Highly functionalized furan derivatives

On the other hand, we also planned alternative completely new approach (Route B) to Nakadomarin A, which involves the spirolactam followed by coupling reaction with furan derivative and subsequent intramolecular electrophilic substitution reaction of an iminium cation generated from an aminal to give highly functionalized tetracyclic core system (Scheme 10.3). 

Simple allenes (209) react with dimethyldioxirane (200) to give the corresponding spiro-dioxides 210 in instances where diastereoisomeric spiro-dioxides are possible, there is usually an acceptable stereochemical preference for epoxidation to occur anti to the alkyl substituents324,325. Allenic alcohol 211 yields the highly functionalized tetrahydro-furan 212 and tetrahydropyran derivatives by intramolecular nucleophilic addition of the hydroxy group to an intermediate allene diepoxide324. 

Notably, this reaction shows a high tolerance towards a wide variety of functional groups, such as CHO, C02R, I, Br, Cl, F, OH and OMe, and also thiophene and furan derivatives, which is a rare feature in Friedel-Crafts-type chemistry. In the reaction with o-xylene, various alcohols were successfully used as benzylation agents, forming the corresponding products in high yield and selectivity (Table 6.1). 

In the above condensation resist designs, the phenolic resin offers a reaction site as well as base solubility. Self-condensation of polymeric furan derivatives has been utilized as an alternative crosslinking mechanism for aqueous base development (Fig. 126) [375]. The copolymer resist is based on poly[4-hydroxy-styrene-co-4-(3-furyl-3-hydroxypropyl)styrene], which was prepared by radical copolymerization of the acetyl-protected furan monomer with BOCST followed by base hydrolysis. The furan methanol residue, highly reactive toward electrophiles due to a mesomeric electron release from oxygen that facilitates the attack on the ring carbons, readily yields a stable carbocation upon acid treatment. Thus, the pendant furfuryl groups serve as both the latent electrophile and the nucleophile. Model reactions indicated that the furfuryl carbocation reacts more preferentially with the furan nucleus than the phenolic functionality. 

The Feist-Benary and Paal-Knorr syntheses are commonly employed in the preparation of furan ring systems. In special cases where furan derivatives are difficult to prepare by other methods, Diels-Alder and retro-Diels-Alder reactions have become important methods for their synthesis. Finally, transition metal-catalyzed cyclization and cycloisomerization reactions have recently gained significant attention for their utility in the synthesis of highly functionalized furans. Key examples of these syntheses are highlighted in the sections below. 

Lewis acids have also been used to synthesize highly functionalized furan derivatives with biological signalling capabilities. For example, Sello and co-workers used scandium(III) triflate in their biomimetic synthesis of several signalling molecules of the bacterium Streptomyces. Reaction of methyl 5-methyl-3-oxohexanoate and 2,2-dimethyl-l,3-dioxan-5-one in the presence of scandium (III) triflate in methanol gave the corresponding furan in 60% yield. 

Some interesting multicomponent syntheses of simple furan derivatives in water have been disclosed. For instance, Yadav reported the preparation of highly functionalized 2-aminofuran derivatives 26 in water via the coupling of aldehydes with dimethyl acetylenedicaiboxylate and cyclohexyl isocyanide [20]. This transformation presumably starts by the initial Michael addition of the isocyanide onto the acetylenedicaiboxylate diester, generating the 1,3-dipole 27, whose subsequent [3+2] cycloaddition to the aldehyde carbonyl followed by tautomerization leads to the observed product (Scheme 1.14). 

A catalyst-free 4 + 3-cycloaddition of in tM-generated azoalkenes (134) with C,(V-cyclicazomethine imines (135) yielded highly functionalized 1,2,4,5-tetrazepine derivatives (136) in high yields (76-92%) under mild conditions (Scheme 40). " The Lewis-acid-promoted 4 + 3-cycloaddition reaction between the allylic cation of a heterocyclic alcohol with a furan or thiophene produced seven-membered ring-fused 5,7,6-tricyclic adducts with high regio- and stereo-selectivity. For the first time, the 2jt components are benzofuran-3-yl alcohols, benzothiophene-3-yl alcohols, and indole-3-yl alcohols. ... 

In the same area, a (5)-tryptophan-derived oxazaborolidine including a p-tolylsulfonylamide function has been used by Corey et al. to catalyse the enantioselective Diels-Alder reaction between 2-bromoacrolein and cyclo-pentadiene to form the corresponding chiral product with an unprecedented high (> 99% ee) enantioselectivity (Scheme 5.27)." This highly efficient methodology was extended to various 2-substituted acroleins and dienes such as isoprene and furan. In addition, it was applied to develop a highly efficient total synthesis of the potent antiulcer substance, cassiol, as depicted in Scheme 5.21... 

When furan was substituted at C-2 by a pyridine function [e.g., 4 -(2, 6 -dimethyl)pyridyl] high yields (>90%) of the 5-bromo derivatives were... 

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