Dihydropyridone

Radical cyclization of dihydropyridones 108 provided piperidine derivatives 109 containing a trifluoromethyl group at the bridgehead position adjacent to nitrogen <96JOC(61)8826>. 

The CDE rings of camptothecin were synthesized via an intramolecular Knoevenagel condensation of 124 (Equation 30) <2004TL7247>. The tricyclic dihydropyridone 125 was aromatized to the pyridone with NBS/ KHMDS (NBS - iV-bromosuccinimide, KHMDS - potassium hexamethyldisilazane). 

The elegant procedure of Schumann to prepare 38 required two compounds, aminoketal 42 (Scheme 11.6a) and dihydropyridone 45 (Scheme 11.6b). As with many syntheses of Lycopodium alkaloids, the synthesis of aminoketal 42 began with... 

A wide range of aliphatic nitrile oxides 370a-k and 372a-e, variously functionalized on the side chain, were added to MCP and its derivatives, on the route for the synthesis of functionalized dihydropyridones (Tables 29 and 30) [92]. 

Halide substituted isoxazolines 371a-f gave bicyclic dihydropyridones 374 after rearrangement. Methoxycarbonyl substituted isoxazolines 371g-k gave the lactams 375, whereas carbonyl substituted isoxazolines 373a-e gave pyrroles 376 (Scheme 51). 

Other multicomponent reactions are exemplified in the following two schemes. A new highly diastereoselective four-component reaction was developed for the synthesis of dihydropyridones 191 substituted with an isocyanide functionality <06OL5369>, thereby generating a synthetically useful complex isocyanide for use in further reactions. In this strategy, a phosphonate, a nitrile, and an aldehyde are used to generate an azadiene intermediate 192, which is trapped by an isocyanoacetate in the same pot. 

As six-membered heterocycles are present in a number of natural products and biologically important molecules, solid-phase synthesis of these has been reported very often (Fig. 3.9). Solid-phase synthesis for nearly every six-membered ring including one nitrogen atom are known piperidines (272) [376], tetrahydropyridines (273) [377, 378], dihydropyridines (274) [219, 379, 380], pyridines (275) [349, 381-386], (Scheme 3.37), piperidinones (276) [387], dihydropyridones (277-279) [313, 378, 388-390], pyridinones (280-281) [328, 329] and piperidindiones (282) [391] derivatives. In contrast, the synthesis of six-membered rings with one single oxygen is rarely described. Nevertheless, solid-phase synthesis of dihydropyrans (283-284) [392-394] and tetrahydropyrans (285) [335, 336] has been reported. 

Ring-closing metathesis seems particularly well suited to be combined with Passerini and Ugi reactions, due to the low reactivity of the needed additional olefin functions, which avoid any interference with the MCR reaction. However, some limitations are present. First of all, it is not easy to embed diversity into the two olefinic components, because this leads in most cases to chiral substrates whose obtainment in enantiomerically pure form may not be trivial. Second, some unsaturated substrates, such as enamines, acrolein and p,y-unsaturated aldehydes cannot be used as component for the IMCR, whereas a,p-unsaturated amides are not ideal for RCM processes. Finally, the introduction of the double bond into the isocyanide component is possible only if 9-membered or larger rings are to be synthesized (see below). The smallest ring that has been synthesized to date is the 6-membered one represented by dihydropyridones 167, obtained starting with allylamine and bute-noic acid [133] (Fig. 33). Note that, for the reasons explained earlier, compounds... 

In 2006, our research group reported a novel MCR based on the reactivity of a-acidic isocyano esters (1) toward 1-azadienes (84) generated by the 3CR between phosphonates, nitriles, and aldehydes [169]. Remarkably, the dihydropyridone products (85) for this 4CR contained the intact isonitrile function at C3. The exceptional formation of the 3-isocyano dihydropyridone scaffold can be explained by the Michael-attack of the a-deprotonated isonitrile (1) to the (protonated) 1-azadiene (84), followed by lactamization via attack of the ester function by the intermediate enamine. Although in principle the isocyano functionality is not required for the formation of the dihydropyridone (85) scaffold, all attempts using differently functionalized esters (e.g., malonates, ot-nitro, and a-cyano esters) gave lower yields of the dihydropyridone analogs [170] (Fig. 26). 

Because of the retained isocyano functionality, the dihydropyridone MCR product 85 can be used in various follow-up (multicomponent) reactions. For example, the Passerini reaction between 85, a carboxylic acid, and an aldehyde or ketone produces a series of dihydropyridone-based conformationally constrained depsipeptides 86 [171]. The subsequent Passerini reaction could also be performed in the same pot, resulting in a novel 6CR toward these complex products containing up to seven points of variation. Reaction of 85 with an aldehyde or ketone and amine component resulted in the isolation of dihydrooxazolopyridines (DHOPs, 87) [172] via a similar approach as the 2,4,5-trisubstituted oxazole variant toward 42 reported by Tron and Zhu (Fig. 15) [155]. The corresponding DHOPs (87), which... 

Fig. 27 Application of 3-isocyano dihydropyridones (85) in the multicomponent approaches toward conformationally constrained depsipeptides (86), dihydrooxazolopyridmes (87), and conformationally constrained peptidomimetics (88)...

Six years later, the same authors reported an improved version of their earlier synthesis of ellipticine (228) (527) (Scheme 5.197) by using the l-(p-methoxybenzyl)-5,6-dihydropyridone (1197) as 3,4-pyridyne surrogate (702,703). Thus, the dimethyl-furoindole 544 was treated with the unsaturated lactam 1197 (prepared from 5-valerolactam in three steps) in the presence of trimethylsilyl triflate (TMSOTf) to afford the carbazole 1199 as a single product in 40% yield. The low yield is presumably a consequence of decomposition of the intermediate adduct 1198 during... 

Starting unsaturated 5(477)-oxazolones 4-aIkylidene(arylidene)-5(4/y)-oxazolones 573 lead to dihydropyridone derivatives 574, whereas 4-(ethoxymethylene)-5(4//)-oxazolones 575 give pyridones 576 (Scheme 7.182). 

Preparation of dihydropyridones by the condensation of ethyl cyano-acetate, cyanoacetamide, or malononitrile with a,j8-unsaturated ketones [186]. 

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