furanones Related to Strigol - American Chemical Society

Chapter 23

Plant-Growth-Inhibiting Properties of Some 5-Alkoxy-3-methyl-2(5H)-furanones Related to Strigol 1

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A. B. Pepperman and H. G. Cutler Downloaded by OHIO STATE UNIV LIBRARIES on June 23, 2012 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch023

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Southern Regional Research Center, Agricultural Research Service, U.S. Department of Agriculture, New Orleans, LA 70179 Richard G. Russell Research Center, Agricultural Research Service, U.S. Department of Agriculture, Athens, GA 30613

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A series of 5-alkoxy-3-methyl-2(5H)-furanones (butenolides), prepared as analogs o f the weed seed germination r e g u l a t o r , s t r i g o l , were a l s o screened f o r p l a n t growth r e g u l a t i n g a c t i v i t y . Several o f the furanones were found t o i n h i b i t the growth of e t i o l a t e d wheat c o l e o p t i l e s at millimolar (mM) c o n c e n t r a t i o n s . Structure- a c t i v i t y f o r t h i s r e l a t i v e l y unexplored aspect of butenolide b i o a c t i v i t y is d i s c u s s e d . S t r i g o l itself is not a c t i v e , whereas e p i s t r i g o l , which d i f f e r s only i n the stereochemistry at one p o s i t i o n of t h i s complex molecule, i s very a c t i v e at 1mM and has some a c t i v i t y a t 0.1mM. A condensation dimer o f 5-hydroxy-3-methyl-2(5H)-furanone and a 2 - r i n g analog o f strigol were a l s o a c t i v e as growth i n h i b i t o r s . Unsaturated lactones occur widely i n nature (1) and possess an unusually wide range o f b i o l o g i c a l a c t i v i t y ( 2 ) . E v a l u a t i o n o f these n a t u r a l products, commonly c a l l e d butenolides, has shown them to have promise as i n s e c t i c i d e s (3), h e r b i c i d e s (4), and p l a n t growth r e g u l a t o r s ( 5 ) . Discovery of butenolide a c t i v i t y has s t i m u l a t e d development of syntheses o f these v a l u a b l e compounds (6). Our i n t e r e s t i n these compounds was s t i m u l a t e d by their structural similarity t o the witchweed seed germination stimulant s t r i g o l , l a , and i t s analogs. S t r i g o l was i s o l a t e d i n 1966 and i t s s t r u c t u r e (see Figure 1) was e s t a b l i s h e d by X-ray c r y s t a l l o g r a p h y s e v e r a l years

l a t e r by Cook and coworkers(7,8).

S y n t h e t i c routes t o

s t r i g o l were soon d e s c r i b e d by two groups, one i n England and one i n the United States using convergent syntheses which s t a r t e d d i f f e r e n t l y but were s i m i l a r i n the l a t t e r steps (9,10). Another E n g l i s h group (11) prepared and t e s t e d s e v e r a l s t r i g o l analogs which contained fewer r i n g s This chapter not subject to U.S. copyright Published 1991 American Chemical Society

In Synthesis and Chemistry of Agrochemicals II; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

Downloaded by OHIO STATE UNIV LIBRARIES on June 23, 2012 | http://pubs.acs.org Publication Date: December 7, 1991 | doi: 10.1021/bk-1991-0443.ch023

23.

