Design and synthesis of novel tubular and cage structures based on thiazole-containing macrolactams related to marine cyclopeptides

Article abstract of DOI:10.1039/b101417j

Tubular and cage structures, i.e. 16 and 18, have been synthesised from modified cyclic peptides following selective cyclotrimerisations of L-ornithine and L-glutamic acid thiazole amino acids under high dilution conditions.

Full text of DOI:10.1039/b101417j

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Design and synthesis of novel tubular and cage structures based on
thiazole-containing macrolactams related to marine cyclopeptides
Gerald Pattenden* and Toby Thompson
School of Chemistry, The University of Nottingham, University Park, Nottingham, UK NG7 2RD.
E-mail: gp@nottingham.ac.uk; Fax: +44 (0)115 951 3535; Tel: +44 (0)115 951 3530
Received (in Cambridge, UK) 13th February 2001, Accepted 8th March 2001
First published as an Advance Article on the web 29th March 2001
Tubular and cage structures, i.e. 16 and 18, have been
amino group of -ornithine 5 as its Z-carbamate followed by
L
synthesised from modified cyclic peptides following selective
Boc protection of the C-2 amino function first led to the
carboxylic acid 6. Amidation of 6 followed by treatment with
Lawesson’s reagent [2,4-bis(4-methoxyphenyl)-1,3,2,4-dithia-
phosphetane-2,4-disulfate] next produced the thioamide 7. A
Hantzsch thiazole ring forming reaction between 7 and ethyl
bromopyruvate9 then gave the substituted thiazole 8 which, on
saponification of the ethyl ester and removal of the Boc
cyclotrimerisations of
L
-ornithine and -glutamic acid thia-
L
zole amino acids under high dilution conditions.
Marine organisms, especially sea-squirts, have delivered an
astonishing variety of novel cyclopeptide alkaloids which
accommodate thiazole and oxazole rings derived from unusual
amino acids, e.g. trunkamide 1,1 ascidiacyclamide 2.2 The
protection, gave the
with !95% ee (Scheme 1).10
The corresponding -glutamic acid based thiazole 14 was
prepared from -glutamic acid 5-methyl ester 10 following Boc
L
-ornithine based thiazole amino acid 9
L
L
protection and coupling with DL-serine benzyl ester benzene-
sulfonate leading to the dipeptide 11. After conversion of 11
into the thioamide 12, cyclodehydration in the presence of
Burgess’ reagent [methyl(carboxysulfamoyl)triethylammon-
ium hydroxide, inner salt]11 next produced the corresponding
thiazoline which was immediately converted into the thiazole
13 upon treatment with BrCCl3–DBU at 0 °C.12 Debenzylation
of 13 under catalytic transfer hydrogenation conditions13 and
Boc deprotection finally gave the free thiazole amino acid 14
with !95% ee (Scheme 2).
When the -ornithine amino acid thiazole 9 was treated with
L
pentafluorophenyl diphenylphosphinate (FDPP) in the presence
of i-Pr2NEt in DMF under high dilution, selective cyclooligo-
merisation took place to give the cyclic trimer 15a in 11% yield.
In a similar manner, cyclooligomerisation of the -glutamic acid
L
based thiazole 14 under the same conditions led cleanly to the
C3-symmetric cyclic trimer 15b in 41% yield (Scheme 3). After
removal of the amine protection in 15a and saponification of the
methyl ester groups in 15b, activation of the tris-carboxylic acid
4b with FDPP and i-Pr2NEt followed by treatment with the tris-
amine 4a under high dilution in DMF led to the formation of the
tubular structure 16 as a powder in 30% yield (Scheme 4).†
Mass spectometry indicated the presence of a monomeric
product. This was reinforced by the NMR spectroscopic data for
sequence of alternating heterocyclic rings and amino acid units
which characterise these structures has led to speculation that
the metabolites may have a role to play in vivo as metal transport
agents, and/or that metals may act as templates in their
biological assembly from constituent amino acids/heterocyclic
rings.3 In previous studies we have examined the self assembly
and metal-templated cyclooligomerisations of amino acid based
thiazoles and oxazoles, culminating in the syntheses of novel
cyclotetramers and cyclotrimers,4 and also in the total synthesis
of the natural cyclopeptide dendroamide A 3.5 In a continuation
of this work we have now investigated the syntheses of the
cyclopeptide scaffolds 4a and 4b, containing additional amino
and carboxylic acid functionality respectively, with a view to
examining their applications in the synthesis of ‘cage-’ and
‘tube-’ like structures for possible use as membrane ion channel
mimics and for the development of macromolecular devices and
scaffolds for protein mimics. Thus, in this Communication we
describe concise syntheses of 4a and 4b6 and their conversion
into the tubular polyamide 16 and into the cage structure
18.7,8
Scheme 1 Reagents and conditions: i, CuCO3, H2O, 30 min, then ZCl,
NaOH, 1 h, then EDTA, 2 M HCl, 2 h, 88%; ii, (Boc)2O, NaOH, THF–H2O,
12 h, 71%; iii, isobutyl chloroformate, NMM (N-methylmorpholine), THF,
NH3 (g), 25 °C, 1 h, 99%; iv, Lawesson’s reagent, THF, 24 h, 99%; v, ethyl
bromopyruvate, KHCO3, DME, 215 °C, then TFAA, collidine, DME,
215 °C, 79%; vi, NaOH, THF–H2O, 18 h, 97%; vii, 4 M HCl, dioxane,
12 h, 98%.
Each of the substituted thiazoles 4a and 4b was prepared by
routes developed in our laboratories and based on well-
established literature precedent. Thus, protection of the C-5
DOI: 10.1039/b101417j
Chem. Commun., 2001, 717–718
This journal is © The Royal Society of Chemistry 2001
717

