J. CHEM. SOC. PERKIN TRANS. 1 1995 Total Synthesis of Pterocarpan: ( k )-Neorautenane Ricardo A. Lichtenfels, Antonio L. Coelho and Paulo R. R. Costa* Ndcleo de Pesquisas de Produto Naturais, Universidade Federal do Rio de Janeiro, CCS, Bl. H, 21941-590 Rio de Janeiro, RJ, Brazil A new approach to the total synthesis of (+)-neorautenane 14 is described, using the chemo- selective coupling of benzodipyran 12 and o-chloromercuriophenol 13 as the key step. Compound 12 is synthesized in four steps from chromanone 7. The number of naturally occurring biologically active pterocarpans identified is ever increasing. This group of compounds is of great interest because of their reputed pathological activity as phytoalexins (e.8. phaseollin 1, phaseollidin 2).’ In 1982, Nakagawa et al.isolated two prenylated pterocarpans, cabenegrine A-I 3 and A-I1 4 from materials used for Brazilian folk medicine, which were active, in uiuo, against the venom of Bothrops atrox2 These bioactive pterocarpans have phenyl moieties in the A and D rings. I Phasedlin 1 Phaseollidin 2 R’ 4R’= ,R2= H CabenegrineA-I 3 OH R2= ,R’ = H CabenegrineA-ll 4 OH Herein, we describe a total synthesis of ( f)-neorautenane 14, which has a 2,2-dimethyl-2H-pyrano moiety as part of its structure. Our strategy employed the chemoselective coupling of benzodipyran 12 and o-chloromercuriophenol 13 as the key step. Results and Discussion We initiated our work with the condensation of 3-methylbut- 2-enoic acid 65 and resorcinol 5 in the presence of methanesulfonic acid and phosphorus pentoxide.Under these conditions the hydroxychromanone 7 was obtained in good yield (see Scheme 1).6 Alkylation of the free phenolic group of 7 0 5 7 9 /lo Scheme 1 Reagents and conditions: i, MeSO,H, P,O,, 7OoC, 30 h; ii, NaH, DMF, O°C, 5 h; iii, toluene, 48 h; iv, NaBH,, EtOH, room temp., 24 h; v,p-TsOH, THF, reflux, 1.5 h; vi,p-TsOH, dioxane, reflux, 3 h; vii, Li,PdCl,, acetone, room temp., 24 h using 3-iodopropanal dimethyl acetal8 in the presence of NaH as base and dimethylformamide (DMF)-toluene under reflux led to the desired ether 9 in excellent yield. Compound 9 was reduced with sodium tetrahydroboranuide to give the alkoxy alcohol 10 in 84.5% yield. Preliminary experiments for obtaining benzodipyran 12 from alkoxy alcohol 10 led to mixtures of desired and side products, whose structures were not determined.This observation indicated that water formed during the dehydration step was compromising the process of cyclization. Some procedures for removal of water (e.g. using Dean-Stark, orthofonnate) were employed, but the results obtained were not satisfactory. Consequently, to avoid this problem, the dehydration step was carried out using toluene-p-sulfonic acid (p-TsOH) in tetrahydrofuran (THF) under reflux giving the alkylated chromene 11 in 76% yield. As expected, further cyclization using catalytic amounts of p-TsOH in dioxane under reflux resulted in the highly regioselective formation of desired benzodipyran 12.Benzodipyran 12 was allowed to react with o-chloromercurio- phenol 13 in the presence of lithium tetrachloropalladate(I1) and acetone, leading to the natural product 14 in 49% yield. This Heck arylation was observed to occur with a high degree of chemoselectivity at the less sterically hindered olefinic bond of 12. It was confirmed by the complete absence of signals in the 'H and 13C NMR spectra that could be attributed to other isomer. Work is now in progress in our laboratory to evaluate the possibility of further developing the described methodology towards the synthesis of other pterocarpans. Experimenta1 Dioxane, THF and toluene were distilled from Na-benzo- phenone. DMF was distilled from CaH, and stored over 4 A molecular sieves.Ethanol was distilled from Mg-I, and stored over 4 A molecular sieves, p-TsOH was dried for 4 h, under reduced pressure ( -1 mmHg) prior to use. 