New cyclic peptides via ring-closing metathesis reactions and their anti-bacterial activities

Article abstract of DOI:10.1016/j.tet.2008.09.031

As part of a program investigating cyclic peptides with an internal aromatic hydrophobic scaffold as potential novel anti-bacterial agents, we explored the synthesis of simple tyrosine-based systems. These were prepared via key intermediates containing internal allylglycine and allyltyrosine residues for subsequent ring-closing metathesis reactions. Although the resulting anti-bacterial activity against Staphylococcus aureus was modest, this represents a novel and simple route to this class of compounds. One intermediate acyclic dipeptide precursor showed good activity against S. aureus with an MIC of 7.8 μg/mL. Crown Copyright

Full text of DOI:10.1016/j.tet.2008.09.031

Tetrahedron 64 (2008) 11270–11290
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New cyclic peptides via ring-closing metathesis reactions
and their anti-bacterial activities
,
b
b
a,
*
Timothy P. Boyle a, John B. Bremner a , Jonathan Coates , John Deadman , Paul A. Keller
,
*
,
b
,
y
Stephen G. Pyne a , David I. Rhodes
*
a School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
b Avexa Ltd, 576 Swan Street, Richmond, VIC 3121, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 May 2008
Received in revised form 27 August 2008
Accepted 11 September 2008
Available online 20 September 2008
As part of a program investigating cyclic peptides with an internal aromatic hydrophobic scaffold as
potential novel anti-bacterial agents, we explored the synthesis of simple tyrosine-based systems. These
were prepared via key intermediates containing internal allylglycine and allyltyrosine residues for
subsequent ring-closing metathesis reactions. Although the resulting anti-bacterial activity against
Staphylococcus aureus was modest, this represents a novel and simple route to this class of compounds.
One intermediate acyclic dipeptide precursor showed good activity against S. aureus with an MIC of
7.8 mg/mL.
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
1. Introduction
hydrophobic scaffold based on a phenyl unit, exemplified by the
cyclic tripeptide 4, together with acyclic peptide precursors of this
system.
The need for new, novel anti-bacterial agents is becoming in-
creasingly important with the escalating number of cases of multi-
drug resistant bacterial infections being reported.1,2 A number of
compounds targeting these resistant strains have recently been
reported, e.g., linezolid,3 however, resistance to these new
molecules has already started to emerge.4–6 Vancomycin has long
been cast as the drug-of-last-resort and has been in use for
a number of years, despite the increasing prevalence of VRE (van-
comycin resistant Enterococci)7 and now vancomycin resistant
Staphylococcus aureus.8 The complicated ring systems of vanco-
mycin limit investigations into extensive structure–activity re-
lationships based on the parent structure. Therefore, we instigated
a programme investigating the synthesis of potential anti-bacterial
agents using some structural elements of vancomycin, but dra-
matically simplifying the hydrophobic scaffold to simple moieties
that hold a tripeptide in a defined conformation. Thus far, we have
reported cyclic peptides containing hydrophobic scaffolds based
on 1,10-binaphthyls,9 carbazoles,10,11 indoles12 and benzo[b]thio-
phenes13 with numerous derivatives showing significant
anti-bacterial activity (Fig. 1). We report here the synthesis and
anti-bacterial activity against S. aureus of an additional, simpler
2. Results and discussion
Ourtargetstructureistypifiedbythecyclicpeptide11 (Scheme1),
the hydrochloride salt of 4 (R¼Lys or Arg side chains). The tripeptide
precursor of 11 features a key protected terminal amino group-con-
taining amino acid (Lys; in later work this was replaced by an Arg
residue with a protected guanidino moiety) and an allyltyrosine,
which provides two roles: the aromatic moiety serves as the
hydrophobic unit and the olefin enables the cyclization to be un-
dertaken via a reliable ring-closing metathesis (RCM) reaction14 with
the third unit of the tripeptide, an allylglycine unit. The modular
synthetic strategy also allows for the rapid generation of analogues
includingvariations in the aminoacidconfiguration (Ror S) as wellas
variations in the amino acid side chains themselves, e.g., the RCM of
two incorporated allyltyrosine units.
The synthesis of 11 was realized (Scheme 1) in a six-step
sequence starting with commercially available L-allylglycine 5. The
acid 5 was esterified15 using thionyl chloride in a solution of an-
hydrous methanol at 0 ꢀC, to give 6 in quantitative yield. The syn-
thesis of the dipeptide 7 used typical EDCI/HOBt peptide coupling
conditions16 reacting 6 with commercially available Fmoc–
D-Lys
* Corresponding authors. Tel.: þ61 2 4221 4692; fax: þ61 2 4221 4287 (P.A.K.);
tel.: þ61 2 4221 4255 (J.B.B.); tel.: þ61 2 4221 3511 (S.G.P.).
(Boc)–OH and resulted in a 94% yield of 7 after column chroma-
tography. Removal of the base labile Fmoc group from the dipeptide
7 was achieved using standard conditions17 of a 1% piperidine/
acetonitrile solution to yield the free amine 8 in 99% yield.
E-mail addresses: jbremner@uow.edu.au (J.B. Bremner), keller@uow.edu.au
(P.A. Keller), spyne@uow.edu.au (S.G. Pyne).
y
Tel.: þ61 3 9208 4181; fax: þ61 3 9208 4100.
0040-4020/$ – see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.031

T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
11271
NH2.HCl
NHAc
MeO2C
NHAc
O
CH3
NH3
N
NH2
O
O
H
NH
+
OMe
N
H
OH
S
H3C
(E/Z)
HO
O
OMe
OH
O
CH3
NH
CO2Me
O
O
(E/Z)
N
O
Cl
O
Boc
MIC 15 mg/mL
2
O
O
MIC 7 mg/mL
HO
Cl
OH
NH
1
O
H
H
N
N
H
N
O
N
H
O
O
NH
(E/Z)
O
O
O
O
(CH2)n
-OOC
HO
+
NH2
NH2
CH3
OH
NH
O
H
O
OH
NH2
O
N
N
O
N
H
N
H
HN
vancomycin
O
O
R
CO2Me
(E/Z)
R = side chains of Lys, Arg, GuanidylLys
n = 1,2,3 MIC >125 mg/mL
3
4
Figure 1.
We next required the N-protected allyltyrosine 14, which was
generated by treating commercially available ethyl (2S)-2-acet-
amido-3-(4-hydroxyphenyl)propanoate 12 with K2CO3 and then
commercial availability of compounds (Scheme 3). Therefore, the
acid catalyzed esterification of -tyrosine 15 with thionyl chloride
D
in methanol yielded the methyl ester 16 in quantitative yield as the
ammonium salt, which was then treated with 5 M sodium acetate
at 0 ꢀC to produce the free amine. Acetic anhydride was added to
the aqueous solution and the N-acetyl derivative 17 precipitated in
76% yield. The last two steps of the synthesis were performed in the
same manner as described for the synthesis of 13 and 14 to yield the
allyl bromide to produce the L-O-allyl-tyrosine derivative 13 in
quantitative yield with no further purification required (Scheme 2).
The ethyl ester 13 was hydrolyzed by reaction with 2 equiv of LiOH
in 3:1 THF/H2O and afforded, after acidification, the free carboxylic
acid 14 in quantitative yield (Scheme 2). The corresponding D-an-
alogue of 14 was also required for the generation of analogues, but
this required a slightly modified synthetic strategy based upon the
corresponding
respectively.
D
-analogues 18 and 19 in 85 and 88% yield,
O
O
NHR
N
H
b
a
HO
O
O
NH2
NH3+Cl-
O
O
6
5
NHBoc
R = Fmoc, 7
R = H,
c
8
d
(E/Z)
O
O
O
O
O
O
H
N
H
5
e
O
O
O
N
N
H
N
8
H
N
H
N
H
2
O
O
O
NHR
R = Boc, 10
R = H.HCl, 11
NHBoc
9
f
Scheme 1. Synthesis of cyclic peptides: (a) MeOH, SOCl2, 0 ꢀC to rt, 16 h, 100%; (b) Fmoc–D-Lys(Boc)–OH, EDCI, HOBt, DIPEA, DMF, 0 ꢀC to rt, 16 h, 94%; (c) 1% piperidine/CH3CN, rt,
3 h, 99%; (d) 14, EDCI, HOBt, DMF, 0 ꢀC to rt, 16 h, 69%; (e) Grubbs [Ru] catalyst, benzylidene bis(tricyclohexylphosphine)dichlororuthenium, CH2Cl2,
D, 48 h, 75%; (f) (i) TFA/CH2Cl2
(1:1); (ii) 1 M HCl/ether, rt, 3 h, 49%.

11272
T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
The synthesis of the cyclic tripeptides containing two tyrosine
OH
O
residues is outlined in Scheme 9. This necessitated access to the
ester protected allyltyrosine 69, which was generated analogously
to those established in the synthesis of the tyrosines 14 and 19
(Schemes 2 and 3). The completion of the synthesis of the cyclic
dityrosine derivatives also used standard conditions as indicated in
Scheme 9. Some acyclic tyrosine dipeptides 70–82 were also gen-
erated to supplement SAR studies and these are summarized in
Scheme 10.
O
O
O
a
b
NHAc
OEt
NHAc
OEt
NHAc
OH
O
(L)-12
(L)-13
(L)-14
Scheme 2. Synthesis of L-N-acetyl-O-allyltyrosine: (a) allyl bromide, DMF, K2CO3, rt,
16 h, 100%; (b) (i) 2 equiv LiOH, THF/H2O, rt, 16 h; (ii) 10% HCl, 100%.
3. Anti-bacterial testing results
The anti-bacterial activity results against S. aureus ATCC6538P
(Fig. 2) were measured as minimum inhibitory concentration
(MIC), the lowest concentration of compound necessary to pre-
OH
OH
O
vent bacterial growth. The activities ranged from an MIC of 7.8
mL for compound 81 to an MIC >125 g/mL (inactive) for
a number of compounds. Vancomycin was used as the standard/
control and typically had an MIC range of 1.25–2.5 g/mL.
The most active cyclic compound tested was the dityrosine
peptide 75, which had a moderate activity of 15.6 g/mL. As
expected, the -lysine cyclic peptide 11, which is conformationally
similar to the binaphthyl lead compound 1 (Fig. 1), had moderate
activity (MIC 62.5 g/mL) and was the most active of the mono-
tyrosine compounds. The -arginine and -lysine cyclic peptides
mg/
m
b
c
NH2
OR
NHAc
OR
m
NHAc
OR
O
O
m
O
D
R = Me, (D)-18
R = H, (D)-19
R = H, (D)-15
R = Me, (D)-16
(R)-17
d
a
m
Scheme 3. Synthesis of D-N-acetyl-O-allyltyrosine: (a) MeOH, SOCl2, 0 ꢀC to rt, 16 h,
100%; (b) Ac2O, NaOAc, 0 ꢀC, 76%; (c) allyl bromide, DMF, K2CO3, rt, 16 h, 85%; (d) LiOH,
THF/H2O, rt, 16 h, 88%.
D
D
(45 and 11, respectively) had the same activity indicating no ad-
vantage in arginine over lysine as the basic residue, although the
lack of activity with the presence of the homoarginine side chains
suggests an optimum chain length for anti-bacterial activity. Gen-
The coupling of the a-amino dipeptide 8 to the allyltyrosine 14
(Scheme 1) used standard EDCI/HOBt peptide coupling conditions
to yield 9 in 69% yield after purification by column chromatography.
A ring-closing metathesis (RCM) reaction of the peptide 9 with
Grubbs0 first generation catalyst (benzylidene bis(tricyclohexyl-
phosphene)dichlororuthenium) gave 10 as a mixture of E and Z
isomers in 75% yield, which could not be separated. The E/Z ratio
and alkene coupling constants could not be determined by analysis
of the 1H NMR spectra due to overlapping peaks, but all the spec-
troscopic data was consistent with the cyclic structure 10. Sub-
sequent Boc deprotection of 10 with TFA and anion exchange by
treatment with HCl/ether followed by precipitation gave the amine
hydrochloride salt 11 in 49% yield.
erally the presence of a C-terminal residue
L-amino acid residue and
an adjacent -amino acid with a basic residue gives rise to better
D
activity, e.g., 49 versus 45 versus 48.
The greatest activity was found, unexpectedly, with the di-
peptide intermediate 81, which was as active as the binaphthyl lead
compound 1 with an MIC of 7.8 mg/mL. This can be attributed to the
Fmoc group acting as a hydrophobic scaffold, in a similar manner to
the binaphthyl moiety of 1. As the molecule also contains a pro-
tonated side chain it meets our previously established criteria for
anti-bacterial activity. This compound also has the minimal struc-
tural features consistent with the anti-staphylococcal pharmaco-
phore proposed for short cationic peptides.18 The other dipeptide
analogues featuring O-allyltyrosine (79, 80 and 82) as the C-
terminal residue instead of C2-allylglycine (50–53) also resulted in
This modular approach to novel cyclic peptide synthesis allowed
for the rapid generation of analogues to probe structure–activity
relationships (SARs) upon testing for anti-bacterial activity. There-
fore, we synthesized and tested a series of analogues that included:
promising anti-bacterial activity (MIC 15.6–31.5
glycine analogues, with either the - or -configuration, all showed
poor anti-bacterial activity (MIC of 125 g/mL) significantly less
mg/mL). The allyl-
D
L
m
(a) Variations in the stereochemistry at C2 (
D
- and
L
-allylGly), C5
active than the corresponding O-allyltyrosine compounds in-
dicating that some form of hydrophobic moiety is required at the
C-terminal end. The tripeptide acyclic intermediates failed to pro-
duce any significant anti-bacterial activity.
(
D
- and -amino acids) and C8 ( - and -allyltyrosine).
L
D
L
(b) Variations in the C5 amino acid including the N-terminal side
chains of Lys, Arg and N-guanidylLys.
(c) Some of the N-deprotected acyclic di- and tripeptide in-
termediates synthesized.
(d) The replacement of allylGly with a second allyltyrosine.
The location of the O-allyltyrosine residue at the C-terminus is
more favourable than a C2-allylglycine residue (e.g., 81 vs 51)
suggesting that a hydrophobic entity is required for optimum ac-
tivity at this end of the molecule. The acyclic dipeptides also show
a preference for arginine over lysine basic side chains. These
smaller dipeptides have a degree of conformational freedom and it
is most likely beneficial, and synthetically easier, to develop smaller
acyclic compounds.
The third major observation was the hydrophobicity of the
molecules. The tyrosine derivative 81, which mimics the binaphthyl
in the lead compound 1, is significantly smaller and less hydro-
phobic than the scaffold/template of the lead 1. The Fmoc fluorenyl
ring system (e.g., in 81) is more hydrophobic than a tyrosine residue
and more isosteric with the binaphthyl ring system of the lead
compound. It is clear that the presence of the more hydrophobic
While not exhaustively producing all possible variations defined
above, a selection of target compounds were synthesized using the
same synthetic strategyas outlined in Scheme 1. Scheme 4 shows the
generation of deprotected cyclic tyrosine-based molecules 11 and
44–49. Schemes 5 and 6 summarize the deprotection of the in-
termediate di- and tripeptides, respectively, that were also tested for
anti-bacterial activity. The acyclic N-guanidineLys derivatives 62 and
63 were also N-deprotected (Scheme 7) toallow for biological testing
as their hydrochloride salts and the corresponding cyclic tyrosine
versions of these derivatives were more conveniently synthesized
from 10 and this is exemplified by the synthesis of 65 (Scheme 8).

T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
11273
O
b
a
5
O
NHFmoc
P
O
HO
NH3+Cl-
N
H
NH2
2
O
X
O
O
Yield %
100
C2
L
L
L
L
C5
P
Bo
Boc
Pmc
Pmc
Pmc
Pmc
Yield %
c 94
7
D-Lys
L-Lys
D-Arg
L-Arg
D-Ar
L-Arg
6
L-Gly
5
L-Gly
22
23
24
25
26
87
90
83
90
21
D-Gly 100
20 D-Gly
D
D
g
89
c
O
O
O
O
H
d
5
5
O
N
O
NH2
P
N
H
N
H
N
8
2
2
H
O
X
O
O
X
P
C5
C2
L
P
Boc
C8 Yield %
C2
L
L
C5
P
Yield %
99
100
80
9
D-Lys
L-Lys
D-Arg
L-Arg
D-Arg
L-Arg
L-Arg
L
L
L
L
L
L
D
69
50
73
72
64
80
87
8
D-Lys
L-Lys
D-Arg
L-Arg
Boc
Boc
32
33
34
35
36
37
L
Boc
27
28
29
30
31
L
Pmc
Pmc
Pmc
Pmc
Pmc
L
L
Pmc
Pmc
L
48
D
D
L
D
D
D-Arg
L-Arg
Pmc
Pmc
78
99
e
(E/Z)
(E/Z)
O
O
O
O
O
O
H
N
f
H
O
O
5
5
O
O
N
N
H
N
H
2
N
H
N
H
8
2
8
X
O
X
O
P
H.HCl
C2
L
C5
P
Boc
C8
L
L
Yield %
75
76
C2
L
C5
D-Lys
C8
L
Yield %
49
10
38
39
40
41
42
43
D-Lys
L-Lys
D-Arg
L-Arg
D-Arg
L-Arg
L-Arg
11
L
L
Boc
44
45
46
47
48
49
L
L-Lys
D-Arg
L-Arg
D-Arg
L-Arg
L-Arg
L
L
L
L
L
D
79
91
59
35
86
34
L
L
100
95
Pmc
Pmc
Pmc
Pmc
Pmc
L
L
L
D
D
L
L
L
99
86
87
D
D
L
D
Scheme 4. ‘X’ in structures represents the amino acid side chain as defined under ‘C5’ in the associated tables. (a) MeOH, SOCl2, 0 ꢀC to rt, 16 h; (b) Fmoc–D or L-Lys(Boc)–OH, EDCI,
HOBt, DIPEA, DMF, 0 ꢀC to rt, 16 h; (c) 1% piperidine/CH3CN, rt, 3 h; (d) 14 or 19, EDCI, HOBt, DMF, 0 ꢀC to rt, 16 h; (e) Grubb [Ru] catalyst – benzylidene bis(tricyclohexyl-
phosphine)dichlororuthenium, CH2Cl2,
D, 48 h; (f) (i) TFA/CH2Cl2 (1:1); (ii) 1 M HCl/ether, rt, 3 h, 49%.
-
-
The compounds do not have to be macrocyclic, but can be
straight chain peptides.
Fmoc group increases the activity of the compounds in relation to
the tyrosine derivative.
The
D-configuration is preferred for the basic residue, and
arginine is preferable over lysine. Also, the side chain
in homoarginine is too long and renders the compounds
inactive.
4. Conclusions
-
-
The L-configuration is preferred for the C-terminal amino acid
residue.
A small hydrophobic group is required near the C-terminus
whereas a larger hydrophobic group is required at the N-
terminus.
We have synthesized a series cyclic peptides based upon allyl-
tyrosine and allylglycine moieties. The key cyclization was achieved
via a ring-closing metathesis reaction. The anti-bacterial activity of
the cyclic peptides and their acyclic precursors revealed that for
optimum activity:

11274
T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
to be of greater than 95% purity based upon 1H NMR and TLC
analyses. The Grubbs ruthenium catalyst used was specifically
benzylidene bis(tricyclohexylphosphine) dichlororuthenium.
O
O
5
5
O
NHFmoc
O
NHFmoc
a
2
2
N
H
N
H
Other general experimental procedures have been reported
O
X.HCl
O
X
previously.11
P
P
Pmc
Pmc
Pmc
Proton and carbon NMR spectra for all compounds were
assigned using the numbering systems as illustrated in Figure 3.
Cyclic peptoids were named using the IUPAC ‘superatom’ conven-
tion, in which the aromatic ring is considered equivalent to, and
sequentially numbered like, all other atoms in the macrocycle.19
C5
D-Arg
L-Arg
C2
L
Yield %
75
47
C2
L
L
C5
50
23
24
25
D-Arg
L-Arg
D-Arg
51
52
53
L
D
D
D
D-Arg
L-Arg
80
51
26
D
L-Arg
Pmc
Scheme 5. Synthesis of the deprotected acyclic dipeptide derivatives. (a) (i) TFA/
CH2Cl2 (1:1); (ii) 1 M HCl/ether, rt, 3 h. ‘X’ in structures represents the amino acid side
chain as defined under ‘C5’ in the associated tables.
5.2. General synthetic procedures
5.2.1. N-Boc and Pmc deprotection (Procedure A)
5. Experimental
5.1. General
The N-Boc or Pmc protected amine (1 equiv) was stirred for
3 h in 1:1 CH2Cl2/TFA solution at rt. The solvent was removed
under reduced pressure, and the residue was resuspended in
a minimal volume of methanol. The solution was then treated
with an excess of 1 M HCl/diethyl ether solution and the solvent
again evaporated. The crude product was purified by re-
crystallization/precipitation from CH2Cl2and/or MeOH by addi-
tion of diethyl ether.
Melting point determinations were carried out on a Gallen-
kamp melting point apparatus. Chemical ionization (CI) and
electron impact (EI) mass spectra were obtained on a Shimadzu
QP-5000 mass spectrometer by a direct insertion technique with
an electron beam energy of 70 eV. Electrospray (ESI) mass spectra
were obtained on a VG Autospec spectrometer. High-resolution
mass spectra (HRMS) were determined on a micromass QTof2
spectrometer using polyethylene glycol or polypropylene glycol
as the internal standard. The m/z values are stated with their
peak intensity as a percentage in parentheses. Optical rotations
were measured using a Jasco polarimeter with a 10 mm path
length. Proton and carbon nuclear magnetic resonance (NMR)
spectra were obtained as specified on a Varian Mercury 300 MHz
or Varian Inova 500 MHz spectrometer. Spectra were recorded in
the specified deuterated solvent, and referenced to the residual
5.2.2. Peptide coupling (Procedure B)
To a solution of the acid (1 equiv) in DMF at rt was added HOBt
(1.1 equiv), EDCI (1 equiv) and the amine (1.2 equiv). If the amine
was a hydrochloride salt, DIPEA (1 equiv) was also added. The
mixture was allowed to stir for 16 h before the reaction was
quenched with water until precipitation occurred. The solid was
collected by vacuum filtration, and washed thoroughly with water.
The amorphous product was dried under vacuum over P2O5 to yield
the desired peptide.
non-deuterated solvent signal. Chemical shifts (
d
) in parts per
5.2.3. N-Fmoc deprotection (Procedure C)
million were measured relative to the internal standard. Where
samples exhibited (E) and (Z) isomers the chemical shifts are
separated by (/). In general, the two forms could not be separated
by flash chromatography. Analytical thin layer chromatography
(TLC) was carried out on Merck silica gel 60 F254 pre-coated al-
uminium plates with a thickness of 0.2 mm. All column chro-
matography was performed under ‘flash’ conditions on Merck
silica gel 60 (230–400 mesh). Chromatography solvent mixtures
were measured by volume. Organic solvent extracts were dried
with anhydrous magnesium sulfate. All compounds were judged
The Fmoc protected amine was stirred in 1% piperidine/aceto-
nitrile for 3 h at rt. The solvent was removed under reduced pres-
sure and the crude product was purified by flash column
chromatography (15:1, CH2Cl2/MeOH) to yield the free amine.
5.2.4. Macrocyclization by olefin metathesis (Procedure D)
To a solution of the precursor tripeptide in CH2Cl2 (to 0.004 M)
was added Grubbs ruthenium catalyst (15 mol %) and the resulting
solution was heated at reflux for 48 h before the solvent was re-
moved by evaporation and the product isolated by flash column
O
O
O
O
O
O
a
H
N
H
N
5
O
5
O
N
H
N
H
8
2
N
H
N
H
8
2
O
X
O
O
X.HCl
O
P
P
Boc
C2 C5
C8
Yield %
37
C2
L
C5
C8
L
54
L
D-Lys
L-Lys
L
L
L
L
L
L
D-Lys
L-Lys
D-Arg
L-Arg
D-Arg
L-Arg
9
55
56
57
58
59
L
60
32
33
34
35
36
L
Boc
L
D-Arg
L-Arg
D-Arg
L-Arg
L
74
L
Pmc
Pmc
Pmc
Pmc
L
L
85
L
L
D
D
100
56
D
D
L
L
Scheme 6. Synthesis of the deprotected acyclic tripeptide derivatives. (a) (i) TFA/CH2Cl2 (1:1); (ii) 1 M HCl/ether, rt, 3 h. ‘X’ in structures represents the amino acid side chain as
defined under ‘C5’ in the associated tables.

