The acylation of hippuric acid (LXI) with methyl succinyl chloride (XIV) in cold 4-picoline gave rise to the acyl oxazolinone (LXII). Subsequent acidic hydrolysis of (LXII) provided delta-aminolevulinic acid. In a related strategy, the lithio-dianion of ethyl hippurate (LXIII) was acylated with succinic anhydride (XII) producing the 2-amino-3-oxoadipic acid derivative (LXIV). Further hydrolysis and decarboxylation of (LXIV) under acidic conditions furnished the target compound.

Tetrahydrofurfurylamine (XLVII) was converted into the corresponding phthalimide (XLVIII) by reaction of phthalic anhydride (V) in boiling chloroform. Subsequent ruthenium-catalyzed oxidation of (XLVIII) produced keto acid (XI), along with a pentanolide by-product, which was removed by column chromatography. Finally, acid hydrolysis of (XI) led to the desired compound. A closely related strategy was based in the ruthenium oxidation of N-benzoyl tetrahydrofurfurylamine (LXX), prepared from amine (XLVII) and benzoyl chloride (XLIX), to afford 5-benzoylaminolevulinic acid (XXXV), which was then hydrolyzed in boiling 6 N HCl .

A related method was based on the oxidation of N-furfuryl phthalimide (LXXI) under irradiation by light in the presence of oxigen gas and a sensitizer, such as Rose Bengal, to afford the 2,5-dihydrofuranone (LXXII) along with its ring-opened isomer (LXXIII). Subsequent catalytic hydrogenation provided phthalimidolevulinic acid (XI), which was then subjected to acidic hydrolysis. Butenolide (LXXII) was also obtained by the photooxygenation of 5-phthalimidomethyl)furfural (LXXIV). Reduction of (LXXII) to phthalimidolevulinic acid (XI) was accomplished using zinc dust in HOAc under sonication.

In a variation of the earlier methods, methyl 5-bromolevulinate (XLIII) was prepared by bromination of levulinic acid (XLII) in methanol. Reaction of bromo ketone (XLIII) with NaN3 in cold DMF provided azide (LXXV). Simultaneous azide reduction and methyl ester hydrolysis was then accomplished by catalytic hydrogenation in the presence of HCl. A further related method consisted in the alkylation of sodium diformylamide (LXXVI) with methyl 5-bromolevulinate (XLIII) in several different solvents to afford the N,N-diformylamino ester (LXXVII), which was finally hydrolyzed under acidic conditions.

In a variation of the earlier methods, methyl 5-bromolevulinate (XLIII) was prepared by bromination of levulinic acid (XLII) in methanol. Reaction of bromo ketone (XLIII) with NaN3 in cold DMF provided azide (LXXV). Simultaneous azide reduction and methyl ester hydrolysis was then accomplished by catalytic hydrogenation in the presence of HCl. A further related method consisted in the alkylation of sodium diformylamide (LXXVI) with methyl 5-bromolevulinate (XLIII) in several different solvents to afford the N,N-diformylamino ester (LXXVII), which was finally hydrolyzed under acidic conditions.

The condensation of the labeled glycine (I) with phthalic anhydride (II) by heating at 160 C gives the labeled phthalimido acetic acid (III), which is treated with refluxing SOCl2 to yield the acyl chloride (IV). The condensation of (IV) with 3-iodopropionic acid ethyl ester (V) by means of the Zn/Cu couple and Pd(PPh3)4 in hot toluene affords the labeled 5-phthalimido-levulinate (VI), which is finally treated with refluxing 6N HCl to provide the target labeled aminolevulinic acid.

Methyl acetylacrylate (III) was obtained by bromination of methyl levulinate (I) followed by dehydrohalogenation of the resultant bromide (II). Isonitrosation of ketone (III) by means of ethyl nitrite in ethereal HCl produced the alpha-keto oxime (IV). Reduction of oxime (IV) and simultaneous ester hydrolysis by means of Sn/SnCl2 in concentrated HCl led to the target 5-aminolevulinic acid.

