Synthesis of a C3-symmetric nanoscale molecular platform based on marine cyclopeptides

Article abstract of DOI:10.1055/s-2004-822906

Efficient synthesis of a conformationally preorganized, C ₃-symmetric molecular platform is reported. The rigid scaffold is based on the structure of marine cyclopeptides and presents three functional groups pointing in the same direction. The bicyclic imidazole building blocks were synthesized in seven steps from trans-4-hydroxy-(S)-proline.

Full text of DOI:10.1055/s-2004-822906

LETTER
1003
Synthesis of a C3-Symmetric Nanoscale Molecular Platform Based on Marine
Cyclopeptides
Synthesis of
a
C3-Seymmetric
Nanoscale
M
h
olecular Plat
a
form
B
ase
r
M
ar
d
ine CyclopeptidesHaberhauer*
Organisch Chemisches Institut, Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax +49(6221)544205; E-mail: gebhard.haberhauer@urz.uni-heidelberg.de
Received 19 January 2004
condensation of ammonia with the ketoester 5, already
Abstract: Efficient synthesis of a conformationally preorganized,
C3-symmetric molecular platform is reported. The rigid scaffold is
based on the structure of marine cyclopeptides and presents three
functional groups pointing in the same direction. The bicyclic imi-
dazole building blocks were synthesized in seven steps from trans-
4-hydroxy-(S)-proline.
bearing the five-membered functionlized ring. The latter
was expected to be obtainable from trans-4-hydroxy-(S)-
proline (Scheme 1).
OH
O
O
Key words: amino acids, condensation, cyclizations, heterocycles,
peptides
N
OP3
NH
N
HN
N
O
O
OH
COOP2
N
O
H
N
P1HN
O
Rigid molecular platforms presenting three functional
groups in the same direction are useful tools in molecular
recognition.1 The conformationally preorganized nature
of these scaffolds allows for pendant functionalities to be
specifically spaced and oriented for the attachment of
recognition elements. For the application of these systems
as synthetic receptors, the distance and the relative orien-
tation of the functional groups play a major role.
2
O
HO
1
OH
OP3
N
O
N
NH
N
HN
N
O
N
We have previously reported the synthesis of functional-
ized trisoxazole and trisimidazole platforms related to ma-
rine cyclopeptides which are characterized by an
alternating sequence of oxazole moieties with hydropho-
bic standard amino acid residues.2 The average distance
between the polar functional groups in the synthetic
macrocycles (e.g. the hydroxyl groups in 1, Scheme 1)
amounts to about 7 Å and is independent from the parent
azole system. Disadvantageously, the polar functional
groups of these platforms are not directly bound to the
scaffold, but via methylene units, which leads to a reduced
preorganization. Herein we discuss efforts toward the
synthesis of a new class of trisimidazole platforms with a
distinctly enhanced distance between the hydroxyl groups
(3 in Scheme 1), which are directly connected to the
scaffold, making these platforms more suitable for the
application in molecular recognition.
COOP2
N
N
H
N
P1HN
N
OH
4
HO
O
3
OP3
OH
OP2
HN
N
OH
P1HN
O
O
O
O
5
6
Scheme 1
Esterification of hydroxy proline 6 led to the hydro-
chloride 7, which was coupled with Z-glycine N-hydroxy-
succinimide ester (Z-Gly-OSu) to the dipetide 8
(Scheme 2). Protection of 8 as its tert-butyldimethylsilyl
ether was followed by basic hydrolysis to give the acid 9.
From the numerous methods known for the conversion of
carboxylic acids to 2-oxo esters4 we favored a method
involving ozonolysis of a-ketocyanophosphoranes origi-
nally described by Wasserman and Ho.5 Treatment of acid
9 with (cyanomethylene)triphenylphosphorane in the
presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodi-
imide (EDCI) and 4-dimethylaminopyridine (DMAP)
yielded the cyano keto phosphorane 10. The ylide 10 was
then oxidatively cleaved with ozone to form an a,b-di-
ketonitrile which was converted in situ with MeOH to the
a-keto ester 11.
The C3-symmetry of the target macrocyclic triamide 3
suggested a synthetic approach employing the bicyclic
imidazole-based, protected amino acid monomer 4
(Scheme 1) for cyclotrimerization. This type of macro-
lactamization has already been successfully applied to
related azole-based cyclotrimers.3
Our synthetic plan for accessing the bicyclic imidazole
monomer 4 envisaged to form the azole system by cyclo-
SYNLETT 2004, No. 6, pp 1003–1006
0
6.
