Tetrahydrofurans substituted synthesis

Begley, M. J., Bowden, M. C., Patel, P., Pattenden, G. New stereoselective approach to hydroxy-substituted tetrahydrofurans. Total synthesis of ( )-citreoviral. J. Chem. Soc., Perkin Trans. 11991, 1951-1958. 

Additional examples of synthetic application of periodic acid as an oxidant include the oxidative iodination of aromatic compounds [1336-1341], iodohydrin formation by treatment of alkenes with periodic acid and sodium bisulfate [1342], oxidative cleavage of protecting groups (e.g., cyclic acetals, oxathioacetals and dithioacetals) [1315, 1343], conversion of ketone and aldehyde oximes into the corresponding carbonyl compounds [1344], oxidative cleavage of tetrahydrofuran-substituted alcohols to -y-lactones in the presence of catalytic PCC [1345] and direct synthesis of nitriles from alcohols or aldehydes using HsIOe/KI in aqueous ammonia [1346],... 

Pd-catalyzed cyclization was also applied to the stereocontrolled preparation of chiral substituted tetrahydrofurans. The synthesis of optically active tetrahydrofurans was pioneered by Stork and Poirier,who described effective chirality transfer in the Pd-assisted cyclization of y-hydroxy allylic esters. Williams and Meyer deployed a variant of the 0-capture of 7r-allylpalladium complexes in the reactions of substimted trimethylenemethane palladium complexes developed by Trost, using aUylstannane (Scheme 32). A key intermediate 156 in the synthesis of amphidinolide K, a marine nam-ral product, was therefore synthesized starting from enantiopure diastereomer 160. Compound 160 was prepared by in situ transmetallation using the Corey chiral sulfonamide 159 with optically active aUylstannane 157 and then condensation with functionalized aldehyde 158. Formation of the c -2,5-disubstituted tetrahydrofuran 156 occurred with an excellent diastereoselectivity (cis/trans 13 1) and a good yield (88%) from the syn-1,4-precursor 160. 

A plausible pathway is that the aromatisation of the cyclohexadienone 92 by a proton shift is accelerated in the presence of Ac20 under formation of acetate 93. The simultaneously generated acetic acid then cleaves the acetate to form the free phenol 94 (Scheme 44). This effect was observed for the first time during studies towards the total synthesis of the lipid-alternating and anti-atherosclerotic furochromone khellin 99 [64].The furanyl carbene chromium complex 96 was supposed to react with alkoxyalkyne 95 in a benzannulation reaction to give the densely substituted benzofuran derivative 97 (Scheme 45). Upon warming the reaction mixture in tetrahydrofuran to 65 °C the reaction was completed in 4 h, but only a dimerisation product could be isolated. This... 

This procedure illustrates a general method for the stereoselective synthesis of ( P)-disubstitnted alkenyl alcohols. The reductive elimination of cyclic /3-halo-ethers with metals was first introduced by Paul3 and one example, the conversion of tetrahydrofurfuryl chloride [2-(chloromethyl)tetrahydrofuran] to 4-penten-l-ol, is described in an earlier volume of this series.4 In 1947 Paul and Riobe5 prepared 4-nonen-l-ol by this method, and the general method has subsequently been applied to obtain alkenyl alcohols with other substitution patterns.2,6-8 (I )-4-Hexen-l-ol has been prepared by this method9 and in lower yield by an analogous reaction with 3-bromo-2-methyltetra-hydropyran.10... 

The application of 1,3-dipolar cycloaddition processes to the synthesis of substituted tetrahydrofurans has been investigated, starting from epoxides and alkenes under microwave irradiation. The epoxide 85 was rapidly converted into carbonyl ylide 86 that behaved as a 1,3-dipole toward various alkenes, leading to quantitative yields of tetrahydrofuran derivatives 87 (Scheme 30). The reactions were performed in toluene within 40 min instead of 40 h under classical conditions, without significantly altering the selectivi-ties [64]. 

Treatment of phenylchalkogen substituted alkenyl alcohols with /-BuOK provided useful tetrahydrofurans stereoselectively <96JOC8200>. A concise synthesis of cis- and trans-theaspirones via oxonium ion-initiated pinacol ring expansion was developed <96JOCl 119>. 

Bis-pyranoside alkenes are reported as novel templates for the stereoselective synthesis of highly substituted, adjacently linked tetrahydrofurans <96TL3619>. 

Transition metal catalysis on solid supports can also be applied to indole formation, as shown by Dai and coworkers [41]. These authors reported a palladium- or copper-catalyzed procedure for the generation of a small indole library (Scheme 7.23), representing the first example of a solid-phase synthesis of 5-arylsulfamoyl-substituted indole derivatives. The most crucial step was the cydization of the key polymer-bound sulfonamide intermediates. Whereas the best results for the copper-mediated cydization were achieved using l-methyl-2-pyrrolidinone (NMP) as solvent, the palladium-catalyzed variant required the use of tetrahydrofuran in order to achieve comparable results. Both procedures afforded the desired indoles in good yields and excellent purities [41]. 

The Williamson ether synthesis remains the most practical method for the preparation of tetrahydrofurans, as can be exemplified by the two examples shown in the following schemes. A simple synthesis of 2-substituted tetrahydrofuran-3-carbonitriles 84 is achieved by generating the alkoxide under a phase transfer condition via reaction between 4-chlorobutyronitrile and non-enolizable aldehydes <00SL1773>. A synthesis of 2-alkylidene-tetrahydrofuran 85 was recorded, in which a dianion can be generated through treatment of the amide shown below with an excess of LDA, and is followed by addition of l-bromo-2-chloroethane. In this way, the more basic y-carbon is alkylated and leads eventually to the nucleophilic cyclization <00SL743>. 

Viewed in a much broader context, C-aldopentofuranosyl derivatives may also be regarded as highly functionalized, chiral derivatives of substituted tetrahydrofuran. As such, they may be useful intermediates in the synthesis of a variety of compounds that contain a chiral, substituted tetrahydrofuran ring. 

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... 

Use of TMSCl in combination with HMPA, DMAP, or TMEDA all favored 1,2-addition over 1,4-addition. Sequential a-alkoxyalkylcuprate conjugate addition, enolate trapping with TMSCl, and silyl enol ether alkylation provides a one-pot synthesis of tetrahydrofurans (Scheme 3.35) [129]. Cyclic enones afford as-fused tetrahydrofurans, while acyclic systems give complex mixtures of diastereomers. a-Alkoxyalkylcopper reagents also participate in allylic substitution reactions with ammonium salts [127]. 

An intramolecular photocyclization approach has been developed for the synthesis of strained tetrahydrofuran and tetrahydropyrrole derivatives from tetronates (Table 1) <2004EJO4582, 2005JOC9798>. The cycloaddition reaction is not sensitive toward the degree of substitution on either reactive center and produces a single diastereoisomer in all cases (Equation 42). 

Intramolecular alkylation has been used in the synthesis of the cyclopropane side chain of the marine sterols Glaucasterol95 and Petrosterol96. During the preparation of the latter the mesylate 1 was reacted with 1.0 equivalent of potassium-tcr -butoxide in tetrahydrofuran/ben-zene at 0°C to give the trans-substituted cyclopropane 2 in >70% yield. 

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