The controlled assembly of modified cyclopeptide cages via scaffolded cyclooligomerisations

Article abstract of DOI:10.1016/S0040-4039(02)00284-8

Novel thiazole- and oxazole-containing modified cyclopeptide C₃-symmetric cages have been synthesised utilising a trimeric linker to control the assembly and cyclooligomerisation of heterocyclic amino acids.

Full text of DOI:10.1016/S0040-4039(02)00284-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2459–2461
The controlled assembly of modified cyclopeptide cages via
scaffolded cyclooligomerisations
Gerald Pattenden* and Toby Thompson
School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, UK
Received 2 January 2002; revised 30 January 2002; accepted 6 February 2002
Abstract—Novel thiazole- and oxazole-containing modified cyclopeptide C3-symmetric cages have been synthesised utilising a
trimeric linker to control the assembly and cyclooligomerisation of heterocyclic amino acids. © 2002 Elsevier Science Ltd. All
rights reserved.
A wide variety of unusual and biologically important
thiazole- and oxazole-containing cyclopeptide alkaloids
have been isolated from the marine environment in
recent years; typical examples include ascidiacyclamide
1 and raocyclamide A 2.1,2 The presence of alternating
amino acid residues and heterocyclic rings in these
secondary metabolites, with heteroatom lone pairs
directed towards the macrocyclic cavity, has led to
speculation that they may function as metal complexa-
tion and transport agents in vivo.3 It has also been
postulated that certain relatives of these marine natural
products, which present multiple functional groups in
one direction e.g. 3, could have applications in the field
of molecular recognition.4 In addition to total synthe-
sis, self-assembly and metal-templated cyclooligomeri-
sation studies of thiazole- and oxazole-containing
amino acids, we have recently reported the design and
synthesis of some cyclopeptide scaffolds, i.e. 3a and 3b,
containing additional functionality on the amino acid
side-chains, and their subsequent conversion into novel
tubular polyamides and cage structures, e.g. 4 (Fig. 1).5
reacted as its amine salt with the known tris-carboxylic
acid in the presence of pentafluorophenyl
diphenylphosphinate (FDPP) and diisopropylethyl-
amine (i-Pr2NEt) in DMF, to produce the tris-amide 8
in 87% yield.5,6 Saponification of the three ethyl esters
6
In continuation of these studies, we now describe a
concise and flexible approach to C3-symmetric molecu-
lar cages viz. 5, using the tris-carboxylic acid linker 6 to
control the assembly and cyclooligomerisation of hete-
rocyclic amino acids (Scheme 1).
Thus, the
L
-ornithine-derived thiazole 7, which was
prepared via an established synthetic route, was first
Keywords: cyclopeptide; cyclooligomerisation; cage; thiazole; oxazole;
amino acid.
* Corresponding author. Tel.: +44 (0)115 9513530; fax: +44 (0)115
9513564; e-mail: gp@nottingham.ac.uk
Figure 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00284-8

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G. Pattenden, T. Thompson / Tetrahedron Letters 43 (2002) 2459–2461
in 8 and removal of the Z-carbamates next led to the
fully deprotected trimeric thiazole amino acid 9. When
a solution of 9 in DMF at high dilution (2.5 mM) was
reacted with FDPP and DBU over 7 days, a controlled
cyclooligomerisation took place, resulting in the forma-
tion of the isomeric cage cyclopeptides 10 and 11 (ratio
2:3; in a combined yield of 19%) which were separated
by preparative TLC (Scheme 2). The spectroscopic data
for each of the cage compounds were characteristic for
C3-symmetric structures and their 1H NMR spectra
showed typical absorptions at l 8.39 /l 8.07 and l
8.41/l 8.11 (10 and 11) relating to their two sets of ring
NH and thiazole protons.7,8
We next extended our study to the synthesis of oxazole-
containing cyclopeptide cages and examined the effect
of a shortened amino acid side-chain on the composi-
tion of the cyclooligomerisation products. Thus, the
L
-serine-derived oxazole 14 was first synthesised from
Boc- -serine 12 involving (i) protection of the alcohol
12 as the TBDMS ether; (ii) coupling with -serine
L
L
benzyl ester benzenesulfonate to yield dipeptide 13; (iii)
conversion of the b-hydroxyamide 13 into the corre-
sponding oxazole 14 following treatment at −78°C with
diethylamino sulfurtrifluoride (DAST) and oxidation of
the resulting oxazoline with BrCCl3–DBU; this
sequence produced the oxazole with ]95% e.e.9 After
deprotection of the silyl ether in 14, the resulting alco-
hol was coupled with the tris-carboxylic acid 6 leading
to tris-ester 15 in 88% yield. Hydrogenolysis of the
three benzyl esters in 15 and subsequent deprotection of
the amino groups then afforded the cyclooligomerisa-
tion precursor 16.
Scheme 2. Reagents and conditions: (a) FDPP, i-Pr2NEt,
DMF, 24 h, 87%; (b) NaOH, THF/H2O, 24 h; (c) 33%
HBr/AcOH, 18 h, 81% (two steps); (d) FDPP, DBU, DMF, 7
days, 19% (ratio 2:3).
We were pleased to find that the scaffolded
cyclooligomerisation of the tris-amino acid 16 in the
presence of FDPP and 4-DMAP, in DMF at high
dilution, led to the formation of two trimeric cage
cyclopeptides, i.e. 17 and 18 (ratio 9:5), in a combined
yield of 19% (Scheme 3). Mass spectrometry and NMR
spectroscopic studies confirmed that the two cage
cyclopeptides were monomeric and variable tempera-
1
ture H NMR studies in DMSO-d6 demonstrated the
clear presence of both ‘inside’ and ‘outside’ tertiary
Scheme 3. Reagents and conditions: (a) TBDMSCl, imidazole,
CH2Cl2, 12 h, 69%; (b) L-serine benzyl ester benzenesulfonate,
EDCI·HCl, NMM, HOBt, CH2Cl2, 0°C, 12 h, 91%; (c)
DAST, CH2Cl2, −78°C, 2 h; (d) BrCCl3, DBU, CH2Cl2, 0°C,
8 h, 47% (two steps); (e) TBAF, THF, 0°C, 1 h, 84%; (f) 6,
EDCI·HCl, 4-DMAP, NMM, CH2Cl2, 0°C, 12 h, 88%; (g)
H2, 10% Pd/C, MeOH, 48 h, 94%; (h) 4 M HCl/dioxane, 3 h,
73%; (i) FDPP, 4-DMAP, DMF, 5 days, 19% (ratio 9:5).
Scheme 1.

