. Synthesis of 2,8-disubstituted-4,7-dioxatricyclo[3.2.1.0 3,6 ]octane and 2,6-dioxabicyclo[3.2.0]heptane derivatives starting from furan

The title compounds have been prepared from previously synthesized 2-endo -acetoxy-3- endo - hydroxy-7-oxabicyclo[2.2.1]hept-5-ene and 3-acetoxy-4-hydroxy-2,5-divinyl-furan via intramolecular electrophilic cyclization. Both types of compounds constitute new functionalized oxetane ring systems.


Introduction
The oxetane ring system 1 constitutes subunits of important naturally occurring compounds such as taxoids, 2 thromboxane A2 (TXA2), 3 some sesquiterpene lactones, 4 diterpenoids 5 and mediumsized cyclic ethers. 6On the other hand these compounds are valuable monomers in different polymerization processes 7 being also well established synthetic intermediates 8 and useful tools in drug discovery. 9n the other hand, compounds possessing the 4,7-dioxatricyclo[3.2.1.0 3,6]octane and 2,6dioxabicyclo[3.2.0]heptane skeletons (structures 1 and 2 respectively, Figure 1) constitute two interesting class of compounds bearing an oxetane subunit.Compounds with structure 1 are efficient herbicides and plant-growth regulators and at least four patents concerning the synthesis and applications of products showing this motif have been reported. 10On the other hand, the bicyclic oxetane 2 constitutes a "sugar" subunit of several conformationally restricted nucleosides.These compounds have been extensively investigated as building blocks for oligonucleotides with important therapeutic and diagnostic applications. 11The "oxetane T" 3 (Figure 1) is an example of this type of molecules. 12 ARKAT USA, Inc.The synthesis of 8-hydroxy derivatives of 1 (compound 5, Scheme 1) has been reported using intramolecular ring-opening of 5,6-exo-epoxy-7-oxa-2-endo-hydroxynorbornane 4. 13,14 Moreover several accounts concerning the preparation of other 8-substituted derivatives of 1 have been carried out by intramolecular halo-, arylsulfanyl-and arylselenil etherification 15 of 2-endohydroxy-7-oxabicyclo[2.2.1]hept-5-ene derivatives 6. 16 It should be pointed out that compounds with structure 7 have been used as starting materials in some useful synthetic transformations. 17egarding compounds 2 (Figure 1), they have usually been synthesized by photochemical cycloaddition reactions of 2,3-dihydrofuran derivatives and carbonyl compounds (the Paternó-Büchi reaction). 18ecently 20 we have reported the synthesis of enantiomerically enriched 7-oxanorbornene derivative 10 (Scheme 3) via Diels-Alder cycloaddition between furan and vinylene carbonate followed by hydrolysis and enzymatic desymmetrization.Compound 10 may be transformed into 2,5-divinyl-3-acetoxy-4-hydroxytetrahydrofuran 11 via ring-opening metathesis (ROM)-cross metathesis (CM) tandem reactions ("metathesis rearrangement") using ethylene as cross metathesis partner.Compound 10 is a suitable starting material for the synthesis of 2,8-disubstituted-4,7-dioxatricyclo[3.2.1.0 3,6]octane derivatives 12 via intramolecular etherification (endo hydroxyl group at the position 2 of the starting material 10) of the epi-cation intermediate generated by electrophilic addition on the double bond of 10 (Scheme 4a).Compounds 12 are fully and differentially substituted tricyclic systems, potentially useful as herbicidal agents or as intermediates in other synthetic transformations.On the other hand compound 11 shows an homoallylic alcohol functionality and, in this way, the electrophilic addition to the double bond at position 5 could be an interesting procedure for the synthesis of new functionalized 2,6dioxabicyclo[3.2.0]heptane derivatives such as 13 (Scheme 4b).In addition this reaction may constitute a possibility for the differentiation of both double bonds at position 2 and 5. Thus, the exploration of this synthetic approach to compounds 12 and 13 constitutes the objective of the present report.

