Bioorganic and medicinal chemistry / Chimie bioorganique et thérapeutique

Structure elucidation of benzopyran-2-ol insolution and in solid state following the reductionof coumarin by DIBAL-HYves Jacquota, Bernard Refouveleta*, Olivier Blacqueb, Marek M. Kubickib,Alain Xiclunaa

a Équipe de chimie thérapeutique, faculté de médecine et de pharmacie, université de Franche-Comté, 25030 Besançoncedex, Franceb Laboratoire de synthèse et d’électrosynthèse organométallique (UMR 5632), faculté des sciences Gabriel, université deBourgogne, 21000 Dijon, France

Communicated by Andrée Marquet

Received 22 January 2001; accepted 9 March 2001

Abstract – Lactols are compounds of increasing interest in the synthesis of active pharmaceutical derivatives. Neverthe-less, the product obtained by the reduction of the carbonyl group of coumarin has been described only twice, andwithout definition of its precise chemical structure. Since these studies, doubts have been raised about the existence of amonomeric or dimeric form. Our study has led us to conclude definitely that the single dimeric form exists and toprecisely define the spectral properties of the two diastereoisomers. © 2001 Académie des sciences / Éditions scientifiqueset médicales Elsevier SAS

coumarin / lactol / acetal / NMR / X-ray data

Résumé – Détermination structurale du benzopyran-2-ol en solution et à l’état solide. Les lactols sont des compo-sés présentant un intérêt croissant dans la synthèse de dérivés pharmacologiquement actifs. Cependant, le produit obtenupar réduction du carbonyle de la coumarine n’a été décrit que deux fois, sans que sa structure chimique exacte ne soitprécisée. Depuis ces études, il existe un doute entre l’existence de la forme monomérique et l’existence de la formedimérique. Notre étude nous a permis de conclure définitivement en faveur de la forme dimérique et de définir lespropriétés spectrales des deux diastéréoisomères. © 2001 Académie des sciences / Éditions scientifiques et médicalesElsevier SAS

coumarine / lactol / acétal / RMN / rayons X

1. Introduction

As part of our studies concerning the reactivity ofα,� unsaturated ketonic compounds [1, 2] in thecontext of the discovery of new pharmaceuticalcompounds active on estrogen receptors, we havestudied the structure of lactol in solid state and insolution, because of its interest as a potential phar-

macophore in antiestrogenic activity [3]. Syntheticcoumarins are used in the elaboration of new drugsin several medicinal domains as a result of theirpharmacological activity. Presently, coumarins havebeen precisely defined as anticoagulant drugs [4],antibacterial agents [5], photosensibilising drugs [6]or new antiprotease HIV–1 agents [7]. Lactols arehemiacetals derived from coumarins and are

* Correspondence and reprints.E-mail address: Bernard.Refouvelet@univ-fcomte.fr (B. Refouvelet). S

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increasingly more interesting in drug design, par-ticularly in the elaboration of potent Selective Estro-gen Receptor Modulators (SERM’S) [3]. Otherchemical analogues are encountered as sugarderivatives [8], antithrombotic drugs such as Desmin370 [9], cytotoxic agents [10], or as anti-inflammatory compounds [11]. The most powerfulorganometallic agent used for the reduction of lac-tones into lactols [12] is diisobutylaluminum hydride(DIBAL-H), a reagent developed by Cook et al. [13],and Corey et al. [14–17] during the course of thetotal stereospecific synthesis of prostaglandins.Other organometallic methods [18–20] have alsobeen described, including the reduction of pyran-2-ones or coumarins. Moreover, the reduction byDIBAL-H is a method of choice to obtain substi-tuted benzopyran-2-ol. Loncar et al. [21] reportedlactol as a non isolable monomer, whereas Wulff etal. [22] have reported the presence of a dimer with-out stating its stereochemistry.

Since the structure and the stereochemistry of theproduct obtained from reduction of the coumarinhas not yet been accurately elucidated by NMR andX-ray, we have determined the structure of thereduced product from coumarin by these methods.Both X-ray and NMR data point to the formation ofa dimer as a mixture of two diastereoisomers.

2. Results and discussion

The reduction of the lactone 1 carbonyl groupsto the corresponding lactol hemiacetal was per-

formed by the action of DIBAL-H in anhydroustoluene (figure 1). This process was followed bymonitoring in liquid FTIR the decrease of theabsorption band at 1 730 cm–1.

Reduction of 1 with diisobutylaluminum hydride(DIBAL-H) gave meso-di-2H-chromen-2-ylether 2 in17 % yield and (±)-threo-di-2H-chromen-2-ylether 3in 83 %.

Compounds 2 and 3 were obtained from theresulting lactol hemiacetal, which was not isolated.The separation of the diastereomeric mixture of 2and 3 was realised through column chromatogra-phy followed by recrystallisation in isopropanol.The separation is somewhat difficult because of thebalance between the two anomeric forms of lactolhemiacetal. A mechanism involving the openingand the closure of the ring of the lactol hemiacetalstructure could be responsible for the balancebetween these two forms [23, 24] (figure 2). Actu-ally, isomer 2 can be transformed easily into isomer3 in acidic conditions. A similar mechanism hasbeen suggested to account for the mutarotation ofsugars.

