Solid-phase synthesis of asymmetrically substituted "AB 3-Type" phthalocyanines

Article abstract of DOI:10.1021/jo800536v

(Chemical Equation Presented) Synthesis of phthalocyanines with asymmetrical substitution on the periphery is often difficult due the problems in purification of the phthalocyanine mixtures obtained. Using a poly(ethylene glycol) (PEG)-based support with

Full text of DOI:10.1021/jo800536v

Solid-Phase Synthesis of Asymmetrically Substituted “AB3-Type”
Phthalocyanines
S. Sibel Erdem, Irina V. Nesterova, Steven A. Soper, and Robert P. Hammer*
Department of Chemistry, Louisiana State UniVersity, Baton Rouge, Louisiana 70803
rphammer@lsu.edu
ReceiVed March 8, 2008
Synthesis of phthalocyanines with asymmetrical substitution on the periphery is often difficult due the
problems in purification of the phthalocyanine mixtures obtained. Using a poly(ethylene glycol) (PEG)-
based support with a Wang-type linker, we have developed the synthesis of monohydroxylated,
oligoethylene glycol substituted phthalocyanines utilizing an amidine-base-promoted phthalonitrile
tetramerization reaction. The use of a hydrophilic support allows symmetrical phthalocyanine product
formed in solution to be readily and completely removed by washing while leaving the “AB3” product
on the support. Acid cleavage with 10% trifluoroacetic acid provides the pure unsymmetrically substituted
Pc. This method was applied to several metallo Pcs. Additionally, methods to avoid premature reactions
on-resin that give A2B2 products are provided.
Introduction
labeling Pcs may also be useful in a number of bioanalytical
detection strategies utilizing time-resolved or resonance energy
transfer techniques.9–11
Phthalocyanines (Pcs) absorb and emit light in the far-red
and near-infrared, which make them important as dyes for
photographic and printing applications and as materials for light
harvesting in photovoltaic devices.1 Pcs, derivatives of the
aromatic tetra-azaporphyrins, have large extinction coefficients,
are generally chemically and photochemically robust, and thus
are useful for a variety of applications in materials and biology.2
For a number of uses, Pcs with two or more different
substituents on the exterior of the ring system would be
advantageous. For example, asymmetrically substituted Pcs with
one group for use in covalent labeling, while the other peripheral
groups improve the solubility in aqueous solution and would
be useful dyes for near-infrared fluorescent tagging of bio-
molecules.3–7 An advantage of Pcs over other common dye
classes is that their photophysical properties are readily altered
by changing the substitution pattern or the metal guest of the
Pc. For example, Zn, Si, and Al metallo-Pcs are strongly
fluorescent, while Ru(II)Pcs are phosphorescent,8 and Cu(II)-Pcs
do not have significant luminescence.2 Thus, water-soluble,
Synthesis of Pcs with asymmetrical substitution on the
periphery is most commonly performed by a statistical con-
densation of two different phthalonitriles, diiminoisoindoles, or
related derivatives, which theoretically yields a mixture of six
(3) Nesterova, I. V.; Verdree, V. T.; Pakhomov, S.; Strickler, K. L.; Allen,
M. W.; Hammer, R. P.; Soper, S. A. Bioconjugate Chem. 2007, 18, 2159–2168.
(4) Peng, X.; Draney, D. R.; Volcheck, W. M.; Bashford, G. R.; Lamb, D. T.;
Grone, D. L.; Zhang, Y.; Johnson, C. M. In Proc. SPIE: Optical Molecular
Probes for Biomedical Applications; Achilefu, S. I., Bornhop, D. J., Raghavachari,
R. Eds.; SPIE: 2006; Vol. 6097, DOI: 10.1117/1112.669173.
(5) Schultz, D. R.; Lin, T. M.; Dandliker, W.; He, F.; Botz, E.; LaGattuta,
P.; Arnold, P. I. Bull. Mar. Sci. 1998, 62, 887–896.
(6) Walker, G. T.; Nadeau, J. G.; Linn, C. P.; Devlin, R. F.; Dandliker, W. B.
Clin. Chem. 1996, 42, 9–13.
(7) Devlin, R.; Studholme, R. M.; Dandliker, W. D.; Blumeyer, K.; Ghosh,
S. S. Clin. Chem. 1993, 39, 2343–2343.
(8) Guez, D.; Markovitsi, D.; Sommerauer, M.; Hanack, M. Chem. Phys.
