2,3,4-Trisubstituted tetrahydrofuran

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. 

Aqueous Diels-Alder reaction has also been applied at the industrial level. 2,2,5-Trisubstituted tetrahydrofurans 21 are a class of active azole antifungals. Workers at Schering-Plough [21] developed a synthetic approach based on a Diels-Alder reaction between 2-arylfurans 22 and ethyl acetylenedicarboxylate (Scheme 6.9). Under thermal conditions the reaction gave a low yield of... 

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. 

Lewis acid mediated [1,3] rearrangement of the 1,3-dioxepines 109 gave the trisubstituted tetrahydrofurans 110 in high yields and with generally high diastereoselectivities. The Lewis acids used included TiCf(7-PrO)2 and TBSOTf <06CC3119>. 

Regioselective ring-opening and cross-coupling metathesis of 2-substituted 7-oxanorbor-nenes (for a review of 7-oxanotbomanes and related compounds see <99T13521>) offers a new stereoselective entry into trisubstituted tetrahydrofurans <99JOC9739>. 

Ether was a better solvent in cases where the propargylic position was unsubstituted (methylene group) since, in THF, a competitive [1,2] -Wittig rearrangement took place and led to diminished yields. When applied to the secondary homoallylic propargyl ethers 388, the zinc-ene-allene cyclization afforded the c -2,3,5-trisubstituted tetrahydrofurans 389 with moderate to satisfactory levels of diastereoselectivity, which could be rationalized by the preferential pseudo-equatorial positioning of the homoallylic substituent in the cyclic... 

Rhodium-catalyzed tandem hydroformylation-acetalization of a,co-alkenediols is a facile entry to perhydrofuro[2,3-6]furans. A benzoannulated tetrahydrofuro[2,3-fc]furan was obtained in this manner <02OL289>. A mixture of trisubstituted tetrahydrofurans was obtained from a n-allylmolybdenum complex and this is depicted in the following scheme <020L2001>. 

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>. 

Preparation of 2,3-m-2,5-trarts-trisubstituted tetrahydrofuranes by this methodology is possible, but presents some problems. Cyclization is not stereospecific or results only in tetrahydropyranes because of unfavorable 1,3-interactions. Moreover, ring contraction can result in the undesired 2,5-cw-diastereomer, even as the major product. 

This method also constitutes a useful approach to m-2,2,5-trisubstituted tetrahydrofurans. In fact, starting from ( )-7-acetoxy-6-benzyloxy-3,7-dimethyl-2-octene (9), the corresponding ether 10 is obtained in 70% yield and 93 7 (cis/trans) diastereomeric ratio. In comparison with the formation of disubstituted tetrahydrofurans, the initial cyclization step reverses more rapidly and even a benzyl group allows a sufficient equilibration between the isomeric oxonium ions, before it is lost9. 

Trisubstituted tetrahydrofurans can be obtained with total stereoselection starting from either anti-(E)- or sjn-(Z)-2-substituted 3-alkenols133,13[Pg.281]

Trisubstituted tetrahydrofurans can also be prepared with total stereoselection by cyclization of 3-alkenols performed with Ar-(phenylseleno)phthalimide (N-PSP) in dichloromethane135. 

Trisubstituted tetrahydrofurans can be synthesized by the intramolecular 5-endo-tr g attack of alkoxides on vinylic sulfones. Starting from 3-benzenesulfonyl homoallylic alcohols, the cycliza-tion is carried out at 25 °C in tetrahydrofuran, using potassium tert-butoxide as the base143 145. 

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>. 

Muscarine 5, one of the active ingredients in the toadstool fly agaric Amanita muscaria), contains a 2,3,5-trisubstituted tetrahydrofuran structure. A number of stereocontrolled syntheses have been worked out for muscarine. One of these starts with methyl vinyl ketone [16] and cyclizes stereoselec-tively the appropriately substituted <5-unsaturated 2,6-dichlorobenzyl ether 3 with iodine ... 

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... 

Saksena, A.K. Girijavallabhan, V.M. Chen, Y.-T. Jao, E. Pike, R.E. Desai, J.A. Rane, D. Ganguly, A.K., Aqueous Diels-Alder reactions of electron deficient 2-arylfurans a highly stereoselective route to 2,2,5-trisubstituted tetrahydrofurans towards a novel class of orally active azole antifungals, Heterocycles, 1993,35,129-34. 

Yang, G., Shen, Y., Li, K., Sun, Y., Hua, Y. (2011). AlClj-promoted highly regio- and diastereoselective [3-1-2] cy do additions of activated cyclopropanes and aromatic aldehydes Construction of 2,5-diaryl-3,3,4-trisubstituted tetrahydrofurans. Journal of Organic Chemistry, 2011, 76, 229-233. 

The (la)-promoted reaction of homopropargyl alcohols (31) with aldehydes affords 2,3,5-trisubstituted tetrahydrofurans (32) and (33) via intramolecular addition... 

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. 

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