Tetrahydrofurans annulated

In contrast, when the X group is oxygen, the reaction appears to follow the cationic alkene cylization-pinacol-like rearrangement pathway. In this case, reaction of an optically pure acyclic oxygen-containing analog of the system in Scheme 71 leads to a product with preservation of optical activity. This reaction protocol, which accomplishes an overall ring expansion with a tetrahydrofuran annulation, has been examined for a-hydroxy-cyclopentanones and -cyclohexanones (Scheme 73 and equations 29-31). ... 

Brown, M. J., Harrison, T., Herrinton, P. M., Hopkins, M. H., Hutchinson, K. D., Overman, L. E., Mishra, P. Acid-promoted reaction of cyclic allylic diols with carbonyl compounds. Stereoselective ring-enlarging tetrahydrofuran annulations. J. Am. Chem. Soc. 1991,113, 5365-5378. 

In a similar manner, the Gansauer group also used this domino methodology for the constructions of annulated tetrahydrofurans 3-150 using epoxides of type 3-149 [63]. In this way, a broad variety of products could be synthesized in a ds-selective fashion in good yields and high diastereoselectivity (Scheme 3.39). 

Bicyclizations of structurally analogous 5-hydroxy-1-pentynyliodonium tri-flates 34 to cyclopentene-annulated tetrahydrofurans 35 have also been reported (Scheme 56) [157]. Because the strained enol ether moiety in 35 is acid sensitive, these compounds were converted to their monobenzyl ketals. In general, bicyclizations of 34 are less efficient and less versatile than those of the tosylamido analogs. 

The stereoselectivity of this reaction rises when more bulky nucleophiles are employed (compare entries 7, 3,1, and 5). This is most impressively demonstrated by comparison of the y-lactol reduction with its allylation leading to 205 or 206, respectively (Scheme 10). Formation of tetrahydrofuran derivative 208, dihydrofuran 209, or unsaturated a-methylen-y-butyrolactone 207 illustrate that various modes of straightforward work-up procedures provide two different five membered heterocycles 93 b-96). A second example without the geminal dialkyl substitution at C-3 of the siloxy-cyclopropane depicted in Eq. 86 making available the annulated tetrahydrofuran-3-carboxylate 210 underlines the generality of the C-C-bond forming hydroxyalkylation reaction via ester enolates. 

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>. 

There exists also a synthesis of cyclopentadecanone (VII/81) and ( )-mus-cone, based on a three-carbon annulation of cyclic ketones followed by the regioselective radical cleavage of the zero bridge of the so formed bicyclic system [44], The synthesis of cyclopentadecanone is summarized in Scheme VII/16. The cyclization of VII/78 to the bicyclic alcohol VII/79 proceeds best (94 % yield) with samarium diiodide in the presence of hexamethylphosphoric acid triamide and tetrahydrofuran [45], The oxidative cleavage of VII/79 to the ring expanded product VII/80, was performed by treatment with mercury(II)-oxide and iodine in benzene, followed by irradiation with a 100 Watt high pressure mercury arc. Tributyltinhydride made the de-iodination possible. 

Dipolar cycloaddition of alkenes with carbonyl ylides generated in situ is a versatile method for tetrahydrofuran synthesis. The synthetic potential of such transformations has been reviewed <2005JOM(690)5533, 2003BMI6-253>. In addition, the stereoselective [3 + 2] annulation of allyl silanes has become a reliable protocol for the synthesis of tetrahydrofurans as demonstrated in several total syntheses . Such a [3 + 2] annulation, for example, affords the tetrahydrofuran product 11 as a single stereoisomer (Scheme 15) <2002OL2945>. Lanthanide salts serve as efficient Lewis acid catalysts in similar [3 + 2] cycloaddition reactions . 

Condensation of 1,2-dielectrophiles with a component that serves as a l,3-C,0-nucleophile is the underlying principle of a number of improved methods for furan synthesis. Bis-silyl enol ethers are suitable enol equivalents for the condensation with dielectrophiles to produce furans. Langer and co-workers have made use of this concept in the synthesis of annulated furans with l-chloro-2,2-dimethoxyethane as electrophile <2005EJ02074>. In a stepwise reaction comprising TMS triflate-assisted aldol reaction and cyclization with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base, 3-methoxy exomethylene tetrahydrofurans are obtained, which finally yield the furan reaction products upon treatment with trifluoroacetic acid (Scheme 18). 

Metal-catalyzed [4- -2] and [5- -2] cycloadditions devoped by Wender and Ttost are powerful transformations for the construction of polycyclic ring skeletons. Their intramolecular versions incorporating an ether group in the tether lead to oxygen heterocycles in good yields. A rhodium N-heterocyclic carbene catalyst has been shown to be particularly effective in such [4-1-2] and [5-1-2] cycloaddition reactions to form [r]-annulated tetrahydrofurans (Scheme 66). In all cases reported, excellent yields have been obtained in less than lOmin reaction time at 15-20 °C <2006JOC91>. 

Normally the terminal double bond is attacked by bulky electrophiles, such as the phenylselenyl cation. A 6-endo cyclization of the -configurated carbinol 6 leads stereoseleclively to the traMS-annulated tetrahydrofuran system 7. The corresponding (Z)-alkene 8 yields a mixture of trans-tetrahydrofuran 7 and the monocyclic compound 9 as a byproduct according to a stepwise process97. 

Using an electron-rich olefin as the terminating group, fra 5-decalins are formed. The examples show that the (Z)-homoallyl alcohol forms the annulated tetrahydrofuran system with particularly higher stereoselectivity than the corresponding tram system100. 

Despite the tremendous amount of work on samarium diiodide mediated reactions, few examples of cyclic ketone reductions have been described. One example is a step in the synthesis of racemic atractyligenin49 where an annulated cyclohexanone was reduced efficiently with samarium diiodide in tetrahydrofuran/ water at 20 C to give the 2/J-alcohol equatorioselectively. 

Amines such as (S)-l-phenylethylamine and (/ )- -phenylethylamine can be used as chrial auxiliaries for the Robinson annulation. The secondary enamine of the ketone 57 with (iS)-l-phenylethylamine reacts with MVK in tetrahydrofuran for 30 h. This is then followed by the addition of 20% of acetic acid for 30 min. The intermediate formed is then cyclized with sodium methoxide in methanol to form (R)-S9 in 50% overall yield and 92% ee ... 

The application of d5-2,3-disubstituted cyclopropane 1,1-diesters to [3 + 2]-annulations with aldehydes under the promotion of AICI3 can result in the formation of the desired polysubstituted tetrahydrofuran products... 

Total syntheses of diterpenoid hydrokempenones have been accomplished by Paquette et al.,f using the Pd-catalyzed [3 + 2] cycloaddition methodology. One example is outlined on Scheme 43 and describes the synthesis of an isomeric compound 208 of 3/3-hydroxy-7/3-kemp-8(9)-en-6-one, a defense secretion agent of the neotropical species Nasutitermes octopilis. 3-AUcoxy-2-cyclohexenone 204 was efficiently functionalized and transformed to bicylic adduct 205 via a Robinson annulation reaction. Reduction of the double bond followed by condensation of dimethyl carbonate and oxidation gave the keto ester 206, which was treated with [2-(acetoxymethyl)-3-allyl]trimethylsilane, palladium acetate, and triisopropyl phosphite in refluxing tetrahydrofuran to afford a 98% yield of 207. Substituted methylenecyclopentane 207 was then functionalized by stereoselective reduction and protections, and final closure was done under basic conditions after an ozonolysis step. A modified Barton-McCombie reaction produced the desired tetracyclic adduct 208. 

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