T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
11275
O
O
O
5
O
H
N
O
O
b
5
H
N
O
N
H
N
H
O
8
2
N
H
N
H
8
2
O
X
O
O
X.HCl
O
P
C2 C5
C8
L
Yield %
78
C2 C5
P
C8
Yield %
62
63
L
L
D-N-guanidineLys
L-N-guanidineLys
L
L
L
L
9
L
L
L
L
D-Lys
L-Lys
Boc
Boc
-
-
L
35
a
32
60
61
a
D-N-guanidineLys diBoc
L-N-guanidineLys diBoc
100
74
Scheme 7. Synthesis of the deprotected acyclic tripeptide derivatives containing the guanidated lysine amino acid side chain. (a) (i) TFA, CH2Cl2 (1:1); (ii) Tf–N]C(NHBoc)2, Et3N, rt,
16 h; (b) (i) TFA/CH2Cl2 (1:1); (ii) 1 M HCl/ether, rt, 3 h. ‘X’ in structures represents the amino acid side chain as defined under ‘C5’ in the associated tables.
chromatography (15:1, CH2Cl2/MeOH) to yield the corresponding
macrocycle.
5.3.3. Methyl (2R)-2-amino-(4-hydroxyphenyl)-2-propanoate
hydrochloride (16)
To a solution of (2R)-2-amino-3-(4-hydroxyphenyl)propanoic
acid 15 (1.07 g, 5.9 mmol) in anhydrous MeOH (10 mL) at 0 ꢀC was
added dropwise thionyl chloride (2 mL). The resulting mixture was
allowed to stir for 16 h before the solvent was removed by evapo-
ration to yield the title compound (1.36 g, 5.9 mmol, 100%) as
a white solid, which was spectroscopically identical to that repor-
5.3. Synthesis of allylated tyrosine amino acids
5.3.1. Ethyl (2S)-2-acetamido-3-(4-allyloxyphenyl)propanoate (13)
To
a
solution of ethyl (2S)-2-acetamido-3-(4-hydroxy-
phenyl)propanoate monohydrate 12 (2.69 g, 9.98 mmol) and an-
hydrous K2CO3 (2.75 g, 20.0 mmol) in DMF (15 mL) was added allyl
bromide (2.42 g, 19.96 mmol). The resulting mixture was allowed
to stir for 16 h under nitrogen before the reaction was quenched
with water (30 mL) and extracted with ethyl acetate (3ꢁ50 mL).
The combined extracts were washed with water (5ꢁ50 mL), dried
and the solvent was evaporated to yield the title compound (2.91 g,
23
24
ted.21
176 ꢀC (lit. 134–136 ꢀC).21
[a
]
ꢂ27.7 (c 0.1, EtOH) (lit. [
a
]
ꢂ27.1 (c 2.0, MeOH)).21 Mp
D
D
5.3.4. Methyl (2R)-2-acetamido-3-(4-hydroxyphenyl)-
propanoate (17)
A solution of the HCl salt 16 (1.09 g, 6.02 mmol) in water (3 mL)
was cooled to 0 ꢀC before the addition of 5 M sodium acetate so-
lution (35 mL) and a small amount of ice. Acetic anhydride (10 mL)
was added and the resulting precipitate was collected by vacuum
filtration and dried to yield the title compound (1.09 g, 4.58 mmol,
76%) as a white solid, which was spectroscopically identical to that
9.98 mmol, 100%) as a white solid, which had spectral data in
25
agreement with that reported.20
70 ꢀC (lit. 69.5 ꢀC).20
[
a]
þ23.1 (c 0.1, EtOH).20 Mp 69–
D
5.3.2. (2S)-2-acetamido-3-(4-allyloxyphenyl)propanoic acid (14)
To a solution of 13 (2.90 g, 9.98 mmol) in THF/water (3:1, 80 mL)
was added lithium hydroxide monohydrate (838 mg, 20.0 mmol)
and the resulting suspension was allowed to stir for 16 h. The re-
action mixture was diluted with water (30 mL) and the THF was
removed by evaporation. The aqueous layer was extracted with
CH2Cl2 (40 mL) to remove unreacted starting material. The aqueous
phase was acidified with 10% HCl and the resulting precipitate was
extracted with CH2Cl2 (3ꢁ40 mL). The combined extracts were
dried and evaporated to yield the title compound (2.62 g,
9.98 mmol, 100%) as white needles, which had spectral data in
agreement with that reported.20 Mp 170–172 ꢀC (lit. 200 ꢀC).20
25
25
reported.21
Mp 132–133 ꢀC (lit. 134–135.5 ꢀC).21
[
a]
ꢂ27.2 (c 0.1, EtOH) (lit. [
a
]
ꢂ26.6 (c 0.1, MeOH)).21
D
D
5.3.5. Methyl (2R)-2-acetamido-3-(4-allyloxyphenyl)-
propanoate (18)
To a solution of 17 (989 mg, 4.17 mmol), and anhydrous
K2CO3 (1.15 g, 8.34 mmol) in DMF (10 mL) was added allyl bro-
mide (1.01 g, 8.34 mmol) and the resulting mixture was allowed
to stir for 16 h under a nitrogen atmosphere. The reaction was
quenched with water (30 mL), extracted with ethyl acetate
(3ꢁ30 mL), and the combined organics were washed with water
(E/Z)
(E/Z)
(E/Z)
O
O
O
O
O
O
O
O
O
H
N
H
N
H
N
a
b
N
H
N
H
N
H
N
H
N
H
N
H
O
O
O
O
O
O
N
NHBoc
NH
Boc
Boc
NH3+HCl-
N
H
N
H
HN
10
64
65
Scheme 8. Synthesis of the cyclic tripeptide containing the guanidated lysine amino acid side chain. (a) (i) TFA/CH2Cl2 (1:1); (ii) Tf–N]C(NHBoc)2, Et3N, rt, 16 h; (b) (i) TFA/CH2Cl2
(1:1); (ii) 1 M HCl/ether, rt, 3 h, 87% (two steps).

11276
T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
OH
OH
O
O
O
O
O
O
O
a
b
c
d
O
NHFmoc
NHBoc
NHBoc
O
N
H
NH2
OH
NHBoc
O
NH3+Cl-
O
O
O
66
67
68
69
70
e
(E/Z)
O
O
O
O
O
O
g
O
f
O
O
O
H
N
H
O
NH2
O
O
O
N
N
N
H
N
H
N
N
H
H
H
O
O
O
O
NHBoc
NHR
NHR
R = Boc, 72
R = H, 73
R = Boc, 74
R = H, 75
71
h
h
Scheme 9. (a) (i) MeOH, SOCl2, 0 ꢀC to rt, 16 h; (ii) (Boc)2O, DMF, rt, 16% (two steps); (b) allyl bromide, DMF, K2CO3, rt, 16 h, 76%; (c) TFA/CH2Cl2 (1:1); (ii) 1 M HCl/ether, rt, 3 h, 100%;
(d) Fmoc–D-Lys(Boc)–OH, EDCI, HOBt, DIPEA, DMF, 0 ꢀC to rt, 16 h, 75%; (e) 1% pip/CH3CN, rt, 3 h, 97%; (f) 14, EDCI, HOBt, DMF, 0 ꢀC to rt, 16 h, 37%. (g) Grubbs [Ru] catalyst –
benzylidene bis(tricyclohexylphosphine)dichlororuthenium, CH2Cl2,
D, 48 h, 41%; (h) (i) TFA/CH2Cl2 (1:1); (ii) 1 M HCl/ether, rt, 3 h, 49%.
(5ꢁ20 mL) before drying. The solvent was evaporated to yield
278 (100%) [MHþ]. HRMS (ESI) calcd for C15H19NO4 277.131408,
found 277.130309.
the title compound (985 mg, 3.56 mmol, 85%) as a pale yellow
25
solid. [
a
]
ꢂ24.2 (c 0.1, EtOH). Mp 90 ꢀC. 1H NMR (CDCl3,
D
300 MHz):
d
6.97 (d, J¼8.7 Hz, 2H, ArH20 and ArH60), 6.80 (d,
5.3.6. (2R)-2-Acetamido-3-(4-allyloxyphenyl)propanoic acid (19)
To a solution of 18 (900 mg, 3.25 mmol) in THF/water, 3:1
(10 mL) was added lithium hydroxide monohydrate (273 mg,
6.5 mmol), and the resulting suspension was allowed to stir for
16 h. The reaction mixture was diluted with water (30 mL) and
the THF was removed in vacuo. The aqueous layer was extracted
with diethyl ether (40 mL) to remove unreacted starting mate-
rial. The aqueous phase was acidified with 10% HCl and the
resulting precipitate was extracted with CH2Cl2 (3ꢁ40 mL). The
J¼8.7 Hz, 2H, ArH30 and ArH50), 6.09 (d, J¼7.8 Hz, 1H, NH), 6.07–
5.95 (m, 1H, H200), 5.37 (dd, J¼1.8, 17.4 Hz, 1H, H3a00), 5.25 (dd,
J¼1.8, 10.5 Hz, 1H, H3b00), 4.83–4.77 (m, 1H, H2), 4.47 (d,
J¼5.5 Hz, 2H, H100), 3.68 (s, 3H, OCH3), 3.08–2.94 (m, 2H, H3),
1.99 (s, 3H, NCOCH3). 13C NMR (CDCl3, 75 MHz):
d 172.1, C1;
169.6, NCO; 157.6, ArC40; 133.1, C200; 130.1, ArCH20 and ArCH60;
127.9, ArC10; 117.5, C300; 114.7, ArCH30 and ArCH50; 68.6, C100;
53.2, C2; 52.2, OCH3; 36.9, C3; 22.9, NCOCH3. MS (CI, þve) m/z
O
O
O
O
O
P
a
b
5
O
NHFmoc
O
N
H
L
NH3+Cl-
O
5
O
NHFmoc
O
X
N
H
L
P
O
X.HCl
69
C5
Yield %
C5
Yield %
70
76
77
78
D-Lys
L-Lys
D-Arg
L-Arg
Boc
Boc
75
77
71
84
79
80
D-Lys
L-Lys
79
68
81
82
D-Arg
L-Arg
79
83
Pmc
Pmc
Scheme 10. Synthesis of the L-allyltyrosine dipeptide derivatives: (a) Fmoc–D- or L-Lys(Boc)–OH or Fmoc–D- or L-Arg(PMC)–OH, EDCI, HOBt, DIPEA, DMF, 0 ꢀC to rt, 16 h; (b) (i) TFA/
CH2Cl2 (1:1); (ii) 1 M HCl/ether, rt, 3 h. ‘X’ in structures represents the amino acid side chain as defined under ‘C5’ in tables.

T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
11277
O
O
O
5
O
NHFmoc
N
H
2
O
X.HCl
O
H
N
C2
L
L
C5
D-Arg
L-Arg
5
MIC µg/mL
O
N
H
N
H
8
2
125
125
50
O
O
X.HCl
51
52
53
D
D
D-Arg
L-Arg
125
125
C2 C5
C8
MIC µg/mL
125
9
L
L
L
L
D
D
L
L
L
D-Lys
L-Lys
D-Arg
L-Arg
D-Arg
L-Arg
L-Arg
L
L
L
L
L
L
D
L
L
32
33
34
35
36
37
62
63
>125
>125
>125
>125
>125
-
D-N-guanidineLys
L-N-guanidineLys
>125
>500
(E/Z)
O
O
O
H
N
O
5
N
H
N
H
2
8
O
X.HCl
O
C2
L
C5
D-Lys
C8
L
MIC µg/mL
O
11
62.5
44
45
46
47
L
L
L
L-Lys
D-Arg
L-Arg
D-Arg
L
L
L
L
>125
62.5
125
O
5
O
NHFmoc
N
H
L
O
X.HCl
D
125
MIC µg/mL
31.3
C5
48
49
65
D
L
L
L-Arg
L-Arg
L
D
L
125
125
79
80
D-Lys
L-Lys
15.6
L-N-guanidineLys
>125
81
82
D-Arg
L-Arg
7.8
15.6
(E/Z)
O
O
O
O
O
H
O
O
O
H
O
N
O
N
N
N
H
N
N
H
H
O
H
O
O
O
NH2
NH2
75
73
MIC µg/mL = 125
MIC µg/mL = 15.6
Figure 2. Minimum inhibitory concentration (MIC) data for the anti-bacterial testing of the acyclic di- and tripeptides and the cyclic tripeptide derivatives synthesized.
combined CH2Cl2 fractions were dried and concentrated to yield
the title compound (750 mg, 2.85 mmol, 88%) as a white solid.
J¼5.1 Hz, 2H, H100), 3.11 (dd, J¼5.4, 14.1 Hz, 1H, 3Ha), 2.93 (dd,
J¼8.1, 14.1 Hz, 1H, 3Hb), 1.89 (s, 3H, NCOCH3). 13C NMR (acetone-
23
[
a]
ꢂ23.2 (c 0.1, EtOH). Mp 75 ꢀC. 1H NMR (acetone-d6,
d6, 75 MHz): d
173.1, C1; 170.4, NCO; 158.4, ArC40; 134.8, C200;
D
300 MHz):
d
7.27 (d, J¼7.8 Hz, 1H, NH), 7.17 (d, J¼8.7 Hz, 2H,
131.1, ArCH20 and ArCH60; 130.2, ArC10; 117.2, C300; 115.3, ArCH30
and ArCH50; 69.2, C100; 54.5, C2; 37.3, C3; 22.6, NCOCH3. MS (CI,
þve) m/z 264 (100%) [MHþ]. HRMS calcd for C14H18NO4
264.123583, found 264.123770.
ArH20 and ArH60), 6.86 (d, J¼8.7 Hz, 2H, ArH30 and ArH50), 6.12–
6.00 (m, 1H, H200), 5.40 (dd J¼1.5, 17.5 Hz, 1H, H3a00), 5.23 (dd,
J¼1.5, 10.5 Hz, 1H, H3b00), 4.67 (dd, J¼8.1, 10.5 Hz 1H, H2), 4.53 (d,

11278
T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
3
CH2Cl2 (25 mL), then the organic layer was washed with brine
2
O
(E/Z)
(2ꢁ25 mL) and water (2ꢁ25 mL) and dried, before being concen-
trated. The crude product was purified by flash column chromato-
graphy (25:1, CH2Cl2/MeOH) to afford the title compound (1.31 g,
2.27 mmol, 87%) as a cream coloured solid. Mp 123–126 ꢀC. 1H NMR
4
1
5
6
14
O
9
O
H
8
10
12
O
N
(CDCl3, 300 MHz):
d
7.76 (d, J¼7.6 Hz, 2H, ArH100 and ArH800), 7.59 (d,
H3COOC 7 N
N
13
11
H
H
J¼7.6 Hz, 2H, ArH400 and ArH500), 7.40 (t, J¼7.6 Hz, 2H, ArH300 and
ArH600), 7.31 (ddd, J¼9.0, 7.2,1.2 Hz, 2H, ArH200 and ArH700), 6.46 (br s,
1H, NH), 5.73–5.62 (m, 1H, H20), 5.44 (s, 1H, NH), 5.12–5.07 (m, 2H,
H30), 4.80 (br s,1H, NH), 4.65–4.61 (m,1H, H2), 4.39 (d, J¼7.2 Hz, 2H,
OCH2-H900), 4.23–4.19 (m, 1H, H5), 4.17 (br s, 1H, H900), 3.74 (s, 3H,
OCH3), 3.16–3.05 (m, 2H, H9), 2.64–2.47 (m, 2H, H10), 1.94–1.76 (m,
2H, H7), 1.75–1.64 (m, 2H, H6), 1.55–1.48 (m 2H, H8), 1.44 (s, 9H,
NH3+Cl-
Figure 3. ‘Superatom’ convention for the numbering of macrocycles.19
C(CH3)3). 13C NMR (CDCl3, 75 MHz):
d 171.9, C4; 171.6, C1; 156.2,
5.4. Synthesis of methylester allyl glycines (6 and 21)
NCO2; 143.7, ArC8a00 and ArC9a00; 142.7, ArC4a00 and ArC4b00; 131.9,
C20; 127.7, ArCH300 and ArCH600; 127.0, ArCH200 and ArCH700; 125.0,
ArCH100 and ArCH800; 119.9, C30; 119.3, ArCH400 and ArCH500; 79.1,
C(CH3)3; 67.0, CH2-C900; 54.5, C5; 52.4, OCH3; 50.6, C2; 47.0, C900; 39.8,
C9; 36.1, C10; 32.0, C6; 29.9, C8; 28.3, C(CH3)3; 22.2, C7. MS (ESI, þve)
m/z 580.5 (10%) [MHþ], 130.5 (100%) [MHþ (less allylGly)]. HRMS
calcd for C32H42N3O7 580.3023, found 580.3025.
5.4.1. Methyl (2S)-2-amino-4-pentenoate hydrochloride (6)
To a suspension of (2S)-2-amino-4-pentanoic acid 5 (200 mg,
1.74 mmol) in MeOH (6 mL) at 0 ꢀC was added dropwise thionyl
chloride (1 mL). The resulting solution was allowed to stir for 16 h
before the solvent was removed by evaporation and the product
crystallized with ether. The ether was removed by evaporation to
yield the title compound (287 mg, 1.74 mmol, 100%) as a white
solid, which had spectral data in agreement with that reported.15
Mp 172–174 ꢀC (lit. 174–176 ꢀC).15
5.5.3. Methyl (2S,5R)-2-allyl-3-aza-5-(9H-9-fluorenylmethyloxy-
carboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-
chromenylsulfonyl)guanidino]-4-oxooctanoate (23)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 6 (287 mg, 1.74 mmol)
and (2R)-2-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-
pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]pe-
5.4.2. Methyl (2R)-2-amino-4-pentenoate hydrochloride (21)
This was prepared from (2R)-2-amino-4-pentenoic acid
(200 mg, 1.74 mmol) in methanol (6 mL) using the same procedure
as for the synthesis of 6 above, to yield the title compound (287 mg,
1.74 mmol, 100%) as a white solid, which was spectroscopically
identical to that reported.22 Mp 135–140 ꢀC.
ntanoic acid (961 mg, 1.45 mmol) to afford 23 (1.01 g, 1.31 mmol,
23
90%) as a brown solid. [
a
]
D
þ11.5 (c 0.011, MeOH). IR (neat) nmax
1538, 1445, 1238, 1166, 1109, 736. Mp 96–100 ꢀC. 1H NMR (CDCl3,
300 MHz):
d
7.70 (d, J¼7.5 Hz, 2H, ArH100 and ArH800), 7.52 (d,
5.5. Synthesis of protected dipeptides (7, 22–26)
J¼7.2 Hz, 2H, ArH400 and ArH500), 7.35 (br s, 1H, NH), 7.33 (dd, J¼7.2,
7.2 Hz, 2H, ArH300 and ArH600), 7.20 (t, J¼7.2 Hz, 2H, ArH200 and
ArH700), 6.35 (s, 2H, NH), 6.026 (br s, 2H, NH), 5.78–5.56 (m, 1H, H20),
5.5.1. Methyl (2S,5R)-2-allyl-3-aza-9-(tert-butoxycarboxamido)-5-
(9H-9-fluorenylmethyloxycarboxamido)-4-oxononanoate (7)
0
5.03 (d, J¼18.0 Hz, 1H, H3a ), 4.98 (d, J¼10.2 Hz, 1H, H3b ), 4.53 (dd,
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 6 (186 mg, 1.62 mmol) and
(2R)-6-tert-butoxycarboxamido-2-(9H-9-fluorenylmethyloxycarbo-
xamido)hexanoic acid (633 mg, 1.35 mmol) to afford 7 (733 mg,
1.27 mmol, 94%) as a cream solid. Mp 117–120 ꢀC. 1H NMR (CDCl3,
J¼7.2, 12.9 Hz, 1H, H2), 4.27 (d, J¼6.6 Hz, 2H, OCH2-H900), 4.17–4.02
(m, 2H, H5 and H900), 3.63 (s, 3H, OCH3), 3.30–3.12 (m, 2H, H8), 2.57
(s, 3H, 7%-CH3), 2.54 (s, 3H, 5%-CH3), 2.50–2.47 (m, 4H, H10 and
H4%), 2.06 (s, 3H, 8%-CH3), 1.96–1.78 (m, 2H, H7), 1.71 (t, J¼6.6 Hz,
2H, H3%), 1.66–1.52 (m, 2H, H6), 1.24 (s, 6H, 2ꢁ2%-CH3). 13C NMR
300 MHz):
d
7.76 (d, J¼7.6 Hz, 2H, ArH100 and ArH800), 7.59 (d,
(CDCl3, 75 MHz): d 172.1, C4; 171.8, C1; 156.2, ArC6%; 153.5, 5-
J¼7.6 Hz, 2H, ArH400 and ArH500), 7.39 (t, J¼7.6 Hz, 2H, ArH300 and
ArH600), 7.31 (ddd, J¼9.0, 7.2, 1.2 Hz, 2H, ArH200 and ArH700), 6.75 (d,
J¼7.2 Hz, 1H, NH), 5.74–5.57 (m, 1H, H20), 5.11–5.05 (m, 2H, H30),
4.70–4.62 (m, 2H, H2 and NH), 4.38 (d, J¼6.7 Hz, 2H, OCH2-H900),
4.26–4.18 (m, 2H, H5 and H900), 3.71 (s, 3H, OCH3), 3.10 (d, J¼6.3 Hz,
2H, H9), 2.62–2.44 (m, 2H, H10),1.88–1.83 (m, 2H, H8),1.70–1.63 (m,
2H, H7), 1.49–1.37 (m 2H, H7), 1.43 (s, 9H, C(CH3)3). 13C NMR (CDCl3,
NCO2; 143.6, ArC8a%; 143.5, CN3; 141.0, ArC8a00 and ArC9a00; 135.3,
ArC4a00 and ArC4b00; 134.7, ArC7%; 132.9, ArC5%; 132.3, C20; 127.5,
ArCH300 and ArCH600; 126.9, ArCH200 and ArCH700; 125.0, ArCH400 and
ArCH500; 124.0, ArC8%; 119.7, ArCH100 and ArCH800; 118.8, C30; 117.8,
ArC4a%; 73.6, C2%; 67.2, CH2-C900; 52.3, C5; 52.0, C2; 52.0, OCH3;
47.0, C900; 40.2, C8; 35.9, C10; 32.7, C3%; 29.8, C6; 26.7, C2%-CH3;
25.5, C7; 21.4, C5%-CH3; 18.6, C7%-CH3; 17.6, C4%; 12.2, C8%-CH3.
MS (ESI, þve) m/z 774 (100%) [MHþ]. HRMS calcd for C41H52N5O8S
774.3537, found 774.3559.
75 MHz):
d 171.6, C4; 171.2, C1; 156.0, NCO2; 156.0, NCO2; 143.5,
ArC8a00 and ArC9a00; 141.1, ArC4a00 and ArC4b00; 131.9, C20; 127.6,
ArCH300 and ArCH600; 126.9, ArCH200 and ArCH700; 125.0, ArCH100 and
ArCH800; 119.8, C30; 119.2, ArCH400 and ArCH500; 79.1, C(CH3)3; 67.1,
CH2-C900; 54.7, C5; 52.5, OCH3; 51.5, C2; 47.1, C900; 39.8, C9; 36.4, C6;
32.2, C6; 29.7, C8; 28.5, C(CH3)3; 22.4, C7. MS (ESI, þve) m/z 579.9
(80%) [MHþ], 479.9 (100%) [MHþꢂ(Boc)]. HRMS calcd for
C32H42N3O7 580.3023, found 580.3041.
5.5.4. Methyl (2S,5S)-2-allyl-3-aza-5-(9H-9-fluorenylmethyloxy-
carboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-
chromenylsulfonyl)guanidino]-4-oxooctanoate (24)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 6 (287 mg, 1.74 mmol)
and (2S)-2-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-
pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]pe-
5.5.2. Methyl (2S,5S)-2-allyl-3-aza-9-(tert-butoxycarboxamido)-5-
(9H-9-fluorenylmethyloxycarboxamido)-4-oxononanoate (22)
To a solution of 6 (430 mg, 2.61 mmol) and (2S)-6-tert-butoxy-
carboxamido-2-(9H-9-fluorenylmethyloxy)carboxamido hexanoic
acid (1.22 g, 2.61 mmol) in CH2Cl2 (10 mL) was added EDCI (500 mg,
2.61 mmol) and a catalytic quantity of DMAP. The resulting mixture
was allowed to stir at rt for 16 h. The reaction was diluted with
ntanoic acid (961 mg, 1.45 mmol) to afford 24 (936 mg, 1.21 mmol,
23
83%) as a brown solid. [
a
]
D
þ12.1 (c 0.013, MeOH). IR (neat) nmax
1543, 1450, 1233, 1109, 741. Mp 90–94 ꢀC. 1H NMR (CDCl3,
300 MHz):
d
7.71 (d, J¼7.5 Hz, 2H, ArH100 and ArH800), 7.54 (d,
J¼7.0 Hz, 2H, ArH400 and ArH500), 7.39 (br s,1H, NH), 7.34 (t, J¼7.5 Hz,
2H, ArH300 and ArH600), 7.22 (t, J¼7.5 Hz, 2H, ArH200 and ArH700), 6.34

