Synthesis and antibacterial activity of some binaphthyl-supported macrocycles containing a cationic amino acid

Article abstract of DOI:10.1016/j.bmc.2011.04.013

As part of a programme investigating antibacterial cyclic macrocycles containing a cationic amino acid with an internal aromatic hydrophobic scaffold, we previously reported a macrocycle anchored at the 3,3′-positions of a 1,1′-binaphthyl unit. This was p

Full text of DOI:10.1016/j.bmc.2011.04.013

Bioorganic & Medicinal Chemistry 19 (2011) 3549–3557
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and antibacterial activity of some binaphthyl-supported
macrocycles containing a cationic amino acid
Daniel R. Coghlan a, John B. Bremner a, , Paul A. Keller a, , Stephen G. Pyne a, , Dorothy M. David a,
⇑
⇑
⇑
Kittiya Somphol a, Dean Baylis b, Jonathan Coates b, John Deadman b, David I. Rhodes b, Alan D. Robertson c
a School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
b Avexa Ltd, 576 Swan St., Richmond, Vic 3121, Australia
c Formerly Amrad Corporation Ltd, Vic, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
As part of a programme investigating antibacterial cyclic macrocycles containing a cationic amino acid
with an internal aromatic hydrophobic scaffold, we previously reported a macrocycle anchored at the
3,30-positions of a 1,10-binaphthyl unit. This was prepared via key intermediates containing an internal
allylglycine and an allyl-substituted binaphthyl unit for a subsequent ring-closing metathesis reaction.
This paper presents some structure–activity relationship studies with additional macrocycles based on
this lead compound against Staphylococcus aureus together with the antibacterial activity of two related
acyclic compounds.
Received 25 January 2011
Revised 2 April 2011
Accepted 8 April 2011
Available online 14 April 2011
Keywords:
Cyclic peptoids
Anti-bacterial agents
Atropisomerism
S. aureus
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Metathesis
1. Introduction
that support a tripeptide unit in a defined orientation. We have
previously reported cationic amino acid containing macrocycles
Major health care issues are currently posed by multidrug
resistant human pathogenic bacteria.1,2 The emergence of Gram-
positive bacteria, for example, Staphylococcus aureus and Enterococ-
cus faecium, resistant to the glycopeptide antibiotic, vancomycin, is
of particular concern.3–5 Some recent approaches aimed at
overcoming this resistance have involved the development of other
novel, high molecular weight vancomycin derivatives such as orit-
avancin6 or vancomycin dimers with a rigid actinocin linking
group.7 An alternative approach is to design simpler cationic biar-
yl-templated amino acid monomacrocycles with some similarity to
structural aspects of vancomycin. Such compounds could still
potentially act in a similar way to vancomycin but have added flex-
ibility for interacting strongly with the changed peptido-glycan cell
wall moiety5 in vancomycin-resistant bacteria. In this context, the
recent report of significant antimicrobial activity in some biaryl-
based cyclic b-hairpin cationic peptidomimetics is of interest.8
We instigated a programme investigating the synthesis of antibac-
terial agents using some structural elements of vancomycin, but
dramatically simplifying the hydrophobic scaffold to core moieties
anchored by hydrophobic scaffolds based on 3,30-amino acid linked
1,10-binaphthyls,9 carbazoles,10,11 indoles,12 benzenes13 and ben-
zo[b] thiophene.14
While numerous derivatives showed antibacterial activity, at
the time, none matched the activity shown by the originally re-
ported binaphthyl-based macrocycle 1 (Fig. 1).9 Although 1 was
likely to possess singular stereogenicity at C*, its configuration
was not known and further, 1 was likely to be a mixture of E/Z iso-
mers. Therefore, we embarked on a structure–activity relationship
(SAR) study based on 1 in an attempt to improve the antibacterial
activity of this new class of cyclic compounds.
NHAc
*
NH3Cl
O
NH
OMe
OMe
S
O
NH
CO2Me
(E/Z)
1
⇑
Corresponding authors. Tel.: +61 2 4221 4255 (J.B.B.); +61 2 4221 4692 (P.A.K.);
+61 2 4221 3511 (S.G.P.); fax: +62 2 4221 4287.
MIC 17 µg/mL against S. aureus
E-mail addresses: jbremner@uow.edu.au (J.B. Bremner), keller@uow.edu.au (P.A.
Keller), spyne@uow.edu.au (S.G. Pyne).
Figure 1. The lead cyclic binaphthyl macrocycle antibacterial agent. The MIC
reported (17 lg/mL) was an average while the median value was 16 lg/mL.
0968-0896/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.04.013

3550
D. R. Coghlan et al. / Bioorg. Med. Chem. 19 (2011) 3549–3557
made starting from 10a.9 Subsequent RCM reactions with Grubbs’
2. Results and discussion
I ruthenium catalyst in CH2Cl2 at reflux produced the macrocycles
16–20,18 as a mixture of E/Z isomers; the assignment of the ratio of
the diastereomers could not be determined due to the overlapping
broad peaks assigned to the olefinic protons. Deprotection of the
amino acid side chains under standard conditions, followed by
treatment with HCl in ether gave the binaphthyl-supported prod-
ucts 21–24 and 19 as their hydrochlorides.19
In a separate experiment, a sample of 16 was subjected to silica
gel column chromatography, giving rise to three separate diaste-
reomers (Scheme 3). The chirality of the axis of these isomers
was determined by CD spectroscopy, and compared with the inde-
pendently synthesised macrocycle containing the (S)-binaphthyl
isomer 209 (from 10a via 15). This indicated the presence of two
(S)-binaphthyl diastereoisomers, 25 and 26, and one (R)-binaph-
thyl diastereomer 27. Unfortunately, a second (R)-binaphthyl
diastereomer produced could not be isolated pure. The two (S)-
All our target compounds required the synthesis of the binaph-
thyl scaffold 10 (Scheme 1) which contained olefinic and carboxylic
acid moieties to enable incorporation of different, suitably pro-
tected dipeptide units and eventual transformation to our cyclic
target compounds (Fig. 2).15
We did not systematically vary individual features, instead
choosing a range of variations including the use of racemic and
(R)- and (S)-binaphthyls, and different basic amino acid side
chains. The incorporation of an allylglycine facilitated a ring-
closing metathesis (RCM) reaction and the inclusion of basic amino
acid side chains, either a lysine or arginine unit, formed part of our
design concept. These cationic side chains are thought to undergo
an ionic interaction with the D-Ala-D-Ala(Lac) moieties of the grow-
ing bacterial cell wall. Most of our derivatives started with the
racemic binaphthyl; however, the (S)-enantiomer was synthesized
in an analogous manner using the same chemistry.9
binaphthyl stereoisomers could differ either at the stereogenic C
a
Therefore, the synthesis of (S)-10a9 and (R,S)-10b (Scheme 1)
started with either (S)-2a or the (R,S)-2b, respectively, following
our previously reported procedure for 10a.9
carbon b to the naphthyl moiety, or the olefingeometry. Although
the assignment of complete configuration was not possible, we
had likely refined the (S)-binaphthyl isomers down to single ster-
eoisomers. Further evidence suggesting that these two (S)-binaph-
thyl isomers might be diastereomers comes from the biological
testing as they show different antibacterial activities; for example,
With the scaffolds 10a and 10b in hand,16 we turned our atten-
tion to the different dipeptides available. Treatment of 10b with
dipeptides under standard diimide peptide coupling conditions
gave the protected acyclic derivatives 11–14 (Scheme 2) in satis-
factory yields17—the corresponding single enantiomer (S)-15 was
compare 1 (MIC 16 lg/mL) with 26 (MIC 8 lg/mL) (Fig. 2). Further
attempts to separate these diastereomers using silica gel HPLC
Z
X
CH2Y
NHAc
CO2Et
OMe
OMe
CO2R
OMe
OMe
g
b
OMe
OMe
OMe
OMe
d
X
a
I
I
2 X = H
6 Z = N=CPh2
Z = NH3Cl
8 Z = NHAc
4 Y = H
9
R = Et
R = H
e
f
c
h
10
3
X = I
a series - (S)-binaphthyl
5
7
Y = Br
b
series - (R,S)-binaphthyl
Scheme 1. Reagents and conditions: (a) n-BuLi, TMEDA, Et2O, rt, 3 h, then I2, ꢀ80 °C ? rt, overnight, 51% ((R,S)-binap), 65% ((S)-binap); (b) n-BuLi, THF, ꢀ80 °C, 1 h, then MeI,
ꢀ80 °C ? rt, 3 h, 51% ((R,S)-binap), 48% ((S)-binap); (c) NBS, CCl4, reflux, then irradiation with a mercury lamp, 1 h, 46% ((R,S)-binap), 62% ((S)-binap); (d) HMPA, DIPA, n-BuLi,
THF, ꢀ10 °C, 10 min, then N-(diphenylmethylene)glycinate, then addition of 5, THF, ꢀ78 °C ? rt, overnight; (e) 3% HCl, Et2O, rt, overnight; (f) MgSO4, CH2Cl2, 0 °C, then Et3N,
Ac2O, DMAP, 0 °C ? rt, overnight, 75% ((R,S)-binap, three steps), 71% ((S)-binap, three steps); (g) PdCl2, PPh3, allyltributyltin, dioxane, reflux, 5 h, 85% ((R,S)-binap), 89% ((S)-
binap); (h) LiOHꢁH2O, H2O, THF, rt, 5 h, 94% ((R,S)-binap), 62% ((S)-binap9).