Lett. 1996, 249, 309–313.
(9) Giepmans, B. N. G.; Adams, S. R.; Ellisman, M. H.; Tsien, R. Y. Science
2006, 312, 217–224.
(10) Jares-Erijman, E. A.; Jovin, T. M. Nat. Biotechnol. 2003, 21, 1387–
1395.
(1) Dini, D.; Hanack, M. J. Porphyrins Phthalocyanines 2004, 8, 915–933.
(2) Verdree, V. T.; Pakhomov, S.; Su, G.; Allen, M. W.; Countryman, A. C.;
Hammer, R. P.; Soper, S. A. J. Fluoresc. 2007, 17, 547–563.
(11) Zhu, L.; Stryjewski, W.; Lassiter, S.; Soper, S. A. Anal. Chem. 2003,
75, 2280–2291.
10.1021/jo800536v CCC: $40.75
Published on Web 05/30/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5003–5007 5003

Erdem et al.
SCHEME 1. Statistical Condensation Method
SCHEME 2. Solid-Phase Synthesis Method
Pc congeners (Scheme 1).12 Isolation of the desired “3 + 1” Pc
product, here referred to as AB3 (or A3B), is often laborious
due to difficulty in separating chemically similar species out of
the Pc mixtures obtained.
To date, several chemoselective techniques for asymmetric
Pc synthesis have been described in the literature including the
subphthalocyanine (subPc) route13 and solid-phase synthesis.14–16
The subPc route is a well-known method for the synthesis of
AB3 type of Pcs, though it is only applicable to certain
phthalonitrile precursors. For example, the condensation of a
diiminoisoindoline having electron-donating groups and an
unsubstituted subPc or one with electron-withdrawing groups
promotes the selective synthesis of AB3-type Pcs. Contrastingly,
the presence of electron-donating substitutents on the subPc
leads to a mixture of Pcs through a scrambling process that
results from disassembly of the subPc under the reaction
conditions to form the Pc.17–19
Solid-phase synthesis of AB3-type asymmetric Pcs is as yet
an underutilized method. Leznoff and co-workers’ solid-phase
synthesis of AB3-type asymmetrically substituted Pcs using a
polystyrene resin support is touted as the first synthesis of pure
asymmetric Pcs.14,15 Solid-phase synthesis of Pcs starts with
one of the phthalonitrile precursors (Scheme 2) attached to the
support via a cleavable linker. Reaction of the solid-supported
phthalonitrile with an excess of phthalonitrile B in solution
produces the AB3-type, asymmetrically substituted Pc on the
solid support while the B4-type symmetrical Pc forms in
solution. Symmetrical Pc is removed by washing and subsequent
cleavage of the linkage of “A” from the resin yields the pure
AB3-type Pc (Scheme 2). Such a strategy has also been utilized
in the polymer-supported synthesis of monofunctionalized meso-
tetraarylporphyrins as developed by Borhan and co-workers.20
One of the challenges of the method of Leznoff is the
requirement for extensive washing via Soxhlet extraction to
remove symmetrical B4 Pc from the hydrophobic polystyrene
resin. Additionally, Soxhlet extraction is required to fully remove
the cleaved asymmetrical AB3 Pc from the polymer support.
For example, Leznoff reports15 that 4-5 days of Soxhlet
extraction are required to isolate pure asymmetrical Pc. The
challenge of removing the symmetrical Pc product was dem-
onstrated in a later paper by Leznoff16 that reported the failure
of even extensive Soxhlet extraction to completely remove the
symmetrical Pc from the resin. This resulted in a contaminated
“AB3” product after cleavage from the support that required
additional chromatographic purification to obtain pure asym-
metrically substituted Pc.
Here we describe the solid-phase synthesis of AB3 type
asymmetrically substituted Pcs utilizing a polyethylene glycol
(PEG)-based support. In a desire to provide a scalable and rapid
synthesis of asymmetrically substituted Pcs, we hypothesized
that a more hydrophilic resin would reduce nonspecific adsorp-
tion of Pc products on the solid support. Thus, we utilized a
hydrophilic, poly(ethylene glycol) (PEG) resin in place of the
more traditional polystyrene support. Using a Wang-type linker,
we have developed the synthesis of monohydroxylated, oligo-
(12) Ng, A. C. H.; Li, X. Y.; Ng, D. K. P. Macromolecules 1999, 32, 5292–
5298.
