Racemic Synthesis of 1 , 2-Seco microminutinin

Rosangela da Silva*, Paulo Marcos Donate, Gil Valdo José da Silva, Susimaire Pedersoli a and Carlos Alemán Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 3900, 14040-901 Ribeirão Preto SP, Brazil Departament d’Enginyería Química, E.T.S. d’Enginyers Industrials de Barcelona, Universitat Politécnica de Catalunya, Diagonal 647, Barcelona E-08028, Spain

These compounds are of special interest since they show very interesting properties depending on their chemical constitution.Many of them are highly toxic, mutagenic or carcinogenic, like aflatoxin B2 (2), a secondary fungal metabolite produced by certain strains of Aspergillus flavus. 1 They can also have useful properties due to their biological and pharmaceutical activity, like the antimalarial activity 2 presented by pseudosemiglabrin derivatives (3 and 4), two flavonoid metabolites isolated from a subtropical plant of the genus Tephrosia.And there still is the anticoagulant activity 3 of coumarins 5 and 6.
Although the relevant biological and chemical properties of these natural products have translated into considerable synthetic interest; the syntheses of the natural products 7 and 8 have not been reported yet.Recently, we described the syntheses and the conformational studies 5 of several model compounds of natural products containing the basic benzofuranofuran skeleton.The intramolecular [2+2] cycloaddition of alkoxyketenes with alkenes, developed by Snider et al. 6 and by Brady et al., 7 was used as a useful synthetic method in the preparation of these polycyclic compounds.As part of our interest in the synthesis of a family of compounds bearing the benzofuranofuran moiety, this methodology was also used to synthesize, for the first time, the racemic cinnamic ester derivative 1,2-secomicrominutinin (25).

