Patent GB-795750-A (GB)
Title: ª‰-kainic acid, its isomers and their derivatives and a method for preparing their inverted compounds
Filed: 1956-03-29
Abstract: The invention comprises b -kainic acid derivatives of the formula: <FORM:0795750/IV (b)/1> wherein R is isopropyl, isopropenyl, isopropyidene or acetyl, R1 is hydrogen except when R is a divalent group, in which case R represents an additional bond, R2 and R3 are each hydrogen or methyl, and R4 is hydrogen or acetyl, or lactones thereof when R is an unsaturated group, and wherein the stereochemical configuration of >CH.COOR3 of the compound is D-form relative to the imino group.  The invention also relates to the preparation of a -kainic acid derivatives having the planar formula as above, but in which the >CH.COOR3 group possesses the L-configuration relative to the imino group by isomerizing the corresponding b -derivatives by heating, preferably in the liquid state.  Upon heating inversion normally takes place only at the C2 position, but in the case of compounds wherein R is acetyl, simultaneous inversion at C4 also occurs.  The new b -kainic acid derivatives are themselves prepared from N-acetylkainic anhydride, which when boiled in aqueous solution yields b -N-acetylkainic acid and then b -kainic acid on hydrolysis, or with methanol gives 2-monomethyl b -N-acetylkainate.  Subsequent esterification, hydrogenation, lactonization or oxidation procedures are then performed; similarly b -allokainic acid (C3 and C4 substitutuents are trans instead of cis) and its derivatives are obtained from N-acetylallokainic acid anhydride.  In examples: (1) b -N-acetylkainic acid is heated with aqueous barium hydroxide in a sealed tube, the product neutralized with H2SO4, BaSO4 separated and the filtrate concentrated yielding a -kainic acid, also prepared (2) and (3) by heating aqueous b -N-acetylkainic acid; or b -kainic acid in a sealed tube; (4) to (8) and (10) as in (2) are prepared a -dihydrokainic acid from its b -isomer and also from b -N-acetyldihydrokainic acid, and from monomethyl b -N-acetyldihydrokainate; methyl a -N-acetylkainate lactone, a -kainic acid lactone and a -allokainic acid from the corresponding b -isomers; (9) b -kainic acid lactone is refluxed in NaOMe solution, the mixture saturated with dry HCl yielding dimethyl b -isokainate, which is distilled in vacuo giving dimethyl a -isokainate; (11) aqueous b -2-carboxy-3-carboxymethyl-4-acetylpyrrolidine is boiled, charcoaled, and concentrated yielding b -allo-2-carboxy-3-carboxymethyl - 4 - acetylpyrrolidine, which is isomerized as in (2) to the a -allo derivative; (12) aqueous N-acetylkainic anhydride is refluxed to give b -N-acetylkainic acid which is saponified (13) to b -kainic acid, which is then: (14) esterified to dimethyl b -kainate; (15) hydrogenated over Pd charcoal to b -dihydrokainic acid; (16) ozonized to b -2-carboxy-3-carboxymethyl-4-acetylpyrrolidine; and (18) treated with concentrated H2SO4 to give b -kainic acid lactone; again (17) b -N-acetylkainic anhydride is refluxed with methanol yielding 2-mono - methyl b  - N - acetylkainate; (19 b -kainic acid lactone is refluxed with methanolic KOH, evaporated, and a methanolic solution then saturated with dry HCl, giving b -dimethyl isokainate (dimethyl ester of 2-carboxy-3 - carboxymethyl - 4 - isopropylidenepyrrolidine); (20) b -N-acetylkainic acid is lactonized in concentrated H2SO4 and (21) then esterified with diazomethane to methyl b -N-acetylkainate lactone.  Table I further gives physical data of a -compounds obtainable by heating the b -isomers of the following: kainic acid, its N-acetyl-, allo-, dihydro-, dihydroallo- and isoderivatives; dimethyl esters of kainic, N-acetylkainic, N - acetylallokainic, N - acetyldihydrokainic and isokainic acids; lactones of kainic acid, N-acetylkainic acid and N-acetyl kainic acid monomethyl ester; 2-carboxy-3-carboxymethyl - 4 - acetylpyrrolidine and allo - 2-carboxy-3-carboxymethyl-4-acetylpyrrolidine.