A synthetic strategy for the preparation of cyclic peptide mimetics based on SET-promoted photocyclization processes

Article abstract of DOI:10.1021/ja030297b

A novel method for the synthesis of cyclic peptide analogues has been developed. The general approach relies on the use of SET-promoted photocyclization reactions of peptides that contain N-terminal phthalimides as light absorbing electron acceptor moieties and C-terminal α-amidosilane or α-amidocarboxylate centers. Prototypical substrates are prepared by coupling preformed peptides with the acid chloride of N-phthalimidoglycine. Irradiation of these substrates results in the generation of cyclic peptide analogues in modest to good yields. The chemical efficiencies of these processes are not significantly affected by (1) the lengths of the peptide chains separating the phthalimide and α-amidosilane or α-amidocarboxylate centers and (2) the nature of the penultimate cation radical α-heterolytic fragmentation process (i.e., desilylation vs decarboxylation). An evaluation of the effects of N-alkyl substitution on the amide residues in the peptide chain showed that N-alkyl substitution does not have a major impact on the efficiencies of the photocyclization reactions but that it profoundly increases the stability of the cyclic peptide.

Full text of DOI:10.1021/ja030297b

Published on Web 08/08/2003
A Synthetic Strategy for the Preparation of Cyclic Peptide
Mimetics Based on SET-Promoted Photocyclization
Processes
Ung Chan Yoon,*,† Ying Xue Jin,† Sun Wha Oh,† Chan Hyo Park,†
Jong Hoon Park,† Charles F. Campana,‡ Xiaolu Cai,§ Eileen N. Duesler,§ and
Patrick S. Mariano*,§
Contribution from the Department of Chemistry, College of Natural Sciences, Pusan National
UniVersity, Pusan, 609-735, Korea, Bruker AXS Inc., 5465 East Cheryl Parkway,
Madison, Wisconsin 53711-5373, and Department of Chemistry, UniVersity of New Mexico,
Albuquerque, New Mexico 87131
Received May 16, 2003; E-mail: mariano@unm.edu; ucyoon@pusan.ac.kr
Abstract: A novel method for the synthesis of cyclic peptide analogues has been developed. The general
approach relies on the use of SET-promoted photocyclization reactions of peptides that contain N-terminal
phthalimides as light absorbing electron acceptor moieties and C-terminal R-amidosilane or R-amidocar-
boxylate centers. Prototypical substrates are prepared by coupling preformed peptides with the acid chloride
of N-phthalimidoglycine. Irradiation of these substrates results in the generation of cyclic peptide analogues
in modest to good yields. The chemical efficiencies of these processes are not significantly affected by (1)
the lengths of the peptide chains separating the phthalimide and R-amidosilane or R-amidocarboxylate
centers and (2) the nature of the penultimate cation radical R-heterolytic fragmentation process (i.e.,
desilylation vs decarboxylation). An evaluation of the effects of N-alkyl substitution on the amide residues
in the peptide chain showed that N-alkyl substitution does not have a major impact on the efficiencies of
the photocyclization reactions but that it profoundly increases the stability of the cyclic peptide.
Introduction
ganization of linear precursors by metal cation templation have
found use in routes for the synthesis of crown ethers.3 In the
Substances that possess macrocyclic, polyheteroatom contain-
ing ring systems have played a central role in numerous
investigations aimed at discovering new materials with chemi-
cally and biologically interesting properties. Crown ethers and
their analogues are prime examples of members of this large
family which have attracted great attention as a consequence
of their selective metal and ammonium cation binding proper-
ties.1 In addition, naturally occurring and synthetic cyclic
peptides and their analogues have been the subjects of efforts
aimed at exploring conformationally defined and hydrolytically
more stable polypeptide mimetics.2
area of cyclic peptide synthesis,4 the incorporation of confor-
mationally biasing N-alkyl amino acid and proline units is
known to facilitate macrocyclization processes. Also, several
interesting approaches, including those that employ backbone
cyclizations5 and cyclization-ring contraction sequences,6 have
been used to efficiently generate novel cyclic peptide mimetics.
Owing to the chemical and biological significance of sub-
stances in the crown ether and cyclic peptide families, synthetic
methods, which can be applied to the preparation of new targets,
are still in demand. In recent reports,7 we described a novel,
Several general methods have been developed to construct
the macrocyclic ring systems present in members of the cyclic
peptide and crown ether families. In some of the approaches,
high dilution techniques are required to maximize cyclization
reaction efficiencies. In addition, methods relying on preor-
(3) For representative examples of templation controlled crown ether and
cyclam synthesis see: (crown ethers) Greene, R. N. Tetrahedron Lett. 1972,
1793. Vitali, C. A.; Masci, B. Tetrahedron 1989, 45, 2201. Bowsher, B.
R.; Rest, A. J. Inorg. Chim. Acta 1981, 53, L175. (cyclams) Busch, D. H.