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16 which were consistent with those expected for a C3-
symmetric polymacrocycle. Most notably, two singlet peaks at
1
d 8.13 and d 8.11 were observed in the H NMR spectrum
corresponding to the two sets of thiazole protons. Additionally,
NMR signals were observed relating to the amide N–H (d 8.47
and d 8.43) and the a-carbon protons (d 5.68 and d 5.58) within
the macrocyclic rings.
A corresponding condensation between the -glutamic acid
L
trimer 4b and tris(aminoethyl)amine 17 in the presence of
FDPP–Pr2NEt led to isolation of the cage structure 18, also as a
solid, in 40% yield.‡ Again, mass spectrometry established that
formation of the desired monomer had occurred. Additionally,
1
the H NMR spectrum confirmed the structure of 18 as C3-
symmetric with peaks at d 8.89 and d 8.11 relating to the ring
N–H and thiazole protons with a signal at d 6.26 corresponding
to the three side-chain amide protons. The applications of the
C3-symmetric cyclic trimers 4a and 4b and their relatives in
asymmetric and library synthesis, and also in molecular
recognition phenomena, will be described in future publica-
tions.
We thank Dr Luis Castro for his interest in this study and
Merck Sharp and Dohme for financial assistance. We also thank
Dr Kate Jolliffe for preliminary work with the synthesis of the
Scheme 2 Reagents and conditions: i, (Boc)2O, Et3N, THF–H2O, 24 h,
90%; ii, HOBt, EDCI·HCl, NMM, CH2Cl2, 0 °C, 30 min, then DL-serine
benzyl ester benzenesulfonate, NMM, 0 °C ? RT, 48 h, 94%; iii,
TBDMSCl, Et3N, DMAP, CH2Cl2, 14 h, 86%; iv, Lawesson’s reagent,
C6H6, 80 °C, 14 h, 94%; v, TBAF, THF, 0 °C, 3 h, 91%; vi, Burgess’
reagent, THF, 65 °C, 30 min; vii, CBrCl3, DBU, CH2Cl2, 0 °C, 4 h, 63%
over two steps; viii, NH4HCO2, 10% Pd/C, EtOH, 78 °C, 24 h, 70%; ix, 2 M
HCl, dioxane, 24 h, 60%.
L
-ornithine thiazole.
Notes and references
294
† 16: mp 236–237 °C (decomp.) (from CHCl3–MeOH–Et2O); [a]D
238.4° [c = 0.5, (CHCl3–MeOH 3:1)]; IR (cm21): 3401, 3007, 2930, 1668,
1541; dH (500 MHz, CDCl3) 8.47 (3H, m), 8.43 (3H, dd, J = 8.1 and 3.0
Hz), 8.13 (3H, s), 8.11 (3H, s), 5.68 (3H, m), 5.58 (3H, m), 3.67–3.01 (6H,
m), 2.68–2.32 (9H, m), 2.31–2.12 (9H, m), 2.02–1.91 (3H, m), 1.57–1.51
(3H, m); dC [125 MHz, (CDCl3)] 173.2 (s), 169.7 (s), 159.7 (s), 159.6 (s),
148.8 (s), 148.7 (s), 124.4 (d), 124.3 (d), 51.4 (d), 50.4 (d), 39.7 (t), 35.9 (t),
34.3 (t), 32.0 (t), 25.9 (t); HRMS (ES) m/z 1196.2198; calcd. for
C
48H51S6N15O9Na ([M + Na]+): 1196.2216.
‡ 18: mp 281–282 °C (decomp.) (from CHCl3–MeOH–Et2O); [a]D
Scheme 3 Reagents and conditions: i, FDPP, i-Pr2NEt, DMF, (15a 3 d,
11%; 15b 9 d, 41%); ii, 33% HBr–AcOH, 6 h, 77%; iii, NaOH, THF–H2O,
12 h, 98%.
294
226.4° [c = 0.5, (CHCl3–MeOH 3:1)]; IR (cm21): 3399, 3007, 1672, 1543;
dH (360 MHz, CDCl3) 8.89 (3H, d, J = 9.5 Hz), 8.11 (3H, s), 6.26 (3H, br
s), 5.94 (3H, d, J = 9.1 Hz), 3.40 (3H, m), 3.12 (3H, m), 2.67–2.41 (12H,
m), 2.32–2.24 (3H, m), 2.18–2.08 (3H, m); dC [90.5 MHz, (CDCl3–CD3OD
9+1)] 173.0 (s), 167.8 (s), 159.3 (s), 148.8 (s), 123.8 (d), 53.0 (t), 48.5 (d),
37.0 (t), 31.8 (t), 28.9 (t); HRMS (ES) m/z 751.1917; calcd. for
C30S3N10O6H36Na ([M + Na]+): 751.1879.
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Scheme 4 Reagents and conditions: i, FDPP, i-Pr2NEt, 4a, DMF, 10 d,
30%; ii, FDPP, i-Pr2NEt, 17, DMF, 3 d, 40%.
13 T. Bieg and W. Szeja, Synthesis, 1985, 76.
718
Chem. Commun., 2001, 717–718