PEPPERMAN AND CUTLER

5-Alkoxy-3-methyl-2(5W)-furanones

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than s t r i g o l and t h e r e f o r e r e q u i r e d fewer steps f o r synthesis. Some of the analogs were a c t i v e as seed germination stimulants f o r both S t r i q a and Orobanche species. Both of these p a r a s i t i c weeds produce numerous small seeds which can remain v i a b l e i n the s o i l f o r up t o twenty years (12.) . U s u a l l y , seed w i l l not germinate unless exposed to a chemical exuded from the roots of a host p l a n t or a few non-host p l a n t s (13). The a c t i v e chemical from cotton roots (a non-host plant) was i d e n t i f i e d as s t r i g o l by Cook and coworkers(2). The germinated seed attaches i t s e l f t o the host through an organ c a l l e d the haustorium and draws a l l the n u t r i e n t s i t r e q u i r e s from the host p l a n t causing severe s t u n t i n g and s u b s t a n t i a l reductions i n crop y i e l d i f the host i s a member of the Gramineae family, i n c l u d i n g such important crops as corn, g r a i n sorghum, and sugarcane(L4). T h i r t y compounds, which are s t r i g o l p r e c u r s o r s , analogs, or fragments, were prepared and t e s t e d as witchweed seed germination r e g u l a t o r s (15). Several of the compounds demonstrated a s u r p r i s i n g degree of a c t i v i t y . Among the a c t i v e compounds were s e v e r a l 5-alkoxy-2(5H)furanones 2 which represent one of s e v e r a l c l a s s e s of butenolides (j5) . The a c t i v i t y of these compounds i n witchweed seed germination and i n other weed and crop seeds (16,17) prompted us t o evaluate other types of b i o l o g i c a l a c t i v i t y and attempt t o r e l a t e s t r u c t u r e to a c t i v i t y . In t h i s report, the e f f e c t of b u t e n o l i d e s of general s t r u c t u r e 2 as growth r e g u l a t o r s f o r e t i o l a t e d wheat c o l e o p t i l e elongation (18.) was examined. Synthesis P r e p a r a t i o n of compounds of type 2, and t h e i r s t a r t i n g m a t e r i a l s are presented below. Structures are given i n Table I and F i g u r e I. Photooxygenation of 3-methvl-2-furoic a c i d . Forty-five grams of 3-methyl-2-furoic a c i d was d i s s o l v e d i n 3 l i t e r s of the solvent i n a 5 l i t e r round bottomed three necked f l a s k . The dye s e n s i t i z e r used (0.5g) was e o s i n and the s o l u t i o n was s t i r r e d by use of a magnetic s t i r r e r while a i r was bubbled through a f r i t i n t o the s o l u t i o n . Into the center neck of the f l a s k was p l a c e d a water jacketed p h o t o c e l l with a uranium g l a s s t i p i n t o which the lamp was p l a c e d (a 500 watt studio q u a r t z l i n e bulb) . Due t o the tremendous amount of heat evolved from the lamp, i c e water was c i r c u l a t e d through the jacket t o keep the temperature of the s o l u t i o n between 25-30 C. I r r a d i a t i o n was c a r r i e d out over 34-45 hours and the course of the r e a c t i o n was monitored by t h i n l a y e r chromatography. Excess solvent was removed under vacuum and the product was vacuum d i s t i l l e d . Only the lower molecular weight a l c o h o l s can be used practically to prepare the alkoxybutenolides by the photooxygenation method since a l a r g e excess of the a l c o h o l i s r e q u i r e d f o r r e a c t i o n and i t must be removed i n the


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SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π TABLE 1 Compounds Tested as Growth Regulators ALKOXYBUTENOLIDES

R'

Compound No.


R hydrogen CH methyl ethyl n-propyl isopropyl η-butyl sec-butyl isobutyl tert-butyl n-lauryl allyl 2-propynyl 2-chloroethyl ·· 2-iodoethyl 3-bromopropy1 2-nitro-2-methylpropyl 2-chloroallyl 2-phenoxyethyl cyclopentyl cyclohexyl 2-methylcyclohexyl 3-methylcyclohexyl 4-methylcyclohexyl tetrahydrofurfuryl 3-methyl-2(5H)furanone-5-yl benzyl meta-nitrobenzyl para-nitrobenzyl methyl Η ethyl Η

