Concise synthesis of stereodefined, thiazole - Containing cyclic hexa- and octapeptide relatives of the Lissoclinums, via cyclooligomerisation reactions

Article abstract of DOI:10.1016/S0040-4020(03)00821-4

The synthesis of a range of thiazole containing cyclic peptides using cyclooligomerisation reactions of amino acid substituted thiazole monomers and by macrolactamisation procedures is reported. The synthetic approaches lead to high yields of novel 18- and 24-membered ring analogues of the naturally occurring Lissoclinum families of cyclic peptides found in marine organisms and algae.

Full text of DOI:10.1016/S0040-4020(03)00821-4

Tetrahedron 59 (2003) 6979–6990
Concise synthesis of stereodefined, thiazole—containing cyclic
hexa- and octapeptide relatives of the Lissoclinums, via
cyclooligomerisation reactions
´
´
Anna Bertram, Alexander J. Blake, Felix Gonzalez-Lopez de Turiso, Jeffery S. Hannam,
*
Katrina A. Jolliffe, Gerald Pattenden and Michael Skae
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
Received 11 March 2003; revised 2 May 2003; accepted 12 May 2003
Abstract—The synthesis of a range of thiazole containing cyclic peptides using cyclooligomerisation reactions of amino acid substituted
thiazole monomers and by macrolactamisation procedures is reported. The synthetic approaches lead to high yields of novel 18- and 24-
membered ring analogues of the naturally occurring Lissoclinum families of cyclic peptides found in marine organisms and algae.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
A large number of cyclic peptides containing ‘unnatural’
D-amino acids, together with modified amino acids in the
form of azole heterocycles, have been isolated from
ascidians, cyanobacteria and other sources in recent years.
Many of these secondary metabolites possess significant
biological activity, including cytotoxic, immunoregulatory
and antibiotic activities. However, relatively small
quantities of cyclic peptides are available from natural
sources and, in general, little is known about the biological
mode of action of these compounds.
The Lissoclinum cyclic peptides e.g. dendroamide A (1),1
lissoclinamide 4 (2)2 and ascidiacyclamide 33 represent a
group of cyclic peptides, characterised by the presence of
oxazoline/oxazole/thiazoline/thiazole heterocycles alternat-
ing with proteinogenic amino acid residues.4
The size and conformations of these macrocycles, and the
nature of the functional groups they possess, have led to
speculation that they have potential for metal ion chelation
and transport in vivo, and that these features may contribute
to their biological activity.5 A number of recent studies have
indicated that these natural products and their analogues do,
indeed, form complexes with a variety of metal ions.6 With
the aim of further investigating the capacity of Lissoclinum-
type cyclic peptides to bind metal ions, we have developed a
concise, high-yielding cyclooligomerisation procedure
which leads to novel thiazole-based analogues of natural
cyclic peptides from appropriate amino acid substituted
thiazole precursors. These studies are now described in
detail.7
Keywords: Lissoclinum; cyclooligomerisation; thiazole.
*
Corresponding author. Tel.: þ44-115-951-3530; fax: þ44-115-951-3564;
e-mail: gp@nottingham.ac.uk
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00821-4

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A. Bertram et al. / Tetrahedron 59 (2003) 6979–6990
Figure 1. Cyclooligomerisation and macrocyclisation approaches to thiazole-containing cyclic peptides.
1
2. Results and discussion
The H NMR spectra of the cyclic trimers, 7a and 7b, and
the corresponding cyclic tetramers 8a and 8b, in CDCl3 at
228C were similar, showing only a single set of signals for
each type of proton, thereby indicating that the compounds
are C3 and C4 symmetric, respectively. In both cases the
resonance signals attributable to the amide protons of the
cyclic trimers (7a and 7b) lie downfield (by 0.6–0.7 ppm)
from those of the corresponding cyclic tetramers (8a and 8b,
respectively), indicating that intramolecular hydrogen bond
networks of the tetramers are not as strong as those of the
corresponding trimers. The temperature dependence of the
chemical shifts of the peptide NH signals of the D-valine
derived trimer 7a (0.02 ppb per degree) and tetramer 8a
(2.4 ppb per degree) in CDCl3 also indicate that intra-
molecular H-bonding is stronger in the trimer than the
tetramer.14 The vicinal 3JNHCH values of 9.3 Hz and 9.1 Hz
The azole heterocycles present in the Lissoclinum peptides
are derived from cyclodehydrations of cysteine, serine and
threonine residues linked to adjacent amino acids in a
peptide sequence.8 The presence of these modified peptide
bonds has been found to induce ‘turn’ structures that
facilitate ring closure of the linear peptide chains.9 We
therefore, became interested in investigating the cyclo-
oligomerisation reactions of thiazole amino acid deriva-
tives, and the macrolactamisations of linear oligomers of
these modified dipeptides (Fig. 1).
The syntheses of thiazole based amino acids have been
reported previously and we prepared the known thiazole
derivatives 4a–c using a modified Holpfazel–Hantzsch
procedure.10 Analysis of the Mosher amide derivatives11 of
these compounds indicated that the valine and alanine
derived thiazoles, 4a and 4b respectively, were both
optically pure (ee$95%). However, despite further
modification of the synthetic procedure, in our hands the
phenylalanine derived thiazole 4c could not be obtained in
.70% ee using this method of synthesis.
2.1. One-pot cyclooligomerisation reactions
Saponification of each of the thiazole esters 4a–c gave the
corresponding carboxylic acids 5a–c which were immedi-
ately subjected to treatment with a 4 M solution of HCl in
dioxane, leading to the heterocyclic amino acids 6, as their
hydrochloride salts, in essentially quantitative yields.
Treatment of the amino acids 6 with the peptide coupling
reagent, pentafluorophenyl diphenylphosphinate (FDPP),12
resulted in smooth cyclooligomerisation and the formation
of mixtures of cyclic peptide products in good overall yield
(Scheme 1).7
Scheme 1. Reagents and conditions: (i) NaOH (10 mol equiv.), THF/H2O,
9:1, rt, 18 h; (ii) 4 M HCl in dioxane, rt, 6 h; (iii) FDPP (1.5 mol equiv.),
i-Pr2NEt (3 mol equiv.), CH3CN, rt, 18 h.
Thus, cyclooligomerisation of the homochiral thiazoles 6a
and 6b led to the cyclic trimers 7a and 7b and the cyclic
tetramers 8a and 8b, respectively as the major products,
albeit in differing ratios depending upon the amino acid
derivative.13 In both cases, the reactions could be carried out
on a gram scale and the enantiomerically pure cyclic trimers
and tetramers could be separated by routine column
chromatography on silica gel (Table 1).
Table 1. Cyclooligomerisation reactions of thiazole amino acids 6
Amino acid
Yield of cyclic productsa (%)
Trimer to tetramer ratiob
6a
6b
6c
rac-6a
91
55
63
75
5:2
9:2
1:3c
1:1d
Trace amounts of higher oligomers (cyclic pentamers,
hexamers, heptamers, octamers and nonamers) were
detected by FAB mass spectrometry from 6a and 6b, but
these compounds were not isolated, separated and/or
characterised.
a
Yields of cyclised products prior to separation.
Determined by HPLC.
Ratio of 9c:8c.
b
c
d
Diastereomeric mixtures of trimers and tetramers.