NHAc
O
Me
NHAc
NH
O
O
NH
NH
N
H
OMe
(S)
NHAc
OMe
OMe
O
AA.HCl
OMe
NH
OMe
OMe
O
(S)
(R,S)
(R,S)
(S)
AA-P
NH
O
O
(S)
(S)
NH
NH3Cl
CO2Me
CO2Me
CO2Me
Binap
21 R/S
22 R/S
23 R/S
24 R/S
AA
MIC µg/mL
C*
62
62
62
62
31
8
D-Lys
D-Arg
L-Lys
L-Arg
D-Lys
D-Lys
D-Lys
D-Lys
30 MIC >250 µg/mL
#
#
#
#
†
†
†
#
AA
P
MIC µg/mL
16
17
18
D-Lys Boc >250
D-Arg PMC 31
L-Lys Fmoc >250
25
26
27
1
S
S
R
S
AA
O
H
(S)
N
CO2Me
31
16
N
H
NHAc
OMe
OMe
O
(R,S)
31 AA = D-Arg MIC 4 µg/mL
32 AA = L-Arg MIC 4 µg/mL
Figure 2. In vitro antibacterial activity of compounds against S. aureus. Vancomycin was used as the standard (MIC 2.0
lg/mL). Values quoted are the median based on
triplicate measurements. AA refers to the amino acid side chain as listed. #Analogues contain a mixture of stereoisomers at C*. Analogues are presumed to be
stereochemically pure at C* but the absolute stereochemistry could not be established.

D. R. Coghlan et al. / Bioorg. Med. Chem. 19 (2011) 3549–3557
3551
NHAc
NH
P
NHAc
O
AA
H
N
CO2Me
O
O
NH
N
OMe
OMe
OMe
OMe
H
AA.HCl
Y
OMe
AA-P
O
a
O
O
b
c
10a/10b
NH
NH
OMe
CO2Me
CO2Me
Yield %
D-Lys Boc 74
D-Arg PMC 75
Y = NHAc
Yield %
Binap
Yield %
60#
89
AA
Binap AA
P
Binap
11 R/S
P
Boc
AA
R/S
21
D-Lys
D-Arg
L-Lys
L-Arg
D-Lys
16 R/S
17 R/S
92
D-Lys
D-Arg
L-Lys
L-Arg
22 R/S
R/S
PMC 66
Fmoc 54
PMC 68
12
23 R/S
51
58
18 R/S L-Lys
Fmoc 72
13 R/S
R/S
24
1
19 R/ S
20
L-Arg
D-Lys
77
72^
PMC
Boc
14 R/ S
S
84^
S
S
49^
15
D-Lys Boc
Scheme 2. Reagents and conditions: (a) NH2CH(AA-P)CO-
L-allylGly-OMe, DCC, DMAP, rt, overnight; (b) benzylidine-bis(tricyclohexylphosphine)-dichlororuthenium (Grubbs’
I catalyst), CH2Cl2, reflux, 18–20 h; (c) for Boc and Pmc (2,2,5,7,8-pentamethylchromane) protected compounds: TFA, CH2Cl2, rt, 25 min, then 1 M HCl–Et2O; for Fmoc
protected compound: 0.02 M piperidine in CH3CN, 60 °C, 43 h, then 1 M HCl–Et2O. AA refers to the amino acid side chain as listed. ^Synthesis previously reported, see Ref. 9.
#Compound 21 was synthesized from an Fmoc protected
D-Lys in a similar sequence to 23—the yield reflects the outcome of the Fmoc deprotection.
deprotection
deprotection
16a
16b
16c
25
26
(S)-binaphthyl derivative
Silica gel
activity (MIC 31 lg/mL). The larger macrocycle containing four
+
chromatography
(S)-binaphthyl derivative
+
16
amino acid residues 30 was inactive (MIC >250 lg/mL). We have
also previously reported19,20 the activity of the macrocycle 1 with
deprotection
27
(R)-binaphthyl derivative
the double bond reduced to the corresponding ‘alkane’ linker, this
molecule revealed an MIC value of 16 lg/mL, suggesting that the
presence of the double bond in either form (E or Z) is not relevant.
As part of the SAR studies we also assessed the activity of an
acyclic analogue. This analogue, 31 (Fig. 2), which was readily ac-
cessed from the synthetic intermediate 12 by acid catalysed cleav-
age of the PMC group, displayed excellent activity against S. aureus
Scheme 3. The separation of diastereomers of cyclic peptide 16 based upon the
chirality of the binaphthyl scaffold and their subsequent deprotection.
were not successful, being hampered by the formation of molecu-
lar aggregates.
Further, the binaphthyl 10b was treated with a protected Gly-
Ala-Lys-tripeptide ester to give the acyclic structure 28 which
was subsequently cyclised using typical Grubbs’ RCM conditions,
yielding the larger macrocycle 29 (Scheme 4). This was then depro-
tected giving the hydrochloride 30, and thus access to the larger
macrocycle containing four amino acid units.20
The antibacterial activities for the synthesised compounds
against S. aureus (wild type; ATCC 6538P) are shown in Figure 2. In-
cluded are the five analogues 21, 25–27 and 1, which differ only in
their stereochemical elements. The (S)-binaphthyl derivative 26
(MIC 4
(MIC 2
l
l
g/mL). The activity of 31 was close to that of vancomycin
g/mL in this test), as was that of the -Arg congener 32,
L
obtained from deprotection of the intermediate 14. While these
were surprising results at the time, subsequent studies by us
revealed22,23 that related acyclic peptides anchored with a binaph-
thyl unit at the 20 position possess significant activity against a
range of Gram-positive bacteria.
In conclusion, we have assessed the antibacterial activity
against S. aureus of 12 different macrocyclic derivatives, including
1, incorporating a cationic amino acid moiety and a hydrophobic
binaphthyl scaffold. While some examples showed notable activ-
was the most active cyclic derivative synthesised (MIC 8
with the other (S)-binaphthyl derivative 1 (MIC 16 g/mL) and a
corresponding (R)-binaphthyl derivative 27 (MIC 31 g/mL)
lg/mL)
l
ity, the D-Lys-analogue 26, the diastereomer of the original lead
l
compound 1, showed an increased activity. Importantly, this work
also revealed a new acyclic lead compound, 31, with strong anti-
bacterial activity. The general principles defined by this latter
molecular structure as an antibacterial agent have been subse-
quently explored by us22,23 and other related work will be reported
in future papers.
decreasing in activity. Interestingly, the independently synthesised
(S)-binaphthyl derivative 1, which was presumably a diastereo-
meric mixture of 25 and 26, had an MIC value between that for
25 and 26 (MIC 16
l
g/mL). Finally the more complex mixture of
g/mL)
diastereomers (21),21 showed weaker activity (MIC 62
l
again. Although the overall effects observed here may be due to
differences in molecular aggregation, an effect originally observed
in associated HPLC studies, and/or antagonist effects between dia-
stereomers, it is likely that differences in activity arise from the dif-
ferent configurations of the isomers.
3. Experimental
General methods were as described previously.23 All NMR spec-
tra were determined in CDCl3 solution at 300 MHz (1H NMR) or
75 MHz (13C NMR).
The protected macrocycles 16 and 18 showed no activity
whereas the PMC-protected 17 surprisingly revealed moderate
O
Me
O
Me
O
O
O
Me
O
N
H
(S)
H
N
N
H
(S)
(S)
OMe
Y
NH
(S)
Y
N
H
N
H
NH
(S)
(S)
(S)
OMe
OMe
(R,S)
Y
O
O
(R,S)
OMe
a
O
b
c
OMe
OMe
O
10b
(R,S)
OMe
(S)
NH
NH3Cl
(S)
NH
NHFmoc
NHFmoc
O
OMe
O
OMe
28
30 Y = NHAc
29
Scheme 4. Reagents and conditions: (a) NH2-
L
-Ala-L-(N -Fmoc)Lys-L-allylGly-OMe, DCC, DMAP, rt, overnight, 39%; (b) benzylidine-bis(tricyclohexylphosphine)dichlororu-
x
thenium, CH2Cl2, reflux, 15 h, quantitative; (c) 0.02 M piperidine in CH3CN, DMF, 70 °C, 12 h, then 1 M HCl–Et2O, 19%.

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D. R. Coghlan et al. / Bioorg. Med. Chem. 19 (2011) 3549–3557
3.1. Synthesis of the hydrophobic scaffold 10b
3.1.8. (S)-3-Bromomethyl-30-iodo-2,20-dimethoxy-1,10-binaph-
thyl 5a
3.1.1. (R,S)-2,20-Dimethoxy-1,10-binaphthyl 2b
This was prepared in the same manner as 5b above (62%).