Acc. Chem. Res. 1978, 11, 392. Beveridge, K. A.; McAuley, A.; Xu, C.
Inorg. Chem. 1991, 30, 2074. Fortiewr, D. G.; McAuley, A. J. Am. Chem.
Soc. 1990, 112, 2640.
(4) For a review of general approaches to cyclic peptide synthesis, see:
Humphrey, J. M.; Chamberlin, A. R. Chem. ReV. 1997, 97, 2243.
(5) (a) Gilon, C.; Zeltzer, I.; Rashiti-Behar, V.; Muller, D.; Bitan, G.; Halle,
D.; Bar-Akiva, G.; Seliger, Z.; Byk, G.; Yanaihara, V. J. Peptide Chemistry;
ESCOMA: Leiden, The Netherlands, 1992; p 482. (b) Gilon, C.; Halle,
D.; Choprez, M.; Seliger, Z.; Byk, G. Biopolymers 1991, 31, 745.
(6) (a) Shao, Y.; Lu, W.; Kent, B. H. Tetrahedron Lett. 1998, 39, 3911. (b)
Mentermans, W. D. F.; Golding, S. W.; Bourne, G. T.; Miranda, L. P.;
Dooley, M. J.; Alewood, P. F.; Smythe, M. L. J. Am. Chem. Soc. 1999,
121, 9790.
† Pusan National University.
‡ Bruker AXS Inc.
§ University of New Mexico.
(1) Gokel, G. W. Crown Ethers and Cryptands; Black Bear Press: Cambridge,
1991.
(2) For representative examples, see: (a) Hruby, V. J. Life Sci. 1982, 31, 189.
(b) Burgess K. Acc. Chem. Res. 2001, 34, 826. (c) Wels, B.; Kruijtzer, J.
A. W.; Liskamp, R. M. J. Org. Lett. 2002, 4, 2173. (d) Fairlie, D. P.;
Abernante, G.; March, D. R. Curr. Med. Chem. 1995, 2, 654. (e) Brugghe,
H. F.; Timmermans, H. A. M.; Van Unen, M. A.; Ten Hove, G. J.; Vande
Werken, G.; Poolman, J. T.; Hoogerhut, P. Int. J. Pept. Protein Res. 1994,
43, 166. (f) Hruby, V. J. Acc. Chem. Res. 2001, 34, 389.
(7) Yoon, U. C.; Oh, S. W.; Lee, J. H.; Park, J. H.; Kang, K. T.; Mariano, P.
S. J. Org. Chem. 2001, 66, 939. Yoon, U. C.; Oh, S. W.; Lee, C. W.
Heterocycles 1995, 41, 2665. Yoon, U. C.; Kim, J. W.; Ryu, J. Y.; Cho, S.
J.; Mariano, P. S. J. Photochem. Photobiol., A 1997, 106, 145.
9
10664
J. AM. CHEM. SOC. 2003, 125, 10664-10671
10.1021/ja030297b CCC: $25.00 © 2003 American Chemical Society

Preparation of Cyclic Peptide Mimetics
A R T I C L E S
Scheme 1
Table 1. Rate Constants for R-Heterolytic Fragmentation
Reactions of Anilinium Radicals11
E
R
Nu: or B:
k (25 °C, MeCN)
H
Me
Me
Me
COMe
Me
AcO-
MeOH
H2O
2.0 × 105 M-1 s-1
7.0 × 105 M-1 s-1
2.3 × 106 M-1 s-1
6.0 × 107 M-1 s-1
1.7 × 106 s-1
SiMe3
SiMe3
SiMe3
MeOH
-
CO2-
CO2
COMe
3.6 × 107 s-1
Scheme 2
general procedure for construction of cyclic polyethers, poly-
thioethers, and polysulfonamides, in which SET-initiated pho-
tochemical reactions are used to generate the macrocyclic ring
systems (Scheme 1). In the first step of this approach, a
polyheteroatom containing chain is linked to an acceptor
chromophore, chosen on the basis of its selective light absorbing
and excited state reduction properties. Irradiation of this
conjugate leads to formation of the excited acceptor moiety,
which is rapidly quenched by intramolecular SET from one of
the n-electron donating, heteroatom sites. By properly choosing
the acceptor, one can ensure that intramolecular SET is
exothermic and, as a result, that it is sufficiently rapid8 to
effectively compete with other inter- and intramolecular modes
of excited-state decay. In addition, SET from heteroatom donor
sites that are close to the excited acceptor will be faster than
those that are more remote or that are located in other substrate
molecules.9 Consequently, the use of high dilution reaction
conditions might be less important in SET-promoted photo-
macrocyclization processes.
one biradical intermediate preferentially. Cyclization of the
biradical then furnishes the targeted macrocyclic product.
