Abstracts

Article

Synthesis and Structural Confirmation of Natural 1,3-Diarylpropanes

Paulo A. de Almeida ^a , Silas V. Fraiz Jr. ^a , and Raimundo Braz-Filho ^{b *} * e-mail: pafonso@ufrrj.br

^aDepartamento de Química, Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro, 23851-970 Seropédica - Rio de Janeiro, Brazil;

^b Setor de Química de Produtos Naturais, LCQUI - CCT, Universidade Estadual do Norte Fluminense, 28051-620 Campos - RJ, Brazil

Introduction

1,3-Diarylpropanes have been isolated mainly from Virola and Iryanthera species (Myristicaceae)^1-4. However, in 1980 Takasugi and co-workers reported the structures of the new 1,3-diarylpropanes broussonins A (1), B (2) and C (3) isolated from Broussonetia papyrifera Vent. (Moraceae), which revealedantifungal activities in tissues of this plant inoculated with Fusarium solani f. sp. mori⁵. These diarylpropanoids, classified as phytoalexins, were not detected in the uninoculated tissues of this same plant and showed activity against Bipolaris leersiae at 10^-4 -10^-5 M⁶.

1,3-Diarylpropanes have been synthesized to confirm structures of natural products^7-9. In a previous study⁷, the synthesis of 1-(2’-hydroxy-5’-methyl-4’-methoxyphenyl)-3-(2"-hydroxy-4",5"-methylenedioxyphenyl)propane (6) was described, in order to confirm the structure proposed for the natural product previously isolated from Iryanthera laevis². Comparison of the spectral data of the synthetic and natural products revealed different compounds and, consequently, a new isomeric structure 1-(4’-hydroxy-5’-methyl-2’-methoxyphenyl)-3-(2"-hydroxy-4",5"-methylenedioxyphenyl)propane (7) was proposed⁷.

In this paper, we report the synthesis of four 1,3-diarylpropanes: 1-(4’-hydroxy-2’-methoxyphenyl)-3-(4’’-hydroxyphenyl)propane (2, broussonin B) to confirm the structure proposal for the natural product isolated from Broussonetia papyrifera Vent.⁵, 1-(4’-hydroxy-5’-methyl-2’-methoxyphenyl)-3-(2"-hydroxy-4", 5"-methylenedioxyphenyl)propane (7) to confirm the structure proposal⁷ for the natural product isolated from Iryanthera laevis², 1-(2’-hydroxy-4’-methoxyphenyl)-3-(4’’-hydroxyphenyl) propane (1, broussonin A), a product previously synthesized by another synthetic pathway⁹, and 1-(2’,4’-dimethoxyphenyl)-3-(4’’-hydroxyphenyl)propane (4), which was prepared for comparative ¹³C-NMR analysis.

The structures of the synthetic compounds were characterized by analysis of spectral data, mainly mass, one- (1D) and two-dimensional (2D) ¹H and ¹³C-NMR.

Results and Discussion

The synthetic pathway employed in order to obtain the desired 1,3-diarylpropanes (1, 2, 4 and 7) involved the base-catalysed condensation of the appropriate acetophenones (16, 18, 19 and 20, Scheme 1) with benzaldehydes (23 and 25, Scheme 2) to produce the corresponding chalcones (8, 9, 10 and 11) which were submitted to catalytic hydrogenation. Acetophenones 15 and 17 were prepared from resorcinol (12, Scheme 1) and protected by hydroxyl group benzylation, before or after appropriate methylation to furnish 16, 18 and 19 or dimethylated 20. Benzaldehyde 22 obtained from piperonal (21, Scheme 2) and 24 were protected by hydroxyl group benzylation, in order to stabilize the substrates towards the basic conditions of the condensation reaction: 18 + 25 ® 8; 19 + 25 ® 9; 20 + 25 ® 10; 16 + 23 ® 11. Thus, 1,3-diarylpropanes 1, 2, 4 and 7 were prepared by catalytic hydrogenation of the chalcones 8, 9, 10, and 11, respectively. Chalcone 9a which has an unprotected 2’-hydroxyl group can undergo chalcone(9a)-flavanone(9b) equilibrium under the catalytic hydrogenation conditions which were used. Thus, a mixture of 1,3-diarylpropane and the corresponding dihydrochalcone was obtained. Using the same conditions, this partial reduction was not observed after the isomeric equilibrium was blocked by a 2’-hydroxyl group benzylation (9) or methylation (10).

