Hetero-Diels-Alder strategy

Jimenez-Alonso S, Estevez-Braun A, Ravelo AG, Zarate R, Lopez M (2007) Double domino Knoevenagel hetero Diels-Alder strategy towards bis-pyrano-l,4-benzoquinones. Tetrahedron 63 3066-3074... 

When combining the hetero-Diels-Alder strategy with the CuAAC reaction, star block copolymers have been obtained (SinnweU et al., 2008b). First, a-diene-co-alkyne... 

Bandini E, Corda G, D Aurizio A, Panunzio M (2010) A straightforward synthesis of conhydrine by hetero Diels-Alder strategy mediated by microwaves. Tetrahedron Lett 51(6) 933-934. doi 10.1016/j.tetlet.2009.12.039... 

Hetero Diels-Alder reacdons using nitroalkenes followed by 1,3-dipolar cycloaddidons provide a nsefid strategy for the constnicdon of polycychc heterocycles, which are found in naturM products. Denmark has coined the term tandem [4t-2 /[3t-2 cycloaddidon of nitroalkenes for this type of reacdon. The tandem [4-i-2 /[3-i-2 cycloaddidon can be classified into font famihes as shown in Scheme 8.31, where A and D mean an electron acceptor and electron donor, respecdvely. " In generril, electron-rich alkenes are favored as dienophdes in [4-i-2 cycloaddidons, whereas electron-deficient alkenes are preferred as dipolarophdes in [3-i-2 cycloaddidons. 

A similar strategy can also be used in a seven-step procedure of preparation of 3/3,25-dihydroxy-cholesta-5,7-diene from ergosterol giving a total yield of 30%. The 3-hydroxy function of ergosterol is protected as /-butyldimethylsilyl ether before the 5,7-diene system is treated with l,4-dihydrophthalazine-l,4-dione. In this case, the key step is a very mild method for the cleavage of the hetero Diels-Alder adduct using lithium naphthalenide <1999S1331>. 

Methods for the synthesis of substituted pyridines remains an intense topic of research. One of the most popular approaches to substituted pyridines remains cycloaddition reactions. While this strategy is not new and many examples are in the current literature <00TL10251>, the state-of-the-art has been expanded. Weinreb and co-workers have reported the regioselective synthesis of pyridines (3) via intramolecular oximino malonate hetero Diels-Alder reactions (1 - 2) <00OL4007>. Similarly, the intramolecular [4 + 2] cycloaddition of... 

More recently, a catalyst-free aqueous version of this strategy was proposed with simple acyclic 1,3-dicarbonyls, formaldehyde, and styrene or anilines derivatives (Scheme 40) [131], In the first case (Scheme 40), the very reactive 2-methylene-1,3-dicarbonyl intermediate reacts smoothly at 80°C with a variety of substituted styrenes to give the corresponding dihydropyrans in moderate to good yields. Remarkably, when styrenes were replaced by A-ethylaniline, a novel five-component reaction involving twofold excess of both formaldehyde and 1,3-dicarbonyl selectively occurred (Scheme 41). The result is the formation of complex fused pyranoquinolines following a Friedel-Craft alkylation - dehydration sequence to furnish the quinoline nucleus, which suffers the Hetero-Diels-Alder cyclization in synthetically useful yields. 

Y. Chapleur and M.-N. Euvrard, Hetero Diels-Alder reactions in carbohydrate chemistry A new strategy for multichiral arrays synthesis, J. Chem. Soc. Chem. Commun. p. 884 (1987). 

The synthetic strategies used for the preparation of pyrans on insoluble supports have mainly been hetero-Diels-Alder reactions of enones with enol ethers and ringclosing olefin metathesis (Table 15.33). Benzopyrans have been prepared by hetero-Diels-Alder reactions of polystyrene-bound o-quinodimethanes with aldehydes. The required quinodimethanes were generated by thermolysis of benzocyclobutanes, which were prepared in solution [308]. Other solid-phase procedures for the preparation of benzopyrans are the palladium-mediated reaction of support-bound 2-iodo-phenols with 1,4-dienes (Entry 5, Table 15.33) and the intramolecular Knoevenagel... 

Since the first report in 1914 of the formation of a butadiene-sulfur dioxide adduct [538], much work has been carried out on the reaction of conjugated dienes with sulfur dioxide and its applications in synthetic strategies. Two pathways can and have been observed a cheletropic reaction (to 2s + ir 4s) yielding 3-sulfolenes and (4 -ns + tt 2s) hetero-Diels-Alder addition yielding sultines (see [539] and [540] and references... 

The retrosynthesis of this compound by Batey and co-workers [96] recognized that the unprecedented hexahydropyrrolo[3,2-c]quinoline core could be synthesized using a three-component Pavarov hetero-Diels-Alder reaction [97]. For this synthetic strategy to be successful, however, reaction conditions that favor the exo approach of the dienophile over the endo approach had to be found. For this purpose, a variety of protic acids were tested, and it was found that the reaction was best carried out in the presence of camphorsulfonic acid (CSA). Indeed, a mixture of 4-aminobenzoate 200 and N-Cbz 2-pyrroline 201 were stirred at room temperature in the presence of catalytic CSA to afford exo cyclo-adduct 203 as the major product (Scheme 12.28). The N-Cbz 2-pyrroline served as both an aldehyde equivalent and a dienophile in this context. The Diels-Alder adduct 203 already bore all the requisite functionalities for the successful completion of the synthesis, which was achieved in six additional steps. 

Pandit and co-workers adopted the same strategy to catalyze a hetero-Diels-Alder reaction in which an aryl-nitroso derivative serves as the dienophile.117 118 Antibodies generated against thebicyclic transition-state analogs 133 and 134 accelerated the reaction between the trans-diene 135 and 136, but the ratio of the two product regioisomers 137 and 138 was the same as for the uncatalyzed reaction (58 42). In experiments with stoichiometric amounts of trans-135 and antibody 309-1G7, derived from hapten 134, this ratio was altered somewhat in favor of product 138 (47 53), in accord with the structure of the... 

Enantiomerically enriched hetero Diels-Alder cycloadducts have found applications in the synthesis of other pharmaceutical intermediates such as compactin and mevinolin [4, 5]. The strategy described in this work should be applicable to these and similar compounds. 

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