An Efficient and Short Route for the Synthesis of Reverse Pyrrole Ribonucleosides

Neste trabalho estão descritas as sínteses dos ribonucleosídeos pirrólicos reversos 5-C-(4acetil-5-metil-pirrol-1-il)-2,3-O-isopropilideno-5-desoxi-β-D-ribofuranosídeo de metila (10), 5-C(4-etoxicarbonil-5-metil-pirrol-1-il)-2,3-O-isopropilideno-5-desoxi-β-D-ribofuranosídeo de metila (11), 5-C-(4-acetil-5-metil-pirrol-1-il)-5-desoxi-β-D-ribofuranosídeo de metila (12), 5-C-(4etoxicarbonil-5-metil-pirrol-1-il)-5-desoxi-β-D-ribofuranosídeo de metila (13), 5-desoxi-5-C-(3’formil-4’-hidroxipropil-pirrol-1’-il)-2,3-O-isopropilideno-β-D-ribofuranosídeo de metila (16) e 5desoxi-5-C-(3’-formil-pirrol-1’-il)-2,3-O-isopropilideno-β-D-ribofuranosídeo de metila (18) a partir do 5-amino-5-desoxi-2,3-O-isopropilideno-β-D-ribofuranosídeo de metila (9), matéria-prima de fácil preparação. A estratégia sintética para a construção do anel heterocíclico baseou-se no ataque nucleofílico da amina 9 aos diidrofuranos: 4-acetil-2-n-butoxi-5-metil-4,5-diidrofurano (4), 4carbetoxi-2-n-butoxi-5-metil-4,5-diidrofurano (5), 4-formil-2-n-butoxi-4,5-diidrofurano (6) e 4formil-1-metil dioxabiciclo[3.3.0]oct-3-eno (8, in situ), obtidos através da reação dos diazo compostos 3-diazo-2,4-pentadiona (1), 2-diazoacetoacetato de etila (2) e diazomalonaldeído (3) com enoléteres, sob catálise de tetraacetato de di-ródio.


Introduction
The pyrrole unit occurs in many interesting classes of compounds such as polymers, 1 molecular electronics 2 and as building blocks in important natural products, such as heme, chlorophyll, bile pigments, and vitamin B 12 .It is also present, for example, in the structure of alkaloids from marine polysources, 3 N-bridged pyrroles and pyrrolizidine and indolizidine alkaloids. 4A large variety of polyhalogenated pyrroles isolated from natural sources showed pronounced physiological activities. 5A series of synthetic 1,2-diarylpyrroles were found to be potent and selective inhibitors of the human cyclooxygenase-2 (COX-2) enzyme. 6Recently, some 1-phenyl-3-(aminomethyl) pyrroles prepared from aniline showed high affinities for D2, D3, and D4 dopamine receptor subtypes. 7he syntheses of pyrrole heterocycles have been featured in a number of review articles and books. 8,9The classical methods for the preparation of pyrroles include the Knorr synthesis, the Paal-Knorr synthesis, the Hantzsch synthesis, and cycloaddition reactions between nitrile ylides and alkynes. 10Although these synthetic approaches are broad, more versatile, selective and efficient methods are still desirable.
In the area of nucleosides, only few methods are suitable for preparing pyrrole nucleoside derivatives. 11The development of synthetic methods that allow access to nucleoside analogs having modifications in both the sugar and heterocycle moieties is decidedly important and have been extensively studied.For example, 2',3'-dideoxyribonucleosides such as 3'-azido-3'-deoxythymidine (AZT), 2', 3'-dideoxyinosine (DDI), 2', 3'-dideoxycytidine (DDC) and β-L-(-)-2'-deoxy-3'-thiacytidine (Lamivudine      , 3TC) are potent antivirals being effective against human immunodeficiency virus (HIV). 12Ganciclovir and Cidofovir      are drugs available for treatment of human cytomegalovirus (HCMV). 13Oxetanocins A and B are carbocyclic nucleosides that show potent antiviral, antitumor, and antibacterial activities, including activity against HCMV. 14s part of an ongoing research program on the synthesis of new nucleoside compounds 15 and on the basis of our experience in the field of the use of a-diazocarbonyl compounds 16 in organic synthesis, we report herein an efficient and short route for the synthesis of reverse pyrrole ribonucleosides employing a methodology that consists in the construction of the heterocyclic ring starting from methyl 5-amino-5-deoxy-2,3-O-isopropylidene-β-Dribofuranoside (9), a readily available starting material.

General procedures
Melting points were determined on a Fisher-Johns apparatus and are uncorrected.Analytical grade solvents were used.Dry tetrahydrofuran was freshly distilled from sodium and benzophenone before being used.Chromatography column was performed on silica gel 60 (Merck 70-230 mesh).Infrared spectra were recorded on a Perkin-Elmer 1420 spectrophotometer.NMR spectra were recorded with a Varian Unity Plus 300 spectrometer, operating at 300 MHz ( 1 H) and 75 MHz ( 13 C), with tetramethylsilane as the internal standard.Low-resolution electron-impact mass spectra (12 eV and 70 eV) were obtained using a Hewlett Packard 5985 instrument.High-resolution electron-impact mass spectra (70 eV) were obtained using VG Auto Spec instrument and high-resolution fast atom bombardment mass spectra (HRFABMS) were recorded in a 3-NBA (3-nitrobenzyl alcohol) matrix in the positive ion mode on a VG ZAB-E mass spectrometer.3-Diazo-2,4-pentadione (1), 17 3-diazoethyl acetoacetate (2), 18 diazomalonaldehyde (3) 19 and aminofuranoside (9) were prepared following the procedures described in the literature.The dihydrofurans 4 and 5 had their preparation reported recently. 20Purified samples were used for measuring physical constants and spectral data.

