Building functionalized peptidomimetics: New electroauxiliaries and the use of a chemical oxidant for introducing N-acyliminium ions into peptides

Article abstract of DOI:10.1021/ol034872s

(Matrix presented) The removal of electroauxiliaries from peptide substrates with chemical oxidants has been examined as a method for inserting N-acyliminium ions into the peptides. To this end, it was found that both 4-methoxyphenyldimethylsilyl and 2,4-

Full text of DOI:10.1021/ol034872s

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3189-3192
Building Functionalized
Peptidomimetics: New Electroauxiliaries
and the Use of a Chemical Oxidant for
Introducing N-Acyliminium Ions into
Peptides
Haizhou Sun and Kevin D. Moeller*
Department of Chemistry, Washington UniVersity, St. Louis, Missouri 63130
moeller@wuchem.wustl.edu
Received May 19, 2003
ABSTRACT
The removal of electroauxiliaries from peptide substrates with chemical oxidants has been examined as a method for inserting N-acyliminium
ions into the peptides. To this end, it was found that both 4-methoxyphenyldimethylsilyl and 2,4-dimethoxyphenyldimethylsilyl electroauxiliaries
were readily cleaved with the use of ceric ammonium nitrate. Of the two groups, the 2,4-dimethoxyphenyldimethylsilyl electroauxiliary was the
most labile under the oxidative conditions. The oxidation reactions were shown to be compatible with the use of a solid-phase substrate.
Peptide libraries that include conformationally constrained
peptidomimetics can potentially provide an attractive means
for gathering information about the three-dimensional re-
quirements of ligand-receptor binding.1 But how does one
conveniently build a peptide library that contains conforma-
tionally constrained analogues? As part of an effort to answer
this question, we recently showed that silylated amino acids
can be used to selectively insert N-acyliminium ions into
peptides.2 The N-acyliminium ions were used to trigger either
the formation of a conformational constraint or introduce
an external nucleophile to the peptide (Scheme 1). This
chemistry worked because a silyl substituent on the carbon
R to the nitrogen of an amide serves as an electroauxiliary3
and lowers the oxidation potential of the amide by 0.5 V.4
Therefore, the insertion of a silyl substituent into the peptide
enabled the selective oxidation of the neighboring amide
relative to any of the other amides in the peptide. In these
cases, the oxidation was accomplished using anodic elec-
trochemistry.
Scheme 1
(1) Burgess, K. Acc. Chem. Res. 2001, 34, 826.
(2) Sun, H.; Moeller, K. D. Org. Lett. 2002, 4, 1547.
(3) (a) Yoshida, J.; Isoe, S. Tetrahedron Lett. 1987, 28, 6621. (b) Yoshida,
J. Top. Curr. Chem. 1994, 170, 39. (c) For a recent application, see:
Kamada, T.; Oku, A. J. Chem. Soc., Perkin Trans 1 1998, 3381. Kamada,
T.; Oku, A. J. Chem. Soc., Perkin Trans 1 2002, 1105.
10.1021/ol034872s CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/15/2003