T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
11279
(br s, 1H, NH), 6.12 (d,0J¼7.5 Hz 1H, NH), 5.71–5.58 (m, 1H, H20), 5.03
900-CH2), 4.06 (t, J¼7.2 Hz,1H, H900), 3.63 (s, 3H, OCH3), 3.23 (br s, 2H,
H8), 2.57 (s, 3H, 7%-CH3), 2.54 (s, 3H, 5%-CH3), 2.41–2.51 (m, 4H,
H10 and H4%), 2.07 (s, 3H, 8%-CH3), 1.86–1.94 (m, 2H, H6), 1.70 (t,
J¼6.7 Hz, 2H, H3%), 1.54–1.62 (m, 2H, H7), 1.23 (s, 6H, 2ꢁ2%-CH3).
0
(d, J¼17.0 Hz, 1H, H3a ), 4.98 (d, J¼10.0 Hz, 1H, H3b ), 4.57–4.50 (m,
1H, H2), 4.40–4.32 (m, 1H, H5), 4.29 (d, J¼7.2 Hz, 2H, OCH2-H900),
4.13–4.08 (m, 1H, H900), 3.65 (s, 3H, OCH3), 3.34–3.14 (m, 2H, H8),
2.58 (s, 3H, 7%-CH3), 2.55 (s, 3H, 5%-CH3), 2.54–2.42 (m, 4H, H10
and H4%), 2.07 (s, 3H, 8%-CH3), 1.95–1.82 (m, 2H, H6), 1.73 (t,
J¼6.5 Hz, 2H, H3%), 1.65–1.54 (m, 2H, H7), 1.26 (s, 6H, 2ꢁ2%-CH3).
13C NMR (CDCl3, 75 MHz):
d 172.0, C4; 171.8, C1; 156.2, ArC6%;
153.2, 5-NCO2; 143.6, CN3; 143.5, ArC8a%; 141.0, ArC8a00 and
ArC9a00; 135.3, ArC4a00 and ArC4b00; 134.7, ArC7%; 133.1, ArC5%;
132.3, C20; 127.5, ArC300 and ArC600; 126.9, ArC200 and ArC700; 125.0,
ArC400 and ArC500; 123.9, ArC8%; 119.7, ArC100 and ArC800; 118.8, C30;
117.8, ArC4a; 73.5, C2%; 67.2, 900-CH2; 52.3, C5; 52.2, C2; 51.9, OCH3;
47.0, C900; 40.5, C8; 35.9, C10; 32.7, C3%; 30.0, C6; 26.7, C2%-CH3;
25.5, C7; 21.4, 5%-CH3; 18.6, 7%-CH3; 17.6, C4%; 12.1, 8%-CH3. MS
(ESI, þve) m/z 774 (12%) [MHþ], 130 (100%) [allylGly]. HRMS calcd
for C41H52N5O8S 774.3537, found 774.3536.
13C NMR (CDCl3, 75 MHz):
d 172.0, C4; 171.0, C1; 156.3, ArC6%;
153.5, 5-NCO2; 143.6, CN3; 143.5, ArC8a%; 141.0, ArC8a00 and
ArC9a00; 137.8, ArC4a00 and ArC4b00; 135.3, ArC7%; 134.7, ArC5%;
132.9, C20; 127.5, ArC300 and ArC600; 126.9, ArC200 and ArC700; 125.0,
ArC400 and ArC500; 124.0, ArC8%; 119.8, ArC100 and ArC800; 118.8, C30;
117.8, ArC4a; 73.6, C2%; 67.2, CH2-C900; 54.1, C5; 52.4, C2; 52.3,
OCH3; 47.0, C900; 40.5, C8; 35.7, C10; 32.7, C3%; 29.9, C6; 26.8, C2%-
CH3; 25.2, C7; 21.4, 5%-CH3; 18.6, 7%-CH3; 17.6, C4%; 12.2, 8%-CH3.
MS (ESI, þve) m/z 774 (20%) [MHþ], 130 (100%) [allylGly]. HRMS
calcd for C41H52N5O8S 774.3537, found 774.3517.
5.6. Synthesis of deprotected dipeptides (8, 27–31)
5.6.1. Methyl (2S,5R)-2-allyl-5-amino-3-aza-9-(tert-butoxy-
carboxamido)-4-oxononanoate (8)
The title compound was synthesized using the general N-Fmoc
deprotection procedure (Procedure C), from 7 (715 mg, 1.23 mmol)
to yield 8 (436 mg, 1.22 mmol, 99%) as a cream oil, and was spec-
troscopically identical to that reported in the literature.9
5.5.5. Methyl (2R,5R)-2-allyl-3-aza-5-(9H-9-fluorenylmethyloxy-
carboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-
chrome-nylsulfonyl)guanidino]-4-oxooctanoate (25)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 21 (287 mg, 1.74 mmol)
and (2R)-2-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-
pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]pe-
5.6.2. Methyl (2S,5S)-2-allyl-5-amino-3-aza-9-(tert-
ntanoic acid (961 mg, 1.45 mmol) to afford 25 (1.01 g, 1.31 mmol,
butoxycarboxamido)-4-oxononanoate (27)
23
90%) as a brown solid. [
a
]
þ5.3 (c 0.008, MeOH). IR (neat) nmax
The title compound was synthesized using the general N-Fmoc
deprotection procedure (Procedure C), from 22 (1.27 g, 2.19 mmol)
to yield 27 (778 mg, 2.18 mmol, 100%) as a cream oil. 1H NMR
D
1724, 1545, 1449, 1236, 1167, 1108, 742. Mp 96–98 ꢀC. 1H NMR
(CDCl3, 500 MHz):
d
7.70 (d, J¼7.5 Hz, 2H, ArH100 and ArH800), 7.53
(d, J¼5.0 Hz, 2H, ArH400 and ArH500), 7.40 (d, J¼4.5 Hz, 1H, NH), 7.34
(t, J¼7.5 Hz, 2H, ArH300 and ArH600), 7.22 (t, J¼7.5 Hz, 2H, ArH200 and
ArH700), 6.34 (s, 2H, NH), 6.12 (br s, 2H, NH), 5.69–5.55 (m, 1H, H20),
(CDCl3, 300 MHz):
d
7.81 (d, J¼8.0 Hz, 1H, NH), 5.85–5.45 (m, 1H,
H20), 5.15–5.02 (m, 2H, H30), 4.76 (br s, 1H, NH), 4.60–4.50 (m, 1H,
H2), 3.75 (s, 3H, OCH3), 3.39 (dd, J¼4.6, 7.6 Hz, 1H, H5), 3.12 (d,
J¼6.3 Hz, 2H, H9), 2.65–2.42 (m, 2H, H10), 1.85–1.45 (m, 8H, H6, H7,
H8 and NH2), 1.44 (s, 9H, C(CH3)3). 13C NMR (CDCl3, 75 MHz):
0
0
5.03 (d, J¼17.0 Hz, 1H, H3a ), 4.98 (d, J¼10.0 Hz, 1H, H3b ), 4.53 (dd,
J¼7.2, 12.9 Hz, 1H, H2), 4.36 (dd, J¼8.5, 12.5 Hz, 1H, H5), 4.29 (d,
J¼7.0 Hz, 2H, 900-CH2), 4.08–4.04 (m, 1H, H900), 3.65 (s, 3H, OCH3),
3.28–3.17 (m, 2H, H8), 3.22 (br s, 1H, NH), 2.58 (s, 3H, 7%-CH3), 2.55
(s, 3H, 5%-CH3), 2.51–2.39 (m, 4H, H10 and H4%), 2.07 (s, 3H, 8%-
CH3), 1.96–1.80 (m, 2H, H7), 1.73 (t, J¼6.5 Hz, 2H, H3%), 1.66–1.54
(m, 2H, H6), 1.25 (s, 6H, 2ꢁ2%-CH3). 13C NMR (CDCl3, 75 MHz):
d
174.8, C4; 172.1, C1; 156.0, NCO2; 132.2, C20; 118.9, C30; 78.9,
C(CH3)3; 54.8, C5; 52.2, C2; 51.1, OCH3; 40.0, C9; 36.4, C10; 34.4, C6;
29.7, C8; 28.3, C(CH3)3; 22.6, C7. MS (ESI, þve) m/z 358.5 (85%)
[MHþ], 258.4 (100%) [MHþꢂ(Boc)]. HRMS calcd for C17H32N3O5
358.2342, found 358.2339.
d
172.0, C4; 171.8, C1; 156.2, ArC6%; 153.4, 5-NCO2; 143.6, ArC8a%;
143.5, CN3; 141.0, ArC8a00 and ArC9a00; 135.2, ArC4a00 and ArC4b00;
134.6, ArC7%; 133.0, ArC5%; 132.2, C20; 127.5, ArCH300 and ArCH600;
126.8, ArCH200 and ArCH700; 125.0, ArCH400 and ArCH500; 123.8,
ArC8%; 119.7, ArCH100 and ArCH800; 118.6, C30; 117.8, ArC4a%; 73.5,
C2%; 67.0, 900-CH3; 52.3, C5; 52.1, C2; 52.2, OCH3; 47.0, C900; 40.4, C8;
35.7, C10; 32.7, C3%; 29.8, C6; 26.7, C2%-CH3; 25.3, C7; 21.4, C5%-
CH3; 18.6, C7%-CH3; 17.5, C4%; 12.1, C8%-CH3. MS (ESI, þve) m/z 774
(100%) [MHþ]. HRMS calcd for C41H52N5O8S 774.3537, found
774.3524.
5.6.3. Methyl (2S,5R)-2-allyl-5-amino-3-aza-8-[(2,2,5,7,8-penta-
methyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]-4-
oxooctanoate (28)
The title compound was synthesized using the general N-Fmoc
deprotection procedure (Procedure C), from 23 (717 mg,
0.93 mmol) to yield 28 (407 mg, 0.74 mmol, 80%) as a cream oil, and
was spectroscopically identical to that reported in the literature.11
5.6.4. Methyl (2S,5S)-2-allyl-5-amino-3-aza-8-[(2,2,5,7,8-penta-
methyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]-4-
oxooctanoate (29)
The title compound was synthesized using the general N-Fmoc
deprotection procedure (Procedure C), from 24 (749 mg,
5.5.6. Methyl (2R,5S)-2-allyl-3-aza-5-(9H-9-fluorenylmethyloxy-
carboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-
chromenylsulfonyl)guanidino]-4-oxooctanoate (26)
The title compound was synthesized using the general
peptide coupling procedure (Procedure B), from 21 (287 mg,
1.74 mmol) and (2S)-2-(9H-9-fluorenylmethyloxycarboxamido)-8-
[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)gua-
0.97 mmol) to yield 29 (259 mg, 0.47 mmol, 48%) as a cream oil,
23
[a
]
ꢂ12.2 (c 0.013, MeOH), which was spectroscopically identical
D
to that reported.11
nidino]pentanoic acid (961 mg, 1.45 mmol) to afford 26 (1.00 g,
5.6.5. Methyl (2R,5R)-2-allyl-5-amino-3-aza-8-[(2,2,5,7,8-penta-
methyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]-4-
oxooctanoate (30)
23
1.29 mmol, 89%) as a brown foam. [
a
]
þ60.2 (c 0.006, MeOH). IR
D
(neat) nmax 1667, 1541, 1449, 1237, 1166, 1107, 761, 741. Mp 90–92 ꢀC.
1H NMR (CDCl3, 300 MHz):
d
7.70 (d, J¼7.6 Hz, 2H, ArH100 and
The title compound was synthesized using the general N-Fmoc
deprotection procedure (Procedure C), from 25 (693 mg,
0.900 mmol) to yield 30 (387 mg, 0.0700 mmol, 78%) as a cream oil.
ArH800), 7.51 (d, J¼7.6 Hz, 2H, ArH400 and ArH500), 7.33 (t, J¼7.2 Hz,
2H, ArH300 and ArH600), 7.20 (t, J¼7.2 Hz, 2H, ArH200 and ArH700), 6.42
(d, J¼7.6 Hz, 1H, NH), 6.34 (s, 1H, NH), 6.20 (br s, 1H, NH), 5.60–5.69
1H NMR (CDCl3, 300 MHz):
d
7.87 (d, J¼7.5 Hz, 1H, NH), 6.35 (br s,
(m, 01H, H20), 5.02 (d, J¼18.1 Hz, 1H, H3a ), 4.97 (d, J¼10.5 Hz, 1H,
3H, NH), 5.75–5.61 (m, 1H, H20), 5.09 (d, J¼16.2 Hz, 1H, H3a ), 5.09
0
0
0
H3b ), 4.53 (dd, J¼7.6, 13.1 Hz, 1H, H2), 4.26 (d, J¼7.2 Hz, 3H, H5 and
(d, J¼12.0 Hz, 1H, H3b ), 4.56–4.50 (m, 1H, H2), 3.72 (s, 3H, OCH3),

11280
T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
3.43–3.40 (m 1H, H5), 3.19 (d, J¼5.4 Hz, 2H, H8), 2.56 (s, 3H, 700-
CH3), 2.54 (s, 3H, 500-CH3), 2.66–2.50 (m, 2H, H10), 2.10 (s, 3H, 800-
CH3), 2.05 (br s, 2H, H7), 1.80 (t, J¼6.3 Hz, 2H, H200), 1.58–1.56 (m,
and water (2ꢁ25 mL) and dried, before being concentrated by
evaporation. The crude product was purified by flash column
chromatography (25:1, CH2Cl2/MeOH) to afford the title compound
(664 mg, 1.10 mmol, 50%) as a 1:1 mixture of two epimers, as
2H, H6), 1.30 (s, 6H, 2ꢁ200-CH3). 13C NMR (CDCl3, 75 MHz):
d 175.2,
C4; 172.0, C1; 156.1, ArC600; 153.4, CN3; 135.3, ArC700; 134.6, ArC500;
133.2, ArC8a00; 132.2, C20; 123.9, ArC800; 118.9, C30; 117.8, ArC4a;
73.6, C200; 54.2, C5; 52.4, OCH3; 51.6, C2; 40.6, C8; 36.2, C10; 32.8,
C400; 32.0, C6; 26.8, 200-CH3; 25.3, C7; 21.5, C300; 18.6, 500-CH3; 17.5,
700-CH3; 12.2, 800-CH3. MS (ESI, þve) m/z 552.1 (40%) [MHþ], 243.0
(100%) [MHþ less allylGly]. HRMS calcd for C26H42N5O6S 552.2856,
found 552.2829.
a white solid. Mp 112–114 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 7.09 (m,
2H, ArH2% and ArH6%), 6.91 (d, J¼8 Hz, 1H, NH), 6.88–6.79 (m, 2H,
ArH3% and ArH5%), 6.69 (d, J¼8.0 Hz, 1H, NH), 6.55 (br s, 1H, NH),
6.10–5.97 (m, 1H, H1&), 5.77–5.60 (m, 1H, H20), 5.42–5.24 (m, 4H,
H30 and H3&), 4.96 (br s, 1H, H2), 4.86 (br s, 1H, H8), 4.80–4.60 (m,
2H, H2&), 4.48 (dd, J¼3.0, 8.4 Hz, 1H, H5), 3.74/3.71 (s, 3H, OCH3),
3.12–2.92 (m, 4H, H400 and ArCH2), 2.57–2.44 (m, 2H, H10), 1.98/1.96
(s, 3H, H11), 1.79 (s, 2H, H200), 1.60 (s, 2H, H100), 1.43 (s, 9H, C(CH3)3),
5.6.6. Methyl (2R,5S)-2-allyl-5-amino-3-aza-8-[(2,2,5,7,8-penta-
methyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]-4-
oxooctanoate (31)
The title compound was synthesized using the general N-Fmoc
deprotection procedure (Procedure C), from 26 (788 mg,
1.28 (s, 2H, H300). 13C NMR (CDCl3, 75 MHz):
d 171.8, C7; 171.7, C1;
171.4/171.2, C4; 170.3, C10; 157.3/157.2, NCO2; 155.9, ArC4%; 133.1/
133.0, C20; 130.2/130.1, ArCH2% and ArCH6%; 128.8/128.7, ArC1%;
118.6, C30; 117.5/117.4, C3&; 114.4/114.3, ArCH3% and ArCH5%; 78.6,
C(CH3)3; 68.5, C1qprime;; 54.0, C5; 52.4, OCH3; 52.1, C8; 52.1, C2;
39.9, C400; 38.0, ArCH2; 35.8, C10; 32.7/32.2, C100; 29.6/29.3, C300;
28.3, C(CH3)3; 22.9/22.7, C11; 22.3/22.0, C200. MS (ESI, þve) m/z
603.4 (35%) [MHþ], 503.4 (100%) [MHþ (less Boc)]. HRMS calcd for
C31H47N4O8 603.3394, found 603.3397.
1.01 mmol) to yield 31 (552 mg, 1.00 mmol, 99%) as a cream oil.
23
[
a]
þ11.6 (c 0.017, MeOH). IR (neat) nmax 1672, 1543, 1445, 1238,
D
1166, 1109. 1H NMR (CDCl3, 300 MHz):
d
7.86 (d, J¼7.5 Hz, 1H, NH),
6.33 (br s, 3H, NH), 5.74–5.60 (m, 1H, H20), 5.12 (d, J¼16.8 Hz, 1H,
0
0
H3a ), 5.11 (d, J¼10.8 Hz, 1H, H3b ), 4.53 (dd, J¼7.2, 12.9 Hz, 1H, H2),
3.71 (s, 3H, OCH3), 3.41 (d, J¼7.2 Hz, 1H, H5), 3.23–3.15 (m, 2H, H8),
2.64–2.43 (m, 2H, H10), 2.57 (s, 3H, 700-CH3), 2.55 (s, 3H, 500-CH3),
2.10 (s, 3H, 800-CH3), 1.82–1.71 (m, 4H, H7 and H300), 1.63–1.52 (m,
5.7.3. Methyl (2S,5R,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-
5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}-
guanidino]propyl)-4,7,10-trioxoundecanoate (33)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B) using 28 (387 mg, 0.70 mmol)
and 14 (153 mg, 0.58 mmol) to afford 33 (336 mg, 0.42 mmol, 73%)
as a light brown solid. IR (neat) nmax 1653, 1636, 1539, 1508, 1241,
2H, H6), 1.30 (s, 6H, 2ꢁ200-CH3). 13C NMR (CDCl3, 75 MHz):
d
175.2,
C4; 172.0, C1; 156.1, ArC600; 153.3, CN3; 135.3, ArC700; 134.6, ArC500;
133.2, ArC8a00; 132.2, C20; 123.9, ArC800; 119.0, C30; 117.8, ArC4a00;
73.6, C200; 54.2, C5; 52.3, OCH3; 51.5, C2; 40.7, C8; 36.1, C10; 32.8,
C400; 31.9, C6; 26.8, 200-CH3; 25.2, C7; 21.5, C300; 18.5, 500-CH3; 17.5,
700-CH3; 12.2, 800-CH3. MS (ESI, þve) m/z 552.1 (50%) [MHþ], 162.7
(100%). HRMS calcd for C26H42N5O6S 552.2856, found 552.2834.
1107. Mp 172–176 ꢀC. 1H NMR (CDCl3, 500 MHz):
d
7.75 (d, J¼7.5 Hz,
1H, NH), 7.11 (d, J¼8.7 Hz, 2H, ArH2& and ArH6&), 6.78 (d,
J¼8.4 Hz, 2H, ArH3& and ArH5&), 6.36 (br s, 2H, NH), 6.18 (br s, 1H,
NH), 6.05–5.92 (m, 1H, H2&0), 5.76–5.62 (m, 1H, H20), 5.36 (dd,
J¼1.5, 17.4 Hz, 1H, H3a0&0), 5.24 (dd, J¼1.5, 10.5 Hz, 1H, H3b&0), 5.08
5.7. Synthesis of protected tripeptides (9, 32–37)
0
(d, J¼15.6 Hz, 1H, H3a ), 5.04 (d, J¼8.4 Hz, 1H, H3b ), 4.52–4.44 (m,
5.7.1. Methyl (2S,5R,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-
5-(4-[tert-butoxycarboxamido]butyl)-4,7,10-trioxoundecanoate (9)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 8 (440 mg, 1.20 mmol) and
14 (270 mg, 1.03 mmol) to afford 9 (424 mg, 0.70 mmol, 69%) as
2H, H2 and H5), 4.42 (d, J¼4.8 Hz, 1H, H1&0), 4.38–4.28 (m, 1H, H8);
3.69 (s, 3H, OCH3), 3.14–3.00 (m, 2H, H300), 3.01–2.85 (m, 2H,
ArCH2), 2.63 (t, J¼6.9 Hz, 2H, H4%), 2.59 (s, 3H, 7%-CH3), 2.57 (s, 3H,
5%-CH3), 2.65–2.45 (m, 2H, H10), 2.09 (s, 3H, 8%-CH3), 1.93 (s, 3H,
H11), 1.80 (t, J¼6.6 Hz, 2H, H3%), 1.56–1.48 (m, 4H, H100 and H200),
a white solid. Mp 149–150 ꢀC. 1H NMR (CDCl3, 300 MHz):
d
7.20 (d,
1.30 (s, 6H, 2ꢁ2%-CH3). 13C NMR (DMSO, 75 MHz):
d 171.3, C4;
J¼8.0 Hz, 1H, NH), 7.11 (d, J¼8.4 Hz, 2H, ArH2% and ArH6%), 6.84
(d, J¼8.4 Hz, 2H, ArH3% and ArH5%), 6.67 (d, J¼8.0 Hz,1H, NH), 6.48
(d, J¼7.2 Hz, 1H, NH), 6.10–5.96 (m, 1H, H2&), 5.72–5.61 (m, 1H,
H20), 5.41 (dd, J¼1.3, 17.3 Hz, 1H, H3a&), 5.28 (dd, J¼1.3, 10.5 Hz, 1H,
H3b&), 5.11–5.07 (m, 2H, H30), 4.75 (t, J¼5.9 Hz, 1H, H2), 4.66–4.53
(m, 1H, H8), 4.50 (d, J¼5.5 Hz, 2H, H1&), 4.42 (dd, J¼7.6, 13.1 Hz, 1H,
H5), 3.71 (s, 3H, OCH3), 3.06–2.96 (m, 4H, H400 and ArCH2), 2.61–
2.43 (m, 2H, H10), 1.97 (s, 3H, H11), 1.44 (s, 9H, C(CH3)3), 1.42–1.32
170.9, C1; 171.0, C11; 169.1, C7; 156.5, ArC6%; 155.6, ArC8a%; 152.4,
CN3; 134.5, ArC7%; 133.9, ArC5%; 133.3, C2&0; 132.5, C20; 132.2,
ArC4&; 129.5, ArCH2& and ArCH6&; 128.3, ArC8%; 122.9, ArC1&;
117.6, ArC4a%; 117.0, C3&0; 116.8, C30; 113.9, ArCH3& and ArCH5&;
72.9, C2%; 68.0, C&0; 55.1, C2; 51.9, C5; 51.9, OCH3; 51.5, C8; 40.3,
C300; 38.6, ArCH2; 36.2, C4%; 35.2, C10; 32.2, C7; 26.2, 2%-CH3; 25.1,
C6; 22.3, C11; 20.8, C3%; 18.0, 5%-CH3; 16.9, 7%-CH3; 11.6, 8%-CH3.
MS (ESI, þve) m/z 797 (100%) [MHþ]. HRMS calcd for C40H57N6O9S
797.3908, found 797.3913.
(m, 6H, H100, H200 and H300). 13C NMR (CDCl3, 75 MHz):
d 172.0, C7;
171.1, C1; 170.7, C4; 170.2, C10; 157.4, NCO2; 155.9, ArC4%; 133.0,
C20; 132.3, C2&; 130.1, ArCH2% and ArCH6%; 128.4, ArC1%; 118.8,
C30; 117.6, C3&; 114.8, ArCH3% and ArCH5%; 79.0, C(CH3)3; 68.8,
C1&; 55.4, C5; 52.8, OCH3; 52.4, C8; 51.8, C2; 40.1, C400; 37.5, ArCH2;
36.3, C10; 31.6, C100; 29.7, C300; 28.5, C(CH3)3; 23.1, C11; 22.3, C200. MS
(ESI, þve) m/z 603.4 (40%) [MHþ], 503.4 (100%) [MHþꢂ(Boc)].
HRMS calcd for C31H47N4O8 603.3394, found 603.3389.
5.7.4. Methyl (2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-
5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}-
guanidino]propyl)-4,7,10-trioxoundecanoate (34)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 29 (236 mg, 0.43 mmol)
and 14 (95 mg, 0.36 mmol) to afford 34 (207 mg, 0.25 mmol, 72%)
24
as a light brown solid. [
a]
þ27.8 (c 0.007, MeOH). IR (neat) nmax
D
5.7.2. Methyl (2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-
5-(4-[tert-butoxycarboxamido]butyl)-4,7,10-
trioxoundecanoate (32)
To a solution of 27 (782 mg, 2.19 mmol) and 14 (576 mg,
2.19 mmol) in CH2Cl2 (10 mL) was added EDCI (420 mg, 2.19 mmol)
and a catalytic quantity of DMAP. The resulting mixture was
allowed to stir at rt for 16 h. The reaction was diluted with CH2Cl2
(25 mL) and the organic layer was washed with brine (2ꢁ25 mL)
1653, 1541, 1512, 1244, 1109. Mp 99–104 ꢀC. 1H NMR (CDCl3,
500 MHz):
d
7.77 (d, J¼7.8 Hz, 1H, NH), 7.69 (br s, 1H, NH), 7.14 (d,
J¼7.5 Hz, 1H, NH), 7.04 (d, J¼8.4 Hz, 2H, ArH2& and ArH6&), 6.74
(d, J¼8.4 Hz, 2H, ArH3& and ArH5&), 6.41 (br s, 2H, NH), 6.05–5.92
(m, 1H, H2&0), 5.76–5.62 (m, 1H, H20), 5.37 (dd, J¼1.5, 17.4 Hz, 1H,
H3a0&0), 5.25 (dd, J¼1.5, 10.5 Hz, 1H, H3b&0), 5.07 (d, J¼15.3 Hz, 1H,
0
H3a ), 5.03 (d, J¼9.3 Hz, 1H, H3b ), 4.78–4.71 (m, 1H, H2), 4.64 (br s,
1H, H5), 4.56 (dd, J¼6.9, 13.5 Hz, 2H, H8), 4.44 (d, J¼5.4 Hz, 2H,

