Synthesis of cyclic peptides using a palladium-catalyzed enyne cycloisomerization

Article abstract of DOI:10.1016/j.tetlet.2006.03.053

In this letter, we report a palladium-catalyzed enyne cycloisomerization of linear peptides to generate small cyclic peptides embedded with a conjugated 1,3-diene. The utility of these resulting macrocyclic dienes is demonstrated by carrying out [4+2] cyc

Full text of DOI:10.1016/j.tetlet.2006.03.053

Tetrahedron Letters 47 (2006) 3569–3571
Synthesis of cyclic peptides using a palladium-catalyzed enyne
cycloisomerizationq
V. Balraju,a,b R. Vasu Dev,a D. Srinivasa Reddya and Javed Iqbala,*
aDiscovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, AP, India
bSchool of Chemistry, University of Hyderabad, Central University PO, Gachibowli, Hyderabad 500 046, AP, India
Received 3 February 2006; revised 21 February 2006; accepted 9 March 2006
Abstract—In this letter, we report a palladium-catalyzed enyne cycloisomerization of linear peptides to generate small cyclic pep-
tides embedded with a conjugated 1,3-diene. The utility of these resulting macrocyclic dienes is demonstrated by carrying out
[4+2] cycloadditions with dienophiles to generate constrained cyclic peptides with cyclic linkers.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Palladium-catalyzed coupling reactions are very efficient
and reliable methods for the introduction of new
carbon–carbon bonds.1 Palladium-catalyzed Heck,
Suzuki, Stille and Sonogashira reactions have already
made significant impact in organic synthesis, whereas
enyne cycloisomerization as developed by Trost is
beginning to attract the attention of organic chemists
for the synthesis of cyclic dienes2,3 (Fig. 1). As part of
an ongoing program in our laboratory on peptidomi-
metics,4 we became interested in applying the palladium-
catalyzed enyne cycloisomerization to incorporate a
diene moiety into a macrocyclic structure, a functional-
ity having significant synthetic application. The palla-
dium-catalyzed enyne cycloisomerization generally
results in a conjugated diene having two exocyclic dou-
ble bonds (Fig. 1, path a). However, the studies demon-
strated here show that cyclization of peptides results in a
conjugated diene having exocyclic and endocyclic dou-
ble bonds5 (Fig. 1, path b) and our preliminary results
on this useful isomerization are disclosed in this letter.
We have synthesized an acyclic Phe-Leu dipetide 1 hav-
ing an alkyne at the C-terminus and an alkene moiety at
the N-terminus. The dipeptide 1 was subjected to palla-
dium-catalyzed
cycloisomerization
conditions
(Pd(OAc)2, (o-tolyl)3P, AcOH–MeCN) as reported by
Trost et al.5 To our delight, the macrocyclization was
successful and the cyclic product was obtained in 28%
yield (Scheme 1). However, the spectral data revealed
that this reaction resulted in macrocyclic diene 2. The
E-stereochemistry of the endocyclic double bond and
s-transoid form of the 1,3-diene were established using
NMR data (1-D and 2-D), which is in accordance with
the literature.6,7 To our knowledge the palladium-cata-
lyzed enyne cycloisomerization to form macrocycles/
cyclic peptides has not been reported, previously.
Pd(0)
Pd(0)
AcOH
AcOH
O
O
path a
path b
O
O
Ph
N
H
Ph
N
H
Pd(OAc)2
Figure 1. Pd-catalyzed enyne cycloisomerization.
HN
HN
3
HN
3
NH
(o-tolyl)3P
O
O
AcOH-MeCN
~110 oC
Keywords: Peptidomimetics; Enyne cycloisomerization; Cyclic peptide;
Diels–Alder reaction.
q DRL Publication No. 555.
*
Corresponding author. Tel.: +91 40 2304 5439; fax: +91 40 2304
5438; e-mail addresses: javediqbaldrf@hotmail.com; javediqbalpr@
yahoo.co.in
2
(28%)
1
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.053

