Diels 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. 

Review "Alkaloid Total Synthesis by Intramolecular Imino Diels Alder Cycloaddiltions"... 

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... 

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... 

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. ... 

The Weinreb group has used an intramolecular imino Diels-Alder cycloaddition as the key step in a total synthesis of the fungal neurotoxin slaframine (74) (equation 25). Thus, thermolysis of acetate (71) produced an intermediate A -acyl imine (72) which underwent [4 + 2] cycloaddition to afford bicyclic lactam (73) as a 1.8 1 mixture of epimers. Both compounds were converted to the natural product in a few steps. 

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. 

The Berkovitz group achieved the synthesis of praziquantel (164) (used to treat schistosomiasis) through an intramolecular imino Diels-Alder route (84JOC5269). They failed in the initial reaction using the methylol acetate. However, the less labile methoxy group of 162 worked reasonably well as a leaving group. Pyrolysis of precursor 162 in various solvents was unsuccessful, but succeeded in the gas phase (49%) (Scheme 23). 

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... 

During the past few years, Weinreb and co-workers have published a series of papers on studies of intramolecular imino Diels-Alder cycloadditions and applications of this methodology to alkaloid total synthesis.84 These cycloadditions have involved Af-acylimines as the dienophiles, generated thermally (hot tube pyrolysis) by acetic acid elimination of methy-lol acetates [Eq. (26)].85... 

The Weinreb group has also applied intramolecular imino Diels-Alder chemistry to the synthesis of the phenanthroindolizidine antitumor alkaloid tylophorine (42) (Scheme 2-XIV).85 86 In this example, a diene incorporated into a phenanthrene unit proved sufficiently reactive in an intramolecular cyclization to provide the pentacyclic alkaloid ring system. A similar strategy was later used to synthesize the phenanthroquinolizidine alkaloid cryptopleurine.89... 

The synthesis of indolizidine alkaloids, including tylophorine and 6-coniceine as well as Elaeocarpus alkaloids, by the intramolecular imino Diels-Alder method (cf. vol.12, p.71) has been pub-... 

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. 

S.M. Weinreb, Alkaloid Total Synthesis by Intramolecular Imino Diels-Alder Cycloadditions, Acc. Chem. Res., 1985, 8, 16. 

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... 

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 ... 

By inventing an intramolecular imino-Diels-Alder cycloaddition of a diene formed by the thermolysis of an oxime-ether, the construction of the alkaloid skeleton, and the usefulness of this methodology, was successfully exemplified, first by the total synthesis of the benzo[c]phenanthridine alkaloid, chelidonine, and then in a beautiful total synthesis of lysergic acid (1). 

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...

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. 

A synthesis of ( )-tylophorine (213) has been based on the discovery that vanadyl trifluoride (VOF3) can be used to convert 1,2-diarylethylene into phenanthrenes in high yield. In the top sequence shown in Scheme 34, ring closure is accompanied by dehydrogenation (77CC826). In a second synthesis, ( )-tylophorine (213) is the result of an intramolecular version of a Diels-Alder cycloaddition of a conjugated diene with an imino dienophile (Scheme 34, lower sequence) (79JA5073). 

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