3. Experimental section

All compounds were characterised using themethods of melting points, FTIR, NMR spectros-copy, X-ray analysis, mass spectrometry (EI–MS).Melting points (mp) were obtained with a KoflerHeizbank Reichert 8.43.21. and were uncorrected.Infrared spectra were performed on a Shimadzu

Figure 1. Synthetic route followed todi-2H-chromen-2-ylether.

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FTIR-8201PC spectrometer in potassium bromidepellets for solids and in the form of liquid films foroils. Proton and carbon NMR spectra were recordedon a Bruker AC200 spectrometer. The samples weredissolved in CDCl3. All the measurements were per-formed at 293 C. The chemical shift values arereported in parts per million (ppm, δ units), refer-enced to internal tetramethylsilane (Me4Si), andspin-spin coupling J is expressed in Hz. Splittingpatterns are designed as s, singlet ; d, doublet ; t,triplet ; q, quartet ; m, multiplet. X-ray analyseswere recorded on a CAD4 Enrof-Nonius diffracto-meter. Mass spectrometry (MS) was done on a Ner-mag R10–10H apparatus with a Coniphot detector.EI–MS was performed with a ionising voltage of

70 eV and in the direct-inlet mode. Thin-layer chro-matography (TLC) was carried out on an AlugramSil G/UV254 plate with appropriate solvents. Col-umn chromatography was done on a MN Kiesel-gel 60 (70–230 mesh). Anhydrous Na2SO4 was usedas the drying agent. All solvent evaporations wereperformed under vacuum. Yields were not opti-mised.

3.1. Synthesis of meso- and threo-di-2H-chromen-ylether(2) and (3)

The reduction of coumarin was performed as fol-lows. Toluene was distilled and dried over 4 Åmolecular sieve (4–8 mesh) and DIBAL-H kept at4 °C. In a typical experiment, 34 mmol of coumarin

Figure 2. Equilibrium between the twoanomeric forms of lactol-hemiacetal.

Figure 3. 5.8–7.0 range 1H-NMR ofcompound 2.

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1 and 34 mmol of DIBAL-H in THF in 50 mL drytoluene were stirred in a dry three-necked flaskequipped with a rubber septum, under a nitrogenatmosphere and cooled to –40 °C with a MeOHbath cooled by liquid nitrogen for 7 h. The yellowsolution was gradually warmed to 0 °C and thenhydrolysed into a large volume of water and stirredfor 10 min. 30 mL of CH2Cl2 was then added andthe resulting mixture stirred for a further 10 min.The filtrate was eliminated by filtration undervacuum and the organic layer was isolated byextraction. The extract was dried over Na2SO4 andevaporated in vacuo. Dissolved in 1 mL of CH2Cl2,the residue was chromatographed on silica gel Kie-selgel 60 using ethyl acetate and n-hexane (0.5:9.5)as the eluent, to give two diastereoisomers 2 and 3.Each isolated diastereoisomer was recrystallisedfrom isopropanol.

The H1-NMR data allowed us to distinguish dias-tereoisomers 2 and 3: two sets of resonances wereobserved for the H2, H3 and H4 protons of com-pounds 2 and 3 (figures 3 and 4).

meso-di-2H-chromen-2-ylether (2). Colourlessprisms. Yield : 17 %. mp 180 °C. 1H-NMR (CDCl3)δ : 5.87 (1H, dd, 3J = 3.8 Hz, 3J = 9.8 Hz), 6.10 (1H,d, 3J = 3.8 Hz), 6.72 (1H, d, 3J = 9.6 Hz), 6.85–7.29

(8H, m). IR νmax cm–1 (KBr) : 3 047.3, 1 635.5,1 608.5, 1 488.9, 1 203.5, 939.3. EI–MS m/z : 277.95(M+, calcd for C18H14O3 : 278.31).

(±)-threo-di-2H-chromen-2-ylether (3). Colourlessprisms. Yield : 83 %. mp 168 °C. 1H-NMR (CDCl3)δ : 5.76 (1H, dd, 3J = 3.8 Hz, 3J = 9.7 Hz), 6.30 (1H,d, 3J = 3.9 Hz), 6.70 (1H, d, 3J = 9.3 Hz), 6.85–7.29(8H, m). IR νmax cm–1 (KBr) : 3 045.0, 1 645.2,1 608.5, 1 488.9, 1 201.6, 956.6. EI–MS m/z : 277.95(M+, calcd for C18H14O3 : 278.31).

3.2. X-ray structure determination for compound 2

The study by X-ray analysis of the minor isolatedisomer 2 showed the existence of a dimer ofbenzopyran-2-ol. The stereochemistry of compound2 was established as meso-dimer. Thus, 3 shouldhave the (±)-threo configuration.

