Highly functionalized furans, synthesis

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. 

Metal-catalyzed cyclization/conjugate addition sequences involving substituted propargyl epoxides have also been employed in the synthesis of highly functionalized furans. These reactions are generally catalyzed by... 

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. 

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... 

For fiirther reactions of this type see <95CC2025>. The synthesis of l,4-dihydrofurano[3,4-d]-3,2-oxathiine-2-oxides, precursors for nonclassical heteroaromatic o-quinodimethanes, and their application in the Diels-Alder reaction were reported <95CC2537>. The intramolecular Diels-Alder reaction with furans (e. g., 47) offers a rapid access to highly functionalized isoquinolines <95 JCS(P 1)2393>. 

The asymmetric total synthesis of the natural enantiomer (—)-nakadomarin A was completed by Nishida et al. in 2004 (Scheme 8.12) [82]. Diels-Alder reaction between siloxydiene 173 and chiral dienophile 172 (prepared from L-serine in 10 steps [83]) gave the highly functionalized key intermediate hydroisoquinoline 174, which was subjected to Luche reduction, cyclization, and HCl treatment to furnish the tricyclic intermediate 175. Compound 175 was converted to 177 via ozonolysis cleavage of ring B followed by recyclization of the unstable bisaldehyde to a five-membered ring by aldol condensation. The Z-olefin 178 was obtained from Wittig reaction of 177, and was further converted to furan 180 via peroxide 179. The... 

Mehta and Likhite used a Lewis acid-catalyzed cyclization route to construct the benzofuran ring system of frondosin B, an IL-8 antagonist, and an inhibitor of protein kinase C (PKC). Treatment of a highly functionalized chiral ketone precursor with boron trifluoride-diethyl etherate gave the corresponding furan in 95% yield over two steps. This strategy was also employed by Ovaska and Li in their synthesis of the same compound. ... 

A domino sequence comprising a cycloaddition and subsequent cycloreversion step can often find a more general application in organic synthesis, especially in the formation of aromatic compounds such as furans or pyrroles. Oxazole moieties as electron-deficient dienes often serve as the crucial reactive centers which cycloadd to a triple bond and eliminate a nitrile upon cycloreversion. If the first step is intramolecular, the impelling enthalpy preserved in the stability of the formed CN function is additionally accompanied by a positive entropy when the nitrile, sometimes volatile, leaves the substrate. In an older example from 1984 [10], Jacobi and coworkers devised a scheme for the preparation of a highly substituted furan on their synthetic way to paniculide A. An intramolecular Diels-Alder reaction was followed by the critical extrusion of volatile acetonitrile, furnishing the bicycle 8 in 94% yield (Scheme 6.2). 

The furan annelation reaction represents a new method for the preparation of this important class of compounds. Furans are widely found in nature, and highly functionalised furans are desirable targets in total synthesis work, either as products themselves, or as intermediates. Commercially available or readily accessible furans are usually limited to substitution at the more reactive 2- and 5-positions of the ring. The need for the preparation of furans with substitution at other positions on the ring, or with sensitive functional groups present, led to the development in 1987 of a palladium-catalysed method for their preparation. ... 

Functionalization of various substrates to produce oxygenated compounds with high selectivity is a permanent challenge in metal-catalyzed organic synthesis. Most of these products present interesting biological properties. For instance polyether antibiotics contain often a furan or a pyran ring [1]. Simi-... 

A flexible means of access to functionalized supports for solid-phase synthesis is based on metallated, cross-linked polystyrene, which reacts smoothly with a wide range of electrophiles. Cross-linked polystyrene can be lithiated directly by treatment with n-butyllithium and TMEDA in cyclohexane at 60-70 °C [1-3] to yield a product containing mainly meta- and para-Iithiated phenyl groups [4], Metallation of noncross-linked polystyrene with potassium ferf-amylate/3-(lithiomethyl)heptane has also been reported [5], The latter type of base can, unlike butyllithium/TMEDA [6], also lead to benzylic metallation [7]. The C-Iithiation of more acidic arenes or heteroar-enes, such as imidazoles [8], thiophenes [9], and furans [9], has also been performed on insoluble supports (Figure 4.1). These reactions proceed, like those in solution, with high regioselectivity. 

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