A. Bertram et al. / Tetrahedron 59 (2003) 6979–6990
6981
dihedral angles of the three amide linkages in 7a were found
to lie between 159 and 1678, which is consistent with the
1
values determined by H NMR spectroscopy. This corre-
lation suggests that the cyclic tetramer 8a adopts a similar
conformation in which the thiazole units form the corners of
a square with all side chains on the same face of the
molecule.16
Comparing the cyclooligomerisation reactions of the
thiazoles 6a and 6b, it is clear that the ratio of cyclic trimer
1
to cyclic tetramer (as measured by H NMR and HPLC)
decreases as the steric bulk of the side chains increases. This
may be attributed to the steric congestion imposed upon the
cyclic trimers 7a and 7b, in which all side chains adopt
pseudoaxial conformations. As the size of the side chains
increases, unfavourable transannular interactions in the
cyclic trimers will increase and we postulate that this
situation must also be reflected in the conformations of the
linear precursors immediately prior to cyclisation. As such,
linear tris-thiazoles with bulkier side chain substituents
might be expected to adopt conformations such that the rate
of addition of a monomer to the linear tris-thiazole would be
comparable to, or faster than, that of cyclisation, leading to
the formation (and subsequent cyclisation) of higher
oligomers.
Figure 2. ORTEP plot of compound 7a derived from X-ray crystal-
lographic data.
for 7a and 8a, respectively correspond to dihedral angles of
1508,u,1808, suggesting that the conformations of both
macrocycles are similar.15
X-ray quality crystals of 7a were obtained by slow diffusion
of diethyl ether into a dichloromethane solution of the cyclic
peptide. The X-ray structure indicates that the 18 membered
macrocycle has a nearly planar structure in which all of the
amide NH and thiazole nitrogen atoms are oriented towards
the centre of the macrocycle, forming a network of
bifurcated hydrogen bonds which rigidifies the molecule
(Fig. 2). As a result of this rigidification, all of the isopropyl
side chains lie on the same face of the molecule and are
forced to adopt pseudoaxial orientations. The NHaCH
Interestingly, none of the expected cyclic trimer 7c was
obtained upon treatment of the enantiomerically enriched
phenylalanine derived thiazole 6c with FDPP. In this case,
the diastereomeric trimer 9c, together with the tetramer 8c
were the major products isolated. The formation of 9c can
be attributed to the contamination of the thiazole amino acid
6c with its enantiomer [ee of the protected thiazole
6c¼70%]. Whilst benzyl groups are generally considered

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A. Bertram et al. / Tetrahedron 59 (2003) 6979–6990
to be less sterically demanding than isopropyl groups, in the
case of the transannular interactions involved in the cyclic
trimers, it might be expected that those involving benzyl
groups would be greater than those involving isopropyl
groups since the ‘reach’ of a benzyl group across the ring
will be greater than that of an isopropyl group. Presumably,
in the case of the thiazole 6c, the repulsive transannular
interactions in the linear tris-thiazole precursor to 7c slow
down the rate of cyclisation to such an extent that the rate of
addition of a monomer is much faster than that of
cyclisation, so that none of the cyclic trimer 7c is actually
obtained. Fewer transannular interactions would be present
in the linear precursor leading to the diastereoisomer 9c, and
cyclisation of this linear tris-thiazole of mixed stereo-
chemistry must be favourable, since no cyclic tetramer with
mixed stereochemistry was obtained from this particular
cyclooligomerisation reaction.17
diastereomeric cyclic tetramers might be expected and any
repulsive transannular interactions should be minimised in
cyclic compounds containing one or more stereocentres of
the opposite chirality. Therefore we examined the cyclo-
oligomerisation of the racemic thiazole amino acid rac-6a.
Upon treatment of rac-6a with FDPP in the presence of
Hu¨nig’s base, a mixture of diastereomeric cyclic peptides
was obtained in 75% yield. This mixture was found to
contain the cyclic trimers rac-7a and rac-9a and the cyclic
tetramers rac-8a, 10, rac-11 and 12.
No higher cyclic oligomers were observed. Separation of
this mixture was achieved by preparative HPLC and the
overall cyclic trimer: cyclic tetramer ratio was found to be
1:1 in contrast to the 5:2 ratio observed for the homochiral
thiazole 6a. As expected, the majority of the products
contained stereocentres of both configurations, although
small amounts of both cyclic trimer rac-7a and cyclic
tetramer rac-8a, in which all side chains are of the same
configuration, were also isolated. Interestingly, a higher
proportion of cyclic tetramers was obtained upon cyclo-
oligomerisation of rac-6a compared to that obtained upon
cyclooligomerisation of homochiral 6a, indicating that
factors other than transannular interactions influence the
Our initial cyclooligomerisation studies with the enantio-
merically enriched phenylalanine derived thiazole 6c
indicated that somewhat different results might be expected
upon cyclooligomerisation of any racemic thiazole amino
acid from those obtained using a homochiral thiazole amino
acid. In the case of a racemic amino acid, the formation of
two diastereomeric cyclic trimers together with four
Scheme 2. Reagents and conditions: (i) 4 M HCl in dioxane, rt, 6 h; (ii) 5a or ent-5a (1 mol equiv.); EDCI (1.5 mol equiv.), HOBt (1.5 mol equiv.), NMM
(3.0 mol equiv.), CH2Cl2, DMF; (iii) NaOH (10 mol equiv.), THF/H2O, 9:1, rt, 18 h; (iv) 18a-d (1 mol equiv.), EDCI (1.5 mol equiv.), HOBt (1.5 mol equiv.),
NMM (3.0 mol equiv.), CH2Cl2, DMF.

A. Bertram et al. / Tetrahedron 59 (2003) 6979–6990
6983
cyclooligomerisation reaction. One contributing factor
may be the relative ease of cyclisation of linear
peptides containing mixtures of D and L amino acid
residues.2d,e
Whilst rac-8a was identified by comparison with the
optically pure material obtained previously, the relative
stereochemistries of the diastereomeric cyclic tetramers,
10–12, were assigned on the basis of their symmetry as
1
determined by H NMR spectroscopy. The unsymmetrical
cyclic tetramer rac-11 was easily identified, since four
1
signals were observed in the H NMR spectrum for each
type of proton present in this molecule, as expected for a
molecule having C1 symmetry. The cyclic tetramers 10 and
12 are both meso-compounds having C2 and Ci symmetry,
respectively. The 1H NMR spectrum of one of these
compounds exhibits only a single set of signals for each
type of proton in the molecule, whilst two sets of signals are
observed for each type of proton in the 1H NMR spectrum of
the other tetramer. Since the cyclic tetramer 10 possesses a
higher element of symmetry than 12, the structure in which
the side chains have alternate configurations was assigned to
the compound which exhibited fewer signals in the 1H NMR
spectrum. This assignment was subsequently confirmed
following its synthesis via the macrolactamisation of linear
peptide amino acids of known relative stereochemistry (see
below).
2.2. Macrolactamisation approach
The cyclooligomerisation approach described above is an
efficient route to the synthesis of large quantities of
Lissoclinum cyclic peptide analogues in which all side
chains lie on the same face of the molecule. However, the
synthesis of compounds with mixed stereochemistry via the
cyclooligomerisation approach results in the formation of
racemates and requires the separation of diastereomers as
illustrated by the cyclooligomerisation of rac-6a. Since
mixtures of D and L stereocentres are commonly found in
the naturally occurring cyclic peptides of interest to us, an
alternative route to such compounds utilising a macro-
cyclisation approach was investigated.
Scheme 3. Reagents and conditions: (i) NaOH (10 mol equiv.), EtOH/H2O,
rt, 14 h; (ii) 4 M HCl in dioxane, rt, 18 h; (iii) FDPP (1.5 mol equiv.),
i-Pr2NEt (3 mol equiv.), CH3CN, rt, 2 h.