The crystal structure of the minor isomer 2,recrystallised from acetonitrile, exhibits, as shownby the ORTEP drawing, a meso dimer form (fig-ure 5)

A colourless crystal recrystallised from acetoni-trile and having the approximate dimensions0.30/0.30/0.25 mm was mounted on a CAD4 Enrof-Nonius diffractometer. The data were collected at

Figure 4. 5.6–6.8 range 1H-NMR of compound 3.

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room temperature Mo Kα radiation (λ = 0.710 73 Å).The unit cell was determined from 25 reflectionsselected by the CAD4 routines [25].

Crystallographic data: C18H14O3, Mw = 278.29,orthorhombic Pbca (No. 61), a = 10.763(1) Å,b = 11.594(2) Å, c = 22.601 Å, V = 2 820.2(7) Å3,Z = 8, ρcalc = 1.311 g·cm–3, F (000) = 1 168,µ = 0.089 mm–1, 2 967 reflections measured, 2 389unique data, with I > 2 σ (I ).

A total of 2 389 intensities were reduced with theXCAD4PC data reduction program [26]. The struc-ture was solved in the orthorhombic space groupPbca by direct method and refined by full-matrixleast-squares methods (based on F 2) [27]. Allthe non-hydrogen atoms were refined with aniso-tropic thermal parameters and the hydrogenatoms bonded to carbons were included in calcu-lated positions and refined with a riding model.Final residuals are: R1(F

2) = 0.056/0.187 andwR2(F

2) = 0.128/0.171 (I > 2 σ(I ) /all data). Othercrystallographic information including atomic coor-dinates, bond lengths and angles may be obtainedfrom the authors.

4. Conclusion

In conclusion, the synthesis of benzopyran-2-olrequires the preliminary synthesis of di-2H-chromen-2-ylether via the reduction of coumarin.The meso and the threo derivatives were isolatedand clearly defined by NMR experiments and byX-ray analysis of the meso dimer.

Acknowledgements. This work was supported in part by ‘La ligue nationale contre le cancer’.

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Figure 5. ORTEP drawing of compound 2. Molecular structure2, as determined by a single crystal X–ray diffraction study.Selected bond lengths (Å) and angles (°). O(1)–C(1) 1.410(5),O(1)–C(10) 1.468(4), O(2)–C(1) 1.395(5), O(2)–C(5) 1.372(4),O(3)–C(10) 1.449(5), O(3)–C(14) 1.417(4), C(1)–C(2) 1.528(6),C(2)–C(3) 1.307(5), C(3)–C(4) 1.510(6), C(4)–C(5) 1.402(5),C(4)–C(9) 1.372(5), C(5)–C(6) 1.436(6), C(6)–C(7) 1.373(6),C(7)–C(8) 1.388(6), C(8)–C(9) 1.423(6), C(10)–C(11) 1.402(5),C(11)–C(12) 1.381(5), C(12)–C(13) 1.458(5), C(13)–C(14)1.307(5), C(13)–C(18) 1.439(6), C(14)–C(15) 1.373(5), C(15)–C(16)1.440(6), C(16)–C(17) 1.273(5), C(17)–C(18) 1.359(6),C(1)–O(1)–C(10) 120.0(3), C(1)–O(2)–C(5) 118.2, C(10)–O(3)–C(14)123.2, O(1)–C(1)–O(2) 102.9(4), O(1)–C(1)–C(2) 112.8(4),O(2)–C(1)–C(2) 114.5(4), C(1)–C(2)–C(3) 120.3(4), C(2)–C(3)–C(4)118.5(4), C(3)–C(4)–C(5) 118.5(4), C(3)–C(4)–C(9) 123.7(4),C(5)–C(4)–C(9) 117.8(4), O(2)–C(5)–C(4) 120.2(4), O(2)–C(5)–C(6)117.2(4), C(4)–C(5)–C(6) 122.6(4), C(5)–C(6)–C(7) 118.2(4),C(6)–C(7)–C(8) 119.7(5), C(7)–C(8)–C(9) 121.6(4), C(4)–C(9)–C(8)120.1(4), O(1)–C(10)–O(3) 114.0(3), O(1)–C(10)–C(11) 109.8(3),O(3)–C(10)–C(11) 105.6(4), C(10)–C(11)–C(12) 120.8(4), C(11)–C(12)–C(13) 124.5(4), C(12)–C(13)–C(14) 113.2(4), C(12)–C(13)–C(18) 129.5(4), C(14)–C(13)–C(18) 117.2(4), O(3)–C(14)–C(13)119.7(4), O(3)–C(14)–C(15) 123.5(4), C(13)–C(14)–C(15) 116.6(4),C(14)–C(15)–C(16) 124.0(4), C(15)–C(16)–C(17) 120.2(5),C(16)–C(17)–C(18) 115.3(5), C(13)–C(18)–C(17) 126.7(4).

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