Syntheses and structure–activity relationship of lignans to develop novel pesticides

Abstract

The syntheses of stereoisomers of butane, butanediol, γ-butyrolactone, tri-substituted tetrahydrofuran (7,9′-epoxy), furofuran, tetra-substituted tetrahydrofuran (7,7′-epoxy and 7,8′-epoxy-8,7′-neolignan), benzylidene, coumarin, indan, and pyran type lignans were achieved. All the stereoisomers of the butane type lignans showed larvicidal activity and anti-phytopathogenic fungal activity. The γ-butyrolactone lignan showed stereospecific cytotoxicity against insect cells. Stereo/enantiospecific plant growth inhibitory activity was observed in tri-substituted tetrahydrofuran, tetra-substituted tetrahydrofuran (7,7′-epoxy), coumarin, and pyran type lignans. The furofuran lignan both inhibited and promoted growth in plants. Stereo/enantiospecific anti-phytopathogenic fungal activity was observed in tetra-substituted tetrahydrofuran (7,7′-epoxy) and E-benzylidene lignans.

Introduction

Lignans, which are biosynthesized by many vegetable plants,^1–3) are natural polyphenol compounds. Although, in general, lignans are constructed by the binding of two phenyl propanoid units at the 8- and 8′-positions, we can find lignan structures binding at the other positions (neolignan) and also structures with three units (sesquilignan).⁴⁾ Homolignans,⁴⁾ which contain additional carbon atoms, and norlignans,^4,5) which lack a carbon atom, are also included in the lignan group. Since many types of oxidative intramolecular cyclization in lignan structures are known, some chiral carbons are also involved in lignan structures. This is an important point in lignan research. Many biological activities have been reported, however, the absolute configurations of the lignan structures employed are not clear in some cases. To apply natural lignans to pesticides and agrochemicals, syntheses of the stereoisomers of each lignan should be done before experiments on the structure–activity relationship are carried out.

In this review, the syntheses and biological activities of stereoisomers of butane (I), butanediol (II), γ-butyrolactone (III), tri-substituted tetrahydrofuran (7,9′-epoxy) (IV), furofuran (V), tetra-substituted tetrahydrofuran (7,7′-epoxy) (VI), benzylidene (VII), coumarin (VIII), and 8,7′-neolignans (7,8′-epoxy (IX), indan (X), and pyran (XI)) are described (Fig. 1). The structures of indan (X) and pyran (XI) were obtained by an unexpected intramolecular Friedel–Crafts reaction and a ring expansion reaction, respectively. The structure–activity relationships of some lignans bearing effective stereochemistry are also described.

Fig. 1. Lignan structures in this review.

1. butane (I), butanediol (II), γ-butyrolactone (III)

All the stereoisomers of dihydroguaiaretic acid (DGA) 1–3 showed larvicidal activity against Culex pipiens (Fig. 2).⁶⁾ The presence of hydroxy groups at both the 9- and 9′-positions prevented this activity. Thus, all the stereoisomers of secoisolariciresinol (SECO) 4–6 were inactive. Derivatives with acute activity were synthesized, the derivatives 7–11 showing 50% mortality at 15 min (LC₅₀=2.01–3.66×10⁻⁵).⁷⁾ All the stereoisomers of DGA 1–3 were also effective against the phytopathogenic fungi, Alternaria alternata Japanese pear pathotype (EC₅₀=50–70 µM).⁸⁾ The most effective derivative 12 (EC₅₀=11.2 µM) was developed in research on the structure–activity relationship (Fig. 2).⁹⁾ The advantage of a small electron-withdrawing atom at the 3-position was shown by Hansch–Fujita analysis. Further research on the structure–activity relationship using 3-F derivatives clarified the importance of both the smaller 3′-electron-withdrawing atom and the 4′-phenolic hydroxy group.

Fig. 2. Larvicidal and anti-phytopathogenic fungal activities of butane type lignans. (A) Larvicidal activity against Culex pipiens of butane type lignan, Ar=4-hydroxy-3-methoxyphenyl. (B) Anti-phytopathogenic fungal activity against A. alternata Japanese pear pathotype (Ar=4-hydroxy-3-methoxyphenyl).