The fully protected tris-thiazole 15 was then prepared on
reacting the carboxylic acid 5a with the bis-thiazole amine
18c, again using standard peptide coupling techniques.
Similarly, the enantiomerically pure linear tetra-thiazoles 16
were prepared in good yield upon coupling the appropriate
bis-thiazole acids 17a and 17b with the bis-thiazole amines
18a–d. Saponification of the linear tris- and tetra-thiazole
esters 15 and 16, respectively, gave the corresponding
carboxylic acids 19b and 20 which were immediately
subjected to treatment with a 4 M solution of HCl in
dioxane, to give the peptides 19c and 21 as their
hydrochloride salts in essentially quantitative yields. Treat-
ment of these salts with FDPP in the presence of Hu¨nigs
base finally gave the cyclic peptides (7a, ent-8a and 10–12)
in yields ranging from 58–85% (Scheme 3).
To date, the majority of syntheses of naturally occurring
Lissoclinum cyclic peptides have relied on the synthesis of a
linear peptide, followed by a macrolactamisation step and
subsequent installation of some or all of the azole
heterocycles.4,18 However, since the azole heterocycles
induce a turn structure in a linear peptide that should
promote cyclisation,9 we chose to reverse the normal
sequence of the latter two steps and prepared the
enantiomerically pure linear thiazole-containing peptides
15 and 16 prior to performing the macrocyclisation step.
Thus, the amines 13 and ent-13 were prepared following
Boc-deprotection of the thiazoles 4a and ent-4a, respect-
ively. Each of these amines were then coupled with each of
the carboxylic acids 5a and ent-5a using standard peptide
coupling techniques19 leading to the four possible dia-
stereomeric bis-thiazoles 14 in good yield (Scheme 2).
Hydrolysis of the ethyl esters of the bis-thiazoles 14a and
14b and Boc-deprotection of the bis-thiazoles 14a–d next
led to the acids 17a and 17b and the amines 18a–d,
respectively.
These macrolactamisation yields are considerably higher
than most of those obtained in previously reported syntheses
of the Lissoclinum natural products, in which the hetero-
cycles were incorporated after macrocyclisation.4,18 This
suggests that incorporation of the turn-inducing thiazoles in
the linear precursor does indeed favour the macrocyclisation
reactions.
3. Conclusions
The synthesis of analogues of the Lissoclinum cyclic

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A. Bertram et al. / Tetrahedron 59 (2003) 6979–6990
peptides has been achieved in high yield via both
cyclooligomerisation and macrocyclisation approaches.
The cyclooligomerisation approach is favoured for the
synthesis of cyclic peptides in which all side chains are
identical and of the same stereochemistry, since it provides
rapid access to large amounts of novel cyclic peptides.
However, the more traditional stepwise approach allows
easy access to cyclic peptides containing side chains that
have different stereochemistry, as this circumvents the
need to separate mixtures of diastereomers. This
stepwise approach is also applicable to the synthesis of
compounds having side chains with different functional
groups.20 The synthesis of such compounds, together with
an investigation of their metal complexation behaviour is
underway in our laboratories, and will be reported at a later
date.
thiazole in a mixture of THF and H2O (9:1 (v/v), 0.5 M in
thiazole) and the mixture was stirred at room temperature
for 18 h. The solution was washed with ethyl acetate, then
the separated aqueous layer was acidified to pH 4 by the
addition of an aqueous solution of citric acid (10% w/v).
The mixture was extracted with ethyl acetate and the
organic extracts were combined and washed with H2O and
brine. The solution was dried (MgSO4) and the solvent was
removed under reduced pressure to leave the carboxylic
acid.
4.3. General procedure 2 for the N-deprotection of
thiazole amino acid derivatives
A solution of HCl in dioxane (4 M) was added to the
protected amino acid (1 mL/mmol) and the mixture was
stirred at room temperature under a nitrogen atmosphere for
6 h. The solvent was removed under reduced pressure, then
toluene (10 mL/mmol) was added to the residue and the
solvent was again removed under reduced pressure to leave
the amine as the hydrochloride salt, which was purified by
trituration with diethyl ether.
4. Experimental
4.1. General
Optical rotations were recorded in spectroscopic grade
chloroform on a Jasco DIP-370 polarimeter, [a]D values are
recorded in units of 1021 deg cm2 g21. Proton NMR spectra
were recorded on either a Bruker DPX 360 (360 MHz) or a
Bruker DPX 500 (500 MHz) spectrometer as dilute
solutions in deuterochloroform, d6-dimethyl sulfoxide or
d4-methanol. Chemical shifts are quoted in parts per million
(ppm) relative to residual chloroform (d 7.26), dimethyl-
sulfoxide (d 2.50) or methanol (d 3.35) as internal standard
and the multiplicity of each signal is designated by the
following abbreviations: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad. All coupling constants, J,
are quoted in Hertz. Carbon-13 NMR spectra were recorded
using the instruments indicated above, at frequencies of
90 MHz or 125 MHz, respectively. Chemical shifts are
reported relative to internal chloroform (d 77.0) as standard
on a broad band decoupled mode, and the multiplicities
were determined using a DEPT sequence. Mass Spectra
were recorded on a VG Autospec, MM-701 CF, a VG
Micromass 7070E or a Micromass LCT using electron
ionisation (EI), fast atom bombardment (FAB) or electro-
spray (ES) techniques. Microanalytical data were obtained
on a Perkin–Elmer 240B elemental analyser at the
University of Nottingham. Flash chromatography was
performed on Merck silica gel 60 as the stationary phase
and the solvents employed were either of analytical grade or
were distilled before use. Analytical HPLC was performed
using either a Waters-Associates 440 or a Hewlett Packard
series 1100 machine with a Nova-Pakw C18 column
(3.9£300 mm internal diameter). Preparative HPLC was
performed using a Waters-Associates 440 machine with a
Dynamax Silica Gel Cartridge Column (30 cm£10 mm
internal diameter).
4.4. General procedure 3 for the linear peptide coupling
of thiazole amino acid units
N-Methylmorpholine (1.5 equiv.) was added to a suspension
of the carboxylic acid (0.25 M) in CH2Cl2. The mixture was
cooled to 08C, and then HOBt (1.5 equiv.) followed by
EDCI (1.5 equiv.) were added. The solution was stirred at
08C for 10 min, then a precooled solution of the amino
acid (1.1 equiv.) in DMF and NMM (1.5 equiv.) was
added. The mixture was warmed to room temperature
and stirred at this temperature for 15 h. The solution was
partioned between ethyl acetate and aq. citric acid (10%
w/v) and the separated aqueous phase was extracted with
ethyl acetate. The combined organic extracts were
washed sequentially with saturated aq. NaHCO3, H2O
and brine, then dried (MgSO4) and the solvent was
removed under reduced pressure. The residue was purified
by column chromatography on silica gel to give the required
amide.
4.5. General procedure 4 for the cyclooligomerisation of
thiazole amino acids
Diisopropylethylamine (3 equiv.) and FDPP (1.5 equiv.)
were added to a suspension of the amino acid in anhydrous
acetonitrile (21 mL/mmol), and the mixture was stirred at
ambient temperature for 18 h and then evaporated to
dryness in vacuo. The residue was partitioned between
ethyl acetate (50 mL) and aq. HCl (2 M, 50 mL) and the
separated organic layer was washed with aq. HCl (2 M,
50 mL). The combined aqueous solutions were back
extracted with ethyl acetate (50 mL) and then the organic
solutions were combined and washed successively with aq.
NaOH (1 M, 2£50 mL), H2O (50 mL) and brine (50 mL).