The high degrees of regioselectivity, expected in these
photocyclization processes, are a consequence of the large rate
differences that exist between different cation radical, R-het-
erolytic fragmentation reactions. As can be seen by viewing
the data gained from studies of equally substituted anilinium
radicals (Table 1),11 base (AcO-) promoted R-deprotonation is
a slow process compared to silophile (MeOH, H2O) induced
R-desilylation. In addition, unimolecular decarboxylation of
R-anilinium carboxylates is the fastest process in this series.
Moreover, electron withdrawing N-acyl groups enhance the rates
of these fragmentation reactions.
Owing to their unique features, SET-promoted photocycliza-
tion reactions are highly compatible with the requirements of
strategies for efficient, regioselective construction of cyclic
peptide mimetics. In one approach (Scheme 2), the substrates
for the photochemical process (4 or 5) would be prepared by
linking a carboxylic acid containing acceptor 1 to the N-terminal
amino group of an intact peptide (2 or 3). Alternatively, the
peptide chain would be sequentially added to an appropriately
functionalized acceptor. The latter protocol would be ideally
suited for use in the construction of cyclopeptide libraries by
using combinatorial techniques. The synthetic plan used for
preparation of the acceptor-linked polypeptides would be guided
by the structural requirements of the target cyclic peptides.
Specifically, a selectively reactive (R-carboxylate or R-trimeth-
ylsilyl) amide cation radical site would be incorporated at a
Following the initial SET event, intrachain SET should take
place rapidly to produce an equilibrating mixture of zwitterionic
biradicals. At equilibrium, the populations of these reactive
intermediates will be governed by the stability of each cation
radical group. In systems containing multiple heteroatom donors
which have nearly the same oxidation potentials, a near equal
population of rapidly interconverting cation radical centers will
be produced. The key event controlling the selectivity of the
photocyclization process is the conversion of one cation radical
site to a neutral radical. Ideal processes for this purpose are
R-hetrolytic fragmentation reactions which involve the transfer
or loss of an electrofugal group (E+) from a carbon center
adjacent to the cation radical site.10 The results of extensive
laser flash photolysis and product distribution studies have
provided important information about how the rates of R-het-
erolytic fragmentation reactions are governed by the nature of
the cation radicals, the type of electrofugal groups, and the
media.11 Thus, based on these data, it is possible to design
polyheteroatom donor substrates that contain single, highly
reactive cation radical sites. In this way, the sequence initiated
by excited state SET can be selectively designed to generate
(8) Rehm, D.; Weller, A. Isr. J. Chem. 1970, 8, 259.
(9) Wasielewski, M. A. In Photoinduced Electron Transfer; Fox, M. A.,
Channon, M., Eds.; Elsevier: New York, 1988; Part A, p 161.
(10) Mariano, P. S.; Stavinoha, J. L. In Synthetic Organic Photochemistry;
Horspool, W. M., Ed.; Plenum Press: London, 1984; Chapter 3, p 145.
(11) (a) Zhang, X. M.; Yeh, S. R.; Hong, S.; Freccero, M.; Albini, A.; Falvey,
D. F.; Mariano, P. S. J. Am. Chem. Soc. 1994, 116, 4211. (b) Su, Z.;
Mariano, P. S.; Falvey, D. E.; Yoon, U. C.; Oh, S. W. J. Am. Chem. Soc.
1998, 120, 10676.
9
J. AM. CHEM. SOC. VOL. 125, NO. 35, 2003 10665

A R T I C L E S
Scheme 3
Yoon et al.
Table 2. Yields for Formation of TMS-Terminated
Phthalimide-Linked Amides 17-18 and Peptides 19-24
(Scheme 3)
amine
phthalimide
product
substrate
n
R1
R2
R3
R4
R5
% yield
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
0
0
1
1
2
2
3
4
H
60
91
88
85
86
82
83
81
Bn
Bn
Me
Bn
Me
Bn
Bn
Bn
Bn
Bn
Me
Bn
Bn
Scheme 4
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Table 3. Yields for Formation of Carboxylic-Acid-Terminated
Phthalimide-Linked Amides 25-27 and Peptides 28-29
(Scheme 4)
amine
phthalimide
product
preselected location within or at the end of the peptide chain.
Irradiation of the substrate would then initiate a reaction cascade
involving near neighbor SET, intrachain SET, and heterolytic
fragmentation at the reactive amide cation radical position.
Cyclization of the biradical, formed by this route, then produces
the target cyclopeptide mimetic (6 or 7).
substrate
n
R1
R2
R3
% yield
glycine
sarcosine
25
26
27
28
29
0
0
0
1
2
H
91
95
95
87
85
Me
Bn
H
NBn-glycine
gly-gly
H
H
gly-gly-gly
H
H
We have embarked on a broad program to investigate SET-
photochemical approaches to the synthesis of cyclic polypeptide
mimetics.12 Our initial efforts in this area focused on the
development of methods to prepare acceptor-linked peptides,
each containing single reactive amide cation radical sites, and
on the assessment of the efficiencies of photocyclization
reactions of these substrates. Reported below are the results of
studies with a group of substrates that contain N-terminal
phthalimide groups as light absorbing acceptors and C-terminal
R-amidosilane and R-amidocarboxylate moieties as reactive
cation radical sites. The effects of N-alkyl substitution and cation
radical desilylation versus decarboxylation on the efficiencies
of the photocyclization reactions have also been evaluated in
this study.
