Semisynthesis of Human Proinsulin, I. Preparation of Arginyl-A-Chain Cyclic Bis-Disulfide

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Abstract
The semisynthesis of Arg-A-(SS)2 is described by the following chemical and enzymatic procedures: A-(SSO3.theta.)4 was acylated with arginine N-carboxyanhydride by the known method. Arg-A-(SSO3.theta.)4 was purified, reduced and oxidized to Arg-A-(SS)2. When A-(SS)2 was acylated under identical conditions a gel-like product was obtained which could be purified after oxidative sulfitolysis. This was then converted to Arg-A-(SS)2 as described above. Both the pathways gave the desired product in 20-25% yield. Boc-Orn(Msc) was quantitatively attached to A-(SS)2 by the mixed anhydride method, the Msc group was then removed and the ensuing N.delta.-free amino function was amindinated. Traces of unconverted Orn derivative (> 6%) were still present. Boc-Arg(HBr) was attached to A-(SS)2 by the mixed anhydride method and Arg-A-(SS)2 was isolated after removal of the Boc group in 25% yield. Boc-Arg(DHCH) was attached to A-(SS)2 by the mixed anhydride method. DHCH and Boc groups were removed in 2 steps and Arg-A-(SS)2 was isolated in 29% yield. Boc-Arg was condensed with A-(SS)2 by trypsin-catalyzed synthesis. The removal of Boc group and purification yielded the desired product in 40-42% yield. This procedure was the most efficient and proceeded stereospecifically.

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