Glyphosate derivatives

Considerably higher product yields resulted under much milder conditions when diaryl phosphites were condensed with ffilTs. Whereas vigorous neat conditions and temperatures exceeding 100 °C were usually necessary with aliphatic phosphites, often quantitative conversions to the desired glyphosate derivatives were obtained in common organic solvents using aromatic or benzylic phosphites (40). 

This HHT procedure is particularly convenient for laboratory-scale syntheses of a wide variety of glyphosate derivatives and intermediates (2). In many cases, fairly sensitive functionalities can often be accommodated because of the mild thermal conditions and the complete absence of water. This method is therefore quite complementary to the other aqueous Mannich procedures, since groups that would not normally tolerate aqueous strongly acidic conditions would frequently decompose or would be difficult to recover in high yield. 

HETEROCYCLIC GLYPHOSATE DERIVATIVES 23.1 Heterocyclic "Masked" Carboxylates... 

Certain 1,3,4-oxadiazole and 1,2,4-triazole glyphosate derivatives have been conveniently prepared in a faster, more efficient manner by heating the thionoester intermediates 73 with the appropriate acid hydrazide (61). These versatile thionoesters 73 have been synthesized in nearly quantitative yield from the readily available nitrile 31a, described previously, through the intermediate imidate ester 72. The oxadiazole products such as 70 obtained using this procedure were identical to those obtained from the HHT approach. 

Disodium glyphosate has been reacted with activated heteroaryl halides, such as 2-chlorobenzothiazole or 2-chlorobenzoxazole 79, in aqueous alcohol at reflux to produce the N heteroaryl glyphosate derivadves 80 (2). Improved yields have often obtained in these reactions using the more soluble bis-quatcmary ammonium salt of glyphosate derived from tetrabutylammonium hydroxide (2). 

The higher solubility of several quaternary ammonium salts of glyphosate in polar aprotic organic solvents such as acetonitrile was discovered (2), which permitted their reaction in solution with various alkyl halides. For example, GLY(n-Bu4N)2H reacted with either o-xylylene dichloride or 1,5-dibromopentane to produce the interesting quaternary glyphosate derivatives 81 and 82, whose structures have been confirmed by x-ray analysis (2). 

About 1200 literature citations (including published articles and abstracts) exist on various aspects of glyphosate, but there are few review articles on the compound. A description of the compound and its general herbicidal properties was published soon after its introduction (10. Updates of the compound s selectivity and characteristics have since been published (, 3, ). Franz ( ) covered both general and specific aspects of glyphosate, including the relationship between structure and activity of glyphosate derivatives and related compounds as well as various proposed modes of action. 

Heterocycles in synthesis of herbicide glyphosate heterocyclic derivatives and analogs of glyphosate 97PHC17. 

At the time of its discovery in 1970, few chemical methods were known for the laboratory syntheses of such molecules. Fewer still were appropriate for their industrial scale production. Unlike many other amino acid derivatives, gl rphosate is stable in strong acid or base, even at elevated temperatures. It can also tolerate strong reductants and some oxidants (1,2). This stability accounts for the diversity of synthetic methods that have been explored and developed to prepare glyphosate and its heterocyclic derivatives over the last 25+ years. 

Glycine and its esters also readily form isolable trimeric HHT derivatives. These interme ates have also been successfully utilized in constructing the glyphosate backbone when they have sufficient thermal stability to tolerate the reaction conditions. For example, good overall yields of GLYH3 were obtained under similar conditions with the stable HHT of sodium glycinate 24 via the phosphonate diester 14b (30). 

Several variations and extensions of this HHT method have recently been reported. The mildness of this reaction was exemplified through the synthesis of glyphosate thiol ester derivatives 35. The requisite thioglycinate HHT 34 was prepared in high yield by a novel, methylene-transfer reaction between r-butyl azomethine and the ethyl thioglycinate... 

In contrast, when excess amounts of the HHTs derived from simple aliphatic glycinate esters, such as 25, were used in excess in reactions with diaryl phosphites (SO), the related glyphosate aminals containing aryl phosphonate esters 46 were isolated in low yield (5-15%). Like many aminals, these triesters 46 were acid-sensitive and were quantitatively converted to the corresponding triester strong acid salts 47 upon treatment with either HCl or methanesulf onic acid (27). 

HHTs derived from AMPA diethyl ester 56 also reacted with acetyl chloride to generate glyphosate nitriles 58 following cyanide displacement with the resulting iV-acetyl-Af-chloro-methyl-AMPA diethyl ester 57. Subsequent acidic hydrolysis of 58 gave GLYH3 (58). 

Another AMPA-derived procedure took advantage of the neat reaction between the N-carbamoyl-HHT 59 and diethyl phosphite catalyzed by boron trifluoride etherate to generate the AMPA carbamate 60. Subsequent alkylation with ethyl bromoacetate and base produced the glyphosate triester carbamate 61, which was hydrolyzed to GLYH3 (59). 

