Syntheses with Aza Diels-Alder Reactions

Hetero Diels-Alder reactions with imino dienophiles have been employed as key step in several syntheses of naturally occuring alkaloids. With regard to stereoselective transformations, the approach to (S)-anabasin worked out by Kunz et al. impressively illustrates the high utility of natural carbohydrates as source of chirality in asymmetric synthesis [505]. The N-galactosyl imine 7-28 underwent a Lewis acid catalysed aza Diels-Alder reaction with Danishefsky s diene which proceeded with excellent induced diastereoselectivity to yield the adduct 7-29. A short sequence then afforded the desired alkaloid 7-30. This work also deals with the suitability of several other dienes and imino dienophiles for such transformations (Fig. 7-7). 

Two very elegant alkaloid syntheses basing on intramolecular cycloadditions of imino dienophiles have been published by Grieco and his coworkers. The preparation of ( )-eburnamonine 7-32 is very efficient since imine 7-31, available from (5-valerolactam in a straightforward sequence, is directly converted into the desired alkaloid 7-32 by aza Diels-Alder reaction and subsequent isomerisation of the newly formed double bond. (Fig. 7-8) [506], 

The in situ release of a reactive iminium ion by cycloreversion of an azanor-bornene [211, 212] and a subsequent intramolecular aza Diels-Alder reaction 

Further applications of imino dienophiles to the synthesis of natural or biologically active compounds have been directed to (-)-cannabisativine [508] and HIV-1 protease inhibitors [509] Bailey s investigations of the enantioselective synthesis of pipecolic acid derivatives have already been discussed in Sect. 3.1. 

The preparation of amphimedine 7-46 published by Echavarren and Stille [512] is a noteworthy application of 2-aza-1,3-butadienes in natural product synthesis since it is an interesting combination of hetero Diels-Alder methodology with a palladium catalysed cross coupling. Thus, dienophile 7-44 was formed by Stille coupling of the triflate 7-42 with the stannyl aniline 7-43. This qui-none then underwent cycloaddition to the 2-aza-l,3-butadiene 7-45 an acid catalysed hydrolysis of the cycloadduct 7-47 and subsequent N-methylation completed the synthesis of amphimedine 7-46 (Fig. 7-11). 

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