Chiral 3-Benzyloxytetrahydrofuran Grass Herbicides Derived from

Chapter 12 Chiral 3-Benzyloxytetrahydrofuran Grass Herbicides Derived from D-Glucose William Loh

Downloaded by UNIV LAVAL on May 9, 2016 | http://pubs.acs.org Publication Date: November 3, 1987 | doi: 10.1021/bk-1987-0355.ch012

Chevron Chemical Company, Ortho Research Center, Richmond, CA 94804 A novel series of chiral grass herbicides based on the benzyloxy substituted tetrahydrofuran ring system has been prepared. These compounds are readily accessible synthetically from diacetone-D-glucose which serves as a chiral template possessing the appropriate stereochemistry for elaboration to the active herbicides. The degree of herbicidal activity is related to the molecular shape of these compounds and especially to the orientation of the substituents around the tetrahydrofuran ring. The chemistry and empirical structure-activity relationships of these compounds will be discussed. Sugar herbicide RE 39571, 5,6-dideoxy-l,2-0-(l-methylethylidene)-3-Cite-methylphenylmethyl)-ohD-xylo-hexofuranose (Figure 1), a representative of a novel series of chiral grass herbicides, has been demonstrated in our laboratories to possess a high level of preemergence herbicidal activity against grassy weeds with safety on soybeans, cotton, peanuts, and several other broadleaf crops. This herbicide has also been demonstrated to possess some broadleaf weed activity. Herbicide RE 39571 and its analogues represent new herbicide chemistry (1) and are chemically based on the common sugar D-glucose. This makes these compounds environmentally attractive products. These compounds are readily accessible synthetically from diacetone-D-glucose which serves as a chiral template possessing the appropriate stereochemistry for elaboration to the active herbicides. Empirical Structure-Activity Relationships In view of the structural novelty of this series of chiral herbicides, it was imperative to determine to what extent herbicidal activity is specifically linked to its molecular structure, and to define its structure-activity relationship requirements as a preliminary step toward designing even more potent representatives for this new series of herbicides. The 0097-6156/87/0355-0130S06.00/0 © 1987 American Chemical Society

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


12. LOH

Chiral 8~Benzyloxytetrahydrofuran

Grass Herbicides

131

original lead compound for this research was derived from our random screening program. In our attempts to optimize the herbicidal activity of this novel series of chiral compounds, a systematic study of the structure-activity relationships was undertaken. Practically all parts of the basic tetrahydrofuran ring were subjected to structural variations. The key structural modifications around the tetrahydrofuran ring can be classified as follows: 1. modifying and varying the shape and size of the substituent at the ring carbon position (using the carbohydrate nomenclature), 2. varying the aromatic substitution pattern around the benzyl group, as well as replacing the phenyl ring entirely by other aromatic or heterocyclic ring systems, 3. modifying the substituents on the dioxolane acetal ring to exploit the stability as well as the steric and lipophilic characters of this ring, ^. changing the ring size of the rings (one or both), and 5. changing the stereochemistry around the tetrahydrofuran ring. A great variety of different substituents were investigated at the C-^ ring carbon position (Figure 2). Of particular interest are compounds substituted with an alkyl or 1-hydroxyalkyl group (but not hydroxymethyl) (2), as these substituents resulted in compounds possessing the highest level of biological activity. Variation from the optimum alkyl chain length of two carbons decreased the activity (Figure 3). The ketone derivatives were also active but the aldehyde was not. We then examined the aromatic substitution pattern around the benzene ring. The substitution pattern as well as the type of substitution on the phenyl ring played an important role in the potency of these compounds. It was apparent from our findings that the highest biological activity was obtained when the phenyl ring was substituted at the ortho position by a F, CH3, or CI atom. However, the ranking of these three atoms could vary depending on what the substitution pattern was around the tetrahydrofuran ring, but they were consistently the most active herbicides (Figure Ψ). In contrast, moving these substituent groups from the ortho to the para position led to a reduction in activity relative to the parent compound. Moreover, moving these substituents to the meta position led to an even further reduction in activity relative to the parent compound. Meta substitution with either electron withdrawing or electron donating groups consistently led to compounds with diminished activity indicating that the meta position cannot tolerate any substitution. As an added example, a trifluoromethyl analogue at the ortho position was active whereas the meta substituted one was inactive. However, not all ortho substitution was favorable. An ortho cyano or an ortho methoxy group led to very weak activity and compounds with an ortho carboxymethyl or carboxyethyl group were devoid of activity. Bulky substituents around the ring led to inactive compounds suggesting some steric effects around these positions. Turning our attention to disubstituted benzyloxy compounds, we found that they in general were weaker except for the 2,6-Cl2 * 2,6-F2 compounds. The activity-lowering effects of the meta or para substituents are seen in the 2,^- and 3,^-disubstituted compounds. a n c


SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS

132

CH2CH3

5

n-C H 3

CH CI >

7

CH 0CH

2

2

R = CH(OH)CH ,

3

>

CH

>>

n-C H 4

CH(OH)C H

3

2

3

CH=CH

>

Î-C4H9

9

»

5

3

>>

CH(OH)C H 3

2

>

7

Figure 3. Effect of C-4 substitution on relative herbicidal activity. CH CH 2

3

.CH Ortho

>

Para

>

Meta

CH

3

3

Ortho Set F OCH

Figure 4. activity.

3

>

CH

>

CN

3

>

CI

>

C0 CH

> 2

H

>

2,6-CI

2

>>

3

Effect of aromatic substitution on relative herbicidal



12. LOH

Chiral 8-Benzyloxytetrahydrofuran

Grass Herbicides

133

Interestingly, when the benzene ring was replaced by other heterocycles such as pyridine or thiophene, herbicidal activity was retained (3). The relative herbicidal activity of the compounds that resulted from the modifications of the dioxolane ring are shown in Figure 5. The size and length of the Rl and substituents had a marked effect on herbicidal potency. The highest biological activity was obtained when the ketal substituents were small alkyl groups such as methyl or ethyl. Increasing the size of these groups led to a reduction in herbicidal activity. The only halogenated alkyl group that resulted in high potency was fluoromethyl. The chloromethyl group in contrast resulted in decreased activity. The following furo-dioxane series was also investigated where the 5-membered acetal ring has been replaced by a 6-membered ring W. In this case, the acetal functional group has been changed to an ether-type function. The trend in the aromatic substitution pattern was found to be similar to the RE 39571 series (Figure 6), but they were slightly weaker. At this point, several other pertinent questions needed to be resolved. Since RE 39571 is chiral and is the D-isomer, the question that can be raised is whether the L-isomer, its enantiomer is herbicidal. Does the biological activity reside in both enantiomers or in just one enantiomer? This question was answered when the desmethyl enantiomer of RE 39571 was synthesized and tested (Figure 7). Interestingly, this enantiomer was inactive (tested at 2.8 kg/ha) demonstrating that all the herbicidal activity resides in the D-isomer. Another question that needed to be raised was whether the configuration at the C-3 carbon position where the benzyloxy group is attached to plays an important role in activity. The 3-epimer was synthesized and tested in our screens and was found to be essentially devoid of herbicidal activity. This result clearly demonstrated that a cis relationship between the ethyl group and the benzyloxy group is required for activity. Removal of the acetal group or the benzyl group led to inactivity. Interestingly, the hydroxymethyl derivative was not active whereas the 1-hydroxyethyl and 1-hydroxypropyl groups at the C-4 carbon position led to good herbicides. The criteria required for optimum herbicidal activity for these sugar compounds can now be summarized as follows: 1. a C-*f ring substituent that is preferably an ethyl group, 2. an ortho substituent on the phenyl ring, preferably a methyl, fluorine, or chlorine group, 3. an acetal with two substituents of appropriate size such as methyl or ethyl, and 4. a D-threo configuration about the C-3 and C-*f carbons with a cis relationship of their substituents. Related Herbicides with Similar Characteristic Structural Features It became increasingly apparent as research progressed that we needed to know if any other known herbicides possibly possessed or shared these same characteristic structural features. A literature survey revealed several herbicides that need to be mentioned here which possess or incorporate the same characteristic structural features. These are the



134


CH F 2

CH

3

CH

CH

3

CH

3

C H

CH

3

2

3

C H

5

3

H

H

H

. (CH ) C H to n - C H

7

C H 2

5

C H

5

2

CH

CH=CH

CH CI

H

2

2

3

4

4

5

> CH CI

2

3

> C H

2

3

CH CI

2

CH

»

9

CH

3

e

C0 CH

5

2

3

Figure 5. Effect of ketal substituents on relative herbicidal activity. CH CH 2

\ «R R = F

A0 >

CI

>

3

N

C CH, 3

Figure 6. Relative herbicidal activity.