The solution was dried (MgSO4) and the solvent was then
removed under reduced pressure to leave a mixture of cyclic
peptide products, which were separated by column chro-
matography (silica gel) or by preparative HPLC (Dynamax
Silica Gel Cartridge Column, 30 cm£10 mm internal
diameter).
The protected thiazoles 4a–c were prepared according to
literature procedures.10
4.2. General procedure 1 for the C-deprotection of
thiazole amino acid derivatives
Sodium hydroxide (10 equiv.) was added to a solution of the

A. Bertram et al. / Tetrahedron 59 (2003) 6979–6990
6985
4.6. General procedure 5 for macrocyclisation of linear
peptides
4.10. Amino acid rac-6a
Thiazole rac-4a (0.99 g, 3.0 mmol) was treated according to
general procedure 1 and gave the carboxylic acid rac-5a as a
pale yellow solid. This material was not purified, but was
immediately treated according to general procedure 2
leading to the amino acid rac-6a (0.69 g, 96%) as a
colourless solid, which was used without purification.
An aqueous solution of NaOH (1 M, 10 equiv.) was added
to a solution of the linear oligomer in ethanol (0.02 g/mL)
and the mixture was stirred at room temperature for 14 h.
The ethanol was removed under reduced pressure and the
aqueous residue was acidifed to pH 2 by the addition of aq.
HCl (2 M). The mixture was extracted with CH2Cl2
(3£25 mL) and then the combined organic extracts were
washed with H2O (2£25 mL) and brine (25 mL). The
solution was dried (MgSO4) and the solvent was removed
under reduced pressure. A solution of HCl in dioxane (4 M,
1 mL/mmol) was added to the residue and the resulting
solution was stirred at room temperature under a nitrogen
atmosphere for 18 h. The solvent was removed under
reduced pressure, then toluene (15 mL) was added to the
residue and the solvent was again removed under reduced
pressure. The residue was suspended in CH3CN (2 mL per
0.01 mmol of compound), and then diisopropylethylamine
(3 equiv.) and FDPP (1.5 equiv.) were added. The mixture
was stirred at room temperature under a nitrogen
atmosphere for 2 h and then the solvent was removed
under reduced pressure. The residue was partitioned
between ethyl acetate (50 mL) and aq. HCl (2 M, 50 mL)
and the separated organic layer was washed with aq. HCl
(2 M, 50 mL). The combined aqueous extracts were back
extracted with ethyl acetate (50 mL) and then the organic
solutions were combined and washed successively with aq.
NaOH (1 M, 2£50 mL), H2O (50 mL) and brine (50 mL).
The solution was dried (MgSO4) and the solvent was then
removed under reduced pressure. The residue was purified
by chromatography on silica gel to give the required cyclic
peptide.
4.10.1. Cyclic trimer 7a and cyclic tetramer 8a. The
thiazole amino acid 6a (0.12 g, 0.51 mmol) was treated
according to general procedure 4 and the crude product was
purified by column chromatography (ethyl acetate/hexane;
7:3) to give the cyclic trimer (0.064 g, 70%) as a colourless
solid; mp 258–2608C (from Et2O); [a]2D3¼þ126.8 (c 0.53,
CHCl3); 1H NMR (360 MHz, CDCl3) d 8.45 (d, J¼9.3 Hz,
3H), 8.09 (s, 3H), 5.43 (dd, J¼9.3, 5.8 Hz, 3H), 2.30 (m,
3H), 1.10 (d, J¼6.8 Hz, 9H), 1.05 (d, J¼6.8 Hz, 9H); 13C
NMR (90 MHz, CDCl3) d 168.6 (C), 159.7 (C), 149.1 (C),
123.4 (CH), 55.4 (CH), 35.3 (CH), 18.8 (CH3), 18.3 (CH3);
m/z (FAB) 547.1582, (C24H31N6O3S3 requires 547.1620,
[MþH]þ); Found C, 52.5; H, 5.6; N, 15.0. C24H30N6O3S3
requires C, 52.7; H, 5.5; N, 15.0%. Further elution gave the
cyclic tetramer (0.023 g, 25%) as a colourless solid; mp
152–1548C (from Et2O); [a]2D3¼þ204.6 (c 0.57, CHCl3);
1H NMR (360 MHz, CDCl3) d 8.06 (s, 4H), 7.84 (d,
J¼9.1 Hz, 4H), 5.22 (dd, J¼9.1, 8.2 Hz, 4H), 2.59 (m, 4H),
1.17 (d, J¼6.7 Hz, 12H), 1.04 (d, J¼6.6 Hz, 12H); 13C
NMR (90 MHz, CDCl3) d 169.3 (C), 160.3 (C), 148.9 (C),
124.2 (CH), 55.3 (CH), 32.6 (CH), 19.6 (CH3), 18.9 (CH3);
m/z (FAB) 729.2152, (C32H41N8O4S4 requires 729.2134,
[MþH]þ); Found C, 50.9; H, 5.5; N, 14.6.
C32H40N8O4S4.0.5 H2O requires C, 50.9; H, 5.7; N, 14.8%.
4.11. Crystal structure determination of compound 7a
4.7. Amino acid 6a
Single crystals of compound 7a suitable for X-ray
diffraction were obtained upon slow diffusion of diethyl
ether into a solution of 7a in dichloromethane. A crystal was
encapsulated in a film of RS3000 perfluoropolyether oil and
mounted on a dual-stage glass fibre before transfer to the
diffractometer.
The thiazole 4a (1.0 g, 3.0 mmol) was treated according
to general procedure 1 and gave the carboxylic acid 5a
as a pale yellow solid. This material was not purified,
but was immediately treated according to general
procedure 2 leading to the amino acid (0.7 g, 97%)
as
purification.
a colourless solid, which was used without
4.11.1. Crystal data†. C24H30N6O3S3, M¼546.72, mono-
˚
clinic,
a¼18.926(5),
b¼7.961(2),
c¼19.455(5) A,
3
˚
4.8. Amino acid 6b
b¼106.89(2)8, U¼2804.8(13) A , T¼150(2) K, space
group I2 (Alt. C2, No. 5), Z¼4, Dc¼1.295 g cm23
,
reflections
The thiazole 4b (0.4 g, 1.3 mmol) was treated according
to general procedure 1 and gave the carboxylic acid 5b
as a pale brown solid. This material was not purified,
but was immediately treated according to general
procedure 2 leading to the amino acid (0.26 g, 94%)
m(Mo–Ka)¼0.300 mm21
,
4094 unique
measured and used in all calculations. Final R1 [3639
F.4s(F)]¼0.0572 and wR(all F 2) was 0.141.
4.11.2. Cyclic trimer 7b and cyclic tetramer 8b. The
thiazole amino acid 6b (0.19 g, 0.92 mmol) was treated
according to general procedure 4 and the crude product was
purified by column chromatography (ethyl acetate/hexane;
7:3 to 9:1) to give the cyclic trimer (0.058 g, 41%) as a
colourless solid; mp 298–3008C (CH2Cl2/Et2O);
as a colourless solid, which was used without
purification.
4.9. Amino acid 6c
The thiazole 4c (100 mg, 0.27 mmol) was treated according
to general procedure 1 and gave the carboxylic acid 5c as a
pale brown solid. This material was not purified, but was
immediately treated according to general procedure 2
leading to the amino acid (72 mg, 95%) as a colourless
solid, which was used without purification.
†
Crystallographic data for the structure in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 153184 and 204593. Copies of the data can
be obtained on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: þ44-1223-336033 or email: deposit@ccdc.cam.ac.uk].