In a different method, N-phthaloylglycine (VII) was obtained by melting a mixture of phthalic anhydride (V) and glycine (VI). Subsequent chlorination of (VII) using SOCl2 provided acid chloride (VIII). Condensation of (VIII) with the sodium derivative of the tricarboxylate compound (IX) gave the keto triester (X). Hydrogenolysis of the benzyl ester groups of (X), followed by decarboxylation in refluxing toluene, gave rise to delta-phthalimidolevulinic acid (XI). This was finally hydrolyzed to the title compound upon refluxing with 7 N HCl.

Alternatively, the mono-methyl ester of succinic acid (XIII) was prepared by refluxing succinic anhydride (XII) with MeOH. Subsequent treatment of (XIII) with SOCl2 gave acid chloride (XIV). This was condensed with diazomethane to produce the diazo ketone (XV), which was further converted to the chloro ketone (XVI) by treatment with HCl. Condensation of chlorolevulinate (XVI) with succinimide (XVII) produced methyl delta-succinimidolevulinate (XVIII). Smooth acidic hydrolysis of the methyl ester group of (XVIII) led to the succinimido acid (XIX), which was further hydrolyzed to the succinamido acid (XX) under basic conditions. The title compound could be obtained by hydrolysis of either (XVIII), (XIX) or (XX) in refluxing 7N HCl.

Benzoylation of furfurylamine (XXI) under Schotten-Baumann conditions provided amide (XXII). The dimethoxy dihydrofuran derivative (XXIII) was then obtained as different diastereomeric mixtures by either the electrolysis of N-benzoylfurfurylamine (XXII) in the presence of NH4Cl in MeOH or by the bromination of (XXII) in MeOH. Oxidative cleavage of (XXIII) using the Jones reagent led to 5-benzamido-4-oxo-2-pentenoic acid (XXIV), which was further hydrogenated to the pentanoic analogue (XXV). Alternatively, (XXV) was also obtained by first hydrogenation of (XXIII) to the tetrahydrofuran (XXVI), which was then subjected to Jones oxidation. Finally, acidic hydrolysis of delta-benzamido levulinic acid (XXV) provided the title compound.

Alkylation of potassium phthalimide (XXVII) with epichlorohydrin (XXVIII) provided N-glycidyl phthalimide (XXIX). Epoxide ring opening in (XXIX) with aqueous HBr led to bromohydrin (XXX), which was further oxidized to bromo ketone (XXXI) by means of CrO3. Coupling of bromo ketone (XXXI) with diethyl malonate (XXXII) to afford (XXXIII) was accomplished in the presence of NaOEt in EtOH/DMF as the solvent. Acid hydrolysis of the malonate ester (XXXIII), followed by thermal decarboxylation, gave rise to phthalimido levulinic acid (XI). The phthaloyl group of (XI) was finally hydrolyzed under acidic conditions to furnish delta-aminolevulinic acid.

In a related strategy, the bromination of levulinic acid (XLII) in MeOH yielded the 3-bromo (XLIV) and 5-bromo (XLIII) esters, which could be separated by distillation. Condensation of methyl 5-bromolevulinate (XLIII) with potassium phthalimide (XXVII) provided methyl phthalimido levulinate (XLV), which was finally hydrolyzed under the same conditions as above for analogous the ethyl ester.

Ethyl 4-oxobutyrate (XLVI) was converted to the sulfite addition compound, which was then displaced by NaCN to afford cyanohydrin (XLVII). Acetylation of cyanohydrin (XLVII) provided the acetoxy nitrile (XLVIII), which was further hydrogenated to the amino diester (XLIX). Intramolecular cyclization of (XLIX) in ethanolic NaOEt led to the hydroxy lactam (L). Optionally, (L) could be obtained by hydrogenation of hydroxy nitrile (XLVII), followed by lactamization in the presence of K2CO3. Subsequent oxidation of hydroxypiperidinone (L) to 2,5-piperidinedione (LI) was carried either using the Jones reagent or under Swern conditions. Finally, acid hydrolysis of keto lactam (LI) gave rise to the title aminolevulinic acid. The preparation of 2,5-piperidinedione (LI) was also reported by a different method. Thus, catalytic hydrogenation of 5-hydroxy-2-pyridone (LIV), which had been obtained by Elbs oxidation of pyridone (LIII), furnished piperidinedione (LI).

