Stereocontrolled syntheses of 2,5-disubstituted tetrahydrofurans using remote asymmetric induction

Stereocontrolled syntheses of cis - and trans -2,5-disubstituted tetrahydrofurans with a 1-methyl-2-benzyloxyethyl group at C(2) are described. The starting material for this work was prepared by the tin(IV) chloride promoted reaction of a 4-methyl-5-benzyloxypent-2-enylstannane with an aldehyde which proceeds with excellent 1


Introduction
Several biologically active natural products are characterized by the presence of cis-2,5disubstituted tetrahydrofurans which have an α-methyl bearing stereogenic centre in the 2substituent.Examples include the pamamycins, e.g.pamamycin 607 1 1 and nonactic acid 2. 2 During recent studies on the reactions of allylstannanes with aldehydes, it was found that the 4methyl-5-benzyloxypent-2-enylstannane 3 was transmetallated stereoselectively to give an allyltin trichloride which reacted with aldehydes with excellent 1,5-stereocontrol to give the (Z)-1,5-anti-alkenols 4. 3 If procedures could be developed for the stereoselective cyclisation of these alkenols to 2,5-cis-disubstituted tetrahydrofurans 5, then it may be possible to develop this strategy to provide total syntheses of nonactic acid and pamamycin 607.
Early studies into the preparation of the tetrahydrofurans 5 from the alkenols 4, were based on dehydration/cyclisation of hydroxyselenides prepared by epoxidation of the alkenols followed by epoxide ring opening using sodium phenylselenide. 4,5However, this chemistry was successful only with relatively simple systems.With more complex substrates, the dehydration/cyclisation step was accompanied by loss of phenylselenenic acid giving the returned alkenol as the major product. 6It transpired that direct cyclisation using either phenylselenenyl chloride 7 or phthalimide 8 in the presence of 20 mol% of tin(IV) chloride was more successful and led to the completion of syntheses of the methyl ester of nonactic acid 2 and pamamycin 607 1. 9 During the course of this work it was necessary to prepare a sample of a cis-2,5-disubstituted tetrahydrofuran by a stereochemically unambiguous route.The results of this study are described herein together with procedures for the synthesis of the diastereoisomeric 2,5-trans-isomers.

Results and Discussion
The reaction between butanal and the allyltin trichloride generated from the 4-methyl-5benzyloxypent-2-enylstannane 3 gave the (Z)-1,5-anti-alkenol 6 with excellent stereocontrol, 1,5-anti : 1,5-syn ≥ 96 : 4, with no (E)-alkenols being detected (Scheme 1). 3 It was decided that one strategy for tetrahydrofuran formation would be to effect regio-and stereoselective hydration of the double-bond and so the alkenol 6 was converted into the syn-epoxide 7 using the wellprecedented vanadyl catalysed synepoxidation procedure. 10This epoxidation was highly stereoselective with only the one stereoisomer being detected (≥95 : 5) in the crude reaction mixture by high field 1 H NMR. Since this stereoselectivity is higher than that usually observed in this kind of epoxidation (more typically 85 : 15 in favour of the syn-diastereoisomer), it may well be that both of the stereogenic centres in the alkenol contribute to this stereocontrol.The next step was to reduce the epoxide regioselectively to give a 1,4-difunctionalised intermediate as the precursor of the tetrahydrofuran ring.To avoid problems of having to differentiate between two secondary hydroxyl groups later in the synthesis, the hydroxy-epoxide 7 was first converted into its SEM-ether 8. Reduction of this epoxyether by Red-Al was found to be usefully regioselective and gave the required alcohol 9 together with its regioisomer 10 in a ratio of ca.85 : 15.The regioselectivity of this reduction was established by a COSY 1 H NMR study of the acetate 11 of the major reduction product 9 and may be due to reduced steric hindrance to attack at C(4) and preferred co-odination by the OSEM substituent.It now remained to convert the hydroxyl group of the alcohol 9 into a good leaving group with inversion of configuration.Preliminary studies into the preparation of its inverted mesylate 12 using a Mitsunobu reaction were not promising since only low conversion into product was observed at room temperature and extensive decomposition took place in toluene heated under reflux (Scheme 2).However, reaction with iodine, imidazole and triphenylphosphine gave the inverted iodide 13 in a reasonable, non-optimized yield of 64%.Removal of the SEM-protecting group using dilute aqueous hydrogen fluoride gave mainly the iodo-alcohol 14 together with a small amount of the tetrahydrofuran 15.Conversion of the remainder of the iodo-alcohol into the tetrahydrofuran was accomplished by treatment with sodium hydride in THF as solvent and gave the 2,5-cis-disubstituted tetrahydrofuran 15 in a 65%yield.The 1,5-cis-configuration assigned to the tetrahydrofuran 15 follows from its method of synthesis and was confirmed by the synthesis of the racemic 1,5-trans-isomer 17 (Scheme 3).Thus deprotection of the mesylate 16 prepared from the racemic alcohol 9 was accompanied by cyclisation and gave the 2,5-trans-disubstituted tetrahydrofuran 17 directly.The 2,5-cis-and 2,5-trans-disubstituted tetrahydrofurans 15 and 17 could be distinguished spectroscopically.These syntheses of the tetrahydrofurans 15 and 17 were found to be highly stereoselective with little, if any (≤5%), contamination by the other stereoisomer being observed.A second synthesis of the racemic 2,5-trans-isomer 17 from the hydroxyepoxide 7 was also developed.Thus treatment of the hydroxyepoxide with tert-butyldimethylsilyl triflate and trimethylaluminium gave a mixture of the hydroxytetrahydrofurans 18 and 19. 11The stereochemical homology between these two compounds was proved by their deprotection which gave the same diol 20.Removal of the hydroxyl group from 19 was accomplished by conversion into the thionocarbonate 21 which, on reduction using tributyltin hydride, gave the 2,5-transdisubstituted terahydrofuran 17 identical to a sample prepared by the earlier procedure (Scheme 4).
This work shows how the alkenols prepared with 1,5-stereocontrol using the allylstannane 3 can be incorporated into stereoselective syntheses of either 2,5-cis-or trans-disubstituted tetrahydrofurans.The synthesis of natural products using this and related chemistry is underway. 9 3 ) was added and the mixture was allowed to warm to room temperature.The mixture was partitioned between dichloromethane (60 cm 3 ) and water (60 cm 3 ) and the organic phase washed with water (40 cm 3 ), brine (40 cm 3 ) and dried (MgSO 4 ).After concentration under reduced pressure, flash chromatography of the residue using light petroleum : ether, (3 : 1) and triethylamine (1%) as eluant gave the title compound, 6 (0.426 g, 78%), as a colourless oil, [α]D 22 -7.