3570
V. Balraju et al. / Tetrahedron Letters 47 (2006) 3569–3571
R2
O
O
R2
R1
O
R1
O
O
N
N
H
Pd(OAc)2
O
H
Ph
N
NH R3
HN
NH R3
NH
HN
O
(o-tolyl)3P
H
O
Ph
N
O
HN
n
HN
O
O
AcOH-MeCN
~110 oC
Ph
N
O
O
N
O
H
O
n
HN
H
n
HN
n
NH
O
O
DCE
N
H
O
85 oC
O
N
3a. R1 = -CH2Ph, R2 = -CH2CH(CH3)2,
O
Ph
R3 = -CH3, n = 1
4a (33%)
4b (45%)
4c (54%)
4d (40%)
4e (46%)
4a n = 1
4c n = 3
7
8
n = 1 (47%)
n = 3 (53%)
3b. R1 = -CH2Ph, R2 = -CH2CH(CH3)2,
R3 = -CH3, n = 2
O
3c. R1= -CH2Ph, R2 = -CH2CH(CH3)2,
O
Ph
N
H
R3 = -CH3, n = 3
O
NC
NC
CN
CN
HN
3
HN
O
O
Ph
N
H
3d. R1 = -CH2Ph, R2 = -CH(CH3)2,
HN
CN
R3 = -CH3, n = 1
HN
3
NH
O
O
DCE
85 oC
3e. R1 = -CH(CH3)CH2CH3, R2 = -CH(CH3)2,
N
H
O
CN
CN
R3 = -CH2Ph, n = 1
CN
Scheme 2.
4c
9
(70%)
Scheme 4.
Next, we synthesized acyclic tripeptides 3a–e by varying
the chain length and the amino acids. All the linear pep-
tides were synthesized using standard solution-phase
peptide coupling procedures.8 The tripeptides 3a–e
underwent cycloisomerization smoothly to furnish the
desired macrocycles 4a–e in fair yields.9 We anticipated
that the linker length might play a role in the E,Z-selec-
tivity of the endocyclic double bond, but only E-isomers
were observed in all cases. The change in amino acids
had little or no effect on the reaction (Scheme 2). The
acyclic tripeptide 5 was synthesized by switching the al-
kyne to the N-terminus and alkene moiety to the C-ter-
minus. The cycloisomerization of 5 produced cyclic
peptide 6 in good yield.10 It is noteworthy that the rigid
aryl acetylene linker had no effect on the cycloisomeriza-
tion or the geometry of the endocyclic double bond of
the resulting cyclic peptide (Scheme 3).
We attempted the Diels–Alder reaction on these com-
pounds to demonstrate the synthetic utility of the conju-
gated diene present in these cyclic peptides. The reactive
dienophile N-phenylmaleimide was refluxed with macro-
cyclic diene 4a in dicholoroethane (DCE) to give com-
pound 7 in a 1:1 diastereomeric ratio.12 Similarly,
macrocyclic diene 4c reacted with N-phenylmaleimide
and tetracyanoethylene to produce the corresponding
adducts 8 and 9, respectively, in moderate to good
yields13 (Scheme 4).
In conclusion, we have demonstrated the utility of palla-
dium-catalyzed enyne cycloisomerization during the
macrocyclization of linear peptides to furnish con-
strained small cyclic peptides with novel linkers. The
resulting macrocycles having a 1,3-diene moiety can be
used for further functionalization to generate a variety
of linkers leading to useful peptidomimetics. We also
demonstrated the Diels–Alder reaction of these cyclic
dienes in several cases by reacting with dienophiles.
The cyclic peptides formed during the cycloisomeriza-
tion possess a conjugated 1,3-diene moiety, a functional
group with several potential synthetic applications.11
O
O
O
O
Acknowledgement
Ph
N
H
Ph
N
H
Pd(OAc)2
HN
HN
HN
HN
HN
HN
(o-tolyl)3P
O
O
We thank Dr. Reddy’s Laboratories Ltd. for the finan-
cial support and encouragement.
AcOH-MeCN
~110 oC
O
O
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.03.053.
6
(49%)
5
Scheme 3.

V. Balraju et al. / Tetrahedron Letters 47 (2006) 3569–3571
3571
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6. It was reported that similar endo-macrocyclization was
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9. Typical procedure for cycloisomerization: 40 mol % of
Pd(OAc)2, and 80 mol % of (o-tolyl)3P were added to
warm HPLC grade acetonitrile (1.5 · 10À3 M) and the
solution refluxed at 110 ꢁC for 30 min. Then, glacial acetic
acid (10 equiv) was added to the refluxing solution. After
10 min the acylic peptide (500 mg) was added in a single
portion and the reaction continued for 15 h at the same
temperature. The reaction mixture was filtered through a
pad of Celite and washed with hot acetonitrile (100 ml).
The filtrate was concentrated and the product was isolated
by flash column chromatography on silica gel using
CH2Cl2/MeOH (98/2) as eluent.
10. All new compounds were characterized from spectral data.
See, Supporting information for details.
11. (a) Larock, R. C. Comprehensive Organic Transformations;
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Chichester, 1983; Vol. 3, pp 139–171.
12. The Diels–Alder adduct 9 was isolated as a diastereomeric
mixture.
13. The diastereomers (1:1) formed in these reaction were
cleanly separated using column chromatography. The
stereochemistry of the substituents on the newly formed
cyclohexene ring were not assigned.