Scheme 16.7. Enantioselective cycloaddition via optically pure furan as diene.

A synthetically interesting methodology is the Diels-Alder/retro-Diels-Alder reaction as a safety-catch procedure. A resin-bound diene temporarily catches a di-enophile by Diels-Alder reaction, this is then modified further on solid support

[12]. Finally, a retro-Diels-Alder reaction releases the transformed dienophiles from the resin by regeneration of the resin-bound diene. Obviously, a major advantage of this method lies in the high chemical and stereochemical purity of the released compounds. Scheme 16.8 displays this procedure with a resin-bound furan in a cycloaddition reaction to an electron-deficient alkyne. The resulting resin-bound bicyclic Michael system undergoes stereoselective addition of thio-phenol, while the desired olefinic product is released from the support by a retro-Diels-Alder reaction. It is noteworthy that the Michael addition carried out in solution shows an E/Z ratio of 81:19.

Scheme 16.8. Solid-phase Diels-Alder/retro-Diels-Alder as a safety-catch procedure. 16.2.2

Diels-Alder Reaction with Resin-bound Dienophiles

Scheme 16.8. Solid-phase Diels-Alder/retro-Diels-Alder as a safety-catch procedure. 16.2.2

Diels-Alder Reaction with Resin-bound Dienophiles

In contrast to the polymer-supported dienes, examples with resin-bound dieno-philes are not so well represented. This may be due to the fact that more dieno-philes than dienes are commercially available. Therefore, in solid-phase Diels-Alder reactions dienophiles are usually used as excess reagents. Nevertheless, few reports with resin-bound dienophiles are published.

One of the first Diels-Alder cycloadditions applied to solid-phase combinatorial chemistry is the reaction between polymer-supported acrylates and butadiene derivatives (Scheme 16.9) [13]. Acrylic acids are first attached to a polystyrene resin via esterification, and the subsequent cycloaddition reactions take place in hot toluene or xylene. After cleavage off the resin with tetrabutylammonium hydroxide and esterification with diazomethane, mixtures of cis/trans isomers are obtained

3) CH2N2 ortho adduct meta adduct major minor

Scheme 16.9. Diels-Alder reaction with resin-bound acrylates.

with high regioselectivities. The observed ortho/meta ratio is in accordance with the results obtained in solution phase. It is well documented that 1-substituted-1,3-butadienes react with 1-substituted alkenes containing an electron-withdrawing group, forming predominantly the ortho adduct.

Polymer-supported dehydroalanine derivatives are used as dienophiles in Diels-Alder reactions (Scheme 16.10) [14]. The dehydroalanines are generated by coupling of N- and S-protected cysteines to the resin, oxidation of the sulfides to the sulfones, and elimination to the desired olefins. After cycloaddition with cyclopentadiene at 80 °C and cleavage with 20% trifluoroacetic acid in dichloro-methane, mixtures of endo/exo isomers (1:2 to 1:4, 51-81% yield) are detected (determined by 1H-NMR). The selectivities are similar to those reported in solution phase.

Scheme 16.10. Diels-Alder reaction with resin-bound dehydroalanine derivatives.

The stereoselectivity of Diels-Alder reactions can be increased by use of chiral auxiliaries, as shown with Evans oxazolidinone. In order to introduce the stereochemical information, enantiomerically pure Boc-L-tyrosine methylester is coupled to hydroxymethyl Merrifield resin using Mitsunobu methodology (Scheme 16.11) [15]. Reduction of the ester and treatment with thionylchloride gives the chiral oxazolidinone, which is then acylated with trans-crotonic anhydride, triethylamine, and dimethylaminopyridine, thus forming the desired resin-bound dienophile. The subsequent cycloaddition with cyclopentadiene is catalyzed by diethylaluminum chloride as Lewis acid and the cycloadduct is cleaved from the resin by lithium benzyloxide. The endo/exo ratio of 21:1 (86% ee) compares nicely with the results obtained in solution phase.

