Monocrotalic acid

When monocrotaline is hydrogenolysed the acid scission product is monocrotalic acid, CgHigOj, m.p. 181-2°, [a]p ° — 5-33° (HgO), which provides a methyl ester, m.p. 79-80°, [ ]d°° — 16-2° (EtOH), containing one active H atom and a p-bromophenacyl ester, m.p. 162-3°. It is a lactonic acid, which on boiling with sodium hydroxide solution loses carbon dioxide and produces a/3-dimethyllaevulic acid (monocrotic acid, II). 

Monocrotalic acid (36) was previously shown to have the (2R, 3R, 4R) absolute configuration.14 All eight stereoisomers of monocrotalic acid have been synthesized by Matsumoto and co-workers.15 ds-Hydroxylation of the ( )-(Z)-alkene... 

R,3/ ,45)- and (25,35,4/ )-acids (38). Resolution of ( )-(E)-2,3,4-trimethyl-2-pentenedioic acid gave the two separate isomers. The configuration of each isomer was assigned by correlation with (-)-(/ )-2-phenylpropanoic acid. Then methylation of the (45)-acid (39), followed by cw-hydroxylation, hydrolysis, and separation of the diastereoisomeric acids, yielded the (2/ ,35,45)- (40) and (25,3/ ,45)-isomers (41) of monocrotalic acid (Scheme 10). The stereochemistry... 

A synthesis of Monocrotalic Acid was interrupted by problems with the 0 sily lation of a hemiacetal with low nudeophilirity [Scheme 4,68].114 Progress resumed when it was found that silver(I)-assisted silylation using terf-butyldi-methylsilyl chloride was efficient, giving a mixture of diastereoisomeric O-silyl acetals (dr = 2,7 1) in 93% yield. 

The absolute configuration of monocrotalic acid (44), the necic acid component of monocrotaline (45), has been elucidated aside from the acid derived from retusamine, whose structure has been defined by X-ray crystallography, this is the first necic acid component of a pyrrolizidine diester alkaloid containing an eleven-membered ring to have its stereochemistry unambiguously established. 

Monocrotaline (45) was reduced (LiAlH4) to 2,3,4-trimethylpentane-l,2,3,5-tetraol (46). Periodate oxidation of (46), followed by hypobromite oxidation of the product, afforded 3-hydroxy-2-methylpropanoic acid, whose hydrazide (48) was shown to be enantiomeric with the known hydrazide" of -configuration. The hydrazide from monocrotaline therefore has the S-configuration and monocrotalic acid has the R-configuration at C-4. 

Since the o.r.d. and c.d. curves of monocrotalic acid are very similar to the corresponding curves exhibited by trichodesmic acid (49), which is known independently to have the same relative configuration at C-2, C-3, and C-4 as monocrotalic acid, the absolute configuration of trichodesmic acid must also be 2R,3R,4R. 

This conclusion concerning monocrotalic acid, which is at variance with the original proposal of Adams et al., is confirmed by a study of the n.m.r. spectra of the phenylboronate esters of monocrotaline and trichodesmine, which shows conclusively that these esters assume identical or nearly identical conformations. This is only possible if the configurations at C-2 and C-3 are the same in monocrotaline and trichodesmine. It is now believed that the original synthesis of... 

The synthesis of monocrotalic acid, fully proving the assigned structure (CLXXII), was achieved by Adams et al. (197) in the following manner. Pure diethyl 2,3-dimethylglutaconate (CLXXXV) was subjected to carbethoxylation with ethyl carbonate in the presence of sodium ethoxide. The sodio derivative was not isolated but was treated directly with 1 mole equivalent of methyl iodide. The product, diethyl... 

Culvenor and Smith (77) hydrolyzed retusine to obtain two lactone acids, C8H12O4, which were identified as epimeric dihydroanhydro-monocrotalic acids (LXXXIIIa) the a-acid (mp 130°-131° [a] + 3.3°), which was the form present in the alkaloid, and the )S-acid (mp 118° ... 

All the acids of this group may accordingly be represented by the general formula LXXXIII. The R configuration at C-2 of monocrotalic acids has been determined by Cervinka et al. (141). 

LXXXIII a, Crispatic and fulvinic acids LXXXIII b, Acids from retusine (lactone form) LXXXIII c, Monocrotalic acid (lactone form) LXXXIII d, Acetylmonocrotalic acid (lactone form)... 

Chart VI. The biosynthesis of tiglio, eohimidinic, and trichodesmic acids, and the C5 unit common to the Cio adipic acids and monocrotalic acid according to Crout. 

Acetate has been reported to be a precursor for the necic acid component, monocrotalic acid [as (48)], of monocrotaline (49). Rigorous attempts to confirm this finding have met only with failure. Although acetate was rapidly taken up into the plant it was not incorporated into (49). The earlier conclusion, it was suggested, may have been occasioned by working with impure alkaloid. 

A more reasonable genesis of monocrotalic acid, at least as far as C-1, -2, -3, -6, and -7 are concerned, would be from isoleucine by analogy with senecic acid biosynthesis (see above) the C5 unit which these atoms constitute is a common feature of the necic acids. Accordingly satisfactory incorporations of l-[[/- Cjisoleucine and its precursor, L-[f/- C]threonine [as (50)], into (49) were observed and the activity was shown to be confined to the necic acid moiety. Moreover, the isoleucine was found to label C-1, -2, -3, -6, and -7 of monocrotalic... 

Of all the Senecio alkaloids, the structure of monocrotaline is known with most certainty as a result of the work of Adams and his co-workers over a period of five years or more. The alkaloid monocrotaline (I) is the ester of retronecine vith monocrotalic acid. The structure of the necine portion has been proved conclusively, while the structure of the necic acid portion is considered the most likely of three possible configurations. The position of attachment of the two portions is known with certainty. The... 

Monocrotalic acid, CJIaOi. A solution of 10.8 g. of monocrotaline in a mixture of 10 cc. of glacial acetic acid and 40 cc. of ethanol was hydrogenated at 2-3 atm. with 0.1 g. of platinum oxide catalyst. Two moles of hydrogen were absorbed in 5 hours. The solution was filtered from the catalyst and evaporated in vacuo. The remaining sirup was taken up in 34 cc. of 1 iV hydrochloric acid and the aqueous solution thus obtained was extracted continuously with ether for 24 hours. The ether solution was dried, the ether was removed, and the crystalline residue of monocrotalic acid was purified by recrystallization from acetone-petroleum ether (b. p. 30-60°) white plates, m.p. 181-182°. 

Retronecanol, CtHuNO. After extraction of the monocrotalic acid with ether, the aqueous solution was clarified with norite, filtered, and made strongly alkaline with sodium hydroxide. The solution was then extracted with five 60-cc. portions of ether. The combined ether extracts were dried. When the ether was removed, the oily basic residue solidified. It was best purified by distillation b.p. 140° (30 mm.) white crystals, m.p. 95-96°. 

The establishment of the structure of monocrotic acid as a, 3-dimethyl-levulinic acid (LXIV) and its formation from monocrotalic acid by loss of carbon dioxide limits very dehnitely the possible structures of the latter. Monocrotalic acid was known to contain one carboxyl group and the presence of a lactone group was indicated on back titration of the acid... 

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