Stereospecific cytotoxicity against insect cells (Sf9 cells and NIAS-AeAl-2 cells) was observed for the γ-butyrolactone lignan, arctigenin (Table 1).¹⁰⁾ The (8R,8′R)-configuration 13 was the most potent against Sf9 cells, with an activity double that of the (8S,8′R)-configuration 16 and 12 times and >15 times more effective than the (8S,8′S)-configuration 14 and (8R,8′S)-configuration 15, respectively. The same tendency was observed in experiments against NIAS-AeAl-2 cells. These facts suggest that the 8′-R configuration is more important than configuration at the 8-position. Stereospecificity was not observed against HL-60 cancer cells.

Table 1. Cytotoxicity of γ-butyrolactone lignan, arctigenin stereoisomers (IC₅₀±SD)

Cancer cells
HL-60 cells	13±3.8 µM	23±3.8 µM	13±2.0 µM	8.5±3.5 µM
Insect cells
Sf9 cells	6.7±1.5 µM	80±11 µM	>100 µM	13±2.1 µM
NIAS-AeAl-2 cells	0.73±0.21 µM	28±4.2 µM	57±4.9 µM	6.3±3.5 µM

2. Tri-substituted tetrahydrofuran (7,9′-epoxy) lignan (IV) and furofuran (7,9′ : 7′,9-diepoxy) lignan (V)

Activity against plants was observed for tri-substituted tetrahydrofuran (7,9′-epoxy) lignan (IV) and furofuran (7,9′ : 7′,9-diepoxy) lignan (V), shown in Fig. 1. The key reactions toward stereoisomers of lariciresinol are illustrated in Scheme 1.^11,12) The triol 17 bearing a secondary benzylic hydroxy and two primary hydroxy groups were subjected to treatment with 10-camphorsulfonic acid followed by hydrogenolyses to give (+)-lariciresinol (18). After tosylation of the primary hydroxy group of diol 19 bearing a secondary benzylic hydroxy group, desilylation followed by hydrogenolyses was performed to give stereoisomer 20. On the other hand, the reaction of diol 19 with 10-camphorsulfonic acid, followed by deprotections gave stereoisomer 21. The all-cis-stereoisomer 23 was obtained from alkene 22 by stereoselective hydroboration followed by hydrogenolyses. The enantiomers, (−)-lariciresinol (ent-18), ent-20, ent-21, and ent-23, were synthesized from the enantiomers of the starting materials. In the phytotoxicity experiments, both (−)-lariciresinol (ent-18) and the stereoisomer 20 showed higher growth inhibitory activity against ryegrass roots, suggesting the importance of the absolute stereochemistry of the 8-position as the S-configuration and a relative trans-form between the 7- and 8′-positions. The structure–activity relationship was also estimated employing derivatives of (−)-lariciresinol (ent-18).¹³⁾

Scheme 1. Syntheses of stereoisomers of tri-substituted tetrahydrofuran (7,9′-epoxy) lignan (Ar=4-benzyloxy-3-methoxyphenyl).

Furofuran lignans, (+)- and (−)-pinoresinol (24) and (+)- and (−)-sesamin (25), which have structures of intramolecular etherification between the 9- and 7′-positions of tri-substituted tetrahydrofuran (7,9′-epoxy) lignan, were synthesized and applied to research on plant growth regulatory activity (Fig. 3).¹⁴⁾ (+)- and (−)-Pinoresinol (24) exhibited growth inhibition against ryegrass roots. (+)- and (−)-Sesamin (25) inhibited the growth of lettuce roots and promoted the growth of lettuce shoots.

Fig. 3. Plant growth inhibitory and promotive activities of furofuran lignans.