The structure of 1-(4’-hydroxy-2’-methoxyphenyl)-3-(4’’-hydroxyphe-nyl)propane (2) proposed for the natural product isolated from Broussonetia papyrifera Vent.⁵ and 1-(4’-hydroxy-5’-methyl-2’-methoxyphenyl)-3-( 2"-hydroxy-4",5"-methylenedioxyphenyl)propane (7) proposed for the natural product isolated from Iryanthera laevis² were confirmed by comparison with the synthetic products.

Comparative analysis of the ¹³C-NMR spectral data of 1, 2 and 4 revealed chemical shift values for the characterization of the aromatic ring A 2’-methoxy-4’-hydroxy-, 2’-hydroxy-4’-methoxy- and 2’,4’-dimethoxy-, as shown in the partial structures 1a, 2a and 4a corresponding to 1,3-diarylpropanoids 1, 2 and 4, respectively. This analysis also allowed observation of chemical shift modifications of the signals of the methine carbons CH-3’ and CH-5’ as a consequence from a g-effect of the methyl group of the 2’-methoxy or 4’-methoxy: i) CH-3’ [d_C =97.61(4a) - 100.84(1a) = - 3.23 ppm and d_C = 97.61(4a) - 98.14(2a) = - 0.53 ppm]; ii) CH-5’ [d_C =103.17(4a) - 105.82(2a) = - 2.65 ppm]. The modifications, a consequence of methylation of a hydroxyl group, may be deduced by comparison of the chemical shifts of the quaternary carbons C-2’ and C-4’ revealing a deshielding b-effect.

The homonuclear ¹Hx¹H-COSY and heteronuclear (¹³C detected, conventional method) ¹³Cx¹H-COSY-¹J_CH (direct spin-spin interaction of carbon-13 and hydrogen via one bond) and ¹³Cx¹H-COSY-ⁿJ_CH [n = 2 and 3, COLOC, long-range coupling of carbon-13 and hydrogen via two (²J_CH) and three (³J_CH) bonds] 2D shift-correlated NMR spectra of the synthetic products were also used to assign unambiguously the chemical shifts of the carbon and hydrogen atoms and to reexamine values described in the literature^10,11. The results obtained by careful analysis of these spectra of 1, 2, 4 and 7 are summarized in Tables 1-4.

The ¹H-NMR, ¹Hx¹H-COSY, ¹³C-NMR, ¹³Cx¹H-COSY-¹J_CH and ¹³Cx¹H-COSY-ⁿJ_CH (n = 2 and 3) spectra of the 1,3-diarylpropane 1 [2’-hydroxy-4’-methoxy- (1a)] and 2 [4’-hydroxy-2’-methoxy- (2a)] were used to unambiguously assign the ¹H and ¹³C chemical shifts of the aromatic ring A (Tables 1 and 2) and on the basis of these data to confirm the presence of a 4’-hydroxy-2’-methoxyphenyl (ring A) moiety in the structure of the natural 1-(4’-hydroxy-2’-methoxyphenyl)-3-(3"-hydroxy-4’’-methoxyphenyl)propane (5) isolated from Knema austrosiamensis (Myristicaceae) and reported by Gonzaléz et al.¹⁰,as well as revealing the interchanged chemical shifts attributed to C-2’ and C-4’ and CH₂-1(shielded by g-effect of the OR located at C-2’) and CH₂-2. The structure 5, 1-(4’-hydroxy-2’-methoxyphenyl)-3-(3"-hydroxy-4’’-methoxyphenyl)propane, had been previously proposed for a natural product isolated from Virola multinervia⁴.However, this structure was later revised to 1-(2’-hydroxy-4’-methoxyphenyl)-3-(3"-hydroxy-4’’- methoxyphenyl) propane⁷. Therefore, the 1,3-diarylpropane 5 isolated from Knema austrosiamensis can be regarded as a novel natural product structure.

Comparative analysis of the ¹H-NMR spectra of the synthetic 1,3-diarylpropanes 6 (previously sinthesized)⁷ and 7 (this paper) with the natural product isolated from I. Laevis² showed, as anticipated, small but significant differences in the chemical shifts of H-3’ and H-3", which were clearly revealed only after recording these spectra: i) natural product isolated from I. laevis [¹H-NMR (60 MHz, CDCl₃): d_H 6.40 (sl, H-3’ and H-3"), Dd_H = 0 ppm]; ii) synthetic 6 [¹H-NMR (100 MHz, CDCl₃): d_H 6.37 (s, H-3’), 6.32 (s, H-3"), Dd_H = 0.05 ppm]]; iii) synthetic 7 [¹H-NMR (200 MHz, CDCl₃): d_H 6.38 (s, H-3’), 6.36 (s, H-3"), Dd_H = 0.02 ppm]. On the basis of this comparative analysis, the synthetic product 7 confirms the structure proposed⁷ for the natural diarylpropanoid isolated from I. laevis².

