The cyclization of diethyl benzyloxycarbonylaminomalonate (I) with 3-methyl-2-butenal (II) by means of sodium ethoxide in ethanol, followed by hydrogenation with H2 over Pd/C in acetic acid gives 2,2-dicarbethoxy-3,3-dimethylpyrrolidine (III), which by a decarboxylative hydrolysis with refluxing aqueous 5M HCl is converted into 3,3-dimethylproline (IV). The protection of the amino group of (IV) with tert-butyl-2,4,5-trichlorophenyl carbonate (V) in hot tert-butanol - water yields N-tert-butoxycarbonyl-3,3-dimethylproline (VI), which by reaction with NH3 by means of isobutyl chloroformate and N-methylmorpholine in THF is converted into N-tert-butoxycarbonyl-3,3-dimethylprolinamide (VII). The deprotection of (VII) with HCl in dioxane affords 3,3-dimethylprolinamide (VIII), which is finally condensed with benzyloxycarbonyl-L-pyroglutamylhistidine (IX) by means of 1-hydroxybenzotriazole (HBT) and dicyclohexylcarbodiimide (DCCD) in THF, and deprotected by hydrogenation with H2 over Pd/C in THF - water.

The cyclization of diethyl benzyloxycarbonylaminomalonate (I) with 3-methyl-2-butenal (II) by means of sodium ethoxide in ethanol, followed by hydrogenation with H2 over Pd/C in acetic acid gives 2,2-dicarbethoxy-3,3-dimethylpyrrolidine (III), which by a decarboxylative hydrolysis with refluxing aqueous 5M HCl is converted into 3,3-dimethylproline (IV). The protection of the amino group of (IV) with tert-butyl-2,4,5-trichlorophenyl carbonate (V) in hot tert-butanol - water yields N-tert-butoxycarbonyl-3,3-dimethylproline (VI), which by reaction with NH3 by means of isobutyl chloroformate and N-methylmorpholine in THF is converted into N-tert-butoxycarbonyl-3,3-dimethylprolinamide (VII). The deprotection of (VII) with HCl in dioxane affords 3,3-dimethylprolinamide (VIII), which is finally condensed with benzyloxycarbonyl-L-pyroglutamylhistidine (IX) by means of 1-hydroxybenzotriazole (HBT) and dicyclohexylcarbodiimide (DCCD) in THF, and deprotected by hydrogenation with H2 over Pd/C in THF - water.