0
5.
2
0
0
4
Advanced online publication: 01.04.2004
DOI: 10.1055/s-2004-822906; Art ID: G02204ST
© Georg Thieme Verlag Stuttgart · New York

1004
G. Haberhauer
LETTER
OH
OH
(Scheme 3). This observation was surprising since the
comparable cyclotrimerization of the amino acids 16b–d
had led to the macrocycles 18b–d in 25–35% yield with
only minor influence of the nature of the coupling reagent
(Scheme 4).2a In order to find out whether the above-men-
tioned transfer hydrogenation of an active ester is an
appropriate method for the synthesis of such trimers, we
synthesized the amino acid 16a and the N-Z protected
active esters 17a and 17b and tried to cyclize them to the
corresponding trimers.
a
b
HN
HCl HN
ZHN
COOSu
COOH
COOMe
6
7
OH
OTBS
c,d
e
N
O
N
COOMe
COOH
ZHN
ZHN
O
8
9
OTBS
OTBS
N
OH
OTBS
f
a
b,c
CN
OMe
O
N
N
N
ZHN
PPh3
ZHN
O
O
O
O
COOMe
COOMe
N
N
ZHN
ZHN
10
11
13
12
OTBS
OH
OTBS
g
+
N
N
OTBS
N
O
COOMe
COOMe
N
N
N
d
ZHN
ZHN
NH
N
HN
N
N
O
12
13
COOPfp
N
N
Scheme 2 Reaction conditions: (a) SOCl2, MeOH, 99%; (b) Et3N,
DCM, 65%; (c) TBSCl, DBU, CH3CN, 95%; (d) NaOH, MeOH,
96%; (e) Ph3PCHCN, DMAP, EDCI, CH2Cl2, 59%; (f) O3, MeOH–
CH2Cl2, 80%; (g) TFA, NH3, xylenes, 130 °C, 47% for 12, 29% for
13.
ZHN
H
N
N
14
OTBS
TBSO
O
15
Scheme 3 Reaction conditions: (a) TBSCl, DBU, CH3CN, 98%; (b)
LiI, pyridine, 110 °C; (c) CF3COOPfp, pyridine, CH2Cl2, 61% (2
steps); (d) Pd/C, cyclohexadiene, i-Pr2NEt, t-BuOH, 85 °C.
The final cyclocondensation of amidoketone 11 to the bi-
cyclic imidazole 12 was examined with various ammonia
reagents. The best yields for the formation of 12 (up to
65%) were obtained when ammonium trifluoroacetate
was used in refluxing xylenes with azeotropic removal of
water. The yields for the cyclization were even higher (up
to 76%) when ammonium trifluoroacetate was formed in
situ from methanolic NH3 and trifluoroacetic acid. How-
ever, under these conditions the TBS protective group was
partially removed, so that beside 12 (47%), the alcohol 13
(29%) could be isolated.6 Since 13 could be almost quan-
titatively reprotected to 12, the latter synthetic method
was nevertheless regarded to be the best (Scheme 3).
N
R
N
COOH
N
a
b
R
N
O
HCl H2N
N
16a–d
NH
N
HN
N
R
O
N
H
N
N
R
COOPfp
N
R
O
18a–d
ZHN
17a,b
16–18a: R = H
16–18b: R = CHMe2
16c, 18c: R = CH2Ph
16d, 18d: R = CH2NHZ
Unfortunately, the hydrolysis of the methyl ester function-
ality of compound 12 proved to be extremely difficult.
After examining many reaction conditions,7 especially
basic aqueous solutions, we found that the best method
is the non-hydrolytic cleavage of the methyl ester with
lithium iodide in pyridine.8 The resulting acid was sub-
sequently converted into the activated ester 14 employing
pentafluorophenyltrifluoroacetate and pyridine in
CH2Cl2.
Scheme 4 Reaction conditions: (a) FDPP or DPPA, i-Pr2NEt,
CH3CN, RT, 25–35% for 18b–d, 0% for 18a. (b) Pd/C, cyclohexadie-
ne, i-Pr2NEt, t-BuOH, 85 °C, 48% for 18b, 0% for 18a.