3

w

M

% Growth I n h i b i t i o n * at 10 M 10 M

2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k 21 2m 2n 2o 2p

42 0 0 40 0 0 0 37 36 41 0 61 99 100 99 55

0 0 0 0 0 0 0 0 0 38 0 0 0 0 0 0

2q 2r 2s 2t 2u 2v 2w 2x

100 100 69 100 100 100 100 0

34 0 29 24 0 0 0 0

2y 2z 2aa 2ab 2ac 2ad

81 100 58 92 100 100

0 0 0 0 38 58

0 94 61

0 18 17

S t r i g o l and analogs strigol epistrigol 2-ring analog of s t r i g o l

la lb lc

* Anything g r e a t e r than 9% i n h i b i t i o n s i g n i f i c a n t (p < 0.01).

i s statistically


S-Alkoxy-3-methyl-2(5R)-furanones


23. PEPPERMAN AND CUTLER


281

282

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS Π

workup. The lower a l i p h a t i c a l c o h o l s (up to C ) were r e a d i l y photooxygenated and g e n e r a l l y gave y i e l d s of 7080% f o r primary and secondary a l c o h o l s . When t - b u t y l a l c o h o l was u t i l i z e d , the y i e l d was d r a m a t i c a l l y reduced to 20-40%. I t was unclear how much of t h i s reduced y i e l d was due to lowered r e a c t i v i t y and how much t o v i s c o s i t y / s o l i d i f i c a t i o n factors. Since t - b u t y l a l c o h o l has a melting p o i n t c l o s e t o room temperature, i t s v i s c o s i t y i s g r e a t e r than the other b u t y l a l c o h o l s . A l s o there was some s o l i d i f i c a t i o n that occurred on the c o o l i n g jacket which surrounded the immersible photochemical c e l l used f o r the irradiation. Cyclohexanol, l i k e t - b u t y l a l c o h o l , has a melting point c l o s e t o room temperature and similar v i s c o s i t y problems. Although i t i s a secondary a l c o h o l , i t a l s o gave a reduced y i e l d i n the photooxyenation reaction. Therefore, i t would appear that at l e a s t part of the problem i s a s s o c i a t e d with the r e d u c t i o n of energy t r a n s f e r caused by the s o l i d i f i c a t i o n / v i s c o s i t y of the a l c o h o l . The use of benzyl a l c o h o l i n the photooxygenation process r e s u l t e d i n no r e a c t i o n . This almost c e r t a i n l y occurred because the aromatic r i n g (in l a r g e excess as the solvent) absorbed the i n c i d e n t r a d i a t i o n and/or the dyeemitted r a d i a t i o n b l o c k i n g the photochemically induced o x i d a t i o n and rearrangement of the f u r o i c a c i d .


4

5-Hvdroxv-3-methvl-2(5H)-furanone (2a). Prepared by a c i d h y d r o l y s i s ( d i l u t e d HC1) of e i t h e r 5-methoxy (2b) or 5ethoxy-3-methyl-2(5H)-furanone (2c). In our experience, 2b was the p r e f e r r e d p r e c u r s o r f o r 2a s i n c e h y d r o l y s i s occurred more r a p i d l y and i n higher y i e l d than f o r 2c. P u r i f i c a t i o n of 2a was accomplished by r e c r y s t a l l i z a t i o n of the s o l i d from e t h y l ether t o g i v e c r y s t a l s with the c o r r e c t m e l t i n g p o i n t and a n a l y s i s . E t h e r i f i c a t i o n of 2a. The general procedure c o n s i s t e d of mixing together 0.044 moles of 2a, a s l i g h t excess of the a l c o h o l (0.048 moles), and 0.25g of p - t o l u e n e s u l f o n i c a c i d (p-TSA) i n 50ml of benzene i n a 100ml s i n g l e neck round bottomed (R.B.) f l a s k . The f l a s k was f i t t e d with a condenser t o which was attached a Dean-Stark t r a p topped with a d r y i n g tube. The contents of the f l a s k were s t i r r e d with a magnetic s t i r r e r while h e a t i n g t o r e f l u x with a heating mantle or o i l bath. Reflux was maintained u n t i l the molar equivalent of water (0.8ml) had evolved or u n t i l no more water e v o l u t i o n was apparent. Workup c o n s i s t e d of washing the benzene l a y e r with 25 ml of s a t u r a t e d sodium bicarbonate s o l u t i o n t o remove the c a t a l y s t and any a c i d i c byproducts, followed by washing with 25 ml of water and d r y i n g of the benzene l a y e r over anhydrous sodium s u l f a t e . The d r i e d benzene l a y e r was evaporated t o dryness under vacuum. L i q u i d s were f r a c t i o n a l l y d i s t i l l e d and s o l i d s r e c r y s t a l l i z e d t o obtain the a n a l y t i c a l samples. Tertiary a l c o h o l s would not react t o form the alkoxybutenolides i n the e t h e r i f i c a t i o n method, as e l i m i n a t i o n t o form alkenes becomes the p r e f e r r e d r e a c t i o n . Thus t e r t i a r y b u t y l