'H NMR spectra were recorded on a Varian Gemini-200 (200 MHz) instrument using tetramethylsilane (TMS) as standard and CDCl, as solvent. J Values are given in Hz. I3C NMR spectra were obtained at 50 MHz. Mass spectra were recorded on a Micromass MM 12F and a VG Autospec spectrometer. 7-( 3,3- Dimethoxypropoxy)-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-one 9.-A mixture of NaH (624 mg, 13 mmol) and 2,2-dimethyl-7-hydroxychroman-4-one7(1 g, 5.2 mmol) in DMF (20 cm3) was stirred for 5 min at 0 "C. 3-Iodopropanal dimethyl acetal 8 (2.4 g, 10.4 mmol) in toluene (20 cm3) was added slowly to the mixture which was then refluxed for 48 h.The reaction mixture was cooled and then washed with aq. 10% NaOH (3 x 20 cm3), brine and water. The organic layer was dried over anhydrous Na2S04, filtered and then concentrated. The crude product was purified by distillation in a bulb-to- bulb apparatus, yielding the title compound 9 as a light yellow oil (1.4 g, 9573, 6" 1.48 (s, 6 H), 2.21 (m, 2 H), 2.68 (s, 2 H), 3.38 (s, 6 H), 4.09 (t, 2 H), 4.61 (t, 1 H), 6.3 (d, 1 H, J, 9), 6.58 (dd, 1 H, J, 3, J,,9) and 7.8 (d, 1 H, J,,9); dC 26.54 (2 x q), 32.34 (t), 48.40 (t), 53.17 (2 x q), 64.18 (t), 79.38 (s), 101.53 (d), 101.68 (d), 109.39 (d), 113.95 (d), 128.06 (s), 161.78 (s), 165.32 (s) and 109.92 (s); m/e 294 (M', loo%), 279 (36), 102 (46) and 75 (74).7-(3,3-Dimethoxypropoxy)-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-01 10.-A solution of alkylated chromanone 9 (100 mg, 0.4 mmol) in THF (14 cm3) was added to NaBH, (128 mg, 3.4 mmol) in ethanol (14 cm3) and this mixture was stirred for 24 h. The solvent was removed and the residue dissolved in saturated aq. NH,Cl (7 cm3) and extracted with EtOAc. The extract was washed with saturated aq. NaHCO,, brine and water. The organic layer was dried over anhydrous Na,SO,, filtered and then concentrated. The crude product was purified by flash column chromatography, yielding the title compound 10 as a light yellow oil (85.1 mg, 84.5%), 6, 1.3 (s, 3 H), 1.45 (s, 3 H), 1.7 (s, 1 H), 1.79 and 2.2 (m, 4 H), 3.35 (s, 6 H), 4.0 (s, 2 H), 4.6 (s, 1 H), 4.7 (t, 1 H), 6.34 (d, 1 H, J,,, 3), 6.52 (dd, 1 H, J, 3, J,, 9.2) and 7.35 (d, 1 H, J, 9.2); 6, 25.69 (q), 28.60 (q), 32.58 (t), 42.69 (t), 53.16 (2 x q), 63.26 (t), 63.79 (d), 77.53 (s), 101.96 (d), 101.97 (d), 107.87 (d), 116.74 J.CHEM. SOC. PERKIN TRANS. I 1995 (d), 128.42 (s), 154.09 (s) and 159.09 (s); m/e 278 (M+ -18, 36%), 263 (loo), 161 (58) and 75 (22). 7-(3,3-Dimethoxypropoxy)-2,2-dimethyl-2H-ben.zopyran11. -To a solution of p-TsOH (catalytic amount) in THF (5 cm3) was added alkoxy alcohol 10 (185 mg, 0.62 mmol) in THF (5 cm3). The mixture was refluxed for 1.5 h under N,. After this time 10% aq. NaOH (10 cm') was added and the mixture was extracted with CH,Cl,, the organic extract washed with 10% aq.NaOH (3 x 10 cm3), brine and water and then dried (Na,SO,). After concentration and filtration over neutral alumina, the title compound 11 was obtained as a light yellow oil (131.8 mg, 76%), 6" 1.4 (s, 6 H), 2.1 (m, 2 H), 3.38 (s, 6 H), 4.0 (t, 2 H), 4.62 (t, 1 H), 5.48 (d, 1 H), 6.28 (d, 1 H), 6.30 (d, 1 H), 6.50 (dd, 1 H) and 6.9 (d, 1 H); m/e 278 (M', 16%), 263 (57), 161 (100) and 75 (59). 