A comparison of the two methods (i.e. steps a and b in
Scheme 4) showed that cyclization via hydrogenation of
an active ester led to even higher yields for the macrocy-
cles. However, independently from the coupling method,
the monomers where the amino acid residue is derived
from glycine (i.e. R = H) gave no cyclic trimers at all.
Evidently, it is necessary to use monomers derived from
amino acids different from glycine (R ≠ H) for a success-
ful cyclotrimerization.
The one-pot hydrogenolysis of the N-Z function and mac-
rotrimerization were tried to be realized under transfer hy-
drogenation conditions.9 Unfortunately, heating a solution
of 14 in tert-BuOH in the presence of Pd/C, cyclohexadi-
ene, and Hünig’s base provided only polymers
Synlett 2004, No. 6, 1003–1006 © Thieme Stuttgart · New York

LETTER
Synthesis of a C3-Symmetric Nanoscale Molecular Platform Based on Marine Cyclopeptides
1005
OH
cleavage of the corresponding a-ketocyanophosphorane.
Cyclocondensation of amidoketone 21 with ammonium
trifluoroacetate (generated in situ) afforded the bicyclic
imidazoles 22 and 23 in an overall yield of 85%.6 Racem-
ization at the a-C-atom of the L-valine-based moiety
which generally occurs during the condensation to related
bicyclic imidazoles10 was not observed.
OH
a
b,c
N
COOMe
HCl HN
ZHN
COOMe
O
7
19
OTBS
OTBS
d,e
Methyl ester 22 was converted into the activated ester 24
via ester cleavage with lithium iodide in pyridine and es-
terification with pentafluorophenyltrifluoroacetate and
pyridine (Scheme 6). As expected, the subsequent one-pot
hydrogenolysis of the N-Z function and macrotrimeriza-
tion of the modified bicyclic imidazole monomer provid-
ed the cyclotrimer 2511 in a satisfactory yield (43%).
Deprotection of the silyl ethers with aqueous HF in
CH3CN afforded the desired triol platform 26.12
OMe
N
N
COOH
ZHN
O
ZHN
O
O
O
20
21
OTBS
OH
f
+
N
N
COOMe
COOMe
N
N
ZHN
ZHN
22
23
Scheme 5 Reaction conditions: (a) Z-Val-OH, HOBt, EDCI, NMM,
CH2Cl2, 93%; (b) TBSCl, DBU, CH3CN, 96%; (c) NaOH, MeOH,
94%; (d) Ph3PCHCN, DMAP, EDCI, CH2Cl2, 87%; (e) O3, MeOH–
CH2Cl2, 66%; (f) TFA, NH3, xylenes, 130 °C, 50% for 22, 35% for
23.
OTBS
OTBS
a,b
N
N
COOMe
COOPfp
Figure 1 Amber* minimized structure of 26: side view (left) and
top view (right); all hydrogen atoms have been omitted for clarity.
N
N
ZHN
ZHN
22
24
OR
1
The resonance of the amide protons (d = 8.19) in the H
N
NMR spectrum of 26 proves that there is an interaction
between the lone pairs of the imidazole nitrogen and the
hydrogen of the secondary amides. This is consistent with
the self-complementary pattern of alternating hydrogen
donors and acceptors pointing into the interior of the
platform, which has already been observed in the original
platforms. Molecular modeling13 of platform 26
(Figure 1) using MacroModel and the Amber* force field
showed that the azole moieties of the macrocycle do not
form a single plane but have a cone-like structure. This
deviation from planarity is in good agreement with the
data obtained from the X-ray crystal structure of the relat-
ed trisimidazole platform 18b2a and is probably caused by
the iso-propyl groups of the valine-based moiety. The
distance between the hydroxyl groups in the minimized
structure amounts to more than 11 Å, which is almost
twice that of other tripodal platforms.14
O
c
N
NH
N
HN
O
25, R = TBS
26, R = H
d
N
N
H
N
N
OR
RO
O
Scheme 6 Reaction conditions: (a) LiI, pyridine, 110 °C; (b)
CF3COOPfp, pyridine, CH2Cl2, 65% (2 steps); (c) Pd/C, cyclohe-
xadiene, i-Pr2NEt, t-BuOH, 85 °C, 43%; (d) HF, CH3CN, 90%.
