Synthesis and Activity of Analogs of the Natural Herbicide

Chapter 13 Synthesis and Activity of Analogs of the Natural Herbicide Cyanobacterin 1

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Janet L. Carlson , Timothy A. Leaf , and Florence K. Gleason

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Downloaded by UNIV OF CALIFORNIA SAN DIEGO on April 1, 2016 | http://pubs.acs.org Publication Date: November 3, 1987 | doi: 10.1021/bk-1987-0355.ch013

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Department of Chemistry, Macalester College, St. Paul, MN 55105 Gray Freshwater Biological Institute, University of Minnesota, Navarre, MN 55392

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The natural product cyanobacterin has been found to inhibit photosynthetic electron transport in other organisms. A series of analogs of cyanobacterin were prepared as potential herbicides. Several of the analogs also inhibit the growth of the test photosyn thetic organisms. The synthesis and structure-activ ity relationships of these analogs are discussed. Cyanobacterin, a natural product isolated from the freshwater cyanobacterium (blue-green alga) Scytonema hofmanni UTEX 2349, has been shown to be highly toxic toward other cyanobacteria and green algae (J_). It interrupts photosynthetic electron transport at a site in Photosystem II, but not at the same site as classical PS II inhibi tors such as DCMU (3-(3,4-dichlorophenyl)-1,1-dimethylurea) act(£). Cyanobacterin, whose structure is shown in Figure 1, is the first example of a halogenated metabolite to be isolated from a freshwater alga. A related compound, the α,3-unsaturated lactone resulting from dehydration of cyanobacterin, was also isolated from Scytonema hofmanni but is not algicidal (3). The total synthesis and x-ray structure determination of racemic cyanobacterin was recently reported by Williard and coworkers (JL). An x-ray structure determination of the natural product has also been published (5). We have prepared a series of analogs (in racemic form) by a modification of the reported synthesis and tested them for inhi bition of PS II. Biological Activity of the Analogs The relative potency of the analogs was determined by the concen tration required to inhibit PS II (6.). In this assay, the con centration of analog which caused complete inhibition of the evo lution of oxygen by thylakoid membranes isolated from Synechococcus sp ATCC 27146 was determined using IUFe(CN) as the electron accep tor. 6

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0097-6156/87/0355-0141$06.00/0 © 1987 American Chemical Society

Baker et al.; Synthesis and Chemistry of Agrochemicals ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS


142

The data shown in Tables I-III indicates that the presence of a halogenated ring is necessary but not sufficient for an analog to inhibit oxygen evolution by the thylakoid membranes. Substitution of the chlorine by bromine yielded an analog whose inhibitory activ ity is similar to the natural product. However, substitution by hydrogen resulted in an inactive analog. Similarly, a closely related analog having a methyl group in the position occupied by the chlorine in cyanobacterin and methoxyls instead of the methylenedioxy group is also inactive. As shown in Table II, removal of the methylenedioxy group pro duces an analog with greatly reduced inhibitory activity. However, replacement of the methylenedioxy group by an additional chlorine in the para position partially restores inhibitory activity. The pre sence of chlorine in the para position alone is not sufficient to cause inhibition. The analog lacking the methoxyl also showed some activity. (See Table III.) Moving the chlorine from one aromatic ring to the other destroyed inhibitory activity. Not surprisingly, the com pletely unsubstituted analog did not inhibit oxygen evolution. Analog Synthesis The analogs were prepared by a modification of the published syn thesis. In the key step, the α -anion of a dihydrocinnamic acid ester was coupled with an acetylenic ketone. (See Scheme A.) After separation of the resulting diastereomers by medium pressure liquid chromatography, the slower moving isomer having the priority antireflective (PARF) (1) configuration shown was allowed to react with silver nitrate in aqueous dimethoxyethane to yield the analog. When the published procedure using methanol was employed, the NMR spectra of the product indicated that additional methoxyls were sometimes added. A representative synthesis of the dihydrocinnamic acid ester (shown in Scheme B) begins with the bromination of vanillin (8). The catechol obtained upon demethylation (J) is not purified as i t i s air sensitive. Instead, the crude product is alkylated with dibromomethane (4) to yield the methylenedioxy compound which can be recrystallized with ease. A Horner-Wittig reaction with triethylphosphonoacetate produces a cinnamate in high yield (4)· The yield varied from 58$ to >99$ for other analogs. The alkene is then reduced with sodium borohydride and nickel chloride in methanol and dimethoxyethane (10). (Catalytic hydrogénation on noble metal catalysts is known to cause extensive dehalogenation of aromatic bromides (11). We observed 10-50$ debromination using NaBH^/NiClp*6H 0 depending on the reaction time.) For other analogs the yield ranged from 44$ to >99$. In some cases, the requisite cinnamic acid was commercially available and could be reduced after esterification. Partial reduction was seen when the carboxylic acid was used as the substrate. After hydrolysis and silylation, the desired intermediate ester was obtained. The synthesis of the acetylenic ketone, shown in Scheme C, began with the appropriately substituted ketone or aldehyde. In the 2


13.

CARLSON ET AL.

Analogs of the Natural Herbicide Cyanobacterin

Ο

CI


Figure 1.

Cyanobacterin.

T a b l e I . Analogs o f C y a n o b a c t e r i n H a v i n g One M o d i f i e d A r o m a t i c R i n g

Ar =

Complete Inhibition of the Hill Reaction with K F e ( C N ) 3

3

6

25 nM (natural

product)

60 nM

Not Active

Not Active CH

3


143

144



T a b l e I I . Analogs o f C y a n o b a c t e r i n H a v i n g One M o d i f i e d A r o m a t i c R i n g

Ar =


3

6

1.5 UM

Not Active

136 nM

Not Active


13.

CARLSON ET AL.

Analogs of the Natural Herbicide Cyanobacterin


T a b l e I I I . Analogs o f C y a n o b a c t e r i n

Ar =

Ar' =


3

6

25 nM (natural product)

143 nM

Not Active

Not Active


145



146

Scheme A.

Synthesis of Cyanobacterin Analogs.


CARLSON ET AL.

Analogs of the Natural Herbicide Cyanobacterin 147


Br I Br /HOAc 93% 2

Ο

Τ

(EtO) '

Ο P s

2

^OR

NaH

97%

Ο Br

Ar C1 B»S(CH ) >99% 3

3

OR

2

1. N a B H / N i C l ' 6 H 0 2. KOH/H 0/EtOH 3. H 0 65% 4

2

2

+

3

Ο

Br Ar

OH

CH Br /KF 89% 2

2

J

Synthesis and Activity of Analogs of the Natural Herbicide

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