Ethyl 4-oxobutyrate (XLVI) was converted to the sulfite addition compound, which was then displaced by NaCN to afford cyanohydrin (XLVII). Acetylation of cyanohydrin (XLVII) provided the acetoxy nitrile (XLVIII), which was further hydrogenated to the amino diester (XLIX). Intramolecular cyclization of (XLIX) in ethanolic NaOEt led to the hydroxy lactam (L). Optionally, (L) could be obtained by hydrogenation of hydroxy nitrile (XLVII), followed by lactamization in the presence of K2CO3. Subsequent oxidation of hydroxypiperidinone (L) to 2,5-piperidinedione (LI) was carried either using the Jones reagent or under Swern conditions. Finally, acid hydrolysis of keto lactam (LI) gave rise to the title aminolevulinic acid. The preparation of 2,5-piperidinedione (LI) was also reported by a different method. Thus, catalytic hydrogenation of 5-hydroxy-2-pyridone (LIV), which had been obtained by Elbs oxidation of pyridone (LIII), furnished piperidinedione (LI).

In a different preparation of the protected piperidinedione (LX), electrochemical oxidation of N-(methoxycarbonyl)piperidine (LIV) in HOAc produced the diacetoxy intermediate (LV) which on further refluxing in HOAc generated the acetoxy tetrahydropyridine (LVI). Smooth hydrolysis of the enol ester (LVI) provided the 3-piperidinone (LVII). In a related method, piperidine (LIV) was subjected to electrochemical oxidation in MeOH leading to tetrahydropyridine (LVIII), which was further converted to piperidinone (LVII) by either chemical or electrochemical oxidation. Ketone (LVII) was protected as the dimethyl ketal, (LIX) and its piperidine ring was then oxidized to lactam (LX) by means of RuO2 in the presence of NaIO4. The protected piperidinedione (LX) was finally hydrolyzed to the title compound in refluxing 7 M HCl.

The acylation of hippuric acid (LXI) with methyl succinyl chloride (XIV) in cold 4-picoline gave rise to the acyl oxazolinone (LXII). Subsequent acidic hydrolysis of (LXII) provided delta-aminolevulinic acid. In a related strategy, the lithio-dianion of ethyl hippurate (LXIII) was acylated with succinic anhydride (XII) producing the 2-amino-3-oxoadipic acid derivative (LXIV). Further hydrolysis and decarboxylation of (LXIV) under acidic conditions furnished the target compound.

Methoxy succinyl cyanide (LXV) was prepared by acylation of cuprous cyanide with methoxy succinyl chloride (XIV). Reduction of the acyl cyanide (XIV) by means of zinc dust in the presence of Ac2O produced the acetylamino ketone (LXVI). Subsequent hydrolysis of (LXVI) in aqueous HCl afforded the target aminoacid.

Tetrahydrofurfurylamine (XLVII) was converted into the corresponding phthalimide (XLVIII) by reaction of phthalic anhydride (V) in boiling chloroform. Subsequent ruthenium-catalyzed oxidation of (XLVIII) produced keto acid (XI), along with a pentanolide by-product, which was removed by column chromatography. Finally, acid hydrolysis of (XI) led to the desired compound. A closely related strategy was based in the ruthenium oxidation of N-benzoyl tetrahydrofurfurylamine (LXX), prepared from amine (XLVII) and benzoyl chloride (XLIX), to afford 5-benzoylaminolevulinic acid (XXXV), which was then hydrolyzed in boiling 6 N HCl .

A related method was based on the oxidation of N-furfuryl phthalimide (LXXI) under irradiation by light in the presence of oxigen gas and a sensitizer, such as Rose Bengal, to afford the 2,5-dihydrofuranone (LXXII) along with its ring-opened isomer (LXXIII). Subsequent catalytic hydrogenation provided phthalimidolevulinic acid (XI), which was then subjected to acidic hydrolysis. Butenolide (LXXII) was also obtained by the photooxygenation of 5-phthalimidomethyl)furfural (LXXIV). Reduction of (LXXII) to phthalimidolevulinic acid (XI) was accomplished using zinc dust in HOAc under sonication.