23.


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a l c o h o l was completely converted to i s o b u t y l e n e i n the presence of c a t a l y t i c p - t o l u e n e s u l f o n i c a c i d . The s t a r t i n g hydroxybutenolide, 2a, was converted t o the dimer, 2y. The y i e l d s i n the e t h e r i f i c a t i o n r e a c t i o n were t y p i c a l l y between 60-90% f o r the primary and secondary a l c o h o l s utilized. Each of the a l c o h o l s r e q u i r e some minor v a r i a t i o n s i n workup procedure but o v e r a l l the e t h e r i f i c a t i o n procedure was s t r a i g h t forward i n a p p l i c a t i o n w i t h i n the limitations mentioned. Details of individual preparations, p h y s i c a l and s p e c t r a l p r o p e r t i e s of the compounds are r e p o r t e d elsewhere (15, Pepperman, A. B. J . A g r i c . Food Chem. In p r e p a r a t i o n ) . 5,5'-oxvbis r3-methvl-2(5H)-furanonel (2v). A mixture of 2a [0.044 moles], 0.25g of p-TSA, and 50ml of e i t h e r benzene, toluene, or xylene was r e f l u x e d together u n t i l c e s s a t i o n of /ater e v o l u t i o n . Workup was conducted as f o r etherificatic ι reactions. Compound 2y r e s u l t s from a dehydration r e a c t i o n between two molecules of 2a, and i s r e f e r r e d t o i n the d i s c u s s i o n as the bis-furanone or dimer. The b i s furanone i s a high-melting s o l i d which was i s o l a t e d as a mixture of isomers p u r i f i e d by r e c r y s t a l l i z a t i o n . A high-melting isomer (HMI, mp 182-184) was r e a d i l y obtained from acetone-cyclohexane mixtures but the lower m e l t i n g isomer (mp 134-136) was not separated completely from the HMI, e i t h e r by r e c r y s t a l l i z a t i o n or by column chromato graphy under a v a r i e t y of c o n d i t i o n s , as evidenced by the NMR spectra (5-10% contamination). Most of the e t h e r i f i c a t i o n s produced 2y as a byproduct i n v a r y i n g amounts.

Bioassav Wheat seed (Triticum aestivum L., cv. Wakeland) were broadcast onto moist coarse sand i n p l a s t i c t r a y s and covered with a l a y e r of sand equal t o twice the diameter of the seed. Trays were then covered with aluminum f o i l and p l a c e d i n a darkroom at 22 + C f o r four days. E t i o l a t e d (wheat seedlings grown i n the dark as described) seedlings were harvested under a s a f e l i g h t at 540 nm and the roots and caryopses (spent seed) were cut from the shoots and d i s c a r d e d . The apices of the shoots were f e d i n t o a Van der Weij g u i l l o t i n e , the a p i c a l 2 mm were d i s c a r d e d and the next 4mm of each c o l e o p t i l e were saved f o r bioassay. Ten c o l e o p t i l e segments were p l a c e d i n each t e s t tube that contained the compound t o be t e s t e d and 2 ml of p h o s p h a t e - c i t r a t e b u f f e r at pH 5.6 p l u s 2% sucrose (20) . The stock s o l u t i o n f o r p r e p a r a t i o n of the molar s e r i e s was formulated by d i s s o l v i n g the t e s t compound i n acetone (7.5 L / l mL of b u f f e r s o l u t i o n ) and b r i n g i n g the mixture t o a s p e c i f i c volume (21). Tubes c o n t a i n i n g the c o l e o p t i l e segments, and the compound i n b u f f e r , were p l a c e d i n a r o l l e r - t u b e apparatus and r o t a t e d at 0.25 rpm f o r approximately 18 hours. Sections were then removed