G. Pattenden, T. Thompson / Tetrahedron Letters 43 (2002) 2459–2461
2461
hydrogen cyclopeptide diastereoisomers.10,11 No coales-
cence of signals was observed in the H NMR spectrum
CH2), 3.57 (m, 3H, 3×CH2CHaHbNH), 3.01 (m, 3H,
3×CH2CHaHbNH), 2.47 (m, 3H, HC(CHaHbCONH)3),
2.38 (m, 1H, HC(CHaHb)3), 2.29 (m, 3H, HC(CHaHb)3),
2.11 (m, 3H, 3×NHCHCHaHb), 1.97 (m, 3H, 3×
NHCHCHaHb), 1.69 (m, 6H, 3×CH2); lC (90 MHz,
CDCl3) 172.4 (s), 169.8 (s), 159. 6 (s), 149.2 (s), 123.7 (d),
49.9 (d), 40.7 (t), 38.8 (t), 35.9 (d), 35.3 (t), 24.8 (t);
HRMS (ES) m/z 728.2101; calcd for C31S3N9O6H38 ([M+
H]+): 728.2107.
1
upon heating the mixture to 100°C and the two sets of
amide protons (l 8.42 and l 8.36) were clearly visible at
elevated temperatures. The presence of diastereoisomers
was further reinforced in the 13C NMR spectrum which
showed differing sets of absorptions for the two
cyclopeptides. The spectroscopic data for the cage
cyclopeptides synthesised in this study, by themselves,
did not allow an unambiguous distinction between the
two sets of ‘inside’ and ‘outside’ diastereoisomers, i.e.
10 and 11 and also 17 and 18.12 Further studies are
underway to resolve the stereochemical assignments
and also to investigate the ion-binding and transport
properties of these novel cyclopeptides.
9. Philips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams,
D. R. Org. Lett. 2000, 2, 1165.
10. Data for 17/18: mp 290–291°C (decomp.) (from CHCl3);
[h]2D93 184.4 [c=1.0, CHCl3]; IR (cm−1): 3388, 1742, 1688,
1600; lH (360 MHz, CDCl3) 8.59 (6H, m, 3×NHCH,
3×NHCH), 8.33 (s, 3H, 3×NCꢀCHO), 8.32 (s, 3H, 3×
NCꢀCHO), 5.49–5.42 (m, 9H, 3×NHCH, 3×CHCHaHb,
3×NHCH), 5.24 (dd, 3H, J=11.5, 1.5 Hz, 3×CHCHaHb),
4.01 (dd, 3H, J=11.5, 1.9 Hz, 3×CHCHaHb), 3.93 (dd,
3H, J=11.8, 2.4 Hz, 3×CHCHaHb), 2.43–1.86 (m, 14H,
HC(CH2)3, HC(CH2)3, HC(CH2)3, HC(CH2)3); lC (90
MHz, CDCl3) 171.0 (s), 170.6 (s), 160.1 (s), 159.8 (s),
158.9 (s), 158.8 (s), 142.4 (d), 142.1 (d), 135.1 (s), 135.1
(s), 64.0 (t), 62.2 (t), 48.8 (d), 48.6 (d), 38.2 (t), 37.2 (t),
34.1 (d), 28.4 (d); HRMS (ES) m/z 621.1239; calcd for
C25N6O12H22Na ([M+Na]+): 621.1193.
Acknowledgements
We thank Dr. Luis Castro for his support during this
study and Merck, Sharp and Dohme for financial
assistance.
11. Variable temperature 1H NMR data for 17/18: lH (360
MHz, DMSO-d6, 298 K) 9.00 (s, 3H, 3×NCꢀCHO), 8.97
(s, 3H, 3×NCꢀCHO), 8.38 (d, 6H, J=7.5 Hz, 3×NHCH,
3×NHCH), 5.66 (d, 3H, J=7.4 H, 3×NHCH), 5.60 (d,
3H, J=7.2 Hz, 3×NHCH), 5.17 (d, 3H, J=11.5 Hz,
3×CHCHaHb), 5.00 (d, 3H, J=10.5 Hz, 3×CHCHaHb),
