2- Pyridones, chiral

Marazano and co-workers have also applied the reactions of tryptamine with various Zincke salts, including 115 (Scheme 8.4.39), in the synthesis of pyridinium salts such as 116. This type of product is useful for further conversion to dihydropyridine or 2-pyridone derivatives. For example, in a different study, Zincke-derived chiral pyridinium salts could be oxidized site-selectively with potassium ferricyanide under basic conditions as a means of chiral 2-pyridone synthesis (117 —> 118, Scheme 8.4.40). 

Enantioselective silver-catalyzed aza-Diels-Alder reactions have also been described. Whereas the use of BINAP as the chiral ligand gave only unsatisfactory enantioselectivities,367,367a Hoveyda etal 6 used the peptidic phosphine 373 which has already been used for silver-catalyzed asymmetric Mannich reactions (see Scheme 108) in the efficient Ag(i)-catalyzed cycloaddition of arylimines 449 with Danishefsky s diene (Scheme 135). After acidic work-up, the chiral pyridones 450 were obtained with excellent yields and enantioselectivities. The presence of isopropanol as a proton source is essential for obtaining high conversions and stereoselectivities. Similar to the Mannich reactions, the cycloaddition is not affected by the presence of air or the use of undistilled THF. 

The Rh(I)/dppf complex-catalysed 2-i-2-i-2-cycloaddition of oximes and diynes formed substituted pyridines in moderate to good yields (88%), under mild conditions. A one-pot procedure has been developed using aldehydes.The Ni-catalysed 2 -I-2 -I-2-cycloaddition of isocyanates (117) with 1,3-dienes (118) in MeCN produced 6-substituted dihydropyrimidine 2,4-diones (119). A key intermediate in this reaction is a five-membered azanickelacyclic species (Scheme 35). " The enantioselective cationic Rh(I)-catalysed 2-i-2-i-2-cycloaddition of diynes and isocyanates formed axially chiral pyridones with high ees (82%). The unique source of chirality is provided by a system containing [Rh(cod)Cl]2, l,4-bis(diphenylphosphino)butane, and the silver phosphate salt Ag(5)-TRIP. " " The Rh-catalysed 2-I-2-I-2-cycloaddition of diynes to sulfonimines in DCE, at r.t. to 80 °C, yielded 1,2-dihydropyridines in good yields (54-86%) and enantioselectivity (61-96%... 

Axially chiral pyridines as well as axially chiral pyridones could be synthesized via rhodium-catalyzed enantioselective [2 + 2 + 2] cycloaddition. The reaction of 1,6-diyne 68 with ethyl cyanoformate (69) in the presence of the cationic rhodium(I)/Segphos catalyst furnished axially chiral arylpyridine 70 as a single regioi-somer with excellent ee value (Scheme 9.25) [19],... 

Scheme 7 Synthesis of chiral bicycUc 2-pyridones via acylketenes and A -thiazolines...

Acyl-2-alkyl-2,3-dihydro-4( 1 //)-pyridones A are readily available heterocycles in both racemic and chiral form. l-Acyl-2-alkyl-l,2-dihydropyridines B are much less readily accessible, especially enantiopure, but are much sought after building blocks for alkaloid synthesis. A very efficient (83-96%) and simple procedure has now been developed for the A — B transformation, illustrated as follows treatment of l-allyloxycarbonyl-2-cyclohexyl-2,3-dihydro-4-pyridone with one equivalent of the Vilsmeier reagent in trichloroethylene at room temperature gave l-allyloxycarbonyl-4-chloro-2-cyclohexyl-l,2-dihydropyridine in 92% yield. 

Since photochemical reactions in inclusion compounds have been described in one chapter of the previous book [1], enantioselective (3-lactam formation reactions are summarized in this present chapter as a typical application of the inclusion technique for enantioselective photosynthesis. In addition, as a representative enantioselective single-crystal-to-single-crystal photoreaction, the photodimerization reactions of coumarin and thiocoumarin in their inclusion compound with a chiral host are also described. Furthermore, a host-catalyzed photodimerization reaction of chalcone and 2-pyridone in the solid state is also added to this chapter as a unique example of the application of inclusion techniques to selective photoreaction. 

Optically pure P-lactam derivatives can also be prepared by an enantioselective photocyclization reaction of 2-pyridone in its inclusion complex with a chiral host. For example, irradiation of the 1 1 inclusion complex of 1 and 4-methoxy-/V-inethyl-2-pyridone (33) in the solid state gave (—)-34 of 100% ee... 

In the case of the formation of the [3-lactam, it was shown that the ability of a compound to crystallize in a chiral space group was increased by using compounds with meta-substituted aryl groups such as 50a-d instead of their ortho- and para-substituted analogues the absolute asymmetric photocyclization of the pyridones resulted in the formation of 51a-d with good ees.[31]... 

In a novel application of 2-azetidinanes, the ready availability of chiral versions enables their reductive ring opening and subsequent functional group manipulation to give chiral versions of 2-pyridones in excellent yields (Scheme 117) <2003T6445>. 

Comins, D.L., Zhang, Y., and Zheng, X. (1998) Photochemical reactions of the chiral 2,3-dihydro-4(lH)-pyridones asymmetric synthesis of (—)-perhydro-histrionicotoxin. Chemical Communications, 2509-2510. 

Stereoselective Syntheses of Chiral Piperidines via Addition Reactions to 4-Pyridones... 

An alternative stereoselective synthesis of chiral heterocycles based on carbohydrate-induced stereodifferentiation includes nucleophilic addition reactions on heterocyclic systems already bound to the carbohydrate auxiliary. An example of this strategy has been shown by stereoselective addition of Grignard reagents to carbohydrate-linked 4-pyridones [61]. For this purpose, trimethylsiloxypyridine was glycosylated regioselectively using pivaloyl-protected glycosyl fluorides. 

Recently, many investigations have been carried out on the [4 + 4] photocycloaddition of 2-pyridones and its application to organic synthesis. Although the studied reactions involved only racemic materials, high diastereoselectivities have been obtained with chiral substrates. This makes this type of cycloaddition very promising for asymmetric synthesis [93]. 

The photochemical electrocyclic [477]-ring closure of 2-pyridones in the presence of chiral lactam ent-44 was found to be very slow at low temperatures. As a consequence, the potential of the host could not be fully exploited. At — 20°C after 96 h of irradiation in toluene, bicyclic (3-lactam 49 was obtained in 51% yield. The presence of 1.5 equivalents of host ent-44 led to 23% ee (Scheme 17) [68]. 

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