T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
11281
H1&0), 3.68 (s, 3H, OCH3), 3.17 (d, J¼4.5 Hz, 2H, H300), 3.17–2.79 (m,
2H, ArCH2), 2.59 (t, J¼6.3 Hz, 2H, H4%), 2.55 (s, 3H, 7%-CH3), 2.53 (s,
3H, 5%-CH3), 2.62–2.43 (m, 2H, H10), 2.08 (s, 3H, 8%-CH3), 1.88 (s,
3H, H11), 1.78 (t, J¼6.3 Hz, 2H, H3%), 1.80–1.72 (m, 2H, H7), 1.61–
1.50 (m, 2H, H6), 1.29 (s, 6H, 2ꢁ2%-CH3). 13C NMR (CDCl3, 75 MHz):
C20; 132.4, ArC4%; 130.0, ArCH2& and ArCH6&; 128.7, ArC8%;
124.0, ArC1&; 118.8, ArC4a%; 117.9, C3&0; 117.4, C30; 114.1, ArCH3&
and ArCH5&; 73.6, C2%; 68.7, C1&0 55.3, C2; 52.9, C5; 52.3, OCH3;
52.2, C8; 40.7, C300; 37.0, ArCH2; 36.1, C4%; 32.8, C10; 29.3, C7; 26.8,
2%-CH3; 25.3, C6; 22.9, C11; 21.5, C3%; 18.6, 5%-CH3; 17.6, 7%-CH3;
12.2, 8%-CH3. MS (ESI, þve) m/z 819 (100%) [MNaþ]. HRMS calcd for
C40H57N6O9S 797.3908, found 797.3873.
d
172.0, C4; 171.8, C1; 171.5, C11; 171.0, C7; 157.2, ArC6%; 156.2,
ArC8a%; 153.4, CN3; 135.2, ArC7%; 134.6, ArC5%; 133.1, C2&0; 133.1,
C20; 132.3, ArC4%; 130.1, ArCH2& and ArCH6&; 128.6, ArC8%;
123.9, ArC1&; 118.6, ArC4a%; 117.8, C3&0; 117.4, C30; 114.5, ArCH3&
and ArCH5&; 73.6, C2%; 68.6, C1&0; 60.4, C2; 54.8, C5; 52.3, OCH3;
52.2, C8; 40.7, C300; 37.2, ArCH2; 36.0, C4%; 32.8, C10; 29.7, C7; 26.8,
2%-CH3; 25.3, C6; 22.9, C11; 21.5, C3%; 18.6, 5%-CH3; 17.6, 7%-CH3;
12.2, 8%-CH3. MS (ESI, þve) m/z 797 (100%) [MHþ]. HRMS calcd for
C40H57N6O9S 797.3908, found 797.3890.
5.7.7. Methyl (2S,5S,8R)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-
5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}-
guanidino]propyl)-4,7,10-trioxoundecanoate (37)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 29 (654 mg, 1.19 mmol)
and 19 (260 mg, 0.99 mmol) to afford 37 (683 mg, 0.86 mmol, 87%)
as a light brown solid. Mp 200–204 ꢀC. 1H NMR (CDCl3, 300 MHz):
5.7.5. Methyl (2R,5R,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-
5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}-
guanidino]propyl)-4,7,10-trioxoundecanoate (35)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B) using 30 (387 mg, 0.700 mmol)
d
7.10 (d, J¼8.4 Hz, 2H, ArH2& and ArH6&), 6.90 (d, J¼4.8 Hz, 1H,
NH), 6.57 (d, J¼8.4 Hz, 2H, ArH3& and ArH5&), 6.34 (d, J¼7.5 Hz,
1H, NH), 6.19 (br s, 2H, NH), 6.08–5.94 (m, 1H, H2&0), 5.79–5.60 (m,
1H, H20), 5.37 (dd, J¼1.8, 17.1 Hz,1H, H3a&0), 5.26 (dd, J¼1.8,10.5 Hz,
1H, 0H3b&0), 5.11 (d, J¼12.0 Hz, 1H, H3a ), 5.03 (d, J¼10.0 Hz, 1H,
0
and 14 (153 mg, 0.580 mmol) to afford 35 (297 mg, 0.37 mmol, 64%)
H3b ), 4.57–4.42 (m, 5H, H2, H5, H8 and H1&0), 3.70 (s, 3H, OCH3),
3.20–3.10 (m, 2H, H300), 3.01–2.98 (m, 2H, ArCH2), 2.63 (t, J¼6.3 Hz,
2H, H4%), 2.59 (s, 3H, 7%-CH3), 2.57 (s, 3H, 5%-CH3), 2.65–2.53 (m,
2H, H10), 2.11 (s, 3H, 8%-CH3), 1.96 (s, 3H, H11), 1.80 (t, J¼6.3 Hz, 2H,
H3%), 1.60–1.48 (m, 2H, H6), 1.30 (s, 6H, 2ꢁ2%-CH3). 13C NMR
23
as a light brown solid. [
a]
þ0.96 (c 0.011, acetone). IR (neat) nmax
D
1645, 1540, 1514, 1245, 1110, 804. Mp 217–220 ꢀC. 1H NMR (CDCl3,
500 MHz):
d
7.22 (br s, 1H, NH), 7.10 (d, J¼8.0 Hz, 2H, ArH2& and
ArH6&), 6.88 (br s, 1H, NH), 6.82 (d, J¼8.5 Hz, 2H, ArH3& and
ArH5&), 6.31 (d, J¼7.0 Hz,1H, NH), 6.17 (br s,1H, NH), 6.04–5.97 (m,
1H, H2&0), 5.73–5.65 (m, 1H, H20), 5.38 (d, J¼17.0 Hz, 1H, H3a&0),
(CDCl3, 75 MHz):
d 171.6, C4; 171.5, C1; 171.3, C11; 169.4, C7; 156.7,
ArC6%; 156.0, ArC8a%; 152.4, CN3; 134.6, ArC7%; 134.1, ArC5%;
133.8, C2&0; 133.7, C20; 133.6, ArC4%; 130.2, ArCH2& and ArCH6&;
129.7, ArC8%; 122.7, ArC1&; 118.0, ArC4a%; 117.7, C3&0; 117.2, C30;
114.1, ArCH3& and ArCH5&; 73.4, C2%; 68.0, C1&0; 54.5, C2; 52.0,
C5; 51.7, OCH3; 51.6, C8; 40.1, C300; 39.8, ArCH2; 37.0, C4%; 32.1, C10;
29.2, C7; 26.4, 2%-CH3; 25.1, C6; 22.4, C11; 20.8, C3%; 18.2, 5%-CH3;
17.1, 7%-CH3; 11.9, 8%-CH3. MS (ESI, þve) m/z 797 (40%) [MHþ], 106
(100%). HRMS calcd for C40H57N6O9S 797.3908, found 797.3926.
5.26 (d, J¼10 Hz, 1H, H3b&0), 5.11 (d, J¼17.0 Hz, 1H, H3a ), 5.08 (d,
0
0
J¼10.5 Hz, 1H, H3b ), 4.58–4.54 (m, 1H, H2), 4.53–4.47 (m, 3H, H5
and H1&0), 4.43 (d, J¼7.5 Hz, 1H, H8), 3.71 (s, 3H, OCH3), 3.15 (br s,
2H, H300), 3.04–2.97 (m, 2H, ArCH2), 2.63 (t, J¼6.5 Hz, 2H, H4%), 2.59
(s, 3H, 7%-CH3), 2.57 (s, 3H, 5%-CH3), 2.55–2.50 (m, 2H, H10), 2.11 (s,
3H, 8%-CH3), 1.97 (s, 3H, H11), 1.80 (t, J¼6.5 Hz, 2H, H3%), 1.58 (s,
6H, 2ꢁ2%-CH3), 1.30 (s, 4H, H100 and H200). 13C NMR (DMSO,
75 MHz):
d 171.3, C4; 171.1, C1; 171.0, C11; 169.1, C7; 156.5, ArC6%;
155.7, ArC8a%; 152.1, CN3; 135.4, ArC7%; 133.9, ArC5%; 133.7, C2&0;
133.3, C20; 130.0, ArC4&; 129.5, ArCH2& and ArCH6&; 129.4,
ArC8%; 122.5, ArC1&; 117.8, ArC4a%; 117.6, C3&0; 117.1, C30; 114.0,
ArCH3& and ArCH5&; 73.4, C2%; 68.0, C&0; 54.4, C2; 51.9, C5; 51.7,
OCH3; 51.6, C8; 36.9, C300; 35.0, ArCH2; 32.1, C4%; 29.3, C10; 26.5, C7;
26.4, 2%-CH3; 25.1, C6; 22.4, C11; 20.8, C3%; 18.2, 5%-CH3; 17.1, 7%-
CH3; 12.0, 8%-CH3. MS (ESI, þve) m/z 797.4 (100%) [MHþ]. HRMS
calcd for C40H57N6O9S 797.3908, found 797.3915.
5.8. Synthesis of protected cyclic tripeptides (10, 38–43)
5.8.1. (7S,10R,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(4-[tert-
butoxycarboxamido]butyl)-7-methoxycarbonyl-2-oxa-9,12-
dioxo-1(1,4)phenylenacyclotetradecaphane-4-ene (10)
The title compound was prepared using the general procedure
for olefin metathesis (Procedure D), from 9 (277 mg, 0.46 mmol) to
yield 10 (199 mg, 0.35 mmol, 75%) as a brown solid. Mp 178–180 ꢀC.
1H NMR (CDCl3, 300 MHz):
d 8.13–7.72 (m, 2H, NH), 7.13–7.03 (m,
5.7.6. Methyl (2R,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-
5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}-
guanidino]propyl)-4,7,10-trioxoundecanoate (36)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 31 (513 mg, 0.930 mmol)
2H, ArH), 6.90–6.65 (m, 2H, ArH), 5.87–5.39 (m, 2H, H4 and H5),
4.65–4.36 (m, 4H, H7, H13 and H3), 4.20–4.06 (m, 2H, NH and H10),
3.61–3.57 (m, 3H, OCH3), 2.87–2.69 (br s, 4H, H40 and H14), 2.58–
2.38 (m, 2H, H6), 1.82–1.75 (m, 3H, NCOCH3), 1.31–0.79 (m, 6H, H10,
H20 and H30), 1.35 (s, 9H, C(CH3)3). 13C NMR (CDCl3, 75 MHz):
and 14 (204 mg, 0.78 mmol) to afford 36 (496 mg, 0.622 mmol,
d 172.8, C9; 172.3, 7-CO; 171.7, 13-NCO; 171.6, C12; 157.2, NCO2;
23
80%) as a light brown solid. [
a
]
þ21.6 (c 0.007, MeOH). IR (neat)
156.5, 1-ArC1; 130.3, 1-ArCH2 and 1-ArCH6; 130.2, C4; 128.6, C5;
127.6, 1-ArCH4; 117.7, 1-ArCH3 and 1-ArCH5; 78.7, C(CH3)3; 66.9,
C3; 55.7, C13; 54.4, C10; 54.1, C40; 51.8, C40; 40.1, C7; 36.0, C14; 29.4,
C10; 27.8, C6; 26.8, C30; 26.2, C(CH3)3; 22.6, NCOCH3; 21.7, C20. MS
(ESI, þve) m/z 575.3 (20%) [MHþ], 475.3 (100%) [MHþꢂ(Boc)].
HRMS calcd for C29H43N4O8 575.3081, found 575.3091.
D
nmax 1653, 1558, 1541, 1508, 1248, 1109. Mp 98–102 ꢀC. 1H NMR
(CDCl3, 500 MHz):
7.71 (d, J¼7.0 Hz, 1H, NH), 7.40 (d, J¼7.0 Hz, 1H,
d
NH), 7.06 (d, J¼8.5 Hz, 2H, ArH2& and ArH6&), 6.99 (br s, 1H, NH),
6.76 (d, J¼9.0 Hz, 2H, ArH3& and ArH5&), 6.38 (br s, 2H, NH), 6.20
(br s, 1H, NH), 6.05–5.98 (m, 1H, H2&0), 5.73–5.65 (m, 1H, H20), 5.38
(dd, J¼1.5, 17.0 Hz, 1H, H30a&0), 5.25 (dd, J¼1.0, 11.0 Hz,01H, H3b&0),
5.09 (d, J¼17.5 Hz, 1H, H3a ), 5.06 (d, J¼10.5 Hz, 1H, H3b ), 4.68–4.64
(m, 1H, H2), 4.57–4.52 (m, 2H, H5 and H8), 4.45 (d, J¼5.5 Hz, 2H,
H1&0), 3.67 (s, 3H, OCH3), 3.20 (d, J¼4.5 Hz, 2H, H300), 3.13–2.81 (m,
2H, ArCH2), 2.61 (t, J¼6.0 Hz, 2H, H4%), 2.57 (s, 3H, 7%-CH3), 2.55 (s,
3H, 5%-CH3), 2.50–2.45 (m, 2H, H10), 2.09 (s, 3H, 8%-CH3), 1.88 (s,
3H, H11), 1.79 (t, J¼7.0 Hz, 2H, H3%), 1.75–1.73 (m, 2H, H7), 1.60–
1.52 (m, 2H, H6), 1.30 (s, 6H, 2ꢁ2%-CH3). 13C NMR (CDCl3, 75 MHz):
5.8.2. (7S,10S,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(4-[tert-
butoxycarboxamido]butyl)-7-methoxycarbonyl-2-oxa-9,12-
dioxo-1(1,4)phenylenacyclotetradecaphane-4-ene (38)
The title compound was prepared using the general procedure
for olefin metathesis (Procedure D) using 32 (311 mg, 0.52 mmol)
to yield 38 as a mixture of epimers and E/Z isomers (228 mg,
0.40 mmol, 76%) as a brown solid. Mp 196–201 ꢀC. 1H NMR (CDCl3,
d
172.2, C4; 171.9, C1; 171.3, C11; 170.9, C7; 157.3, ArC6%; 156.2,
300 MHz):
d 7.62–7.46 (m, 2H, NH), 7.34 (br s, 1H, NH), 7.11–7.01
ArC8a%; 153.5, CN3; 135.3, ArC7%; 134.7, ArC5%; 133.2, C2&0; 133.1,
(m, 2H, ArH), 6.81/6.73 (d, J¼8.0 Hz, 2H, ArH), 5.66 (d, J¼16.4 Hz,

11282
T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
1H, H4-trans), 5.57–5.36 (m, 1H, H5), 5.52–4.84 (m, 2H, H7 and
H13), 4.76–4.56 (m, 3H, H2 and H10), 3.80/3.77 (s, 3H, OCH3),
3.15–2.98 (m, 4H, H6 and H40), 2.80–2.58 (m, 2H, H14), 2.10 (s, 3H,
NCOCH3), 1.50–1.19 (m, 6H, H10, H20 and H30), 1.44/1.40 (s, 9H,
to yield 41 (160 mg, 0.210 mmol, 99%) as a grey solid. Mp 205–
207 ꢀC. 1H NMR (CD3OD, 300 MHz):
8.10–8.00 (m, 2H, NH), 7.10–
d
6.95 (m, 2H, ArH), 6.80–6.60 (m, 2H, ArH), 6.48 (br s, 1H, NH),
5.90–5.60 (m, 2H, NH), 5.60–5.30 (m, H4 and H5), 4.62 (br s, 2H,
H3), 4.60–4.25 (m, 3H, H7, H10 and H13), 3.66 (s, 3H, OCH3), 3.30–
2.80 (m, 4H, H30 and H14), 2.70–2.50 (m, 6H, 500-CH3 and 700-CH3),
2.50–2.30 (m, 2H, H400), 2.00 (s, 3H, 800-CH3), 1.75 (s, 3H, NCOCH3),
1.60–1.40 (m, 2H, H10), 1.34 (br s, 2H, H300), 1.27 (s, 6H, 2ꢁ200-CH3).
C(CH3)3). 13C NMR (CDCl3, 75 MHz):
d 172.5, C9; 171.5/171.3, 7-CO;
170.8/170.7, 13-NCO; 170.0, C12; 156.9, NCO2; 156.3, 1-ArC1; 130.1,
1-ArCH2 and 1-ArCH6; 128.5, C4; 128.1, C5; 127.7, 1-ArCH4; 117.0/
115.4, 1-ArCH3 and 1-ArCH5; 79.1, C(CH3)3; 66.2, C3; 55.0, C13;
53.2/53.0, C10; 52.4, C40; 40.5/39.7, C7; 35.9/35.1, C14; 29.8/29.4,
C10; 28.6, C6; 27.2/27.0, C30; 26.6, C(CH3)3; 23.7/23.4, NCOCH3;
22.7, C20. MS (ESI, þve) m/z 575.3 (25%) [MHþ], 475.3 (40%)
[MHþꢂ(Boc)]. HRMS calcd for C29H43N4O8 575.3081, found
575.3092.
13C NMR (CD3OD, 125 MHz):
d 171.8, COOCH3; 171.7, C11; 171.4,
C9; 171.1, NCOCH3; 157.0, ArC600; 155.9, CN3; 155.5, 1-ArC4; 152.4,
ArC8a00; 134.2, ArC500; 134.0, ArC700; 130.4, 1-ArCH2 and 1-ArCH6;
129.6, 1-ArC1; 128.7, C4; 127.5, C5; 122.8, ArC800; 117.7, ArC4a; 114.2,
1-ArCH3 and 1-ArCH5; 73.5, C200; 66.4, C3; 55.0, C7; 53.3, C10; 52.9,
C13; 52.3, C30; 51.9, OCH3; 40.6, C6; 37.4, C14; 32.2, NCOCH3; 26.7,
200-CH3; 22.5, C300; 21.0, C400; 18.2, 500-CH3; 17.2, 700-CH3; 15.2, C20;
12.0, 800-CH3. MS (ESI, ꢂve) m/z 769.5 (85%) [MHþ]. HRMS calcd for
C38H53N6O9S 769.3595, found 769.3631.
5.8.3. (7S,10R,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3[{2,2,5,7,8-
pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]-
propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)-
phenylenacyclotetradecaphane-4-ene (39)
The title compound was prepared using the general procedure
for olefin metathesis (Procedure D), from 33 (104 mg, 0.13 mmol) to
yield 39 (103 mg, 0.13 mmol, 100%) as a grey solid. Mp 172–175 ꢀC.
5.8.6. (7R,10S,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3-imino-
[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}-
guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-
1(1,4)phenylenacyclotetradecaphane-4-ene (42)
1H NMR (CDCl3, 300 MHz):
d 7.18–6.98 (m, 2H, ArH), 6.88–6.62 (m,
2H, ArH), 6.37 (br s, 1H, NH), 5.88–5.35 (m, H4 and H5), 4.95–4.62
(m, 2H, H3), 4.62–4.22 (m, 3H, H7, H10 and H13), 3.63 (s, 3H, OCH3),
3.22–2.80 (m, 4H, H30 and H6), 2.70–2.22 (m, 10H, H14, 700-CH3, 500-
CH3 and H400), 2.06 (s, 3H, 800-CH3), 1.90 (s, 3H, NCOCH3), 1.95–1.76
(m, 2H, H10), 1.70–1.30 (m, 2H, H300), 1.27 (s, 6H, 2ꢁ200-CH3). 13C
The title compound was prepared using the general procedure
for olefin metathesis (Procedure D), from 36 (262 mg, 0.330 mmol)
to yield 42 (217 mg, 0.280 mmol, 86%) as a grey solid. Mp 174–
176 ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d 8.28–8.09 (m, 2H, NH),
7.11–7.01 (m, 2H, ArH), 6.77–6.72 (m, 2H, ArH), 6.54–6.44 (br s, 1H,
NH), 5.72–5.68 (m, 2H, NH), 5.41–5.34 (m, H4 and H5), 4.62 (br s,
2H, H3), 4.52–4.04 (m, 3H, H7, H10 and H13), 3.55 (s, 3H, OCH3),
3.06–2.96 (m, 2H, H30), 2.92–2.67 (m, 2H, H14), 2.60–2.50 (m, 6H,
500-CH3 and 7%-CH3), 2.35–2.20 (m, 2H, H400), 2.00 (s, 3H, 800-CH3),
1.73 (s, 3H, NCOCH3),1.67–1.44 (m, 2H, H10),1.35 (br s, 2H, H300),1.23
NMR (CDCl3, 75 MHz): d 172.0, COOCH3; 171.2, C11; 170.5, C9; 170.3,
NCOCH3; 157.1, ArC600; 156.2, CN3; 155.4, 1-ArC4; 153.3, ArC8a00;
135.2, ArC500; 134.6, ArC700; 133.3, 1-ArCH2 and 1-ArCH6; 130.2, 1-
ArC1; 128.4, C4; 128.3, C5; 123.9, ArC800; 117.8, ArC4a00; 114.7, 1-
ArCH3 and 1-ArCH5; 73.6, C200; 67.7, C3; 65.9, C7; 56.2, C10; 52.5,
C13; 52.2, C30; 51.7, OCH3; 40.1, C6; 34.9, C14; 32.8, NCOCH3; 26.8,
200-CH3; 21.5, C300; 18.6, C400; 17.6, 500-CH3; 17.2, 700-CH3; 15.2, C20;
12.2, 800-CH3. MS (ESI, ꢂve) m/z 767 (100%) [MHþ]. HRMS calcd for
C38H53N6O9S 769.3595, found 769.3558.
(s, 6H, 2ꢁ200-CH3). 13C NMR (DMSO-d6, 125 MHz):
d 171.7, COOCH3;
171.5, C11; 171.3, C9; 171.1, NCOCH3; 156.6, ArC600; 155.8, CN3; 155.4,
1-ArC4; 152.2, ArC8a00; 134.4, ArC500; 133.9, ArC700; 130.0, 1-ArCH2
and 1-ArCH6; 129.5, 1-ArC1; 128.8, C4; 127.5, C5; 122.6, ArC800;
117.6, ArC4a00; 114.1, 1-ArCH3 and 1-ArCH5; 73.4, C200; 66.4, C3;
54.9, C7; 53.3, C10; 52.6, C13; 52.2, C30; 51.9, OCH3; 40.6, C6; 37.2,
C14; 32.2, NCOCH3; 26.5, 200-CH3; 22.5, C300; 20.8, C400; 18.2, 500-CH3;
17.2, 700-CH3; 15.2, C20; 12.0, 800-CH3. MS (ESI, þve) m/z 767 (65%)
[MHþ]. HRMS calcd for C38H53N6O9S 769.3595, found 769.3630.
5.8.4. (7S,10S,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3-[{2,2,5,7,8-
pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]-
propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)-
phenylenacyclotetradecaphane-4-ene (40)
The title compound was prepared using the general procedure
for olefin metathesis (Procedure D), from 34 (127 mg, 0.16 mmol) to
yield 40 (117 mg, 0.15 mmol, 95%) as a grey solid. Mp 224–228 ꢀC.
5.8.7. (7R,10S,13R,4E/Z)-13-Acetamido-8,11-diaza-10-(3-
[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}-
guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-
1(1,4)phenylenacyclotetradecaphane-4-ene (43)
1H NMR (CDCl3, 300 MHz):
d 7.18–6.82 (m, 2H, ArH), 6.77–6.60 (m,
2H, ArH), 6.41 (br s, 1H, NH), 5.77–5.53 (m, H4 and H5), 4.68–4.46
(br s, 5H, H3, H7, H10 and H13), 3.67 (s, 3H, OCH3), 3.30–3.05 (m,
2H, H30), 2.70–2.40 (m, 10H, H14, 700-CH3, 500-CH3 and H400), 2.08 (s,
3H, 800-CH3), 1.78 (s, 3H, NCOCH3), 1.65–1.30 (m, 2H, H10), 1.40–1.21
(m, 2H, H300), 1.30 (s, 6H, 2ꢁ200-CH3). 13C NMR (CDCl3, 75 MHz):
The title compound was prepared using the general pro-
cedure for olefin metathesis (Procedure D), from 37 (366 mg,
0.46 mmol) to yield 43 (307 mg, 0.40 mmol, 87%) as a grey solid.
Mp 186–190 ꢀC. 1H NMR (DMSO-d6, 500 MHz):
d 8.20–7.85 (m,
d
172.0, COOCH3; 171.2, C11; 170.6, C9; 170.2, NCOCH3; 156.3,
3H, NH), 7.15–6.98 (m, 2H, ArH), 6.85–6.60 (m, 2H, ArH), 6.41 (br
s, 1H, NH), 6.00–5.60 (m, 1H, H5), 5.60–5.38 (m, 1H, H4), 4.65–
4.10 (m, 5H, H3, H7, H10 and H13), 3.69 (s, 3H, OCH3), 3.30–3.10
(m, 2H, H30), 2.90–2.62 (m, 2H, H400), 2.60–2.50 (m, 8H, H14, 700-
CH3, and 500-CH3), 2.08 (s, 3H, 800-CH3), 1.85 (s, 3H, NCOCH3),
1.70–1.60 (m, 2H, H10), 1.50–1.30 (m, 2H, H300), 1.26 (s, 6H, 2ꢁ200-
ArC600; 156.2, CN3; 155.4, 1-ArC4; 153.3, ArC8a00; 135.3, ArC500;
134.7, ArC700; 130.4, 1-ArCH2 and 1-ArCH6; 129.7, 1-ArC1; 128.4,
C4; 127.7, C5; 123.9, ArC800; 117.8, ArC4a00; 115.2, 1-ArCH3 and 1-
ArCH5; 73.6, C200; 67.7, C3; 65.9, C7; 56.2, C10; 52.6, C13; 52.2, C30;
51.7, OCH3; 40.1, C6; 34.9, C14; 33.6, NCOCH3; 26.8, 200-CH3; 21.5,
C300; 18.7, C400; 17.6, 500-CH3; 17.2, 700-CH3; 15.2, C20; 12.2, 800-CH3. MS
(ESI, þve) m/z 769 (100%) [MHþ]. HRMS calcd for C38H53N6O9S
769.3595, found 769.3574.
CH3). 13C NMR (DMSO-d6, 125 MHz):
d 171.8, COOCH3; 171.6, C11;
170.8, C9; 169.5, NCOCH3; 156.8, ArC600; 156.4, CN3; 156.0, 1-
ArC4; 152.4, ArC8a00; 134.6, ArC500; 134.5, ArC700; 130.2, 1-ArCH2
and 1-ArCH6; 129.4, 1-ArC1; 128.3, C4; 127.9, C5; 122.7, ArC800;
117.8, ArC4a; 114.9, 1-ArCH3 and 1-ArCH5; 73.5, C200; 67.0, C3;
66.9, C7; 54.8, C10; 54.5, C13; 51.9, C30; 51.8, OCH3; 40.1, C6;
36.8, C14; 32.1, NCOCH3; 26.5, 200-CH3; 22.4, C300; 20.8, C400; 18.2,
500-CH3; 17.2, 700-CH3; 15.2, C20; 12.0, 800-CH3. MS (ESI, þve) m/z
769 (40%) [MHþ], 106 (100%). HRMS calcd for C38H53N6O9S
769.3595, found 769.3600.
5.8.5. (7R,10R,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3-imino-
[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}-
guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-
1(1,4)phenylenacyclotetradecaphane-4-ene (41)
The title compound was prepared using the general procedure
for olefin metathesis (Procedure D), from 35 (170 mg, 0.210 mmol)

