2.5- Disubstituted tetrahydrofuranes

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... 

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. 

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. 

Permanganate oxidation of 1,5-dienes to prepare f r-2,5-disubstituted tetrahydrofurans is a well-known procedure (Equation 80). The introduction of asymmetric oxidation methodology has revived interest in this area. Sharpless-Katsuki epoxidation has found widespread application in the catalytic enantioselective synthesis of optically active tetrahydrofurans and the desymmetrization of w ro-tetrahydrofurans <2001COR663>. A general stereoselective route for the synthesis of f-tetrahydrofurans from 1,5-dienes has been developed which uses catalytic amounts of osmium tetroxide and trimethyl amine oxide as a stoichiometric oxidant in the presence of camphorsulfonic acid <2003AGE948>. 

A cobalt(II)-catalyzed oxidative cyclization converted a secondary alcohol to the trans-2,5-disubstituted tetrahydrofuran <03JA14702>. Oxidants such as vanadium(V) complex <03EJO2388>, ruthenium tetroxide <03TL5499> and osmium tetroxide <03AG(E)948> were all employed to convert either homoallyl alcohol or polyenes to molecules that contain... 

When phenylseleno derivatives are employed to prepare tetrahydrofurans from 4-alkenols, moderate stereoselectivity is generally observed. Cyclization of syn-(Z,Z)-7-benzyloxy-3,9-di-en-6-ol (22) with phenylselenyl chloride in dichloromethane at — 78 °C affords the corresponding 2,5-disubstituted tetrahydrofuran in 89% yield and 75 25 (trans/cis) diastereomeric ratio12. 

Unsaturated ten-butyl esters can also be cyclized under thermodynamic conditions to give c -2,5-disubstituted tetrahydrofurans in high yield as single products121. 

In analogy to this approach, the cyclization of unsaturated furanosides and pyranosides, performed with iodonium dicollidine perchlorate [I(collidine)2C104] in dichloromethane, allows ris-2,5-disubstituted tetrahydrofurans to be obtained in moderate yield and with good to high diastereoselection122 -124. 

Since the vinylmercury intermediates are not useful for reactions other than methoxycarbonyl-ation, the iodocyclization of y-(trimethylsilyloxy)allenes has been carried out in order to obtain iodovinyl tetrahydrofurans. By using A -iodosucciiiimide in dicliloromethane, 2,5-disubstituted tetrahydrofurans are obtained in good yield and high d.r., the m-isomer always being the major component of the diastereomeric mixture126. 

Some 4,5-dihydroisoxazoles give 2,5-disubstituted tetrahydrofurans in good yield by cycliza-tion with iodine in refluxing dichloromethane. The 2,5-/ra s-isomers are predominant in the reaction mixture, although the selectivity is low and depends on the solvent employed. Thus, a change in solvent from dichloromethane to benzene results in a complete loss of stereoselectivity. The diastereomeric ratios are determined by capillary GLC and isomers are separated by preparative HPLC37,38,137. 

Synthesis of rr i.v-2,5-Disubstituted Tetrahydrofurans by Ring Contraction of 3-Halotetrahydro-2//-pyrans... 

Synthesis of 2,5-Disubstituted Tetrahydrofurans by Cyclization Involving if1- or -Complexes... 

The synthesis of 5-substituted tetrahydro-2-vinylfurans, starting from 4-alkenols, proceeds with a catalytic amount of palladium(II) acetate, in the presence of copper(ll) acetate, under oxygen atmosphere in methanol/water. The resulting 2,5-disubstituted tetrahydrofurans are obtained in moderate yield. When (E)-1 -phenyl-4-hcxcn-1 -ol (1) is used as starting material, traus-tetrahydro-2-phenyl-5-vinylfuran (2) is the sole compound isolated from the reaction mixture, albeit in 40% yield40. 

A preferential 2,5-trans relationship is also observed in the cyclization of unsaturated epoxythio-carbonylimidazolides to 2,5-disubstituted tetrahydrofurans. By treatment with tributyltin hy-dride/2,2 -azobisisobutyronitrile, an allyloxy radical, generated by epoxide cleavage, attacks the double bond, and the corresponding tetrahydrofurans are obtained in low to moderate yield. The diastereoselection is low, with the trans-isomer predominant in the reaction mixture46. 

Moreover, the free radical addition of either dichloromethane or chloroform to a number of alkenes bearing a secondary peroxy function at C-5 allows 2,5-disubstituted tetrahydrofurans to be obtained with moderate diastereoselection the r/.s-isomer being the major component of the reaction mixture139. 

Oxidative cyclization of selected 5,6-dihydroxyalkenes to ci.v-2,5-disubstituted tetrahydrofurans has been realized with chromium(VI) reagents. In fact, when Collins reagent or pyridinium chlorochromate are employed at 20 °C for 3 min, the cyclization affords the cis-2,5-products in moderate yield. The resulting (tetrahydrofuranyl)diols are diastereomerically pure by H- and i5C-NMR spectroscopy. Moreover, a comparison of the reaction mixture with authentic 2,5-trans samples indicates a stereoselectivity of 99.5%47. 

The Michael conjugate addition of an oxygen to an activated double bond has also been exploited in order to obtain 2,5-disubstituted tetrahydrofurans. The diacetoxynonenoate 1 is cyclized with methanolic potassium hydroxide to give the tetrahydrofuranyl derivative 2 in 97 % yield after esterification with diazomethane. The 1,3-asymmetric induction is low as indicated by the cisf trans diastereomeric ratio (67 33) which was determined by a GLC comparison with known material50. 

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