Comparison of the ¹³C-NMR spectral data of the synthetic 1,3-diarylpropane 7 with values reported by Conserva et al¹¹, for the same natural product isolated later from I. ulei, confirmed the identity of these two compounds. However, the possibility of interchange of the chemical shifts of C-1’ (d_C 119.4) and C-1" (d_C 119.6) was reported¹¹. Homonuclear ¹H x ¹H-COSY and heteronuclear ¹³C x ¹H-COSY - ⁿJ_CH (n = 1; n = 2 and 3, COLOC) 2D shift-correlated spectra of the synthetic product 7 were used for unambiguous assignment of chemical shifts of hydrogen and carbon atoms (Table 4). In fact, the chemical shifts of the quaternary carbon atoms C-1’ (d_C 119.4) and C-1’’ (d_C 119.6) had been interchanged [d_C 121.95 (C-1’) and 121.35 (C-1’’)], the same occurring with C-1 (d_C 29.81)and C-3 (d_C 30.34), as shown in Table 4. Other heteronuclear spin-spin interactions (ⁿJ_CH, n = 1; n = 2 and 3) of hydrogen and carbon-13 are summarized in Table 4.

Homonuclear ¹H x ¹H-COSY and heteronuclear ¹³C x ¹H-COSY - ⁿJ_CH (n = 1; n = 2 and 3, COLOC) 2D shift-correlated spectra were also used for unambiguous assignment of chemical shifts of hydrogen and carbon atoms of the compounds 1 (Table 1), 2 (Table 2) and 4 (Table 3).

Experimental

General experimental procedures

Melting point determinations were made in open capillaries and are uncorrected. Identification of compounds was established by TLC, IR, MS, ¹H-NMR, ¹³C-NMR (PND and DEPT) and two-dimensional (2D) carbon-hydrogen shift correlation [carbon-hydrogen spin-spin interaction via one bond (¹J_CH) and two (²J_CH) and three (³J_CH) bonds, long-range coupling of carbon-hydrogen]. TLC was carried out on Merck kieselgel 60 GF 254. TMS was used as int. standard in NMR spectra. EIMS spectra were recorded at 70 eV on a low resolution spectrometer.

Preparation of the chalcones

In accordance with the literature¹², appropriately substituted acetophenones and benzaldehydes gave, by aldol condensation, 8 (yield, 85 %), 9 (88 %), 10 (72 %) and 11 (74 %).

4,4’-Di-O-benzyl-2’-methoxychalcone (8)

Mp 88-90° (MeOH). IR (neat) 1648, 1620, 1602, 1575 cm^-1. ¹H-NMR (200 MHz, CDCl₃) d_H 7.71 (dd, J = 8.5, 2,0 Hz, H-6), 7.63 (d, 16.0 Hz, H-7), 7.53 (d, J = 8.3 Hz, 2H-2’,6’), 7.36 ( d, J = 16.0 Hz, H-8), 7.35 (m, phenyl), 6.96 (d, J = 8.3 Hz, 2H-3’,5’), 6.61 (d, J = 8.5 Hz, H-5), 6.57 (d, J = 2.0 Hz, H-3), 5.10 (s, OCH₂C₆H₅), 5.08 (s, OCH₂C₆H₅), 3.86 (s, OMe).

2’,4-Di-O-benzyl-4’-methoxychalcone (9)

Mp 101-103° (MeOH). IR (neat) 1652, 1624, 1604, 1575, 1512 cm^-1. ¹H-NMR (200 MHz,CDCl₃) d_H 7.89 (d, J = 8.4 Hz, H-6), 7.66(d, J = 15.8 Hz,H-7), 7.52 (d, J = 15.8 Hz, H-8), 7.44 -7.26 (m, phenyl and 2H-2’,6’), 6.86 (d, J = 8.9 Hz, 2H-3’,5), 6.60 (dd, J = 8.4 and 2.4 Hz, H-5), 6.58 ( d, J = 2.4 Hz, H-3), 5.14 (s, 2’-OCH₂C₆H₅), 5.10 (s, 4-OCH₂C₆H₅), 3.88 (s, OMe).