4.09 (d, 3H, J=10.0 Hz, 3×CHCHaHb), 4.01 (d, 3H,
J=11.5 Hz, 3×CHCHaHb), 3.30 (d, 6H, J=8.6 Hz,
References
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HC(CH2CO2)3),
2.70
(d,
3H,
J=13.3
Hz,
HC(CHaHbCO2)3), 2.46–2.10 (m, 2H, HC(CH2CO2)3,
HC(CHaHbCO2)3), 2.00 (m, 3H, HC(CHaHbCO2)3); lH
(360 MHz, DMSO-d6, 373 K) 8.71 (s, 3H, 3×NCꢀCHO),
8.67 (s, 3H, 3×NCꢀCHO), 8.42 (m, 3H, 3×NHCH), 8.36
(m, 3H, 3×NHCH), 5.56 (m, 6H, 3×NHCH, 3×NHCH),
5.05 (d, 3H, J=11.4 Hz, 3×CHCHaHb), 4.97 (d, 3H,
J=11.8 Hz, 3×CHCHaHb), 4.17 (d, 3H, J=11.2 Hz,
3×CHCHaHb), 4.12 (d, 3H, J=11.4 Hz, 3×CHCHaHb),
2.68 (m, 9H, HC(CH2CO2)3, HC(CHaHb)3), 2.45 (m, 2H,
HC(CH2CO2)3, HC(CHaHbCO2)3), 2.06 (dd, 3H, J=
14.6, 11.0 Hz, HC(CHaHbCO2)3).
4. Mink, D.; Mecozzi, S.; Rebek, J., Jr. Tetrahedron Lett.
1998, 39, 5709.
5. Pattenden, G.; Thompson, T. J. Chem. Soc., Chem. Com-
mun. 2001, 717.
6. Nasielski, J.; Chao, S. H.; Nasielski-Hinkens, R. Bull.
Soc. Chim. Belg. 1989, 98, 375.
7. Data for 10: mp 273–274°C (decomp.) (from CHCl3–
Et2O); [h]3D01 4.80 (c=0.5, CHCl3); IR (cm−1): 3435, 3400,
2960, 1672, 1549; lH (360 MHz, CDCl3) 8.39 (d, 3H,
J=9.6 Hz, 3×NHCH), 8.07 (s, 3H, 3×NCꢀCHS), 6.69, (t,
3H, J=5.9 Hz, 3×CH2NH), 5.59 (m, 3H, 3×
NHCHCH2), 3.42 (m, 3H, 3×CH2CHaHbNH), 3.19 (m,
3H, 3×CH2CHaHbNH), 2.61 (m, 1H, HC(CH2CONH)3),
2.39 (m, 6H, HC(CH2CONH)3), 2.08 (m, 3H, 3×
NHCHCHaHb), 1.92–1.71 (9H, m, 3×NHCHCHaHb, 3×
CH2); lC (90 MHz, CDCl3) 171.8 (s), 169.9 (s), 159.5 (s),
149.2 (s), 123.4 (d), 49.2 (d), 39.3 (t), 38.4 (t), 36.4 (t),
31.5 (d), 26.1(t); HRMS (ES) m/z 728.2108; calcd for
C31S3N9O6H38 ([M+H]+): 728.2107.
12. In an attempt to resolve these issues, we carried out
energy minimisation and Monte Carlo conformational
searches on the diastereoisomers 10/11 and 17/18 using
the MacroModel 5.5 implementation of the AMBER*
force field. These data could be interpreted, based on the
assumption that the observed ratios of diastereomeric
products reflected the relative ease of the final cyclisation
steps, to indicate that structures 11 and 17 would be the
major products resulting from the cyclooligomerisations
of 9 and 16, respectively, i.e. the minimum energy con-
formers were calculated to have the following values: 10:
E=−67.0 kJ mol−1, 11: E=−77.4 kJ mol−1, 17: E=57.82
8. Data for 11: mp 252–253°C (decomp.) (from CHCl3–
Et2O); [h]3D00 −44.0 [c=0.5, CHCl3]; IR (cm−1): 3402,
2927, 2855, 1729, 1666, 1549; lH (360 MHz, CDCl3) 8.49
(d, 3H, J=9.1 Hz, 3×NHCH), 8.11 (s, 3H, 3×NCꢀCHS),
6.84 (br m, 3H, 3×CH2NH), 5.70 (m, 3H, 3×NHCH-
kJ mol−1, 18: E=−122.62 kJ mol−1
.