284


from the incubation f l u i d , b l o t t e d on paper towels, placed on a g l a s s sheet, and images (x3) were produced from a photographic e n l a r g e r . Controls c o n s i s t e d of c o l e o p t i l e s e c t i o n s incubated i n acetone-sucrose-buffer solution. Data were s t a t i s t i c a l l y analyzed (22.) .


Results and

Discussion

The d e r i v a t i v e s of 2, l i s t e d i n Table 1, were prepared by e i t h e r the e t h e r i f i c a t i o n or photooxygenation method. All of the d e r i v a t i v e s were t e s t e d f o r a c t i v i t y as e t i o l a t e d wheat c o l e o p t i l e growth r e g u l a t o r s at t e n f o l d d i l u t i o n s from 10" to 10" molar concentrations. None of the butenolides t e s t e d had a c t i v i t y at the two lower concentrations. A c t i v i t y at higher concentration is represented i n Table I f o r simple a l i p h a t i c groups, none showed a c t i v i t y at 10" M and only three showed any a c t i v i t y at a l l . These were the η-propyl (2e), isobutyl (2h), and t e r t - b u t y l (2i) d e r i v a t i v e s , a l l of which gave about 40% i n h i b i t i o n . This was about the same as the hydroxybutenolide 2a. A l l of the other 2-4 carbon s u b s t i t u e n t s a f f o r d e d i n a c t i v e compounds. If a C-12 d e r i v a t i v e i s used, then a c t i v i t y of about 40% i n h i b i t i o n i s obtained at both 10" and 10" M. There i s no d e f i n i t e s t r u c t u r a l t r e n d present i n t h i s set of compounds as s t r a i g h t - c h a i n compounds were both a c t i v e (2d and 2j) and i n a c t i v e (2b,2c, and 2f) . Branching at the a l p h a - p o s i t i o n gave a c t i v i t y with one compound (2i) and no a c t i v i t y with two others (2e and 2g). The only compound of t h i s s e r i e s which had branching at the b e t a - p o s i t i o n (2h) was a c t i v e . The most a c t i v e compound i n t h i s s e r i e s was the n - l a u r y l d e r i v a t i v e (2j) which demonstrated moderate a c t i v i t y at both 1 and 0.1 mM. The greater a c t i v i t y of 2j may be a t t r i b u t a b l e to i t s greater l i p o p h i l i c c h a r a c t e r . Spotty a c t i v i t y was a l s o shown by the a l i p h a t i c s u b s t i t u e n t s as seed germination r e g u l a t o r s of weed and crop seeds with mostly i n h i b i t o r y e f f e c t s being observed (J/7) . F u n c t i o n a l i z a t i o n of the a l i p h a t i c s u b s t i t u e n t produced compounds which i n seven of the eight examples were a c t i v e at the highest concentration of 10" M. Unsaturation at the b e t a - p o s i t i o n produced a c t i v e compounds f o r t r i p l e bonds (3-propyne, 21) and conjugated double bonds (benzyl, 2z) but no a c t i v i t y f o r a simple double bond ( a l l y l , 2k). The benzyl d e r i v a t i v e gave complete i n h i b i t i o n and the 3propyne d e r i v a t i v e 61% i n h i b i t i o n at 10* M. Heteroatom s u b s t i t u t i o n on the a l i p h a t i c s i d e c h a i n a l s o produced compounds of greater a c t i v i t y than t h e i r u n s u b s t i t u t e d analogs. Thus the c h l o r o e t h y l (2m) and i o d o e t h y l (2n) d e r i v a t i v e s gave complete i n h i b i t i o n at ImM as compared t o no a c t i v i t y f o r the e t h y l d e r i v a t i v e , 2c. S u b s t i t u t i o n of c h l o r i n e i n t o the i n a c t i v e a l l y l s i d e c h a i n produced the beta-chloroallyl derivative (2q) which gave complete i n h i b i t i o n at 1 mM and 35% at 0.1 mM. The 3-bromopropyl d e r i v a t i v e (2o) gave complete i n h i b i t i o n at 1 mM compared


