Hetero Diels-Alder reaction intramolecular Lewis acid

Intramolecular versions of the ene reaction using Lewis acids can be applied to nonconjugated dienes. Thus, 2.8-dienoic acid derivatives lead to cyclohexane systems27. Side products in this conversion stem from intramolecular hetero-Diels-Alder cycloaddition. Chiral Lewis acids, such as titanium alkoxidcs modified with tartaric acid derived chiral diols, lead to asymmetric induction with up to 98% ee27,88. 

An intramolecular hetero-Diels-Alder reaction has been used to prepare octahydro-14//-benzo[g]quinolino[2,3- 7]-quinolidines (Scheme 38) <1998BML2881>. The same researchers have published a major study on the mechanism of this hetero-Diels-Alder reaction and have shown that under Lewis acid-catalyzed conditions it proceeds via a stepwise mechanism <1996T955>. 

One approach to tetrahydropyridinones is the Lewis acid mediated hetero-Diels-Alder reaction of electron-rich dienes with polystyrene-bound imines (Entries 3 and 4, Table 15.23). The Ugi reaction of 5-oxo carboxylic acids and primary amines with support-bound isonitriles has been used to prepare piperidinones on insoluble supports (Entry 5, Table 15.23). Entry 6 in Table 15.23 is an example of the preparation of a 4-piperidinone by amine-induced 3-elimination of a resin-bound sulfinate followed by Michael addition of the amine to the newly generated divinyl ketone. The intramolecular Pauson-Khand reaction of propargyl(3-butenyl)amines, which yields cyclopenta[c]pyridin-6-ones, is depicted in Table 12.4. 

Asymmetric intramolecular hetero-Diels-Alder reactions mediated by a sulfinyl group not directly bonded to n systems involved in the cycloadditions have also been reported [177]. Thus, Lewis acid catalysed intramolecular cyclization of tt -sulfinyl-a,/Lunsaturated ketone, shown in Scheme 108, gave mixtures of... 

In search for control of absolute stereochemistry, the reaction of thio-chalcones was investigated with unsaturated amides bearing an Evans chiral oxazolidinone [223] and dimenthyl fumarate [224, 225]. For the first time with thiocarbonyl compounds, the efficiency of Lewis acid addition was demonstrated, and reactions could be conducted at room temperature. With EtAlCl2 (Table 4, entry 2) or A1C13 (entry 3), levels of induction up to 92% were attained for the endo isomer. Yb(OTf)3 in DMSO also caused the acceleration of the reaction with chiral acrylamides with p-facial selectivity [226]. This group has also reported [227] an intramolecular hetero Diels-Alder reaction with divinyl thioketones and the double bond of an allyloxy group (Table 4, entry 4). 

The enantioselective hetero Diels-Alder reaction of 1-oxa-1,3-butadienes using chiral non-racemic Lewis acids is a widely unexplored field. The first successful example was the intramolecular cycloaddition of the heterodiene 2-194,... 

Although it is a stoichiometric procedure, the intramolecular hetero-Diels-Alder reaction of l-oxa-l,3-butadienes, obtained in situ by a Knoevenagel condensation of aromatic aldehydes and N,N -dimethylbarbituric acid, is mediated by a chiral titanium Lewis acid 29 which has l,2 5,6-di-0-isopropylidene-a-D-glucofuranose as a ligand. The highest ee-value was obtained in the reaction of 30 with 31 in isodurene as illustrated in Scheme 13[26]. 

A remarkable observation is the cyclization of biscarbamate (194) to y-lactone (195) mediated by methanesulfonic acid (equation 133). No trace of the expected 8-lactone is formed, presumably because of the unfavorable ester geometry in the transition state required for six-membered ring formation. Such problems with 8-lactone formation have been observed also in Diels-Alder chemistry. A nice example related to A-acyliminium chemistry is the thermal hetero Diels-Alder reaction of acylimine precursor (196) to bicyclic -y-lactone (197) in good yield. The corresponding intramolecular cycloaddition of (198) fails. Finally, Lewis acid mediated cyclization of allylsilane (199) is unsuccessful, although lactonization of (200) proceeds very well (equation 135, cf. equation 119). ... 

A common problem in Diels-Alder reactions is the regioselectivity. It is usually controlled by the coefficients of the interacting orbitals in the transition structures and can be improved in many cases by using Lewis acids. However, the application of high pressure also has a great influence as shown for the intramolecular hetero-Diels-Alder reaction of the benzylidenebarbituric acid derivative 48 (Scheme 8.13). In this transformation the ortho-adduct 49 and the meta-adduct 50 are formed. 

Tietze also reported an increase in the enantioselectivity of a cycloaddition reaction which was carried out in the presence of a chiral Lewis acid under high pressure. The intramolecular hetero Diels-Alder reaction (HIMDA) [68] of the benzyli-dine compound 186 proceeds by a mcte-addition to give two enantiomeric bridged cycloadducts 187 and 188 (Scheme 45). At ambient pressure (dichloromethane, RT, 31 h), in the presence of the chiral titanium Lewis acid catalyst, product 187 was formed preferentially (with 4.5% ee). In addition to die increase in chemical yield obtained at normal pressure (from 50%), enantioselectivity of the cycloaddition at 5 kbar was increased to (20.4% ee), in favor of the (-) enantiomer 188. 

As another type of hetero Diels-Alder reaction catalyzed by aluminum Lewis acid, Denmark and coworkers recently demonstrated rich chemistry on [4 + 2]cycloaddition of nitroalkenes with vinyl ethers. The reaction of nitroalkenes having an external alkene moiety with vinyl ether proceeds via intermolecular [4 + 2]cycloaddition followed by intramolecular [3 + 2]cycloaddition to give a mixture of tricyclic nitrosoacetals (150) (Scheme 6.150) [178]. In this reaction, stereoselectivity was affected by Lewis acid. In the case of bulky aluminum Lewis acids, such as MAPH and ATPH, (159b) was obtained as a major product. On the other hand, the use of less bulky titanium Lewis acids, for example, TiCU and TiCl3(Oi-Pr), resulted in selective formation of (150a). 

Lewis acid catalysts have been used in this approach.225-236-238 There are also a number of examples of hetero intramolecular Diels-Alder reactions.225 238-241... 

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]. 

The first total synthesis of the cytotoxic agent (+)-euplotin A was completed by the research team of R.L. Funk. The key step of the synthetic effort was the intramolecular hetero DIels-Alder cycloadditlon of a 3-acyl oxadiene (generated from 5-acyl-4H-1,3-dioxins via thermal retrocycloaddition) with a substituted dihydrofuran to afford the tricyclic skeleton of the natural product. The correct relative stereochemistry of the required dihydrofuran substrate was established using the Paterno-Buchi reaction between ethyl glyoxylate and furan. Subsequently, the oxetane ring was opened stereoselectively under Lewis acid catalysis. 

The first example of an intramolecular asymmetric Diels-Alder reaction of a diene bearing an optically active sullinyl group has recently been reported [195]. The reaction of the a-keto-a,P-unsaturated sulfoxide (258) in the presence of various monodentate Lewis acids (see Table 5.8) gave the nonracemic hetero-... 

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