Convenient preparation of [Orn(Tfa)<sup>2</sup>]‐ and [Orn(Boc)<sup>2</sup>, Orn(Tfa)<sup>2′</sup>]gramicidin S, versatile unsymmetrically protected derivatives of gramicidin S

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<jats:p><jats:bold>Abstract:</jats:bold> Treatment of gramicidin S (GS) with trifluoroacetic anhydride afforded a derivative in which only one of the two Orn side chains was trifluoroacetylated in 72% yield, furnishing the first efficient method for the preparation of a monoprotected derivative of GS. The mono(Tfa) derivative [Orn(Tfa)<jats:sup>2</jats:sup>]GS was treated with di‐<jats:italic>tert</jats:italic>‐butyl dicarbonate to yield dually protected derivative [Orn(Boc)<jats:sup>2</jats:sup>,Orn(Tfa)<jats:sup>2′</jats:sup>]GS from which another monoprotected derivative [Orn(Boc)<jats:sup>2</jats:sup>]GS was prepared in high yield. These unsymmetrically protected GS derivatives are versatile starting materials for the preparation of various other GS derivatives. As an example of application of the unsymmetrically protected derivatives, a dimeric GS derivative was prepared via a singly <jats:italic>p</jats:italic>‐nitrobenzenesulfonyl(NBS)‐activated derivative [Orn(Boc)<jats:sup>2</jats:sup>,Orn(NBS)<jats:sup>2′</jats:sup>]GS.</jats:p>

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