While this strategy enabled the rapid synthesis of a variety
of peptide analogues, the use of electrochemistry for the
oxidation limited its applicability to the construction of solid-
phase peptide libraries. Such a scenario would require the
oxidation of a solid-phase substrate using a solid-phase
reagent (the electrode). For this reason, a directly analogous
strategy that used a solution-phase chemical oxidant for the
key step was needed. Normally, routes to N-acyliminium ion
intermediates using chemical oxidants5 are limited in scope
due to the high oxidation potential of the starting amide and
the lack of selectivity between oxidation of the amide
substrate and oxidation of the methoxylated or hydroxylated
product. However, by reducing the oxidation potential of the
amide substrate, the presence of a silyl electroauxiliary in
the molecule should eliminate both of these problems. For
example, Mariano and co-workers studied the chemical
oxidation of simple trimethylsilyl-substituted amides and
carbamates and utilized the subsequent N-acyliminium ions
for the synthesis of alkaloid ring skeletons.6 Yet while these
reactions were successful, the yields of the oxidations ranged
from 25 to 86% and were sensitive to changes in the nature
of the substrate. On the basis of these efforts, it was not
clear that a chemical oxidant could be used to efficiently
insert N-acyliminium ions into a series of more difficult to
oxidize peptide substrates.7 With this in mind, an investiga-
tion was undertaken in order to determine the viability of
using chemical oxidants for selectively functionalizing pep-
tide substrates. We report herein that peptides containing
modified silyl-based electroauxiliaries can be selectively
oxidized in high yield using a solution-phase chemical
oxidant.
in a 54% isolated yield along with 18% of the recovered
starting material. The oxidation of 3a gave rise to a 41%
yield of the desired methoxylated compound along with 15%
of the recovered starting material. While both reactions
afforded the desired product, it was clear that a method for
raising the yield was needed if the reactions were to prove
useful for solid-phase synthesis. A potential solution to this
problem suggested itself when we observed that the reaction
using the acyclic substrate was very sensitive to the nature
of the electroauxiliary. When a trimethylsilyl electroauxiliary
(substrate 3b) was used for this reaction, only a 22% yield
of the methoxylated product was obtained. For comparison,
the corresponding electrolysis of 3b afforded a 92% isolated
yield of the methoxylated product 4. This observation was
consistent with a chemical oxidation that was occurring near
the oxidation potential limit for ceric ammonium nitrate. This
made the chemical oxidation sensitive to variations in the
structure, and hence oxidation potential, of the substrate. The
corresponding electrochemical reaction was not adversely
effected because the reaction automatically adjusted to the
oxidation potential of the substrate.
In principle, there were two ways to solve this problem.
Either the strength of the chemical oxidant could be increased
or the electroauxiliary could be altered in order to further
lower the oxidation potential of the substrates.
Since the oxidation of the amide needed to be not only
selective relative to other amides in the backbone but also
selective relative to the side chains of the peptide, the strategy
taken was to alter the electroauxiliary. The plan called for
studying a series of electroauxiliaries in a dipeptide model
system. As in the synthesis of 3a and 3b (Scheme 3), each
Initial efforts to oxidize peptides with a chemical reagent
focused on the oxidation of substrates 1 and 3a (Scheme 2).
Scheme 3
Scheme 2
new substrate for this study was synthesized by alkylating
phenyl alanine methyl ester with an appropriately substituted
silyl methyl chloride derivative and then coupling the
resulting alkylated amine with a Boc-protected glycine.
Once the substrates were in hand, they were oxidized using
ceric ammonium nitrate in a solution of 15-20% methanol
in dichloromethane (Table 1). The reactions originating from
3a and 3b are included as the first three entries in Table 1
so that direct comparisons with the new electroauxiliaries
can be made. Our first attempt to improve the reaction
In these cases, a phenyl dimethylsilyl electroauxiliary was
utilized along with ceric ammonium nitrate as the oxidant.
The oxidation of 1 led to the desired methoxylated product
(4) Yoshida, J.; Wtanabe, M.; Toshioka, H.; Imagawa, M.; Suga, S. In
NoVel Trends in Electroorganic Synthesis; Torii, S., Ed.; Springer: Tokyo,
1998; p 99.
(5) Murahashi, S. I. Angew. Chem., Int. Ed. Engl. 1995, 34, 2443.
(6) (a) Wu, X.-D.; Khim, S.-K.; Zhang, X.; Cederstrom, E. M.; Mariano,
P. S. J. Org. Chem. 1998, 63, 841. (b) Kim, H.-J.; Yoon, U.-C.; Jung, Y.-
S.; Park, N. S.; Cederstrom, E. M.; Mariano, P. S. J. Org. Chem. 1998, 63,
860.
3190
Org. Lett., Vol. 5, No. 18, 2003