This was synthesized as previously reported.20
3.1.9. Ethyl (R,S)-3-[3-(30-iodo-2,20-dimethoxy-1,10-binaphthyl)]-
2-[(diphenylmethylene)amino]propanoate 6b
3.1.2. (S)-2,20-Dimethoxy-1,10-binaphthyl 2a9
To a ꢀ10 °C solution of HMPA (0.7 mL, 4.02 mmol) and diisopro-
pylamine (0.24 mL, 1.71 mmol) in dry THF (40 mL) was added
n-butyllithium (1.32 M in hexanes, 1.4 mL, 1.85 mmol). The pale
yellow solution was stirred for 10 min then cooled to ꢀ78 °C. To
this solution was added a solution of ethyl N-(diphenylmethyl-
ene)glycinate (0.450 g, 1.68 mmol) in dry THF (20 mL) using a
cannula and precooling the addition solution by running the drops
down the side of the receiving flask. The resulting mixture was
stirred for 30 min then a solution of the binaphthyl derivative 5b
(0.895 g, 1.68 mmol) in dry THF (40 mL) was added using a can-
nula. The reaction mixture was allowed to slowly warm to rt and
stirred overnight. The yellow solution was quenched with aqueous
ammonium chloride solution (1 mL). The reaction mixture was
evaporated to dryness to give a yellow oil that contained 6b which
was used without further purification. TLC (10% ethyl acetate/hex-
ane), Rf 0.15; 1H NMR d 1.21, t, J = 5.0 Hz, 3H; 3.00, s, 3H; 3.20, s,
3H; 3.40, dd, J = 7.0, 10.0 Hz, 1H; 3.71, dd, J = 3.0, 10.0 Hz, 1H;
4.11–4.22, m, 2H; 4.50, q, J = 3.0 Hz, 1H; 6.82, d, J = 5.0 Hz, 1H;
7.78–6.98, m, 19H; 8.49, s, 1H; m/z (CI, +ve) 720 (M+H+, 52%),
674 (9), 672 (8), 648 (17), 608 (8), 556 (27) and 268.
This was prepared in the same manner as 2b above (95%);
½
a 2D3
ꢂ
ꢀ53.1 (c 1.2, CDCl3), CD (CHCl3) 235 nm + 100 mdeg
(c 0.08 mg/10 mL).
3.1.3. (R,S)-3,30-Diiodo-2,20-dimethoxy-1,10-binaphthyl 3b
This was synthesized as previously reported.20
3.1.4. (S)-3,30-Diiodo-2,20-dimethoxy-1,10-binaphthyl 3a9
This was prepared in the same manner as 3b above (65%);
½
a 2D3
+29.8 (c 1.2, CDCl3), CD (CHCl3) 245 nm + 100 mdeg
ꢂ
(c 0.09 mg/10 mL).9
3.1.5. (R,S)-2,20-Dimethoxy-3-iodo-30-methyl-1,10-binaphthyl 4b
To a ꢀ80 °C solution of 3b (2.016 g, 3.6 mmol) in dry THF
(80 mL, 0.044 M) was added n-butyllithium (2.8 mL, 3.9 mmol)
dropwise. The reaction mixture turned yellow and was stirred for
1 h before dry methyl iodide (0.35 mL, 5.6 mmol) was added. The
reaction mixture was allowed to gradually warm to rt and stirred
for a further 3 h before saturated aqueous ammonium chloride
solution (four drops) was added. The reaction mixture was evapo-
rated to dryness, the residue taken up in diethyl ether and washed
with water. The organic layer was dried (MgSO4), and the filtrate
evaporated to dryness to give a pale yellow solid. Purification of
the crude material by flash column chromatography (4% ethyl ace-
tate/hexane) yielded 4b (0.678 g, 42%). TLC (10% ethyl acetate/hex-
ane), Rf of 0.54; 1H NMR d 2.55, s, 3H; 3.36, s, 6H; 7.06, d, J = 8.0 Hz,
1H; 7.12, d, J = 8.0 Hz, 1H; 7.16–7.42, m, 2H; 7.80, t, J = 8.0 Hz, 2H;
7.81, s, 3H; 8.52, s, 1H. 13C NMR d 17.2, 60.2, 60.9, 92.6, 124.0,
124.7, 125.4 (ꢃ2), 125.5, 126.0, 126.7, 126.8, 127.2, 130.1, 130.6,
131.5, 132.1, 132.7, 134.1, 139.3, 154.4, 155.4. m/z (CI, +ve) 455
(M+H+, 62), 329 ([455–I]+ꢁ, 100), 313 (57) and 185 (62). C23H20O2I
+ H+ requires m/z 455.0508, Found 455.0505.
3.1.10. Ethyl (S)-3-[3-(30-iodo-2,20-dimethoxy-1,10-binaphthyl)]-
2-[(diphenylmethylene)amino]propanoate 6a
This was prepared in the same manner as 6b above and was
used without isolation.
3.1.11. Ethyl (R,S)-2-amino-3-[3-(2,20-dimethoxy-30-iodo-1,10-
binaphthyl)]propanoate hydrochloride salt 7b
To a solution of the alkylated product 6b (1.208 g, 1.68 mmol) in
diethyl ether (30 mL) was added HCl (15 mL, 3% aqueous,
4.6 mmol) and the mixture was stirred at rt overnight giving a yel-
low oil underneath the aqueous layer and a yellow organic layer.
The mixture was evaporated to dryness, the sticky yellow residue
was taken up in ethanol and evaporated to dryness. This was re-
peated twice. The final residue was dried under high vacuum then
freeze dried. The crude product was used without further purifica-
tion. 13C NMR d 13.8, 13.9, 33.0, 33.6, 53.2, 53.7, 61.0, 61.1, 61.2,
62.3, 92.3, 117.4, 124.1, 124.2, 125.1, 125.3, 125.5, 125.6, 125.8,
126.0, 126.2, 126.5, 126.70, 126.75, 126.9, 127.05, 127.65, 127.85,
128.2, 130.0, 130.4, 131.3, 132.0, 132.1, 132.4, 132.8, 132.9,
133.3, 134.8, 133.9, 134.1, 139.7 (ꢃ2), 152.5, 154.4, 154.7, 154.9,
168.6, 169.0. C27H2NO4I2 + H+ (ammonium ion) requires m/z
556.0985, Found 556.0991.
3.1.6. (S)-3-Iodo-2,20-dimethoxy-30-methyl-1,10-binaphthyl 4a
This was prepared in the same manner as 4b above (28%); ½a D23
ꢂ
+39.5 (c 1.4, CHCl3), CD (CHCl3) 237 nm + 29 mdeg (c 0.11 mg/
10 mL).
3.1.7. (R,S)-3-Bromomethyl-30-iodo-2,20-dimethoxy-1,10-binaph-
thyl 5b
To a solution of 4b (1.737 g, 3.8 mmol) in carbon tetrachloride
(100 mL) was added N-bromosuccinimide (1.316 g, 7.4 mmol).
The mixture was heated to reflux followed by irradiation with a
500 W mercury lamp for 1.5 h. The cooled reaction mixture was fil-
tered (to remove succinimide), and the filtrate evaporated to dry-
ness to give a red solid. The residue was purified by flash column
chromatography (4% ethyl acetate/hexane) to yield a colourless
crystalline solid (1.130 g) that was a mixture from which 5b
(0.942 g, 46%) was isolated by column chromatography using the
same conditions. 1H NMR d 3.36, s, 3H; 3.40, s, 3H; 4.72 d,
J = 9.9 Hz, 1H; 4.91, d, J = 9.9 Hz, 1H; 7.08, d, J = 8.7 Hz, 1H; 7.18,
d, J = 8.7 Hz, 1H; 7.23–7.44, m, 4H; 7.80, d, J = 8.4 Hz, 1H; 7.88, d,
J = 8.4 Hz, 1H; 8.07, s, 1H; 8.54, s, 1H. 13C NMR (CDCl3) d 29.3;
61.0; 61.4; 92.5; 124.4; 125.1; 125.3; 125.6; 125.9; 126.8; 127.0;
127.1; 128.0; 130.2; 131.4; 132.1; 132.2; 133.9; 134.1; 139.7;
154.38; 154.44; m/z (CI, +ve) 535 (94) & 533 (M+H, 92), 455 (74),
453 (100), 409 (14), 407 (27), 405 (18), 329 (24) and 313 (14).
3.1.12. Ethyl (S)-2-amino-3-[3-(30-iodo-2,20-dimethoxy-1,10-
binaphthyl)]propanoate hydrochloride salt 7a
This was prepared in the same manner as 7b above and was
used directly in the next step.
3.1.13. Ethyl (Ra,Sa)-2(R,S)-acetamino-3-[3-(2,20-dimethoxy-30-
iodo-1,10-binaphthyl)]propanoate 8b
The residue obtained after acid hydrolysis of 6b containing the
binaphthyl salt 7b (0.993 g, 1.68 mmol) was dissolved in CH2Cl2
(dry, distiled, 100 mL). The solution was stirred with MgSO4 (anhy-
drous) briefly then cooled in an ice/salt bath. Triethylamine
(0.70 mL, 5.02 mmol) was added, followed by acetic anhydride
(0.4 mL, 4.24 mmol) and DMAP, after stirring for 5 min. The reac-
tion mixture was allowed to warm to rt and was stirred overnight.
