Tetrahydrofuran derivatives synthesis

In MeOH, l,4-dimethoxy-2-cyclohexene (379) is obtainejl from 1,3-cydo-hexadiene[315]. Acetoxylation and the intramolecular alkoxylation took place in the synthesis of the naturally occurring tetrahydrofuran derivative 380 and is another example of the selective introduction of different nucleo-philes[316]. In intramolecular 1,4-oxyacetoxylation to form the fused tetrahy-drofurans and tetrahydropyrans 381, cis addition takes place in the presence of a catalytic amount of LiCI, whereas the trans product is obtained in its absence[317]. The stereocontrolled oxaspirocyclization proceeds to afford the Irons product 382 in the presence of Li2C03 and the cis product in the presence of LiCl[ 318,319]. 

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]. 

The 10 OC route was followed for the synthesis of tetrahydrofurans possessing a y-amino alcohol moiety 247 (Eq. 29) 118]. Aldoximes 21a-f (see also Eq. 3 and Table 2), when heated in benzene in a sealed tube at 110 -120 °C for 6 h, underwent smooth intramolecular cycloaddition to the tetrahydrofuranoisoxazo-lidines 246a-f in 70-83% yield (Eq. 29). This ring closure proceeded stereo-specifically to generate three adjacent stereogenic centers. LAH reduction of 246 b resulted in isolation of stereospecifically functionalized tetrahydrofuran derivative 247b in 75% yield. 

The synthesis of tetrahydrofuran derivatives from unsaturated alcohols via hydroformylation intermediates was developed many years ago. Moderate yields are obtained from but-2-en-l,4-diol (Scheme 54)94 but hydroformylation is not the major pathway when coniferyl alcohol is subjected to the oxo process (Scheme 55).9S A more complicated reaction is involved... 

The oxacarbene in (2.1) is usually trapped by water or an alcohol to give hydroxy- or alkoxy tetrahydrofuran derivatives. This sequence has been connected with the synthesis of prostaglandines (2.3) 206). 

Miyafuji and Katsuki95 reported the desymmetrization of meso-tetrahydrofuran derivatives via highly enantioselective C-H oxidation using Mn-salen catalysts. The optically active product lactols (up to 90% ee) are useful chiral building blocks for organic synthesis (Scheme 8-48). 

Shibasaki et al. developed a polymer-supported bifunctional catalyst (33) in which aluminum was complexed to a chiral binaphtyl derivative containing also two Lewis basic phosphine oxide-functionahties. The binaphtyl unit was attached via a non-coordinating alkenyl Hnker to the Janda Jel-polymer, a polystyrene resin containing flexible tetrahydrofuran-derived cross-Hnkers and showing better swelling properties than Merifield resins (Scheme 4.19) [105]. Catalyst (33) was employed in the enantioselective Strecker-type synthesis of imines with TMSCN. 

The Paal-Knorr method can be applied to the synthesis of a variety of 1-substituted pyrroles using commercially available 2,5-dialkoxytetrahydrofurans as a butane-1,4-dial equivalent. When an appropriate tetrahydrofuran derivative is available, the reaction can be used for more highly substituted pyrroles. Aliphatic and aromatic amines react readily and even weakly nucleophilic sulfonamides undergo cyclization (equation 66) (73SC303). 

As for oxygen heterocycles, several reports involving the diastereoselective synthesis of highly substituted tetrahydrofuran derivatives have appeared. SnCLj-mediated [3 + 2] cycloaddition of allylsilane with optically active a-ketoesters affords 211 with excellent diastereoselectivity (equation 173)314-317. 

An efficient synthesis of tetrahydrofuran-derived spiro-p-lactams has been reported to be performed by a Staudinger-type reaction of either 2- or 3-tetra-hydrofuroyl chloride with imines [66]. The reaction was carried out by adding Et3N... 

Scheme 16 Synthesis of tetrahydrofuran-derived spiro-J3-lactams...

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... 