(13) Kobayashi, N.; Kondo, R.; Nakajima, S.; Osa, T. J. Am. Chem. Soc.
1990, 112, 9640–9641.
(14) Leznoff, C. C.; Hall, T. W. Tetrahedron Lett. 1982, 23, 3023–3026.
(15) Hall, T. W.; Greenberg, S.; McArthur, C. R.; Khouw, B.; Leznoff, C. C.
New J. Chem. 1982, 6, 653–658.
(16) Leznoff, C. C.; Svirskaya, P. I.; Khouw, B.; Cerny, R. L.; Seymour, P.;
Lever, A. B. P. J. Org. Chem. 1991, 56, 82–90.
(17) Sastre, A.; delRey, B.; Torres, T. J. Org. Chem. 1996, 61, 8591–8597.
(18) Sastre, A.; Torres, T.; Hanack, M. Tetrahedron Lett. 1995, 36, 8501–
8504.
(19) Weitemeyer, A.; Kliesch, H.; Wohrle, D. J. Org. Chem. 1995, 60, 4900–
4904.
(20) Yang, Q. F.; Streb, K. K.; Borhan, B. Tetrahedron Lett. 2005, 46, 6737–
6740.
5004 J. Org. Chem. Vol. 73, No. 13, 2008

Solid-Phase Synthesis of “AB3-Type” Phthalocyanines
SCHEME 3. Activation of Wang Resin for Attachment of Phthalonitrile via an Ether Linkage
SCHEME 4. Solid-Phase Synthesis of Oligo(ethylene
glycol)-Substituted Pcs
ethylene glycol substituted Pcs utilizing an amidine-base
promoted, solid-supported phthalonitrile tetramerization reaction.
The use of the hydrophilic support allows symmetrical Pc
product formed in solution to be readily and completely removed
by washing, while retaining the AB3 product on the support.
Results and Discussion
Wang-ChemMatrix resin was chosen as the point of attach-
ment for a hydroxy-functionalized phthalonitrile to the solid
support since the benzyl ether linkage would be stable to the
basic reaction conditions for Pc formation. We chose this system
of almost symmetrical oligo(ethylene glycol)-substituted Pcs as
a demonstration of the method as it would be nearly impossible
to separate mixtures of congeners of such similar Pcs by
chromatographic or other methods. The Wang linker was
activated by tricholoroacetonitrile, and the resulting trichloro-
acetimidate resin21 1 was treated with an excess of hydroxy-
functionalized phthalonitrile 2, synthesized from commercially
available 4-nitrophthalonitrile and diethylene glycol,12 to give
resin-bound
phthalo-
nitrile 3 in high yield with a loading capacity of 0.54 mmol/g
(90% yield based on starting loading capacity of the Wang resin,
0.6 mmol/g) (Scheme 3). As further evidence for the integrity
of the reaction, FT-IR shows the disappearance of the acetimi-
date NH band at 3055 cm-1 of resin 1 and the appearance of a
Ct N band at 2229 cm-1 of polymer-bound phthalonitrile 3.
Phthalonitrile 4 was synthesized from commercially available
4-nitrophthalonitrile and triethylene glycol monomethyl ether
in 74% yield.12 Condensation of resin-bound phthalonitrile 3
with phthalonitrile 4 in solution in the presence of Zn(OAc)2
and DBU in refluxing BuOH for 24 h produced a mixture of
resin-bound AB3 Pc and the corresponding symmetrically
substituted Pc 5 in solution (Scheme 4). The resin was washed
with hot BuOH and CH2Cl2 until a colorless filtrate was
collected. The absorbance spectrum of each successive wash
solution showed decreasing absorbance. Dramatic decrease of
the absorbance was observed after the first two washes indicating
the most of the Pc 5 was washed away by the first BuOH and
CH2Cl2 washes (typical washing times, 3-5 h).