T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
11283
5.9. Synthesis of tripeptide hydrochloride salts (11, 44–49)
to yield 46 as a white solid (38 mg, 0.076 mmol, 59%). Mp 218–
220 ꢀC. 1H NMR (CD3OD, 300 MHz):
7.14–7.04 (m, 2H, ArH), 6.85–
d
5.9.1. (7S,10R,13S,4E/Z)-13-Acetamido-10-(4-aminobutyl)-8,11-
diaza-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenyl-
enacyclotetradecaphane-4-ene hydrochloride (11)
6.68 (m, 2H, ArH), 5.80–5.65 (m, 1H, H5), 5.55–5.35 (m, 1H, H4),
4.65–4.10 (m, 5H, H3, H7, H10 and H13), 3.68 (br s, 3H, OCH3), 3.18–
3.00 (m, 2H, H30), 3.00–2.85 (m, 2H, H14), 2.70–2.40 (m, 2H, H6),
1.99 (s, 3H, NCOCH3), 1.80–1.65 (m, 2H, H10), 1.65–1.40 (m, 2H, H20).
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 10 (49 mg,
0.084 mmol) to yield 11 (17 mg, 0.033 mmol, 49%) as a highly
13C NMR (CD3OD, 75 MHz):
d 173.5, COOCH3; 173.3, C11; 173.2, C9;
172.2, NCOCH3; 158.9, CN3; 157.8, 1-ArC4; 131.5, C4; 129.9, C5;
129.1, 1-ArCH2 and 1-ArCH6; 129.0, 1-ArC1; 116.2, 1-ArCH3 and 1-
ArCH5; 66.8, C3; 57.6, C7; 56.0, C10; 54.1, C10; 53.6, C30; 52.9, OCH3;
42.0, C6; 38.0, C14; 35.3, NCOCH3; 26.2, C10; 22.6, C20. MS (ESI, þve)
m/z 503 (100%) [MHþ]. HRMS calcd for C24H35N6O6 503.2618, found
503.2603.
hygroscopic yellow solid. 1H NMR (CD3OD, 300 MHz):
d 7.14–7.03
(m, 3H, ArH and NH), 6.85 (br s, 1H, NH), 6.71 (d, J¼7.5 Hz, 2H,
ArH), 6.03–5.68 (m, 2H, H4 and H5), 4.50–4.02 (m, 5H, H3, H7,
H10 and H13), 3.68 (s, 3H, OCH3), 2.93–2.48 (m, 4H, H6 and H40),
1.93 (s, 3H, NCOCH3), 1.80–0.83 (m, 6H, H10, H20 and H30). 13C
NMR (CD3OD, 75 MHz):
d 173.5, C9; 173.1, 7-CO; 173.0, 13-NCO;
172.6, C12; 157.7, 1-ArC1; 132.4, 1-ArCH2 and 1-ArCH6; 131.1, C4;
129.6, C5; 129.3, 1-ArC4; 116.8, 1-ArCH3 and 1-ArCH5; 70.0, C3;
57.9, C13; 54.9, C10; 53.5, C40; 53.0, OCH3; 40.7, C7; 38.2, C14;
32.1, C10; 31.7, C6; 28.0, C30; 23.5, NCOCH3; 22.6, C20. MS (ESI,
þve) m/z 475.3 (100%) [MHþ]. HRMS calcd for C24H35N4O6
475.2557, found 475.2534.
5.9.5. (7R,10R,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3-
[guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-
1(1,4)phenylenacyclotetradecaphane-4-ene hydrochloride (47)
The title compound was synthesized using the general N-Boc
deprotectionprocedure (Procedure A), from 41 (108 mg, 0.140 mmol)
to yield 47 (25 mg, 0.049 mmol, 35%) as a white solid. Mp 170–176 ꢀC.
1H NMR (CD3OD, 300 MHz):
d 7.14–7.04 (m, 2H, ArH), 6.83–6.70
5.9.2. (7S,10S,13S,4E/Z)-13-Acetamido-10-(4-aminobutyl)-8,11-
diaza-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenyl-
enacyclotetradecaphane-4-ene hydrochloride (44)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A) using 38 (220 mg,
0.380 mmol) to yield 44 as a mixture of epimers and E/Z isomers
(152 mg, 0.300 mmol, 79%) as a highly hygroscopic yellow solid. 1H
(m, 2H, ArH), 6.08–5.79 (m,1H, H5), 5.54–5.45 (m,1H, H4), 4.66–4.12
(m, 5H, H3, H7, H10 and H13), 3.70–3.68 (m, 3H, OCH3), 3.13–3.02
(m, 2H, H30), 3.00–2.85 (m, 2H, H14), 2.57–2.37 (m, 2H, H6), 1.94 (s,
3H, NCOCH3),1.80–1.45 (m, 2H, H10),1.42–1.28 (m, 2H, H20). 13C NMR
(CD3OD, 75 MHz):
d 173.8, COOCH3; 173.5, C11; 173.2, C9; 172.6,
NCOCH3; 158.4, CN3; 157.2, 1-ArC4; 131.4, C4; 130.6, C5; 129.7, 1-
ArCH2 and 1-ArCH6; 129.3, 1-ArC1; 115.9, 1-ArCH3 and 1-ArCH5;
67.3, C3; 57.2, C7; 54.0, C10; 53.7, C13; 53.2, C30; 52.9, OCH3; 42.0, C6;
37.9, C14; 35.2, NCOCH3; 26.1, C10; 22.6, C20. MS (ESI, þve) m/z
503 (35%) [MHþ]. HRMS calcd for C24H35N6O6 503.2618, found
503.2644.
NMR (CD3OD, 300 MHz):
d
8.19 (d, J¼8.4 Hz, 1H, NH), 6.98/6.92 (d,
J¼8.0 Hz, 2H, ArH), 6.74/6.64 (d, J¼8.0 Hz, 2H, ArH), 5.57 (d,
J¼16.0 Hz, 2H, H4-trans), 5.46–5.35 (m, 1H, H5), 4.56–4.37 (m, 4H,
H7, H13 and H2), 4.26–4.19 (m, 1H, H10), 3.93 (br s, 1H, NH), 3.63/
3.60 (s, 3H, OCH3), 2.89–2.57 (m, 6H, H6, H40 and H14), 1.99/1.89 (s,
3H, NCOCH3), 1.73–1.58 (m, 2H, H20), 1.58–1.42 (br s, 2H, H30), 1.35–
5.9.6. (7R,10S,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3-
1.16 (m, 2H, H10). 13C NMR (CD3OD, 75 MHz):
d
174.5, C9; 173.3,
[guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-
1(1,4)phenylenacyclotetradecaphane-4-ene hydrochloride (48)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 42 (129 mg,
0.16 mmol) to yield 48 as a white solid (71 mg, 0.14 mmol, 86%).
7-CO; 173.1, 13-NCO; 172.5, C12; 157.7, 1-ArC1; 131.4, 1-ArCH2 and
1-ArCH6; 131.1, C4; 129.5, C5; 129.1, 1-ArC4; 116.4, 1-ArCH3 and
1-ArCH5; 66.9, C3; 57.7, C13; 53.9, C10; 53.1, C40; 53.0, OCH3; 40.5,
C7; 38.1, C14; 32.0, C10; 31.8, C6; 28.0, C30; 23.5, NCOCH3; 22.5, C20.
MS (ESI, þve) m/z 475.4 (100%) [MHþ]. HRMS calcd for C24H35N4O6
475.2557, found 475.2581.
Mp 134–138 ꢀC. 1H NMR (CD3OD, 300 MHz):
d 7.18–7.04 (m, 2H,
ArH), 6.88–6.67 (m, 2H, ArH), 6.00–5.70 (m, 1H, H5), 5.51–5.36
(m, 1H, H4), 4.65–4.26 (m, 5H, H3, H7, H10 and H13), 3.72/3.69
(2ꢁs, 3H, OCH3, two rotomers 1:3), 3.31–3.29 (m, 2H, H30), 2.25–
2.82 (m, 2H, H14), 2.70–2.40 (m, 2H, H6), 1.94 (s, 3H, NCOCH3),
1.90–1.74 (m, 2H, H10), 1.69–1.53 (m, 2H, H20). 13C NMR (CD3OD,
5.9.3. (7S,10R,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3-
[guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-
1(1,4)phenylenacyclotetradecaphane-4-ene (45)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 39 (60 mg,
0.078 mmol) to yield 45 (38 mg, 0.071 mmol, 91%) as a white solid.
75 MHz): d 174.0, COOCH3; 173.6, C11; 173.3, C9; 173.0, NCOCH3;
158.4, CN3; 157.2, 1-ArC4; 131.3, C4; 130.6, C5; 129.7, 1-ArCH2
and 1-ArCH6; 129.5, 1-ArC1; 115.8, 1-ArCH3 and 1-ArCH5; 67.7,
C3; 57.8, C7; 54.9, C10; 54.0, C10; 53.2, C30; 52.9, OCH3; 42.0, C6;
37.7, C14; 33.2, NCOCH3; 26.5, C10; 22.3, C20. MS (ESI, þve) m/z
503.4 (100%) [MHþ]. HRMS calcd for C24H35N6O6 503.2618,
found 503.2666.
Mp 218–224 ꢀC. 1H NMR (CD3OD, 300 MHz):
d 7.14–7.05 (m, 2H,
ArH), 6.85–6.68 (m, 2H, ArH), 5.86–5.70 (m, 1H, H5), 5.11–4.95 (m,
1H, H4), 4.68–4.44 (m, 5H, H3, H7, H10 and H13), 3.73–3.69 (m, 3H,
OCH3), 3.30–3.10 (m, 2H, H30), 3.04–2.94 (m, 2H, H14), 2.81–2.48
(m, 2H, H6), 1.94 (s, 3H, NCOCH3), 1.71–1.91 (m, 2H, H10), 1.41–1.33
(m, 2H, H20). 13C NMR (CD3OD, 75 MHz):
d
173.6, COOCH3; 173.5,
5.9.7. (7S,10S,13R,4E/Z)-13-Acetamido-8,11-diaza-10-(3-
C11; 173.1, C9; 172.4, NCOCH3; 158.4, CN3; 157.4, 1-ArC4; 131.5, C4;
129.5, C5; 129.1, 1-ArCH2 and 1-ArCH6; 129.0, 1-ArC1; 116.5, 1-
ArCH3 and 1-ArCH5; 66.9, C3; 57.5, C7; 56.2, C10; 54.3, C10; 53.6,
C30; 52.5, OCH3; 42.1, C6; 38.7, C14; 35.3, NCOCH3; 26.6, C10; 22.7,
C20. MS (ESI, þve) m/z 503 (100%) [MHþ]. HRMS calcd for
C24H35N6O6 503.2618, found 503.2626.
[amino{imino}methylamino]propyl)-7-methoxycarbonyl-2-oxa-
9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-ene (49)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 43 (128 mg,
0.17 mmol) to yield 49 as a highly hygroscopic solid (29 mg,
0.058 mmol, 34%). 1H NMR (CD3OD, 300 MHz):
d 8.39–8.06 (m, 3H,
NH), 7.63 (br s, 1H, NH), 7.16–7.00 (m, 2H, ArH), 6.83–6.64 (m, 2H,
ArH), 5.88–5.78 (m, 1H, H5), 5.39–5.08 (m, 1H, H4), 4.67–4.19 (m,
5H, H3, H7, H10 and H13), 3.58 (br s, 3H, OCH3), 3.15–2.98 (m, 2H,
H30), 2.92–2.60 (m, 2H, H14), 2.59–2.30 (m, 2H, H6), 1.77 (s, 3H,
NCOCH3), 1.84–1.66 (m, 2H, H10), 1.39–1.26 (m, 2H, H20). 13C NMR
5.9.4. (7S,10S,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3-
[guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-
1(1,4)phenylenacyclotetradecaphane-4-ene hydrochloride (46)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 40 (91 mg, 0.12 mmol)
(CD3OD, 75 MHz):
d 171.3, COOCH3; 171.6, C11; 171.3, C9; 169.4,

11284
T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
NCOCH3; 156.8, CN3; 155.8, 1-ArC4; 130.2, C4; 128.8, C5; 128.2, 1-
ArCH2 and 1-ArCH6; 127.9, 1-ArC1; 114.9, 1-ArCH3 and 1-ArCH5;
67.1, C3; 55.2, C7; 54.7, C10; 52.9, C10; 51.8, C30; 51.6, OCH3; 42.0,
C6; 36.9, C14; 33.9, NCOCH3; 29.0, C10; 22.4, C20. MS (ESI, þve) m/z
503 (30%) [MHþ], 102 (100%). HRMS calcd for C24H35N6O6 503.2618,
found 503.2638.
H2), 4.20 (d, J¼7.0 Hz, 2H, OCH2-H900), 4.03 (t, J¼7.0 Hz, 1H, H5),
3.99 (t, J¼7.0 Hz, 1H, H900), 3.51 (s, 3H, OCH3), 3.01 (br s, 2H, H8),
2.41–2.26 (m, 2H, H10), 1.64 (br s, 2H, H7), 1.47 (br s, 2H, H6). 13C
NMR (CD3OD, 75 MHz):
d 174.1, C4; 173.1, C1; 158.4, CN3; 158.2, 5-
NCO2; 145.1, ArC8a00 and ArC9a00; 142.4, ArC4a and ArC4b; 133.9,
C20; 128.6, ArCH300 and ArCH600; 128.0, ArCH200 and ArCH700; 126.0,
ArCH400 and ArCH500; 120.8, ArCH100 and ArCH800; 118.8, C30; 67.9,
CH2-C900; 55.6, C900; 53.6, C2; 52.7, OCH3; 49.3, C5; 42.1, C8; 36.7,
C10; 30.4, C7; 26.2, C6. MS (ESI, þve) m/z 508 (45%) [MHþ]. HRMS
calcd for C27H34N5O5 508.2560, found 508.2592.
5.10. Synthesis of dipeptide hydrochloride salts (Scheme 5,
50–53)
5.10.1. Methyl (2S,5R)-2-allyl-3-aza-5-(9H-9-fluorenylmethyl-
oxycarboxamido)-8-(guanidino)-4-oxooctanoate
hydrochloride (50)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 23 (81 mg, 0.105 mmol)
5.10.4. Methyl (2R,5S)-2-allyl-3-aza-5-(9H-9-fluorenylmethyl-
oxycarboxamido)-8-(guanidino)-4-oxooctanoate
hydrochloride (53)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A) using 26 (94 mg, 0.12 mmol)
giving 50 (43 mg, 0.079 mmol, 75%) as a highly hygroscopic solid.
23
[
a
]
þ17.7 (c 0.008, MeOH). IR (neat) nmax 1662, 1540, 1210, 1178,
to yield 53 (33 mg, 0.061 mmol, 51%) as a highly hygroscopic white
D
22
1098, 1030, 1004, 742. Mp 203–208 ꢀC. 1H NMR (CD3OD, 300 MHz):
7.88–7.85 (m, 2H, ArH100 and ArH800), 7.66–7.77 (m, 2H, ArH400 and
solid. [
a
]
ꢂ19.6 (c 0.005, MeOH). IR (neat) nmax 1662, 1537, 1213,
D
d
1107, 1050, 1031, 738. 1H NMR (CD3OD, 300 MHz):
d 7.79 (d,
ArH500), 7.45–7.27 (m, 4H, ArH300 and ArH600 and ArH200 and ArH700),
5.81–5.71 (m,1H, H20), 5.16–5.03 (m, 2H, H3), 4.46 (dd, J¼5.4, 8.4 Hz,
1H, H2), 4.39 (d, J¼6.3 Hz, 2H, OCH2-H900), 4.35–4.29 (m, 1H, H5),
4.2–4.15 (m,1H, H900), 3.68 (s, 3H, OCH3), 3.17 (br s, 2H, H8), 2.61–2.41
(m, Hz, 2H, H10), 1.88–1.75 (m, 2H, H7), 1.75–1.55 (m, 2H, H6). 13C
J¼7.5 Hz, 2H, ArH100 and ArH800), 7.67–7.63 (m, 2H, ArH400 and
ArH500), 7.39 (t, J¼7.2 Hz, 2H, ArH300 and ArH600), 7.30 (t, J¼7.2 Hz,
2H, ArH200 and ArH700), 5.78–5.65 (m, 1H, H20), 5.09 (d, J¼16.5 Hz,
0
0
1H, H3a ), 5.04 (d, J¼9.6 Hz, 1H, H3b ), 4.46 (dd, J¼5.7, 8.4 Hz, 1H,
H2), 4.40 (d, J¼6.3 Hz, 2H, OCH2-H900), 4.22 (t, J¼6.6 Hz, 1H, H5),
4.24–4.13 (m, 1H, H900), 3.69 (s, 3H, OCH3), 3.17 (t, J¼6.6 Hz, 2H, H8),
2.60–2.40 (m, 2H, H10), 1.86–1.78 (m, 2H, H7),1.67–1.50 (m, 2H, H6).
NMR (CD3OD, 75 MHz): d 174.1, C4; 172.9, C1; 158.4, 5-NCO2; 146.3,
ArC8a00 and ArC9a00; 142.4, ArC4a and ArC4b; 134.1, C20; 129.1,
ArCH300 and ArCH600; 128.0, ArCH200 and ArCH700; 126.6, ArCH400 and
ArCH500; 120.8, ArCH100 and ArCH800; 118.9, C30; 67.9, CH2-C900; 55.8,
C900; 53.4, C2; 52.8, OCH3; 51.1, C5; 42.0, C8; 36.8, C10; 30.5, H7; 26.3,
H6. MS (ESI, þve) m/z 508 (100%) [MHþ]. HRMS calcd for C27H34N5O5
508.2526, found 508.2570.
13C NMR (CD3OD, 75 MHz):
d 174.0, C4; 172.9, C1; 158.4, CN3; 158.2,
5-NCO2; 145.1, ArC8a00 and ArC9a00; 142.4, ArC4a00 and ArC4b00; 134.1,
C20; 128.7, ArCH300 and ArCH600; 128.0, ArCH200 and ArCH700; 126.0,
ArCH400 and ArCH500; 120.8, ArCH100 and ArcH800; 118.9, C30; 67.9,
CH2-C900; 55.8, C900; 53.4, C2; 52.8, OCH3; 49.3, C5; 42.0, C8; 36.8,
C10; 30.5, C7; 26.3, C6. MS (ESI, þve) m/z 508 (25%) [MHþ], 179
(100%) [sodium allylglycinamide]. HRMS calcd for C27H34N5O5
508.2560, found 508.2555.
5.10.2. Methyl (2S,5S)-2-allyl-3-aza-5-(9H-9-fluorenylmethyl-
oxycarboxamido)-8-(guanidino)-4-oxooctanoate
hydrochloride (51)
The title compound was synthesized using the general N-Boc
5.11. Synthesis of acyclic tripeptide hydrochloride salts
(Scheme 6: 54–59)
deprotection procedure (Procedure A) using 24 (81 mg, 0.105 mmol)
23
giving 51 (27 mg, 0.05 mmol, 47%) as a highly hygroscopic solid. [a]
D
þ6.4 (c 0.005, MeOH). IR (neat) nmax 1663, 1528, 1210, 1179, 1098,
5.11.1. Methyl (2S,5R,8S)-2-allyl-8-(4-allyloxyphenyl)-5-
(4-aminobutyl)-3,6,9-triaza-4,7,10-trioxoundecanoate
hydrochloride (54)
1030, 741. Mp 176–182 ꢀC. 1H NMR (CD3OD, 500 MHz):
d
7.79 (d,
J¼7.5 Hz, 2H, ArH100 andArH800), 7.68–7.56(m, 2H, ArH400 andArH500),
7.44–7.27 (m, 4H, ArH300 andArH600 andArH200 andArH700), 5.81–5.65
(m, 1H, H20), 5.15–5.02 (m, 2H, H30), 4.46 (dd, J¼6.0, 8.1 Hz, 1H, H2),
4.34 (d, J¼7.2 Hz, 2H, OCH2-H900), 4.34–4.28 (m, 1H, H5), 4.22–4.12
(m,1H, H900), 3.71/3.69 (2ꢁs, 3H, OCH3, two rotomers 1:3), 3.28–3.08
(m, 2H, H8), 2.59–2.40 (m, 2H, H10), 1.95–1.72 (m, 2H, H7), 1.75–1.52
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 9 (64 mg, 0.11 mmol)
to yield 54 (22 mg, 0.041 mmol, 37%) as a cream coloured highly
hygroscopic solid. 1H NMR (CD3OD, 500 MHz):
d
7.15 (d, J¼8.0 Hz,
2H, ArH2% and ArH6%), 6.87 (d, J¼8.0 Hz, 2H, ArH3% and ArH5%),
6.09–6.01 (m, 1H, H2&), 5.77–5.69 (m, 1H, H20), 5.39 (d, J¼17.0 Hz,
1H, H3&), 5.24 (d, J¼10.5 Hz, 1H, H3&), 5.08 (d, J¼17.0 Hz, 1H, H30),
5.04 (d, J¼10.0 Hz, 1H, H30), 4.52 (d, J¼5.5 Hz, 2H, H1&), 4.43–4.37
(m, 2H, H2 and H5), 4.15 (d, J¼6.5 Hz, 1H, H8), 3.69 (s, 3H, OCH3),
2.96–2.90 (m, 2H, H10), 2.83 (br s, 2H, H400), 2.60–2.48 (m, 2H,
ArCH2), 1.93 (s, 3H, H11), 1.74 (br s, 2H, H100), 1.50 (br s, 2H, H200),
(m, 2H, H6). 13C NMR (CD3OD, 75 MHz):
d 174.4, C4; 173.2, C1; 158.4,
CN3; 158.3, 5-NCO2; 144.2, ArC8a00 and ArC9a00; 142.4, ArC4a00 and
ArC4b00; 134.1, C20; 129.1, ArCH300 and ArCH600; 128.7, ArCH200 and
ArCH700; 126.7, ArCH400 and ArCH500; 120.9, ArCH100 and ArCH800;
119.0, C30; 67.9, CH2-C900; 55.6, C900; 53.5, C2; 52.8, OCH3; 48.1, C5;
42.0, C8; 36.6, C10; 30.3, H7; 26.2, H6. MS (ESI, þve) m/z 508 (100%)
[MHþ]. HRMS calcd for C37H34N5O5 508.2560, found 508.2574.
1.00 (br s, 2H, H300). 13C NMR (CD3OD, 75 MHz):
d 174.3, C7; 173.7,
C1; 173.2, C4; 173.1, C10; 158.8, ArC4%; 134.8, C20; 134.5, C2&;
131.3, ArCH2% and ArCH6%; 129.9, ArC1%; 118.4, C30; 117.5, C3&;
115.8, ArCH3% and ArCH5%; 69.8, C1&; 57.6, C5; 54.2, OCH3; 53.8,
C8; 52.7, C2; 40.3, C40; 37.4, ArCH2; 36.4, C10; 31.7, C100; 28.0, C300;
23.5, C11; 22.4, C200. MS (ESI, þve) m/z 503.7 (100%) [MHþ]. HRMS
calcd for C26H39N4O6 503.2870, found 503.2881.
5.10.3. Methyl (2R,5R)-2-allyl-3-aza-5-(9H-9-fluorenylmethyl-
oxycarboxamido)-8-(guanidino)-4-oxooctanoate
hydrochloride (52)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 25 (80 mg, 0.10 mmol)
to yield 52 (45 mg, 0.083 mmol, 80%) as a highly hygroscopic white
23
solid. [
a
]
ꢂ50.6 (c 0.002, MeOH). IR (neat) nmax 1715, 1653, 1558,
5.11.2. Methyl (2S,5S,8S)-8-acetamido-2-allyl-9-(4-allyloxy-
phenyl)-5-(4-aminobutyl)-3,6-diaza-4,7-dioxononanoate
hydrochloride (55)
The title compound was synthesized using the general pro-
cedure (Procedure A), by deprotection of 32 (104 mg, 0.170 mmol)
to yield 55 as a 1:1 mixture of epimers (55 mg, 0.10 mmol, 60%) as
D
1540, 1212, 1046, 738. 1H NMR (CD3OD, 500 MHz):
d 7.61 (d,
J¼7.5 Hz, 2H, ArH100 and ArH800), 7.47 (d, J¼8.5 Hz, 2H, ArH400 and
ArH500), 7.20 (t, J¼7.5 Hz, 2H, ArH300 and ArH600), 7.12 (t, J¼7.5 Hz,
2H, ArH200 and ArH700), 5.62–5.54 (m, 1H, H20), 4.93 (d, J¼17.0 Hz,
0
0
1H, H3a ), 4.87 (d, J¼10.0 Hz, 1H, H3b ), 4.28 (dd, J¼6.0, 8.0 Hz, 1H,