(2R)-1-{(2R,3S)-3-[(1S)-2-(Benzyloxy)-1-methylethyl]oxiran-2-yl}pentan-2-ol (7).
Vanadyl ac-etoacetonate (4 mg, 2 mol%, 0.016 mmol) and tert-butyl hydroperoxide (0.24 cm 3 , 5 M solution in nonane, 1.20 mmol) were added to a solution of the alkene 6 (0.21 g, 0.801 mmol) in dichloromethane (7 cm 3 ) at 0 o C.After 10 min, the solution was allowed to warm to room temperature and stirred for a further 20 h.Saturated aqueous sodium thiosulfate (5 cm 3 ) was added and the mixture extracted with ether (3 x 10 cm 3 ).The combined organic phase was washed with water (10 cm 3 ), brine (10 cm 3 ), dried (MgSO 4 ) and concentrated under reduced pressure.Flash chromatography of the residue using light petroleum : ether, ( ) at 0 °C.The solution was then heated under reflux for 15 h.The reaction mixture was cooled to room temperature and saturated aqueous ammonium chloride (2 cm 3 ) was added.The precipitate was removed by filtration and the filtrate was extracted with ether (3 x 3 cm 3 ).The organic phase was washed with water (3 cm 3 ), brine (3 cm 3 ), dried (MgSO 4 ) and the solvent was removed under reduced pressure.Flash chromatography of the residue using light petroleum : ether, ( ) at room temperature.The resultant suspension was stirred at room temperature for 15 h.Saturated sodium hydrogen carbonate solution (2 cm 3 ) was added and the mixture stirred for 10 mins.Iodine was then added until the organic layer remained iodine coloured.After a further 10 mins stirring saturated sodium thiosulfate solution (5 cm 3 ) was added.The two layers were separated and the aqueous layer was extracted with ether (3 x 5 cm 3 ).The combined organic layers were washed with brine (5 cm 3 ), dried (MgSO 4 ) and the solvent was removed under reduced pressure.The residue was preabsorbed onto silica and purified by flash chromatography using light petroleum : ether, (4 : 1) as eluant to afford the title compound, 13 (210 mg, 64%), as a colourless oil, (Found: M + +NH

ISSN 1424-6376 Page63 © ARKAT USA, Inc Experimental Section
Optical rotations were measured on an Optical Activity AA-100 polarimeter operating at 589 nm.Light petroleum refers to the fraction with b.p. 40° C -60°C and was redistilled before use.Ether refers to diethyl ether.All solvents were distilled and purified by standard procedures.All products were obtained as colourless oils after chromatography.