4-O-Benzyl-2’,4’-dimethoxychalcone (10)

Mp 74-76° (MeOH). IR (neat) 1644, 1619, 1575, 1512 cm^-1. ¹H-NMR (200 MHz, CDCl₃) d_H 7.74 (d, J = 8.5 Hz, H-6), 7.65 (d, J = 15.8 Hz, H-7), 7.55 (d, J = 8.8 Hz, 2H-2’,6’), 7.39 (d, J = 15.8 Hz, H-8), 7.35 (s, phenyl), 6.99 (d, J = 8.5 Hz, 2H-3’,5’), 6.56 (dd, J = 8.7 and 2.1 Hz, H-5), 6.50 (d, J = 2.1 Hz, H-3), 5.11 (s, OCH₂C₆H₅), 3.90 (s, OMe), 3.87 (s, OMe).

4’,2-Di-O-benzyl-5’-methyl-4,5-methylenedioxy-2’-methoxychalcone (11)

Yellow oil. IR (neat) 1648, 1624,1610, 1580, 1500 cm^-1. ¹H-NMR (200 MHz, CDCl₃) d_H 8.06 (d, J = 16.0 Hz, H-7), 7.50 ( d, J = 16.0 Hz, H-8), 7.53 (s, H-6), 7.46-7.26 (m, phenyl), 7.08 (s, H-2’), 6.53 (s, H-3), 6.44 (s, H-6’), 5.93 (s, O-CH₂-O), 5.13 (s, OCH₂C₆H₅), 3.75 (s, OMe ), 2.20 (s, MeAr).

Hydrogenation of the chalcones

A soln. of chalcone (1 g) in CHCl₃ (5 ml) and EtOH (50 ml), in Parr apparatus was flushed with N₂. Catalyst (0.5 g, 10 % Pd-C) and AcOH (10 mL) was added, vacuum applied and H₂ was admitted under pressure (50 psi, 4.5 hr). The usual work-up, followed by crystallization or silica gel chromatography of the crude reaction mixture, gave from 8 ® 2 (yield 98 %), 9 ® 1 (85 %), 10 ® 4 (80 %) and 11 ® 7 (90 %).

1-(2’-Hydroxy-4’-methoxyphenyl)-3-(4"-hydroxyphenyl) propane (1)

Mp 81-82° (C₆H₆). IR (neat) 3388, 1617, 1590, 1512 cm^-1. EIMS m/z (rel. int. ): 258 ([M]^.+, 20), 151 (9), 137 (100), 121 (10), 120 (14), 107 (38), 91 (6). ¹H and ¹³C-NMR: Table 1.

1-(4’-Hydroxy-2’-methoxyphenyl)-3-(4"-hydroxyphenyl) propane (2)

Mp 80-82° (C₆H₆ ). IR (neat) 3230, 1617, 1605, 1513 cm^-1. EIMS m/z (rel. int.): 258 ([M]^.+, 14), 152 (23), 151 (13), 138 (10), 137 (100), 121 (6),107 (55), 78 (30), 77 (19). ¹H and ¹³C-NMR: Table 2.

1-(2’,4’-Dimethoxyphenyl)-3-(4"-hydroxyphenyl) propane (4)

Oil. IR (neat) 3408, 1617, 1584, 1512 cm-¹. EIMS m/z (rel. int.) : 272 ([M]^.+, 28), 165 (10), 151 (100), 138 (6), 120 (5). ¹H and ¹³C-NMR: Table 3.

1-(4’-Hydroxy-5’-methyl-2’-methoxyphenyl)-3-(2"-hydroxy-4",5"-methylenedi-

oxyphenyl)propane (7)

Mp 137-139° (C₆H₆). IR (neat) 3322, 1623, 1602, 1520, 1499 cm^-1. EIMS m/z (rel. int.): 316 ([M]^.+, 4), 178 (11), 165 (7), 166(25), 152 (26), 151 (100), 149 (10), 121 (16). ¹H and ¹³C-NMR: Table 4.

Acknowledgments

The authors are grateful to CAPES and FAPERJ for fellowships and to professor Anselmo A. Morais for furnishing the 2-hydroxy-4,5-methylenedioxybenzaldehyde.

References

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Received: March 16, 1998

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