Tetrahedron Letters No.39, pp. 4765-W& 196 Printed in Great Britain.

THE PREPARATION OF ALKYLOXYCARBONYL

Pergamon Press Ltd.

AMINO ACIDS AND

THEIR N-HYDROXYSUCCINIMIDE ESTERS

Max Frsnkel, D. Ladksny, C. Gilon and Y. Wolman

Department of Organio Chemistry

The Hebrew University of Jerusalem, Jerusalem, ISRAEL.

(Received 17 July 1966)

The t-butyloxyoarbonyl (t-BOC) moeity became since its

introduction as an amino protecting group in peptide

synthesis second in use only to the benzyloxyoarbonyl

group (1). Owing to the instability of the t-butylchloro-

formate, the t-butyloxyoarbonyl derivatives of amino

acids have to be obtained by reaotion of the corresponding

isooyanate with t-butanol (2) or by the aotion of the

amino aoids with either t-butyl-p-nitrophenyl carbonate

(3), t-butylazidoformate (4) or t-butylcysnoformate (5).

The above methods suffer from various disadvantages, e.g.,

the vigorous conditions required for the synthesis of

isocyanate from amino acid esters, the elaborate purifi-

cation from p-nitrophenol of the t-butyloxycarbonyl amino

acids, the reaction conditions employed with the t-butyl-

azidoformate (45-50' for 18-24 hours).

We wish to report a new, rapid and tidy method for

4765

1766 No.39

the preparation of t-butvloxyoarbonyl derivatives of amino

acids. Aminolysis of t-butyloxycarbonyl N-hydroxysucoin-

imide eater by the .50aium salt of various amino acids

yields the corresponding t-butyloxycarbonyl amino acids

in good yield; the N-hydroxysuccinimide formed being water

soluble is easily separable from the t-butyloxyoarbonyl

amino acids. The aminolysis is carried out at 90' for

l+-2 hours: the reaotion does not suffer from any of

the disadvantages of the other methods.

t-Butyloxyoarbonyl N-hydroxysuooinimide ester (m.p.

98-100' %, CgH13N105: Cal& C, 50.23; H, 6.09; N, 6.51.

Found: C, 49.98; H, 5.91; N, 6.70.), obtained by reacting

N-hydroxysucoinimide in presenoe of pyridine with t-butyl-

owoarbonyl chloride, prepared in situ at -74' (61, gave

t-butyloxycarbonyl amino adids in 7O-804L yield; t-butyl-

oxyoarbonyl glyoine (m.p. 80°, 78% yield), t-butyloxy-

oarbonyl-Ltryptophane (m.p. 139-41°, 81% yield), t-butyl-

oxyoarbonyl-L-leuoine.H20 (m.p. 74', 78s yield), t-butyl-

oxyoarbonyl-L-isoleucine.j)H20 (m.p. 59', 83% yield).

Other alkyloxycarbonyl derivatives of amino aoids

were pregared,employing the corresponding alkyloxyoarbonyl

N-hydroxysuocinimide esters. Aminolysis of beneyloxy-

carbonyl N-hydroxysuccinimide ester (m.p. 78-80'

f All melting points are uncorrected; m.ps.of the various amino acid derivatives are in good agreement with those rep&ted in the literature and mixed m.ps.with the respective authentio compounds gave no depression.

No.39 4767

Cl~2ff11N,~(+ : CaIcd. C, K7.82; H, 4.45: X, 5.62. Found:

c, 57.82: h, 4.55; Ei, 5.691, obtained by reacting N-

nydroxvsucciniuide with benzvlchloroformate, gave benzyl-

oxycarbony? a:rino acids in over oC% yield; henzyloxy-

carbonyl g?ycine (m.pO 115' , 98% yield), benzvloxycarbonyl-

L-alanine (m.n. El-?', 9'7% yie'd!, bensvloxvcarbonyl-I.-

rlutamic acid (m.~. 116-7', 98% yield), benzyloxycarbonyl-

L-glutanine (m.p. 128-9', 91% yie'd).

The reaction mixtures contain after completion of the

anknati on,alkyloxycarbonyl amino acids end free N-hydroxy

succinimide. After adjusting the pH to about nH 7 by

addition of hyr?-ochloric acid.followad by an equivalent

of dicyclohexylcarbodiimide we found that the alkyloxy-

carhonyl amino acids W-hydroxysuccinimide esters were

formed in 55-7546 vie'd based on the free amino acid.

Thus the followinF derivatives were prepared: benzyloxy-

carbongl-glycine N-hydroxgsuccinimide ester (m.p. 112',

72% yield), benzyloxycarbonyl-L-alanine N-hydroxysuccin-

imide ester (m.p. 117-g', 75% yield), t-butyloxycarbonyl-

L-leucine N-hydroxyeuccinimide ester (m.~. 11.1-3’, 57%

y i e 1 d) . These compo.mds which are obtained in good yield

er?.Iloyin$< a simple reaction procedure are veluable inter-

medistes in pep+.ide s.nt:iesi,: i7j.

4768

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No.59

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