oxidation potential measured for substrate 3e. In any event,
the ease with which the dimethoxylated electroauxiliary could
be removed relative to either the 2-methoxylphenyldimeth-
ylsilyl or the trimethylsilyl electroauxiliary suggested that
more than one site for N-acyliminium ion generation can be
inserted into a peptide and then selectively unmasked.
Having established that electroauxiliaries can be used in
conjunction with chemical oxidants, we sought to demon-
strate the compatibility of the reactions with solid-phase
substrates. For this reason, the Merrifield resin-based sub-
strate 6 was synthesized8 and then oxidized using ceric
ammonium nitrate (Scheme 4). Since the methoxylated
Table 1.
yield
a
X
Ep/2
time
temp
4
3a PhMe2Si
3b Me3Si
3b Me3Si
3c Ph2MeSi
3d (2-methoxy-phenyl)Me2Si
3d (2-methoxy-phenyl)Me2Si
+1.67 V 12 h
+1.63 V 12 h
+1.63 V 30 min
12 h
25 °C 41%b
25 °C 22%
25 °C 0%c
25 °C 0%c
25 °C 87%
+1.64 V 30 min
+1.64 V 90 min -40 °C 0%c
3e (2,4-dimethoxy-phenyl)Me2Si +1.38 V 15 min
3e (2,4-dimethoxy-phenyl)Me2Si +1.38 V 35 min
25 °C 80%
0 °C 82%
Scheme 4
3e (2,4-dimethoxy-phenyl)Me2Si +1.38 V 90 min -40 °C 86%
a Measured by cyclic voltammetry using a silver/silver chloride reference
electrode, a solution of tetrabutylammonium perchlorate in acetonitrile
electrolyte, and Pt electrodes. b Product was isolated along with 15% of
recovered starting material. c No reaction was observed for this substrate
using the conditions indicated.
involved the addition of a second phenyl ring to the
electroauxiliary (substrate 3c). This change was found to
interfere with the oxidation process, and none of the desired
product was obtained. Fortunately, varying the nature of the
phenyl ring in substrate 3a proved to be more rewarding. A
dramatic improvement in the oxidation reaction was observed
when an electron-donating oxygen substituent was added to
the phenyl ring. In this case, the oxidation of substrate 3d
led to an 87% isolated yield of the desired oxidized product
after only 30 min. For comparison, no product was obtained
from a similar oxidation using a trimethylsilyl electroaux-
iliary (entry 3). Cyclic voltammetry indicated that the
improvement in the reaction was not a result of the methoxy
group lowering the oxidation potential of the substrate.
Apparently, the electron-rich aromatic ring on the silyl
substituent aids in the elimination step once the radical cation
is formed from the oxidation. The addition of a second
methoxy group to the phenyl ring on the silyl substituent
led to a further improvement in the reaction (3e). In this
case, the yield of the oxidation improved as the temperature
was lowered. Even at -40 °C, the ceric ammonium nitrate
oxidation led to an 86% isolated yield of the methoxylated
compound. For comparison, the oxidation of 3d led to no
reaction at -40 °C. Interestingly, one of the side products
from the oxidation of substrate 3e was 1,3-dimethoxyben-
zene. The formation of this product would appear to be the
result of an initial oxidation of the phenyl ring followed by
elimination of the silyl group and hydrogen atom abstraction
from solvent. This suggestion was consistent with the lower
product was not compatible with cleavage from the resin,
the methoxy group of the product was exchanged for an allyl
substituent. The allylated product could be readily cleaved
from the resin and identified. The combined yield for the
oxidation and subsequent allylation reaction on the solid-
phase substrate was 66%.
The yield for this reaction was obtained by dividing
substrate 6 into two fractions. For the first fraction, the
substrate was oxidized, the resulting methoxylated product
used to introduce an allyl nucleophile, and then the peptide
cleaved from the resin.9 For the second fraction, the substrate
was simply cleaved from the resin. By comparing the yield
of product obtained from the two fractions, success of the
oxidation/trapping sequence could be ascertained. Since the
exchange of the methoxy group for the allyl substituent is
known to proceed in about 80% yield,10 it would appear that
the oxidation of the solid-phase substrate produced the
methoxylated amide in approximately 80% yield.
In conclusion, it has been found that an electroauxiliary
can be used in conjunction with a chemical oxidant to
selectively insert N-acyliminium ion precursors into peptides.
This work is compatible with the use of solid-phase-bound
(7) For difficulties associated with the oxidation of amides having
heteroatoms R to the carbonyl group, see: (a) Li, W.; Hanau, C. E.;
d'Avignon, A.; Moeller, K. D. J. Org. Chem. 1995, 60, 8155. Selected
dipeptides can be oxidized using high current densities: (b) Cornille, F.;
Fobian, Y. M.; Slomczynska, U.; Beusen, D. D.; Marshall, G. R.; Moeller,
K. D. Tetrahedron Lett. 1994, 35, 6989 and (c) Cornille, F.; Slomczynska,
U.; Smythe, M. L.; Beusen, D. D.; Moeller, K. D.; Marshall, G. R. J. Am.
Chem. Soc. 1995, 117, 909. The success of these reactions is highly
dependent upon the nature of the substitutents.
(8) Peptide was added to the solid-phase resin using the standard protocol.
Tesser, G. I.; Buis, J. T.; Wolters, E. T. M.; Bothe-Helmes, E. G.
Tetrahedron 1976, 32, 1069.
(9) Product was cleaved off of the resin using sodium hydroxide in a
10:3 ratio of dioxane and water for 2 min.
(10) (a) Beal, L. M.; Liu, B.; Chu, W.; Moeller, K. D. Tetrahedron 2000,
56, 10113. (b) Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N. D.; Moeller, K.
D. J. Org. Chem. 2000, 65, 2484.
Org. Lett., Vol. 5, No. 18, 2003
3191

substrates. Studies aimed at utilizing this methodology in
the synthesis of peptide libraries containing constrained
peptidomimetics are currently underway.
and the Washington University Mass Spectrometry Resource
Center, partially supported by NIHRR00954, for their
assistance.
Supporting Information Available: Sample experimen-
tal procedure for the oxidation reaction along with charac-
terization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the National Science Foun-
dation (CHE-9023698) for their generous support of our
work. We also gratefully acknowledge the Washington
University High Resolution NMR Facility, partially sup-
ported by NIH Grants RR02004, RR05018, and RR07155,
OL034872S
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Org. Lett., Vol. 5, No. 18, 2003