To the reaction mixture was added a solution of HCl (50 mL, aque-
ous 3%) and CH2Cl2 (50 mL). The aqueous layer was removed and

D. R. Coghlan et al. / Bioorg. Med. Chem. 19 (2011) 3549–3557
3553
extracted with CH2Cl2. The combined organic layers were washed
with a solution of 3% aqueous hydrochloric acid (1ꢃ), a solution
of 1:1 aqueous saturated LiCl (2ꢃ) then water (ꢃ1). The solution
was dried (MgSO4) and the filtrate evaporated to dryness to give
a yellow liquid. The crude product was purified by (short) column
chromatography (10% ethyl acetate/hexane ? ethyl acetate) to
yield 8b as a pale yellow solid (0.75 g, 75% from 5b) (average
91% yield per step). TLC (25% ethyl acetate/hexane), Rf of 0.06; 1H
NMR d 1.25, t, J = 7.0 Hz, 3H; 1.98, s, 3H; 3.26, s, 3H; 3.28, s, 3H;
3.30–3.42, m, 2H; 4.23, m, 2H; 4.73, q, J = 7.0 Hz, 1H; 6.79, d,
J = 7.0 Hz, 1H; 7.05–7.82, m 7H; 7.86, s, 1H; 8.54, s, 1H; 13C
NMR24 d 14.2, 22.7, 22.9, 32.8, 33.0, 34.9, 54.2, 54.8, 60.3, 60.5,
60.6, 60.7, 60.8, 61.1, 61.2, 116.0, 116.1, 123.7, 124.1, 124.5,
124.6, 124.7, 124.9, 125.3, 125.5, 125.6, 126.0, 126.1, 127.4,
127.5, 129.2, 129.3, 129.4, 129.7, 130.2, 130.3, 130.40, 130.45,
130.5, 132.8, 133.0, 133.3, 133.4, 133.6, 136.7, 154.7, 154.7,
155.1, 155.3, 170.0, 170.1, 171.2, 171.7; m/z 598 (M+H+, 35%),
552 (13), 550 (12), 472 (100), 328 (20), 85 (79).
(MgSO4). The filtrate was evaporated to dryness to give 10b as a
white solid (0.462 g, 94%). TLC (ethyl acetate) Rf of 0.05; 1H NMR
d 2.07, s, 3H; 3.07, s, 3H; 3.20, s, 3H; 3.28–3.77, m, 4H; 4.55,
2 ꢃ t, J = 5.0 Hz, 1H; 5.11–5.19, m, 2H; 6.07–6.20, m, 1H;
7.16–7.56, m, 6H; 7.74, br s, 1H; 7.84, d, J = 8.0 Hz, 1H; 7.88, s,
4H. 13C NMR24 d 15.2; 22.5; 22.7; 25.5; 32.2; 34.9; 55.3; 60.4;
60.6; 60.7; 60.8; 60.9; 65.8; 67.8; 116.0; 116.1; 123.8; 124.3;
124.55; 124.59; 124.7; 124.9; 125.3; 125.5; 125.67; 125.75;
126.0; 126.2; 127.4; 127.6; 129.27; 129.34; 129.7; 130.3; 130.47;
130.50; 130.58; 132.85; 133.0; 133.27; 133.31; 133.6; 136.7;
154.6; 155.0; 155.3; 171.5; 172.0; 173.5; 173.7. m/z (CI, +ve) 484
(M+H+, 100%), 466 (13) and 444 (19).
3.1.18. (Sa)-2(R,S)-Acetylamino-3-[3-(30-allyl-2,20-dimethoxy-
1,10-binaphthyl)]propanoic acid 10a
This was prepared in the same manner as 10b (75%).
3.2. Synthesis of acyclic peptides 11–1524
3.1.14. Ethyl (Sa)-2(R,S)-acetamino-3-[3-(2,20-dimethoxy-30-iodo-
1,10-binaphthyl)]propanoate 8a
This was prepared in the same manner as 8b above (71% over
three steps).
3.2.1. Methyl (2S,5R)-2-allyl-9-[2-(30-allyl-2,20dimethoxy-1,10-
(Ra,Sa)-binaphthalen-3-yl)]-5-[4-(tert-butoxycarbonylamino)-
butyl]-8(R,S)-acetamido-3,6-diaza-4,7-dioxononanoate 11
The binaphthyl derivative 10b (0.258 g, 0.53 mmol) was dis-
solved in dry CH2Cl2 (3 mL) and a solution of the protected dipep-
3.1.15. Ethyl (Ra,Sa)-2(R,S)-acetylamino-3-[3-(30-allyl-2,20-dimeth-
tide (NH2-D-(N -Boc)Lys-L
-allylGly-OMe9 (0.22 g, 0.61 mmol) in
oxy-1,10-binaphthyl)]propanoate 9b
x
CH2Cl2 (3 mL) was added. To the resulting solution was added a
crystal of 4-dimethylaminopyridine and then the solution was
cooled in an ice/water bath. To the chilled solution was added
1,3-dicyclohexylcarbodiimide (0.111 g, 0.54 mmol). The reaction
mixture was allowed to warm to rt and was stirred overnight. To
the reaction mixture was added CH2Cl2 (10 mL) which was then fil-
tered through celite. The filtrate was evaporated to give 11 as a
pale yellow crystalline solid (0.404 g, 92%). TLC (4% isopropanol/
CH2Cl2) Rf of 0.50; 1H NMR 1.17–1.93, m, 6H; rotamers 1.41/1.43,
s, 9H; rotamers 2.01/2.02 s, 3H; 2.42–2.70, m, 2H; 2.93–3.07, m
2H; rotamers 3.10/3.14, 3H; 3.23–3.74, m, 4H; rotamers 3.23/
3.25, s, 3H; rotamers 3.71/3.74, s, 3H; 4.43–4.70, m, 3H;
5.04–5.24, m, 4H; 5.60–5.83, m, 1H; 6.08–6.23, m, 1H; 7.00–7.60,
m, 6H; 7.79–7.95, m, 4H; m/z (ES, +ve) 845 (M+Na+, 2%), 823
(M+H+, 2), 723 (823–Boc, 0.6), 415 (8), 393 (9), 145 (79), 106
(83) and 104 (100).
To
a solution of the binaphthyl derivative 8b (0.740 g,
1.24 mmol) in 1,4-dioxane (dry, 40 mL) was added palladium chlo-
ride (0.025 g, 0.14 mmol) and triphenylphosphine (0.136 g,
0.52 mmol). The solution was deoxygenated with argon for
10 min then allyltributyltin (0.39 mL, 1.26 mmol) was added. The
resulting mixture was heated at reflux for 5 h. After cooling the
solution was filtered through celite and evaporated to dryness.
The residue was purified by (short) column chromatography, to re-
move stannanes, then flash column chromatography (50% ethyl
acetate/hexane) to give 9b as a colourless oil (0.54 g, 85%). 1H
NMR d 0.92, t, J = 7.2 Hz, 3H; 1.26, t, J = 7.2 Hz, 3H; 1.98, s, 3H;
2.04, s, 3H; 3.17, s, 3H; 3.24, s, 3H; 3.25–3.33, m, 2H; 3.58–3.72,
br m, 2H; 4.12, q, J = 7.3 Hz, 2H; 4.21, q, J = 7.1 Hz, 2H; 4.71, q,
J = 7.2 Hz, 1H; 4.84, q, J = 7.0 Hz, 1H; 5.13–5.19, m, 2H; 6.08–6.22,
m, 1H; 6.78, d, J = 7.2 Hz, 1H; 6.91, d, J = 7.2 Hz, 1H; 7.14–7.26,
m, 4H; 7.35–7.46, m, 2H; 7.81–7.85, m, 4H; 13C NMR24 d 14.2;
22.7; 22.9; 32.8; 33.0; 34.9; 54.2; 54.8; 60.3; 60.5; 60.5; 60.7;
60.8; 61.1; 61.2; 116.0; 116.0; 123.7; 124.1; 124.5; 124.6; 124.6;
124.9; 125.3; 125.5; 125.6; 126.0; 126.1; 127.4; 127.4; 129.2;
129.3; 129.3; 129.7; 130.2; 130.3; 130.4; 130.4; 130.5; 132.8;
133.0; 133.3; 133.3; 133.6; 136.7; 154.7; 154.7; 155.1; 155.3;
3.2.2. Methyl (2S,5S)-2-allyl-9-[2-(30-allyl-2,20dimethoxy-1,10-
(Ra,Sa)-binaphthalen-3-yl)]-8(R,S)-acetamido-3,6-diaza-4,7-
dioxo-5{3-[3-(2,2,5,7,8-pentamethylchroman-6-ylsulfonyl)-
guanidine]propyl}nonanoate 12
The binaphthyl derivative 10b (0.188 g, 0.39 mmol) was dis-
170.0; 170.1; 171.2; 171.7. m/z (CI, +ve) 512 (100%). C32H33NO5
+
H+ requires m/z 512.2437. Found 512.2452.
solved in dry CH2Cl2 (3 mL) and N -PMC-D-arginine-L-allylglycine
x
methyl ester in CH2Cl2 (3 mL) was added. To the resulting solution
was added a crystal of 4-dimethylaminopyridine and then the
solution was cooled in an ice/water bath. To the chilled solution
was added 1,3-dicyclohexylcarbodiimide (0.096 g, 0.46 mmol).
