A method for cleaving an allyl protecting group at the amide nitrogen of peptides by one-pot olefin isomerization-oxidation

Article abstract of DOI:10.1021/jo801915c

(Chemical Equation Presented) A facile method for N-deallylation at the amide nitrogen of peptides is described. One-pot deallylation of a substrate through ruthenium hydride-catalyzed terminal olefin isomerization and subsequent ozonolysis gave the corresponding deallylated product under mild conditions.

Full text of DOI:10.1021/jo801915c

A Method for Cleaving an Allyl Protecting
Group at the Amide Nitrogen of Peptides by
One-Pot Olefin Isomerization-Oxidation
Kouki Kajihara, Mitsuhiro Arisawa,* and Satoshi Shuto*
FIGURE 1. An amide 1 and a peptide 2 with some functional groups.
Faculty of Pharmaceutical Sciences, Hokkaido UniVersity,
Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812 Japan
to the steric demand of the substrate. We also encountered the
same problem in an N-allylated peptide 2, with many more
functional groups. Some natural and unnatural peptides are
important with regard to their biological functions, sequences,
sites of action, and the strategies used to improve their
pharmacological properties.4 We report here the first successful
development of a facile protocol for the N-deallylation of
peptides under mild conditions. This is a one-pot deallylation
via ruthenium-catalyzed isomerization and subsequent ozonolysis.
Despite its great synthetic interest, the deprotection of
N-allylic amides, especially peptides, has been relatively
unexplored. Initially, we attempted the N-dellaylation of 1 and
shu@pharm.hokudai.ac.jp; arisawa@pharm.hokudai.ac.jp
ReceiVed August 30, 2008
2 using previously reported procedures.5 However, with the use
A facile method for N-deallylation at the amide nitrogen of
peptides is described. One-pot deallylation of a substrate
through ruthenium hydride-catalyzed terminal olefin isomer-
ization and subsequent ozonolysis gave the corresponding
deallylated product under mild conditions.
5a,b,d
of Rh catalysis, such as RhCl(PPh3)3
and RhCl3,5a,c,e Pd
catalysis,5f,g an Al-Ni(cat.) system,5h Fe(CO)5,5i Ir catalysis,5j
and Ru catalysis, 2 was recovered or decomposed, and none of
the desired N-deallylated product was obtained. Oxidative
cleave5p and traditional basic conditions5q-s also did not work
for the N-deallylation of 2.
On the basis of these miserable results, we considered some
of the above methods that involve initial isomerization of the
carbon-carbon double bond of the allyl unit and subsequent
oxidative cleavage of the resulting enamide. Recently, we
reported the selective isomerization of N-allylated amide,
carbamate, and sulfonamide with the combination of second-
generation Grubbs catalyst and electron-rich olefin, such as
vinyloxytrimethylsilane or vinyl ethyl ether,6 where ruthenium
hydride generated in situ was identified as the actual active
species of this reaction.7 Through the research, we also
demonstrated that a ruthenium hydride, Ru(CO)HCl(PPh3)4,
The proper selection of efficient protecting groups and the
search for selective deprotection methodologies are still crucial
issues in modern organic chemistry. Protective groups on
heteroatoms such as nitrogen and oxygen are particularly
important, and the use of an allyl group to protect a nitrogen
atom of amines and amides is becoming increasingly popular,
since in contrast to classical protecting groups such as carbam-
ates, amides, and sulfonamide, it is inert under both acidic and
basic conditions.1 Furthermore, an ally group is less hindered
and accordingly can easily protect nitrogens, even those with
significantly bulky neighboring groups. In fact, cleaving of an
allyl protecting group in amines is a well-documented meth-
odology, especially with the use of π-allyl palladium catalysis
and ruthenium or rhodium hydride complexes.2
In our work on medicinal chemistry with cyclopropane as a
key conformationally restricted unit,3 we prepared functionalized
amides, such as 1 (Figure 1), using an allyl group as a protecting
group for an amide nitrogen to address a serious problem in its
removal from N-allylated amides. Although we examined a
variety of protecting groups on the amide nitrogen, none of them,
except for the allyl group, could be introduced, probably due
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9494 J. Org. Chem. 2008, 73, 9494–9496
10.1021/jo801915c CCC: $40.75 2008 American Chemical Society
Published on Web 11/04/2008

