ORGANIC
LETTERS
2010
Vol. 12, No. 10
2282-2285
Preparation and Use of Cysteine
Orthoesters for Solid-Supported
Synthesis of Peptides
Zedu Huang, Darren J. Derksen, and John C. Vederas*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta, Canada T6G 2G2
Received March 18, 2010
ABSTRACT
Synthesis of a chiral cysteine derivative 2 with the carboxyl protected by an acid-labile 4-methyl-2,6,7-trioxabicyclo[2.2.2]octyl (OBO) orthoester
is reported. A disulfide anchoring strategy is used to link the sulfur of this OBO cysteine derivative onto modified trityl polystyrene resin for
synthesis of peptides having C-terminal cysteine (Cys) residues. Fmoc-based solid phase peptide synthesis affords model tripeptides without
significant epimerization. The approach is used to make the orally active analgesic crotalphine and its Cys1 diastereomer.
The acid-labile 4-methyl-2,6,7-trioxabicyclo[2.2.2] octyl
(OBO) orthoester functionality was developed as a protecting
group for the carboxyl of R-amino acids by Lajoie and co-
workers.1 It has proven to be very useful in recent work on
construction of peptidomimetics and amino acid derivatives,2
such as serine-derived aldehydes,1,3 that would otherwise be
likely to epimerize. Cysteine (Cys) is notably absent from
the list of common R-amino acids protected with OBO
because the standard approach for its direct conversion fails.
However, such derivatives would be desirable as cysteine
esters are especially prone to epimerization or elimination
under basic conditions. These side reactions can occur to a
significant extent during the esterification of a cysteine to a
solid support for peptide synthesis and also during subsequent
chain elongation by solid-supported peptide synthesis (SSPS)
using Fmoc methodology to make peptides with a C-terminal
Cys residue.4 C-Terminal cysteines occur in many natural
biologically active peptides, for example, somatostatin,5
conotoxins,6 neopetrosiamides,7 and crotalphine.8 The pres-
ence of Cys within the backbone is convenient for synthesis
of larger proteins by chemical ligation.9 In the present study
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10.1021/ol100645t 2010 American Chemical Society
Published on Web 04/21/2010