The reaction mixture was allowed to warm to rt and was stirred
overnight. To the reaction mixture was added CH2Cl2 (10 mL)
which was then filtered through celite. The filtrate was evaporated
to give 12 as a colourless crystalline solid (0.259 g, 66%). 1H NMR
1.29, s, 6H; 1.40–2.06, m, 6H; 2.09, s, 3H; 2.44, s, 3H; 2.48–2.69,
m, 4H; 3.54, s, 3H; 2.60, s, 3H; 3.04–3.43, m, 4H; rotamers
3.07/3.10, s, 3H; rotamers 3.23/3.30, s, 3H; 3.57–3.70, m, 2H;
rotamers 3.69/3.71, s, 3H; 4.54–4.65, m, 3H; 5.03–5.18, m, 4H;
5.72–5.81, m, 1H; 6.07–6.21, m, 1H; 6.33–6.44, m, 3H; 7.18–7.55,
m, 6H; 7.64–7.95, m, 4H. m/z (ES, +ve) 1017 (M+H+, 15), 920 (4),
3.1.16. Ethyl (Sa)-2(R,S)-acetylamino-3-[3-(30-allyl-2,20-dimeth-
oxy-1,10-binaphthyl)]propanoate 9a
This was prepared in the same manner as 9b above (75% over
the three steps from 6b).
3.1.17. (Ra,Sa)-2(R,S)-Acetylamino-3-[3-(30-allyl-2,20-dimethoxy-
1,10-binaphthyl)]propanoic acid 10b
To
a solution of the binaphthyl derivative 9b (0.522 g,
1.02 mmol) in THF (22 mL) in an ice/water bath was added a solu-
tion of LiOH (0.196 g, 4.67 mmol) in water (9 mL). The mixture was
allowed to gradually warm to rt and was stirred for 5 h. To the
reaction mixture was added diethyl ether, the aqueous layer was
washed with diethyl ether and the combined diethyl ether layers
extracted with water (2ꢃ). The combined aqueous layer was acid-
ified (3% aqueous HCl), extracted with diethyl ether (3ꢃ) and dried
316 (37) and 288 (100).
1017.4796. Found 1017.4796.
C56H69N6O10S +
H+ requires m/z

3554
D. R. Coghlan et al. / Bioorg. Med. Chem. 19 (2011) 3549–3557
3.2.3. Methyl (2S,5R)-2-allyl-9-[2-(30-allyl-2,20dimethoxy-1,10-
(Ra,Sa)-binaphthalen-3-yl)]-8(R,S)-acetamido-3,6-diaza-5-{4-
[(9H-fluoren-9-yl)methoxycarbonylamino]butyl}-4,7-dioxon-
onanoate 13
argon gas for 10 min before the addition of benzylidenebis(tri-
cyclohexylphosphine)dichloro ruthenium (0.022 g, 0.027 mmol).
The reaction mixture was heated at reflux for 18 h, cooled and
the evaporated to dryness. The residue was subjected to silica gel
column chromatography and elution with MeOH (2.5%) in CH2Cl2
gave 16 (0.152 g, 77%) as a pale brown solid. 1H NMR 1.04–2.08,
m, 9H; rotamers 1.38/1.39, s, 9H; 2.40–2.75, m, 2H; 2.90–3.79,
m, 15H; 4.28–5.20, m, 3H; 5.62–6.30, m, 2H; 6.80–7.60, m, 6H;
7.70–8.00, m, 4H. C45H54N4O9 + H+ requires 795.4004. Found
795.3969. The resulting residue was subjected to flash column
chromatography (4% MeOH in CH2Cl2 then 10% MeOH in CH2Cl2)
to give diastereomers of 16 in three fractions (isomers).
The binaphthyl derivative 10b (0.447 g, 0.92 mmol) was dissolved
in dry CH2Cl2 (1 mL) and a solution of the dipeptide (0.450 g,
0.94 mmol) in CH2Cl2 (2 mL) was added. To the resulting solution
was added a crystal of 4-dimethylaminopyridine and then the solu-
tion was cooled in an ice/water bath. To the chilled solution was
added 1,3-dicyclohexylcarbodiimide (0.195 g, 0.94 mmol). The
reactionmixturewasallowedtowarmtortandwasstirredovernight.
To the reaction mixture was added CH2Cl2 (10 mL) which was then
filtered through celite. The filtrate was evaporated to dryness and
the residue purified by flash column chromatography (4% MeOH/
CH2Cl2) to give 13 as an off-white crystalline solid (0.474 g, 54%). 1H
NMR 1.05–1.71, m, 6H; 1.86–2.02, m, 3H; 2.45–2.60, m, 2H; 2.99–
3.73, m, 15H; 4.14–4.42, m, 3H; 4.45–4.70, m, 3H; 5.04–5.19, m, 4H;
5.60–5.78, m, 1H; 6.05–6.20, m, 1H; 6.82–6.49, m, 10H; 7.56–7.58,
m, 2H; 7.74–7.88, m, 6H; m/z (ES, +ve) 945 (M+H+, 36%) and 225
(100). C57H60N4O9 + H+ requires m/z 945.4389. Found 945.4439.
Compound 16a. Pale yellow glass like solid (0.038 g). m/z (ES,
+ve) 817 (M+Na+, 4%), 795 (M+H+, 16), 593 (48) and 297 (100);
Compound 16b. Light brown solid (0.041 g). m/z (ES, +ve) 795
(M+H+, 54%), 593 (35), 297 (100), 145 (44), 104 (33) and 86 (64);
Compound 16c. Very pale yellow glass like solid (0.073 g). m/z
(ES, +ve) 795 (M+H+, 15%), 147 (32), 145 (66), 106 (16), 104
(52) and 86 (100).
3.2.4. Methyl (2S,5R)-2-allyl-9-[2-(30-allyl-2,20dimethoxy-1,10-
(Ra,Sa)-binaphthalen-3-yl)]-8(R,S)-acetamido-3,6-diaza-4,7-
dioxo-5-{3-[3-(2,2,5,7,8-pentamethylchroman-6-
3.3.2. (6R,9S)-1(3,30)-2,20-Dimethoxy-(Ra,Sa)-1,10-binaphthylena-
3(R,S)-acetamido-5,8-diaza-9-methoxycarbonyl-6-{3-[3-(2,2,5,-
7,8-pentamethylchroman-6-ylsulfonyl)guanidine]propyl}-4,7-
dioxocyclododecaphane-11-ene 17
ylsulfonyl)guanidine]propyl}nonanoate 14
The binaphthyl derivative 10b (0.127 g, 0.26 mmol) and
Prepared from the protected acyclic compound 12 (0.20 g,
0.2 mmol) dissolved in CH2Cl2 (50 mL). The solution was deoxy-
genated with argon gas for 10 min before the addition of benzylid-
enebis(tricyclohexylphosphine)dichloro ruthenium (0.020 g, 0.024
mmol). The reaction mixture was heated at reflux for 18 h, cooled
and then evaporated to dryness. The residue was subjected to silica
gel column chromatography and elution with MeOH (2.5%) in
CH2Cl2 gave 17 as a pale brown solid (0.147 g, 74%). 1H NMR d
1.28, s, 6H; 1.49–2.17, m, 9H; 2.23, s, 3H; 2.52–2.65, m, 10H;
3.01–3.46, m, 4H; 3.13, s, 3H; 3.30, s, 3H; 3.60–3.73, m, 2H; 3.69,
s, 3H; 4.37–4.75, m, 2H; 5.00–5.46, m, 1H; 6.10–6.54, m, 5H;
6.89–7.44, m, 6H; 7.61–8.05, m, 4H; 8.25, s, 1H; m/z (ES, +ve)
989 (M+H+, 17), 495 (15), 371 (27), 316 (75), 297 (88), 288 (85),
217 (73) and 199 (100).
N -PMC-L-arginine-L-allylglycine methyl ester (freshly deprotected
x
from the terminal Fmoc derivative) (0.150 g, 0.27 mmol) were dis-
solved in CH2Cl2 (dry, 1.5 mL). To the resulting solution was added
4-dimethylaminopyridine(crystal)andthenthesolutionwascooled
in an ice/water bath. To the chilled solution was added 1,3-dicyclo-
hexylcarbodiimide (0.053 g, 0.25 mmol). The reaction mixture was
allowedto warmto rt and was stirredovernight. To thereactionmix-
ture was added CH2Cl2 (10 mL) which was then filtered through cel-
ite. The filtrate was evaporated to dryness and the residue purified
by flash column chromatography (4% MeOH/CH2Cl2) to give 14 as
a colourless solid (0.176 g, 68%). 1H NMR d 1.29, s, 6H; 1.54–2.04,
m, 6H; 1.91, s, 3H; 2.08, s, 3H; 2.47–2.68, m, 10H; 3.10, s, 3H;
3.12–3.50, m, 4H; 3.19, s, 3H; 3.59–3.68, m, 2H; 3.71, s, 3H; 4.42–
4.70, m, 3H; 5.07–5.19, m, 4H; 5.65–5.83, m, 1H; 6.05–6.23, m, 1H;
6.18–6.49, m, 3H; 7.10–8.00, m, 10H; m/z (ES, +ve) 1040 (M+Na+,
16), 1018 (M+H+, 64), 1017 (M+ꢁ, 100), 920 (13), 624 (14) and 225
(24). C56H69N6O10S + H+ requires m/z 1017.4796. Found 1017.4799.