CH CH 2

RE 39571 enantiomer

3

3-epîmer

Figure 7. Comparison compounds.


12. LOH

Chiral 3-Benzyloxytctrahydrofuran

Grass Herbicides

135


cineole Shell Cinch (5), dioxolane Shell WL 29226 (6,7), and dioxane FMC 39871 (8) (Figure 8). Relationships that immediately become apparent between RE 39571 and the other compounds are: 1. the presence of a short alkyl chain, i.e., methyl or ethyl vicinal to the benzyloxy group, 2. a benzyl group preferentially substituted at the ortho position, 3. a cis relationship between the above two groups, and 4. a common glycol or glycerol fragment. Additionally, computer and Dreiding modelling immediately demonstrated that all four of these structures can be overlapped or superimposed on top of each other (Figure 8), the alkyl groups overlapping over each other, as well as the benzyl groups and the glycol oxygen atoms. Hypothetical Biological Binding Site for Sugar Herbicide It is now apparent that the degree of herbicidal activity is related to the molecular shape of the sugar molecule and especially to the orientation of the benzyloxy and alkyl groups. These observations therefore suggest a hypothetical biological binding site that might appear in partial cross section as shown (Figure 9) in this representation. This representation of the binding site consists of a cleft capable of accommodating the benzyl portion of the molecule and a pocket or cavity that accepts the alkyl group. The herbicide fits the binding site in a lock-and-key or complementary relationship and can bind only to those compounds that can share a common denominator of structure and that is, the backbone that contains the benzyloxy group and the alkyl group oriented as shown. The binding site clearly demonstrates complete stereospecificity as it can distinguish between stereoisomeric forms. This offers an explanation as to why the enantiomer of RE 39571 is not herbicidal. It cannot fit the binding^site and therefore cannot elicit the biological response. Even though there is great diversity in molecular structure of these related herbicides such as RE 39571, Cinch, WL 29226, and FMC 39871, the similar spectrum of biological activity possessed by all of these herbicides therefore lead us to postulate that they all appear to fit the same binding site and share a common mode of action. Metabolite Studies The metabolic fate of the desmethyl analogue of RE 39571 has been evaluated in barnyard grass shoots. The major metabolite was identified as the debenzylated sugar derivative which was devoid of any herbicidal activity. Synthesis The first step in the 5-step synthesis sequence of RE 39571 involved benzylation of the commercially available diacetone-D-glucose with a-chloro-o-xylene employing either NaH or NaOH as base. The use of differently substituted benzyl halides afforded the corresponding substituted products. Selective deisopropylidenation at the 5,6-position with aqueous acetic acid then gave the terminal diol (Scheme 1). The terminally unsaturated sugar can be generated from the 5,6-diol via a



Figure 8. Structural overlap of herbicides related to RE 39571.

Shell Cinch


>

o o w o

W

o > o

>

M

e

s

•< Z H

C*

Chiral S-Benzyloxytetrahydrofuran

Grass Herbicides


12. LOH

Scheme 1. Synthesis of RE 39571 via D-glucose.


