2.3- Disubstituted tetrahydrofuran

The allyloxy and propargyloxy compounds are easily prepared by the opening of mono-substituted epoxides with sodium aryl tellurolates, followed by allylation and propargyla-tion of the obtained -hydroxytellurides, submitted to irradiation with a sun lamp in the presence of hexabutylditin, and suffer group-transfer cyclization under 5-exo-mode to give the 2,4-disubstituted tetrahydrofuran derivatives. ... 

A chemoselective addition of allylic alcohols (82) to 3-halogenovinyl sulfones (81) has been accomplished using KF-basic alumina as the basic medium.55 The resulting adducts (83) can be stereoselectively cyclized by a radical process, affording 2,4-disubstituted tetrahydrofurans (84) (Scheme 22, Eq. 1). The same group has recently reported an analogous protocol using allylic amines (85) for the synthesis of 2,4-disubstituted pyrrolidines (87) (Scheme 22, Eq. 2)56... 

From epoxides. A very efficient access to tetrahydrofuran derivatives has been developed based on ring opening of oxiranes with selenolates. For instance, preparation of 2,4-disubstituted tetrahydrofurans from epoxides is shown in Eq. (3) [ 11 ]. Opening of the epoxide 19 with diphenyldiselenide/NaBH4 followed by prenylation gives the radical precursor 20 in excellent yield. Cyclization furnishes the tetrahydrofuran 21 in almost quantitative yield but with a modest stereocontrol. The oxirane opening approach described here competes with the electrophilic alkoxyselenenylation reported below (Sect. 2.1.2). 

Terminal olefins such as 1476 react in an unusual Prins reaction [33] with formaldehyde in F3CC02H/Me3SiCl 14 to give in ca 75-90% yield a mixture of the cis/ trans 3,4-disubstituted tetrahydrofurans 1477 and 1478 [34] (Scheme 9.19). 

A new entry to exocyclic dienes was reported by Sha who uncovered that a radical cyclization of the vinyl iodide 100 can lead to the formation of an exocyclic dienes fused with a tetrahydrofuran ring. The cyclization is proposed to proceed in a 5-(n-exo)-exo-dig fashion <00OL2011>. 3,4-Disubstituted tetrahydrofurans can also be constructed via the cyclization of O-stannyl ketyls and allylic 0-stannyI ketyls onto electron-rich or electron-poor alkenes <00TL8941>. 

Starting from substituted allyl bis-(2,4-dimethyl-3-pentyl)-L-tartrate boronic acid, synthesis of a,/l-disubstituted tetrahydrofurans (134, n = 1) or tetrahydropyrans (134, n = 2) can be accomplished with high enantioselectivity (Scheme 3-46).79... 

The isomeric propargylic stannylated aldehyde intermediate, on the other hand, could be prepared from the alcohol precursor without competing cyclization to an seven-membered enol ether product (Eq. 9.105). Treatment of this stannane with SnCl4 afforded the cis-disubstituted tetrahydrofuran stereoselectively. Presumably, this reaction proceeds through an allenyl trichlorostannane intermediate. 

In analogy with the strategy of carbocyclic construction, 1,6-enynes containing an oxygen heteroatom in the carbon atom sequence have been used for 3,4-disubstituted tetrahydrofuran synthesis. The simplest example is given by the hydrosilylation of enyne at room temperature (Reaction 7.38) [49]. Tetrahydrofurans with an exocyclic methylene functionality can also be prepared from the appropriate alkynes, such as 32, with (TMS)3SiH in refluxing benzene which afforded exclusive formation of the exomethylene in the Z conformation (Reaction 7.39) [50]. 

Alkenyl-substituted -dicarbonyl compounds, upon the same conditions, give rise to 2,5-disubstituted tetrahydrofurans bearing exocyclic double bonds. The products, upon treatment with NaBH, are reduced to the corresponding tellurides which in turn are converted into tellurium-free methyl derivatives by treatment with TBTH. ... 

Substituted 4-alkenols (1) are converted by Tl(OAc)3 at 0-25° into trans-2,5-disubstituted tetrahydrofurans (2) in 60-80% yield with only traces of the ds-isomer or a tetrahydropyranyl regioisomer.2 The same reaction using Pb(OAc)4 gives 2 in only 31% yield. 

Examples of high levels of 1,4-asymmetric induction in kinetically controlled cyclofunctionalizations are rare. Cyclizations of 5-hydroxyalkenes to form 2,5-disubstituted tetrahydrofurans (equation 47) proceed with low selectivity in most cases.lp Exceptions shown in Table 13 are the palladium-catalyzed cy-clization to a trans 2-vinyl system (entry l )30.i04f gjyj cyclization of a 2-phenyl system with mercury(II) chloride to give a preponderance of the cis isomer (entry 2), presumably through equilibration.136 Equilibration with substituents other than phenyl (Me or f-butyl) resulted in much lower selectivity.136-138... 

