The acylation of (-)-2,10-camphorsultam (II) with octanoyl chloride (I) provides the N-octanoyl sultam (III). Diastereoselective alkylation of the lithium enolate of (III) with allyl bromide (IV) gives rise to the (2S)-2-propenoyloctanoyl sultam (V). Hydrolysis of the N-acyl sultam (V) to furnish acid (VI) is then effected by treatment with hydrogen peroxide-tetrabutylammonium hydroxide. Finally, catalytic hydrogenation of the unsaturated acid (VI) in the presence of either Pd/C or Pt/C yields the required (R)-2-propyloctanoic acid. Alternatively, the title compound is obtained by hydrogenation of the N-acyl sultam (V) to the saturated derivative (VII), followed by hydrolytic removal of the camphorsultam moiety.

In a related procedure, the N-octanoyl sultam (I) is alkylated by propargyl bromide (II) to produce (III). Hydrolysis of (III) by means of hydrogen peroxide-tetrabutylammonium hydroxide or lithium hydroxide-hydrogen peroxide furnishes acid (IV). Then, catalytic hydrogenation of the propargyloctanoic acid (IV) in the presence of either Pd/C or Pt/C provides the title compound.

The acylation of (-)-2,10-camphorsultam (II) with octanoyl chloride (I) provides the N-octanoyl sultam (III). Diastereoselective alkylation of the lithium enolate of (III) with allyl bromide (IV) gives rise to the (2S)-2-propenoyloctanoyl sultam (V). Hydrolysis of the N-acyl sultam (V) to furnish acid (VI) is then effected by treatment with hydrogen peroxide-tetrabutylammonium hydroxide. Finally, catalytic hydrogenation of the unsaturated acid (VI) in the presence of either Pd/C or Pt/C yields the required (R)-2-propyloctanoic acid. Alternatively, the title compound is obtained by hydrogenation of the N-acyl sultam (V) to the saturated derivative (VII), followed by hydrolytic removal of the camphorsultam moiety.

In a related procedure, the N-octanoyl sultam (I) is alkylated by propargyl bromide (II) to produce (III). Hydrolysis of (III) by means of hydrogen peroxide-tetrabutylammonium hydroxide or lithium hydroxide-hydrogen peroxide furnishes acid (IV). Then, catalytic hydrogenation of the propargyloctanoic acid (IV) in the presence of either Pd/C or Pt/C provides the title compound.

Reaction of L-prolinol (XII) with pentanoyl chloride (XIII) by means of triethylamine (TEA) in dichloromethane gives N-pentanoyl-L-prolinol (XIV), which is stereoselectively alkylated with hexyl iodide (XV) by means of butyl lithium and diethylamine (DEA) in THF to yield N-[2(R)-propyloctanoyl]-L-prolinol (XVI). This compound is subjected to purification via its esterification with 4-nitrobenzoyl chloride (XVII) and pyridine to the corresponding ester (XVIII) and recrystallization to form n-hexane. Hydrolysis of the pure ester (XVIII) with LiOH in water affords pure N-[2(R)-propyloctanoyl]-L-prolinol (XVI), which is finally treated with HCl in AcOH.

Acylation of 4(R)-benzyloxazolidin-2-one (XXXIV) with octanoyl chloride (XX) by means of t-BuOK in THF gives 3-octanoyl-4(R)-benzyloxazolidin-2-one (XXXV), which is alkylated with allyl iodide (XXXVI) and LiHMDS in THF to yield the chiral 2-allyloctanoyl amide (XXXVII). Hydrogenation of amide (XXXVII) with H2 over Pd/C in ethanol affords the corresponding 2-propyl derivative (XXXVIII), which is finally submitted to hydrolysis of the chiral auxiliary.

Alkylation of dimethyl malonate (I) with hexyl bromide (II) by means of NaOMe in methanol gives dimethyl 2-hexylmalonate (III), which is alkylated again with 2-propynyl bromide (IV) by means of NaOMe in methanol to yield dimethyl 2-hexyl-2-(2-propynyl)malo-nate (V). Selective monodecarboxylation of malonate (V) by means of LiCl in hot DMSO affords methyl 2-(2-propyn- yl)octanoate (VI), which is hydrolyzed to the corres- ponding carboxylic acid (VII) by means of NaOH in methanol. Then, racemic acid (VII) is submitted to optical resolution by crystallization with 1(R)-phenylethylamine (VIII), followed by hydrolysis with HCl to provide 2(S)-(2-propynyl)octanoic acid (IX), which is finally hydrogenated with H2 over Pd/C in ethyl acetate. Alternatively, the racemic acid (VII) can also be obtained by alkylation of ethyl octanoate (X) with 2-pro-pynyl bromide (IV) by means of LDA in HMPA/THF to give ethyl 2-(2-propynyl)octanoate (XI) and then hydrolysis with NaOH in ethanol.