3.3.3. (6S,9S)-1(3,30)-2,20-Dimethoxy-(Ra,Sa)-1,10-binaphthylena-
3(R,S)-acetamido-5,8-diaza-6-(4-{[(9H-fluoren-9-yl)methoxy]-
carbonylamino}butyl)-9-methoxycarbonyl-4,7-dioxocyclodo-
decaphane-11-ene 18
3.2.5. Methyl (2S,5R)-2-allyl-9-[2-(30-allyl-2,20dimethoxy-1,10-
(Ra,Sa)-binaphthalen-3-yl)]-5-[4-(tert-butoxycarbonylamino)-
butyl]-8(R,S)-acetamido-3,6-diaza-4,7-dioxononanoate 159
This was prepared in the same manner as described for 11 above
The acyclic compound 13 (0.470 g, 0.50 mmol) was dissolved in
CH2Cl2 (120 mL). The solution was deoxygenated with argon gas
for 10 min before the addition of benzylidene-bis(tricyclohexyl-
phosphine)dichlororuthenium (0.022 g, 0.027 mmol). The reaction
mixture was heated at reflux for 18 h. The cooled reaction mixture
was evaporated to dryness the resulting residue purified by flash
column chromatography (4% methanol/ CH2Cl2) to give 18 as an
off-white crystalline solid (0.329 g, 72%). 1H NMR 1.05–1.71, m,
6H; 1.99, s, 3H; 2.47–2.60, m, 2H; 2.99–3.16, m, 2H; 3.21, s, 3H;
3.28, s, 3H; 3.58–3.67, m, 2H; 3.69, s, 3H. m/z (ES, +ve) 917 (M+H+,
5), 593 (9), 522 (3) and 297 (100%). C55H56N4O9 + H+ requires 917.
using 10a (0.149 g, 0.31 mmol), the dipeptide (NH2-D-(N -Boc)Lys-
x
L-allylGly-OMe (0.120 g, 0.33 mmol freshly N-Boc deprotected)
DMAP (1 crystal) and CH2Cl2 (5 mL) to produce 15 (0.123 g, 49%)
and was used directly in the following cyclisation reaction; 1H
NMR 1.18–1.53, m, 5H; 1.41, s, 9H; 1.54–1.75, m, 1H; 2.01, s, 3H;
2.37–2.69, m, 2H; 2.88–3.16, 2H; 3.09, s, 3H; 3.17–3.42, m, 2H;
3.58–3.80, m, 2H; 3.29, s, 3H; 3.72, s, 3H; 4.43–4.70, m, 3H; 4.75–
4.94, m, 1H; 5.01–5.25, m, 4H; 5.59–5.85, m, 1H; 6.04–6.23, m, 1H;
6.98–7.45, m, 6H; 7.54, d, J = 7.2 Hz, 1H; 7.75–7.99, m, 4H.
C
55H56N4O9 + H+ requires m/z 917.4110. Found 917.4126.
3.3. Synthesis of protected macrocycles 16–20
3.3.4. (6S,9S)-1(3,30)-2,20-Dimethoxy-(Ra,Sa)-1,10-binaphthylena-
3(R,S)-acetamido-5,8-diaza-9-methoxycarbonyl-6-{3-[3-(2,2,5,-
7,8-pentamethylchroman-6-ylsulfonyl)guanidine]propyl}-4,7-
dioxocyclododecaphane-11-ene 19
The acyclic compound 14 (0.176 g, 0.17 mmol) was dissolved in
CH2Cl2 (50 mL). The solution was deoxygenated with argon for
10 min before the addition of benzylidene-bis(tricyclohexylphos-
phine)dichlororuthenium (0.015 g, 0.017 mmol). The reaction
3.3.1. (6R,9S)-1(3,30)-2,20-Dimethoxy-(Ra,Sa)-1,10-binaphthylena-
3(R,S)-acetamido-5,8-diaza-6-[4-(tert-butoxycarbonylamino)-
butyl]-9-methoxycarbonyl-4,7-dioxocyclotridecaphane-11-ene
16
The binaphthyl derivative 11 (0.205 g, 0.25 mmol) was dis-
solved in CH2Cl2 (50 mL). The solution was deoxygenated with

D. R. Coghlan et al. / Bioorg. Med. Chem. 19 (2011) 3549–3557
3555
mixture was heated at reflux for 20 h. The cooled reaction mixture
was evaporated to dryness the resulting residue purified by flash
column chromatography (4% methanol/ CH2Cl2) to give 19 as a
light brown glass (0.132 g, 77%). 1H NMR 1.27, s, 6H; 1.75–2.17,
m, 9H; 2.43–2.57, m, 3H; 2.89–3.79, m, 10H; 4.36–4.80, m, 2H;
5.00–5.60, m, 1H; 6.14–6.50, m, 5H; 6.99–7.40, m, 6H; 7.70–7.96,
3.4.2. (6R,9S)-1(3,30)-2,20-dimethoxy-(Ra,Sa)-1,10-binaphthylena-
3(R,S)-acetamido-5,8-diaza-6-(3-guanidinopropyl)-9-methoxy-
carbonyl-4,7-dioxocyclododecaphane-11-ene hydrochloride 22
This was prepared from a solution of the protected macrocyclic
17 (0.099 g, 0.10 mmol) in CH2Cl2 (2 mL) and trifluoroacetic
acid (2 mL). The mixture was stirred at rt for 25 min and then
evaporated to dryness. The residue was taken up in CH2Cl2 and
evaporated to dryness again. This was repeated twice more. The
residue was taken up in CH2Cl2 (3 mL) and a solution of 1.0 M
hydrogen chloride in diethyl ether (1 mL) was added. The resulting
mixture was stirred at rt for 10 min before being evaporated to
dryness. The residue was taken up in CH2Cl2 and evaporated to
dryness again. This was repeated twice more. The deprotected
macrocyclic 22 was isolated (0.068 g, 89%) as an off-white solid.
1H NMR d 0.83–2.22, m, 9H; 2.49–2.54, m, 2H; 3.04–4.14, m,
13H; 4.34–4.65, m, 3H; 5.15–5.55, m, 2H; 5.75–5.97, m, 1H;
7.09–7.96, m, 10H; m/z (ES, +ve) 723 (M+H+, 15), 316 (28), 288
(78), 217 (100), 199 (79), 111 (41); C40H46N6O7 + H+ requires m/z
723.3520. Found 723.3533.
m, 4H; m/z (ES, +ve) 1011 (M+Na+) and 989 (M+H+). C54H64N6O10
S
+ H+ requires m/z 989.4533. Found 989.4483.
3.3.5. (6R,9S)-1(3,30)-2,20-Dimethoxy-(Sa)-1,10-binaphthylena-
3(R,S)-acetamido-5,8-diaza-6-[4-(tert-butoxycarbonylamino)-
butyl]-9-methoxycarbonyl-4,7-dioxocyclotridecaphane-11-
ene 209
This was prepared from the (S)-acyclic compound 15 (0.120 g,
0.14 mmol) and benzylidenebis(tricyclohexylphosphine)-dichlo-
roruthenium (0.011 g, 0.013 mmol) using the method as set out for
16. After column chromatography the protected macrocyclic (S)-
20 was isolated as a colourless glass (0.083 g, 72%). 1H NMR d
1.17–1.98, m, 6H; 1.42, s, 9H; 2.17, s, 3H; 2.36–2.77, m, 2H; 2.94–
3.17, m, 2H; 3.15, s, 3H; 3.18–3.55, m, 4H; 3.32, s, 3H; 3.52, s, 3H;
4.26–4.39, m, 2H; 4.40–4.65, m, 1H; 4.80–4.90, m, 1H; 5.00–5.20,
m, 2H; 6.16–6.23, m, 1H; 6.38, d, J = 7.2 Hz, 1H; 6.53, d, J = 6.0 Hz,
1H; 6.63, d, J = 6.9 Hz, 1H; 6.92, d, J = 8.4 Hz, 1H; 7.00, d, J = 7.8 Hz,
1H; 7.10–7.19, m, 2H; 7.31–7.38, m, 2H; 7.69, s, 1H; 7.75, s, 1H;
7.81, d, J = 8.1 Hz, 2H; m/z (ES, +ve) 817 (M+Na+, 4%), 795 (M+H+,
13), 593 (20), 297 (100). C45H54N4O9 + H+ requires m/z 795.3969.
Found 795.3974.
3.4.3. (6S,9S)-1(3,30)-2,20-Dimethoxy-(Ra,Sa)-1,10-binaphthylena-
3(R,S)-acetamido-6-(4-aminobutyl)-5,8-diaza-9-methoxycar-
bonyl-4,7-dioxocyclododecaphane-11-ene hydrochloride 23
To the macrocyclic 18 (0.123 g, 0.13 mmol) was added dry
CH3CN (9 mL). The mixture was warmed to 60 °C in a sealed sys-
tem and a solution of piperidine in CH3CN (0.02 M, 0.54 mL) was
added. The reaction mixture was heated at 60 °C for 43 h. The
cooled mixture was filtered, the filtrate evaporated to dryness to
give a white solid. The solid was purified by flash column chroma-
tography (10% MeOH/CH2Cl2, followed by 10% MeOH/CH2Cl2con-
taining 2% triethylamine). The isolated product was dissolved in
CH2Cl2 (5 mL) and 1.0 M HCl in diethyl ether (0.5 mL) was added.
The solution was stirred for 10 min then evaporated to dryness
and dried under high vacuum to give 23 as a pale yellow crystalline
solid (0.048, 51%). 1H NMR d 0.86–2.55, m, 11H; 3.00–3.71, m, 13H;
4.40–4.92, m, 3H; 5.02–5.60, m, 2H; 6.02–6.29, m, 1H; 7.08–7.61,
m, 6H; 7.62–8.20, m, 4H; m/z (ES, +ve) 695 (M+H+, 100%) and
498 (25); C40H46N4O7 + H+ requires m/z 695.3445. Found 695.3419.