General procedure for obtaining 16 and 18
A solution of diazomalonaldehyde (3) in 10.0 cm 3 of freshly distilled vinyl ether was slowly added at a rate of 1.0 cm 3 /h (syringe pump) to a stirred suspension of dirhodium tetraacetate (0.03 mmol) in 15.0 cm 3 of the same vinyl ether as solvent, under nitrogen atmosphere.Stirring was carried on for 24 hours or more.The organic mixture was concentrated under reduced pressure, the catalyst was removed by chromatography column on Florisil      using nhexane:chloroform (1:1) as eluent.The organic mixture was concentrated under reduced pressure, followed by the addition of 10.0 cm 3 of methanol, the appropriate amine and 0.2 cm 3 of glacial acetic acid.The mixture was stirred for 48 hours.The solvent was removed under reduced pressure and the residue was purified by chromatography column on silica gel, using n-hexane:chloroform (1:1) or chloroform: acetone (9:1) as the eluent.

Results and Discussion
The syntheses of the pyrrole compounds were carried out in two steps.The first one involved the preparation of 3carbonyldihydrofuran derivatives 4-8, which were obtained from the reaction of diazo carbonyl compounds 1-3 with enol ethers under dirhodium tetraacetate catalysis, as outlined in Scheme 1.The diazo compounds reacted easily with n-butyl vinyl ether to produce the dihydrofurans 4, 5 and 6 as previously reported. 21All attempts to perform the reaction between 1 or 2 and cyclic enol ethers were unsuccessful.The same reactions with diazomalonaldehyde (3) produced the dihydrofuran derivatives 7 and 8, which were difficult to isolate.It is important to note that some of these dihidrofurans have been used in many syntheses of furanoid terpenes, 22 and more recently by us in the synthesis of substituted N-alkylpyrroles. 21he nucleophilic attack of methyl 5-amino-5-deoxy-2,3-O-isopropylidene-β-D-ribofuranoside 23 (9) on the dihydrofurans 4 and 5 was performed under two different conditions: a) acetic acid, methanol, 80 o C; b) acetic acid, isopropanol/water (2:1), 100 o C. It is expected a slightly different reactivity between 4 and 5 since the former reaction involves a nucleophilic attack to vinylogous carbonyls of 3-carbonyl-dihydrofurans.In fact, in this reaction, dihydrofuran 4 proved to be more reactive than the dihydrofuran 5 since the former reacted at less drastic conditions.Usual work up and purification of the crude products by chromatography column led to the nucleosides 10 and 11 in moderate yields.Their structures were confirmed mainly based on their 13 C and 1 H NMR spectra.Selective deprotection of 2' and 3' hydroxyl groups of the later compounds, in refluxing iodine/methanol, produced the crystalline ribonucleoside derivatives 12 and 13 in 70% and 66% yield, respectively.Diazomalonaldehyde (3) was easily decomposed with dirhodium tetracetate catalyst in the presence of n-butyl vinyl ether or the cyclic enol ethers to produce the dihydrofurans 6, 7 and 8 (Scheme 3) which are very sensitive to acid and partially decompose during work up in the process of removing Rh 2 (OAc) 4 by filtration through silica gel column.On the other hand, with the use of a Florisil  column in this procedure it was possible to isolate 7 as a sufficiently pure compound for spectroscopic purpose.We suppose this dihydrofuran is more stable than 6 and 8 due to the methyl group of the ring junction.
In order to circumvent the instability problem of the dihydrofurans 6, 7 and 8, the reaction of these compounds with benzylamine without their previous purification was investigated next.The reaction of diazomalonaldehyde (3) with n-butyl vinyl ether, dihydropyran or methyl-dihydrofuran, in the presence of catalytic amount of dirhodium tetraacetate, produced the crude mixtures of the 3-carbonyldihydrofurans 6, 7 and 8.After removal of the rhodium catalyst by filtration through a Florisil  pad eluted with hexane/chloroform 50%, the organic mixture was concentrated under vacuum and the reaction with benzylamine was performed in methanol/acetic acid yielding the corresponding pyrroles 14, 15 and 17 in 50%, 53% and 16% yields, respectively (Scheme 3).
Having succeeded in these reactions, dihydrofurans 6 and 8 were reacted with the aminoribofuranoside 9, using this previously established general procedure.This led to the desired pyrrole ribonucleoside derivatives 18 (73%) and 16 (37%), respectively (Scheme 3).The lower yield in the synthesis of 16 is probably related to the lower stability of the dihydrofuran intermediate 8 in the acidic condition.The structures of these pyrrole derivatives were assigned mainly based on their 13 C and 1 H NMR spectra.The pyrroles 14, 15, 16 and 18 are new compounds in the literature, while 17 was previously synthesized by two other different routes. 24,25

Conclusions
Novel methodologies concerning the preparation of pyrroles continue to be extensively studied during these years leading to new dimensions in the design of synthetic strategies for the construction of the heterocyclic ring.This work highlights the applicability of a simple methodology based on the pyrrole ring construction for the synthesis of reverse nucleoside analogues.Even though this methodology was not tested for a large number of dihydrofurans and for other amine-carbohydrates, this seems to be a good process for obtaining new reverse pyrrole nucleosides in few steps.