Selective tert-butyl ester deprotection in the presence of acid labile protecting groups with use of ZnBr2

Article abstract of DOI:10.1021/jo0491206

Chemoselective hydrolysis of tert-butyl esters in the presence of other acid-labile groups has been explored by employing α-amino esters and ZnBr₂ in DCM. Although N-Boc and N-trityl groups were found to the labile, PhF protected amines were compatible with these Lewis acid deprotection conditions such that a variety of N-(PhF)amino acids were prepared in good yields from their corresponding tert-butyl esters.

Full text of DOI:10.1021/jo0491206

Exploring one of these protocols for the synthesis of
(3S,6R,10S)-3-N-(Boc)amino quinolizidin-2-one-10-car-
boxylic acid,8 we treated the corresponding tert-butyl
ester9 1a with 500 mol % of ZnBr2 in DCM at room
temperature for 12 h. After aqueous workup as de-
scribed,6 TLC analysis of the crude product showed a
baseline material corresponding to the free amino acid
indicating that both the N-(Boc)amino and tert-butyl ester
groups were cleaved. The quinolizidinone amino acid 2a
was then recovered as its N-Boc derivative by treating
the aqueous solution with Boc anhydride and sodium
bicarbonate.
In our hands, this failure provoked a more detailed
investigation of the use of ZnBr2 in DCM for the selec-
tive removal of tert-butyl esters in the presence of acid
labile protecting groups. In particular, we examined the
ZnBr2 conditions on substrates bearing Boc, trityl, and
9-(9-phenylfluorenyl) (PhF) amino protecting groups as
well as allyl esters and tert-butyl ethers. A series of
N-protected amino tert-butyl esters were treated under
the same standard conditions, namely, the substrates
were dissolved in DCM and exposed to 500 mol % of
ZnBr2 with stirring at room temperature for 24 h (12 h
in the case of N-(Boc)glycine tert-butyl ester 1b for
comparison with the earlier report).6
Selective ter t-Bu tyl Ester Dep r otection in
th e P r esen ce of Acid La bile P r otectin g
Gr ou p s w ith Use of Zn Br 2
Ramesh Kaul, Yann Brouillette, Zohreh Sajjadi,
Karl A. Hansford, and William D. Lubell*
De´partement de chimie, Universite´ de Montre´al,
C.P. 6128, Succursale Centre Ville, Montre´al,
Que´bec, Canada H3C 3J C
lubell@chimie.umontreal.ca
Received May 25, 2004
Abstr a ct: Chemoselective hydrolysis of tert-butyl esters in
the presence of other acid-labile groups has been explored
by employing R-amino esters and ZnBr2 in DCM. Although
N-Boc and N-trityl groups were found to be labile, PhF
protected amines were compatible with these Lewis acid
deprotection conditions such that a variety of N-(PhF)amino
acids were prepared in good yields from their corresponding
tert-butyl esters.
The acid labile protecting groups, such as the tert-butyl
ester and tert-butyloxycarbonyl (Boc) amine protecting
groups, are commonly used in amino acid, peptide and
natural product synthesis.1,2 When such protecting groups
are used ensemble, their selective deprotection often
becomes a desirable step for an effective synthesis se-
quence. Typically, strong protic acids,1 such as HCl,
H2SO4, and TFA, are not selective under aqueous condi-
tions and effect cleavage of all acid labile protection. On
the other hand, in organic solvents, such acids have
demonstrated practical selectivity. For example, the
N-Boc group can be specifically removed in the presence
of a tert-butyl ester by using 1 M HCl in ethyl acetate,3
as well as by using concentrated H2SO4 in tert-butyl
acetate.4 These protocols have proven effective for the
selective deprotection of the amine of a variety of N-(Boc)-
amino tert-butyl esters. Recently, the opposite selectivity
was reported and it was claimed that tert-butyl esters
could be selectively cleaved in the presence of an N-Boc
group by using Lewis acids such as CeCl3‚7H2O-NaI in
acetonitrile,5 and ZnBr2 in DCM.6 Previously, reports
have also claimed that ZnBr2 in DCM could mediate
selective N-Boc deprotection from secondary amines in
the presence of N-Boc protected primary amines.7
N-(Boc)glycine tert-butyl ester 1b had been reported
to be selectively converted to its respective acid without
loss of Boc protection with use of ZnBr2 in DCM for 12
h.6 Revisiting this claim, N-(Boc)glycine tert-butyl ester
1b was treated with ZnBr2 under the identical conditions.
After 12 h, both the N- and C-terminal protecting groups
were lost and baseline material was detected by TLC.
Treatment of the aqueous phase from the reaction
workup with 1.5 equiv of 9-fluorenylmethyl succinimidyl
carbonate (Fmoc-OSu) for 12 h provided N-(Fmoc)gly-
cine in 80% overall yield from 1b. Similarly, N-(Boc)-,
N-(trityl)-, and N-(PhF)alanine tert-butyl esters (1c-e)
were treated with ZnBr2 in DCM and both the Boc and
trityl groups were cleaved along with the tert-butyl ester
as demonstrated by TLC (4:1:1 nBuOH:AcOH:H2O). Free
alanine was similarly recovered as its Fmoc derivative
by treatment of the aqueous phase as described above
for 2b. On the other hand, N-(PhF)alanine tert-butyl ester
1e was selectively hydrolyzed to its corresponding
N-(PhF)amino acid 2e in 75% yield.
On investigation of the scope of the deprotection of tert-
butyl esters in the presence of PhF amino protection, the
use of no less than 500 mol % of ZnBr2 and longer
reaction times (24 h) provided good conversion and yield
(Table 1). In DCM, ZnBr2 forms a suspension. Although
ZnBr2 is readily soluble in THF, no reaction was observed
in THF. Coordination of ZnBr2 by the Lewis basic THF
may likely compete with ester complexation and thereby
prevent hydrolysis.
(1) Green, T. W.; Wuts, P. G. M. Protecting Groups in Organic
Synthesis; J ohn Wiley & Sons: New York, 1999; pp 65-67 and 404-
408.
(2) Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthesis,
2nd Ed.; Springer-Verlag: Berlin, Germany, 1994.
(3) Gibson, F. S.; Bergmeier, S. C.; Rapoport, H. J . Org. Chem. 1994,
59, 3216.
(4) Lin, L. S.; Lanza, T.; Laszlo, Stephen E. de.; Truoung, Q.;
Kamenecka, T.; Hagmann, W. K. Tetrahedron Lett. 2000, 41, 7013.
(5) Marcantoni, E.; Massaccesi, M.; Torregiani, E. J . Org. Chem.
2001, 66, 4430.
A series of functional groups were shown to be compat-
ible with these hydrolysis conditions including olefins (2f)
and methyl (2g and 2h ) and allyl esters (2n and 2o) as
(6) Wu, Y-Q.; Limburg, D. C.; Wilkinson, D. E.; Vaal, M. J .;
Hamilton, G. S. Tetrahedron Lett. 2000, 41, 2847.
(7) Nigam, S. C.; Mann, A.; Taddei, M.; Wermuth, C. G. Synth.
Commun. 1989, 19, 3139.
(8) Halab, L.; Becker, J . A. J .; Darula, Z.; Tourwe´, D.; Kieffer, B.
L.; Simonin, F.; Lubell, W. D. J . Med. Chem. 2002, 45, 5353.
(9) Gosselin, F.; Lubell, W. D. J . Org. Chem. 2000, 65, 2163.
10.1021/jo0491206 CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/12/2004
J . Org. Chem. 2004, 69, 6131-6133
6131

