A synthesis of RGD model cyclic peptide by palladium-catalyzed carbonylative macrolactamization

Article abstract of DOI:10.1021/ol702965r

Cyclic peptidic RGD models were efficiently synthesized by Pd(P(t-Bu) ₃)₂-catalyzed carbonylative macrolactamization in the presence of 4 A molecular sieves under 10 atm of carbon monoxide.

Full text of DOI:10.1021/ol702965r

ORGANIC
LETTERS
2008
Vol. 10, No. 5
817-819
A Synthesis of RGD Model Cyclic
Peptide by Palladium-Catalyzed
Carbonylative Macrolactamization
Takayuki Doi,* Seiji Kamioka, Sayaka Shimazu, and Takashi Takahashi*
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama,
Meguro, Tokyo 152-8552, Japan
doit@apc.titech.ac.jp; ttak@apc.titech.ac.jp
Received December 8, 2007
ABSTRACT
Cyclic peptidic RGD models were efficiently synthesized by Pd(P(t-Bu)3)2-catalyzed carbonylative macrolactamization in the presence of 4 Å
molecular sieves under 10 atm of carbon monoxide.
Peptidomimetics are important for drug discovery, especially
macrocyclic ones that are useful to find potent drug
candidates by precise tuning of their conformation.1 Several
approaches to construction of the macrocyclic peptide
mimetics have been reported, such as SN2 alkylation with
S-nucleophiles,2,3 SNAr macrocyclization,3 alkene metathesis,4
Mizoroki-Heck reaction,5 Suzuki coupling,6 Sonogashira
coupling,7 (3 + 2)-cycloaddition,8 radical cyclization,9 and
ene-yne cycloisomerization.10
formed on solid phase, utilizing various alkenyl iodides,
alkenyl bromides, aryl iodides, and aryl triflates that are good
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Recently, we reported palladium-catalyzed carbonylation
is a powerful reaction in a combinatorial library synthesis.
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10.1021/ol702965r CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/31/2008

methyl)benzoic acid, and an ω-amino acid. Assembly of
(aminomethyl)benzoic acids substituted at the ortho, meta,
and para positions and ω-amino acids with different numbers
of the methylene unit would lead to a variety of cyclic RGD
models. As a part of the synthesis of a combinatorial library
of cyclic RGD models, we initially planned the syntheses
of 1a (R ) H) and 1b (R ) CH2Ph), containing m-
(aminomethyl)benzoic acids14d,15 and ω-aminovaleric acid.
Synthetic strategy for 1 is illustrated in Scheme 1. The cyclic
peptide 1 can be synthesized by palladium-catalyzed carbo-
nylative macrolactamization of 2. It would be of interest to
know the effect of the R-substituent in 2 in this cyclization.
The cyclization precursor 2 would be prepared by sequential
amidation of m-iodobenzylamines 3, Fmoc-Asp(Ot-Bu)-OH
(4), Fmoc-Gly-OH (5), Fmoc-Arg(Boc)2-OH (6), and N-Fmoc-
ω-aminovaleric acid (7).
Scheme 1. Strategy for the Synthesis of Cyclic RGD Model 1
The cyclization precursors 2 were prepared as shown in
Scheme 2. Coupling of amine 3a and Fmoc-Asp(Ot-Bu)-
OH (4) was performed using PyBrop-diisopropylethylamine
(DIEA) in CH2Cl2-DMF (9:1) at ambient temperature.16
Removal of the Fmoc group using diethylamine in acetoni-
Scheme 2. Synthesis of Cyclization Precursors 2
precursors as masked activated esters.11 It was also applied
to the construction of macrocyclic lactones.12,13 For example,
we reported a combinatorial synthesis of a 128-member
macrosphelide library, utilizing palladium-catalyzed carbo-
nylative macrolactonization on solid-phase.11d We report an
efficient synthesis of cyclic peptidic RGD models utilizing
palladium-catalyzed carbonylative macrolactamization.
Cyclic RGD models have been studied as a selective
integrin receptor antagonist.2,3,14 We designed RGD pepti-
domimetics 1 that contain a RGD sequence, an (amino-
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Doi, T.; Sunazuka, T.; Omura, S. Angew. Chem., Int. Ed. 2003, 42, 5230-
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Comb. Chem. 2008, 10, 135-141.
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Craig, W. S.; Mullen, D.; Tschopp, J. F.; Dixon, D.; Pierschbacher, M. D.
J. Med. Chem. 1994, 37, 1-8. (d) Jackson, S.; DeGrado, W.; Dwivedi, A.;
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818
Org. Lett., Vol. 10, No. 5, 2008