OAc
Change of the experimental conditions (ratio 10:NIS and reaction time) did not modify this result.The formation of compounds 18 and 21 appears to be the result of a competition between two intramolecular attacks (hydroxy-or acetoxy-groups) on the epiiodoium cation intermediate 22 (Scheme 7). 22It should be indicated that this reaction path has previously been proposed, for instance, in the 1,2-hydroxyiodination of acetoxycyclohex-2-ene. 23his different behaviour of compound 10 in their reaction with NIS may be explained on the basis of the grater stability of cation 22 regarding the analogous derived from NCS and NBS. 24

Synthesis of substituted 2,6-dioxabicyclo[3.2.0]heptane derivatives 13
The reaction of compound 11 with NIS, NBS, NIS and p-nitrophenylsulphanylchloride afforded the expected oxetanes 23-26 in moderate-good yields.The results are summarized in Scheme 8.In the case of electrophilic cyclization of a homoallylic alcohol incorporated into a cyclic structure such as 11 some precedents indicate that the tetrahydrofuran derivative is the only reaction product.A representative example is shown in Scheme 10. 25 In this way the formation of compounds 23-26 is noteworthy. 26heme 10.Tetrahydrofuran formation in the electrophilic cyclization of a cyclic homoallylic alcohol.

Conclusions
In this report two types of oxetane derivatives have been synthesized using the intramolecular etherification protocol.Firstly we have described an efficient method for the preparation of 2,8disubstituted-4,7-dioxatricyclo[3.2.1.0 3,6]octane derivatives starting from readily accessible oxanorbornenic compounds.Different types of substituents have been introduced at position 8 and the final tricyclic systems constitute promising materials on the biological (potentially herbicides by analogy with other previously described) and synthetic point of view.On the other hand, the electrophilic heterocyclization of 2,5-divinyltetrahydrofuran derivatives allows for the preparation of functionalized 2,6-dioxabicyclo[3.2.0]heptane being the oxetane the only product observed.The described reaction also allowed for the chemical differentiation of both double bonds at position 2 and 5 of the starting materials.

Experimental Section
General.All reactions were carried out under an argon atmosphere employing standard techniques.All solvents were reagent grade.Dichloromethane was freshly distilled from calcium hydride.All other reagents and solvents were used as supplied.Flash chromatography was performed with silica gel 60 (230-400 mesh).Yields refer to cromatography and spectroscopically pure compounds.Starting materials.The synthesis of compounds 10 and 11 have been previously described. 20

Synthesis of compounds (14-18). General procedure
To a solution of 1.0 eq. of 10 in acetonitrile (50 mL/mmol) at r.t., 1.1 eq. of the electrophilic reagent was added.The solution was stirred at r.t.during 24 h.After this time the solvent was removed at vacuo and the reaction crude was purified by column chromatography (SiO2, hexane:AcOEt, 7:3).

Reaction of compound (10) with m-CPBA
To a solution of 27 mg of 10 (0.16 mmol) in 1.6 mL CH2Cl2, 54 mg of m-CPBA (0.32 mmol) was added.The mixture was stirred at r.t.during 24 h.After this time the reaction crude was treated with 6 mL NaHCO3 (5 %) and extracted with CH2Cl2 (5 x 10 mL).The organic extracts were dried with MgSO4, filtered and the solvent was removed at vacuo affording 24 mg (89 %) of 19 as colourless oil.

Synthesis of compounds (23-26). General procedure
To a solution of 1.0 eq. of 11 in 6.5 mL of acetonitrile, 1.1 eq. of the electrophilic reagent was added.The mixture was stirred under Ar at r.t.After the reaction time, the solvent was removed under reduced pressure and the crude product was purified by column chromatography (SiO2, hexane: AcOEt 7:3).Compound (23).From 25 mg of 11 (0.13 mmol) and 18 mg of NCS (0.14 mmol) in 6.3 mL anh.CH3CN, after 9 days of reaction 20 mg of 23 (69 %) were obtained as pale yellow oil. 1  Compound (25).From 25 mg of 11 (0.13 mmol) and 32 mg of NIS (0.14 mmol) in 6.5 mL anh.CH3CN, after 6 days of reaction 30 mg of 25 (73 %) were obtained as pale yellow oil. 1
1H And 13 C Nuclear Magnetic Resonance spectra were recorded on a Bruker AM-300 (300 MHz) and a Bruker AVIII-700 (700 MHz) NMR spectrometer in deuterocloroform, deuterated acetone and hexadeuterobenzene.Assignments of proton ( 1 H NMR) and carbon ( 13 C NMR) signals have been secured by DEPT 135, COSY 45, HMQC and HMBC experiments.Coupling constants are given in Hz, and chemical shifts are expressed as δ values in ppm.Melting points are uncorrected and were determined using a Gallenkamp instrument.IR spectra were obtained on a Perkin-Elmer apparatus in solution of CHCl3.Elemental analyses were carried out using a Perkin-Elmer 2400 CHN apparatus at the Complutense University, Madrid.