TABLE 1. N-P r otected Am in o Acid s 2 fr om N-P r otected Am in o ter t-Bu tyl Ester s 1
a
b
Isolated yield after reprotection with Boc. Isolated yield after reprotection with Fmoc. c 1000 mol % of ZnBr2.
well as tert-butyl ethers (2l). On the other hand, more
Lewis basic functionality such as alcohols (2k ) and
amides (2m ) inhibited the reaction. For example, expo-
sure of (2S,4R)-4-hydroxy-N-(PhF)proline tert-butyl ester
1k to 500 mol % of ZnBr2 in DCM for 24 h gave only 14%
of the corresponding acid 2k along with 45% of recovered
starting material. Increasing the amount of ZnBr2 to 1500
mol % only doubled the yield (27%) of acid 2k . Similarly,
the amide, (2S)-N-(PhF)pyroglutamate tert-butyl ester
1m , reacted with 500 mol % of ZnBr2 to give acid 2m in
only 26% yield; however, employment of 1000 mol % of
ZnBr2 improved the yield to 61%. In addition, in the
presence of 1000 mol % of ZnBr2, diamino azelate ketone
1p gave diacid 2p in only 36% yield along with monoacid
2p ′ in 38% yield, presumably because of catalyst inhibi-
tion by the ketone moiety.
Remarkable selectivity was observed with N-(PhF)-
glutamate R,γ-di-tert-butyl ester 1i. After treatment with
1000 mol % of ZnBr2 in DCM for 24 h followed by aqueous
1
workup, H NMR spectral analysis showed cleavage of
one tert-butyl ester group. The resulting crude monoester
monoacid (2i) was converted to its corresponding methyl
tert-butyl diester (3) by using diazomethane in diethyl
ether. Comparison of the proton spectra of authentic
R-tert-butyl-γ-methyl-N-(PhF)glutamate (4)10 with the
(10) Koskinen, A. M. P.; Rapoport, H. J . Org. Chem. 1989, 54, 1859.
6132 J . Org. Chem., Vol. 69, No. 18, 2004

