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Table 2. Deprotection of Benzyl and Cyclohexyl Esters of Aspartic and Glutamic Acid in TFA at
55° c
k(10" 7 x s" 1)
krel
t 1/2 (h)
Boc-Giu (OBzi)-OH
160
1.9
210
1.0
0.012
1.3
12.0
1013.2
9.2
Boc-Giu(OQHex)-OH
2.4
0.015
802.1
Boc-Asp(OBzi)-OH
Boc-Asp(O£Hex)-OH
Table 3. HF Cleavage of Boc-Asp(O~Hex)-OH
Condition
TempeC) Time (h)
0
-15
(388 min). Boc-Asp(O~Hex) was then
prepared from Asp(0£Hex) with
dit.cr.tbutyldicarbonate in DMF using
triethylamine as base.
Chemical Stability of the
Cyclohexyl Esters of Aspartic and
Glutamic Acids
The cyclohexyl esters of aspartic
and glutamic acids are stable to prolonged TFA treatment (Figure 6). The
rate constants k 1 for acidolytic loss of
kHex esters at 55° C in ne~ TFA were
determined to be 1.9 x 10- s- 1 for Asp
(O.c.Hex) and 2.4 X 10"7s" 1 for Glu
(O~Hex). These rate constants indicate
84- to 88-foJd more stability in TFA
than their respective benzyl esters
(Table 2). They are consistent with the
acid stability of Tyr(~Hex), which is
100 times more stable than Tyr(Bzl)
(10). Thus, the repetitive loss of the
cyclohexyl ester protecting group per
synthetic cycle due to 0.5 h of TFA
treatment will be about 0.0002%,
making this protecting group one of the
most stable in the TFA-HF protecting
group strategy. The added acid stability
should be useful in the synthesis of
large polypeptides or proteins and
prevent acidolytic loss of the side chain
protecting group during long synthesis.
Both aspartyl- and glutamyl-cyclo-
0.4
0.3
()=
8oc-Asp(O£Hex)-OH
• · !loc-Asp(OBzl
)-ou
,6.=
!loc-Glu(O~_tlex)-OH
A=
Boc-Glu(OBzl)-OH
, • 90
0.009
160•00
0.760
2·40
210·ll0
0.0110
0.2
0.1
20
25
Time (h)
Figure 6. Acidolytic loss of benzyl and cyclohexyl esters in trinuoroacetic acid at 55° C.
LO
Cleavage
Asp(%)
0.25
0.50
0.75
75
1.00
100
0.50
1.00
1.50
2.00
68
86
97
100
93
98
hexyl ester protecting groups were
completely removed by treatment with
HF:anisole (9: 1, v/v) for 1 hat 0° Cor
2 h at -15° C (Table 3 ). They could also
be conveniently removed by 1 M
TFMSA-thioanisole-TFA in 1 h at
0° C. However, the reaction was extremely sluggish in HOAc-HBr-TFA
(1:1:1, v/v), and only 78% of the esters
were removed after 18 h. The rate of
acidolytic removal of .c.Hex ester in HF
or TFA could be conveniently quantitated by ion-exchange chromatography, since the end products, Asp (r.t.
92 min) and Glu-Asp-Giy-Thr (r.t. 73
min), were well separated from their
starting materials, Asp(O~Hex) (r.t.
189 min) and Glu-Asp(O.c.Hex)-GlyThr (r.t. 489 min). The observed acidolytic deprotection rates of the .c.Hex
esters in HBr or HF were consistent
with those of kHex carbamate observed
by McKay and Albertson (21 ), Blaha
and Rudinger (5) and Munakata et al.
(25). They are consistent with the expected properties of the cyclohexyl
ester that it could be removed more
favorably by the A-1 mechanism in
strong acid.
The cyclohexyl esters were more
stable towards nucleophile than the
corresponding benzyl ester. This
property is particularly useful with
glutamic acid, since the y-protected
benzyl ester is prone to intramolecular
cyclization to fonn pyrolidone-1-carboxylic acid (pyroglutamic acid) neutalization and coupling. This side reaction leads to significant termination of
peptide chain and is a serious problem
in long peptide synthesis. The use of ycyclohexyl glutamic acid is expected to
greatly minimize this side reaction.
Several recent syntheses have been
successful using this strategy. The cyclohexyl esters were also completely
stable towards hydrogenation. The
hydrogenolytic stabilities improve the
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