlJMO(kctcnc) and LUMO(ketone)/ HOMO(ketcnc) interactions may be important, but they lead to the same conclusions about regioselectivity. Lewis acid catalysis is commonly employed in this reaction presumably the Lewis acid lowers the energy of the LUMO of the ketene (or that of the ketone) in the same way that it does with dienophiles. Ketenes also dimerise with ease, since they are carbonyl compounds. The regiochemistry, whether it is forming a /3-lactone 6.256, 6.257 or a 1,3-cyclobutanedione 6.258, is that expected from the frontier orbitals of Fig. 6.39. 

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