T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
11285
22
a highly hygroscopic yellow solid. Mp 150–154 ꢀC. 1H NMR (CD3OD,
300 MHz):
[a
]
þ16.0 (c 0.008, MeOH). IR (neat) nmax 1652, 1543, 1512, 1222,
D
d
7.14 (d, J¼8.0 Hz, 2H, ArH2% and ArH6%), 6.84 (t,
1181, 1047, 1005, 834, 752. 1H NMR (CD3OD, 300 MHz):
d 7.15 (d,
J¼8.0 Hz, 2H, ArH3% and ArH5%), 6.08–5.99 (m, 1H, H2&), 5.81–
5.73 (m, 1H, H20), 5.37 (d, J¼17.3 Hz, 1H, H3a&), 5.22 (d, J¼9.7 Hz,
1H, H3b&), 5.15–5.04 (m, 2H, H30), 4.52–4.36 (m, 5H, H2, H5, H8
and H1&), 3.69/3.67 (s, 3H, OCH3), 3.08–2.76 (m, 4H, H10 and H400),
2.62–2.40 (m, 2H, ArCH2),1.93/1.91 (s, 3H, H11),1.50 (s, 6H, H100, H200
J¼8.4 Hz, 2H, ArH2% and ArH6%), 6.86 (d, J¼8.7 Hz, 2H, ArH3% and
ArC5%), 6.08–6.00 (m, 1H, H2&), 5.78–5.70 (m, 1H, H20), 5.38 (dd,
J¼1.5, 17.4 Hz, 1H, H3a&), 05.23 (dd, J¼1.2, 10.5 Hz, 1H, 0H3b&), 5.09
(dd, J¼1.2, 16.8 Hz,1H, H3a ), 5.06 (d, J¼10.6 Hz,1H, H3b ), 4.45–4.40
(m, 4H, H2& and H2), 4.39 (dd, J¼5.7, 8.1 Hz, 1H, H5), 4.26 (dd,
J¼4.5, 8.7 Hz, 1H, H8), 3.68 (s, 3H, OCH3), 3.07 (t, J¼7.2 Hz, 2H, H300),
2.89–2.82 (m, 2H, ArCH2), 2.59–2.42 (m, 2H, H10), 1.95 (s, 3H, H11),
1.75–1.59 (m, 2H, H100), 1.11–1.08 (m, 2H, H200). 13C NMR (CD3OD,
and H300). 13C NMR (CD3OD, 75 MHz):
d 173.7/173.6, C7; 173.4, C1;
173.1, C4; 173.0/172.9, C10; 158.7, ArCH4%; 134.8, C20; 134.3/134.0,
C2&; 131.2/131.1, ArCH2% and ArCH6%; 130.2/130.1, ArC1%; 118.8/
118.5, C30; 117.4/117.3, C3&; 115.7/115.6, ArCH3% and ArCH5%;
69.8/69.7, C1&; 57.2, C5; 54.0, OCH3; 53.8/53.7, C8; 52.8/52.7, C2;
40.6/40.5, C40; 37.8/37.7, ArCH2; 36.6/36.5, C10; 31.9, C100; 28.0, C300;
23.4, C11; 22.5, C200. MS (ESI, þve) m/z 503.3 (100%) [MHþ]. HRMS
calcd for C26H39N4O6 503.2870, found 503.2894.
75 MHz): d 173.7, C4; 173.6, C11; 173.4, C1; 172.9, C7; 158.8, ArC4%;
158.4, CN3; 134.8, C2&; 134.3, C20; 131.2, ArC1%; 130.0, ArCH2% and
ArCH6%; 118.6, C30; 117.4, C3&; 115.7, ArCH3% and ArCH5%; 69.8,
C1&; 57.2, C2; 53.8, C5; 53.8, C8; 52.8, OCH3; 50.1, C300; 37.7, ArCH2;
36.5, C10; 29.7, C200; 22.9, C11; 22.3, C100. MS (ESI, þve) m/z 531.5
(80%) [MHþ]. HRMS calcd for C26H39N6O6 531.2931, found 531.2936.
5.11.3. Methyl (2S,5R,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-
5-(3-[guanidino]propyl)-4,7,10-oxoundecanoate hydrochloride (56)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 33 (70 mg,
5.11.6. Methyl (2R,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-
5-(3-[guanidino]propyl)-4,7,10-oxoundecanoate hydrochloride (59)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 36 (87 mg, 0.11 mmol)
0.088 mmol) to yield 56 (37 mg, 0.065 mmol, 74%) as a highly hy-
24
groscopic solid. [
a
]
þ17.4 (c 0.007, MeOH). IR (neat) nmax 1734,
to yield 59 (35 mg, 0.062 mmol, 56%) as a highly hygroscopic solid.
D
1652, 1543, 1507, 1445, 1217, 1052, 1000, 767. 1H NMR (CD3OD,
300 MHz):
[a
]
þ16.0 (c 0.008, MeOH). IR (neat) nmax 1652, 1543, 1512, 1222,
22
D
d
7.12 (d, J¼7.5 Hz, 2H, ArH2% and ArH6%), 6.83 (d,
1181, 1047, 1005, 834, 752. 1H NMR (CD3OD, 300 MHz):
d 7.16 (d,
J¼7.5 Hz, 2H, ArH3% and ArC5%), 6.05–5.96 (m, 1H, H2&), 5.76–
6.64 (m, 1H, H20), 5.35 (d, J¼17.4 Hz, 1H, H3a&), 5.19 (d, J¼9.9 Hz,
1H, H3b&), 5.08–5.02 (m, 2H, H30), 4.48–4.47 (m, 2H, H2&), 4.42–
4.342 (m, 2H, H2 and H5), 4.18–4.14 (m, 1H, H8), 3.65 (s, 3H, OCH3),
3.36–3.26 (m, 2H, H300), 3.06–2.96 (m, 2H, ArCH2), 2.54–2.46 (m,
2H, H10), 1.92 (s, 3H, H11), 1.85–1.64 (m, 2H, H100), 1.40–1.16 (m, 2H,
J¼8.5 Hz, 2H, ArH2% and ArH6%), 6.83 (d, J¼8.0 Hz, 2H, ArH3% and
ArH5%), 6.10–5.98 (m, 1H, H2&), 5.84–5.70 (m, 1H, H20), 5.38 (dd,
J¼1.5, 17.5 Hz, 1H, H3a&), 5.23 (dd, J¼1.0, 10.5 Hz, 1H, H3b&), 5.12
0
0
(d, J¼17.0 Hz, 1H, H3a ), 5.08 (d, J¼10.5 Hz, 1H, H3b ), 4.50 (d,
J¼5.0 Hz, 2H, H1&), 4.42–4.37 (m, 3H, H2, H5 and H8), 3.71 (s, 3H,
OCH3), 2.97 (t, J¼7.5 Hz, 2H, H300), 3.02–2.85 (m, 2H, ArCH2), 2.63–
2.45 (m, 2H, H10), 1.93 (s, 3H, CH3, H11), 1.84–1.73 (m, 2H, H100),
H200). 13C NMR (CD3OD, 75 MHz):
d 174.0, C4; 173.4, C11; 172.9, C1;
169.0, C7; 158.8, ArC4%; 158.2, CN3; 134.7, C2&; 134.3, C20; 131.2,
ArC1%; 129.8, ArCH2% and ArCH6%; 118.4, C30; 117.4, C3&; 115.7,
ArCH3% and ArCH5%; 69.8, C1&; 57.7, C2; 54.0, C5; 53.7, C8; 52.8,
OCH3; 50.1, C300; 37.5, ArCH2; 36.4, C10; 29.5, C200; 24.0, C11; 22.3,
C100. MS (ESI, þve) m/z 531 (100%) [MHþ]. HRMS calcd for
C26H39N6O6 531.2931, found 531.2939.
1.63–1.60 (m, 2H, H200). 13C NMR (CD3OD, 75 MHz):
d 173.9, C4;
173.4, C11; 173.1, C1; 172.9, C7; 158.8, ArC4%; 158.4, CN3; 134.8,
C2&; 134.1, C20; 131.1, ArC1%; 130.2, ArCH2% and ArCH6%; 118.9,
C30; 117.2, C3&; 115.6, ArCH3% and ArCH5%; 69.7, C1&; 56.9, C2;
53.8, C5; 53.6, C8; 52.8, OCH3; 50.1, C300; 37.7, ArCH2; 36.9, C10; 26.1,
C200; 22.5, C11; 20.7, C100. MS (ESI, þve) m/z 531.1 (85%) [MHþ].
HRMS calcd for C26H39N6O6 531.2931, found 531.2952.
5.11.4. Methyl (2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-
5-(3-[guanidino]propyl)-4,7,10-oxoundecanoate hydrochloride (57)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 34 (63 mg,
5.12. Synthesis of acyclic guanidinelysine derivatives
(Scheme 7)
0.079 mmol) to yield 57 (38 mg, 0.036 mmol, 85%) as a highly hy-
5.12.1. Methyl (2S,5R,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-
5-(4[{N,N-di-tert-butoxycarbonyl}guanidino]butyl)-4,7,10-
trioxoundecanoate (60)
21
groscopic solid. [
a
]
þ46.1 (c 0.001, MeOH). IR (neat) nmax 1740,
D
1631, 1543, 1512, 1254, 1093. 1H NMR (CD3OD, 300 MHz):
d
7.13 (d,
J¼8.7 Hz, 2H, ArH2% and ArH6%), 6.82 (d, J¼8.7 Hz, 2H, ArH3% and
ArH5%), 6.09–5.97 (m, 1H, H2&), 5.84–5.70 (m, 1H, H20), 5.36 (dd,
J¼1.5, 17.4 Hz, 1H, H3a&), 5.22 (dd, J¼1.5, 10.5 Hz,01H, H3b&), 5.13
Toasolutionof9 (56 mg, 0.093 mmol)inCH2Cl2 (2 mL)wasadded
TFA (2 mL) and the resulting mixture was allowed to stir for 3 h. The
solvent was concentrated and the intermediate trifluoroacetate salt
was precipitated by addition of diethyl ether and collected as a solid
by vacuum filtration. To this solid were added N-tert-butoxycarbox-
amido(trifluoromethylsulfonylimino)methyl propanamide (65 mg,
0.17 mmol), triethylamine (0.2 mL) and CH2Cl2 (2 mL). The resulting
solution was allowed to stir for 16 h under N2. The solvent was
evaporated and the crude product was purified by flash column
chromatography (15:1, CH2Cl2/MeOH) to yield the title compound as
a 1:1 mixture of epimers (70 mg, 0.093 mmol, 100%) as an orange/
0
(d, J¼18.3 Hz, 1H, H3a ), 5.08 (d, J¼9.6 Hz, 1H, H3b ), 4.50–4.48 (m,
3H, H1& and H5), 4.42–4.36 (m, 2H, H2 and H8), 3.69 (s, 3H, OCH3),
3.21–3.15 (m, 2H, H300), 3.02 (dd, J¼5.7, 13.8 Hz, 1H, ArCHH), 2.82
(dd, J¼9.0, 14.1 Hz, 1H, ArCHH), 2.60–2.41 (m, 2H, H10), 1.92 (s, 3H,
H11), 1.88–1.81 (m, 2H, H100), 1.70–1.58 (m, 2H, H200). 13C NMR
(CD3OD, 75 MHz):
d 173.9, C4; 173.5, C11; 173.4, C1; 173.2, C7;
158.8, ArC4%; 158.4, CN3; 134.9, C2&; 134.2, C20; 131.2, ArC1%;
130.3, ArCH2% and ArCH6%; 117.4, C30; 116.2, C3&; 115.6, ArCH3%
and ArCH5%; 69.7, C1&; 56.6, C2; 53.8, C5; 53.6, C8; 52.8, OCH3;
50.1, C300; 36.6, ArCH2; 36.5, C10; 30.3, C200; 23.0, C11; 22.5, C100. MS
(ESI, þve) m/z 531.1 (100%) [MHþ]. HRMS calcd for C26H39N6O6
531.2931, found 531.2916.
yellow solid. Mp 112–114 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 8.31 (br s,
1H, NH), 7.20 (d, J¼8.0 Hz, 1H, NH), 7.11–7.04 (m, 2H, ArH2% and
ArH6%), 6.94 (d, J¼7.6 Hz, 1H, NH), 7.11–6.79 (m, 2H, ArH3% and
ArH5%), 6.72 (d, J¼7.2 Hz, 1H, NH), 6.60 (d, J¼7.6 Hz, 1H, NH), 6.07–
5.96 (m, 1H, H2&), 5.71–5.61 (m, 1H, H20), 5.38 (d, J¼17.3 Hz, 1H,
H3a&), 5.26 (d, J¼10.5 Hz, 1H, H3b&), 5.14–5.06 (m, 2H, H30), 4.70–
4.34 (m, 5H, H2, H5, H8 and H2&), 3.74/3.70 (s, 3H, OCH3), 3.32 (d,
J¼6.7 Hz, 2H, H400), 3.00–2.86 (m, 2H, ArCH2), 2.56–2.43 (m, 2H, H10),
1.97/1.96 (s, 3H, H11), 1.40–1.05 (m, 6H, H100, H200 and H300), 1.49 (s,
5.11.5. Methyl (2R,5R,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-
5-(3-[guanidino]propyl)-4,7,10-oxoundecanoate hydrochloride (58)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 35 (48 mg, 0.60 mmol)
to yield 58 (32 mg, 0.060 mmol, 100%) as a highly hygroscopic solid.
18H, 2ꢁC(CH3)3). 13C NMR (CDCl3, 75 MHz):
d 172.1/171.7, C7; 171.4/

