Oxa-hetero-Diels-Alder reaction

For a long period, chiral Lewis adds were the most studied catalysts. Only recently have chiral bases, Br0nsted acids, and N-heterocycUc carbenes been utilized as effective organocatalysts for the oxa-hetero-Diels-Alder reaction. 

Through the double hydrogen bonding catalysis, the desired cycloadducts 120 were obtained in moderate to good yields with up to 87% ee (Scheme 38.33). Moreover, in recent years, a few hydrogen-bonding catalysts have also been developed for the oxa-hetero-Diels-Alder reaction [54]. 

Tietze L. E., Kettschau G., Gewert J. A., Schuffenhauer A. Hetero-Diels-Alder Reactions of l-Oxa-l,3-Bntadienes Curr. Org. Chem. 1998 2 19 62... 

So far, only those domino Knoevenagel/hetero-Diels-Alder reactions have been discussed where the cycloaddition takes place at an intramolecular mode however, the reaction can also be performed as a three-component transformation by applying an intermolecular Diels-Alder reaction. In this process again as the first step a Knoevenagel reaction of an aldehyde or a ketone with a 1,3-dicarbonyl compound occurs. However, the second step is now an intermolecular hetero-Diels-Alder reaction of the formed 1 -oxa-1,3 -butadiene with a dienophile in the reaction mixture. The scope of this type of reaction, and especially the possibility of obtaining highly diversified molecules, is even higher than in the case of the two-component transformation. The stereoselectivity of the cycloaddition step is found to be less pronounced, however. 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cy-doaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the 1-oxa-l,3-butadiene moiety in 2-816. The formed spirocydic ketones 2-818/2-819 can be used in natural products synthesis and in medidnal chemistry [410]. They have also been used in the preparation of exotic amino adds these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

Today, multi-parallel synthesis lies at the forefront of organic and medicinal chemistry, and plays a major role in lead discovery and lead optimization programs in the pharmaceutical industry. The first solid-phase domino reactions were developed by Tietze and coworkers [6] using a domino Knoevenagel/hetero-Diels-Alder and a domino Knoevenagel/ene protocol. Reaction of solid-phase bound 1,3-dicarbonyl compounds such as 10-22 with aldehydes and enol ethers in the presence of piperidinium acetate led to the 1-oxa-1,3-butadiene 10-23, which underwent an intermolecular hetero-Diels-Alder reaction with the enol ethers to give the resin-bound products 10-24. Solvolysis with NaOMe afforded the desired dihydro-pyranes, 10-25 with over 90 % purity. Ene reactions have also been performed in a similar manner [7]. 

An example for the combination of mechanistically different reactions is the anionic-pericydic process such as the domino-Knoevenagd-hetero-Diels-Alder reaction. In the inter-intramolecular version of this process an aldehyde 1 containing a dienophile moiety and a 1,3-dicarbonyl compound 2 can be mixed together to give unusual heterocycles of diversified structures such as 4 via the intermediate formation of an 1-oxa-l,3-butadiene 3 (scheme 1).[41... 

In this process the primary step is the formation of an anion, which is a synonym for a nucleophile, mostly by deprotonation using a base. It follows a reaction with an electrophile to give a new anion which in the anionic-anionic process again reacts with an electrophile The reaction is then completed either by addition of another electrophile as a proton or by elimination of an X group. Besides the anionic-anionic process there are several examples of anionic-pericydic domino reactions as the domino-Knoevenagel-hetero-Diels-Alder reaction in which after the first step an 1-oxa-l,3-butadiene is formed. 

Inverse type hetero-Diels-Alder reactions between p-acyloxy-a-phenylthio substituted a, p-unsaturated cabonyl compounds as 1-oxa-1,3-dienes, enol ethers, a-alkoxy acrylates, and styrenes, respectively, as hetero-dienophiles result in an efficient one step synthesis of highly functionalized 3,4-dihydro-2H-pyrans (hex-4-enopyranosides). These compounds are diastereospecifically transformed into deoxy and amino-deoxy sugars such as the antibiotic ramulosin, in pyridines having a variety of electron donating substituents, in the important 3-deoxy-2-gly-culosonates, in precursors for macrolide synthesis, and in C.-aryl-glucopyranosides. 

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

An attractive entry to the carbohydrate synthesis is provided by the cycloaddition reaction. Hetero-Diels-Alder reaction, either between an oxa-diene (a,[3-unsaturated aldehyde) and an nucleophilic dienophile, or between activated diene and carbonyl compound (usually an aldehyde), leads to dihydropyrans, which can be subsequently functionalized to sugars in the desired manner (Scheme 3). 