the highest cleavage yield (as judged by absorbance of the
washes) without loss of the metal from the Pc core and thus
was selected as the standard cleavage cocktail.22
Analysis of the crude cleavage solution showed that none of
the symmetrical B4 product was present, but that the desired
AB3 Pc was accompanied by a significant amount (∼20%,
MALDI-MS) of the A2B2 Pc. This may have been due to
increased rate of intraresin reactions23,24 due to the relatively
high loading of the resin (0.54 mmol/g). That is, reactions
between phthalonitrile active sites on the resin 3 are similar in
rate to reactions between activated phthalonitrile species in
solution and resin-bound phthalonitriles, thus producing the
undesired A2B2 Pc. In order to overcome this problem, we
reduced the loading of the resin (Scheme 3) by reaction of
trichloroacetimidate resin (1) with only 1.2 equiv of hydroxy-
phthalonitrile 2 followed by capping of the remaining amidate
sites with an excess of MeOH to give a phthalonitrile resin 3 at
a loading of 0.28 mmol/g. Resin-bound phthalonitrile 3 was
reacted as before with an excess of 4 in the presence of
Zn(OAc)2. Following the removal of symmetrical 5a by
washing, the desired Pc was cleaved from the polymer support.
Polymer-bound p-alkoxybenzyl ethers can be cleaved in
1-10% TFA in CH2Cl2 solution.21 High concentrations of TFA
(>70%) resulted in decomposition of Pc as well as removal of
the metal from the Pc core. Cleavage conditions were optimized
by monitoring the absorbance of the cleavage cocktail at 1%,
5%, and 10% TFA in CH2Cl2. 10% TFA in CH2Cl2 resulted in
(22) Later experiments showed that addition of scavengers such as triiso-
propylsilane to the cleavage cocktail or increased TFA concentrations as high
as 20% do not degrade the Pc product purity.
(23) Regen, S. L.; Lee, D. P. Macromolecules 1977, 10, 1418–1419.
(21) Hanessian, S.; Xie, F. Tetrahedron Lett. 1998, 39, 733–736.
(24) Jayalekshmy, P.; Mazur, S. J. Am. Chem. Soc. 1976, 98, 6710–6711.
J. Org. Chem. Vol. 73, No. 13, 2008 5005

Erdem et al.
TABLE 1. Oligoethylene Glycol Substituted Pc
compd no.a metal salt
Pc
yieldb (%) solvent λmax (abs) (nm) log ε (cm-1 M-1
)
λ
max(em) (nm)c
φfc
ssymmetric Pcs (AB3)
symmetric Pcs (B4)
6a
6b
6c
6d
5a
5b
5c
5d
5e
Zn(OAc)2 ZnPc
12
13
11
16
21
15
17
18
20
DMSO
DMSO
THF
DMSO
DMSO
DMSO
THF
680
681
671
646, 676,706
681
681
671
676, 706
682
4.9
4.8
4.3
3.4, 3.5, 3.4
5.5
5.1
5.1
3.5, 3.5
5.5
690
n.d.
678
709
691
n.d.
678
709
691
0.15
n.d.
0.0003
0.08
0.15
n.d.
0.0038
0.06
0.31
CuBr2
NiCl2
MgCl2
CuPc
NiPc
H2Pc
Zn(OAc)2 ZnPc
CuBr2
NiCl2
CuPc
NiPc
H2Pc
MgPc
DMSO
DMSO
MgCl2
a Asymmetrical Pcs 6 were purfied by filtration through silica gel, except for 6b and 6d which were purified by Sephadex LH-20 chromatography.
b Yields of asymmetrically substituted Pcs were calculated based on the loading of the phthalonitrile on the support. c Fluorescence spectra and quantum
yield determinations were done using 605 nm excitation wavelength for 6a, 6c, 6d, 5a, 607 nm for 5c and 5e, and 615 nm for 5d. CuPcs 5b and 6b did
not show any detectable fluorescence, which is noted in the table as “n.d.”. Fluorescence quantum yield measurements for all Pcs were done using
methylene blue as a standard at absorbance 0.04 - 0.05 for both Pc and standard solutions to avoid any error due to inner-filter effect.26
0.15, which is in the range of the reported quantum yields of
tetrasubstituted ZnPcs.25
To synthesize the metal-free Pc (5d, 6d), the same strategy
was employed except without any metal ion. But in this case,
cleavage of metal-free Pc resin yielded two products, the AB3
metal-free Pc (6d) and an A2B2 H2Pc in 3:2 molar ratio. As an
alterative route to the asymmetrical H2Pc, Mg2+ ion was utilized
to template the tetramerization, as it is known that the acidity
of the cleavage cocktail is sufficient for the removal of Mg from
the Pc core to yield metal free Pc. Thus, condensation of 3 with
4 in the presence of MgCl2 (Scheme 4) gave, following the
cleavage, AB3 H2Pc 6d without any contamination by the A2B2
product in 17% yield.