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t o 41% f o r the n-propyl, 2d. S u b s t i t u t i o n of hydrogen by a n i t r o group was l e s s e f f e c t i v e than halogen s u b s t i t u t i o n as the 2-methyl-2-nitropropyl compound (2p) gave 55% i n h i b i t i o n which was somewhat higher than the analogous i s o b u t y l d e r i v a t i v e ' s (2h) value of 37%. A phenol group at the b e t a - p o s i t i o n i n the 2-phenoxyethyl d e r i v a t i v e (2r) caused a c t i v i t y s i m i l a r to the halogen s u b s t i t u e n t s . D e r i v a t i v e s i n which the s u b s t i t u e n t i s a r i n g , rather than an a l i p h a t i c chain, were g e n e r a l l y a c t i v e , with both the c y c l o p e n t y l (2s) and c y c l o h e x y l (2t) d e r i v a t i v e s having a c t i v i t y at 1 mM and 0.1 mM. Methyl-substituted cyclohexyl d e r i v a t i v e s were a c t i v e only at the higher concentration, but the p o s i t i o n of the methyl group (2-methyl=2u, 3methyl=2v, 4-methyl=2w) on the r i n g was unimportant as a l l three showed the same l e v e l of a c t i v i t y . The two h e t e r o c y c l i c r i n g s u b s t i t u e n t s t e s t e d showed c o n t r a s t i n g behavior as t h e t e t r a h y d r o f u r f u r y l d e r i v a t i v e (2x), which i s a c y c l o p e n t y l analog with one carbon replaced by oxygen, was the only compound with a s i n g l e r i n g as s u b s t i t u e n t that was not a c t i v e . The dimer (2y), which i s simply two r i n g s of the parent s t r u c t u r e connected by an oxygen, was a c t i v e at 1 mM but i n a c t i v e at the lower concentrations. Only the c y c l o h e x y l compound had been t e s t e d as a seed germination r e g u l a t o r i n previous work (Γ7) and i t s a c t i v i t y v a r i e d , a c t i n g as a stimulant f o r wheat and as an i n h i b i t o r f o r sorghum and two amaranth s p e c i e s . Three benzyl d e r i v a t i v e s were evaluated and a l l three were a c t i v e at 1 mM, but none were a c t i v e at 0.1 mM. The u n s u b s t i t u t e d benzyl compound (2z) demonstrated the most a c t i v i t y with complete i n h i b i t i o n , the p a r a - n i t r o b e n z y l d e r i v a t i v e (2ab) was s i m i l a r with 90 % i n h i b i t i o n , whereas the meta-nitrobenzyl compound gave only 60% i n h i b i t i o n . The d i f f e r e n c e s i n a c t i v i t y are not great but may be a t t r i b u t a b l e to lowered e l e c t r o n d e n s i t y at the ether oxygen due to the i n d u c t i v e e f f e c t of the n i t r o group. Only the u n s u b s t i t u t e d benzyl compound (2z) was p r e v i o u s l y t e s t e d as a seed germination r e g u l a t o r (17) and shown to be i n a c t i v e with monocot seeds but i t had a c t i v i t y against d i c o t s , being stimulatory of redroot pigweed and i n h i b i t o r y of l e t t u c e and cucumber. The next two e n t r i e s i n Table 1 are compounds prepared by photooxygenation of f u r o i c a c i d i n methanol or ethanol. These normethyl compounds are strong growth i n h i b i t o r s , showing complete i n h i b i t i o n at 1 mM with 37% i n h i b i t i o n f o r the methyl d e r i v a t i v e (2ac) and 52% f o r the ethyl d e r i v a t i v e (2ad)at 0.1 mM. S t r i g o l and some of i t s analogs were a l s o evaluated. S t r i g o l i t s e l f (la) has no s i g n i f i c a n t a c t i v i t y as a growth i n h i b i t o r , whereas i t s epimer e p i s t r i g o l (lb) i s h i g h l y a c t i v e at 1 mM causing 90% i n h i b i t i o n and r e t a i n e d some a c t i v i t y at 0.1 mM. This d i f f e r e n c e i n a c t i v i t y i s the opposite of that observed f o r witchweed seed germination where s t r i g o l causes germination of 80% of the seed at concentrations as low as 10" M and e p i s t r i g o l r e q u i r e s 1



