Substituted tetrahydrofuran synthesis

Scheme 3-97. Substituted tetrahydrofuran synthesis using chiral a-siloxyethylallylsilanes and aldehydes.

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 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. 

A very interesting application of the above methodology is the synthesis of hetero-cycles60. Thus, substituted tetrahydrofurans 121-123 are obtained easily with perfect diastereoselectivities (equation 57)60a. 

The advent of the polyether antibiotics with the challenging aspect of stereocontrolled construction of the substituted tetrahydrofuran units has greatly extended the chemistry of this oxygen heterocycle. The nonactins (194), lasalocid A (195) and monensin (196) are among the ionophores for which syntheses have been achieved. Detailed reviews on synthesis of reduced furans are available (65HOU(6/3)l, 80H(14)1825). 

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. 

Dihydroxy-l,3-dioxepins readily undergo vinylacetal rearrangement in the presence of a Lewis acid to give tetrahydrofuran-3-carbaldehydes (CHEC-II(1996)). This methodology was applied in a tandem Heck reaction -rearrangement process for the synthesis of a variety of 2,4-substituted tetrahydrofuran-3-carbaldehydes (Scheme 19) <2006CC3119>. 

Brovetto M, Seoane G (2008) Stereoselective Synthesis of 3-Oxygenated-cw-dialkyl-2,5-substituted Tetrahydrofurans from Cyclohexadienediols. J Org Chem 73 5776... 

The synthesis of highly substituted tetrahydrofurans by means of a multicomponent reaction based on this palladium-mediated cyclization process was reported by Balme and co-workers [94]. In this reaction, formation of enolate 103 by the initial 1,4-addition of an allylic alcohol to the conjugate acceptor 102 is followed by a... 

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 synthesis of dihydrofuran derivatives such as 177 has been performed to explore scope and limitations of the Lewis acid promoted hydroxyalkylation of siloxycyclopropanes. Table 6 shows that aromatic as well as aliphatic ketones can efficiently be incorporated. Enolization of ketones does not occur and a 1-methyl group at the cyclopropane is no obstacle for the reaction, which now binds the carbonyl compound to a quartemary center with surprisingly high efficiency (entry 5). Albeit there are some restrictions with regard to the substitution pattern of the cyclopropanes, bicyclic siloxycyclopropanes also give good yields (e.g. entry 6 and Eq. 76). Further examples of the tetrahydrofuran synthesis from intermediate y-lactols with... 

Table 9. Synthesis of 5-substituted Tetrahydrofuran-3-carboxylates 204 According to Eq. 85...

The synthesis of polysubstituted tetrahydrofurans was also achieved in a stereoselective manner by a formal [3+2] cycloaddition of an allylsilane with a-triethylsiloxy aldehydes. An example showing the mechanism is illustrated <02JA3608>. In another approach, allylsilane was also allowed to react with a-keto esters in a [3+2] annulation reaction, providing highly substituted tetrahydrofurans in good yields as single diastereomers <02OL2945>. 

The Michael-aldol process with methacrylates described in Section II.B can be also applied to the synthesis of substituted tetrahydrofurans, 245. If the reaction is carried out in THF, the yield and selectivity of the sequence decrease. It was proposed that the lithium coordination with THF molecules hinders the formation of the product 245. The authors concluded that the Lewis acidity of naked lithium cation is the key driving force for the reaction to proceed successfully. The tandem reaction with lithium thiophenolate, fumarate ester and benzaldehyde constitutes an useful methodology for the preparation of y-butyrolactone (Scheme 75)89,90. 

Allylic alcohols can serve as 7t-allyl cation precursors to act as electrophiles in Sn reactions with a tethered O-nucleophile giving rise to the formation of spiroannulated tetrahydrofurans <2000TL3411>. Michael acceptors are also suitable electrophiles for the cyclization to tetrahydrofuran rings <2003T1613>. The Tsuji-Trost allylation has found widespread application in the synthesis of carbo- and heterocyclic compounds. Allylic substitution has been employed in the stereoselective synthesis of 2-vinyl-5-substituted tetrahydrofurans <2001H(54)419>. A formal total synthesis of uvaricin makes twofold use of the Tsuji-Trost reaction in a double cyclization to bis-tetrahydrofurans (Equation 73) <20010L1953>. 

Similarly, intramolecular Pauson-Khand reactions can be utilized for tetrahydrofuran synthesis, when the tethers are oxa substituted. Ligand effects on stereoselectivity in Rh(i)-catalyzed asymmetric Pauson-Khand-type reactions have been investigated and ee s of up to 92% have been achieved with the 2,2-bis(diphenyl-phosphanyl)-l,l-binaphthyl (BINAP) ligand and a Rh(i) precatalyst (Equation 91). However, it has to be noted that the ee is highly substrate dependent, and considerably lower in most other cases <2006S4053>. 

Styrenes and styrene oxides can be combined in a highly chemo- and regioselective fashion to yield 2,4-bis-aryl-substituted tetrahydrofurans using an iron catalyst <2005CC1996>. This tetrahydrofuran synthesis developed by Hilt et al. opens an unprecedented way for the one-step synthesis of racemic calyxolane A and calyxolane B with moderate diastereoselectivities. The iron-catalyzed ring-expansion reaction of epoxyalkenes was considerably... 

The synthesis of unsynunetrical nonadjacently linked tetrahydrofurans was accomplished by Mootoo through (4a) catalyzed cross metathesis of the protected substituted-tetrahydrofuran components. These compounds are potential intermediates for acetogenins having potent antitumor activity... 

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. 

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