A convenient, general synthesis of 1,1-dimethylallyl esters as protecting groups for carboxylic acids

Article abstract of DOI:10.1021/ol0476117

(Chemical Equation Presented) Carboxylic acids were converted in high yield to their 1,1-dimethylallyl (DMA) esters in two steps. Palladium-catalyzed deprotection of DMA esters was shown to be compatible with tert-butyl, benzyl, and Fmoc protecting groups, and Fmoc deprotection could be carried out selectively in the presence of DMA esters. DMA esters were also shown to be resistant to nucleophilic attack, suggesting that they will serve as alternatives to tert-butyl esters when acidic deprotection conditions need to be avoided.

Full text of DOI:10.1021/ol0476117

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1473-1475
A Convenient, General Synthesis of
1,1-Dimethylallyl Esters as Protecting
Groups for Carboxylic Acids
Minoo Sedighi and Mark A. Lipton*
Department of Chemistry and Cancer Center, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
lipton@purdue.edu
Received November 19, 2004
ABSTRACT
Carboxylic acids were converted in high yield to their 1,1-dimethylallyl (DMA) esters in two steps. Palladium-catalyzed deprotection of DMA
esters was shown to be compatible with tert-butyl, benzyl, and Fmoc protecting groups, and Fmoc deprotection could be carried out selectively
in the presence of DMA esters. DMA esters were also shown to be resistant to nucleophilic attack, suggesting that they will serve as alternatives
to tert-butyl esters when acidic deprotection conditions need to be avoided.
Allyl-based protecting groups have become a popular choice
for the protection of carboxylic acids, especially in peptide
and glycopeptide synthesis, due primarily to the mildness
and selectivity of deprotection using catalytic palladium(0).1
Allyl-based protection strategies for the synthesis of peptides
are an attractive complement to Boc- and Fmoc-based
strategies for both solid- and solution-phase peptide synthesis,
particularly of sensitive glyco-, nucleo-, and sulfopeptides,
providing another level of “orthogonality” in biopolymer
synthesis.2
Barany, Albericio, and co-workers in 19984a offers a general
method for preparing cyclic peptides on solid support and
requires the use of a C-terminal allyl ester.4 However, a side-
reaction noted in this and other applications of allyl esters
is the unwanted nucleophilic attack on the allyl ester; in the
case of the BAL linker, this resulted in the unwanted
formation of diketopiperazines.5 Whereas the sterically
hindered tert-butyl ester is known to resist nucleophilic
attack, the strongly acidic conditions needed to deprotect it
often preclude its use for the preparation of acid-sensitive
molecules. For instance, in the case of the BAL linker, the
acidic conditions needed to deprotect a tert-butyl ester would
also result in cleavage of a substrate from the BAL linker.
The logical solution is the use of a tertiary ester that can be
deprotected under mild conditions. Herein, we report a
general approach to the protection of carboxylic acids as 1,1-
On-resin cyclization of peptides is an important case where
a combination of Fmoc and allyl protection is needed to
selectively free the required carboxyl group.3 In particular,
the backbone amide linker (BAL) approach reported by
(1) Lipton, M. A. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons: New York, 2002;
Vol. 2, p 1904.
(2) Spivey, A. C.; Woodhead, S. J. Annu. Rep. Prog. Chem., Sect. B
1998, 94, 77.
(3) (a) Albericio, F.; Kates, S. A.; Barany, G.; Sole, N. A.; Johnson, C.
R.; Hudson, D. Tetrahedron Lett. 1993, 34, 1549. (b) Tromelin, A.;
Fulachier, M. H.; Mourier, G.; Me´nez, A. Tetrahedron Lett. 1992, 33, 5197.
(4) (a) Barany, G.; Albericio, F.; Jensen, K. J.; Alsina, J.; Songster, M.
F.; Vagner, J. Am. Chem. Soc. 1998, 120, 5441. (b) Kurth, M. J.;
Sammelson, R. E. Chem. ReV. 2001, 101, 137-202.
(5) (a) Shute, R. E.; Daniel, H. J. Chem. Soc., Chem. Commun. 1987,
15, 1155. (b) Fields, G. B.; Noble, R. L. Int. J. Pept. Protein Res. 1990,
35, 161.
10.1021/ol0476117 CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/22/2005