The acylation of (-)-2,10-camphorsultam (II) with octanoyl chloride (I) provides the N-octanoyl sultam (III). Diastereoselective alkylation of the lithium enolate of (III) with allyl bromide (IV) gives rise to the (2S)-2-propenoyloctanoyl sultam (V). Hydrolysis of the N-acyl sultam (V) to furnish acid (VI) is then effected by treatment with hydrogen peroxide-tetrabutylammonium hydroxide. Finally, catalytic hydrogenation of the unsaturated acid (VI) in the presence of either Pd/C or Pt/C yields the required (R)-2-propyloctanoic acid. Alternatively, the title compound is obtained by hydrogenation of the N-acyl sultam (V) to the saturated derivative (VII), followed by hydrolytic removal of the camphorsultam moiety.

In a related procedure, the N-octanoyl sultam (I) is alkylated by propargyl bromide (II) to produce (III). Hydrolysis of (III) by means of hydrogen peroxide-tetrabutylammonium hydroxide or lithium hydroxide-hydrogen peroxide furnishes acid (IV). Then, catalytic hydrogenation of the propargyloctanoic acid (IV) in the presence of either Pd/C or Pt/C provides the title compound.

The acylation of (-)-2,10-camphorsultam (II) with octanoyl chloride (I) provides the N-octanoyl sultam (III). Diastereoselective alkylation of the lithium enolate of (III) with allyl bromide (IV) gives rise to the (2S)-2-propenoyloctanoyl sultam (V). Hydrolysis of the N-acyl sultam (V) to furnish acid (VI) is then effected by treatment with hydrogen peroxide-tetrabutylammonium hydroxide. Finally, catalytic hydrogenation of the unsaturated acid (VI) in the presence of either Pd/C or Pt/C yields the required (R)-2-propyloctanoic acid. Alternatively, the title compound is obtained by hydrogenation of the N-acyl sultam (V) to the saturated derivative (VII), followed by hydrolytic removal of the camphorsultam moiety.

The acylation of (-)-2,10-camphorsultam (II) with octanoyl chloride (I) provides the N-octanoyl sultam (III). Diastereoselective alkylation of the lithium enolate of (III) with allyl bromide (IV) gives rise to the (2S)-2-propenoyloctanoyl sultam (V). Hydrolysis of the N-acyl sultam (V) to furnish acid (VI) is then effected by treatment with hydrogen peroxide-tetrabutylammonium hydroxide. Finally, catalytic hydrogenation of the unsaturated acid (VI) in the presence of either Pd/C or Pt/C yields the required (R)-2-propyloctanoic acid. Alternatively, the title compound is obtained by hydrogenation of the N-acyl sultam (V) to the saturated derivative (VII), followed by hydrolytic removal of the camphorsultam moiety.

Reaction of 1-bromo-2-(methoxymethoxy)benzene (XXVII) with 1(S)-phenylethylamine (XXVIII) by means of Pd2(dba)3, BINAP and t-BuONa in toluene gives the chiral secondary amine (XXIX), which is condensed with octanoyl chloride (XX) by means of BuLi in THF to yield the octanamide (XXX). Cleavage of the MOM protecting group of compound (XXX) by means of HCl and Sc(OTf)3 in methanol affords N-(2-hydroxyphenyl)-N-[1(S)-phenylethyl]octanamide (XXXI), which is stereoselectivelly alkylated with allyl bromide (XXII) and LDA in THF to provide the chiral 2-allyloctanamide (XXXII). Hydrogenation of amide (XXXII) with H2 over Pd/C in methanol yields the corresponding 2-propyl derivative (XXXIII), which is finally submitted to the cleavage of the chiral auxiliary by means of Fe(NO3)3 in refluxing dioxane/water

The acylation of (-)-2,10-camphorsultam (II) with octanoyl chloride (I) provides the N-octanoyl sultam (III). Diastereoselective alkylation of the lithium enolate of (III) with allyl bromide (IV) gives rise to the (2S)-2-propenoyloctanoyl sultam (V). Hydrolysis of the N-acyl sultam (V) to furnish acid (VI) is then effected by treatment with hydrogen peroxide-tetrabutylammonium hydroxide. Finally, catalytic hydrogenation of the unsaturated acid (VI) in the presence of either Pd/C or Pt/C yields the required (R)-2-propyloctanoic acid. Alternatively, the title compound is obtained by hydrogenation of the N-acyl sultam (V) to the saturated derivative (VII), followed by hydrolytic removal of the camphorsultam moiety.