3. Tetra-substituted tetrahydrofuran (7,7′-epoxy) lignan (VI)

The intramolecular etherification between the 7- and 7′-postions of butane type lignan (I) gives tetra-substituted tetrahydrofuran (7,7′-epoxy) lignan (VI) (Fig. 1). In our experiment, we employed compounds bearing 4-hydroxy-3-methoxyphenyl groups to compare the activity with butane type lignan (DGA 1–3) (Fig. 2). The key reactions, which provided each stereochemistry, are shown in Scheme 2 and 3.^15–17) Treatment of benzyl hemiacetal 26 with H₂ in the presence of Pd(OH)₂/C gave the same stereochemistry as (−)-verrucosin (27) (Scheme 2). The diol 28 bearing two secondary benzylic hydroxy groups with the same stereochemistry as the target compound was transformed to (+)-fragransin A2 (29) by treatment with 10-camphorsulfonic acid, followed by reductive removal of the primary hydroxy groups and deprotection. (+)-Saucernetin diol (31) and (+)-machilin-I (32) were obtained from diene 30 by hydroborations followed by reduction of the 9- and 9′-positions and deprotection. The steric configuration of nectandrin B (34) was constructed by treatment of benzyl alcohol 33 with MsCl in the presence of Et₃N (Scheme 3). Isomerization of meso-diol 35 was successful through two steps; elimination of two hydroxy groups followed by stereoselective hydroboration. This isomerized meso-diol was transformed to the all-cis-stereoisomer, tetrahydrofuroguaiacin B (36). After all the enantiomers were synthesized from each enantiomeric starting material, biological tests were carried out.

Scheme 2. Syntheses of stereoisomers of tetra-substituted tetrahydrofuran (7,7′-epoxy) lignan-1 (Ar=4-benzyloxy-3-methoxyphenyl).

Scheme 3. Syntheses of stereoisomers of tetra-substituted tetrahydrofuran (7,7′-epoxy) lignan-2 (Ar=4-benzyloxy-3-methoxyphenyl).

Some of these showed phytotoxicity (Table 2).¹⁸⁾ Because (−)-verrucosin (27) and nectandrin B (34) had higher growth inhibitory activity against lettuce roots, it can be assumed that the relative configuration of (7S*,7′R*,8′R*) is important. In addition to (−)-27 and 34, (+)-verrucosin (ent-27) and (−)-machilin I (ent-32) inhibited the growth of ryegrass roots. The effect of substitution of a benzene ring on the activity was also examined by syntheses of the derivatives bearing the same stereochemistry as (−)-verrucosin (27).¹⁹⁾ In the anti-phytopathogenic fungal tests (Fig. 4),²⁰⁾ (−)-verrucosin (27) was the most potent against Alternaria alternata Japanese pear pathotype (EC₅₀=89.2 µM). The activities of (+)-saucernetin diol (31) and nectandrin B (34) were half as potent. Derivatives bearing the same stereochemistry as (−)- verrucosin (27) were prepared and their activities were estimated; the most potent was (3-CF₃,4-OH,3′-F)-derivative 39 (EC₅₀=0.72 µM). It was assumed that the existence of both a higher electron-withdrawing group at the 3-position and a phenolic group at the 4-position would be important for higher activity, because of the lower activities of (4-OH,3′-F)-derivative 37 (EC₅₀=41 µM) and (3-CF₃,3′-F)-derivative 38 (EC₅₀=148 µM). The (3-F,4-OH,3′-F)-derivative 40 (EC₅₀=13 µM) and (3-OCF₃,4-OH,3′-F)-derivative 41 (EC₅₀=2.9 µM) were less potent than (3-CF₃,4-OH,3′-F)-derivative 39. Exchanging the CF₃ group of 39 with the electron-donating CH₃ group decreased the activity, the (3-CH₃,4-OH,3′-F)-derivative 42 being 10 times less potent than 39. These facts suggest the advantage of the higher electron-withdrawing group at the 3-position. Comparing (3-CF₃,4-OH,3′-F)-butane lignan 43 and (3-F,3′-CF₃,4′-OH)-γ-butyrolatone lignan 44 with (3-CF₃,4-OH,3′-F)-derivative 39 showed the latter to be 38 times and 164 times more potent than 43 and 44, respectively, confirming the importance of the tetra-substituted tetrahydrofuran (7,7′-epoxy) lignan structure for higher anti-phytopathogenic fungal activity.