Results and Discussion
The synthesis started with the treatment of commercial methyl 2,6-dihydroxybenzoate with benzyl bromide and tetrabutylammonium fluoride (TBAF), to selectively protect only one of the hydroxyl groups, 8 producing compound 9 in 85% yield (Scheme 1).Attempts to use other bases (NaH, KOH, t-BuOK) instead of TBAF favors the protection of both hydroxyl groups.The protection of the second hydroxyl group 9 by reaction of 9 with methoxymethyl chloride and N,N-diisopropylethylamine (DIPEA) 10 furnished compound 10 in 95% yield.The reduction of the carboxyl group 11 of compound 10 with LiAlH 4 furnished the corresponding alcohol 11 in 96% yield.The aldehyde 12 was obtained in 90% yield after the oxidation of 11 with pyridinium dichromate (PDC). 12Wittig reaction 13 of 12 with ethylidenetriphenylphosphorane furnished compound 13 in 79% yield.Compound 14, with only one of the hydroxyl group deprotected, was obtained in 90% yield after selective cleavage of the methoxymethyl group of 13 with HCl in methanol. 14Reaction of 14 with bromoacetic acid produced compound 15 in 88% yield, which, after intramolecular [2+2] cycloaddition reaction, 6,7 furnished the tricyclic benzocyclobutafuranones 16 in 73% yield.The benzofuranofuranone 17 (R = Bn) was obtained in 81% yield through a Baeyer-Villiger oxidation of 16.Studies on the Baeyer-Villiger reaction indicate that the regioselectivity of asymmetric ketones is directed by the migratory aptitude of the groups adjacent to the carbonyl, reflecting the ability of the migrant group to accept a partial positive charge in the transition states. 15In the case of compound 16, the cationstabilizing effect of the unshared oxygen electron pairs increases the relative migratory aptitude of the attached carbon.Hydrogenolysis of the benzyl group of 17 produced the corresponding hydroxybenzofuranofuranone 18 (R = H), in 97% yield, and 18 is an analogue of the biologically active compounds 5 and 6.Attempts to remove the protective benzyl group resulted in hydrogenation of the exocyclic double bond.Because of that, the hydroxyfuranone 18 was reacted with methoxymethyl chloride and N,Ndiisopropylethylamine (DIPEA) 10 to furnish the protected compound 19 (R = MOM) in 95% yield.Reaction of 19 with phenylselenenyl chloride, using LDA as a base, 16 produced the selenophenyl derivative 20 in 70% yield.Reaction of compound 20 with H 2 O 2 at 0 o C furnished 98% of a mixture of the unsaturated furanone 21a with an exocyclic methylene group, and its isomer 21b with an endocyclic double bond (ratio 2:1).After the separation of the two isomers, the treatment of lactone 21a with diisobutylaluminium hydride (DIBAL-H) yielded lactol 22 (not isolated), which, by reaction with triethylsilane and trifluoroacetic acid, furnished ether 23 in 72% yield in two steps. 17The use of this two-step procedure, which joins a low-temperature reduction followed by a highly chemoselective deoxygenation, was more favorable in terms of operational simplicity and overall yield when compared with other methods. 17The methoxymethyl protective group in compound 23 was cleaved in 80% yield by treatment with HCl in methanol 14 to produce 3-methylene-2,3a,8a,trihydro-benzo[b]furano [3,2-d]furan-4-ol (24), which is a precursor of the natural products 7 and 8.
The traditional Pechmann reaction 18 cannot be used to prepare the coumarinic ring of microminutinin (7) and its derivatives directly from compound 24 because this compound is very sensitive to the acidic conditions generally used in that reaction.Hoefnagel et al. 19 synthesized several coumarins in moderate yields through the reaction of resorcinol and propynoic acid catalyzed by Amberlyst-15 or zeolite H-beta, at 150 o C.However, the ketal function of compound 24 was cleaved under these conditions.Yavari et al. 20 obtained coumarins in good yields by the reaction between phenols and dimethyl acetylenedicarboxylate in the presence of triphenylphosphine under reflux in dichloromethane.Nevertheless, decomposition of the starting material was also observed when this reaction was carried out with compound 24.Therefore, this latter methodology was adapted to be employed in very mild conditions.Under these milder conditions, the coumarinic ring is not produced, but instead, very interesting 1,2secomicrominutinin derivatives are obtained.These cinnamic ester derivatives are the unsaturated analogues of the natural product 8, and may be used as very valuable intermediates for the synthesis of natural products with the benzofuranofuran skeleton.Thus, compound 24 and triphenylphosphine were dissolved in dichloromethane and a solution of methyl propiolate in dichloromethane was slowly added, maintaining the reaction mixture under stirring for 24 hours at room temperature.Analysis by 1 H NMR, 13  and IR revealed that the product obtained in 81% yield was a mixture of the unsaturated isomers 25 and 26 in the proportion of 2:1, respectively (Scheme 2).Presumably, these two isomers are formed because the electrophilic attack of the vinyltriphenylphosphonium cation (resulting from the initial addition of triphenylphosphine to the acetylenic ester followed by concomitant protonation) 20 on the aromatic ring of 24 is influenced by the strong ortho/para activating groups on the aromatic ring.
Stereochemical assignment of the acrylate double bond is usually based on the magnitude of the vicinal coupling constant of the corresponding hydrogens in the 1 H NMR spectra.The range for E isomers is 12 to 18 Hz, and 6 to 12 Hz for Z isomers.In this work, the measured values for compounds 25 and 26 were 12.1 and 12.4 Hz, respectively, making an unequivocal attribution difficult.On the other hand, the chemical shifts of the hydrogens on the acrylic β-carbons of these compounds were 7.80 and 7.66, respectively.Based on numerous examples from the literature, 21 we can suggest that the prepared compounds are E isomers.
All attempts to obtain microminutinin (7) either straightforward from compound 24 by reaction with several kinds of reagents, [18][19][20] or by the ring closure of the 1,2secomicrominutinin (25) were unproductive.This failure can be another evidence for the fact that the double bond of compound 25 has an E configuration, since it is wellknown that E isomers of 3-(2-hydroxyaryl)propenoic esters are difficult to cyclize to the corresponding coumarins by traditional methods. 21The lability of the ketal function present in the compounds under investigation prevents the use of more drastic methods such as heating or pyrolisis.

Conclusions
We have reported the first successful racemic synthesis of the cinnamic ester derivative 1,2-secomicrominutinin (25) by the intramolecular cycloaddition of an (alkenyloxy)ketene followed by the reaction, under mild conditions, of a benzofuranofuran moiety with methyl propiolate.

Experimental
All 1 H and 13 C NMR spectra were recorded at 300 and 75 MHz, respectively, using a Bruker DPX-300 instrument and chloroform-d (CDCl 3 ) as solvent; chemical shifts are in ppm downfield from tetramethylsilane internal standard.IR spectra were measured KBr) with a Perkin Elmer Spectrum RX IFTIR System, and the most intense or representative bands are reported (in cm -1 ).Mass spectra were determined at an ionizing voltage of 70 eV, using a HP 5988-A spectrometer.The mass spectra of compounds 25 and 26 were performed by electronspray ionization (ESI), using a Micromass Quattro LC spectrometer.Solutions were infused into the Z-spray source at 10 µL min -1 (0.5 mg mL -1 ), and the protonated parent ions were observed at m/z 275.TLC was performed on plates precoated with silica gel 60 F 254 (0.25 mm thick, Merck) and column chromatography separations were performed with silica gel 60 (70-230 mesh, Merck).Melting points were determined on a Reichert Kofler block apparatus and are uncorrected.