resulting diester demonstrated the predominant product
to be R-methyl-γ-tert-butyl-N-(PhF)glutamate (3). Rela-
tive to the singlet of γ-methyl ester 4, the corresponding
singlet for R-methyl ester 3 appeared at 0.4 ppm down-
field due to the influence of the neighboring aromatic PhF
group. Similarly, the R-tert-butyl ester singlet appeared
at 0.2 ppm downfield of its γ-tert-butyl singlet counter-
part. Integration of the methyl ester singlets at 3.2 and
3.6 ppm demonstrated that the ratio of R- to γ-methyl
esters 3:4 was 18:1. γ-tert-Butyl N-(PhF)glutamate 2i was
thus produced regioselectively in 85% yield. Selectivity
for the R- versus the γ-tert-butyl ester of N-(PhF)-
glutamate likely arises from initial coordination of ZnBr2
by the PhF-bearing nitrogen prior to Lewis acid activa-
tion of the tert-butyl ester. Similar coordination of the
R-amine and R-carboxylate groups by copper carbonate
has been used for the selective protection of the ω-amine
of Orn and Lys.11 Moreover, complexation of the R-amine
and R-carboxylate groups by copper carbonate has been
used to selectively hydrolyze the R-methyl ester of
aspartate R,â-dimethyl ester.12 To the best of our knowl-
edge, this application of ZnBr2 represents the first
example of selective hydrolysis of an R-tert-butyl ester
of an R-amino R,ω-di-tert-butyl dicarboxylate. In addition,
the selective hydrolysis of tert-butyl ester 1l in the
presence of R-tert-butyl ether was observed and may also
be due to precoordination of ZnBr2 to the PhF nitrogen
prior to ester cleavage.
of zinc to both oxygens of the ester followed by decom-
plexation with water.6 In the case of PhF amino esters,
the alkylamine likely coordinates to the zinc prior to the
coordination of R-carbonyl oxygen and cleavage of the
tert-butyl ester with evolution of isobutene.
In conclusion, attempts failed to selectively remove tert-
butyl esters in the presence of N-(Boc)amines and in
contrast to an earlier report,6 instead of the N-(Boc)amino
acid, N-deprotected amino acid was produced. On the
other hand, selective deprotection of tert-butyl esters in
the presence of N-(PhF)amines with ZnBr2 in DCM
provided an effective means for obtaining N-(PhF)amino
acids possessing a wide range of functional group diver-
sity. Lewis basic groups, such as alcohols, amides, and
ketones, may retard the reaction. Notable regiocontrol
was demonstrated by the selective hydrolysis of the
R-tert-butyl ester of R,γ-di-tert-butyl N-(PhF)glutamate
with these conditions. This chemoselective Lewis acid
hydrolysis of acid functional groups should be of general
utility for the synthesis of multifunctional systems.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Selective Rem ova l of ter t-
Bu tyl Ester s. A stirred solution of N-protected amino acid tert-
butyl ester (1 mmol) in 5 mL of dichloromethane was treated
with 500 mol % of ZnBr2 at room temperature, stirred for 24 h,
treated with water (20 mL), and stirred again for 2 h. The
organic phase was separated. The aqueous layer was extracted
twice with dichloromethane (20 mL). The organic portions were
dried, filtered, and evaporated to yield the corresponding acid.
The resulting acids were chromatographed with 1:1 ethyl
acetate/hexane containing 1% acetic acid as eluant.
(2S)-N-(P h F )a zetid in e-2-ca r boxylic a cid (2j): yield 80%
from 1j; mp 107.5-108.5 °C; [R]20D 130.1 (c 1.0, CHCl3); 1H NMR
δ 7.68-7.08 (m, 13H), 3.63 (m, 1H), 3.5 (dd, 1H, J ) 16.9, 8.31
Hz), 3.31 (dd, 1H, J ) 9.07, 7.75 Hz), 2.04 (m, 2H); 13C NMR δ
172.5, 75.9, 59.5, 46.8, 20.3; HRMS calcd for C23H19NO2 [M+]
341.1415, found 341.1406.
Evidence that the ZnBr2 ester cleavage proceeded
without R-epimerization was provided from examples 2a ,
2k , and 2p , which were delivered as pure diastereomers.
Moreover, specific rotations of R-amino acids after tert-
butyl ester removal compared well with those of materi-
als obtained from independent synthesis indicating that
racemization had not occurred after the ZnBr2 treatment.
A probable mechanism for ZnBr2-mediated tert-butyl
ester hydrolysis has been proposed involving coordination
Ack n ow led gm en t. This work was supported by
grants from Fonds Que´be´cois de la Recherche sur la
Nature et les Technologies (FQRNT), Valorisation-
Recherche Que´bec (VRQ), and the Natural Sciences and
Engineering Research Council of Canada (NSERC). We
thank Mr. Dalbir Sekhon for mass spectral analysis.
Mr. Guillaume J eannotte and Mr. Simon Surprenant
are respectively thanked for supplying N-(trityl)- and
N-(PhF)alanine tert-butyl esters.
(11) Crivici, A.; Lajoie, G. Synth. Commun. 1993, 23, 49.
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R. J . Org. Chem. 1994, 59, 2467.
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Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal details and characterization data for 1a , 1g, 1h , 1m , 1p ,
2e, 2g, 2h , and 2p , as well as 1H and 13C NMR spectra of
1d -f, 1i-o, 2a , 2f, and 2i-p . This material is available free
of charge via the Internet at http://pubs.acs.org.
J O0491206
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