3.4. Synthesis of deprotected macrocycles 22–27
3.4.1. (6R,9S)-1(3,30)-2,20-Dimethoxy-(Sa)-1,10-binaphthylena-
3(R,S)-acetamido-6-(4-aminobutyl)-5,8-diaza-9-methoxycar-
bonyl-4,7-dioxocyclotridecaphane-11-ene hydrochloride 25
To a solution of the macrocycle 16a (0.038 g, 0.05 mmol) in
CH2Cl2 (2 mL) was added trifluoroacetic acid (2 mL) and the mix-
ture stirred at rt for 25 min. It was then evaporated to dryness,
and the residue taken up in CH2Cl2 and evaporated to dryness
again. This was repeated twice more. The residue was taken up
in CH2Cl2 (3 mL) and a solution of 1.0 M hydrogen chloride in
diethyl ether (1 mL) was added. The resulting mixture was stirred
at rt for 10 min before being evaporated to dryness. The residue
was taken up in CH2Cl2 and evaporated to dryness again. This
was repeated twice more. The product 25 was crystallized from
the residue with diethyl ether and CH2Cl2. The product was
isolated using centrifugation to yield afforded 25 as a pale yellow
solid (0.021 g, 60%) (S-isomer). 1H NMR d 0.86–2.58, m, 11H;
2.80–3.80, m, 13H; 4.25–4.95, m, 3H; 5.00–5.40, m, 2H;
6.00–6.30, m, 1H; 6.95–7.60, m, 6H; 7.65–8.00, m, 4H; m/z
(ES, +ve) 697 (32%) and 696 (100) and 695 (M+H+, 96);
C40H46N4O7 + H+ requires m/z 695.3445. Found 695.3435.
3.4.4. (6S,9S)-1(3,30)-2,20-Dimethoxy-(Ra,Sa)-1,10-binaphthylena-
3(R,S)-acetamido-5,8-diaza-6-(3-guanidinopropyl)-9-methoxy-
carbonyl-4,7-dioxocyclododecaphane-11-ene hydrochloride 24
The macrocyclic 19 (0.047 g, 0.05 mmol) was dissolved in
CH2Cl2 (2 mL) then trifluoroacetic acid (2 mL) was added. The mix-
ture was stirred at rt for 25 min. The mixture was evaporated to
dryness, the residue taken up in CH2Cl2 and evaporated to dryness
again. This was repeated twice more. The residue was taken up in
CH2Cl2 (3 mL) and a solution of 1.0 M HCl in diethyl ether (1 mL)
was added. The resulting mixture was stirred at rt for 10 min be-
fore being evaporated to dryness. The residue was taken up in
CH2Cl2 and evaporated to dryness again. This was repeated twice
more. The product 24 was crystallized from the residue with
diethyl ether and CH2Cl2. The product was isolated using centrifu-
gation to yield 24 as an off-white solid (0.021 g, 58%). 1H NMR d
0.83–2.22, m, 9H; 2.49–2.54, m, 2H; 3.04–4.14, m, 13H; 4.34–
4.65, m, 3H; 5.15–5.55, m, 2H; 5.75–5.97, m, 1H; 7.09–7.96, m,
10H; m/z (ES, +ve) 724 (M+H+, 100%); C40H46N6O7 + H+ requires
m/z 723.3506. Found 723.3488.
3.4.1.1. (6R,9S)-1(3,30)-2,20-Dimethoxy-(Sa)-1,10-binaphthylena-
3(R,S)-acetamido-6-(4-aminobutyl)-5,8-diaza-9-methoxycar-
bonyl-4,7-dioxocyclotridecaphane-11-ene hydrochloride 26.
Similarly 16b (0.041 g, 0.05 mmol) afforded 26 as a pale yellow
solid (0.023 g, 60%) (S-isomer). m/z (ES, +ve) 696 (9%), 695
(M+H+, 20); 111 (12) and 60 (100); C40H46N4O7 + H+ requires m/z
695.3445. Found 695.3427.
3.4.1.2. (6R,9S)-1(3,30)-2,20-Dimethoxy-(Ra)-1,10-binaphthylena-
3(R,S)-acetamido-6-(4-aminobutyl)-5,8-diaza-9-methoxycar-
bonyl-4,7-dioxocyclotridecaphane-11-ene hydrochloride 27.
Similarly 16c (0.073 g, 0.09 mmol) 27 as a pale yellow crystalline
solid (0.055 g, 82%) (R-isomer). m/z (ES, +ve) 696.5 (41%) and
695.8 (53) and 695.4 (M+H+, 73), 111 (48) and 60 (100);
3.4.5. (6R,9S)-1(3,30)-2,20-Dimethoxy-(Sa)-1,10-binaphthylena-
3(R,S)-acetamido-6-(4-aminobutyl)-5,8-diaza-9-methoxycar-
bonyl-4,7-dioxocyclotridecaphane-11-ene hydrochloride 19
The macrocyclic 20 (0.041 g, 0.05 mmol) was dissolved in
CH2Cl2 (2 mL) then trifluoroacetic acid (2 mL) was added. The
C
40H46N4O7 + H+ requires m/z 695.3445. Found 695.3400.

3556
D. R. Coghlan et al. / Bioorg. Med. Chem. 19 (2011) 3549–3557
mixture was stirred at rt for 25 min. The mixture was evaporated
to dryness, the residue taken up in CH2Cl2 and evaporated to dry-
ness again. This was repeated twice more. The residue was taken
up in CH2Cl2 (3 mL) and a solution of 1.0 M HCl in diethyl ether
(1 mL) was added. The resulting mixture was stirred at rt for
10 min before being evaporated to dryness. The residue was taken
up in CH2Cl2 and evaporated to dryness again. This was repeated
twice more. The product 1 was crystallized from the residue with
diethyl ether and CH2Cl2. The product was isolated using centrifu-
gation to yield 1 (0.032 g, 84%) as an off-white solid. m/z (ESI, +ve)
696 (85%), 695 (M+H+, 100); C40H46N4O7+H+ requires m/z 695.3445
Found m/z 695.3455.
3.6. Synthesis of the (5S,9S,12S)-1(3,30)-2,20-dimethoxy-(Ra,Sa)-
1,10-binaphthylena-3(R,S)-acetamido-9-(4-aminobutyl)-8,11-
diaza-12-methoxycarbonyl-5-methyl-4,7,10-trioxocyclohexa-
decaphane-14-ene 30
A solution of 10b (0.25 g, 0.52 mmol), the tripeptide NH2-
L-Ala-
L
-(N -Foc)Lys- -allylGly-OMe (0.286 g, 0.52 mmol), DMAP (1 crys-
L
x
tal), DCC 90.109 g, (0.53 mmol) in CH2Cl2 (3 mL) at 0 °C was then
allowed to come to rt and then stirred overnight. The reaction
was filtered, concentrated by rotary evaporation and the residue
then subjected to column chromatography and elution with 5%
isopropanol in CH2Cl2 gave the peptide 28 (0.206 g, 39%) as a white
solid. 1H NMR d 1.34, d, J = 7.2 Hz, 3H; 1.38–1.51, m, 3H; 1.71–1.93,
m, 3H; 1.98, s, 3H; 3.13–3.27, m, 5H; 3.32, s, 3H; 3.60–3.69, m, 2H;
3.73, s, 3H; 3.98–4.07, m, 1H; 4.15–4.22, m, 1H; 4.28–4.53, m, 4H;
4.60–4.67, m, 1H; 5.11–5.17, m, 4H; 5.41–5.61, m, 1H, 5.69–5.78,
m, 1H; 6.07–6.19, m, 1H; 6.91, br s, 1H, NH; 7.10–7.13, m, 1H;
7.18–7.30, m, 5H; 7.35–7.41, m, 4H; 7.55–7.60, m, 3H; 7.73–7.75,
m, 2H; 7.80–7.86, m, 4H. m/z (ES, +ve) 1016 (M+H+, 100%).