TABLE 1. N-Deallylation of Amides (1, 3, 6, and 7) and Peptides
(2 and 11-13)
SCHEME 1. Our N-Deallylation of Amide 3
effectively catalyzes the isomerization of terminal olefins to give
the isomerized products in high yields.
Therefore, we thought that, with Ru(CO)HCl(PPh3)4 as an
olefin isomerization catalyst, we could develop an efficient
method for the N-deallylation of amides with various functional
groups including peptides by the combining it with the
subsequent oxidation (Scheme 1). Thus, we planned to examine
the reaction of this catalysis with 3 as a model substrate.
Thus, a solution of 3 and 5 mol % of Ru(CO)HCl(PPh3)4 in
toluene was refluxed for 2 h to give the expected 4 quantitatively
as a mixture of cis and trans isomers. Without purification of
the product 4, subsequent standard ozonolysis gave the corre-
sponding stable N-formyl intermediate, which was readily
hydrolyzed under basic conditions to yield 5 [95% yield from
3 (3 steps), Table 1, entry 1]. With the same method, N-allyl
groups at other amides (6 and 7) were cleaved to yield 8 and 9
in respective yields of 78% and 88% (3 steps) (entries 2 and
3). It should be noted that the deallylation of the sterically
hindered N-allylated amide 1 with functional groups also
proceeded in 61% yield, which has not been achieved by
conventional methods (entry 4).
With these results in hand, we then examined the present
one-pot protocol for the deallylation of peptide 2 (entry 5). As
a result, the expected 14 was obtained in good yield without
racemization. The reaction can tolerate a wide range of steric
and electronic environments. The reaction of 11-13 gave the
corresponding deallylated peptides (15-17) without any prob-
lems in respective yields of 68%, 75%, and 62% (entries 6-8).
This kind of effective N-deallylation protocol for peptides has
not yet been reported, and therefore this method may be useful
in the synthesis of compounds with amide groups including
peptides.
a Isolated yield (3 steps).
In conclusion, we have developed a one-pot deallylation
through facile isomerization and ozonolysis that worked well
for N-allylated amides with functional groups, such as N-
allylated peptides. The isomerization of N-allyl amides was
promoted by Ru(CO)HCl(PPh3)4 catalyst, and ozonolysis of the
enamide directly produced the desired N-deallylated amide via
an N-formyl intermediate. Although allyl groups offer several
advantages compared to classical protecting groups for protect-
ing amides even under steric crowding, there have been
problems with their cleavage. Thus, this method may make allyl
groups effective as useful protective groups on peptides and
functionalized amides.
Experimental Section
General Procedure for Deallylation of an N-Allylated
Peptide or Amide. To a solution of an N-allylated substrate in
toluene (0.1 M) was added Ru(CO)HCl(PPh3)4 catalyst (5 mol%)
under an Ar atmosphere. The mixture was refluxed for 2 h. After
removal of the solvent, the residue was diluted in CH2Cl2 (0.05
M) and cooled to -78 °C. After bubbling of O3 gas into the mixture
for 30 min O3 was substituted with Ar. To the mixture was added
Me2S (10 equiv), then the whole was warmed to room temperature
and solvent was removed. To a solution of residue in (CH2Cl)2
(0.1 M) was added Et2NH (3 equiv) and the mixture was refluxed
overnight. After removing the solvent the residue was purified by
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J. Org. Chem. Vol. 73, No. 23, 2008 9495

column chromatography on silica gel to give the corresponding
deallylated product.
67.24, 67.04, 50.41, 48.19, 18.58, 18.25; LRMS (EI) m/z 91 (100%,
base peak), 384 (%, M+); [R]23D -23.3 (c 2.0, CHCl3) [lit.10 [R]22
D
N-Benzoylbenzylamine (5):8 yield, 95% from 3, a colorless
needle; mp 107-108 °C from hexane/AcOEt (lit. mp 104-105 °C
-20.9 (c 2.0, CHCl3)].
1
Acknowledgment. We are grateful to the Center for Instru-
mental Analysis, Hokkaido University for technical assistance
with NMR, MS, and elemental analyses. This research was
partially supported by a Grants-in-Aid from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT),
Japan.
from MeOH); H NMR (500 MHz, CDCl3) δ 7.80-7.78 (2 H, d,
J ) 7.3 Hz), 7.48 (2 H, t, J ) 7.3 Hz), 7.34 (4 H, d, J ) 4.1 Hz),
7.30(1 H, m, aromatic), 6.56 (1 H, br s), 4.63 (2 H, d, J ) 6.0 Hz);
13C NMR (125 MHz, CDCl3) δ 167.32, 138.14, 134.31, 131.49,
128.73, 128.54, 127.86, 127.55, 126.92, 44.05; LRMS (EI) m/z 105
(100%, base peak), 211 (26%, M+).
Z-Ala-Ala-OBn (14):9 yield, 70%, a colorless powder; mp
1
139-142 °C (lit. mp 139 °C); H NMR (400 MHz, CDCl3) δ
Supporting Information Available: Experimental proce-
dures and full characterizations of compounds 1, 2, 5, and 8-17.
This material is available free of charge via the Internet at
http://pubs.acs.org.
7.37-7.35 (10 H, m), 6.52 (1 H, broad), 5.34 (1 H, broad),
5.21-5.11 (4 H, m), 4.60 (1 H, m), 4.24 (1 H, br s), 1.41-1.36 (6
H, m); 13C NMR (125 MHz, CDCl3) δ 172.48 171.70, 155.87,
136.14, 135.20, 128.63, 128.54, 128.49, 128.20, 128.17, 128.08,
JO801915C
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9496 J. Org. Chem. Vol. 73, No. 23, 2008