Table 2. Growth inhibitory activity of tetra-substituted tetrahydrofuran lignan (7,7′-epoxy) at 1000 µM (% from control) Ar=4-hydroxy-3-methoxyphenyl

Lettuce
Shoots	60%	51%	3.4%	6.6%	24%	36%
Roots	94%	31%	0%	5.0%	15%	15%
Ryegrass
Shoots	33%	63%	0%	0%	18%	37%
Roots	81%	98%	3.8%	0%	53%	73%
	Lettuce
	Shoots	21%	38%	38%	19%
	Roots	7.7%	18%	69%	0%
	Ryegrass
	Shoots	37%	50%	44%	18%
	Roots	57%	88%	85%	37%

Fig. 4. Anti-phytopathogenic fungal activities of tetra-substituted tetrahydrofuran (7,7′-epoxy) lignans and β-benzyl-α-benzylidene-γ-butyrolactone (Ar₁=4-hydroxy-3-methoxyphenyl, Ar₂=2-methoxyphenyl, Ar₃=4-methoxyphenyl).

4. Benzylidene (VII) and coumarin lignan (VIII)

Considering the biosynthesis of coumarin,^21,22) there is a possibility that E-α-(2-hydroxybenzylidene)-γ-butyrolactone 45 is transformed via the Z-form by non-enzymatic isomerization to coumarin 46 bearing a phenylpropanoid unit at the 3-position (Scheme 4). This coumarin is a lignan type bearing a phenylpropanoid unit at the 3-position. We planned to synthesize both 45 and 46 to compare their biological activities. Scheme 4 illustrates the syntheses of benzylidene and coumarin.²³⁾ Benzylidene 47, which is a mixture of the E- and Z-forms, was subjected to debenzylation using BCl₃ to give a phenolic mixture of E- and Z-forms. This mixture was treated with aqueous NaOH solution followed by aqueous HCl solution, giving separable E-benzylidene 48 and coumarin 49. The phenolic hydroxy group of 48 was methylated to give E-50. The primary hydroxy group of coumarin 49 was converted to methyl ether 51 using Ag₂O and CH₃I. In this reaction, Z-benzylidene 50 was also produced. The reductive removal of the primary hydroxy group of coumarin 49 gave 52 along with the rearranged product 53. The enantiomers ent-48, ent-E-50, ent-Z-50, and ent-49 were also prepared from ent-47.

Scheme 4. Syntheses of benzylidene and coumarin lignans (Ar=4-methoxyphenyl).

As the plant growth inhibitory activities given in Table 3 show,²³⁾ coumarin lignan is more favorable than benzylidene lignan. (R)-Coumarin bearing a hydroxy group at the 9′-position 49 was most potent, showing growth inhibitory activity against ryegrass and lettuce roots and lettuce shoots. The activity against lettuce ceased for ent-49 (S-form). Both 9′-methoxy 51 and the 9′-reductive compound 52 were inactive, suggesting the necessity of hydrophilicity at the 9′-position. The activity of (R)-coumarin 49 with the 9′-hydroxy group against ryegrass roots was accelerated by introduction of a methoxy group to the 7- or 8-position (derivatives 54, 55); especially, the 8-methoxy derivative 55 was 4 times more potent than (R)-coumarin 49 (IC₅₀=56.7 µM).²⁴⁾ On the other hand, the benzylidene structure was advantageous against anti-phytopathogenic fungi (Fig. 4).²⁵⁾ Comparing the activities of E- and Z-benzylidene 50 with ent-E- and ent-Z-benzylidene 50, it is clear that the structure with the (R)-configuration is more potent than that with the (S)-configuration, and the R-E-form (E-50) shows a 10-fold higher activity than the R-Z-form (Z-50). Thus, R-E-benzylidene 50 has the most potent stereochemistry for the activity, with an EC₅₀ value of 0.57 µM. The activities of the corresponding (8R,8′R)-α,β-dibenzyl-γ-butyrolactone and (8R,8′S)-α,β-dibenzyl-γ-butyrolactone without the carbon–carbon double bond of benzylidene were 8 times and 273 times less potent, respectively, suggesting the benzylidene structure with the α,β-unsaturated carbonyl structure plays an important role as a Michael acceptor or fixed conformation. Structure–activity relationship research discovered that the higher active compounds, (2-OCH₃,4′-CH₃)-, (2-OCH₃,4′-CF₃)-, (2-OCH₃,6-CH₃,4′-OCH₃)-, (2-F,6-OCH₃,4′-OCH₃)-derivatives 56, 57, 58, 59 had EC₅₀ values of 0.13–0.25 µM. The presence of the hydrophobic group at the 4′-position and substituents at both the 2- and 6-positions increased the activity. An antifungal lignan without a phenolic hydroxy group was developed.