From the results of the synthesis of the metal-free Pc 6d, it
is clear that the metal ion plays a crucial role in the tetramer-
ization process. Adding divalent metal ion improves the site-
FIGURE 1. Absorbance and emission spectra of 6a.
isolation of the reactive groups in the resin matrix. As argued
by Jayalekshmy and Mazur, this improved “pseudodilution”24
The crude mixture was filtered through a silica gel column to
of sites is a kinetic phenomena since we know that phthalonitrile
remove low molecular weight impurities to give Zn-Pc 6a in
cyclotetramerization is faster in the presence of metal ion. We
12% yield (based on 0.28 mmol/g loading capacity) without
propose a pathway that accounts for this pseudodilution in the
contamination from the A2B2 Pc product (Scheme 4). Reducing
presence of metal ion, which follows from the proposed
the loading capacity resulted in the pure AB3 type Pc, but the
mechanism of DBU-promoted phthalonitrile tetramerization in
overall yield, based on the initial loading of the phthalonitrile,
alcohol.27 That is, metal chelated isoindolines (or other similar
was not reduced. All the symmetric Pc products 5were recovered
and purified by precipitation of a MeOH solution into ether.
Asymmetrical Pcs 6were purified by filtration through silica gel
column, except for 6b and 6d which were purified by Sephadex
phthalonitrile derived precursors) present in solution react faster
with resin-bound phthalonitriles than the resin-bound phtha-
lonitriles can react with themselves, resulting in only AB3
products. In the absence of metal, the reaction of resin-bound
LH-20 chromatography. We have found that LH-20 is the
phthalonitriles with solution intermediates is slowed so that
preferred method of purification as there is less nonspecific
resin-bound intermediates have a longer time to find a proximate
adsorption of Pcs to the LH-20 matrix and results in improved
Pc recovery.
resin-bound phthalonitrile with which to react, thus giving rise
to a significant fraction of A2B2 H2Pc products (Scheme 5).
Solid-phase synthesis is a fundamental methodology in
organic synthesis, and it has been utilized for preparation of
The same synthetic route to 6a was applied to synthesize Cu,
Ni, and metal-free Pcs. Condensation of 4with 3 in the presence
of CuBr2 and DBU in refluxing BuOH for 24 h gave a dark
myriad different molecular classes and cyclization reaction types.
Since the development of solid-phase synthesis28 related
phenomena such as intrasite interaction and site isolation have
been extensively studied. It has been shown that the outcome
of a reaction on solid support is significantly influenced from
intrasite reactions, which can be diminished by altering the
loading or the cross-linked density of the polymer, changing
blue solution and resin (Scheme 4). Following purification, 6b
was obtained in 13% yield (Table 1). In the case of Ni Pcs (5c,
6c) NiCl2 was employed as a metal source. Due to the low
solubility of NiCl2 in BuOH, the reaction was carried out at
higher temperature and Ni-Pc 6c was purified by filtration
through a silica gel column in 11% yield (Table 1). All Pcs
prepared in this work were characterized by absorbance and
fluorescence spectroscopy, HPLC, and mass spectrometry.
Figure one shows example spectra of ZnPc 6a that had a sharp
Q-band at 680 nm in the absorbance spectrum and band at 690
nm (Figure 1), which are typical for these kinds of chromo-
phores. Fluorescence quantum yield of 6a was calculated as
(25) Ogunsipe, A.; Chen, J. Y.; Nyokong, T. New J. Chem. 2004, 28, 822–
827.
(26) Fery-Forgues, S.; Lavabre, D. J. Chem. Educ. 1999, 76, 1260–1264.
(27) Montfortz, F. P. In The Porphyrin Handbook; Kadish, K. M., Smith,
K. M., Guilard, G. Eds.; Academic Press: New York, 2003; Vol. 19, p 105.
(28) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149–2154.
5006 J. Org. Chem. Vol. 73, No. 13, 2008

Solid-Phase Synthesis of “AB3-Type” Phthalocyanines
SCHEME 5. Formation of A2B2 Pcs in Solid Support
coproducts by washing of the resin as well as to prevent
noncovalent adsorption of the desired AB3 Pc to the support.
