Tetrahedron Letters 47 (2006) 5159–5161
Decomposition of copper–amino acid complexes by sodium sulfide
Shaik Nowshuddin and A. Ram Reddy*
Department of Chemistry, University College of Science, Osmania University Campus, Hyderabad 500 007, India
Received 6 January 2006; revised 2 May 2006; accepted 11 May 2006
Abstract—Sodium sulfide very efficiently removes copper from protected amino acid–copper complexes. The copper in the amino
acid complex was reduced to insoluble cuprous sulfide and the free amino acid was released in pure form. This method is very con-
venient and rapid, requiring only 5–10 min and 0.55–0.75 equiv of sodium sulfide.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Since the synthesis of glycylglycine from a diketopiper-
azine by Emil Fisher1 in 1901, peptide synthesis has
undergone tremendous progress and now it is possible
to routinely synthesize a protein consisting of up to
200 amino acids. Research involving over a hundred
years of peptide synthesis,2 including solid phase and
chemical ligation methods, reveals the use of protection
and deprotection techniques for efficient, ordered and
specific protein synthesis. One of the simplest routes
for simultaneous protection of a-amino and a-carboxyl
functional groups of an amino acid is by copper com-
plexation. When the amino acids involved are trifunc-
tional, the protection of the third functional group on
the side-chain is essential. Thus, protection of the e-ami-
no group in lysine, the c-amino group of ornithine, the
c-carboxylic group of glutamic acid, the b-carboxylic
group of aspartic acid, the phenolic group of tyrosine,
the hydroxy groups of serine and threonine and the thiol
group of cysteine assumes significance in peptide synthe-
ses. The regioselective protection of the side-chain
amino groups of lysine3–7 and ornithine6,8,9 is invariably
carried out with Diboc, Fmoc-Nosu, benzyl chlorofor-
mate, benzoyl chloride, acetic anhydride, N-ethoxy-
phthalimide, and p-toluene sulfonyl chloride. The
phenolic group of tyrosine6,10 is protected as the corre-
sponding benzyl ether, whereas the side-chain carboxyl
groups of aspartic acid11,12 and glutamic acid11,12 are
protected as benzyl esters, methyl esters and as other
alkyl esters.
In copper complex-mediated peptide syntheses, the
amino acid is first reacted with a copper(II) ion to give a
stable square planar copper(II) complex. Subsequently,
the copper–amino acid complex is reacted with the
amino acid side-chain protecting reagent as the a-amino
and a-carboxyl groups are bound to copper(II); the
protecting group selectively reacts with the side-chain
functional group of a given amino acid. In order to
recover the side-chain protected amino acid, it is neces-
sary to decompose the copper–amino acid complex, for
which several methods are available. A few important
examples include EDTA,5,13 chelating ion exchange
resins7,11 potassium cyanide,14 8-quinolinol,9 hydrogen
sulfide,3,4,8,10 hydrochloric acid,10 thioacetamide6 and
sodium borohydride.15 EDTA is one of the most widely
employed copper sequestering reagents. However, the
copper–EDTA complex formed during the course of
the reaction is water soluble causing effluent problems
with the water-soluble side-chain protected amino acids.
Cleavage of copper from the complex using toxic potas-
sium cyanide is hazardous, while using hydrogen sulfide
needs prolonged heating in a highly acidic solution
which leads to racemization of the amino acid, and a
non-colloidal copper sulfide solution. The use of thioac-
etamide for the removal of copper requires a strongly
acidic medium where migration of side-chain alkyl
groups and the presence of colloidal copper sulfide
restrict its wider use. When copper is removed from
the complex employing 8-quinolinol, low yields of
protected amino acids are obtained due to new
copper(II)–quinolinate complex formation. Similarly,
when copper is removed using a chelating ion exchange
resin (chelex-100), regeneration of resin becomes labori-
ous and the entire operation works out costly. Recent
advances in the area of drug delivery have led to a
Keywords: Sodium sulfide; Copper–amino acid complex; Protected
amino acids.
*
Corresponding author. Tel.: +91 40 27682337; fax: +91 40
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.069