Scheme 5
Scheme 6
Scheme 7
Results
Preparation of N-Terminal Phthalimidopeptides. To evalu-
ate the SET-photochemical strategy presented above for cyclo-
peptide synthesis, several amides and peptides, containing an
N-terminal phthalimide acceptor moiety, were prepared. Either
an R-amidotrimethylsilane or R-amidocarboxylate electrofugal
group is incorporated at the C-terminal position in each of these
substances to direct the photocyclization process. In addition,
substances having both NH and N-alkyl amide nitrogen centers
were included in the series so that the effects of N-substituents
on photocyclization reaction efficiencies could be determined.
The substrates were prepared by amide coupling of preformed
amines and peptides to N-phthalimidoglycine acid chloride 8
(Schemes 3 and 4). Accordingly, condensation of the trimeth-
ylsilyl-terminated amines 9-10 and peptides 11-16 (Supporting
Information) with acid chloride 8 leads to formation of the
glycinamides 17-18 and phthalimidopeptides 19-24 in reason-
ably high yields (Scheme 3, Table 2). In a similar manner, the
carboxylic-acid-terminated phthalimidoamides 25-27 and
phthalimidopeptides 28-29 are efficiently generated by reaction
of the corresponding amino acids and peptides with 8 (Scheme
4, Table 3). Also, the phthalimide derivative of the glycine-
proline dipeptide is prepared by reaction of proline with 8
(Scheme 5). Finally, addition of potassium 3-nitrophthalimide
with the silicon-substituted R-bromoacetamide 31 is used to
produce the nitrophthalimidoglycinamide 32 (Scheme 6).
Cyclopeptide Forming Photocyclization Reactions. Car-
boxylate anions, serving as the reactants in photocyclization
reactions of 25-30, were generated in situ by reaction of the
acids 25-30 with nBu4NOH. Accordingly, photoreactions were
conducted by irradiation of 9-13 mM solutions of 25-30,
containing 1 equiv of nBu4NOH, in 35% H2O-MeCN at 17 °C
by using Pyrex glass filtered light (λ > 290 nm) under an N2
atmosphere for time periods that bring about ca. 90% conversion
of the substrates. Silica gel column chromatography was used
to separate the respective cyclopeptide products 33-38 (Schemes
7 and 8) in the yields given in Table 4.
Surprisingly, the cyclopeptide derivatives 33, 36, and 37, each
lacking N-alkyl amide substituents, are highly unstable materials.
These substance completely decompose over a 1 day period by
processes which can be monitored, but not characterized, by
(12) During the course of our investigations in this area, a similar approach to
cyclopeptide analogue synthesis was reported by Griesbeck, A. G.; Heinrich,
T.; Oelgemoller, M.; Lex, J.; Molis, A. J. Am. Chem. Soc. 2002, 124, 10972.
9
10666 J. AM. CHEM. SOC. VOL. 125, NO. 35, 2003

Preparation of Cyclic Peptide Mimetics
A R T I C L E S
Table 4. Yields of Photocyclization Reactions of the
Carboxylate-Terminated Substrates Derived from 25-30
(Schemes 7 and 8)
Scheme 10
concd
(mM)
irradiation
time (h)
substrate
product
n
R1
R2
R3
% yield
25
26
27
28
29
30
12.7
12.0
9.5
10.4
8.9
10
1
1
10
10
1
33
34
35
36
37
38
0
0
0
1
2
0
H
35
63
65
20
41
30
Me
Bn
H
H
H
H
H
11.0
Table 5. Yields of Photocyclization Reactions of the
TMS-Terminated 17-24 (Schemes 9)
(Scheme 10) along with minor amounts of the diazocine-trione
48 (unknown benzyl location) and secondary amide 49.
concd
substrate
(mM)
solventa productb
n
R1
R2
R3
R4
R5
% yield
17
18
19
20
21
21
22
23
24
11.5
8.8
6.3
7.4
4.9
4.9
6.4
4.1
3.4
A
A
A
A
A
B
A
B
B
33
35
39
40
41
41
42
43
44
0
0
1
1
2
2
2
3
4
H
Bn
18
60
40
40
47
55
15
70
61
Bn Bn
Me Bn
Bn Bn Bn
Bn Bn Bn
Me Me Bn
To obtain a qualitative evaluation of the relative efficiencies
of photocyclization reactions of the TMS- and carboxylate-
terminated phthalimidopeptides, time versus percent conversion
profiles for photoreactions of 18 and 27 were determined.