The cyclization of (Z)-l-substituted-5-silyl-4-penten-l-ols 90, shown in equation 50, gave 2,5-disubstituted tetrahydrofurans 91 and 92 with a high trans-selectivity (% tram > 86 for R = Ph, i-Pr, C6Hi3)114. 

An iodine-mediated 6(0) " -exo-Trig cyclization has been used in the synthesis of (25, 4/ )-4-hydroproline from (S)-O-benzylglycidol219. Stereocontrolled 5(0) " -endo-Trig iodoetherification has provided an entry to traw.s-2.5-disubstituted tetrahydrofuran derivatives220. On treatment with iodine, trichloroimidates of primary a-allenic alcohols are converted into oxazolines with high stereoselectivity221. 

Iodolactonization of y, o-unsaturated alcohols results in preferential formation of tram-2, 5-disubstituted tetrahydrofuranes. However, the corresponding benzyl ethers cyclize preferentially to the cis-isomers. The alkyl group must be bulky enough to exert a steric effect, but not to prevent cyclization. Substituted benzyl ethers are particularly useful. Examples of this steric control are illustrated for the preparation of tram- and c/s-linalyl oxide (equations I and II).10... 

G. T. Wang, S. Wang, R. Gentles, T. Sowin, C. J. Maring, D. J. Kempf, W. M. Kati, V. Stoll, K. D. Stewart, and G. Laver, Design, synthesis, and structural analysis of inhibitors of influenza neuraminidase containing a 2,3-disubstituted tetrahydrofuran-5-carboxylic acid core,... 

A stereoselective synthesis of substituted tetrahydrofurans (69) via Pd-catalysed reactions of aryl and vinyl bromides with y -hydroxy terminal alkenes (68) has been described. This transformation affords trans-2,5- and frara-2,3-disubstituted tetrahydrofurans with up to >20 1 dr. This methodology also provides access to bicyclic and (g) spirocyclic tetrahydrofuran derivatives in good yield with 10-20 1 dr. The effect of... 

Phenylselenoetheriflcation (10, 18).1 Cyclization of the homoallylic alcohol 1 with C6H5SeCl and K2C03 to a 2,5-disubstituted tetrahydrofuran (2) proceeds with... 

Disubstituted tetrahydrofurans. Semmelhack has extended his synthesis of tetrahydrofurans by alkoxycarbonylation of 5-hydroxy-1-pentenes (12, 372)2 to... 

Intramolecular addition of acyl radicals to enoates proceeds in high yields. The acyl radicals are generated conveniently from acyl selenides. The application of this methodology in the stereoselective synthesis of cis-2,5-disubstituted tetrahydrofuran-3-ones is illustrated [95TL31],... 

A number of complex heterocycles have been assembled using dipolar cycloadditions (Fig. 6). The Affymax group [32] published an approach to the synthesis of tetrasubsti-tuted pyrrolidines by the reaction of azomethine ylids with electron-deficient olefins. A similar approach was described by researchers at Monsanto however, the aldehyde component was bound to the resin instead of the amino acid [33]. Kurth and co-workers [34] described a route to 2,5-disubstituted tetrahydrofurans using a nitrile oxide cycloaddition as the key reaction. Mjalli et al. [35] synthesized highly substituted pyrroles using the dipolar cycloaddition of intermediate 5 with mono- or disubstituted acetylenes. 

TMS)3SiH-mediated acyl radical reactions of phenylseleno esters have been utilized for the diastereoselective synthesis of cyclic ethers by Evans s group. Equation 44 shows that the acyl selenide 83 affords the cA-disubstituted tetrahydrofuran 84 in good yield on exposure at room temperature to (TMS SiH and the Et3 B/02 combination as the initiator via a 5-exo-trig cyclization97 98. 

Beebe X, Schore NE, Kurth MJ, Polymer-supported synthesis of 2,5-disubstituted tetrahydrofurans, J. Am. Chem. Soc., 114 10061-10062, 1992. 

Intramolecular cohalogenation is a related process which leads to halogenation with cyclization. Recent examples are the polymer supported synthesis of 2,5-disubstituted tetrahydrofuran (equation 54)459 and the iodolactonization of co-unsaturated carboxylic acids (equation 55)460. 

Indolines and indoles were prepared by a direct electrochemical reduction of arenediazonium salts. As a result, radical intermediates were generated from which 3,4-disubstituted tetrahydrofuran skeleta were constructed <02OL2735>. A short and stereoselective total synthesis of furano lignans was realized by radical cyclization of epoxides using a transition-metal radical source <02JOC3242>. Other preparations of tetrahydrofurans using radical cyclization include the synthesis of novel amino acids L-bis-... 

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