Diels-Alder reactions intramolecular imino

In contrast LP-DE gives disappointing results for intramolecular imino Diels-Alder reactions, even in the presence of CSA. This is due to the fact that weak acids become strong acids in highly polar media such as 5.0m LP-DE and the protonation of diene, with concomitant diene isomerization, competes with cycloaddition [42]. This observation was supported by using trifluoroacetic acid (TEA). The imine 33 (Scheme 6.21) in LP-DE at room temperature in the presence of TEA gave a 1 1 mixture of cycloadduct 34 and the isomerized diene 35 within the unreacted imine 33. No Diels-Alder cycloadduct 36 was detected. 

Oppolzer, W., Francotte, E., Battig, K. (1981) Total Synthesis of ( )-Lysergic Acid by an Intramolecular Imino-Diels-Alder Reaction. Helvetica ChimicaActa, 64, 478 81. 

Diels-Alder, imino dienophiles, 65, 2 Diels-Alder, intramolecular, 32, 1 Diels-Alder, maleic anhydride, 4, 1 [4 -h 3], 51, 3 of enones, 44, 2 of ketenes, 45, 2 of nitrones and alkenes, 36, 1 Pauson-Khand, 40, 1 photochemical, 44, 2 retro-Diels-Alder reaction, 52, 1 53, 2 [6-h4], 49, 2 [3-h2], 61, 1 Cyclobutanes, synthesis ... 

Imino Diels-Alder reactions. The neurotoxic fungal toxin slaframine (2) has been synthesized by an intramolecular imino Diels-Alder reaction. The substrate is obtained from the amide 1 via a methylol derivative. These derivatives are best prepared by reaction of the amide with Cs2C03 and paraformaldehyde in dry THF (equation I). When heated they lose acetic acid and undergo cyclization. 

The seco-phenanthroindolizidine alkaloid septicine has been synthesized by a nitrone route. A cycloaddition of 1-pyrroline 1-oxide with 2,3-bis-(3,4-dimethoxyphenyl)butadiene gives two stereoisomeric isoxazolidines, one of which is converted into ( ) septicine.10 ( )-Tylophorine and 5-coniceine have been prepared by a new route that makes use of an intramolecular imino-Diels-Alder reaction.11 A stereoselective synthesis of 3,5-dialkyl-indolizidines has been applied to the synthesis of a stereoisomer of the trail pheromone of the Pharaoh ant and to a stereoisomer of gephyrotoxin 223.12 A stereoselective total synthesis of ( )-perhydrogephyrotoxin (21)13 and a simple synthesis of ( )-gephyran14 have been reported. 

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... 

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],... 

Chiral Auxiliary for Asymmetric Induction. Numerous derivatives of (—)-8-phenylmenthol have been utilized for asymmetric induction studies. These include inter- and intramolecular Diels-Alder reactions, dihydroxylations, and intramolecular ene reactions of a,p-unsaturated 8-phenylmenthol esters. These reactions usually proceed in moderate to good yield with high diastereofacial selectivity. a-Keto esters of 8-phenylmenthol (see 8-Phenylmenthyl Pyruvate) have been used for asymmetric addition to the keto group, as well as for asymmetric [2 -F 2] photoadditions and nucleophilic alkylation. Ene reactions of a-imino esters of 8-phenylmenthol with alkenes provide a direct route to a-amino acids of high optical purity. Vinyl and butadienyl ethers of 8-phenylmenthol have been prepared and the diastereofacial selectivity of nitrone and Diels-Alder cycloadditions, respectively, have been evaluated. a-Anions of 8-phenylmenthol esters also show significant diastereofacial selectivity in aldol condensations and enantiose-lective alkene formation by reaction of achiral ketones with 8-phenylmenthyl phosphonoacetate gives de up to 90%. ... 

Over the past ten years, intramolecular imino Diels-Alder reactions have become a useful tool for alkaloid synthesis. This subject has been thoroughly reviewed ° ° and the discussion below is intended to exemplify various important aspects of the methodology. ... 

Recently, lupinine 4 and epi-lupinine 139 were also synthesized by Takayama s group (85H2913) based on an intramolecular imino Diels-Alder reaction (Scheme 20). Thermolysis of acetate 141 in toluene containing sodium hydrogen carbonate in a sealed tube at 200 C for 2 hr gave lactam 143 in 80% yield via desulfonylation and subsequent intramolecular cycloaddition of 142. 

Oppolzer et al. devised a clever total synthesis of lysergic acid (40) that has as its key step an intramolecular imino Diels-Alder reaction (Scheme... 

An intramolecular imino Diels-Alder reaction has also been used as the key step in a total synthesis of the neurotoxic fungal metabolite slaframine (49) 91 [4 2] cycloaddition of an ( , )-diene was used to establish... 