6986
A. Bertram et al. / Tetrahedron 59 (2003) 6979–6990
[a]2D8¼þ48.1 (c 1.0, CHCl3); 1H NMR (360 MHz, CDCl3) d
8.68 (d, J¼6.8 Hz, 3H), 8.17 (s, 3H), 5.64 (app. quintet,
J¼6.8 Hz, 3H), 1.74 (d, J¼6.8 Hz, 9H); 13C NMR
(125 MHz, CDCl3); d 171.2 (C), 159.5 (C), 148.8 (C),
124.0 (CH), 47.4 (CH), 25.0 (CH3); m/z (FAB) 485.0512
(C18H18O3N6S3Na requires 485.0500, [MþNa]þ). Further
elution gave the cyclic tetramer (0.018 g, 13%) as a
colourless solid; mp 268–2718C; [a]2D3¼þ17.1 (c 0.7,
(C), 167.5 (C), 167.1 (C), 160.3 (C), 160.2 (C), 160.1
(C), 149.6 (C), 148.9 (C), 148.7 (C), 124.9 (CH), 123.5
(CH), 123.0 (CH), 57.0 (CH), 56.5 (CH), 55.7 (CH), 37.2
(CH), 35.4 (CH), 33.5 (CH), 19.6 (CH3), 19.4 (CH3), 18.2
(CH3), 18.0 (CH3), 17.3 (CH3), 16.1 (CH3); MS (EI) m/z
569.1432, (C24H30N6O3S3Na requires 569.1433,
[MþNa]þ).
1
CHCl3); H NMR (360 MHz, CDCl3) d 8.12 (s, 4H), 7.99
Concentration of fraction B (retention time: 14 min) gave
the cyclic tetramer 10 as a colourless solid, mp 330–3358C
(CH2Cl2/Et2O). 1H NMR (360 MHz, CDCl3) d 8.31 (d,
J¼9.7 Hz, 4H), 8.11 (s, 4H), 5.39 (dd, J¼6.9, 9.7 Hz, 4H),
2.24 (m, 4H), 1.03 (d, J¼6.9 Hz, 12H), 0.94 (d, J¼6.9 Hz,
12H); 13C NMR (90 MHz, CDCl3) d 169.1 (C), 159.9 (C),
149.7 (C), 123.5 (CH), 55.3 (CH), 35.1 (CH), 19.1 (CH3),
18.7 (CH3); MS (EI) m/z 751.1912, (C32H40O4N8S4Na
requires 751.1953, [MþNa]þ).
(d, J¼8.1 Hz, 4H), 5.61 (app. quintet, J¼6.9 Hz, 4H), 1.86
(d, J¼6.9 Hz, 12H); 13C NMR (125 MHz, CDCl3) d 170.8
(C), 159.9 (C), 148.2 (C), 124.8 (CH), 46.0 (CH), 21.2
(CH3); m/z (FAB) 639.0666 (C24H24O4N8S4Na requires
639.0701, [MþNaþ]).
4.11.3. Cyclic trimer 9c and cyclic tetramer 8c. The
thiazole amino acid 6c (50 mg, 0.18 mmol) was treated
according to general procedure 4 and the crude product was
purified by column chromatography (ethyl acetate/hexane;
7:3) to give the cyclic trimer (4.0 mg, 10%) as a colourless
solid; mp 248–2498C (CH2Cl2/Et2O); [a]2D8¼20.4 (c 1.0,
CHCl3); 1H NMR (360 MHz, CDCl3) d 8.57 (d, J¼4.6 Hz,
1H), 8.62 (d, J¼5.2 Hz, 1H), 8.69 (d, J¼5.8 Hz, 1H), 8.14
(s, 1H), 8.04 (s, 1H), 8.01 (s, 1H), 7.18–7.31 (m, 9H), 7.02–
7.05 (m, 6H), 5.86–5.87 (m, 1H), 5.65–5.66 (m, 1H), 5.46–
5.48 (m, 1H), 3.74 (dd, J¼4.2, 12.9 Hz, 1H), 3.57 (dd,
J¼4.2, 12.9 Hz, 1H), 3.55 (dd, J¼4.2, 12.9 Hz, 1H), 3.21
(dd, J¼8.4, 13.7 Hz, 1H), 2.90 (dd, J¼9.1, 12.8 Hz, 1H),
2.89 (dd, J¼9.1, 12.8 Hz, 1H); 13C NMR (90 MHz, CDCl3)
d 169.1 (C), 168.1 (C), 168.0 (C), 160.0 (C), 159.9 (C),
159.5 (C), 149.1 (C), 148.5 (C), 148.3 (C), 130.1 (CH),
129.9 (CH), 129.7 (CH), 129.3 (CH), 128.7 (CH), 127.5
(CH), 127.3 (CH), 127.2 (CH), 124.9 (CH), 123.9 (CH),
123.5 (CH), 120.3 (CH), 54.1 (CH), 53.8 (CH), 52.9 (CH),
43.6 (CH2), 43.3 (CH2), 43.1 (CH2), 9 signals obscured or
overlapping; m/z (FAB) 713.1450 (C36H30O3N6S3Na
requires 713.1439, [MþNa]þ). Further elution gave the
cyclic tetramer (17 mg, 41%) as a colourless solid; mp 250–
Concentration of fraction C (retention time: 15.5 min) gave
the cyclic trimer rac-7a as a colourless solid, which was
identical in all respects other than optical rotation, to the
compound obtained upon cyclooligomerisation of amino
acid 6a.
Concentration of fraction D (retention time: 16.5 min) gave
the cyclic tetramer 12 as a colourless solid, mp 312–3158C
(CH2Cl2/Et2O). 1H NMR (360 MHz, CDCl3) d 8.16 (s, 2H),
8.11 (s, 2H), 8.03 (d, J¼8.8 Hz, 2H), 7.92 (d, J¼9.2 Hz,
2H), 5.26 (m, 4H), 2.75–2.68 (m, 2H), 2.56–2.51 (m, 2H),
1.08 (d, J¼6.7 Hz, 6H), 1.04 (d, J¼6.8 Hz, 6H), 0.97 (d,
J¼6.7 Hz, 6H), 0.89 (d, J¼6.8 Hz, 6H); 13C NMR (90 MHz,
CDCl3) d 170.4 (C), 170.2 (C), 161.1 (C), 160.6 (C), 148.6
(C), 148.5 (C), 124.7 (CH), 124.6 (CH), 57.4 (CH), 56.0
(CH), 33.8 (CH), 31.9 (CH), 19.72 (CH3), 19.68 (CH3),
17.65 (CH3), 17.45 (CH3); MS (EI) m/z 751.1957, (C32H40-
O4N8S4Na requires 751.1953, [MþNa]þ).
Concentration of fraction E (retention time: 19 min) gave
the cyclic tetramer rac-11 as a colourless solid mp 110–
2548C; [a]2D8¼25.79 (c 1.5, CHCl3); H NMR (360 MHz,
1
1
CDCl3) d 7.99 (s, 4H), 7.95–7.98 (d, J¼8.5 Hz, 4H), 7.15–
7.30 (m, 20H), 5.68–5.74 (m, 4H), 3.49–3.57 (m, 8H); 13C
NMR (90 MHz, CDCl3) d 159.4 (C), 148.6 (C), 135.9 (C),
130.0 (CH), 129.6 (CH), 127.2 (CH), 123.9 (CH), 52.7
(CH), 43.9 (CH2), 3 signals obscured or overlapping; m/z
(FAB) 920.2004, (C48H40O4N8S4 requires 920.2055, Mþ).