Site-isolation on the PEG-based resin can be accomplished using
slightly lower loadings and by inclusion of a divalent metal ion
in alkoxide-promoted phthalonitrile tetramerization.
The method described here provides pure asymmetrically
substituted Pcs is very efficient, taking <3 days to complete
including loading, Pc formation, washings, cleavage, and simple
chromatography. Using alternative solid-support linking strate-
gies and Pc synthesis conditions, this time-effective method is
now being applied to the synthesis of functionalized asym-
metrically substituted Pcs with a variety of physical and spectral
properties.
Experimental Section
General Procedure for Synthesis of Pc (5 and 6). Resin 3 (0.6
g) was swelled in anhydrous BuOH (15 mL) overnight. A 9-fold
molar excess of phthalonitrile 4(3.24 mmol, 0.94 g) and metal salt
(0.9 mmol) were dissolved in anhydrous BuOH (7 mL) and added
to well swelled resin under Ar. Concentration of phthalonitrile in
the reaction mixture was kept around 0.16 M. The mixture was
heated up to 90 °C and DBU (1.8 mmol, 0.27 mL) was added to
mixture. The reaction was carried out at 110 °C for 24 h. The resin
was washed until a colorless filtrate was obtained, first with hot
BuOH (10 × 25 mL), CH2Cl2 (5 × 25 mL), and then BuOH/CH2Cl2
(1:1) (3 × 25 mL) and CH2Cl2 (2 × 25 mL).
the structure of the linker, increasing the concentration of
incoming reagent, or changing the solvent and reaction tem-
perature.29 While intrasite interaction generally leads to unde-
sired products, it can be utilized for selective synthesis of
dimeric cross-linked molecules. Schreiber et al. showed the
synthesis of homodimeric molecules via intrasite olefin cross-
metathesis on solid support using highly loaded (1-2 mmol/g)
and lightly cross-linked (1% DVB) polystryene resin with the
goal of split-pool synthesis of homodimer libraries.30 Thus, it
may be possible through optimization of resin, solvent, and other
reaction conditions to prepare “2 + 2” (A2B2) Pc products as
the predominant or only product, which may unique applications
as well.
General Procedure for Cleavage of the AB-Type Pc (6). The
resin was suspended into a solution of TFA/CH2Cl2 (1:9) (50 mL)
and shaken for 3 h at room temperature. The filtrate was evaporated
to dryness, and the crude mixture was purified by filtration through
a silica gel or LH-20 column.
General Procedure for Purification of Symmetrical Pcs
(5). Filtrate solutions were combined and evaporated to dryness.
A portion (100 mg) of the crude mixture was dissolved in ∼3 mL
of CH3OH, and 50 mL of diethyl ether was added to solution.
Solution was left at -20 °C overnight, and the suspension was
centrifuged to give Pc 5 as a blue-green solid.
Determination of the Loading Capacity of Resin 3. Resin 3(0.5
g) was suspended into a solution of TFA/CH2Cl2 (1:9) (50 mL)
and left in the shaker for 3 h. at room temperature. Filtrate was
evaporated to dryness and the product was filtered through a pad
of silica gel with EtOAc as the eluent.
Conclusion
The advantage of the solid-phase method described here is
the ability to synthesize a variety of asymmetrical phthalocya-
nines quickly and easily without the need for extensive
purification steps to get homogeneous Pc products. The method
is a significant advancement of previous solid-phase synthesis
of Pcs and applicable to Pcs with wide variety of substituents.
The use of hydrophilic PEG-based resin is key for the success
of this method to allow easy removal of symmetrical Pc
Acknowledgment. We thank the National Science Founda-
tion (CHE-0304833, EPS-0346411) and the National Institutes
of Health (EB006639 and HG01499) for financial support and
Ms. Brooke Delhomme for technical assistance.
Supporting Information Available: Experimental proce-
dures, spectroscopic data, and HPLC for 1-6e. This material
is available free of charge via the Internet at http://pubs.acs.org.
(29) Shi, R. R.; Wang, F.; Yan, B. Int. J. Pept. Res. Ther. 2007, 13, 213–
219.
(30) Blackwell, H. E.; Clemons, P. A.; Schreiber, S. L. Org. Lett. 2001, 3,
1592–1592.
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