Therefore, we decided to synthesize a bicyclic imidazole
monomer, which is based on L-valine. We favored L-va-
line because monomers derived from this amino acid had
given the highest yields in comparable cyclotrimerization
reactions.2a Furthermore, the L-configuration at the a-C-
atom guarantees that in the desired platform, the iso-pro-
pyl groups of the valine-based moiety point into a direc-
tion opposite to the hydroxyl groups.
In summary, a new class of C3-symmetric nanoscale mo-
lecular platforms has been synthesized in good yield from
trans-4-hydroxy-(S)-proline. While they still realize the
basic concept of the original scaffold, these platforms ad-
vantageously show an enhanced distance between the
functional groups, which are bound directly to the scaf-
fold and thus fixed. The synthetic results show that for a
successful cyclotrimerization it is necessary to use mono-
mers derived from amino acids different from glycine.
The revised approach is outlined in Scheme 5. Treatment
of hydrochloride 7 with Z-Val-OH in the presence of ED-
CI, 1-hydroxybenztriazole (HOBt) and N-methylmorpho-
line (NMM) gave dipeptide 19 (93%), which was
protected as its TBS ether and subsequently hydrolyzed to
acid 20. The transformation of carboxylic acid 20 into the
a-keto ester 21 was again performed via the oxidative
Synlett 2004, No. 6, 1003–1006 © Thieme Stuttgart · New York

1006
G. Haberhauer
LETTER
74.1, 122.2, 127.6, 127.7, 128.2, 136.9, 141.0, 143.7, 156.1,
162.8. HRMS (FAB+): m/z [M + H+] calcd for C17H20N3O5:
346.1403; found: 346.1384. Data for 22: 1H NMR (300
MHz, CDCl3): d = 0.10 (s, 6 H), 8.85 (d, J = 6.7 Hz, 3 H),
0.88 (s, 9 H), 0.98 (d, J = 6.7 Hz, 3 H), 2.15–2.30 (m, 1 H),
2.95 (dd, J = 4.2, 17.0 Hz, 1 H), 3.34 (dd, J = 6.6, 17.0 Hz, 1
H), 3.85 (s, 3 H), 3.86–3.94 (m, 1 H), 4.07–4.18 (m, 1 H),
4.46 (t, J = 8.7 Hz, 1 H), 4.98–5.14 (m, 3 H), 5.56 (d, J = 9.1
Hz, 1 H), 7.25–7.37 (m, 5 H). 13C NMR (75 MHz, CDCl3):
d = –5.0, –4.9, 17.9, 18.5, 19.4, 25.6, 32.8, 34.7, 51.5, 53.4,
54.0, 66.8, 75.5, 124.1, 127.9, 128.0, 128.4, 136.3, 141.8,
143.9, 156.2, 163.6. HRMS (FAB+): m/z [M + H+] calcd for
C26H40N3O5Si: 502.2737; found: 502.2736. Data for 23: 1H
NMR (300 MHz, CDCl3): d = 0.85 (d, J = 6.7 Hz, 3 H), 0.98
(d, J = 6.7 Hz, 3 H), 2.14–2.28 (m, 1 H), 3.00–3.11 (m, 1 H),
3.32 (dd, J = 5.9, 17.5 Hz, 1 H), 3.84 (s, 3 H), 4.08 (m, 2 H),
4.44 (t, J = 8.7 Hz, 1 H), 5.00–5.13 (m, 3 H), 5.76 (d, J = 9.3
Hz, 1 H), 7.25–7.37 (m, 5 H). 13C NMR (75 MHz, CDCl3):
d = 18.7, 19.4, 32.8, 34.5, 51.5, 53.6, 54.2, 66.9, 75.3, 124.1,
127.9, 128.0, 128.5, 136.3, 142.1, 144.2, 156.4, 163.5.
HRMS (FAB+): m/z [M + H+] calcd for C20H26N3O5:
388.1872; found: 388.1858.
Acknowledgment
Financial support from the Deutsche Forschungsgemeinschaft is
gratefully acknowledged. The author thanks Dr. Andreea Schuster
for helpful discussions.