137



138

cyclic thionocarbonate, followed by treatment with trimethyl phosphite (9). However, the acid catalyzed decomposition of the cyclic ethyl orthoformic ester provided a simpler, higher yielding route generating only innocuous side-products and was the method of choice. This method also offered consistent results with different aromatic substituents. Subsequent reduction by catalytic hydrogénation with Pd/C then afforded cleanly the saturated sugar derivative in high yield with no debenzylation being observed. If debenzylation is desirable, this is accomplished cleanly by hydrogenolysis under catalytic transfer hydrogénation conditions (10) employing 20% Pd(OH)2/C and cyclohexene as hydrogen donor. An alternate approach to the synthesis of these sugar derivatives employed the commercially available diacetone-D-xylose as starting material (Scheme 2). Deprotection of the 3,5-isopropylidene group followed by selective tosylation of the primary hydroxyl group gave the known 5-O-tosyl-a-D-xylofuranose derivative (11). Coupling of the tosylate with a Grignard reagent in the presence of dilithium tetrachlorocuprate as catalyst (12) produced the ethyl substituted tetrahydrofuran derivative which was then benzylated with the appropriately substituted benzyl halide. This procedure was satisfactory for the synthesis of a variety of different aryl derivatives and also allowed entry into different C-^ substituted derivatives. The enantiomer of the desmethyl analogue of RE 39571 was prepared in a similar manner employing L-xylose instead of D-xylose. Modification of the ketal substituents involved deketalization of RE 39571 with aqueous trifluoroacetic acid followed by reaction with the appropriately substituted ketone or aldehyde and anhydrous copper sulfate as the dehydrating agent (Scheme 3). If the glycoside-ether is the desired product, this can readily be obtained by glycosidation with methanol in the presence of hydrogen chloride followed by alkylation of the 2-hydroxyl group with the appropriate halide. The 3-epimer sugar derivative was synthesized in a similar manner as the parent compound except that the hydroxyl group at the C-3 position in diacetone-D-glucose was initially epimerized (13) by oxidation with methyl sulfoxide and acetic anhydride followed by reduction with sodium borohydride. The furo-dioxanes can also be synthesized from RE 39571 by conversion to the glucoside with methanol and hydrogen chloride, followed by alkylation of the hydroxyl group at the C-2 position with ethyl bromoacetate. The product was then reduced with lithium aluminum hydride to the alcohol and cyclized by acid catalysis (Scheme Summary In summary, these compounds represent a novel series of chiral grass herbicides that provide yet another example where chirality is very important for herbicidal activity. Additionally, the use of the sugar D-glucose as a chiral and enantiomerically pure starting material also offers the advantage of having the correct stereochemistry established inherently in the molecule.


12. LOH

Chiral S-Benzyloxytetrahydrofuran CH OH

CH 0H

2

CH OTs

2

1er ^

139

Grass Herbicides

2

-JQW

OH

\"

0

\^

0

CH MgBr LI CuCI 3

2

ÇH CH


2

4

®-CH CI

3

ÇH CH

2

2

°Λ

CH

3

3

Λ

0

Scheme 2. Alternate synthesis route via D-xylose. CH CH 2

CH

CH CH

3

2

3

CH CH

0

2

3

R

3

ΛΙΙ

CH

3

CH 0H VHCI 3

CH CH v n ^ n 2

2

CH CH- -

3

2

3

3

*OCH

3

^ \

\ CH

lu

CH

0 H

OR

U

3

3

Scheme 3. Ketal and glycoside synthesis. CH CH 2

\

H

CH CH

3

2

OH

J

\H

3

0CH C0 C H 2

3

2

2

LIAIH

4

CH CH 2

CH CH

3

2

ν

VCH^

η 0

y

CHCI

3

^

f

3

\

VCH .

3

OCH CH 0H 0CH 2

Scheme 4. Furo-dioxane synthesis.


2

5


140 Acknowledgments

I wish to thank A. Omid for his contribution to the biological testing and Y. S. Chen for the metabolism studies. I am also grateful to M. S. Singer for his computer-assisted modelling studies and to D. C. Aven for her technical assistance. Literature Cited


1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Loh, W. U.S. Patent 4 429 119, 1984. Loh, W. U.S. Patent 4 521 240, 1985. Loh, W. U.S. Patent 4 515 618, 1985. Loh, W. U.S. Patent 4 534 785, 1985. Payne, G. B.; Soloway, S. B.; Powell, J. E.; Roman, S. Α.; Kollmeyer, W. D. U.S. Patent 4 542 244, 1985. Kirby, P.; Turner, R. G. Proc. 12th Br. Weed Control Conf. 1974, 2, 817. Barker, M. D.; Isaac, E. R.; Kirby, P.; Smith, G. C. U.S. Patent 3 919 252, 1975. Konz, M. J. U.S. Patent 4 207 088, 1980. Horton, D.; Thomson, J. K.; Tindall, C. G., Jr. Methods Carbohydrate Chem. 1972, 6, 297. Hanessian, S.; Liak, T. J.; Vanasse, B. Synthesis 1981, 396. Tipson, R. S. Methods Carbohydrate Chem. 1963, 2, 247. Fouquet, G.; Schlosser, M. Angew. Chem. Internat. Edit. 1974, 13, 82. Stevens, J. D. Methods Carbohydrate Chem. 1972, 6, 123.

RECEIVED May 12, 1987


Chiral 3-Benzyloxytetrahydrofuran Grass Herbicides Derived from

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