Equimolar solutions of these substrates in 35% H2O-MeCN
were irradiated while monitoring the time course for low
conversion disappearance of starting materials by UV spectros-
copy. The results demonstrate the photocyclization reaction of
the carboxylate derivative 27 has a ca. 3-fold greater quantum
efficiency than that of its TMS-substituted analogue 18.
Stereoregular Cyclic Peptide Analogues. The TMS-
terminated glycine-((S)-alanine)n peptides 53-55 were prepared
in order to show that the SET-photocyclization based methodol-
ogy can be used to prepare stereoregular cyclic peptide
analogues. An important feature of photoreactions of these
substrates resides in the fact that a new chiral center is created
at the bicyclic amidol carbon in the products 57-59. Earlier
studies with a wide variety of related phthalimide derived
photoproducts have demonstrated that configurational inversion
at amidol centers of this type, via either reversible N-acyliminum
ion or amido ketone forming pathways, is slow under neutral
conditions.13 As a consequence, stereochemical preferences in
photocyclization reactions of alaninyl peptides 53-55 would
need to be the result of kinetic factors governing the rates of
cyclization of the ultimate biradical intermediates 56 (Scheme
11).
In light of these considerations, it was interesting to find that
irradiation of the peptides 53-54 in 35% H2O-MeCN leads
to modestly efficient formation of the cyclic peptides 57-59,
each as a single diastereomer. X-ray crystallographic analysis
was used to make structural and stereochemical assignments to
these photoproducts (Table 6). As can be seen by viewing the
Chem-3D plots of the atomic coordinates displayed in Figures
1-3, the macrocyclicpeptides formed by cyclization of the
biradical intermediates 56 have different absolute configurations
at the amidol centers (i.e., (R) for 57, (S) for 58, and (S) for
59). To determine if the kinetically preferred diastereomers,
produced by irradiation of the phthalimido-gly-(ala)n sub-
strates 53-54, are also the thermodynamically favored diaster-
eomers, the cyclic peptides were subjected to reaction conditions
Bn Bn Bn Bn
Bn Bn Bn Bn Bn
a Solvents: A, 35% H2O-MeCN; B, MeOH. b Irradiation times: 1 h.
Scheme 8
Scheme 9
1H NMR spectroscopy. In each case, the initial sharp resonances
associated with the products slowly broaden and then become
nondescriptive. In contrast, the corresponding N-alkyl deriva-
tives 34, 35, and 38 are stable substances.
Photoreactions of the TMS-terminated phthalimidoamides and
phthalimidopeptides 17-24 are carried out on 3-11 mM
solutions in either 35% H2O-MeCN or MeOH by using
irradiation with Pyrex glass filtered light at 17 °C for 1-1.5 h
time periods (ca. 90% conversion). Concentration of the crude
photolysates followed by silica gel chromatography affords the
cyclopeptide analogues 33, 35, and 39-44 (Scheme 9) in the
yields given in Table 5.
1H NMR analysis of the concentrated photolysates from the
photoreactions described above in most cases does not reveal
the presence of significant quantities of other identifiable
photoproducts. Exceptions do exist. For example, the desilylated
N-methylamide 45 is formed as a minor product (15%) when
the N-benzyl-N-trimethylsilymethylglycinamide 18 is irradiated
in 35% H2O-MeCN. Also, the secondary amide 46 is isolated
in 25% yield from the photolysate produced by irradiation of
glycinamide 17 in aqueous MeCN. Finally, the nitrophthalim-
idoglycinamide 32 undergoes an efficient and regioselective
photoreaction in aqueous MeCN to form the cyclic product 47
(13) Yoon, U. C.; Kim, D. U.; Lee, C. W.; Choi, Y. S.; Lee, Y.-J.; Ammon, H.
L.; Mariano, P. S. J. Am. Chem. Soc. 1995, 117, 2698.
9
J. AM. CHEM. SOC. VOL. 125, NO. 35, 2003 10667

A R T I C L E S
Yoon et al.
Table 6. X-ray Crystallographic Data for Compounds 40, 41a, 57, 58, and 59
compd
40
41a
57
58
59
formula
fw
C21H23N3O5
397.42
C36H34N4O5‚H2O
620.69
C28H27N3O4
469.53
C38H38N4O5
630.72
C48H49N5O6
862.82
cryst syst
space grp
Z
orthorombic
P212121
4
triclinic
P1h
2
orthorombic
P212121
4
triclinic
P212121
4
orthorombic
P212121
4
a, Å
b, Å
c, Å
R, deg
â, deg
γ, deg
V, Å3
7.469(3)
8.452(4)
31.817(12)
90.00
90.00
90.00
2008.5(15)
293(2)
2614/0/272
1.059
6.6763(14)
15.329(3)
16.572(4)
111.772(6)
97.093(13)
93.043(14)
1553.9(6)
293(2)
10.8635 (12)
13.9599 (17)
15.9849(18)
90.00
90.00
90.00
2424.2(5)
294(2)
4254/0/317
1.158
10.2589(13)
13.3262(12)
24.287(3)
90.00
90.00
90.00
3320.3(6)
293(2)
5830/0/482
1.028
9.8833(5)
24.7789(12)
37.5458(19)
90.00
90.00
90.00
9194.9(8)
100(2)
temp (K)
dat/res/par1
GOF (F2)
4713/0/424
1.064
0.0576, 0.1154
1.127
0.0987,0.2161
b
R1,a wR2
0.1054, 0.1581
0.0646, 0.1182
0.0497, 0.0877
Scheme 11
Figure 2. Chem-3D plot of the X-ray crystallographically determined
atomic coordinates of macrocyclic peptide analogue 58.