1148C (CH2Cl2/Et2O). H NMR (360 MHz, CDCl3) d 8.48
(d, J¼8.9 Hz, 1H), 8.23 (d, J¼8.7 Hz, 1H), 8.12 (s, 1H),
8.09 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.98 (d, J¼7.8 Hz,
1H), 7.88 (d, J¼9.9 Hz, 1H), 5.47 (dd, J¼4.9, 8.9 Hz, 1H),
5.32 (dd, J¼9.9, 9.9 Hz, 1H), 5.23 (dd, J¼6.7, 8.7 Hz, 1H),
5.00 (d, J¼7.8, 8.3 Hz, 1H), 2.71–2.86 (m, 1H), 2.43–2.37
(m, 2H), 2.25–2.22 (m, 1H), 1.21 (d, J¼6.6 Hz, 3H), 1.15
(d, J¼6.8 Hz, 3H), 1.09 (d, J¼6.6 Hz, 3H), 1.04 (d,
J¼6.8 Hz, 3H), 1.00–0.95 (m, 9H), 0.84 (d, J¼6.7 Hz,
3H); 13C NMR (90 MHz, CDCl3) d 170.3 (C), 169.5 (C),
169.0 (C), 168.3 (C), 160.6 (C), 160.2 (C), 160.1 (C), 160.0
(C), 150.0 (C), 149.6 (C), 149.1 (C), 148.7 (C), 124.4 (CH),
124.1 (CH), 124.0 (CH), 123.8 (CH), 56.7 (CH), 55.7 (CH),
55.0 (CH), 34.9 (CH), 34.8 (CH), 33.3 (CH), 32.6 (CH),
20.0 (CH3), 19.8 (CH3), 19.4 (CH3), 19.2 (CH3), 19.1 (CH3),
18.9 (CH3), 18.4 (CH3), 18.2 (CH3) (1 signal overlapping);
MS (EI) m/z 751.1936, (C32H40O4N8S4Na requires
751.1953, [MþNa]þ).
4.11.4. Cyclooligomerisation of rac-6a. The thiazole
amino acid rac-6a (0.50 g, 2.1 mmol) was treated according
to general procedure 4 and the crude product was separated
by preparative HPLC (ethyl acetate/hexane; 62:48; flow rate
1 mL/min) producing 6 fractions A-F (combined yield 75%)
in the ratio 38:12:6:18:21:5.
Concentration of fraction A (retention time: 9 min) gave the
cyclic trimer rac-9a as a colourless solid, mp 150–1558C
(CH2Cl2/Et2O). 1H NMR (360 MHz, CDCl3) d 8.52 (d,
J¼9.3 Hz, 1H), 8.50 (d, J¼8.1 Hz, 1H), 8.46 (d, J¼6.9 Hz,
1H), 8.20 (s, 1H), 8.12 (s, 2H), 5.70 (dd, J¼3.0, 9.3 Hz, 1H),
5.52 (dd, J¼3.8, 8.1 Hz, 1H), 5.25 (dd, J¼5.6, 6.9 Hz, 1H),
2.56–2.48 (m, 1H), 2.42–2.28 (m, 2H), 1.10 (d, J¼6.7 Hz,
3H), 1.08 (d, J¼6.7 Hz, 3H), 0.94 (d, J¼6.8 Hz, 3H), 0.91
(d, J¼6.8 Hz, 3H), 0.85 (d, J¼6.8 Hz, 3H), 0.81
(d, J¼6.8 Hz, 3H); 13C NMR (90 MHz, CDCl3) d 170.5
Concentration of fraction F (retention time: 31 min) gave
the cyclic tetramer rac-8a as a colourless solid, which was
identical in all respects, other than optical rotation, to the
compound obtained upon cyclooligomerisation of amino
acid 6a.

A. Bertram et al. / Tetrahedron 59 (2003) 6979–6990
6987
4.12. Amine 13
0.98 (d, J¼6.8 Hz, 3H), 0.96 (d, J¼6.8 Hz, 3H), 0.94 (d,
J¼6.8 Hz, 3H), 0.89 (d, J¼6.8 Hz, 3H); 13C NMR (90 MHz,
CDCl3) d 171.7 (C), 171.6 (C), 161.2 (C), 160.7 (C), 155.3
(C), 149.2 (C), 147.4 (C), 126.9 (CH), 123.3 (CH), 80.1 (C),
61.3 (CH2), 56.4 (CH), 56.3 (CH), 33.0 (CH), 32.9 (CH),
28.2 (CH3), 19.6 (CH3), 19.2 (CH3), 17.9 (CH3), 17.3 (CH3),
14.2 (CH3); m/z (ES) 533.1813 (C23H34N4O5S2Na requires:
533.1868, [MþNa]þ); Found: C, 53.9; H, 6.7; N, 10.8.
C23H34N4O5S2 requires: C, 54.1; H, 6.7; N, 11.0%.
The thiazole 4a (5.0 g, 15 mmol) was treated according to
general procedure 2 to give the amine (3.9 g, 97%) as the
hydrochloride salt which was used without purification.
4.13. Amine ent-13
The thiazole ent-4a (5.0 g, 15 mmol) was treated according
to general procedure 2 to give the amine (4.0 g, 99%) as the
hydrochloride salt which was used without purification.
4.13.4. Bis-thiazole 14d. The amine 13 (0.50 g, 1.9 mmol)
and the acid ent-5a (0.57 g, 1.9 mmol) were coupled
according to general procedure 3. The crude product was
purified by column chromatography (ethyl acetate/
petroleum ether; 1:1) to give the dithiazole (0.76 g, 79%)