dimethylallyl (DMA) esters, which combine the mild depro-
tection conditions of allyl esters with the resistance to
nucleophilic attack of tert-butyl esters.
N-protected amino acids were esterified using these condi-
tions (Table 1). In all cases, the DMA esters were synthesized
in good yield and with complete regiochemical control.
Subsequent reduction by partial hydrogenation of the alkyne
afforded the corresponding DMA esters in very high yields.
The DMA esters of Fmoc-, Boc-, and Cbz-protected amino
acids were synthesized using these conditions.
With various DMA esters in hand, it remained to be seen
whether the DMA ester would prove to be orthogonal to the
other protecting groups. In Table 2, it is shown that both
Several previous syntheses of DMA esters have been
reported,6 but to date no general method for their synthesis
from carboxylic acids has been reported. Direct synthesis
of DMA esters through the esterification of 2-methyl-3-
buten-2-ol proved to be impractical due to the hindered nature
of the tertiary alcohol. Likewise, trapping of various 1,1-
dimethyl π-allylmetal complexes with carboxylate nucleo-
philes gave prenyl esters rather than DMA esters due to the
greater stability of the prenyl ester and kinetic preference
for prenyl ester formation. Instead, the approach adopted for
the synthesis of DMA esters involves the intermediacy of
1,1-dimethylpropargyl esters, which can be subsequently
reduced to DMA esters. This approach was suggested to us
by a copper-catalyzed synthesis of aryl propargyl ethers via
nucleophilic attack on tertiary propargylic leaving groups.7
Table 2. Selective Deprotection of DMA Ester and Fmoc
Group
PG
AA
yield of 5 (%)
yield of 8 (%)
Treatment of 3-chloro-3-methyl-1-butyne (1) with benzoic
acid in the presence of anhydrous copper(I) iodide did in
fact afford the desired 1,1-dimethylpropargyl ester 3 in good
yield (Scheme 1). Although initial results were obtained using
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Boc
Val (7a)
Pro (7b)
Abu (7d)
Tyr(t-Bu) (7e)
Orn(Boc) (7f)
Glu(t-Bu) (7g)
Val (7k)
82
90
90
91
83
87
84
93
93
73
70
88
86
92
b
Scheme 1
Cbz
Phe (7l)
b
a Deprotection conditions for Fmoc can be found in Supporting Informa-
tion; Boc deprotection was carried out using various concentrations of TFA
in CH2Cl2 with various acid scavengers; Cbz deprotection was carried out
by hydrogenolysis over various Pd catalysts. b Deprotection of Boc and Cbz
lacked selectivity, resulting in loss of DMA ester.
K2CO3 as the base, use of Cs2CO3 as base was found to give
superior results. The selectivity for formation of the tertiary
ester likely results from attack of the carboxylate ion on a
copper metallocumulene.7 Partial hydrogenation of the alkyne
afforded the desired DMA ester 4 in excellent yield. With
the viability of this approach thus established, a series of
the Fmoc group and the DMA ester can be removed
selectively in the presence of the other. Moreover, DMA
deprotection using catalytic Pd(0) and N-methylmorpholine
proceeded in high yield and was compatible with tert-butyl
protection of various amino acid side chains. While DMA
esters could be readily deprotected in the presence of Fmoc,
Boc, and Cbz groups, neither Boc or Cbz could be selectively
deprotected in the presence of a DMA ester. Thus, DMA
esters should be considered orthogonal only with the Fmoc
group. The competitive deprotection of a DMA ester in the
presence of an alloc group was also carried out, but no
significant kinetic selectivity was observed.
Table 1. Synthesis of DMA Esters from Protected Amino
Acids
It is especially noteworthy that, during deprotection of the
γ-amino acid Fmoc-Abu (7d), the liberated primary amine
8d does not cyclize to form γ-butyrolactam 9 (Scheme 2).
R
yield of 6 (%)
yield of 7 (%)
Fmoc-Val (5a)
Fmoc-Pro (5b)
81
85
91
76
90
87
82
79
88
89
72
82
96
96
94
97
98
96
97
97
94
99
96
92
Fmoc-Thr(Trt) (5c)
Fmoc-Abu (5d)
Fmoc-Tyr(t-Bu) (5e)
Fmoc-Orn(Boc) (5f)
Fmoc-Glu(t-Bu) (5g)
Fmoc-MeVal (5h)
Fmoc-Gly (5i)
Fmoc-Ala (5j)
Boc-Val (5k)
Cbz-Phe (5l)
Scheme 2
The fact that this normally facile reaction fails to occur under
the reaction conditions suggests that, like tert-butyl esters,
DMA esters resist nucleophilic attack under all but the most
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Org. Lett., Vol. 7, No. 8, 2005

forcing conditions. It is therefore suggested that DMA esters
could successfully prevent unwanted diketopiperazine forma-
tion when using the BAL linker for peptide synthesis.
In conclusion, it has been demonstrated that carboxylic
acids can be protected as their 1,1-dimethylallyl (DMA)
esters in two steps. This methodology should prove to be
quite general. Using this methodology, several DMA esters
of different amino acids with various side chain protecting
groups were prepared and selectively deprotected. The DMA
ester was shown to be orthogonal to the Fmoc group and
compatible with tert-butyl and benzyl-based protecting
groups. The DMA ester should prove to be a useful
alternative to the tert-butyl ester for acid-sensitive substrates
and provide protection against nucleophilic attack on the ester
carbonyl.
Acknowledgment. We thank the National Institutes of
Health (AI-50888) for support of this work.
Supporting Information Available: Experimental pro-
cedures and full characterization of compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(6) (a) Saigo, K.; Usui, M.; Kikuchi, K.; Shimada, E.; Mukaiyama, T.
Bull. Chem. Soc. Jpn. 1977, 7, 1863. (b) Badet, B.; Julia, M.; Ramirez-
Munoz, M.; Sarrazin, C. A. Tetrahedron 1983, 3111. (c) Gauchet, F.; Julia,
M.; Mestdagh, H.; Rolando, C. Bull. Soc. Chim. Fr. 1990, 268.
(7) Bell, D.; Davies, M. R.; Green, G. R.; Mann, I. S. Synthesis 1995,
707.
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