Figure 1. Chem-3D plot of the X-ray crystallographically determined
atomic coordinates of macrocyclic peptide analogue 57.
which should promote epimerization at the amidol center via a
reversibly formed N-acyliminum ion. Accordingly, treatment
of 58 with dilute HCl for 12 h at 25 °C results in equilibrium
production of a mixture of 58 and its â-OH epimer in a ratio of
2.4:1, along with nonequilibrium formation of the dehydration
product 60. Under these conditions, 57 does not undergo
epimerization. Finally, it is difficult to monitor the progress of
a similar reaction of the cyclic peptide analogue 59 owing to
the complexity of its 1H NMR spectrum caused by the presence
Figure 3. Chem-3D plot of the X-ray crystallographically determined
atomic coordinates of macrocyclic peptide analogue 59.
of slowly interconverting conformers (see below). The results
suggest that 57 and 58 are the thermodynamically more stable
epimers of the cyclic peptides. If this conclusion is correct, the
factors governing the kinetically controlled, stereochemical
course of cyclization reactions of biradicals 56 are similar to
9
10668 J. AM. CHEM. SOC. VOL. 125, NO. 35, 2003

Preparation of Cyclic Peptide Mimetics
A R T I C L E S
1
Figure 4. Regions (2.2-5.3 ppm) of H NMR spectra of the macrocyclic peptide analogue 39 in (a) CDCl3 and (b) d6-DMSO.
those that influence the thermodynamic stability of the stereo-
isomeric products.
The 1H and 13C NMR spectra of CDCl3 solutions of the cyclic
tripeptides 39, 40, and 59 demonstrate that these substances exist
as two or more slowly interconverting conformers. This is
reflected by the presence of two sets of approximately equal
Assignments of Photoproduct Structures. Structure assign-
ments to the photoproducts generated in the photoreactions
described above are based on a full compliment of spectroscopic
data, internal comparisons of data for related photoproducts,
and, in two cases, the results of X-ray crystallographic analysis
(see above). In most cases, interpretation of the data is
reasonably straightforward. However, issues related to the
regiochemical assignment of the nitrophthalimide derived pho-
toproduct 47 and the structures and conformations of the
macrocyclic peptides 39-44 do require comment. First, distinc-
tion between the regioisomeric photoproducts 47 and 47a that
could be formed by SET-induced photocyclization of nitro-
phthalimide 32 was made on the basis of 1H NMR spectroscopic
analysis. The major distinguishing feature of these substances
resides in the influence of the electron withdrawing nitrocarbonyl
and amide carbonyl groups on the aromatic proton resonances.
In 47, both groups have a combined influence on the 1H NMR
chemical shift of the easily assigned arene proton that has no
vicinal arene proton neighbors. Based on data for closely related,
structurally more simple analogues, this effect should cause the
bis-ortho proton to resonate at ca. 8.4 ppm. In contrast, the
related proton in 47a is ortho to the NO2 group but meta to the
amide carbonyl. Consequently, it is expected to appear at ca.
7.8 ppm. Thus, the observed chemical shift of 8.45 ppm for
this proton is consistent with the assignment of structure 47 to
this photoproduct.
1
intensity resonances in the H NMR spectrum of 39, which
indicates a ca. 1:1 mixture of conformers (Figure 4a). The
situation changes when the NMR solvent is d6-DMSO (Figure
4b). In this case, the cyclic peptide exists either as a rapidly
interconverting mixture of two conformers or as one conformer
nearly exclusively. In a similar manner, the 1H NMR spectrum
of 59 also simplifies when the solvent is changed to d6-DMSO.
Additional information about the variable conformational prefer-
ences in the macrocyclic peptides 39-44 arises from the
observation that the cyclic tetrapeptide 41 can be isolated in
two different, conformationally stable forms, 41a (mp 155-
158 °C) and 41b (mp 163-166 °C).
Although these observations are consistent with the expected
conformational properties of large ring tertiary polyamides, they
cloud the unambiguous structural assignments of these photo-
products. Thus, to gain a higher level of confidence for these
assignments, X-ray crystallographic analyses were performed
on photoproducts 40 and 41a (Table 6). As seen by viewing
the Chem 3D plots of X-ray crystallographically derived atomic
coordinates, shown in Figures 5 and 6, both substances possess
the expected cyclic peptide structures. Interestingly, in contrast
to the crystal structure of 40, in which the two ring amide groups
have cis stereochemistry, that of the cyclic tetrapeptide 41a has
two of its three ring amide groups with trans stereochemistry.
