Furofurane synthesis

A convenient approach to the synthesis of fused furofuran derivatives is provided by the tetrabutylammonium peroxydisulfate-mediated oxidative cycloaddition of 1,3-dicarbonyl compounds to cyclic enol ethers. In the presence of a base such as potassium acetate in acetonitrile, several fused acetal derivatives of type 39 have been prepared in 82-90% yield (Equation 62) <200081091 >. 

An interesting application of the asymmetric alkoxyselenenylation of alkenes to natural product synthesis was reported recently by Wirth, who described a short procedure to obtain some furofuran lignans 147]. The total synthesis of (+)-Samin 53 [47 a] is shown in Scheme 7. The protected allylic alcohol 50 was treated with the selenyl triflate derived from diselenide 29 in the presence of 2,3-butadien-l-ol, and afforded the addition product 51 in 55% yield and with a diastereomeric ratio of 15 1. The favored 5-exo-trig radical cyclization of the major isomer afforded the tetrahydrofuran derivative 52 from which the final product was obtained through few classical steps. 

Swain, N. A, Brown, R. C. D., Bruton, G. A Versatile Stereoselective Synthesis of endo,exo-Furofuranones Application to the Enantioselective Synthesis of Furofuran Lignans. J. Org. Chem. 2004, 69,122-129. 

This methodology furnished also an efficient access into the furofuran skeleton, Scheme (19). A tandem Michael addition-aldol reaction was used to provide lactone 107 in 62% yield as a mixture of diastereomers in a ratio of 60 40. Dithiane 107 was converted into ketone 108 using HgO in combination with BF3 Et20. Subsequent reduction using an excess of LiAlH4 afforded tetraol 109 in 67% yield. The synthesis of (-)-eudesmin (110) was completed in 16% overall yield by dehydratation of 109 with BF3 Et20. 

All of the routes described so far can be readily adapted to provide asymmetric syntheses of lignans. Thus, Koga et al. have synthesised (+)-yatein (36) and (+)-/rfl/j5-burseran (37) by conjugate addition to a chiral butenolide (35) (scheme 8) [54,55]. The more readily available menthyloxybutenolide (38) has been utilised by other groups [56,57]. The products (39) and (40) after desulfurisation, serve as precursors for the synthesis of dibenzocyclooctadienes, furofurans and aryltetralins (scheme... 

Another simple synthesis of lignans of the lariciresinol type (11) involves a straightforward reduction of a functionalised dibenzylbutyrolactone such as (75) or (76) followed by acid-catalysed cyclisation (scheme 24) [77,78]. Cyclisation of the doubly functionalised precursor (77) affords access to the furofuran skeleton (78) (scheme 25). A second synthesis which has also been extended to the furofuran series involves a radical cyclisation step, which proceeds with high stereoselectivity (scheme 26) [79]. This route has been used to synthesise (79) which is a precursor for the synthesis of sesamin and eudesmin [80]. 

As already demonstrated tra 5-dibenzylbutyrolactones are valuable as precursors for the synthesis of a wide range of lignans. For example, the keto-lactones (90) and (91), which have both been prepared by tandem conjugate addition reactions, provide key intermediates for the synthesis and asymmetric synthesis respectively of lignans of the furofuran type (scheme 30) [85,86]. 

Related to this topic, our group has also developed an interesting cascade process for the enantioselective synthesis of furofuranes in a single step by the 31a-catalyzed reaction between dihydroxyacetone dimer and a,p-unsaturated... 

Scheme 7.54 Enantioselective synthesis of furofuranes by cascade oxa-Michael/aldol/ hemiacetalization reaction.

Upon treatment of a triol with HCl in a mixture of EtOH and CH2CI2, biomimetic cyclization occurred efficiently through the quinomethide intermediate to afford exo-exo furofuran as a single diastereomer in 72% yield. This process was applied in the synthesis of (+)-hedyotol A (140L1976). 

Radical addition to carbon-carbon unsaturated bonds has also been carried out in microflow reactors. Tributyltin hydride-mediated radical reactions of organic halides have been successfully carried out in a continuous microflow system [20]. Rapidly decomposing radical initiators such as V-65 and V-70 are fairly effective and the reactions proceed within a very short period of time. The continuous flow reaction system can be applied to gram-scale synthesis (7.6 g, 185 min) of a key intermediate for furofuran lignans (Figure 5.2). 

A highly efficient bicyclization reaction for the construction of 3a, 6a-dihydrofuro[2,3-b]furan derivatives was developed for the synthesis of fused furofuran compounds from methyl ketones (130L456). 

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