as a colourless foam; mp 60–638C; [a]2D2¼228.6 (c 1.8,
CHCl3); 1H NMR (360 MHz, CDCl3) d 8.06 (s, 1H), 8.01 (s,
1H), 7.95 (d, J¼9.2 Hz, 1H), 5.28 (m, 1H), 5.25 (d,
J¼8.1 Hz, 1H), 4.86 (bs, 1H), 4.38 (q, J¼7.1 Hz, 2H), 2.61
(m, 1H), 2.35 (m, 1H), 1.43 (s, 9H), 1.37 (t, J¼7.1 Hz, 3H),
1.00 (d, J¼6.8 Hz, 3H), 0.98 (d, J¼6.8 Hz, 3H), 0.97 (d,
J¼6.8 Hz, 3H), 0.91 (d, J¼6.8 Hz, 3H); 13C NMR (90 MHz,
CDCl3) d 173.1 (C), 171.7 (C), 161.2 (C), 160.8 (C), 155.4
(C), 149.2 (C), 147.4 (C), 126.9 (CH), 123.4 (CH), 80.2 (C),
61.3 (CH2), 57.9 (CH), 56.4 (CH), 33.1 (CH), 32.9 (CH),
28.2 (CH3), 19.6 (CH3), 19.2 (CH3), 18.0 (CH3), 17.3 (CH3),
14.3 (CH3); MS (EI) m/z 533.1819 (C23H34N4O5S2Na
requires: 533.1868, [MþNa]þ); Found: C, 54.2; H, 6.7; N,
11.1. C23H34N4O5S2 requires: C, 54.1; H, 6.7; N, 11.0%).
4.13.1. Bis-thiazole 14a. The amine ent-13 (0.50 g,
1.9 mmol) and the acid 5a (0.57 g, 1.9 mmol) were coupled
according to general procedure 3. The crude product was
purified by column chromatography (ethyl acetate/
petroleum ether; 1:1) to give the dithiazole (0.83 g, 86%)
as a colourless foam; mp 61–648C; [a]2D3¼þ31.4 (c 1.7,
CHCl3); 1H NMR (360 MHz, CDCl3) d 8.07 (s, 1H), 8.03 (s,
1H), 7.95 (d, J¼9.2 Hz, 1H), 5.31 (dd, J¼6.8, 9.2 Hz, 1H),
5.21 (d, J¼8.1 Hz, 1H), 4.88 (bs, 1H), 4.41 (q, J¼7.1 Hz,
2H), 2.64 (m, 1H), 2.37 (m, 1H), 1.46 (s, 9H), 1.39 (t,
J¼7.1 Hz, 3H), 1.03 (d, J¼6.8 Hz, 3H), 1.00 (d, J¼6.8 Hz,
3H), 0.99 (d, J¼6.8 Hz, 3H), 0.93 (d, J¼6.8 Hz, 3H); 13C
NMR (90 MHz, CDCl3) d 173.1 (C), 171.7 (C), 161.3 (C),
160.8 (C), 155.4 (C), 149.2 (C), 147.5 (C), 127.0 (CH),
123.4 (CH), 80.2 (C), 61.3 (CH2), 58.0 (CH), 56.5 (CH),
33.2 (CH), 33.0 (CH), 28.3 (CH3), 19.7 (CH3), 19.3 (CH3),
18.0 (CH3), 17.3 (CH3), 14.3 (CH3); MS (EI) m/z 533.1837
(C23H34N4O5S2Na requires: 533.1868, [MþNa]þ); Found:
C, 53.9; H, 6.3; N, 11.05. C23H34N4O5S2 requires: C, 54.1;
H, 6.7; N, 11.0%.
4.13.5. Bis-thiazole amine 18a. The carbamate 14a (0.20 g,
0.39 mmol) was treated according to general procedure 2
and gave the hydrochloride salt of the amine (0.16 g, 91%)
as a colourless solid; mp 137–1408C (CH2Cl2/Et2O);
4.13.2. Bis-thiazole 14b. The amine ent-13 (0.50 g,
1.9 mmol) and the acid ent-5a (0.57 g, 1.9 mmol) were
coupled according to general procedure 3. The crude
product was purified by column chromatography (ethyl
acetate/petroleum ether; 1:1) to give the dithiazole (0.78 g,
81%) as a colourless foam; mp 912938C; [a]2D3¼25.5 (c
1
[a]2D3¼þ10 (c 1.0, CHCl3); H NMR (360 MHz, CD3OD)
d 8.62 (d, J¼8.7 Hz, 1H), 8.42 (s, 1H), 8.41 (s, 1H), 5.33
(dd, J¼8.7, 6.8 Hz, 1H), 4.76 (d, J¼6.8 Hz, 1H), 4.43 (q,
J¼7.1 Hz, 2H), 2.85–2.23 (m, 2H), 1.43 (t, J¼7.1 Hz, 3H),
1.16 (d, J¼6.9 Hz, 3H), 1.12 (d, J¼6.7 Hz, 3H), 1.07 (d,
J¼6.8 Hz, 3H), 1.02 (d, J¼6.8 Hz, 3H), signals due to
amino group protons not observed; 13C NMR (90 MHz,
CDCl3) d 172.4 (C), 164.0 (C), 161.4 (C), 160.7 (C), 148.8
(C), 146.5 (C), 128.2 (CH), 125.2 (CH), 61.5 (CH2), 58.3
(CH), 57.8 (CH), 32.3 (CH), 32.2 (CH), 19.8 (CH3), 19.1
(CH3), 18.6 (CH3), 18.0 (CH3), 14.3 (CH3); m/z (ES)
1
1.0, CHCl3); H NMR (360 MHz, CDCl3) d 8.06 (s, 1H),
8.00 (bs, 1H), 7.93 (d, J¼9.2 Hz, 1H), 5.31–5.22 (m, 2H),
4.86 (bs, 1H), 4.38 (q, J¼7.1 Hz, 2H), 2.60 (m, 1H), 2.35
(m, 1H), 1.42 (s, 9H), 1.37 (t, J¼7.1 Hz, 3H), 1.00 (d,
J¼6.8 Hz, 3H), 0.98 (d, J¼6.8 Hz, 3H), 0.96 (d, J¼6.8 Hz,
3H), 0.91 (d, J¼6.8 Hz, 3H); 13C NMR (90 MHz, CDCl3) d
172.9 (C), 171.6 (C), 161.2 (C), 160.8 (C), 155.3 (C), 149.3
(C), 147.4 (C), 126.9 (CH), 123.3 (CH), 80.2 (C), 61.3
(CH2), 57.8 (CH), 56.4 (CH), 33.1 (CH), 32.9 (CH), 28.2
(CH3), 19.6 (CH3), 19.2 (CH3), 18.0 (CH3), 17.3 (CH3), 14.3
(CH3); m/z (ES) 533.1822 (C23H34N4O5S2Na requires:
533.1868, [MþNa]þ); Found: C, 54.2; H, 6.6; N, 11.3.
C23H34N4O5S2 requires: C, 54.1; H, 6.7; N, 11.0%.
843.2788
[2MþNa]þ).
(C36H52N8O6S4Na
requires:
843.2795,
4.13.6. Bis-thiazole amine 18b. The carbamate 14b (0.40 g,
0.78 mmol) was treated according to general procedure 2
and gave the hydrochloride salt of the amine (0.34 g, 99%)
as a colourless solid; mp 120–1238C; [a]2D3¼þ35.2 (c 1.0,
CHCl3); 1H NMR (360 MHz, d6-DMSO) d 8.95 (br s, 4H),
8.46 (s, 1H), 8.42 (s, 1H), 5.10 (dd, J¼8.5, 8.4 Hz, 1H), 4.72
(m, 1H), 4.29 (q, J¼7.1 Hz, 2H), 2.60–2.45 (m, 1H), 2.39–
2.30 (m, 1H), 1.29 (t, J¼7.1 Hz, 3H), 1.02 (d, J¼6.6 Hz,
3H), 1.00 (d, J¼6.8 Hz, 3H), 0.91 (d, J¼6.9 Hz, 3H), 0.89
(d, J¼6.8 Hz, 3H); m/z (ES) 821.2908 (C36H53N8O6S4
requires 821.2971, [2MþH]þ).
4.13.3. Bis-thiazole 14c. The amine 13 (0.67 g, 2.5 mmol)
and the acid 5a (0.7 g, 2.3 mmol) were coupled according to
general procedure 3. The crude product was purified by
column chromatography (ethyl acetate/petroleum ether;
1:1) to give the dithiazole (1.2 g, 90%) as a colourless
1
foam; mp 93–948C; [a]2D3¼þ5.6 (c 1.0, CHCl3); H NMR
(360 MHz, CDCl3) d 8.07 (s, 1H), 8.02 (bs, 1H), 7.92 (d,
J¼9.2 Hz, 1H), 5.31 (dd, J¼9.2, 7.0 Hz, 1H), 5.18 (bs, 1H),
4.85 (bs, 1H), 4.42 (q, J¼7.2 Hz, 2H), 2.63–2.54 (bm, 1H),
2.38–2.29 (bm, 1H), 1.40 (s, 9H), 1.34 (t, J¼7.2 Hz, 3H),
4.13.7. Bis-thiazole amine 18c. The carbamate 14c (0.40 g,
0.78 mmol) was treated according to general procedure 2
and gave the hydrochloride salt of the amine (0.32 g, 91%)

6988
A. Bertram et al. / Tetrahedron 59 (2003) 6979–6990
as a colourless solid; mp 121–1238C; [a]2D4¼242.2 (c 1.0,
CHCl3); 1H NMR (360 MHz, d6-DMSO) d 8.92 (br s, 4H),
8.46 (s, 1H), 8.42 (s, 1H), 5.10 (dd, J¼8.5, 8.4 Hz, 1H), 4.73
(m, 1H), 4.29 (q, J¼7.1 Hz, 2H), 2.60–2.45 (m, 1H), 2.39–
2.30 (m, 1H), 1.29 (t, J¼7.1 Hz, 3H), 1.02 (d, J¼6.6 Hz,
3H), 0.99 (d, J¼6.8 Hz, 3H), 0.91 (d, J¼6.9 Hz, 3H), 0.89
(d, J¼6.8 Hz, 3H); m/z (ES) 821.2921 (C36H53N8O6S4
requires 821.2971, [2MþH]þ).
