ORGANIC
LETTERS
2011
Vol. 13, No. 1
34-37
Solvent-Free Thermocyclization of the
Unactivated Linear Gramicidin S
Precursor and Analogues
Lin-Kun An,* Run-Lin Li, Ying-Lin Zuo, and Lian-Quan Gu
School of Pharmaceutical Sciences, Sun Yat-sen UniVersity, Guangzhou 510006, China
Received October 8, 2010
ABSTRACT
A convenient thermocyclization of the linear gramicidin S precursor and its analogues is demonstrated. With the preorganized ꢀ-sheet
conformation, the unactivated linear precursors can cyclize into the corresponding head-to-tail cyclic products in high yield after being heated
under solvent-free conditions.
D
Gramicidin S (GS) is a naturally occurring cationic antimi-
crobial peptide from Bacillus breVis1 and is active against
several bacteria and fungi.2 Its synthesis has attracted intense
efforts in the past decades due to its interesting bioactivity
and its challenging structure.3,4 The cyclization of the linear
precursor is the major yield-limiting step, and this has been
carried out in highly diluted solution with the assistance of
activating agent or enzymes. The yield of cyclization is
generally low to moderate, and it is difficult to get specific
and high-yielding cyclized product. GS, cyclo(DPhe-Pro-Val-
Orn-Leu)2 (Figure 1), adopts a pleated ꢀ-sheet structure that
is stabilized by four intramolecular hydrogen bonds between
the Leu and Val residues. The Pro and Phe residues hold
two type II′ ꢀ-turns. In the most stable conformation, the
hydrophobic residues of Leu and Val and the hydrophilic
residues of Orn locate on opposite sides of the ꢀ-sheet
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10.1021/ol102800j 2011 American Chemical Society
Published on Web 12/01/2010