References
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(11) Data for 25: Mp 136 °C. 1H NMR (500 MHz, CDCl3): d =
0.06 (s, 9 H), 0.07 (s, 9 H), 0.84 (s, 27 H), 1.02 (d, J = 6.7
Hz, 9 H), 1.03 (d, J = 6.7 Hz, 9 H), 2.06–2.15 (m, 3 H), 2.94
(dd, J = 3.7, 16.9 Hz, 3 H), 3.35 (dd, J = 6.4, 16.9 Hz, 3 H),
3.74 (dd, J = 3.7, 11.2 Hz, 3 H), 4.08 (dd, J = 5.8, 11.2 Hz, 3
H), 4.93 (dd, J = 6.1, 8.7 Hz, 3 H), 5.02 (m, 3 H), 8.32 (d,
J = 8.7 Hz, 3 H). 13C NMR (125 MHz, CDCl3): d = –5.0,
–4.8, 17.9, 18.4, 19.3, 25.7, 34.1, 35.0, 51.3, 53.3, 76.1,
126.5, 138.2, 142.6, 162.8. HRMS (FAB+): m/z [M + H+]
calcd for C51H88N9O6Si3: 1006.6165; found: 1006.6116.
(12) Data for 26: Mp >250 °C. 1H NMR (500 MHz, CDCl3): d =
0.92 (d, J = 6.7 Hz, 9 H), 1.04 (d, J = 6.7 Hz, 9 H), 1.92–
2.01 (m, 3 H), 3.22–3.30 (m, 6 H), 3.78 (dd, J = 4.4, 11.5 Hz,
3 H), 4.41 (d, J = 11.5 Hz, 3 H), 4.64 (dd, J = 8.1, 9.6 Hz, 3
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(6) Preparation of Compounds 12, 13, 22 and 23. To a
solution of the amidoketone (11 or 21; 8.40 mmol) in
xylenes (200 mL) were added TFA (3.1 mL, 40.0 mmol) and
a solution of NH3 in MeOH (7 M, 5.7 mL, 40.0 mmol) at r.t.
The solution was stirred at 150 °C with azeotropic removal
of water for 6 h and then cooled to r.t. The mixture was
concentrated and the residue was dissolved in EtOAc, then
washed with sat. NaHCO3 solution and brine. The organic
layer was dried over MgSO4 and concentrated in vacuo.
Purification was accomplished by flash chromatography on
silica gel (CH2Cl2–EtOAc–MeOH, 75:25:5). Data for 12: 1H
NMR (300 MHz, CDCl3): d = 0.09 (s, 6 H), 0.87 (s, 9 H),
2.94 (dd, J = 4.2, 17.0 Hz, 1 H), 3.31 (dd, J = 6.6, 17.0 Hz, 1
H), 3.77–3.89 (m, 4 H), 4.20 (dd, J = 6.2, 11.6 Hz, 1 H), 4.37
(d, J = 6.1 Hz, 2 H), 4.97–5.12 (m, 3 H), 5.57 (m, 1 H), 7.24–
7.36 (m, 5 H). 13C NMR (75 MHz, CDCl3): d = –4.99, –4.87,
17.9, 25.6, 34.7, 37.6, 51.4, 53.6, 67.0, 75.7, 123.9, 128.0,
128.1, 128.5, 136.1, 140.7, 142.8, 156.3, 163.4. HRMS
(FAB+): m/z [M + H+] calcd for C23H34N3O5Si: 460.2268;
found: 460.2260. Data for 13: Mp 148–150 °C. 1H NMR
(300 MHz, DMSO-d6): d = 2.77 (dd, J = 2.3, 17.1 Hz, 1 H),
3.18 (dd, J = 6.1, 17.1 Hz, 1 H), 3.70 (s, 3 H), 3.80 (dd, J =
2.1, 11.8 Hz, 1 H), 4.09 (dd, J = 5.3, 11.8 Hz, 1 H), 4.21 (d,
J = 5.9 Hz, 2 H), 4.88 (s, 1 H), 5.05 (s, 2 H), 5.57 (d, J = 4.3
H), 5.09 (m, 3 H), 5.38 (s, 3 H), 8.19 (d, J = 9.8 Hz, 3 H). 13
C
NMR (125 MHz, CDCl3): d = 18.9, 19.3, 34.1, 35.6, 50.8,
53.3, 75.6, 125.5, 139.2, 142.8, 163.2. HRMS (FAB+): m/z
[M + H+] calcd for C33H46N9O6: 664.3571; found: 664.3578.
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Hz, 1 H), 7.25–7.40 (m, 5 H), 7.88 (t, J = 5.9 Hz, 1 H). 13
C
NMR (75 MHz, DMSO-d6): d = 34.0, 37.2, 50.6, 53.4, 65.5,
Synlett 2004, No. 6, 1003–1006 © Thieme Stuttgart · New York