The first example of an intramolecular imino Diels-Alder reaction was described by Oppolzer, who found that on heating a benzocyclobutene derivative a mixture of epimeric tricyclic adducts was formed [Eq. (231].80... 

Oppolzer et al. devised a clever total synthesis of lysergic acid (40) that has as its key step an intramolecular imino Diels-Alder reaction (Scheme 2-XIII). A thermal retro-Diels-Alder reaction of 39 liberating cyclopen-tadiene was used to afford a diene oxime ether which cyclized to give a tetracyclic indole as a 3 2 mixture of diastereomers. Three additional steps served to convert this adduct to ( )-lysergic acid (40). Of particular interest here is the fact that simple oximino compounds are not normally reactive dienophUes, and the intramolecularity of the conversion is apparently crucial to the success of this transformation. 

Grieco PA, Kaufman MD (1999) Intramolecular imino Diels-Alder reaction of a 3-vinyl indole application to a total synthesis of (+-)-ebumamonine. J Org Chem... 

Lysergic acid Intramolecular Imino-Diels-Alder-Reaction starting from 4-hydroxymethyl-1-tosylindole [30]... 

The methodology based on nitroso DieIs-alder reaction that proved useful in the synthesis of tropane alkaloids also seemed to open an attractive route to some other alkaloids. Compared to the intramolecular imino Diels-Alder reaction (ref. Ic) the intramolecular variant of the nitroso Diels-Alder reaction has received far less attention (refs. 6b 12), despite the enormous potential it holds for alkaloid synthesis. With this in mind we proceeded to examine the application of the intramolecular nitroso Diels-Alder cycloaddition in the synthesis of alkaloids possessing saturated nitrogen heterocyclic ring systems. 

Van de Weghe disclosed an intramolecular hetero Diels-Alder reaction with an imino diene as part of a synthetic strategy for the synthesis of uncialamycin. In the key Diels-Alder reaction, boron trifluoride promotes the cycloaddition followed by DDQ-mediated oxidation to afford aromatic product 70. ... 

Ramesh E, SreeVidhya TK, Raghunathan R (2008) Indium chloride/silica gel supported synthesis of pyrano/thiopyranoquinolines through intramolecular imino Diels-Alder reaction using microwave irradiation. Tetrahedron Lett 49 2810-2814... 

The Diels-Alder reaction of 1-azadienes has been used to construct indolizines and homologous systems. Hence, acyl azadienes (122), prepared by thermal elimination of acetic acid from N-acyl-O-acetyl-N-allylhydroxylamines, undergo intramolecular Diels-Alder cyclization to form indolizidine (123) and related ring systems. A closely related paper describes the synthesis of the indolizine ring system (124) by utilization of an imino Diels-Alder cyclization. 

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) ... 

Grieco s synthesis of cryptopleurine 70 and julandine 68 (see end of section 2.3.1), via an intramolecular imino Diels-Alder reaction for construction of the quinolizidine nucleus, failed in the case of the related indolizidine alkaloid, tylophorine [38]. Submitting phenanthryl amine 113 to the identical aza Diels-Alder conditions used for cryptopleurine only yields by-products (114), as a result of a Clarke-Eschweiler type of cyclization. No tylophorine is detected under these conditions ... 

Raghunathan et al. reported an intramolecular imino Diels-Alder reaction from imines assembled in situ [194] (Figure 8.84). The reaction was also extended to the use of amine substrates that are essentially two linked anihnes, but required... 

Fig. 8.84 InCb-catalyzed intramolecular imino Diels-Alder reaction. Me...

The intramolecular aza Diels-Alder cycloaddition is also a valuable tool for the synthesis of alkaloids as demonstrated by the stereocontrolled synthesis of ( )-lepadifor-mine 137 (Scheme 41.29). This tricyclic alkaloid has been isolated from several species of Clavenia and Polycitoridae sea squirts and is moderately cytotoxic toward various tumor cell lines and effective to block potassium ion channels. Initial attempts to perform the aza Diels-Alder reaction with the racemic imino-diene t-butyl ester 134 in toluene at temperatures up to 165°C did not lead to the observation of any cycloadducts but to double bonds isomerization products. The corresponding free carboxylic acid only suffered decarboxylation. The addition of trifluoroacetic acid to generate an imminium species was also unsuccessful. 

Desrat, S. and van de Weghe, P. (2009) Intramolecular imino Diels-Alder reaction progress toward the synthesis of undalamycin. Journal of Organic Chemistry, 74(17), 6728-6734. 

Intramolecular imino Diels-Alder cyclization is a useful method in alkaloid synthesis. The reaction is highly stereoselective but gives results opposite to those usually found in closely analogous all-carbon systems. Thus, the diene (284) on pyrolysis gives the single trans cycloadduct (286). The reaction is rationalized by assuming initial formation of the... 

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