The selective intramolecular nucleophilic addition of a hydroxy group at Cyof a ruthenium allenylidene generated by activation of propargylic alcohol by RuCl(Cp)(PPh3)2/NH4PF6 provides a ruthenium vinylidene species, which reacts with allylic alcohols as previously described in the section Formation of Unsaturated Ketones (Eq. 11, Scheme 18) [79]. This unprecedented tandem reaction makes possible the construction of tetrahydrofuran derivatives in good yields and has been used as a key step in the synthesis of (-)calyculin A [80]. 

An efficient and operationally simple synthesis of tetrahydrofuran-derived spiro-P-lactams 15 and 16 using the Staudinger reaction of unsymmetrical cyclic ketones has been described <02JCS(P1)571 02SL69>. Similarly, spiro-P-lactams 17 were synthesized via Staudinger reaction of imines derived from 7-oxanorbomenone with alkoxyacetyl chlorides <02TL6405>. 

In a synthesis of tetronomycin (45) published in 1994 [14], Semmelhack et al. probe the scope of intramolecular alkoxypalladations. The retro-synthetic analysis (Scheme 4) shows that the chosen strategy exploits such Pd-catalyzed transformations even twice. The pre-target structure 46 is formally derived from 47 by Pd-mediated cy-clization. Compound 47 can be traced back via 48 to the tetrahydrofuran derivative 49, which in turn should be available by alkoxycarbonyla-tion from a precursor of type 50. 

Allyl propargyl ethers are easily cyclized to tetrahydrofuran derivatives by titanocene- and zirconocene-mediated reactions. Thus, these compounds are convenient starting materials for the stereoselective synthesis of highly substituted 3-alkylidenetetrahydrofurans (Scheme 72) <1996TL9059>. It is noteworthy that the titanocene- and zirconocene-mediated reactions show opposite (Z)/( )-selectivities. 

A Ni-catalyzed cyclization cross-coupling reaction of iodoalkenes with alkyl zinc halides has been employed for the synthesis of various tetrahydrofuran derivatives <2007AGE-ASAP>. The TiCU-catalyzed anti-Markovnikov hydration of alkynes has been applied to the synthesis of various benzo[3]furans <2007JOC6149>. 

An interesting application of the asymmetric alkoxyselenenylation of alkenes to natural product synthesis was reported recently by Wirth, who described a short procedure to obtain some furofuran lignans 147]. The total synthesis of (+)-Samin 53 [47 a] is shown in Scheme 7. The protected allylic alcohol 50 was treated with the selenyl triflate derived from diselenide 29 in the presence of 2,3-butadien-l-ol, and afforded the addition product 51 in 55% yield and with a diastereomeric ratio of 15 1. The favored 5-exo-trig radical cyclization of the major isomer afforded the tetrahydrofuran derivative 52 from which the final product was obtained through few classical steps. 

Although less commonly used, Raney Ni cleavage of the C—S bond of sulfoxides and sulfones is also of interest. For example, the removal of sulfoxides is one of the steps in the synthesis of spiroketals and of tetrahydrofuran derivatives (Scheme 2). Exceptionally, the desulfurization is not accompanied by the hydrogenolysis of a benzyl ether group. 

Nakada, M., Iwata, Y., Takano, M. Reaction of dianions of acetoacetic esters with epibromohydrin derivatives a novel synthesis of tetrahydrofuran derivatives and tetrahydropyran derivatives. Tetrahedron Lett. 1999,40, 9077-9080. 

Hirai, H.. Ueda, K.. and Matsui. M.. Studies on chrysanthemic acid. Part 25. Alternative synthesis of chrysanthemic acid via tetrahydrofuran derivatives. Agr. Biol. Chem., 40, 153, 1976. 

Selectivity in the epoxidation of dienes where the two alkene residues are a widely differing nucleophilicities is not difficult to achieve and we will return to this point later in this review. However, it is worth pointing out that quite good diastereofacial selectivity was reported in the epoxidation shown in Eq. (12), part of a total synthesis of (+ )-altholactone. The epoxidation using MCPB A proceeded with poor selectivity whereas MMPP gave predominant attack on the P-face and a 3.5 1 mixture of the substituted tetrahydrofuran derivatives was obtained after acid catalysed cyclisation [26]. 

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