Imino Diels-Alder approach

In an alternative approach to this group of alkaloids, ( )-elaeokanine A (9) has been made by an intramolecular imino-Diels-Alder reaction. Pyrolysis of (15) in toluene solution yielded a mixture of the diastereoisomers (16), which, by a sequence of reactions, were converted into ( )-elaeokanine A (9).5 The possible derivation of the Elaeocarpus alkaloids from a common biosynthetic intermediate 3-(l-pyrrolinium)propionaldehyde (17), and the use of (17) in a synthetic approach to these alkaloids, have been discussed.6... 

Kouznetsov VV, Puentes CO, Bohorquez APP et al (2006) A straightforward synthetic approach to antitumoral pyridinyl substituted 7H-indeno[2, l-c]quinoline derivatives via three-component imino Diels-Alder reaction. Lett Org Chem 3 300-304... 

The Povarov reaction is related to the previous examples in that it can be defined as the formal imino Diels-Alder reaction between aromatic imines and electron-rich olefins. It is one of the most popular methods for the synthesis of tetrahydro-quinolines [40], and two examples of Povarov reactions in water are summarized in Scheme 1.27. In an eaily example of the use of ceric ammonium nitrate as a catalyst in synthesis [41], Perumal reported a few examples of a CAN-catalyzed Povarov reaction of aldehydes, amines and N-viitylpyrroUdin-2-ones as the olefin component in water for the synthesis of heteroaiyl-substituted tetrahydroquinolines 54 [42]. Using a different approach, Vaultier later described an onium salt-supported Povarov three-component reaction in water at room temperature affording tricyclic compounds 55. In this study, either the aldehyde or the amine components were linked to a side chain containing an onium salt, which confers solubility to the reactant [43]. 

Two general approaches to aza-Diels-Alder reactions have been reported. One incorporates the requisite nitrogen atom into the 2rt component (imine), while the other incorporates the requisite nitrc en in the 4rt component (azadiene). Chiral copper Lewis acids have been used with success in both approaches. Jorgensen and coworkers reported enantioselective imino Diels-Alder reactions catalyzed by CuC104 MeCN in the presence of phosphino-oxazoline (287) or BINAP (290) (Scheme 17.64) [93]. Phosphino-oxazoline (287) proved to be the ligand of choice in the aza-Diels-Alder reaction of N-tosyl a-imino ester (142) with Danishefsky s diene (286), while BINAP (290) gave the highest selectivity when dimethyl-substituted Danishefsky s diene (289) was used. 

It is noteworthy that, in the corollary intramolecular imino Diels-Alder reaction reported by Weinreb et al where A-acyl imines are employed as heterodienophiles [21], exclusive preference for boat-like transition states is observed, wherein the carbonyl group is restrained in the s-cis conformation within the A-acyl imine and approach is endo to the diene (Scheme 2.8). For example, in the intramolecular acyl imine Diels-Alder reaction en route to the synthesis of the quinolizidine alkaloids epi-lupinine (56) and lupinine (57) ... 

After extensive preliminary studies (68, 69), Weinreb and coworkers completed the first total synthesis of streptonigrin in 1980 ref. (70). The central strategy in their approach involved the use of an imino Diels-Alder reaction for construction of the CD framework. The quinoline system was ultimately synthesized by a new modification of the Fried-lander condensation after complete elaboration of all of the necessary pyridine substituents. 

Other classical synthetic approaches to 2-furanamine have failed, including the Curtius method and Beckmann rearrangement of 2-benzoylfuran oxime. However, hydrazinolysis of AT-(2-furyl)phthalimide, obtained from phthalimide and 2,5-dimethoxy-2,5-dihy-drofuran, gives 2-furanamine which was not isolated but detected by GLC-MS and H NMR spectroscopy. The latter reveals the absence of imino tautomers (75AP713). The chemistry of 2-dialkylamino-5-phenylfurans is typical of enamines protonation occurs on carbon to produce iminium salts. They are stable to base but afford 5-phenylfuran-2(3//)-one on hydrolysis with dilute acid. 2-Morpholino-5-phenylfuran couples with diazonium salts and affords Diels-Alder adducts with maleic anhydride and IV-phenylmaleimide (73JCS(P1)2523). 

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). 

A number of diverse structural types of cyclic imino dienophiles have been used in cycloadditions. For instance, dehydrohydantoins are useful partners in hetero Diels-Alder reactions. Two methods have been developed for in situ generation of these species. In one approach, methoxyhydantoins such as (24) (equation 8) are heated or are treated with acid to promote elimination of methanol, affording dienophile (25).22 2 This intermediate can be trapped regio- and stereo-selectively with 1,3-dienes. For example, with 1,3-cyclohexadiene only endo adduct (26) is formed. There is no ambiguity in this case concerning the dienophile configuration, and thus product (26) clearly derives from an endo transition state. 

Another general approach towards imino sugars is based on the formation of cyclic imines and their subsequent reactions. The versatility of imines results from a number of possible transformations they can undergo reduction to amines/ nucleophilic addition/ and aza-Diels-Alder cycloadditions are among the most common. 

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