3.5. Synthesis of the deprotected acyclic peptides 31–32
3.5.1. Methyl (2S,5R)-2-allyl-9-[2-(30-allyl-2,20-dimethoxy-1,10-
(Ra,Sa)-binaphthalen-3-yl)]-8(R,S)-acetamido-3,6-diaza-5-
(3-guanidinopropyl)-4,7-dioxononanoate 31
The acyclic compound 12 (0.056 g, 0.05 mmol) was dissolved in
CH2Cl2 (2 mL) then trifluoroacetic acid (3 mL) was added. The mix-
ture was stirred at 0 °C for 45 min, and then warmed to rt followed
by stirring for 15 min. The mixture was then diluted with CH2Cl2
(15 mL) and then evaporated to dryness. The residue taken up in
CH2Cl2 and evaporated to dryness again. This was repeated twice
more. The residue was taken up in CH2Cl2 (3 mL) and a solution
of 1.0 M HCl in diethyl ether (1 mL) was added. The resulting
mixture was stirred at rt for 10 min before being evaporated to
dryness. The residue was taken up in CH2Cl2 and evaporated to
dryness again. This was repeated twice more. The product 31
was crystallized from the residue with diethyl ether and CH2Cl2
Compound 28 (0.068 g, 0.07 mmol) and benzylidene-bis(tricy-
clohexylphosphine)dichlororuthenium (0.004 g, 0.005 mmol) in
deoxygenated CH2Cl2 (15 mL) were then heated at reflux for
15 h. The solvent was then evaporated and the residue subjected
to flash column chromatography and elution with 10% MeOH in
CH2Cl2 to give the cyclic protected tetrapeptide 29 (0.069 g). 1H
NMR 1.19–2.05, m, 6H; 2.04–2.24, m, 2H; 3.06–3.73, m, 15H;
4.11–4.64, m, 3H; 5.69–5.78, m, 1H; 6.00–6.22, m, 1H; 7.13–7.84,
m, 10H. This product was immediately added to dry CH3CN
(4 mL) and DMF (1 mL) with piperidine (0.32 mL, 0.006 mmol)
and the mixture heated at 70 °C for 12 h. The reaction mixture
was then cooled and centrifuged at 2100 rpm for 5 min and the so-
lid separated. The solid was then added to HCl in ether (1.0 M,
0.3 mL) and MeOH (2 mL), filtered and the filtrate concentrated
and dried to yield the cyclic tetrapeptide 30 (10 mg, 19%) as a pale
yellow solid. The 1H NMR spectra of 30 was exceptionally broad
(see Ref. 18), probably exacerbated by slow conformational tum-
bling in solution, and was not able to be deconvoluted into mean-
ingful data. m/z (ES, +ve) 766.5 (100%), 767 (79) and 767.5 (58);
to afford 31 that was isolated as
a pale yellow solid
(0.034 g, 79%). 1H NMR: 1.25–1.45, m, 1H; 1.50–2.00, m, 6H;
2.44–2.70, m, 2H; 2.89–3.02, m, 1H; 3.22–3.45, m, 9H; 3.68–3.72,
m, 2H; 4.52–4.59, m, 2H; 4.62–4.80, m, 1H; 5.11–5.20, m, 4H;
5.71–5.88, m, 1H; 6.12–6.24, m, 1H; 7.06–7.12, m, 2H; 7.22–7.25,
m, 2H; 7.39–7.44, m, 2H; 7.89–7.94, m, 4H. m/z (ESI, +ve) 751
(MꢀCl+H+, 55%); C42H50N6O7
+
H+ requires m/z 751.3819
Found 751.3826.
C
43H51N5O8 + H+ requires m/z 766.3816. Found 766.3768.
3.5.2. Methyl (2S,5S)-2-allyl-9-[2-(30-allyl-2,20dimethoxy-1,10-
(Ra,Sa)-binaphthalen-3-yl)]-8(R,S)-acetamido-3,6-diaza-5-
(3-guanidinopropyl)-4,7-dioxononanoate 32
3.7. Determination of minimum inhibitory concentration (MIC)
Compound preparation: Compounds were accurately weighed
out (between approx. 1–2 mg) and dissolved in 10% methanol/
water (v/v) to a final stock concentration of 10 mg/mL. Compounds
were then diluted 1/10 in water to a test concentration of 1000
The acyclic compound 14 (0.054 g, 0.05 mmol) was dissolved
in CH2Cl2 (2 mL) then trifluoroacetic acid (3 mL) was added. The
mixture was stirred at 0 °C for 2 h, and then warmed to rt fol-
lowed by stirring for 15 min. The mixture was then diluted with
CH2Cl2 (15 mL) and then evaporated to dryness. The residue taken
up in CH2Cl2and evaporated to dryness again. This was repeated
twice more. The residue was taken up in CH2Cl2 (1 mL) and a
solution of 1.0 M HCl in diethyl ether (1 mL) was added. The
resulting mixture was stirred at rt for 10 min before being
evaporated to dryness. The residue was taken up in CH2Cl2
(15 mL) and evaporated to dryness again. This was repeated
twice more. The product 32 was crystallized from the residue
with diethyl ether and CH2Cl2. The deprotected non-cyclic com-
pound 32 that was isolated as a pale yellow solid (0.031 g,
74%). 1H NMR: 1.28–1.40, m, 1H; 1.55–2.00, m, 6H; 2.47–2.67,
m, 2H; 2.90–3.00, m, 1H; 3.15–3.49, m, 9H; 3.64–3.72, m, 2H;
4.39–4.64, m, 2H; 4.65–4.75, m, 1H; 4.91–5.20, m, 4H; 5.76–
5.82, m, 1H; 6.15–6.23, m, 1H; 7.05–7.12, m, 2H; 7.21–7.27, m,
2H; 7.39–7.44, m, 2H; 7.88–7.94, m, 4H. m/z (ESI, +ve) 751
(MꢀCl+H+, 100%); C42H50N6O7 + H+ requires m/z 751.3819 Found
751.3817.
lg/mL and used immediately.
3.7.1. Starter culture
The day prior to MIC determinations, an overnight (14 h) cul-
ture of Staphylococcus aureus in Luria Broth (LB) was grown at
37 °C. The culture was then diluted 1 in 1,000 prior to use in the
assay. This dilution provided a clear suspension of cells sufficient
for overnight growth and to enable the clear visual determination
of inhibition of growth.
In a 96 well round bottom plate, 50
pounds were assayed in triplicate as 8 dilutions in each assay and
to the upper well of each of the three columns 50 L of compound
at 1,000 g/mL was added. The compounds were then diluted 1 in
2 from the top row to the bottom row giving the eight dilutions.
lL LB/well was added. Com-
l
l
After the dilutions, 50
added to each well.
lL of the diluted overnight culture was
Each assay also contained a media only control, bacteria but no
compound, and bacteria with vancomycin in triplicate. Compounds

D. R. Coghlan et al. / Bioorg. Med. Chem. 19 (2011) 3549–3557
3557
10. Bremner, J. B.; Coates, J. A.; Keller, P. A.; Pyne, S. G.; Witchard, H. M. Tetrahedron
2003, 59, 8741.
11. Bremner, J. B.; Coates, J. A.; Keller, P. A.; Pyne, S. G.; Witchard, H. M. Synlett
2002, 219.
were generally tested in the two fold dilution series 250
down to 1.95 g/mL. Vancomycin was tested in the two fold dilu-
tion series with a starting concentration of 7.8 g/mL. The highest
lg/mL
l
l
12. Au, V. S.; Bremner, J. B.; Coates, J.; Keller, P. A.; Pyne, S. G. Tetrahedron 2006, 62,
9373.
13. Boyle, T. P.; Bremner, J. B.; Coates, J.; Deadman, J.; Keller, P. A.; Pyne, S. G.;
Rhodes, D. I. Tetrahedron 2008, 64, 11270.
concentration of solvent in the assay was 0.25% v/v and assays
demonstrated the solvent to have no adverse effect on the over-
night growth of the cultures.
14. 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.
Assays were set up in a blinded fashion such that the structures
of the compounds were unknown to the operator. MICs were
determined by eye, where the compound concentration at the low-
er dilution to the well of obvious growth was recorded as the MIC.
Results of the triplicates were recorded and the median values
(rounded to whole numbers) stated in this manuscript.
15. All new compounds reported in this paper were fully characterised using 1H
and 13C NMR, MS, and HRMS unless otherwise stated. All compounds were
judged to be of >95% purity based on 1H NMR analysis. The macrocyclic free
amines were also judged to be homogenous by TLC analysis and the
subsequent salts were recrystallised.
16. We also attempted the stereoselective alkylation of the (S)-bromide 5 using the
Seebach chiral imidazolidinone auxiliary, see Seebach, D.; Sting, A. R.;
Hoffmann, M. Angew. Chem., Int. Ed. 1996, 35, 2708. In our hands, it gave
modest yields of the desired alkylated product (ꢄ50%) with subsequent
hydrolysis being slow and not producing the required amino acid intermediate,
but instead an unwanted amide.
Acknowledgments
We thank Amrad Corporation Ltd, Avexa Ltd, the University of
Wollongong, and the National Health and Medical Research Coun-
cil (Development Grants 303415 and 404528) for support.
17. As a result of the presumed epimeric mixture of the N-acetyl protected glycine
residue, and the rotamers present, 13C NMR was not productive in the
assignment of structure.
18. For all macrocycles synthesised here, peaks in the 1H NMR spectra were
notably broad but were consistent with the assigned structures. Hence, a
greater emphasis was placed on MS and in particular, HRMS, for elucidation of
structure.
References and notes
19. The synthesis of compounds 15, 20 and 1, were described previously, see Ref. 9.
20. For examples of typical procedures used, see Ref. 9 and Bremner, J. B.; Pyne, S.
G.; Keller, P. A.; Coghlan, D. R.; Garas, A.; Witchard, H. M.; Boyle, T. P.; Coates, J.
A. WO 03/002545 A1, Patent, Peptoid Compounds, AU2002/00850 2003.
21. The E/Z mixture arises from the RCM reaction and the ratio is unknown due to
the lack of resolution of the NMR spectra (see Ref. 18).
1. (a) Nordmann, P.; Naas, T.; Fortineau, N.; Poirel, L. Curr. Opin. Microbiol. 2007,
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6. Projan, S. J.; Bradford, P. A. Curr. Opin. Microbiol. 2007, 10, 441.
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8. Srinivas, N.; Moehle, K.; Abou-Hadeed, K.; Obrecht, D.; Robinson, J. A. Org.
Biomol. Chem. 2007, 5, 3100.
24. The presence of diastereomers and rotamers accounts for the excess peaks
appearing in the NMR spectra.
9. Bremner, J. B.; Coates, J. A.; Coghlan, D. R.; David, D. M.; Keller, P. A.; Pyne, S. G.
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