open novel opportunities for the on-resin synthesis of
peptidomimetics and heterocyclic products. The significantly
reduced nucleophilicity of resin 2, however, posed a major
challenge to find efficient acylation conditions. Resin 2 could
be obtained from methyl R-bromoacetate5-7 and the com-
mercially available triphenylphosphane resin 1 under gentle
microwave heating, yielding the intermediary phosphonium
salt which was deprotonated with triethylamine as a base
(Scheme 1). Complete alkylation of the phosphane was
Table 1. Acylation of Amino Acids on Linker Reagents Using
Various Acylation Methods
yield 3a
entry Fmoc-amino acid
activation methods
[%]a
1
2
3
4
5
6
7
8
9
Fmoc-F-OH
Fmoc-F-OH
Fmoc-F-OH
Fmoc-F-OH
Fmoc-F-OH
Fmoc-L-OH
Fmoc-G-OH
Fmoc-T(tBu)-OH
EDC (5 equiv)/
DMAP (0.74 equiv)
DIC (5 equiv)/
DMAP (0.75 equiv)
HATU (5 equiv)/
DIPEA (0.75 equiv)
TFFH (5 equiv)/
DIPEA (10 equiv)
MSNT (5 equiv)/
2,6-lutidin (4, 9 equiv)
MSNT (5 equiv)/
2,6-lutidin (4, 9 equiv)
MSNT (5 equiv)/
2,6-lutidin (4, 9 equiv)
MSNT (5 equiv)/
46
33
29
86
85
84
79
82
84
Scheme 1. Phosphoranes 2a,b Acylated Efficiently with
Aliphatic and Aromatic Carboxylic Acids
2,6-lutidin (4, 9 equiv)
Fmoc-D(OtBu)-OH MSNT (5 equiv)/
2,6-lutidin (4, 9 equiv)
a Yields are determined by spectrophotometric quantification of Fmoc
groups cleaved off a weighed and dried resin sample.
ization as proven by total hydrolysis and chiral separation
of the products.4 C-Acylation of phosphorane 2a could be
performed with a broad choice of carboxylic acids and
tolerated the standard side-chain protecting groups used in
peptide synthesis such as tert-butyl, Boc, and trityl. The
method works well with Fmoc-protecting groups. The
basicity of the phosphorane reagents 2 did not cleave
detectable amounts of the Fmoc-protecting group as verified
by a negative Kaiser test subsequent to all acylations.
Following the C-acylation reaction, the Fmoc group could
be removed under standard conditions (20% piperidine in
DMF) and the liberated N-terminus could be used for peptide
synthesis yielding peptidyl 4-amino-3-oxo-2-phosphora-
nylidene butanoates 4a,b (Scheme 1).
Oxidative cleavage16-18 of 4a employing dimethyldiox-
irane in acetone afforded the peptidyl 4-amino-2,3-dioxo-
butanoates (“peptidyl diketoesters”) 5 (Scheme 2). To our
knowledge, this novel class of compounds has not been
described in the literature so far. In aqueous solution,
compounds 5 were present as the 2-hydrates as observed in
the ES mass and the NMR spectra. HPLC analysis displayed
a narrow peak unlike the broad signals observed for classical
peptide aldehydes (Figure 1).19 If MSNT/lutidine was
employed for C-acylation, no epimerization products were
detected, an observation which is in accordance with the
accomplished within 15 min. The acylation of 2a,b was
investigated employing various Fmoc-protected amino acids
under a variety of coupling conditions. Standard conditions
used for peptide couplings failed completely, including the
use of DIC/HOBt, TBTU, and PyBOP.8-13 Stronger activa-
tion such as the use of N-ethyl-N′-(3-dimethylaminopropyl)-
carbodiimide (EDC) with catalytic DMAP that succeeded
in acylations of the 2-phosphoranylidene acetonitrile3,4
furnished only low yields of products (Table 1, entries 1-3).
On the contrary, efficient acylations could be performed
with fluoro-N,N,N′,N′-tetramethylformamidinium hexafluo-
rophosphate (TFFH) or with 1-(2-mesitylenesulfonyl)-3-
nitro-1H-1,2,4-triazole (MSNT).14,15
Coupling yields of acylated products 3a were determined
by spectrophotometric quantification of Fmoc groups cleaved
off a dried resin sample. Acylations of amino acids activated
with MSNT and lutidine as base proceeded without racem-
(5) Hungerbu¨hler, E.; Seebach, D.; Wasmuth, D. HelV. Chem. Acta 1981,
64, 1467-1487.
(6) Adamaczyk, M.; Akireddy, S.; Reddy, E. Tetrahedron 2000, 56,
2379-2390.
(7) Ahmed, A.; Hoegenauer, E.; Mulzer, J. J. Org. Chem. 2003, 68,
3026-3042.
(8) Fuchi, N.; Doi, T.; Cao, B.; Khan, M.; Takahashi, T. Synlett 2002,
285-289.
(9) Colarusso, S.; Gerlach, B.; Koch, U.; Murgalia, E.; Conte, I.;
Standfield, O.; Matassa, V. G.; Jarjies, F. Bioorg. Med. Chem. Lett. 2002,
12, 705-708.
(10) Aldington, R. M.; Baldwin, J. E.; Catterick, D.; Prichard G. J. J.
Chem. Soc., Perkin Trans. 2002, 299-302.
(16) Zeller, K. P.; Kowallik, M.; Schuler, P. Eur. J. Org. Chem. 2005,
5151-5153.
(11) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
(12) Coste, J.; Le-Nguyen, D.; Castro, B. Tetrahedron Lett. 1990, 31,
205-208.
(17) Wassermann, H.; Oliver, Y.; Parr, Y. Tetrahedron Lett. 2003, 44,
361-363.
(18) Wassermann, H.; Lee, K.; Xia, M. Tetrahedron Lett. 2000, 41,
2511-2514.
(13) Munson, M. C.; Barany, G. J. Am. Chem. Soc. 1993, 115, 10203.
(14) Blankemeyer-Menge, B.; Nimtz, M.; Frank, R. Tetrahedron Lett.
1990, 31, 1701-1704.
(19) Al-Gharabli, S. I.; Ali Shah, S. T.; Weik, S.; Schmidt, M. F.; Kuhn,
D.; Mesters, J.; Klebe, G.; Hilgenfeld, R.; Rademann, J. ChemBioChem
2006, 7, 1048-1055.
(15) Nielsen, J.; Lyngso¨, L. Tetrahedron Lett. 1996, 37, 8439-8442.
950
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