In a variation of the earlier methods, methyl 5-bromolevulinate (XLIII) was prepared by bromination of levulinic acid (XLII) in methanol. Reaction of bromo ketone (XLIII) with NaN3 in cold DMF provided azide (LXXV). Simultaneous azide reduction and methyl ester hydrolysis was then accomplished by catalytic hydrogenation in the presence of HCl. A further related method consisted in the alkylation of sodium diformylamide (LXXVI) with methyl 5-bromolevulinate (XLIII) in several different solvents to afford the N,N-diformylamino ester (LXXVII), which was finally hydrolyzed under acidic conditions.

Iodolactonization of 4-pentenoic acid (LXXX) provided (LXXXI), which was converted to azido lactone (LXXXII) by treatment with NaN3 in DMF. Reduction of the azido group was performed by stirring (LXXXII) with a suspension of Raney nickel in H2O/Et2O. Oxidation of the resulting (LXXXIII) by means of Jones reagent, followed by sulfate-chloride exchange, furnished aminolevulinic acid hydrochloride.

The organozinc reagent (LXXIX) was prepared by treatment of [(1-ethoxycyclopropyl)oxy]trimethylsilane (LXXVIII) with ZnCl2. Palladium-catalyzed coupling of (LXXIX) to phthalimidoacetyl chloride (VIII) furnished ethyl phthalimodolevulinate (XLI), which was finally hydrolyzed as in precedent methods.

The bromination of ethyl acetylsuccinate (XXXIV) produced initially the beta-bromo derivative (XXXV), which upon standing for further 12 hours in the presence of the HBr generated in the reaction underwent rearrangement to the delta-bromo isomer (XXXVI). Hydrolysis and decarboxylation of (XXXVI) in the presence of HCl produced the expected delta-bromolevulinic acid (XXXVII) along with the chloro analogue (XXXVIII). Esterification of this mixture of acids with ethanol and sulfuric acid led to the respective ethyl esters (XXXIX) and (XL). Condensation of halo esters (XXXIX) and (XL) with potassium phthalimide (XXVII) furnished ethyl delta-phthalimidolevulinate (XLI), which was finally converted to the title compound by acidic hydrolysis.

The condensation of 3-(chloroformyl)propionic acid ethyl ester (I) with labeled CuCN (II) in refluxing acetonitrile gives 3-(cyanoformyl)propionic acid ethyl ester (III), which is reduced with Zn, AcOH and Ac2O to yield labeled 5-(acetamido)-4-oxopentanoic acid ethyl ester (IV). Finally, this compound is hyrolyzed by means of refluxing 6M HCl to afford the target labeled aminolevulinic acid.

The condensation of phthalic anhydride (I) with glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol, affords 4-phthalimidoaetoacetic acid ethyl ester (VI), which is condensed with 1-13C-labeled 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, this compound is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

The condensation of phthalic anhydride (I) with 1-13C-labeled glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol affords 4-phthalimidoaetoacetic acid ethyl ester (VI). This compound is condensed with 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, the compound is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

The condensation of phthalic anhydride (I) with glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol affords 4-phthalimidoaetoacetic acid ethyl ester (VI). This compound is condensed with 2-13C-labeled 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, this compound is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

The condensation of phthalic anhydride (I) with glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with 2-13C-labeled Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol affords 4-phthalimidoaetoacetic acid ethyl ester (VI). This compound is condensed with 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, the ester is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

The condensation of 13C-labelled methyl phenyl sulfone (I) with 2-(tert-butyldimethylsilyloxy)acetic acid ethyl ester (II) by means of BuLi in THF gives the labelled propanone derivative (III), which is condensed with ethyl 2-bromoacetate (IV) by means of NaH in THF to yield the gamma-oxo ester (V). Desulfurization of (V) by means of Al/Hg in THF/water affords the silylated 5-hydroxy-4-oxopentanoic acid ethyl ester (VI), which is desilylated by means of AcOH in THF/water to provide the free hydroxyester (VII). The condensation of (VII) with phthalimide (VIII) by means of DEAD and PPh3 in toluene gives the phthalimido derivative (IX), which is finally treated with refluxing 6N HCl to provide the target labelled aminolevulinic acid.