11286
T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
171.3, C1; 170.9, C4; 170.7, C10; 163.1, CN3; 157.5/157.4, ArC4%; 156.0/
155.9, NCO2; 153.0, NCO2; 133.1/133.0, C20; 132.1/131.9, C2&; 130.0,
ArCH2% and ArCH6%; 128.2/128.0, ArC1%; 119.1/118.9, C30; 117.5/
117.3, C3&; 114.8/114.7, ArCH3% and ArCH5%; 83.2/83.1, C(CH3)3;
79.5/79.4, C(CH3)3; 68.7, C1&; 55.4/54.6, C5; 52.9, OCH3; 52.5/52.8,
C8; 51.9/51.8, C2; 40.7/40.5, C400; 37.2, ArCH2;36.3, C10; 36.1, C100; 31.9/
31.5, C300; 28.6/28.3, C(CH3)3; 22.9/22.7, C11; 22.5, C200. MS (ESI, þve)
m/z 745.4 (100%) [MHþ]. HRMS calcd for C37H57N6O10 745.4136,
found 745.4138.
solid. 1H NMR (CD3OD, 300 MHz):
d 7.10 (br s, 2H, ArH2% and
ArH6%), 6.79 (br s, 2H, ArH3% and ArH5%), 6.10–5.90 (m, 1H, H2&),
5.84–5.62 (m, 1H, H20), 5.36–4.99 (m, 4H, H3& and H30), 4.45–4.10
(m, 5H, H2, H5, H8 and H1&), 3.65 (s, 3H, OCH3), 3.11–2.70 (m, 4H,
H10 and H400), 2.49 (br s, 2H, ArCH2), 1.87 (s, 3H, H11), 1.47–1.23 (m,
6H, H100, H200 and H300). 13C NMR (CD3OD, 75 MHz):
d 174.2, C4; 174.1,
C11; 173.6, C1; 173.2, C7; 159.4, ArC4%; 158.4, CN3; 134.6, C2&;
134.2, C20; 131.2, ArC1%; 130.3, ArCH2% and ArCH6%; 119.6, C30;
118.2, C3&; 116.3, ArCH3% and ArCH5%; 70.0, C1&; 57.4, C2; 54.4,
C5; 53.9, C8; 52.4, OCH3; 42.2, C400; 37.6, ArCH2; 36.6, C10; 32.5, C200;
29.5, C300; 23.6, C11; 22.8, C100. MS (ESI, þve) m/z 545.3 (100%) [MHþ].
HRMS calcd for C27H41N6O6 545.3088, found 545.3066.
5.12.2. Methyl (2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-
5-(4[{N,N-di-tert-butoxycarbonyl}guanidino]butyl)-4,7,10-
trioxoundecanoate (61)
To a solution of 32 (41 mg, 0.081 mmol) in CH2Cl2 (2 mL) were added
N-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methyl prop-
anamide (35 mg, 0.089 mmol) and triethylamine (0.1 mL). The resulting
solution was allowed to stir for 16 h under N2. The solvent was evapo-
rated and the crude product was purified by flash column chromato-
graphy (15:1, CH2Cl2/MeOH) to yield the title compound as a 1:1
mixture of epimers (45 mg, 0.060 mmol, 74%) as an orange/yellow solid.
5.13. Synthesis of cyclic guanidinelysine derivatives
(Scheme 8)
5.13.1. (7S,10S,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(4-[{N,N-di-
tert-butoxycarbonyl}guanidino]butyl)-7-methoxycarbonyl-2-oxa-
9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-ene (64)
Toasolutionof10 (75 mg, 0.15 mmol)inCH2Cl2 (2 mL)were added
N-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methyl pr-
opanamide (115 mg, 0.29 mmol), triethylamine (0.1 mL) and CH2Cl2
(2 mL). The resulting solution was allowed to stir for 16 h under N2.
The solvent was evaporated and the crude product was purified by
flash column chromatography (15:1, CH2Cl2/MeOH) to yield 64 as
a 1:1 mixture of epimers (96 mg, 0.13 mmol, 87%)as anorange/yellow
Mp 114–118 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 8.26 (br s, 1H, NH), 7.08
(t, J¼8.4 Hz, 2H, ArH2% and ArH6%), 6.99–6.94 (m, 1H, NH), 6.83 (t,
J¼8.4 Hz, 2H, ArH3% and ArH5%), 6.73 (d, J¼8.0 Hz, 1H, NH), 6.57 (t,
J¼9.3 Hz, 1H, NH), 6.09–5.96 (m, 1H, H2&), 5.74–5.59 (m, 1H, H20), 5.39
(d, J¼17.3 Hz,1H, H3a&), 5.26 (d, J¼10.1 Hz,1H, H3b&), 5.14–5.06 (m, 2H,
H30), 4.70–4.33 (m, 5H, H2, H5, H8 and H1&), 3.74/3.71 (s, 3H, OCH3),
3.33 (br s, 2H, H400), 3.05–2.88 (m, 2H, H10), 2.59–2.46 (m, 2H, ArCH2),
1.97 (s, 3H, H11), 1.50–1.20 (m, 6H, H100, H200 and H300), 1.49 (s, 18H,
solid. Mp 104–102 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 8.28–8.24 (m, 1H,
NH), 7.14–6.71 (m, 4H, ArH), 6.00–5.50 (m, 2H, H4 and H5), 4.77–4.55
(m, 5H, H2, H7, H10 and H13), 3.79/3.78 (s, 3H, OCH3), 3.34–3.23 (m,
2H, H40), 2.99–2.87 (m, 2H, H6), 2.77–2.637 (m, 2H, H14), 2.09/2.07 (s,
3H, NCOCH3), 1.60–1.50 (m, 6H, H10, H20 and H30), 1.49/1.48 (s, 18H,
C(CH3)3). 13C NMR (CDCl3, 75 MHz):
d 171.7/171.6, C7; 171.3/171.2, C1;
170.9/170.7, C4; 170.6, C10; 163.2/163.1, CN3; 157.5/157.4, ArC4%; 156.0,
NCO2; 153.1/151.4, NCO2; 133.1/133.0, C20; 132.0/131.9, C2&; 130.1,
ArCH2% and ArCH6%; 128.2/128.1, ArC1%; 119.2/119.0, C30; 117.5, C3&;
114.8/114.7, ArCH3% and ArCH5%; 83.2/83.1, NCO2; 79.5/79.4, NCO2;
68.7, C1&; 55.2/54.5, C5; 53.1/53.0, OCH3; 52.4, C8; 52.4/51.9, C2; 40.7/
40.5, C400; 37.2, ArCH2; 36.1, C10; 32.0/31.6, C100; 28.6/28.3, C(CH3)3; 28.1/
27.8, C(CH3)3; 22.9, C11; 22.6, C200. MS (ESI, þve) m/z 745.2 (100%)
[MHþ]. HRMS calcd for C37H57N6O10 745.4136, found 745.4105.
C(CH3)3). 13C NMR (CDCl3, 75 MHz):
d 172.1/171.8, C9; 170.8/170.7, 7-
CO; 170.3,13-NCO; 169.9, C12; 163.6, CN3; 156.7,1-ArC1; 156.3/156.2,
NCO2; 153.4/153.3, NCO2; 130.4, 1-ArCH2 and 1-ArCH6; 129.9, C4;
128.4, C5; 127.6, 1-ArC4; 116.8, 1-ArCH3 and 1-ArCH5; 83.4/83.3,
C(CH3)3; 79.5/79.4, C(CH3)3; 66.2, C3; 54.8, C13; 53.8, C10; 52.1, OCH3;
41.1, C40; 33.9, C7; 31.3, C14; 30.0, C6; 29.2, C(CH3)3; 27.5, C30; 23.5,13-
NCOCH3; 22.6, C20. MS (ESI, þve) m/z 717.4 (100%) [MHþ]. HRMS calcd
for C35H53N6O10 717.3823, found 717.3806.
5.12.3. Methyl (2S,5R,8S)-2-allyl-9-(4-allyloxybenzyl)-5-(4-
[guanidino]butyl)-3,6,9-triaza-4,7,10-trioxoundecanoate
hydrochloride (62)
5.13.2. (7S,10S,13S,4E/Z)-13-Acetamido-10-(4-[guanidino]butyl)-
8,11-diaza-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenyle-
nacyclotetradecaphane-4-ene hydrochloride (65)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 60 (71 mg,
0.095 mmol) to yield 62 (43 mg, 0.074 mmol, 78%) as a yellow hy-
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 64 (86 mg, 0.12 mmol)
to yield 65 (50 mg, 0.097 mmol, 81%) as a highly hygroscopic yellow
groscopic solid. 1H NMR (CD3OD, 300 MHz):
d 8.25–8.15 (m, 2H,
NHꢁ2), 7.15 (d, J¼8.4 Hz, 2H, ArH2% and ArH6%), 6.87 (d, J¼8.4 Hz,
2H, ArH3% and ArH5%), 6.10–5.96 (m, 1H, H2&), 5.80–5.66 (m, 1H,
H20), 5.39 (d, J¼17.3 Hz, 10H, H3a&), 5.24 (d, J¼10.5 Hz0, 1H, H3b&),
5.12 (d, J¼6.0 Hz, 1H, H3a ), 5.05 (d, J¼9.9 Hz, 1H, H3b ), 4.52–4.37
(m, 4H, H2, H5 and H1&), 4.17 (dd, J¼4.0, 8.7 Hz, 1H, H8), 3.72 (s,
3H, OCH3), 3.18–2.80 (m, 4H, H10 and H400), 2.62–2.42 (m, 2H,
ArCH2), 1.94 (s, 3H, H11), 1.83–1.39 (m, 4H, H200 and H300), 1.05–0.97
solid. 1H NMR (CD3OD, 500 MHz):
d 10.34 (br s, 1H, NH), 7.55–7.36
(m, 2H, ArH), 7.18–7.07 (m, 2H, ArH), 5.97–5.80 (m, 2H, H4 and H5),
4.98–4.68 (m, 5H, H2, H7, H10 and H13), 3.65 (s, 3H, OCH3), 3.32–
3.31 (m, 2H, H40), 3.10–3.00 (m, 2H, H6), 2.42–2.40 (m, 2H, H14),
2.10 (s, 3H, NCOCH3), 2.10–2.00 (m, 2H, H30), 1.90–1.80 (m, 2H, H10),
1.54–1.42 (m, 2H, H20). 13C NMR (CD3OD, 125 MHz):
d 173.3/173.2,
(m, 2H, H100). 13C NMR (CD3OD, 75 MHz):
d
174.3, C4; 174.0, C11;
C9; 172.7/173.6, 7-CO; 172.5, 13-NCO; 169.4, C12; 158.5/158.4, 1-
ArC1; 131.4/131.3, 1-ArCH2 and 1-ArCH6; 131.0, C4; 129.3, C5;
129.0, 1-ArC4; 116.5, 1-ArCH3 and 1-ArCH5; 67.0, C3; 58.2, C7; 57.5,
C13; 57.4, C10; 53.9, OCH3; 42.1, C40; 33.9, C14; 29.0, C6; 23.5, C30;
22.7, C10; 22.5, NCOCH3; 22.5, C20. MS (ESI, þve) m/z 517.4 (100%)
[MHþ]. HRMS calcd for C25H37N6O6 517.2775, found 517.2765.
173.3, C1; 173.2, C7; 159.0, ArC4%; 158.5, CN3; 134.9, C2&; 134.5,
C20; 131.4, ArC1%; 130.4, ArCH2% and ArCH6%; 118.6, C30; 117.5,
C3&; 115.9, ArCH3% and ArCH5%; 69.8, C1&; 57.5, C2; 54.3, C5;
53.8, C8; 52.7, OCH3; 42.1, C400; 37.5, ArCH2; 36.4, C10; 31.9, C200;
29.2, C300; 23.6, C11; 22.4, C100. MS (ESI, þve) m/z 545.4 (100%)
[MHþ]. HRMS calcd for C27H41N6O6 545.3088, found 545.3073.
5.14. Synthesis of dityrosine cyclic peptides (Scheme 9)
5.12.4. Methyl (2S,5S,8S)-2-allyl-9-(4-allyloxyphenyl)-5-(4-
[guanidino]butyl)-3,6,9-triaza-4,7,10-trioxoundecanoate
hydrochloride (63)
5.14.1. Methyl (2S)-(4-hydroxyphenyl)-2-tert-butoxy-
carboxamidopropanoate (67)
The title compound was synthesized using the general N-Boc
deprotectionprocedure(ProcedureA), from61 (40 mg, 0.054 mmol)
to yield 63 (11 mg, 0.019 mmol, 35%) as a highly hygroscopic yellow
To a solution of (2S)-2-amino-3-(4-hydroxyphenyl)propanoic
acid 66 (5.23 g, 28.9 mmol) in anhydrous MeOH (20 mL) at 0 ꢀC was
added dropwise thionyl chloride (2 mL). The resulting mixture was

T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
11287
allowed to stir for 40 h before the solvent was removed by evapo-
ration and the resulting hydrochloride salt was dissolved in DMF
(15 mL). To this solution was added di-tert-butyl-dicarbonate
(9.44 g, 43.3 mmol) and the reaction mixture was allowed to reach
rt whilst stirring. After 16 h the reaction was quenched with water
(30 mL) and extracted with EtOAc (3ꢁ30 mL). The combined ex-
tracts were washed with water (5ꢁ20 mL), dried and evaporated.
The crude product was purified by flash column chromatography
(25:1, CH2Cl2/MeOH) to yield the title compound (1.32 g,
4.48 mmol, 16%) as a yellow oil, which was spectroscopically
J¼7.2 Hz, 1H, NH), 5.34 (d, J¼16.8 Hz, 1H, H3a00), 5.23 (d, J¼10.5 Hz,
1H, H3b00), 4.81 (d, J¼5.8 Hz,1H, H2), 4.70 (t, J¼5.9 Hz,1H, H5), 4.38–
4.34 (m, 3H, OCH2 and OCH2-H9%), 4.20–4.18 (m, 2H, H100), 3.68 (s,
3H, OCH3), 3.05–3.04 (m, 4H, H9 and ArCH2), 1.76–1.70 (m, 2H, H6),
1.60–1.50 (m, 2H, H7),1.42 (s, 9H, C(CH3)3),1.23–1.21 (m, 2H, H8). 13
C
NMR (CDCl3, 75 MHz):
d 171.7, C4; 171.2, C1; 157.4 , NCO; 155.9,
NCO%; 143.6, ArC40; 143.3, ArC8a% and ArC9a%; 141.0, ArC4a% and
ArC4b%; 133.0, C200; 130.0, ArCH20 and ArCH60; 127.7, ArCH3% and
ArCH6%; 127.5, ArCH2% and ArCH7%; 126.9, ArCH1% and ArCH8%;
124.9, ArCH4% and ArCH5%; 119.8, ArC10; 117.4, C300; 114.6, ArCH30
and ArCH50; 79.0, C(CH3)3; 68.6, CH2-C9%; 67.1, C100; 54.6, C5; 53.2,
C2; 52.3, OCH3; 47.0, C9%; 39.9, C9; 37.0, ArCH2; 32.2, C6; 29.6, C8;
28.4, C(CH3)3; 22.3, C7. MS (ESI, þve) m/z 708.4 (100%) [MNaþ].
HRMS calcd for C39H48N3O8 686.3439, found 686.3441.
identical to that reported.25 1H NMR (CDCl3, 300 MHz):
d 6.95 (d,
J¼8.4 Hz, 2H, ArH20 and ArH60), 6.73 (d, J¼8.4 Hz, 2H, ArH30 and
ArH50), 6.51 (br s, 1H, OH), 5.05 (d, J¼8.4 Hz, 1H, NH), 4.57–4.50 (m,
1H, H2), 3.71 (s, 3H, OCH3), 3.06–2.91 (m, 2H, H3), 1.42 (s, 9H,
C(CH3)3). 13C NMR (CDCl3, 75 MHz):
d 172.5, C1; 155.2, NCO; 155.1,
ArC40; 130.2, ArCH20 and ArCH60; 127.2, ArCH30 and ArCH50; 115.4,
ArC10; 80.2, C(CH3)3; 54.6, C2; 52.3, OCH3; 37.6, C3; 28.3, C(CH3)3.
MS (CI, þve) m/z 196 (100%) [MHþ (less Boc)]. HRMS calcd for
C16H22NO5 296.1498, found 296.1503.
5.14.5. Methyl (2S,5R)-2-(4-allyloxybenzyl)-5-amino-3-aza-9-
(tert-butoxycarboxamido)-4-oxononanoate (71)
The title compound was synthesized using the general N-Fmoc
deprotection procedure (Procedure C), from 70 (198 mg,
0.290 mmol) to yield 71 (131 mg, 0.280 mmol, 97%) as a cream oil.
5.14.2. Methyl (2S)-3-(4-allyloxyphenyl)-2-tert-
butoxycarboxamidopropanoate (68)
1H NMR (CDCl3, 300 MHz):
d
7.63 (d, J¼8.4 Hz, 1H, NH), 7.04 (d,
J¼8.4 Hz, 2H, ArH20 and ArH60), 6.83 (d, J¼8.4 Hz, 2H, ArH30 and
ArH50), 6.11–5.98 (m, 1H, H200), 5.40 (dd, J¼1.7, 17.3 Hz, 1H, H3a00),
5.28 (dd, J¼1.7, 11.8 Hz, 1H, H3b00), 4.81–4.75 (m, 1H, H2), 4.66 (br s,
1H, NH), 4.51–4.49 (m, 2H, H100), 3.71 (s, 3H, OCH3), 3.32 (dd, J¼4.2,
7.6 Hz, 1H, H5), 2.60–2.54 (m, 4H, ArCH2 and H8), 1.81–1.25 (m, 6H,
H6, H7 and H8), 1.43 (s, 9H, C(CH3)3). 13C NMR (CDCl3, 75 MHz):
To a solution of 67 (1.30 g, 4.39 mmol) in DMF (15 mL) under an
N2 atmosphere was added K2CO3 (1.21 g, 8.79 mmol) and the
resulting suspension was allowed to stir for 20 min before the ad-
dition of allyl bromide (0.76 mL, 8.79 mmol). The reaction mixture
was allowed to stir for 16 h before quenching with water (40 mL)
and extracting with EtOAc (3ꢁ40 mL). The combined extracts were
washed with water (4ꢁ40 mL), dried and evaporated to yield the
title compound (1.21 g, 3.35 mmol, 76%) as a colourless solid, which
was identical to that reported.23 Mp 142–144 ꢀC (lit. 145 ꢀC).23
d
175.0, C4; 172.3, C1; 157.9, NCO2; 156.3, ArC40; 133.5, C200; 130.4,
ArCH20 and ArCH60; 128.5, ArC10; 118.0, C300; 115.0, ArCH30 and
ArCH50; 79.4, C(CH3)3; 69.1, C100; 55.3, C2; 54.4, C5; 52.7, OCH3; 40.6,
C9; 37.5, ArCH2; 34.8, C6; 30.3, C8; 28.9, C(CH3)3; 23.1, C7. MS (ESI,
þve) m/z 464.3 (100%) [MHþ]. HRMS calcd for C24H38N3O6
464.2761, found 464.2749.
5.14.3. Methyl (2S)-2-(4-allyloxyphenyl)-2-aminopropanoate
hydrochloride (69)
To a solution of 68 (1.10 g, 3.28 mmol) in CH2Cl2 (5 mL) was
added TFA (5 mL) dropwise. After stirring for 16 h the solvent
was removed by evaporation and the resulting trifluoroacetate salt
was resuspended in methanol (2 mL) and treated with 1 M HCl/
diethyl ether (2 mL). The solution was stirred for 5 min before the
solvent was evaporated to yield the crude hydrochloride salt. The
crude product was purified by precipitation (CH2Cl2/diethyl ether)
to give the title compound (889 mg, 3.28 mmol, 100%) as a white
5.14.6. Methyl (2S,5R,8S)-2,8-di(4-allyloxybenzyl)-3,6,9-triaza-5-
(4-[tert-butoxycarboxamido]butyl)-4,7,10-trioxoundecanoate (72)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 71 (220 mg, 0.600 mmol)
and 14 (132 mg, 0.500 mmol) to yield 72 (130 mg, 0.180 mmol, 37%)
as a white solid. Mp 185–186 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 7.36
(d, J¼7.6 Hz, 2H, NH), 7.08 (d, J¼8.4 Hz, 2H, ArH20 and ArH60), 7.02
(d, J¼8.4 Hz, 2H, ArH2& and ArH6&), 6.82 (d, J¼8.4 Hz, 4H, ArH30,
ArH50, ArH3& and ArH5&), 6.63 (d, J¼7.2 Hz,1H, NH), 6.10–5.94 (m,
2H, H200 and H2&0), 5.43–5.24 (m, 4H, H300 and H3&0), 4.82–4.75 (m,
2H, H2 and H8), 4.62–4.58 (m, 1H, H5), 4.91–4.44 (m, 4H, H100 and
H1&0), 3.67 (s, 3H, OCH3), 3.04–2.89 (m, 6H, Ar0-CH2, Ar&-CH2 and
H4%), 1.93 (s, 3H, H11), 1.43 (s, 9H, C(CH3)3), 1.37–1.26 (m, 6H, H1%,
solid. Mp 216–220 ꢀC. 1H NMR (CD3OD, 300 MHz):
d 7.16 (d,
J¼8.4 Hz, 2H, ArH20 and ArH60), 6.93 (d, J¼8.8 Hz, 2H, ArH30 and
ArH50), 6.11–5.98 (m, 1H, H200), 5.38 (dd, J¼17.3, 1.7 Hz, 1H, H3a00),
5.24 (dd, J¼11.8, 1.3 Hz, 1H, H3b00), 4.55–4.53 (m, 2H, H100), 4.26 (t,
J¼7.2 Hz 1H, H2), 3.81 (s, 3H, OCH3), 3.23–3.06 (m, 2H, H3). 13C NMR
(CD3OD, 75 MHz):
d
170.3, C1; 159.6, ArC40; 139.6, C200; 131.4, ArCH20
H2% and H3%). 13C NMR (CDCl3, 75 MHz):
d 172.2, C7; 170.8, C4;
and ArCH60; 127.0, ArC1; 117.4, C300; 116.2, ArCH30 and ArCH50; 69.7,
C100; 55.3, C2; 53.6, OCH3; 36.6, C3. MS (CI, þve) m/z 236 (90%)
[MHþ]. HRMS calcd for C13H18NO3 236.1287, found 236.1276.
170.6, C1; 170.1, C10; 157.4, NCO2; 157.3, ArC4&; 155.8, ArC40; 133.0,
C200 and C2&0; 130.1, ArCH20 and ArCH60; 130.1, ArCH2& and
ArCH6&; 128.4, ArC1&; 128.0, ArC10; 117.5, C300 and C3&0; 114.7,
ArCH30 and ArCH50; 114.6, ArCH3& and ArCH5&; 78.9, C(CH3)3;
68.7, C100; 68.7, C1&0; 55.1, C2; 53.3, C5; 52.6, OCH3; 52.3, C8; 40.1,
C4%; 37.5, Ar0CH2; 37.2, Ar&CH2; 31.9, C1%; 29.7, C3%; 28.5,
C(CH3)3; 23.0, C11; 22.1, C2%. MS (ESI, þve) m/z 709.3 (100%) [MHþ].
HRMS calcd for C38H52N4O9 709.3813, found 709.3793.
5.14.4. Methyl (2S,5R)-2-(4-allyloxybenzyl)-3-aza-9-(tert-
butoxycarboxamido)-5-(9H-9-fluorenylmethyl-
carboxamido)-4-oxononanoate (70)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 69 (200 mg, 0.74 mmol)
and (2R)-6-tert-butoxycarboxamido-2-[(9H-9-fluorenylmethyloxy)-
carboxamido]hexanoic acid (291 mg, 0.62 mmol) to afford 70
(317 mg, 0.47 mmol, 75%) as a pale yellow solid. IR (neat) nmax 1734,
1684, 1653, 1539, 1510, 1250, 1174, 738. Mp 114–116 ꢀC. 1H NMR
5.14.7. Methyl (2S,5R,8S)-2,8-di(4-allyloxybenzyl)-5-(4-
aminobutyl)-3,6,9-triaza-4,7,10-trioxoundecanoate
hydrochloride (73)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 72 (33 mg,
0.051 mmol) to yield 73 (18 mg, 0.028 mmol, 55%) as a yellow solid.
(CDCl3, 300 MHz):
d
7.74 (d, J¼7.6 Hz, 2H, ArH1% and ArH8%), 7.57
(d, J¼6.3 Hz, 2H, ArH4% and ArH5%), 7.38 (t, J¼7.2 Hz, 2H, ArH3%
and ArH6%), 7.28 (t, J¼7.6 Hz, 2H, ArH2% and ArH7%), 6.99
(d, J¼7.6 Hz, 2H, ArH20 and ArH60), 6.82 (d, J¼7.2 Hz, 1H, NH), 6.76
(d, J¼8.0 Hz, 2H, ArH30 and ArH50), 5.99–5.95 (m, 1H, H200), 5.67 (d,
Mp 186–190 ꢀC. 1H NMR (CD3OD, 500 MHz):
d 7.50 (br s, 1H, NH),
7.41 (br s, 4H, ArH), 7.26–7.10 (m, 4H, ArH), 6.46–6.30 (m, 2H, H200
and H2&0), 5.80–5.64 (m, 4H, H300 and H3&0), 4.99–4.70 (m, 6H, H2,