9
J. AM. CHEM. SOC. VOL. 125, NO. 35, 2003 10669

A R T I C L E S
Yoon et al.
Scheme 12
than other typical excited state reaction modes (e.g., H-atom
abstraction).14 In addition, the efficiencies of these processes
are not significantly affected by the length of the ploypeptide
chain separating the centers at which bonding occurs. This result
indicates that, following the initial SET event, migration of the
radical cation center (hole migration) to the position in the
peptide chain where the reactive electrofugal group (TMS or
CO2) is located takes place at a rate which is competitive with
both back electron transfer (leading to the ground-state reactant)
and proton loss from benzylic sites in intervening cation
radicals.15 Furthermore, the apparent chain length independence
of the efficiencies of these processes suggests that the rates of
the biradical cyclization reactions that serve as ultimate
mechanistic steps in the reaction sequences are not significantly
influenced by entropy.16 It is tempting to propose a universal
explanation for this phenomenon, which invokes the interme-
diacy of conformationally preorganized biradicals as precursors
of the cyclic products in intramolecular SET-promoted cycliza-
tion reactions. A unique feature of cyclization reactions of linked
donor-acceptor systems, promoted in this manner, is that the
final neutral biradical intermediates arise by fragmentation
reactions of zwitterionic biradicals. The electronic nature of the
zwitterionic biradicals could cause them to exist in folded
conformations 61 that minimize the distance between the
oppositely charged centers (Scheme 13). Thus, if the rates of
ion radical fragmentation and biradical coupling are in the range
of those for complete conformational randomization, the cy-
clization processes would not be as entropically disfavored as
conventional non-SET promoted cyclization reactions.
Figure 5. Chem-3D plot of the X-ray crystallographically determined
atomic coordinates of macrocyclic peptide analogue 40.
Figure 6. Chem-3D plot of the X-ray crystallographically determined
atomic coordinates of macrocyclic peptide analogue 41a.
Discussion
The results of the investigation described above demonstrate
the feasibility of the photochemical based strategy for prepara-
tion of cyclic peptide analogues. The key step in routes, which
follow this design, involves SET-photoinduced cyclization of
N-acceptor-linked peptides that contain C-terminal R-amido-
trimethylsilyl or R-amidocarboxylate groups. Photomacrocy-
clization reactions of the phthalimide-linked peptides take place
by a sequence of events (Scheme 12) involving (1) intramo-
lecular SET from near neighbor amide donor sites to the excited
phthalimide chromophore, (2) amide cation radical migration
to the R-amidosilane or R-amidocarboxylate centers, (3) desi-
lylation or decarboxylation to form 1,ω-biradical intermediates,
and (4) biradical cyclization.
Another interesting feature of observations made in this
investigation relates to the relative efficiencies of photoinduced
cyclization reactions of trimethylsilyl- and carboxylate-termi-
nated phthalimidopeptides. The finding that photocyclization
of the carboxylate-terminated phthalimidoglycinamide 27 has
a ca. 3-fold higher quantum efficiency than that of the similarly
(14) For a recent comprehensive review, see: Coyle, J. D. In Synthetic Organic
Photochemistry; Horspool, W. M., Ed.; Plenum: New York, 1984; p 259.
(15) (a) For hole transfer through small peptides, see for example: Isied, S. S.;
Moreira, I.; Ogawa, M. Y.; Vassilian, B. A.; Sun, J. J. Photochem.
Photobiol., A 1994, 82, 203. Defelippis, M. R.; Faraggi, M.; Klapper, M.
H. J. Am. Chem. Soc. 1990, 112, 5640. (b) For hole transfer through
proteins, see for example: Gray, H. B.; Winkler, J. R. Annu. ReV. Biochem.
1996, 65, 537. Symons, M. C. R. Free Radical Biol. Med. 1997, 22, 1271.
(16) Kanaoka, Y. Acc. Chem. Res. 1978, 11, 407. Machida, M.; Takechi, H.;
Kanaoka, Y. Synthesis 1982, 1078. Coyle, J. D.; Newport, G. L. Synthesis
1979, 381-382. Sato, Y.; Nakai, H.; Ogiwara, H.; Mizoguchi, T.; Migita,
Y.; Kanaoka, Y. Tetrahedron Lett. 1973, 4565.
The modestly high yields observed for photocyclization
reactions of substrates, which have a phthalimide acceptor group,
suggest that SET from amide donor sites in the peptide chains
to the excited phthalimide chromophore occurs more rapidly
9
10670 J. AM. CHEM. SOC. VOL. 125, NO. 35, 2003

Preparation of Cyclic Peptide Mimetics
A R T I C L E S
Scheme 13. Schematic for Conformational Control of
SET-Promoted Photocyclization Reactions of Linked
Acceptor-Donor Systems
Scheme 15
Scheme 14
One of the more unusal observations made in this study is
that the cyclic peptide analogues 33, 36, and 37, formed by
photocyclization reactions of the secondary amide containing
amide 25 and peptides 28 and 29, are highly unstable substances.