Scheme 16.10. Diels-Alder reaction with resin-bound dehydroalanine derivatives.


Scheme 16.11. Optically pure oxazolidinones as chiral auxiliaries in cycloaddition.


Scheme 16.11. Optically pure oxazolidinones as chiral auxiliaries in cycloaddition.

Besides Lewis acids, the application of high pressure also facilitates the cycloaddition reaction. Especially highly substituted and unreactive starting materials, which show no reaction under normal conditions, can be forced to react. In a microwave-assisted Knoevenagel reaction between resin-bound nitroalkenes and aldehydes, E/Z mixtures of trisubstituted dienophiles are generated (Scheme 16.12) [16]. Treatment with 2,3-dimethylbutadiene under high pressure conditions (15 kbar, 25 °C) yields the cycloadducts, whereas stereoselective reduction with lithium aluminumhydride gives the cyclic amines via a traceless linker strategy. The stereoselective formation of one diastereomer from a diastereomeric mixture of two cycloadducts (from a E/Z mixture of nitroalkenes) is rationalized by an aci-nitro intermediate.

Scheme 16.12. Diels-Alder reaction under high-pressure conditions.

During the synthesis of oligomers via tandem Diels-Alder reactions, solid-phase methodology is superior to solution-phase chemistry (Scheme 16.13) [17], whereas under homogeneous reaction conditions, the reaction of an acrylate and a bisdiene would lead to mixtures of oligomers and polymers. Oligomerization can be pre-

Scheme 16.12. Diels-Alder reaction under high-pressure conditions.

Scheme 16.13. Oligomerization via iterative Diels-Alder reaction on solid support.

cisely controlled on solid support. Starting with a resin-bound acrylate derivative, the Diels-Alder reaction with an excess of bisdiene gives only one cycloadduct. The second cycloaddition is performed with the bisdienophile divinyl ketone in the presence of 15 equiv. of ZnCl2 and the final cycloaddition is achieved by capping the resin-bound dienophile with butadiene. Treatment with Triton B® and iodo-methane then reveals the tricyclic ester. All cycloadditions reported proceed in a regioselective way and, after aromatization with palladium/carbon in boiling di-chlorobenzene, the desired acetophenones are obtained.

Intramolecular Diels-Alder Reaction on Solid Support

In cycloaddition chemistry the intramolecular strategy is an elegant method of reaction management. By tethering both components it is possible to bring the reactive centers spatially together, so that the reaction proceeds under milder conditions and the turnovers are also improved.

The intramolecular Diels-Alder reaction (IMDA) with furan as the diene partner has been widely used to prepare rigid oxygenated tricyclic compounds. A resin-bound furan can easily be prepared through reductive alkylation of resin-bound glycine and a set of furaldehydes (Scheme 16.14) [18]. Introduction of an activated dienophile is then realized by acylation with different acrylic acids and cleavage with trifluoroacetic acid provides the tricyclic lactams in high yields and purities (> 90%). Owing to the pericyclic and intramolecular reaction pathway just the exo isomers are obtained. In order to overcome the limitation of the commercial availability of activated dienophiles, maleic anhydride is used, which can be hydrolyzed and further reacted with amines.

Scheme 16.14. Intramolecular Diels-Alder reaction with furan derivatives. TMOF, trimethylorthoformate. (PFPTFA, trifluoroacetic acid pentafluorophenylester).

In order to increase the stereoselectivity, novel unsaturated amino acids are used as dienophiles (Scheme 16.15) [19]. Phosphonoacetyl Wang resin [20] is hence treated with an optically pure fluorenylmethoxycarbonyl (Fmoc)-protected amino acid aldehyde, forming the electron-deficient dienophile with the intention of in-

Scheme 16.14. Intramolecular Diels-Alder reaction with furan derivatives. TMOF, trimethylorthoformate. (PFPTFA, trifluoroacetic acid pentafluorophenylester).