Hetero-Diels-Alder reaction with inverted electron demand between a, 3-unsatu-rated carbonyl compounds (1-oxa-l,3-butadienes 11 Scheme 6) and enol ethers provides an access to 6-alkoxy-3,4-dihydro-2/f-pyrans 12 [31,32]. These heterocycles are also useful... 

A similar chiral bis(oxazoline)/Cu(II) catalyst is useful for the asymmetric hetero Diels-Alder reaction of Danishefsky s diene and glyoxylates [63] (Eq. 8A.39). Other bis(oxa-zoline)/M(OTf)2 (M = Sn, Mg) complexes are not effective. This method provides new routes to asymmetric aldol synthesis upon hydrolysis of the resulting adducts. 

Solid-phase three-component domino-Knoevenagel-hetero-Diels-Alder reaction can also be performed using a resin-linked 1,3-dicarbonyl compound such as 100 with aldehydes and an enol ether to give dihydropyrans 102 via the intermediately formed 1-oxa-l,3-butadiene 101 (Scheme 5.18) [30], The resin can be deaved off after the reaction by solvolysis, for instance using sodium methanolate to give the corresponding methyl ester 103 as a mixture of diastereomers. The overall yield varies from 12 to 37% and the selectivity from 1 1 to 1 5 in favor of the tis-product depending on the applied aldehyde. The crude dihydropyrans thus obtained are reasonably pure (> 90% HPLC). 

Scheme 1-2. Transition structures for the intermolecular hetero Diels-Alder reaction of 1 -oxa-1,3-butadienes...

One of the first calculations on hetero Diels-Alder reactions was done in our group in collaboration with Anders on the 1-oxa-1,3-butadiene (acrolein)/ethene system [41, 42]. The performed ab initio und semiempirical calculations show... 

In addition to the purely mechanistical studies calculations on the stereochemistry of more complex molecules have been performed the data obtained nicely matched the experimental results [54]. Finally, several experiments have been performed to prove the concertedness of the hetero Diels-Alder reactions of 1-oxa-l,3-butadienes [55] and show that the transition structure is un-symmetrical [56]. 

The thermal reactions of l-oxa-l,3-butadienes such as acroleine 2-78 with alkenes such as 2-79 usually need relatively harsh conditions (150°C-250°C) [120]. As a side reaction polymerisation of the a,/l-unsaturated carbonyl compound can take place addition of radical inhibitors such as hydroquinone or 2,6-di-ferf-butyl-4-methylphenol can be helpful in avoiding this unwanted transformation. In the described hetero Diels-Alder reaction the cycloadduct 2-80 was obtained which was then transformed into racemic-/3-santalene 2-81 (Fig. 2-22). 

Also ynamines can be used in the hetero Diels-Alder reaction of 1-oxa-1,3-butadiene. Novel examples are described by Dell et al. [138] using e.g. the 2-ben-zylidene-indane-l,3-dione 2-117 and 2-118 to give 2-119 (Fig. 2-32). However, the yields are only modest. 

Novel complex heterocycles such as 2-148 can easily be obtained using the hetero Diels-Alder reaction of enol ethers like 2-147 and 2-146 as l-oxa-1,3-butadiene (Fig. 2-40) [149]. 

A high asymmetric induction in intramolecular hetero Diels-Alder reactions was found using chiral 1-oxa-1,3-butadienes with a stereogenic center in the tether [54]. Such compounds can easily be obtained by a Knoevenagel condensation of a 1,3-dicarbonyl compound such as iV,N-dimethylbarbituric acid with a chiral aldehyde bearing a dienophile moiety [169 a] (Scheme 2-3). With the stereogenic center in a-position relative to the oxadiene or dienophile moiety an excellent induced diastereoselectivity is obtained for the nearly exclusively formed trans-cycloadduct (simple diastereoselectivity = 97.9 2.1 and 98.3 1.7,... 

An interesting approach to directly linked C-disaccharides 2-191 was developed by Dondoni et al. [171] via a hetero Diels-Alder reaction of sugar derived 1-oxa-1,3-butadienes as 2-190 bearing a thiazole moiety at position 2 as activating group (Fig. 2-54). 

The enantioselective hetero Diels-Alder reaction of 1-oxa-1,3-butadienes using chiral non-racemic Lewis acids is a widely unexplored field. The first successful example was the intramolecular cycloaddition of the heterodiene 2-194,... 

---