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10/000 times as much or 10~* M c o n c e n t r a t i o n t o achieve 80% germination (15). These vast d i f f e r e n c e s i n a c t i v i t y are caused by the stereochemistry of the ether l i n k a g e between the C- and D-rings. The two-ring analog of s t r i g o l (2-RAS, l c ) , which i s made up of only the C- and D-rings of the s t r i g o l nucleus, has a c t i v i t y p a r a l l e l l i n g t h a t of epistrigol. While 2-RAS causes only 60% i n h i b i t i o n at 1 mM, i t r e t a i n s some a c t i v i t y at 0.1 mM. This s i m i l a r i t y of activity between 2-RAS and epistrigol i n wheat c o l e o p t i l e growth i n h i b i t i o n might be i n d i c a t i v e of the stereochemistry of 2-RAS. This i s supported by the observation (15.) that i n witchweed seed germination the a c t i v i t y of 2-RAS approaches that of e p i s t r i g o l but i s much l e s s than s t r i g o l . A c t i v i t y of s i m i l a r magnitude was demonstrated by s e v e r a l known a n t i b i o t i c s , i n c l u d i n g novobiocin, neomycin, gentamicin, and cephalexin (23). Mycotoxins evaluated i n the wheat c o l o p t i l e assay were extremely a c t i v e as growth i n h i b i t o r s , r e t a i n i n g a c t i v i t y at concentrations as low as 10" M f o r v e r u c a r i n A and J and f o r t r i c h o v e r r i n Β (24). Several of the t r i c h o t h e c e n e s and c y t o c h a l a s i n s evaluated were active at 10" M with cytochalasin H_ and deacetylcytochalasin H still active at 10" M c o n c e n t r a t i o n s . One very a c t i v e compound i n t h i s assay i s a b s c i s i c a c i d (ABA) which, as yet, has no agrochemical a p p l i c a t i o n i n i t s n a t i v e s t a t e . ABA i n h i b i t s 100, 90, and 69% at 10", 10 and 10 M r e s p e c t i v e l y (18) . 6

Conclusions Many of the t i t l e compounds showed a c t i v i t y as growth i n h i b i t o r s f o r wheat c o l e o p t i l e s . Of t h i r t y - t h r e e 2(5H)furanones t e s t e d , twenty-five showed s i g n i f i c a n t a c t i v i t y at 1 mM. Eight of those r e t a i n e d some a c t i v i t y at 0.1 mM. Generally spotty a c t i v i t y was shown by simple a l i p h a t i c s u b s t i t u e n t s which could u s u a l l y be improved by the a d d i t i o n of a heteroatom t o the a l i p h a t i c chain. Tying back the chain i n t o an a l i c y c l i c r i n g or the a d d i t i o n of benzyl s u b s t i t u e n t s to the furanone r i n g , produced a c t i v e compounds. The stereochemical s e n s i t i v i t y of the wheat c o l e o p t i l e t e s t was demonstrated by the d i f f e r e n c e s i n a c t i v i t y between s t r i g o l and i t s epimer e p i s t r i g o l , with s t r i g o l being i n a c t i v e and e p i s t r i g o l having i n h i b i t o r y a c t i v i t y at both 0.1 and 1 mM c o n c e n t r a t i o n s . A two-ring s t r i g o l analog was a l s o a c t i v e at both 0.1 and 1 mM i n d i c a t i n g stereochemistry s i m i l a r to e p i s t r i g o l . Several of the compounds showing a c t i v i t y as growth i n h i b i t o r s were previously shown to be a c t i v e as seed germination regulators. The high a c t i v i t y of the two normethyl d e v i v a t i v e s i n d i c a t e that f u r t h e r e f f o r t s to prepare other d e v i v a t i v e s should be made. Acknowledgment s The authors wish to acknowledge the able t e c h n i c a l a s s i s t a n c e of Lynda H. W a r t e l l e i n the synthesis and i s o l a t i o n of many of the compounds.