Table 3. Plant growth inhibition by coumarin bearing phenylpropanoid at 3-position (IC₅₀±SD or inhibition ratio at 1000 µM, % from control)

Compounds		Italian Ryegrass seedlings		Lettuce seedlings
		Shoots	Roots	Shoots	Roots
	49: R=OH	35%	221±13.4 µM	659±20.1 µM	360±20.3 µM
	51: R=OCH3	4%	1%	12%	0%
	52: R=H	7%	4%	5%	4%
	54: R=7-OCH3	21%	121±21.7 µM	27%	50%
	55: R=8-OCH3	46%	56.7±5.40 µM	31%	228±10.8 µM
		14%	498±32.1 µM	32%	35%

5. 8,7′-Neolignan : 7,8′-epoxy (IX), indan (X), and pyran (XI)

The synthesis of 7,8′-epoxy-8,7′-neolignan (IX) (Fig. 1), which is a positional isomer of tetra-substituted tetrahydrofuran (7,7′-epoxy) lignan (VI) (Fig. 1), was attempted (Schemes 5, 6). To obtain 7,8-trans stereoisomers, Evans′ anti-aldol product²⁶⁾ 60 was selected as a starting material (Scheme 5).²⁷⁾ After conversion to diol 61, iodoetherification was attempted to give 8′S- and 8′R-iodomethyltetrahydrofurans 62. Reductive removal of iodine and oxidation of the secondary hydroxy groups, followed by reactions with 4-benzyloxy-3-methoxyphenyllithium gave 8′R-and 8′S-tertiary benzyl alcohols 63. Silane reduction of the benzyl alcohol 8′R-63 gave the unexpected indan structure 64 and the stable all-trans-tetrahydrofuran ring (7′R,8′R)-65. It might be assumed that ring cleavage of the unstable intermediate 7′,8′-cis-isomer (7′S,8′R)-65 by reaction with Lewis acid gave rise to the benzylic cation on the 7-position, thus causing the intramolecular Friedel–Crafts reaction to give the stereoselective all-trans-indan 64. The reductive removal of the secondary hydroxy group of 64, followed by hydrogenolysis gave the indan derivative. Indan type lignans have been isolated from Acorus calamus.²⁸⁾ Our synthetic method for optically active indan type lignans would contribute to research on the structure–activity relationship of indan type lignans. Furan-1 was obtained from the all-trans-tetrahydrofuran ring, (8′R,7′R)-65, by hydrogenolysis. Silane reduction of 8′R-63 at lower temperature gave (7′S,8′R)-65, which was converted to Furan-2, and silane reduction of 8′S-63, followed by hydrogenolysis afforded Furan-3. Furan-4 was obtained by treatment of 8′S-63 with NaBH₃CN in the presence of ZnI₂, followed by hydrogenolysis. ent-Furan-1–ent-Furan-4 and ent-Indan derivative were also synthesized from ent-60. The syntheses of the 7,8-cis-stereoisomers were started from the Evans′ syn-aldol product²⁹⁾ 66, which was transformed to the styrene derivative 68 (Scheme 6).³⁰⁾ After stereoselective hydroboration, the resulting primary alcohol 69 was converted to alkene 70. The iodoetherification of 70 in THF gave both (7′S,8′R)-71 and (7′S,8′S)-71. Oxidation of the primary alcohol 69, followed by epimerization of the resulting aldehyde gave 72, which was transformed to (7′R,8′S)-71 and (7′R,8′R)-71. The reductive removal of iodine from (7′S,8′R)-71, (7′S,8′S)-71, and (7′R,8′S)-71, followed by hydrogenolysis gave Furan-5, Furan-6, and Furan-7, respectively. However, treatment of (7′R,8′R)-71 with NaBH₄ or H₂/Pd-C gave the pyran structure 73 by an unexpected ring expansion reaction (Scheme 7). This 73 was converted to pyran by deprotection. In addition to previous reports on the syntheses of homolignans³¹⁾ and norlignans³²⁾ bearing pyran structures, a neolignan type of pyran was obtained in our research. The enantiomers ent-Furan-5–ent-Furan-7, and ent-Pyran were synthesized from ent-66.