Various heterocyclic moieties have been incorporated at the glyphosate carboxylate center as potential "masked" carboxyl derivatives 62. All of those reported to date contain a fully unsaturated heteroaromatic ring. 

The parent tetrazole derivative of glyphosate 78 has been reported as a product of the 1,3-dipolar cycloaddition of n-Bu3SnN3 across the nitrile linkage in 76 and subsequent hydrolysis of the resulting diester 77 (62). 

The effects of glyphosate on phenolic compound production are two-fold 1) accumulation of phenolic compounds that are derivatives of aromatic amino acids is reduced and 2) pools of phenolic compounds derived from constituents of the shikimate pathway prior to 5-enolpyruvylshikimate-3-phosphate become larger. Assays that do not distinguish between effects on these two groups, such as that for hydroxyphenolics of Singleton and Rossi (18), can lead to equivocal and difficult to interpret results (e.g. 3-5). 

Anthocyanins are Che most easily assayed and commonly studied derivatives of aromatic amino acids (Figure 1). Glyphosate drastically reduces accumulation of anthocyanin flavonoids in treated tissues (6, 19) (Figure 3). Levels of rutin and procyanidin, both flavonoids, are reduced in glyphosate-treated buckwheat hypocotyls (6). Glyphosate would presumably similarly affect levels of flavonoids and flavonoid derivatives that are known to be allelochemicals. 

Many herbicides and other chemicals have been reported to influence levels of various phenolic compounds in higher plants by unknown mechanisms. It is unlikely that more than a few of these compounds have a primary influence on secondary phenolic compound synthesis. For instance, in our survey of the effects of 17 herbicides on anthocyanin accumulation, only glyphosate appeared to directly influence accumulation (31). The effects of several compounds on secondary phenolic compound production for which the mechanism of influence is unknown are summarized in Table II. A much longer list could be derived from the literature. Unfortunately, many of these compounds are phytotoxic or are known to have effects other than on secondary aromatic compound production. In most cases the effects on these compounds correlate well with extractable PAL activity (31, 71, 72, 73, 74) (Figure 5), even though they do not directly affect the enzyme. 

Other carboxylic acids that have become popular herbicides, though they are not phenoxyacetic acid derivatives, are dicamba and glyphosate or Roundup . Notice that dicamba does have a methoxy group and two chlorines, so it is similar to 2,4-D. Glyphosate is used on cotton and... 

All carbons are derived from either erythrose 4-phosphate (light purple) or phosphoenolpyruvate (pink). Note that the NAD+ required as a cofactor in step (3) is released unchanged it may be transiently reduced to NADH during the reaction, with formation of an oxidized reaction intermediate. Step (6) is competitively inhibited by glyphosate (COO—CH2—NH—CH2—PO ), the active ingredient in the widely used herbicide Roundup. The herbicide is relatively nontoxic to mammals, which lack this biosynthetic pathway. The chemical names quinate, shikimate, and chorismate are derived from the names of plants in which these intermediates have been found to accumulate. 

Glyphosate is toxic to plants and free-living microorganisms because it inhibits aromatic amino acid biosynthesis. On the other hand, it is extremely nontoxic to humans and animals because humans derive their amino acids from the diet. Additionally, it is broken down in the soil, so it is non-persistent. The only problem with glyphosate herbicides is that they will kill crop plants as readily as weeds. Recently, genetically engineered crop varieties have been introduced which are resistant to the herbicide, allowing weeds to be killed preferentially. 

Although the weak acid hypothesis appears to explain the mobility of compounds such as chlorophenoxy derivatives, there are several exceptions to the weak-acid hypothesis (4, 1A> 15). For example, some xenobiotics are phloem mobile but are not weak acids and do not appear to be converted to a weak acid prior to transport (e.g., amitrole, oxamyl). Also, some xenobiotics (e.g., glyphosate) which have an ionizable COOH group are loaded into the phloem independently of apoplast pH. These should lose their mobility under pH conditions which ionize the chemical in the free space. Furthermore, accumulation of the weak acid glyphosate against a concentration gradient does not occur (14). 

Alfalfa plants, derived from tissue culture and tolerant to Roundup, were evaluated to investigate their mechanism of resistance. No difference was found in the level of shikimate-3-biphosphate which accumulated in both resistant and susceptible lines upon treatment with glyphosate. 

Figure 12. HG-2 glyphosate tolerant alfalfa derived from tissue culture selection. A. Abnormal multifoliate leaf structure. B. Abnormal flower morphology.

Glyphosate or N-(phosphono-methyl) glycine Glycine derivative Inhibits amino acid synthesis nonselective, fast-acting herbicides Used as general weed control and weed control in transgenic maize 11-6... 

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