Imino-Diels-Alder reactions cycloaddition with

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. 

Imino Diels-Alder reactions.1 The cycloaddition of dihydro-p-carbolines with... 

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. 

Intermolecular cycloaddition reactions constitute an important and convergent route to piperidines and related compounds. The research group of Franklin Davis at Temple University published a novel route to optically active piperidines that proceeded through an imino Diels-Alder reaction with enantiomerically enriched compound 84 (Scheme 16) <02OL655>. On reaction with ftww-l,3-pentadiene, intermediate 85 was produced as a single diastereomer in 89% yield. Hydrogenation of this strained intermediate yielded the 2,6-disubstituted piperidine 86 in 75% yield. 

As alluded to above, no detailed studies of the mechanism of the imino Diels-Alder reaction have been reported to date. However, it has been suggested that [4 + 2] cycloadditions of most C=N, N=N, C=0 and N=0 dienophiles are HOMOdiene-LUMOdienopwie controlled. Whether, in fact, these reactions are concerted pericyclic processes has yet to be firmly established. In any case, a simple dipolar mechanistic model (Scheme 2-1) can often be used to qualitatively predict the regiochemistry of imino dienophile cyclizations with unsymmetrical dienes, which usually proceed with high selectivity. This model may, in fact, be indicative... 

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. 

Aznar, et al. reported a proline-catalyzed imino-Diels-Alder reactions of acyclic a,p-unsaturated ketones 96 with imines 92 for the synthesis of mc50-2,5-diaryl-4-piperidones 98, Scheme 3.35 [50], The 2-amino-1,3-butadiene was generated in situ by the reaction of a,p-unsaturated ketones 96 with L-proline, followed by Diels-Alder cycloaddition with imine 92 to provide tetrahydropyridine adduct which was then hydrolyzed to the 4-piperidone 98. 

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%. ... 

A number of diverse stmctural 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 tqjproach, methoxyhydantoins such as (24) (equation S) are heated or are treated with acid to promote elimination of methanol, affording dienophile (25).22- 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. 

Several examples exist of inverse electron demand Diels-Alder reactions involving electron-deficient sym-tetrazines acting as dienes. However, the neutral, electon-rich imino compounds involved in these cycloadditions do not generally e pear to be useful dienophiles with other types of dienes. 

Cycloadditions of iminium compounds with 1,3-dienes to afford Diels-Alder adducts seems to be a reaction of general applicability.46 On the other hand, simple electron-rich imino species are less reliable dienophiles. Some electron-rich imines will undergo Diels-Alder reactions under acid catalysis and thus are probably actually reacting as iminium salts. However, inverse electron demand [4 + 2] cycloadditions of neutral imines with electron-deficient dienes have been reported, as have additions to exceptionally reactive dienes (vide infra). 

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. ... 

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. 

As a rule, cycloadditions with acyclic -acyl imino dienophiles are useful synthetic reactions which demonstrate excellent regio- and stereo-selectivity. A commonly used source of IV-acyl immonium dienophiles are bis-urethanes such as (13) (equation S), which upon treatment with a Lewis acid and a diene afford Diels-Alder adducts. In this case, (13) reacts with boron trifluoride etherate to afford immonium ion (14) which adds to diene (15), yielding tetrahydfopyridine (16). ... 

Cycloaddition reactions of 1,3-dienes with sulfur dioxide, unlike its mono and bis imino derivatives, usually produce five-membered ring 2,5-dihydrothiophene dioxides rather than Diels-Alder adducts [Eq. (36)]. 

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