Scheme 5. Syntheses of stereoisomers of 7,8-trans-7,8′-epoxy-8,7′-neolignan and indan type lignan (Ar=4-benzyloxy-3-methoxyphenyl).

Scheme 6. Syntheses of stereoisomers of 7,8-cis-7,8′-epoxy-8,7′-neolignan (Ar=4-benzyloxy-3-methoxyphenyl).

Scheme 7. Syntheses of pyran type lignan and enantiomers (Ar=4-benzyloxy-3-methoxyphenyl).

Examination of the plant growth inhibitory activity (Table 4) against lettuce showed only ent-Pyran to be potent against roots (IC₅₀=221 µM). For ryegrass, ent-Pyran was also the most effective against roots (IC₅₀=74.3 µM). Furan-3, ent-Furan-3, Furan-5, ent-Furan-5, Furan-6, and Pyran showed weaker activities against roots (IC₅₀=390–694 µM). Unlike 7,7′-epoxylignan, 7,8′-epoxy-8,7′-neolignans were not potent against lettuce. Indan and ent-Indan were not effective against plants, however, antifungal activities are shown in our current experiment.

Table 4. Plant growth inhibitory activity of 8,7′-neolignan, Ar=4-hydroxy-3-methoxyphenyl, IC₅₀ μM±SD or inhibition ratio at 1000 µM (p<0.05, One-way ANOVA and Turkey’s post-test among compounds)

Lettuce
Shoots	12%	18%	8%	12%	34%	32%	19%	30%
Roots	0%	11%	0%	8%	49%	958±177b	37%	25%
Ryegrass
Shoots	4%	12%	16%	17%	14%	32%	0%	26%
Roots	40%	35%	526±53.4b	43%	566±103b	517±2.30b	18%	390±24.9b
Lettuce
Shoots	19%	15%	26%	16%	19%	17%	19%	45%
Roots	25%	21%	47%	19%	34%	36%	17%	221±22.1a
Ryegrass
Shoots	6%	18%	27%	17%	15%	2%	0%	887±289
Roots	40%	43%	682±88.0b	42%	694±118b	48%	33%	74.3±1.10a

^a,b The same letters between different columns do not show significant difference, on the other hand, the different letters between different columns show significant difference.

Conclusion

Methods for synthesizing the stereoisomers of some lignans have been developed. In the course of synthetic research, new reactions to obtain indan type and pyran type lignans were discovered. A new type of coumarin structure bearing phenylpropanoid was also synthesized. Acute larvicidal activity in butane type lignan was shown. Stereospecific cytotoxicity against insect cells were discovered in γ-butyrolactone lignan. More potent activity against anti-phytopathogenic fungi was stereo/enantiospecifically observed in tetra-substituted tetrahydrofuran (7,7′-epoxy) lignan and E-α-benzylidene lignan. More potent growth inhibition against plants were enantiospecifically shown in coumarin and pyran type lignans. It was shown that furofuran lignan both inhibits and promotes plant growth. In addition to the previously reported insecticidal sesquilignan, haedoxan,³³⁾ this work on the biological activities of each of these lignans and neolignans provides new information that can be used in the development of novel agrochemicals.

Acknowledgements

I would like to thank the Pesticide Science Society of Japan for presenting me with an honorary award. Part of this study was performed at Division of Material Science Research Support and Genetic Research Support in Advanced Research Support Center (ADRES), Ehime University. I am grateful to Prof. Hisashi Nishiwaki (Graduate School of Agriculture, Ehime University) and Prof. Koichi Akiyama (Genetic Research Support in ADRES, Ehime University) for biological research.

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