R1 2) 20% piperidine

m NaBH(OAc)3

Scheme 16.15. Enantioselective cycloaddition with unsaturated amino acid derivatives.

troducing the required stereochemical information into the cycloaddition process. Deprotection of the amine allows the introduction of the diene component using different methods. The first example shows the acylation with 2,4-hexadionic acid using isobutyl chloroformate as an activator. The following reductive alkylation with benzaldehyde gives the benzylated precursor for the intramolecular Diels-Alder reaction, which is complete within 30 h at room temperature. Cleavage from the resin provides a major diastereomer (> 90%) derived from the endo transition state, which is influenced by the 1,3-allylic interaction of the dienophile and steric effect of the substituent R1.

An alternative transformation of the primary unsaturated amines is to connect them directly to a diene by reductive alkylation with 2,4-hexadienal [19] (Scheme 16.16). Coupling to the resin-bound amine is realized by reductive alkylation of the aldehyde or by acylation of the corresponding furanacrylic acids. Again, during the cycloaddition only one stereoisomer is formed but after prolonged reaction times of up to 2 days. The side-chain double bond of the vinylfuran acts as a part of the diene participating in the Diels-Alder reaction and the aromaticity of the furan ring is restored through final rearrangement.

Scheme 16.16. Formation of tricyclic products by intramolecular cycloaddition.

450 | 16 Cycloadditions in Combinatorial and Solid-phase Synthesis 16.2.4

Hetero-Diels-Alder Reaction on Solid Support

The hetero-Diels-Alder reaction is a well-established method for the synthesis of six-member heterocycles. An efficient way to access dihydropyrans lies in the reaction of a,b-unsaturated ketones with enols. Starting with resin-bound acetoacetate, the unsaturated ketones are formed by Knoevenagel reactions with different aliphatic aldehydes (Scheme 16.17) [21]. Treatment with a variety of enol ethers at 60 °C for 3 days sets up a hetero-Diels-Alder reaction with inverse electron demand. Final cleavage with sodium methanolate provides the cycloadducts with excellent purities of 90%. However, the diastereoselectivities are not very satisfying, displaying a ratio of 1:1 to 5:1 for the endo and exo products.

endo/exo mixture

Scheme 16.17. Formation of dihydropyrans by hetero-Diels-Alder reaction.

Diastereoselectivity can be increased by the use of chiral Lewis acids. Scheme 16.18 shows another cycloaddition to dihydropyrans with inverse electron demand. The synthesis commences with resin-bound benzylidenepyruvic acid [22] and the hetero-Diels-Alder reactions with electron-rich enol ethers are catalyzed by Eu(fod)3. Cleavage off the resin is achieved by reduction with lithium alumi-numhydride and the corresponding alcohols are formed in high yields with an endo/exo selectivity of up to >97:3. The results are similar to those obtained under homogeneous liquid-phase conditions.

R2 Eu(fod)3

2) LiAIH4

endo ex0

Scheme 16.18. Chiral Lewis acids as catalyst in a hetero-Diels-Alder reaction.

The aza-Diels-Alder reaction allows one of the most convenient and versatile approaches to nitrogen-containing six-member heterocycles. In a typical reaction imines act as dienophiles and react with dienes to the precious cycloadducts. In most cases the imines can be prepared in situ from amines and aldehydes, and even simply mixing all three components (amine, aldehyde, and olefin) together gives good results using Lewis acids for catalysis. A very short synthesis is the one-pot reaction between amino-methylated polystyrene resin, aldehydes, and diene catalyzed by ytterbium triflate (Scheme 16.19) [23]. The cycloaddition proceeds smoothly at room temperature over 12-48 h and yields and purities are >90%. The cycloadducts are released from the resin utilizing a tertiary amine N-dealkyla-tion method which involves chloroethyl chloroformate treatment and methanolic decomposition of the resulting carbamates [24]. Only the desired [4 + 2] products are released from the solid support, enabling a clean resin cleavage.

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