Tbutyl Esters of Amino Acids and Peptides and Their Use in Peptide Synthesis

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J uly 5 , 1960

& BUTYL STERS PEPTIDEYNTHESIS
E
IN
S

g roup occupies t he same position of the peptide
chain in both mercaptalbumin and non-mercaptalbumin.

3359

Acknowledgments.-The authors are grateful to
Mrs. J . O’Brien and Mr. 0. Griffith for their
technical assistance.

[ CONTRIBUTION T HE O RCAXIC
FROM
CHEMICAL
RESEARCH
SECTION,
LEDERLE
LABORATORIES v r s r o x , MERICAN VASAMID
U~
A
C
R
Co., PBARLIVER,X. Y . ]

&Butyl Esters of Amino Acids and Peptides and their Use in Peptide Synthesis1 BY GEORGEv. ANDERSON
i

A ND

FRANCIS. C.4LLAHAN
M

R ECEIVED
NOVEMBER 1959
30,

T he s ynthesis of t-but)-1 esters of amino acids and peptides and their use in peptide synthesis is described. T h e most convenient method was the acid-catalyzed reaction of isobutylene with benzyloxycarbonylamino acids or peptides followed by catalytic hydrogenation to produce the basic esters. Another general method entailed the u se of silver salts and t-butyl iodide. &Butyl esters are particularly useful in peptide synthesis in t h a t the ester group may be removed by acid catalysis and thus side reactions encountered in alkaline hydrolysis may be avoided. Other advantages arise from the stability of a mino acid or peptide esters a s free bases, particularly in allowing their storage and use as such. Comparative stabilities to ethyl esters are reported in s everal examples. T h e synthesis of several t-butyl peptides is reported a s well a s selective removal of this ester group or of amine-protecting groups when both are present.

I n recent years naturally occurring peptides with
high biological activities in such diverse fields as
antibiotics, bacterial growth factors, hormones,
smooth muscle stimulants and pain-producing subs tances have been isolated. Synthesis of such peptides has not kept up with structure determination largely because present methods are time-consuming and frequently give poor yields.2 As p art of an investigation of synthetic methods, the work reported here was directed toward improvements of carboxyl-protecting groups.

I t h as been found that t-butyl esters of amino
acids and peptides have advantages over the customarily used methyl and ethyl esters. Specifically, they are much more stable as the free bases to self-condensation reactions (Table IV) and thus
may usually be stored and used as such. This
avoids the customary neutralization of hydrohalide
salts with bases such as t riethylamine during a
peptide synthesis, a complicating procedure which
adds to the danger of racemization in sensitive
cases a s ell.^,^ P erhaps more important, the
many side reactions of saponification of peptide
csters2 can be avoided since the t-butyl group is
readily removed by acid catalysis under mild
conditions. In comparison to benzyl esters, t-butyl
esters are much more readily removed by acid
catalysis and are not affected by hydrogenation in
the presence of palladium or platinum.
T wo general procedures for the synthesis of
a mino acid and peptide t-butyl esters have been
investigated. I n b oth an amine-protecting group
which was subsequently removed was used. In
spite of the extra steps necessary it seems likely
that the utility of t-butyl esters will make this worth
while.

T he first method entailed the reaction of silver
salts of acylamino acids or acylpeptides with t-butyl
iodide (example 1 in Experimental and Table I ).
Although this is straightforward, the second method
is simpler, gives better yields and is preferable for
large-scale reactions. In the latter, acylamino
acids or acylpeptides were treated with a large
excess of isobutylene in the presence of sulfuric
acid or p-toluenesulfonic acid as catalyst. The
products were isolated by treatment with aqueous
alkali (example 2 a nd Table I). The preferred
amine-protecting group in this investigation was
benzyloxycarbonyl (carbobenzoxy) but others were
used (see experimental).
T he...
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