11288
T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
H8, H100 and H1&0), 4.55–4.42 (m, 1H, H5), 3.70 (s, 3H, OCH3), 3.42–
3.18 (br s, 6H, H4%, Ar0-CH2 and Ar&-CH2), 2.27 (s, 3H, H11), 2.05–
1.65 (m, 4H, H100 and H300), 1.33 (m, 2H, H200). 13C NMR (CD3OD,
7.59 (d, J¼6.9 Hz, 2H, ArH4% and ArH5%), 7.39 (t, J¼7.5 Hz, 2H,
ArH3% and ArH6%), 7.30 (dd, J¼1.2, 7.5 Hz, 2H, ArH2% and ArH7%),
6.98 (d, J¼8.4 Hz, 2H, ArH20 and ArH60), 6.77 (d, J¼8.7 Hz, 2H, ArH30
and ArH50), 6.58 (d, J¼7.2 Hz, 1H, NH), 6.02–5.92 (m, 1H, H200), 5.56
(d, J¼6.9 Hz, 1H, NH), 5.35 (dd, J¼1.5, 17.1 Hz, 1H, H3a00), 5.24 (dd,
J¼1.5, 10.8 Hz, 1H, H3b00), 4.81 (dd, J¼6.0, 13.8 Hz, 1H, H2), 4.70 (t,
J¼5.1 Hz, 1H, H5), 4.43–4.35 (m, 4H, H100 and OCH2-H9%), 4.20 (d,
J¼7.2 Hz, 2H, H100), 3.70 (s, 3H, OCH3), 3.10–3.02 (m, 4H, H9 and
ArCH2), 1.83–1.78 (m, 2H, H6), 1.66–1.64 (m, 2H, H7), 1.43 (s, 9H
125 MHz): d 173.9, C7; 173.7, C4; 173.1, C1; 172.0, C10; 158.5, ArC4&
and ArC40; 134.7, C200 and C2&0; 131.3, ArCH20 and ArCH60; 131.1,
ArCH2& and ArCH6&; 130.0, ArC1&; 129.8, ArC10; 117.8, C300; 117.5,
C3&0; 115.8, ArCH30 and ArCH50; 115.6, ArCH3& and ArCH5&; 70.0,
C100; 69.8, C1&0; 57.2, C2; 55.2, C5; 53.8, OCH3; 52.4, C8; 40.7, C4%;
37.4, Ar0-CH2; 37.1, Ar&-CH2; 31.7, C1%; 27.9, C3%; 23.2, C11; 22.2,
C2%. MS (ESI, þve) m/z 609.7 (100%) [MHþ]. HRMS calcd for
C33H45N4O7 609.3288, found 609.3301.
C(CH3)3), 1.36–1.33 (m, 2H, H8). 13C NMR (CDCl3, 75 MHz):
d 171.7,
C4; 171.3, C1; 157.7, NCO2; 156.1, NCO2%; 143.7, ArC40; 141.2,
ArC8a% and ArC9a%; 141.0, ArC4a% and ArC4b%; 133.1, C200; 130.1,
ArCH20 and ArCH60; 127.7, ArCH3% and ArCH6%; 127.5, ArCH2% and
ArCH7%; 127.0, ArCH1% and ArCH8%; 125.0, ArCH4% and ArCH5%;
119.9, ArC10; 117.6, C300; 114.7, ArCH30 and ArCH50; 79.0, C(CH3)3;
68.6, CH2-C9%; 67.1, C100; 54.6, C5; 53.3, C2; 52.3, OCH3; 47.0, C9%;
39.8, C9; 36.8, ArCH2; 32.0, C6; 29.5, C8; 28.4, C(CH3)3; 22.2, C7. MS
(ESI, þve) m/z 686.4 (10%), 708.4 (100%) [MNaþ]. HRMS calcd for
C39H48N3O8 686.3441, found 686.3454.
5.14.8. (10S,13R,16S,4E/Z)-16-Acetamido-11,14-diaza-13-([tert-
butoxycarboxamido]butyl)-10-methoxycarbonyl-2,7-dioxa-12,15-
dioxo-1(1,4),8(4,1)-diphenylenecycloheptadecaphane-4-ene (74)
The title compound was prepared using the general procedure
for olefin metathesis (Procedure D), from 72 (56 mg, 0.079 mmol)
to yield 74 (22 mg, 0.032 mmol, 41%) as a brown solid. Mp 190–
194 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 7.13–6.73 (m, 8H, ArH), 6.02–
5.83 (m, 2H, H4 and H5), 5.02–4.94 (m, 1H, H10), 4.86–4.76 (m, 1H,
H16), 4.61–4.50 (m, 4H, H3 and H6), 4.18–4.10 (m, 1H, H13), 3.74 (s,
3H, OCH3), 3.30–3.25 (m, 2H, H40), 3.01–2.52 (m, 4H, H9 and H17),
1.97 (s, 3H, NCOCH3),1.25 (s, 9H, C(CH3)3),1.93–0.88 (m, 6H, H10, H20
5.15.2. Methyl (2S,5R)-2-(4-allyloxybenzyl)-3-aza-5-(9H-9-
fluorenylmethylcarboxamido)-4-oxo-8-[(2,2,5,7,8-pentamethyl-3,4-
dihydro-2H-6-chromenylsulfonyl)guanidino]nonanoate (77)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 69 (200 mg, 0.74 mmol)
and (2R)-2-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-
pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]pe-
ntanoic acid (411 mg, 0.62 mmol) to afford 77 (386 mg, 0.44 mmol,
71%) as a pale yellow solid. Mp 86 ꢀC. 1H NMR (CDCl3, 300 MHz):
and H30). 13C NMR (CDCl3, 75 MHz):
d
171.8, C12; 170.0, NCOCH3;
169.8, 10-CO; 169.2, C15; 157.3, 1-ArC1; 157.3, 8-ArC1; 156.1, NCO2;
130.8, 8-ArC4; 130.4, 8-ArCH2 and 8-ArCH6; 130.3, 1-ArCH2 and 1-
ArCH6; 128.7, C4; 128.5, C5; 126.3, 1-ArCH4; 115.1, 8-ArCH3 and 8-
ArCH5; 114.7, 1-ArCH3 and 1-ArCH5; 79.3, C(CH3)3; 68.2, C3; 67.9,
C6; 54.8, C16; 52.5, C13; 52.3, OCH3; 52.1, C10; 39.5, C40; 38.0, C9;
35.8, C17; 34.9, C10; 31.9, C30; 28.5, C(CH3)3; 26.2, 16-NCOCH3; 23.3,
C20. MS (ESI, ꢂve) m/z 725.4 (100%) [MHþþformate], 681 (85%)
[MHþ]. HRMS calcd for C36H49N4O9 681.3500, found 681.3521.
d
7.70 (d, J¼7.5 Hz, 2H, ArH1% and ArH8%), 7.52 (d, J¼8.7 Hz, 2H,
ArH4% and ArH5%), 7.33 (dd, J¼7.8, 7.8 Hz, 2H, ArH3% and ArH6%),
7.23–7.16 (m, 2H, ArH2% and ArH7%), 6.90 (d, J¼8.1 Hz, 2H, ArH20
and ArH60), 6.68 (d, J¼8.1 Hz, 2H, ArH30 and ArH50), 6.32 (br s, 2H,
NH), 6.15 (d, J¼8.1 Hz, 1H, NH), 5.97–5.84 (m, 1H, H200), 5.29 (d,
J¼17.4, 1H, H3a00), 5.18 (d, J¼10.5 Hz, 1H, H3b00), 4.71 (dd, J¼7.8,
13.5 Hz, 1H, H2), 4.31–4.24 (m, 5H, H100, OCH2-H9% and H5), 4.15–
4.04 (m, 1H, H9%), 3.62 (s, 3H, OCH3), 3.23–313 (m, 2H, H8), 3.09–
2.95 (m, 2H, ArCH2), 2.58 (s, 3H, 7&-CH3), 2.58–2.52 (m, 2H, H4&),
2.55 (s, 3H, 5&-CH3), 2.06 (s, 3H, 8&-CH3), 1.71 (t, J¼6.6 Hz, 2H,
H3&), 1.62–1.57 (m, 2H, H6), 1.50–1.42 (m, 2H, H7), 1.24 (s, 6H,
5.14.9. (10S,13R,16S,4E/Z)-16-Acetamido-13-(4-aminobutyl)-
11,14-diaza-10-methoxycarbonyl-2,7-dioxa-12,15-dioxo-
1(1,4),8(4,1)-diphenylenecycloheptadecaphane-4-ene (75)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 74 (22 mg,
0.038 mmol) to yield 75 (20 mg, 0.034 mg, 89%) as a yellow solid.
Mp >260 ꢀC. 1H NMR (CD3OD, 300 MHz):
d 8.16–8.03 (m, 3H, NH),
7.13–7.02 (m, 4H, ArH), 6.83–6.70 (m, 4H, ArH), 6.04–5.93 (m, 2H,
H4 and H5), 4.66 (br s, 4H, H3 and H6), 4.60–4.50 (m, 1H, H10),
4.42–4.36 (m, 1H, H16), 4.16–4.06 (m, 1H, H13), 3.75–3.67 (m, 3H,
OCH3), 3.09–2.73 (m, 6H, H9, H17 and H40), 1.92 (s, 3H, NCOCH3),
1.52–1.28 (m, 4H, H10 and H20), 0.98–0.75 (m, 2H, H30). 13C NMR
2ꢁ2&-CH3). 13C NMR (CDCl3, 75 MHz):
d 172.1, C1; 172.0, C4; 157.4,
ArC6&; 156.8, NCO2; 156.2, ArC8a&; 153.6, CN3; 143.7, ArC40; 141.2,
ArC8a% and ArC9a%; 141.0, ArC4a% and ArC4b%; 135.4, ArC7&;
134.8, ArC5&; 133.1, C200; 130.1, ArCH20 and ArCH60; 128.7, ArC8&;
128.3, ArCH3% and ArCH6%; 127.6, ArCH2% and ArCH7%; 127.0,
ArCH1% and ArCH8%; 125.1, ArCH4% and ArCH5%; 119.8, ArC10;
117.9, ArC4a&; 117.5, C300; 114.6, ArCH30 and ArCH50; 73.6, C2&;
68.6, C100; 67.2, CH2-C9%; 60.4, C9%; 53.7, C5; 52.3, OCH3; 46.9, C2;
40.3, C8; 36.6, ArCH2; 32.6, C4&; 26.7, 2&-CH3; 21.3, C6; 21.0, C3&;
18.5, C7; 17.5, 7&-CH3; 14.2, 5&-CH3; 12.0, 8&-CH3. MS (ESI, þve)
m/z 880 (100%) [MHþ]. HRMS calcd for C48H58N5O9S 880.3955,
found 880.3944.
(CD3OD, 75 MHz): d 171.1, C12; 170.3, NCOCH3; 169.9, 10-CO; 169.4,
C15; 157.3, 1-ArC1; 157.13, 8-ArC1; 130.9, 8-ArC4; 130.5, 8-ArCH2
and 8-ArCH6; 130.1, 1-ArCH2 and 1-ArCH6; 128.8, C4; 128.4, C5;
126.3, 1-ArCH4; 115.5, 8-ArCH3 and 8-ArCH5; 114.4, 1-ArCH3 and
1-ArCH5; 68.6, C3; 67.9, C6; 54.8, C16; 52.6, C13; 52.4, OCH3; 52.2,
C10; 39.5, C40; 38.0, C90; 35.8, C17; 34.9, C10; 32.0, C30;þ26.5, 16-
NCOCH3; 23.3, C20. MS (ESI, ꢂve) m/z 581.6 (100%) [MH ]. HRMS
calcd for C31H41N3O7 581.2975, found 581.2980.
5.15.3. Methyl (2S,5S)-2-(4-allyloxybenzyl)-3-aza-5-(9H-9-
5.15. Synthesis of
salts (Scheme 10)
L
-tyrosine acyclic dipeptides hydrochloride
fluorenylmethylcarboxamido)-4-oxo-8-[(2,2,5,7,8-pentamethyl-3,4-
dihydro-2H-6-chromenylsulfonyl)guanidino]nonanoate (78)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 69 (200 mg, 0.74 mmol)
and (2S)-2-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-
pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]pe-
ntanoic acid (411 mg, 0.62 mmol) to afford 78 (460 mg, 0.52 mmol,
84%) as a pale yellow solid. Mp 88–90 ꢀC. 1H NMR (CDCl3,
5.15.1. Methyl (2S,5S)-2-(4-allyloxybenzyl)-3-aza-9-(tert-
butoxycarboxamido)-5-(9H-9-fluorenylmethyl-
carboxamido)-4-oxononanoate (76)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 69 (200 mg, 0.74 mmol)
and (2S)-6-tert-butoxycarboxamido-2-[(9H-9-fluorenylmethyloxy)
carboxamido]hexanoic acid (291 mg, 0.62 mmol) to afford 76
(328 mg, 0.48 mmol, 77%) as a pale yellow solid. Mp 52–54 ꢀC. 1H
300 MHz):
d
7.70 (d, J¼7.8 Hz, 2H, ArH1% and ArH8%), 7.53 (d,
J¼6.6 Hz, 2H, ArH4% and ArH5%), 7.40–7.25 (m, 2H, ArH3% and
ArH6%), 7.21–7.18 (m, 2H, ArH2% and ArH7%), 6.98 (d, J¼8.1 Hz, 2H,
ArH20 and ArH60), 6.70 (d, J¼8.1 Hz, 2H, ArH30 and ArH50), 6.34 (br s,
NMR (CDCl3, 300 MHz):
d
7.75 (d, J¼7.5 Hz, 2H, ArH1% and ArH8%),

T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
11289
2H, NH), 6.13 (br s, 1H, NH), 5.99–5.87 (m, 1H, H200), 5.30 (dd, J¼1.5,
17.1 Hz, 1H, H3a00), 5.19 (d, J¼1.5, 10.5 Hz, 1H, H3b00), 4.72–4.65 (m,
1H, H2), 4.35–4.26 (m, 5H, H100, OCH2-H9% and H5), 4.15–4.06 (m,
1H, H9%), 3.60 (s, 3H, OCH3), 3.26–3.16 (m, 2H, H8), 3.04–2.88 (m,
2H, ArCH2), 2.58 (s, 3H, 7&-CH3), 2.56–2.54 (m, 2H, H4&), 2.54 (s,
3H, 5&-CH3), 2.07 (s, 3H, 8&-CH3), 1.85–1.78 (m, 2H, H6), 1.72 (t,
J¼6.9 Hz, 2H, H3&), 1.58–1.52 (m, 2H, H7), 1.25 (s, 6H, 2ꢁ2&-CH3).
C5; 55.2, C2; 55.1, OCH3; 52.8, C9%; 40.4, C9; 37.3, ArCH2; 32.4, C6;
27.9, C8; 23.6, C7. MS (ESI, þve) m/z 586.7 (100%) [MHþ]. HRMS
calcd for C34H40N3O6 586.2917, found 586.2925.
5.15.6. Methyl (2S,5R)-2-(4-allyloxybenzyl)-3-aza-5-(9H-9-
fluorenylmethylcarboxamido)-8-guanidino-4-oxononanoate
hydrochloride (81)
13C NMR (CDCl3, 75 MHz):
d
172.2; C1; 172.0, C4; 157.4, ArC6&;
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 77 (62 mg,
0.068 mmol) to yield 81 (35 mg, 0.054 mmol, 79%) as a white solid.
156.8, NCO2; 156.3, ArC8a&; 153.6, CN3; 143.8, ArC40; 141.1, ArC8a%
and ArC9a%; 141.0, ArC4a% and ArC4b%; 135.4, ArC7&; 134.8,
ArC5&; 133.2, C200; 130.1, ArCH20 and ArCH60; 128.7, ArC8&; 128.2,
ArCH3% and ArCH6%; 127.6, ArCH2% and ArCH7%; 127.0, ArCH1%
and ArCH8%; 125.2, ArCH4% and ArCH5%; 119.8, ArC10; 117.9,
ArC4a&; 117.5, C300; 114.6, ArCH30 and ArCH50; 73.6, C2&; 68.5, C100;
67.1, CH2-C9%; 60.4, C9%; 54.0, C5; 52.2, OCH3; 46.9, C2; 40.4, C8;
36.5, ArCH2; 32.6, C4&; 26.7, 2&-CH3; 25.1, C6; 21.3, C3&; 18.5, C7;
17.5, 7&-CH3; 14.2, 5&-CH3; 12.0, 8&-CH3. MS (ESI, þve) m/z 880
(30%), 902 (100%) [MNaþ]. HRMS calcd for C48H58N5O9S 880.3955,
found 880.3943.
Mp 158–162 ꢀC. 1H NMR (CD3OD, 300 MHz):
d
7.78 (d, J¼7.5 Hz, 2H,
ArH1% and ArH8%), 7.64 (d, J¼8.1 Hz, 2H, ArH4% and ArH5%), 7.38
(t, J¼6.9 Hz, 2H, ArH3% and ArH6%), 7.40–7.26 (m, 2H, ArH2% and
ArH7%), 7.04 (d, J¼8.4 Hz, 2H, ArH20 and ArH60), 6.72 (d, J¼8.4 Hz,
2H, ArH30 and ArH50), 6.00–5.86 (m,1H, H200), 5.28 (d, J¼17.1 Hz,1H,
H3a00), 5.16 (d, J¼10.8 Hz, 1H, H3b00), 4.61 (dd, J¼5.1, 9.0 Hz, 1H, H2),
4.34–4.32 (m, 4H, H100 and OCH2-H9%), 4.21–4.16 (m, 1H, H5), 4.08–
4.06 (m, 1H, H9%), 3.69 (s, 3H, OCH3), 3.12–3.07 (m, 2H, H8), 2.94–
2.86 (m, 2H, ArCH2), 1.69–1.59 (m, 2H, H6), 1.57–1.43 (m, 2H, H7).
13C NMR (CD3OD, 75 MHz):
d 172.0, C4; 171.8, C1 156.8, CN3; 156.6,
5.15.4. Methyl (2S,5R)-2-(4-allyloxybenzyl)-9-amino-3-aza-5-(9H-
9-fluorenylmethyloxycarboxamido)-4-oxononanoate
hydrochloride (79)
ArC40; 155.9, NCO2; 143.8, ArC8a% and ArC9a%; 140.8, ArC4a% and
ArC4b%; 135.5, C200; 130.1, ArC10; 129.6, ArCH4% and ArCH5%;
127.7, ArCH2% and ArCH7%; 127.2, ArCH1% and ArCH8%; 125.4,
ArCH3% and ArCH6%; 120.2, ArCH20 and ArCH60; 117.3, C300; 114.3,
ArCH30 and ArCH50; 68.0, C100; 65.8, CH2-C9%; 59.3, C9%; 54.0, C5;
52.0, OCH3; 46.7, C2; 40.3, C8; 36.1, ArCH2; 29.1, C6; 24.9, C7. MS
(ESI, þve) m/z 614.6 (100%) [MHþ]. HRMS calcd for C34H40N5O6
614.2979, found 614.3007.
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 70 (132 mg, 0.19 mmol)
to yield 79 (92 mg, 0.15 mmol, 79%) as a white solid. Mp 162–170 ꢀC.
1H NMR (CD3OD, 300 MHz):
d
8.02 (d, J¼8.0 Hz, 1H, NH), 7.79 (d,
J¼7.6 Hz, 2H, ArH1% and ArH8%), 7.64 (t, J¼8.4 Hz, 2H, ArH4% and
ArH5%), 7.38 (t, J¼7.2 Hz, 2H, ArH3% and ArH6%), 7.41–7.26 (m, 2H,
ArH2% and ArH7%), 7.04 (d, J¼8.4 Hz, 2H, ArH20 and ArH60), 6.73 (d,
J¼8.4 Hz, 2H, ArH30 and ArH50), 6.00–5.87 (m, 1H, H200), 5.28 (d,
J¼17.3 Hz, 1H, H3a00), 5.16 (d, J¼10.5 Hz, 1H, H3b00), 4.62 (dt, J¼5.0,
8.8 Hz, 1H, H5), 4.35–4.32 (m, 4H, H10 and OCH2-H9%), 4.19 (t,
J¼6.7 Hz,1H, H9%), 4.07 (dd, J¼5.1, 8.0 Hz,1H, H2), 3.70(s, 3H, OCH3),
3.14–3.07 (m, 2H, H9), 2.93–2.82 (m, 2H, ArCH2), 1.63–1.53 (m, 4H,
H6 and H7), 1.33–1.28 (m, 2H, H8). 13C NMR (CD3OD, 75 MHz):
5.15.7. Methyl (2S,5S)-2-(4-allyloxybenzyl)-3-aza-5-(9H-9-
fluorenylmethylcarboxamido)-8-guanidino-4-oxononanoate
hydrochloride (82)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 78 (93 mg, 0.10 mmol)
to yield 82 (54 mg, 0.083 mmol, 83%) as a white solid. Mp 170–
175 ꢀC. 1H NMR (CD3OD, 300 MHz):
d
7.90 (d, J¼7.2 Hz, 2H, ArH1%
d
174.2, C4; 173.2, C1; 158.1, NCO2; 145.1, ArC40; 145.0, ArC8a% and
and ArH8%), 7.75–7.70 (m, 2H, ArH4% and ArH5%), 7.45–7.31 (m, 4H,
ArH3%, ArH6%, ArH2% and ArH7%), 7.14 (d, J¼8.1 Hz, 2H, ArH20 and
ArH60), 6.82 (d, J¼8.1 Hz, 2H, ArH30 and ArH50), 6.05–5.92 (m, 1H,
H200), 5.34 (d, J¼17.1 Hz,1H, H3a00), 5.21 (d, J¼10.8 Hz,1H, H3b00), 4.47–
4.42 (m, 2H, H2 and H5), 4.29–4.24 (m, 4H, H100 and OCH2-H9%),
4.09–4.07 (m, 1H, H9%), 3.59 (s, 3H, OCH3), 3.19–3.12 (m, 2H, H8),
3.03–2.92 (m, 2H, ArCH2), 1.70–1.60 (m, 2H, H6), 1.54–1.52 (m, 2H,
ArC9a%; 142.4, ArC4a% and ArC4b%; 134.7, C200; 131.1, ArCH20 and
ArCH60; 129.8, ArCH3% and ArCH6%; 128.7, ArCH2% and ArCH7%;
128.7, ArCH1% and ArCH8%; 128.1, ArCH4% and ArCH5%; 120.8,
ArC10; 117.3, C30; 115.6, ArCH30 and ArCH50; 69.6, CH2-C9%; 68.0,
C100; 56.1, C5; 55.2, C2; 55.1, OCH3; 52.8, C9%; 40.5, C9; 37.3, ArCH2;
32.6, C6; 28.1, C8; 23.6, C7. MS (ESI, þve) m/z 586.3 (100%) [MHþ].
HRMS calcd for C34H40N3O6 586.2917, found 586.2935.
H7). 13C NMR (CD3OD, 75 MHz):
d 171.9, C4; 171.8, C1 157.0, CN3;
156.6, ArC40; 155.9, NCO2; 143.9, ArC8a% and ArC9a%; 140.7, ArC4a%
and ArC4b%; 133.8, C200; 130.1, ArC10; 129.0, ArCH4% and ArCH5%;
127.7, ArCH2% and ArCH7%; 127.1, ArCH1% and ArCH8%; 125.4,
ArCH3% and ArCH6%; 120.1, ArCH20 and ArCH60; 117.3, C300; 114.4,
ArCH30 and ArCH50; 68.1, C100; 65.7, CH2-C9%; 59.3, C9%; 53.9, C5;
51.8, OCH3; 46.7, C2; 40.3, C8; 35.7, ArCH2; 29.0, C6; 25.1, C7. MS (ESI,
þve) m/z 614.8 (100%) [Mþ]. HRMS calcd for C34H40N5O6 614.2979,
found 614.2972.
5.15.5. Methyl (2S,5S)-2-(4-allyloxybenzyl)-9-amino-3-aza-5-(9H-
9-fluorenylmethyloxycarboxamido)-4-oxononanoate
hydrochloride (80)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 76 (73 mg,
0.106 mmol) to yield 80 (48 mg, 0.07 mmol, 68%) as a white solid.
Mp 160–168 ꢀC. 1H NMR (CD3OD, 300 MHz):
d
7.79 (d, J¼7.2 Hz, 2H,
ArH1% and ArH8%), 7.65 (d, J¼7.2 Hz, 2H, ArH4% and ArH5%), 7.39
(t, J¼7.2 Hz, 2H, ArH3% and ArH6%), 7.29 (t, J¼7.2 Hz, 2H, ArH2%
and ArH7%), 7.07 (d, J¼8.4 Hz, 2H, ArH20 and ArH60), 6.77 (d,
J¼8.4 Hz, 2H, ArH30 and ArH50), 6.01–5.88 (m, 1H, H200), 5.29 (dd,
J¼1.2, 18.3 Hz, 1H, H3a00), 5.16 (dd, J¼1.2, 10.5 Hz, 1H, H3b00), 4.67–
4.59 (m, 1H, H5), 4.40–4.30 (m, 4H, H10 and OCH2-H9%), 4.22–4.18
(m, 1H, H9%), 4.12–4.07 (m, 1H, H2), 3.67 (s, 3H, OCH3), 3.11–3.04
(m, 2H, H9), 2.97–2.87 (m, 2H, ArCH2), 1.73–1.60 (m, 4H, H6 and
5.16. Anti-bacterial testing
Anti-bacterial testing against Staphylococcus aureus ATCC6538P
was performed at Avexa Ltd, Melbourne, Australia.
Assay procedure: a standardized inoculate for assays was pre-
pared in 1/10 dilution of seed culture. To a 96 well microtitre plate
H7), 1.45–1.30 (m, 2H, H8). 13C NMR (CD3OD, 125 MHz):
d
174.4, C4;
was added 50 mL of liquid medium [Mueller–Hinton broth medium
173.3, C1; 158.1, NCO2; 145.2, ArC40; 145.0, ArC8a% and ArC9a%;
142.4, ArC4a% and ArC4b%; 134.7, C200; 131.2, ArCH20 and ArCH60;
129.8, ArCH3% and ArCH6%; 128.8, ArCH2% and ArCH7%; 128.1,
ArCH1% and ArCH8%; 126.2, ArCH4% and ArCH5%; 120.9, ArC10;
117.4, C30; 115.6, ArCH30 and ArCH50; 69.6, CH2-C9%; 68.0, C100; 55.9,
(MHB) and Mueller–Hinton agar medium (MHA)]. The peptoid
compounds were dissolved in a 50% MeOH/H2O solution for the
final concentration of 1 mg/mL. Test solution (50 mL) was added
into the top row of the plate. A dilution series were continued until
it reached the last row of the plate the excess was discarded. The

11290
T.P. Boyle et al. / Tetrahedron 64 (2008) 11270–11290
12. Au, V. S.; Bremner, J. B.; Coates, J. A.; Keller, P. A.; Pyne, S. G. Tetrahedron 2006,
62, 9373–9382.
13. Bremner, J. B.; Keller, P. A.; Pyne, S. G.; Robertson, A. D.; Skelton, B. W.; White,
A. H.; Witchard, H. M. Aust. J. Chem. 2000, 53, 535–540.
plates (two peptoid samples were tested per plate) were incubated
at 37 ꢀC and shaken at 100 rpm for 18 h.
14. Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–2238.
Acknowledgements
15. McGrady, K. A. W.; Overberger, C. G. Polym. J. 1987, 19, 539–555.
16. The ECDI peptide coupling reaction conditions were initially performed in
the absence of HOBt and led to epimerization.24 This only became evident
when the peptide chain was three residues long, and was observed as
a doubling up of some signals in the 1H NMR spectrum of compounds fea-
TPB would like to thank the Australian Research Council (ARC)
for a Ph.D. scholarship. The authors would like to thank Sarah
Murphy for technical assistance.
turing L-Lys as the cationic residue. The inclusion of HOBt resulted in no
epimerization being observed. This occurred in the synthesis of cyclic pep-
tides 11, 44 and 62–63 and their associated cyclic and acyclic precursors. The
majority of our cyclic peptides (45–49) and their associated cyclic and acyclic
precursors had only one epimer present. Given the final outcome of the anti-
bacterial activity, we concluded that the presence of the epimer in our initial
examples was unlikely to affect the activity and these were not
resynthesized.
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