Synthesis of 1-Methyl-3-oxo-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic Acid Methyl Ester

A simple and efficient method for the preparation of 1-methyl-3-oxo-7-oxabicyclo[2.2.1]hept-5-en-2-carboxylic acid methyl ester (1) is described. The first step is a highly regioselective Diels-Alder reaction between 2-methylfuran and methyl-3-bromo-propiolate. A remarkably difficult ketal hydrolysis reaction was effected by treatment with HCl, a simple reagent that was shown to be more efficient, in this case, than commonly used more elaborate methods.


Introduction
7-Oxabicyclo[2.2.1]hept-5-ene derivatives are important intermediates and the base-induced opening of the oxygen bridge of these types of compounds has been used in the stereoselective syntheses of a number of shikimic acid derivatives and other natural products [1][2][3]. These systems have also acquired increasing importance as starting materials ("naked sugars") for the synthesis of numerous sugars, C-nucleosides, etc. [3][4][5].  In this paper we describe a short and efficient synthesis of methyl 1-methyl-3-oxo-7oxabicyclo[2.2.1]hept-5-en-2-carboxylic acid methyl ester (1, Figure 1), starting with a Diels-Alder reaction between 2-methylfuran (2) and methyl 3-bromopropiolate (3) (Scheme 1). In spite of its apparent simplicity, each of the three steps of this synthesis has a remarkable aspect due to the special properties of these compounds. (2) is commercially available, whereas the dienophile, methyl-3-bromopropiolate (3) had to be prepared by the reaction of methyl propiolate with N-bromosuccinimide in acetone with silver nitrate as catalyst (86% yield) [6]. The methyl propiolate was previously prepared by esterification of propiolic acid with methanol/sulfuric acid (2 days, 65% yield).

2-Methylfuran
The Diels-Alder reaction between the diene 2 and dienophile 3 (benzene, 24 h reflux, Scheme 2) resulted in a 15.7:1 mixture of the regioisomers 4a and 4b, respectively, which were separated by column chromatography and analyzed by nuclear magnetic resonance (NMR), with the assignment of all hydrogens, carbons and coupling constant values being accomplished using a combination of 1 H-NMR, 13 C-NMR, gsHMQC and gsHMBC. A remarkable aspect of this reaction is the high regioselectivity observed. The treatment of adduct 4a with sodium methoxide in methanol at room temperature gave ketal 5a, the endo product, as expected for a kinetic protonation process [7]. Compound 5a was isolated by column chromatography in 87% yield. The next step was the hydrolysis of ketal 5a. Leroy, in his paper concerning the synthesis of analogous compounds [3], emphasized the difficulties of the ketal hydrolysis step. After some attempts he found that the H + form of the perfluorosulfonic acid resin Nafion ® -501, (Nafion-H), led to the corresponding ketone in 68-83% yield. However, this reagent is expensive and requires long reaction times (4 days).
We investigated several reagents and reaction conditions such as oxalic or sulfuric acid on wet silica gel, lithium tetrafluoroborate in wet acetonitrile, Amberlyst ® -15 in wet acetone, but none led to the desired hydrolysis. The treatment of 5a with PPTS (pyridinium p-toluenesulfonate) gave less than 10% of 1, and required a large (tenfold) excess of PPTS and 16 hours at reflux [8]. Finally, we found that in conc. HCl solution in methanol (room temperature, 7 hours), ketal 5a was converted to ketone 1 in 82% yield. The unusual lack of reactivity of 5a can be attributed to the retarding inductive effect of the 7-oxa bridge on the formation of cationic intermediates at C-3.
However, the double bond of 5a also seems to play a stabilizing effect on the intermediate carbocation (possibly through conjugation forming a non-classical ion, as shown in Scheme 3), because after reduction of the double bond (H 2 /Pd), the hydrolysis occurred readily providing a complex mixture from which only 7% of the corresponding ketone could be isolated (Scheme 4).

Scheme 4 O OMe
OMe Further support for a favorable role of the double bond in the hydrolysis was provided by the fact that we found that lactone 10 [9] (which was prepared from 5a as shown in Scheme 5 to confirm its stereochemistry) did not undergo any transformation when treated with conc. HCl solution for 4 days.

Conclusions
The desired product title compound 1 was obtained in 38% overall yield in a short and efficient 3step synthesis. The high regioselectivity of the Diels-Alder reaction gives an important contribution to the efficiency of the process. Also remarkable are the stereoselectivity of the ester 5a formation, and the hydrolysis of the resistant ketal with a very simple reagent, while more sophisticated methods proved to be inefficient.

Acknowledgements
The autors wish to thank the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for financial support.

General
Melting points were determined on a Reichert Kofler block melting point apparatus and are uncorrected. 1 H-NMR and 13 C-NMR spectra were measured using a Bruker DPX-400 instrument (at 400 MHz and 100 MHz, respectively); deuteriochloroform was used as solvent and tetramethylsilane as an internal standard. IR spectra were measured with a Perkin-Elmer Spectrum RX IFTIR System. TLC was performed on precoated silica gel 60 F254 plates (0.25 mm thick, Merck), and silica gel 60 (70-230 mesh, Merck) was used for column chromatography. A solution of compound 4a (1.01 g, 4.12 mmol) in methanol (6 mL) was added dropwise to a 1M solution of sodium methoxide in methanol (20 mL), cooled with an ice bath. The reaction mixture was stirred for 2 h and then allowed to warm slowly to room temperature. The mixture was cooled again to 4 °C and then treated with 1:1 aqueous hydrochloric acid solution until pH 5. The methanol was removed under vacuum and the products were extracted with ethyl ether. The combined organic extracts were washed with saturated brine and dried over anhydrous MgSO 4 . The solvent was removed under vacuum and the residue was purified by chromatography in a silica gel column, eluting with hexane/ethyl acetate (7:3), yielding 0.818 g (87%) of 5a as a yellow solid; m.p. 60-62 °C; 1 H-NMR δ:  (1) Conc. hydrochloric acid solution (1.0 mL) was added dropwise at room temperature to a solution of compound 5a (103.5 mg; 0.454 mmol) in methanol (1.5 mL). The reaction mixture was stirred for 7 h. The resultant mixture was treated with water (1 mL) and extracted with ethyl ether. The organic extracts were washed with saturated NaHCO 3 solution, then dried over anhydrous MgSO 4  (1S*,2R*,4R*)-3,3-Dimethoxy-1-methyl-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid (9) Compound 5a (102.1 mg, 0.448 mmol) was stirred with 5% NaOH solution (2.6 mL) cooled with an ice bath for 4.5 h or until complete dissolution of 5a. The resultant mixture was diluted with water (8.5 mL) and washed with light petroleum (8.5 mL). The aqueous phase was cooled to 4 °C, treated with 1:1 aqueous HCl to pH 2 and then the product was extracted with chloroform. The organic extracts were dried over anhydrous MgSO 4