Core hetero-Diels-Alder reaction

The retrosynthesis of this compound by Batey and co-workers [96] recognized that the unprecedented hexahydropyrrolo[3,2-c]quinoline core could be synthesized using a three-component Pavarov hetero-Diels-Alder reaction [97]. For this synthetic strategy to be successful, however, reaction conditions that favor the exo approach of the dienophile over the endo approach had to be found. For this purpose, a variety of protic acids were tested, and it was found that the reaction was best carried out in the presence of camphorsulfonic acid (CSA). Indeed, a mixture of 4-aminobenzoate 200 and N-Cbz 2-pyrroline 201 were stirred at room temperature in the presence of catalytic CSA to afford exo cyclo-adduct 203 as the major product (Scheme 12.28). The N-Cbz 2-pyrroline served as both an aldehyde equivalent and a dienophile in this context. The Diels-Alder adduct 203 already bore all the requisite functionalities for the successful completion of the synthesis, which was achieved in six additional steps. 

An intramolecular hetero-Diels-Alder reaction has been used to produce the cyclopentaquinoline core of a series of alkaloids <20030L2509>. They form in high diastereoselectivity, generating up to four contiguous stereogenic atoms (Equation 134). 

A direct route to 5,8-disubstituted indolizidines and 1,4-disubstituted quinolizidines was reported by Barluenga and co-workers <02OL1971> (Scheme 30). Hetero-Diels-Alder reaction followed by reduction and desilylation gave good yields of the key piperidine core 51. Further elaboration of the hydroxymethyl side chain followed by RCM and hydrogenation gave the targets in moderate yields. 

SCHEME 7 Construction of iridoid core using a hetero-Diels-Alder reaction. 

Deoxyloganin (24) has previously been synthesized by Tietze and coworkers, utilizing an intramolecular hetero-Diels-Alder reaction to construct the iridoid core (Scheme 10). The synthesis commenced with conversion of (5)-citronellal (47) to enol ether 48 in seven steps. Knoevenagel condensation of the aldehyde with Meldrum s acid, followed by in situ intramolecular hetero-Diels-Alder reaction afforded pyran 49, with all the carbons required for the natural product core installed. Conversion of 49a, via methanolysis and a reduction/elimination sequence, to lactol acetate 50, was achieved in four steps. Finally, glycosylation and deprotection provided the natural product in a total of 14 steps. 

The hetero-Diels-Alder reaction of Danishefsky s diene with 3-(dimethylamino) propanal followed by a Mannich reaction resulted in the formation of highly functionalized hexahydro-2//-pyrano[3,2-c]pyridin-4(3//)-one core. ... 

Moody and coworkers have employed a biomimetic hetero-Diels-Alder-aroma-tization sequence for the construction of the 2,3-dithiazolepyridine core unit in amythiamicin D and related thiopeptide antibiotics (Scheme 6.243 a) [426]. The key cycloaddition reaction between the azadiene and enamine components was carried out by microwave irradiation at 120 °C for 12 h and gave the required 2,3,6-tris(thi-azolyl)pyridine intermediate in a moderate 33% yield. Coupling of the remaining building blocks then completed the first total synthesis of the thiopeptide antibiotic... 

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