completely consumed when Pd(P(t-Bu)3)2 was used as a
catalyst. The desired product 1a was obtained in 41% yield
(entry 1). POPd and Pd(PPh3)4 are less effective (12%, 9%
yield, entries 2 and 3). Probably, P(t-Bu)3 ligand electroni-
cally and sterically accelerates both the oxidative addition
of 2a to palladium(0) and final reductive elimination in the
formation of amide 1a.
Scheme 3. Palladium-Catalyzed Carbonylative
Macrocyclization of 2a
Because the Boc group was partially removed under the
above reaction conditions, we examined the effect of various
additives in place of NEt3-DMAP (3 Å MS, 4 Å MS, Ag2-
CO3, TMEDA). Actually, the yield was dramatically affected
by the base, and the use of 4 Å MS increased the yield up
to 64% (entry 5), and the Boc group was sustained.20 A small
amount of double carbonylated product 11a was detected
by LC-MS (7%).21 Then, the effect of CO pressure was
investigated. When the reaction was carried out under 5 atm
of CO, the reaction was not complete, but only a trace
amount of 11a was observed (entry 8). On the other hand,
no effect of the higher pressure of CO under 20 and 30 atm
was observed (entries 9 and 10 vs entry 5).
The solvent effect was found to be crucial. It was found
that THF is an effective solvent in this reaction. The yield
of 1a increased to 79%, and double carbonylative product
11a was also observed in 9% yield (entry 11 vs entries 5,
12, 13, and 14). Interestingly, the desired reaction did not
proceed in 1,4-dioxane (entry 14). The reaction temperature
is also important to control the reaction. The reaction was
not complete at 40 °C (entry 15), whereas removal of the
Boc group was observed at 65 °C (entry 16).
trile afforded 8a (R ) H) in 86% yield.17 Sequential peptide
elongation with Fmoc-Gly-OH (5), Fmoc-Arg(Boc)2-OH (6),
and N-Fmoc-ω-aminovaleric acid (7) under the same reaction
conditions described above provided 2a in good yield.
N-Benzyl derivative 2b was also prepared from N-benzyl-
m-iodobenzylamine (3b) in a similar manner.
Palladium-catalyzed carbonylative macrolactamization of
2a was investigated (Table 1). We initially compared the
Table 1. Optimization of Palladium-Catalyzed Carbonylative
Macrocyclization of 2a
Using the optimized reaction conditions, we performed
cyclization of N-benzyl derivative 2b. The palladium-
catalyzed carbonylative macrolactamization efficiently pro-
ceeded [Pd(P(t-Bu)3)2 (10 mol %)/CO (10 atm)/4 Å MS/
THF/50 °C/12 h] to furnish the desired 1b in 83% yield.
Since the double carbonylation product was not detected, it
was found that the N-benzyl substituent in 2b suppresses
the double carbonylation.
In conclusion, we have demonstrated the palladium-
catalyzed carbonylative macrolactamization of 2a and 2b in
the synthesis of RGD cyclic peptide mimetics 1a and 1b.
The reaction of N-benzyl group 2b provided 1b in better
yield than in 2a. It was suggested that the N-benzyl group
can be effectively utilized as a linker on solid-phase toward
a combinatorial library synthesis of various RGD cyclic
models.
CO
temp yield (%)
entry Pd catalyst
additives (atm)
solvent
(°C) 1a (11a)
1
2
3
4
5
6
7
8
9
Pd(P(t-Bu)3)2 NEt3-DMAP 10 DMF
50 41
50 12
POPd
NEt3-DMAP 10 DMF
NEt3-DMAP 10 DMF
Pd(PPh3)4
50
9
Pd(P(t-Bu)3)2 3 Å MS
Pd(P(t-Bu)3)2 4 Å MS
Pd(P(t-Bu)3)2 Ag2CO3
Pd(P(t-Bu)3)2 TMEDA
Pd(P(t-Bu)3)2 4 Å MS
Pd(P(t-Bu)3)2 4 Å MS
10 DMF
10 DMF
10 DMF
10 DMF
50 49
50 64(7)
50 51
50 21
5
DMF
50 43(trace)
50 61(9)
50 63(7)
50 79(9)
50 32
20 DMF
30 DMF
10 THF
10 NMP
10 DMPU
10 Pd(P(t-Bu)3)2 4 Å MS
11 Pd(P(t-Bu)3)2 4 Å MS
12 Pd(P(t-Bu)3)2 4 Å MS
13 Pd(P(t-Bu)3)2 4 Å MS
14 Pd(P(t-Bu)3)2 4 Å MS
15 Pd(P(t-Bu)3)2 4 Å MS
16 Pd(P(t-Bu)3)2 4 Å MS
50 41
10 1,4-dioxane 50 trace
10 THF
10 THF
40 49
65 21
effect of palladium-catalysts [Pd(P(t-Bu)3)2,18 POPd,19 Pd-
(PPh3)4]. The reaction was carried out in the presence of 10
mol % of the Pd-catalyst with NEt3-DMAP in DMF at 50
°C for 12 h under CO (10 atm). The starting material was
Acknowledgment. This work was supported by Grant-
in-Aid for Scientific Research on Priority Areas (No.
16350051) from MEXT.
Supporting Information Available: Experimental de-
tails, NMR spectra of 8a-10a, 8b-10b, 2a, 2b, 1a, and
1b. This material is available free of charge via the Internet
at http://pubs.acs.org.
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OL702965R
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