The short lifetimes of these substances appear to be associated
with polymerization reactions that result in the production of
insoluble oligomers. Clearly, this instability is not merely the
consequence of the presence of secondary amide centers since
a wide variety of stable NH-amide containing cyclic peptides
have been prepared and characterized previously. A possible
reason for the unique of instability of 33, 36, and 37 arises from
a consideration of the consequences of reversible amidol forming
reactions that are open to these substances. Accordingly, amidol
63 to amido ketone 64 conversion (Scheme 15) could be
followed by intermolecular amidol forming reactions of 64
leading to eventual formation of oligomers.
Although the studies carried out thus far have shown that
the SET-photocyclization based strategies for cyclic peptide
analogue synthesis is viable, further efforts are required to probe
the generality and uncover the potential limitations of this
methodology. Our continuing studies in this area are designed
to further explore these features. Special attention will be given
to photoreactions of TMS-terminated peptides that have other
photoreactive acceptor groups and those that have the capability
of producing branched and diversely functionalized cyclopeptide
products.
structured TMS analogue 18 is fully consistent with the relative
rates of amide cation radical R-desilylation versus R-decar-
boxylation (Table 1).11b Despite this difference, the chemical
yields of these processes are nearly identical (65% and 60%,
respectively). Thus, the lower quantum efficiency for reaction
of the TMS-substrate 18 must be a consequence of a lower ratio
of the rate of zwitterionic biradical desilylation versus quenching
by back electron transfer and not due to the intervention of
competing, yield diminishing photochemical processes which
generate side products.
This observation has a potentially important consequence on
the design of photochemical based sequences for the preparation
of complex cyclic peptide analogues. It is well-known that
carboxylate groups, even when they are not located adjacent to
amine and amide centers, participate as donors in photoinduced
SET reactions with a variety of acceptors (e.g., phthalimides,17
iminium salts18). As a result, photocyclization reactions of
carboxylate-terminated, acceptor-linked polypeptides, which also
contain other carboxylate centers (aspartate, glutamate), could
be complicated by the intervention of competitive photoreac-
tions. From this perspective, the use of TMS-terminated
substrates (62, Scheme 14) might be more desirable in that it
would avoid the need for selective carboxylate protection
schemes. Thus, irradiation of substrates of this type in low pH
solutions, where aspartate and glutamate side chains exist in
the acid form, should bring about selective conversion to the
cyclic peptide products arising by sequential SET-desilylation-
biradical cyclization routes.
Acknowledgment. We dedicate this publication to the
memory of Gary A. Epling, an outstanding teacher and sensitive
person who served as the doctoral mentor of U.C.Y. and
graduate student colleague of P.S.M.. U.C.Y. acknowledges the
financial support provided by the Korea Science and Engineering
Foundation through the program of International Cooperative
Research (2002-5-123-01-2). P.S.M. acknowledges the financial
support provided by the NSF (CHE-0130943 and INT-0121510).
(17) Griesbeck, A. G.; Henz, A.; Peters, K.; Peters, E. M.; von Schering, H. G.
Angew. Chem., Int. Ed. Engl. 1995, 34, 474.
(18) (a) Kurauchi, Y.; Ohga, K.; Nobuhara, H.; Morita, S. Bull. Chem. Soc.
Jpn. 1985, 58, 2711. (b) Kawanisi, M.; Nozaki, H. Tetrahedron 1969, 25,
1125.
(19) Sheehan, J. C.; Frank, V. R. J. Am. Chem. Soc. 1950, 72, 1312.
(20) The preparation of this substance has been reported on several occasions:
Ando, Y; Takemura, S.; Tokunaga, T.; Kurozumi, M. Kinki Daigaku
Yakugakubu Kiyo 1963, 4, 45. Smirnova, N. V.; Skoldinov, A. P. Zh. Org.
Khim. 1966, 2, 1269. Bartoschek, A.; Griesbeck, A. G.; Oelgemoller, M.
J. Inf. Rec. 2000, 25, 119.
Supporting Information Available: Contained in this infor-
mation are all experimental procedures, 1H and 13C NMR spectra
for all previously uncharacterized compounds which were
prepared in this study, and X-ray crystallographic data for 40,
41a, 57, 58, and 59. This material is available free of charge
via the Internet at http://pubs.acs.org.
(21) Chrisment, J.; Delpuech, J. J.; Rajerison, W.; Selve, C. Tetrahedron 1986,
42, 4743. Scapira, C. B.; Abasolo, M. I.; Perillo, I. A. J. Heterocycl. Chem.
1985, 22, 577.
JA030297B
9
J. AM. CHEM. SOC. VOL. 125, NO. 35, 2003 10671