23. PEPPERMAN AND CUTLER

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Dean, F. M. Naturally Occurring Oxygen Ring Compounds; Butterworths: London, 1963. Haynes, L. J.; Plimmer, J . R. Q. Rev. Chem. Soc. 1960, 14, 292. Siddall, J . B. U. S. Patent 3,700,694, 1972.


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Rebstock, T. L.; S e l l , H. M. J. Am. Chem. Soc. 1952, 74, 274. 5. Payne, G. B. U. S. Patent 3,177,227, 1965. 6. Rao, Y. S. Chem. Rev. 1976, 76, 625. 7. Cook, C. E . ; Whichard, L. P.; Turner, B.; Wall,, M. E . ; Egley, G. H. Science 1966, 154, 1189-90. 8. Cook, C. E . ; Whichard, L.P.; Wall, M. E . ; Egley, G. H.; Coggon, P.; Luhan, P. Α . ; McPhail, A. T. J . Am. Chem. Soc. 1974, 96, 1976-77. 9. MacAlpine, G. Α . ; Raphael, R. Α . ; Shaw, Α . ; Taylor, A. W.; Wild, H. J . J . Chem. Soc., Chem. Commun. 1974, 834-35; J . Chem. Soc., Perkin Trans. I 1976, 410-16. 10. Heather, J . B.; Mittal, R. S. D.; Sih, C. J . J . Am. Chem.Soc 1974, 96, 1976-77; J . Am. Chem. Soc. 1976, 98, 3661-69. 11. Johnson, A. W.; Rosebery, G.; Parker, C. Weed Res. 1976, 16, 223-27. 12. Saunders, A. R. Union of South Africa Dep. Agric. Sci. Bull. 1933, No. 128, 56 pp. 13. Brown, R. Nature 1945, 155, 455-56. 14. Shaw, W. C.; Shepherd, D. R.; Robinson, E. C.; Sand, P. F. Weeds 1962, 10, 182-92 15. Pepperman, A. B.; Connick, W. J., J r . ; V a i l . S. L.; Worsham, A. D.; Pavlista, A. D.; Moreland, D. E. Weed Science 1982, 30, 561-66. 16. Bradow, J . M.; Connick, W. J.; Pepperman, A. B. J . Plant Growth Regul. 1988, 7, 227-239. 17. Pepperman, A. B.; Bradow, J . M. Weed Science, 1988, 36, 719-725. 18. Cutler, H. G.; LeFiles, J . H.; Crumley, F. G.; Cox, R. H. J . Agric. Food Chem. 1978, 26, 632-35. 19. Farina, F.; Martin, M. V. An. Quim. 1971, 67, 315. 20. Nitsch, J . P.; Nitsch, C. Plant Physiol. 1956, 31, 94-111. 21. Cutler, H. G. Plant & Cell Physiol. 1968, 9, 593-598. 22. Kurtz, T. E . ; Link, R. F.; Tukey, J . W.; Wallace, D. L. Technometrics 1965, 7, 95-165. 23. Cutler, H. G. Proc. Plant Growth Regul. Soc. Am. 1984, 11, 1-9. 24. Cole, R. J.; Cutler, H. G.; Dorner, J . W. in "Modern Methods in the Analysis and Structural Elucidation of Mycotoxins", Academic Press, New York, 1986, pp 1-28. Received June 29, 1990


furanones Related to Strigol - American Chemical Society

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