2,3,4-Trisubstituted tetrahydrofuran synthesis

In the synthesis of 2,2,5-trisubstituted tetrahydrofurans, a novel class of orally active azole antifungal compounds, Saksena95 reported that the key step of Diels-Alder reaction in water led to the desired substrate virtually in quantitative yields (Eq. 12.34), while the same reaction in organic solvent resulted in a complicated mixture with only less than 10% of the desired product being isolated. This success made the target compounds readily accessible. 

Corey s asymmetric allylation methodology was utilized in the total synthesis of amphidinolide T3 (95), a marine natural product that exhibits significant antitumor properties37 (Scheme 3.1gg). The asymmetric allylation of the aldehyde 96 was carried out successfully with chiral allylborane reagent generated in situ from allyltributylstannane and (R,R)-82 to furnish the homoallylic alcohol desired (97) in 85% yield with excellent diastereoselectivity. Subsequent conversion of the alcohol to the tosylate ester followed by treatment with potassium hydroxide resulted in formation of the trisubstituted tetrahydrofuran 98. 

A double iodoetherification of C2-symmetric acetals has been used for the desymmetrization of 1,6-dienes in an asymmetric total synthesis of rubrenolide (Equation 78) <2005AGE734>. Remarkably, four stereogenic centers have been installed in one reaction step. Stereoelectronic effects in the diastereoselective synthesis of 2,3,5-trisubstituted tetrahydrofurans via iodoetherification have been studied in detail, and I(2,4,6-collidine)2C104 proved to be an efficient reagent for highly stereoselective iodoetherifications <20010L429>. 

A one-pot synthesis of 2,3>S-trisubstituted tetrahydrofurans by a double Hosomi-Sakurai reaction has been described. The product was obtained without the contamination of any regio- or stereoisomers. This remarkable selectivity has been explained by the difference in reactivity between the allylic starting material and the allylic silane formed in situ and between that of the two aldehydes employed (Scheme 80) <2004AGE1417>. 

A one-pot synthesis of 2,3,5-trisubstituted tetrahydrofurans by a double Sakurai-Hosomi reaction was reported and an example is shown below <04AG(E)1417>. Another procedure featuring the pivotal use of an 0-alkylation route is also known <04T115>. 

Nishiyama Y, Katoh T, Deguchi K, Morimoto Y, Itoh KJ (1997) Stereoselective synthesis of 2,2,5-trisubstituted tetrahydrofurans via the Lewis acid assisted reaction of cyclic hemiketals with nucleophiles. J Org Chem 62 9339-9341... 

Knight et al. have employed a ring contraction via the Ireland-Claisen rearrangement of an aryl lactone to generate a 2,3,4-trisubstituted tetrahydrofuran intermediate in the synthesis of ( )-samin (Scheme 4.143) [138], The rearrangement proceeded via a boat transition state of the cyclic -silyl ketene acetal. 

The utility of this approach to five-membered heterocycles is illustrated by the synthesis of 2,3,5-trisubstituted tetrahydrofuran 8, which is a building block for synthesis of natural tetronomycin (Scheme 15.5). High stereoselectivity of cyclization of substrate 7 is controlled by removable substituent in the a-allylic position. ... 

Cassidy JH, Marsden SP, Stemp G. Stereoselective synthesis of 2,3,5-trisubstituted tetrahydrofurans by an allyl silane metathesis-nucleophilic addition sequence. Synlett 1997 1411-1413. 

More recently, Castillon et al. employed Zhang and Mootoo s precedence for the synthesis of 2,4,5-trisubstituted tetrahydrofurans 49 (Scheme 37.13)." Both Castillon and Zhang and Mootoo reported that the cycliza-tion becomes stereorandom when the unprotected vicinal diol is used instead of the acetonide. 

Cerium(IV) ammonium nitrate in aqueous acetonitrile will also cleave a p-methoxyp/zeny/ ether (presumably to benzoquinone).335 The reaction was used in a synthesis of Stigmastellin A [Scheme 4.183] to release a primary alcohol in the presence of a benzyl ether.339 In an extension of the method, a bidirectional strategy for the synthesis of 2,3 5-trisubstitute d tetrahydrofuran components of annonaceous acetogenins benefited from the simultaneous protection of two primary hydroxyls as their Cj-symmetric hydroquinone ether [Scheme 4.184].340... 

Selective epoxidation of polyene compound has also achieved with ent 2, the enantiomer of ketone 2. In Morimoto s total synthesis of polyether (+)-aurilol, Shi epoxidation was utilized twice, with ketone 2 and ent-2, respectively." Epoxidation of 79 with ketone 2 gave epoxide 80 with high diastereoselectivity. Epoxide 80 underwent acid catalyzed 5-exo-tet cyclization to produce tetrahydrofuran 81 with the desired stereochemistry. Subsequently, diene 82 was selectively epoxidized with ent-2 only at the trisubstituted olefin to give epoxide 83. Epoxides 80 and 83 played important roles in setting stereocenters in the final product. 

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