2,2-Dimethyl-2H,8H-benzo[l,2-b:5,4-b1]d@yran 12.-To a solution of p-TsOH (catalytic amount) in dioxane (5 cm3) was added alkylated chromene 11 (47.5 mg, 0.17 mmol) in dioxane (5 cm3). The mixture was refluxed for 3 h under N,. After this time 10% aq. NaOH (10 cm3) was added and the mixture was extracted with CH,Cl,, the organic extract washed with 10% aq.NaOH (3 x 10 cm3), brine and water and then dried (Na,SO,). After concentration and filtration over neutral alumina, the title compound 12 was obtained as a light yellow oil (28.5 mg, 77.4%);6H 1.40(s, 6 H), 4.78 (m, 2 H), 5.48 (d, 1 H), 5.62 (m, 1 H), 6.24 (d, 1 H), 6.26 (s, 1 H), 6.34 (1 H) and 6.60 (s, 1 H); m/e M+ 214 (19%) and 199 (100). 9,9- Dimethyl-4b7 12 b-dihydro-2H ,5H-[1,3]dioxolo[5,6] benzo- fur0 [3,2-c] pyrano[ 3,2-g] [1lbenzopyran 14.-To a mixture of PdC1, (30 mg, 0.17 mmol) and LiCl (14.3 mg, 0.34 mmol) in acetone (5 cm3) was added benzodipyran 12 (35.6 mg, 0.17 mmol) in acetone (5 cm3). This mixture was stirred for 15 min and then 2-chloromercurio-4,5-methylenedioxyphenol13 (64 mg, 0.17 mmol) in acetone (15 cm3) was added to it.The suspension thus obtained was stirred for 24 h at 25 "C. After this time, brine (20 cm3) was added to it and the mixture was extracted with CH,Cl,, the organic extract dried (Na,SO,), filtered and then concentrated. The product was purified by preparative chromatography to give the title compound 14 as a colourless solid (28.7 mg, 4979, mp 166-167 "C (lit.,', mp 166 "C) (Found: M+, 350.115813. C21H1805 requires M', 350.115424), 6" 1.40 (s, 3 H), 1.43 (s, 3 H), 3.44 (m, 1 H, J 6.6, 10.8, 4.7), 3.60 (t, 1 H, J 10.8), 4.20 (dd, 1 H, J 10.8, 4.7), 5.42(d, 1 H, J, 6.6), 5.54(d, 1 H, J9.8), 5.9(2 x d, 2H, J 5.6, 1.3), 6.30 (d, 1 H, J 9.8), 6.38 (s, 1 H), 6.42 (s, I H), 6.7 (s, 1 H) and 7.1 (s, 1 H); 6, 27.8 (q), 28.1 (q), 40.2 (d), 66.4 (t), 77.5 (s), 78.5 (d), 93.7 (d), 101.2 (t), 104.6 (d), 105.0 (s), 112.2 (s), 116.3 (s), 117.9 (d), 121.5 (d), 128.1 (d), 129.0 (d), 141.6 (s), 148.0 (s), 154.1 (s), 154.5 (s) and 156.2 (s); m/e M + 350 (40.5%) and 335 (100).Acknowledgements We thank the CNPq, FINEP, CEPG and FUJB for financial support. The authors are grateful to the Analytic Center at NPPN for the 'H NMR, NMR and mass spectra. References 1 (a) P. M. Dewick and M. J. Steele, Phytochemistry, 1981, 1599; (b) L. Zechmeister, Progress in the Chemistry of Organic Natural Products, New York, Springer-Verlag, 1983, vol. 43, ch. I, pp. 1-22. 2 M. Nakagawa, K. Nakanishi, L. L. Darko and J. A. Vick, Tetrahedron Lett., 1982, 23, 3855. 3 A. L. Coelho, M. L. A. A. Vasconcellos,A. B. C. Simas, J. A. Rabi and P. R. R. Costa, Synthesis, 1992, 914. J. CHEM. SOC. PERKIN TRANS. I 1995 951 4 J. C. Breytenbach and G. J. H. Rall, J. Chem. Suc., Perkin Trans. I, 7 G. L. Larson and R. J. Klesse, J. Org. Chem., 1985,50, 3627. 1980, 1804. 5 A. I. Vogel, in Vogel’s Textbook of Practical Organic Chemistry, New York, Longman Scientific and Technical, 1984,670. Paper 4/06069E 6 F. Camps, J. Coil, A. Messeguer, M. A. Pericas and S. Ricart, Synth. Received 4th October 1994 Cummun., 1980,725. Accepted 18th October 1994
展开▼