In a related procedure, the N-octanoyl sultam (I) is alkylated by propargyl bromide (II) to produce (III). Hydrolysis of (III) by means of hydrogen peroxide-tetrabutylammonium hydroxide or lithium hydroxide-hydrogen peroxide furnishes acid (IV). Then, catalytic hydrogenation of the propargyloctanoic acid (IV) in the presence of either Pd/C or Pt/C provides the title compound.

Alkylation of dimethyl malonate (I) with hexyl bromide (II) by means of NaOMe in methanol gives dimethyl 2-hexylmalonate (III), which is alkylated again with 2-propynyl bromide (IV) by means of NaOMe in methanol to yield dimethyl 2-hexyl-2-(2-propynyl)malo-nate (V). Selective monodecarboxylation of malonate (V) by means of LiCl in hot DMSO affords methyl 2-(2-propyn- yl)octanoate (VI), which is hydrolyzed to the corres- ponding carboxylic acid (VII) by means of NaOH in methanol. Then, racemic acid (VII) is submitted to optical resolution by crystallization with 1(R)-phenylethylamine (VIII), followed by hydrolysis with HCl to provide 2(S)-(2-propynyl)octanoic acid (IX), which is finally hydrogenated with H2 over Pd/C in ethyl acetate. Alternatively, the racemic acid (VII) can also be obtained by alkylation of ethyl octanoate (X) with 2-pro-pynyl bromide (IV) by means of LDA in HMPA/THF to give ethyl 2-(2-propynyl)octanoate (XI) and then hydrolysis with NaOH in ethanol.

Reaction of L-prolinol (XII) with pentanoyl chloride (XIII) by means of triethylamine (TEA) in dichloromethane gives N-pentanoyl-L-prolinol (XIV), which is stereoselectively alkylated with hexyl iodide (XV) by means of butyl lithium and diethylamine (DEA) in THF to yield N-[2(R)-propyloctanoyl]-L-prolinol (XVI). This compound is subjected to purification via its esterification with 4-nitrobenzoyl chloride (XVII) and pyridine to the corresponding ester (XVIII) and recrystallization to form n-hexane. Hydrolysis of the pure ester (XVIII) with LiOH in water affords pure N-[2(R)-propyloctanoyl]-L-prolinol (XVI), which is finally treated with HCl in AcOH.

Reaction of 1-bromo-2-(methoxymethoxy)benzene (XXVII) with 1(S)-phenylethylamine (XXVIII) by means of Pd2(dba)3, BINAP and t-BuONa in toluene gives the chiral secondary amine (XXIX), which is condensed with octanoyl chloride (XX) by means of BuLi in THF to yield the octanamide (XXX). Cleavage of the MOM protecting group of compound (XXX) by means of HCl and Sc(OTf)3 in methanol affords N-(2-hydroxyphenyl)-N-[1(S)-phenylethyl]octanamide (XXXI), which is stereoselectivelly alkylated with allyl bromide (XXII) and LDA in THF to provide the chiral 2-allyloctanamide (XXXII). Hydrogenation of amide (XXXII) with H2 over Pd/C in methanol yields the corresponding 2-propyl derivative (XXXIII), which is finally submitted to the cleavage of the chiral auxiliary by means of Fe(NO3)3 in refluxing dioxane/water

Acylation of 4(R)-benzyloxazolidin-2-one (XXXIV) with octanoyl chloride (XX) by means of t-BuOK in THF gives 3-octanoyl-4(R)-benzyloxazolidin-2-one (XXXV), which is alkylated with allyl iodide (XXXVI) and LiHMDS in THF to yield the chiral 2-allyloctanoyl amide (XXXVII). Hydrogenation of amide (XXXVII) with H2 over Pd/C in ethanol affords the corresponding 2-propyl derivative (XXXVIII), which is finally submitted to hydrolysis of the chiral auxiliary.