1H), 1.43 (s, 9H), 1.38 (t, J¼7.1 Hz, 3H), 1.05 (d, J¼7.1 Hz,
3H), 1.03 (d, J¼7.1 Hz, 3H), 1.02 (d, J¼7.0 Hz, 3H), 1.00
(d, J¼6.8 Hz, 3H), 0.98 (d, J¼6.4 Hz, 3H), 0.91 (d,
J¼6.8 Hz, 3H); 13C NMR (90 MHz, CDCl3) d 173.5 (C),
171.9 (C), 171.8 (C), 161.3 (C), 160.9 (C), 160.8 (C), 155.4
(C), 149.3 (C), 149.2 (C), 147.4 (C), 126.9 (CH), 123.5
(CH), 80.3 (C), 61.4 (CH2), 57.9 (CH), 56.5 (CH), 56.2
(CH), 32.9 (CH), 32.9 (CH), 28.2 (CH3), 19.6 (CH3), 19.5
(CH3), 19.3 (CH3), 17.8 (CH3), 17.6 (CH3), 17.4 (CH3), 14.3
(CH3), 2 signals obscured or overlapping; m/z (ES)
693.2629 (C31H45N6O6S3 requires 693.2563 [MþH]þ);
Found: C, 53.4; H, 6.3; N, 12.1. C31H44N6O6S3 requires:
C, 53.75; H, 6.4; N, 11.8%.
4.13.8. Bis-thiazole amine 18d. The carbamate 14d (0.20 g,
0.39 mmol) was treated according to general procedure 2
and gave the hydrochloride salt of the amine (0.15 g, 86%)
as a colourless solid; mp 140–1438C; [a]2D3¼20.3 (c 1.5,
CHCl3); 1H NMR (360 MHz, CD3OD) d 8.62 (d, J¼8.7 Hz,
1H), 8.42 (s, 2H), 5.33 (dd, J¼8.7, 6.8 Hz, 1H), 4.76 (d,
J¼6.3 Hz, 1H), 4.43 (q, J¼7.1 Hz, 2H), 2.47 (m, 2H), 1.43
(t, J¼7.1 Hz, 3H), 1.16 (d, J¼6.9 Hz, 3H), 1.11 (d,
J¼6.7 Hz, 3H), 1.07 (d, J¼6.8 Hz, 3H), 1.02 (d,
J¼6.8 Hz, 3H), signals due to amino group protons not
observed; 13C NMR (90 MHz, CDCl3) d 172.4 (C), 164.0
(C), 161.4 (C), 160.7 (C), 148.8 (C), 146.5 (C), 128.2 (CH),
125.2 (CH), 61.5 (CH2), 58.3 (CH), 57.8 (CH), 32.3 (CH),
32.2 (CH), 19.8 (CH3), 19.1 (CH3), 18.6 (CH3), 18.0 (CH3),
14.3 (CH3); m/z (ES) 433.1822 (C18H26N4O3S2Na requires:
433.1868, [MþNa]þ).
4.13.12. Linear tetra-thiazole 16a. The amine 18b (0.15 g,
0.31 mmol) and the acid 17b (0.17 g, 0.31 mmol) were
coupled according to general procedure 3, and the crude
product was purified by column chromatography (ethyl
acetate/petroleum ether (7:3) to give the tetramer (0.24 g,
92%) as a colourless solid; mp 107–1088C (CH2Cl2/Et2O);
[a]2D8¼þ28.0 (c 1.0, CHCl3); 1H NMR (360 MHz, CDCl3) d
8.03 (s, 1H), 8.02 (s, 1H), 8.01 (br s, 1H), 7.99 (s, 1H), 7.90
(d, J¼9.1 Hz, 1H), 7.82 (d, J¼9.2 Hz, 1H), 7.80 (d,
J¼9.2 Hz, 1H), 5.35–5.24 (m, 4H), 4.82 (bs, 1H), 4.35 (q,
J¼7.2 Hz, 2H), 2.64–2.43 (bm, 3H), 2.28 (m, 1H), 1.38 (s,
9H), 1.33 (t, J¼7.1 Hz, 3H), 1.03–0.91 (m, 21H), 0.85 (d,
J¼6.8 Hz, 3H); 13C NMR (90 MHz, CDCl3) d 173.7 (C),
172.0 (C), 171.8 (C), 161.1 (C), 160.7 (C), 160.6 (C), 155.3
(C), 149.3 (C), 149.1 (C), 147.3 (C), 126.8 (CH), 123.6
(CH), 123.5 (CH), 123.4 (CH), 80.3 (C), 61.2 (CH2), 57.9
(CH), 56.4 (CH), 56.3 (CH), 56.2 (CH), 32.9 (CH), 32.8
(CH), 32.7 (CH), 28.1 (CH3), 19.5 (CH3), 19.4 (CH3), 19.3
(CH3), 19.1 (CH3), 17.6 (CH3), 17.5 (CH3), 17.4 (CH3), 17.2
(CH3), 14.2 (CH3), 4 signals obscured or overlapping; m/z
(ES) 897.2871 (C39H54N8O7S4Na requires 897.2896,
[MþNa]þ); Found: C, 52.9; H, 6.2; N, 12.4. C39H54N8O7-
S4.0.5H2O requires: C, 53.0; H, 6.3; N, 12.7%.
4.13.9. Bis-thiazole acid 17a. The ester 14a (0.60 g,
1.2 mmol) was treated according to general procedure 1
and gave the acid (0.54 g, 96%) as a colourless solid; mp
105–1088C (CH2Cl2/Et2O); [a]2D4¼þ20.8 (c 1.0, CHCl3);
1H NMR (360 MHz, CDCl3) d 8.99 (br s, 1H), 8.17 (s, 1H),
8.10 (s, 1H), 8.03 (d, J¼8.6 Hz, 1H), 6.59 (br s, 1H), 5.30
(dd, J¼7.4, 8.6 Hz, 1H), 4.86 (m, 1H), 2.58 (m, 1H), 2.32
(m, 1H), 1.42 (br s, 9H), 1.05–0.86 (m, 12H); 13C NMR
(90 MHz, CDCl3) d 173.1 (C), 171.9 (C), 163.9 (C), 161.9
(C), 155.6 (C), 149.0 (C), 147.0 (C), 128.3 (CH), 123.9
(CH), 80.3 (C), 56.5 (CH), 58.0 (CH), 33.2 (CH), 32.9 (CH),
28.3 (CH3), 19.7 (CH3), 19.3 (CH3), 18.1 (CH3), 17.4
(CH3); m/z (ES) 505.1548 (C21H30N4O5S2Na requires:
505.1555, [MþNa]þ).
4.13.13. Linear tetrathiazole 16b. The amine 18a (0.15 g,
0.31 mmol) and the acid 17a (0.17 g, 0.31 mmol) were
coupled according to general procedure 3, and the crude
product was purified by column chromatography (ethyl
acetate/petroleum ether (7:3) to give the tetramer (0.20 g,
77%) as a colourless solid, mp 79–838C (CH2Cl2/Et2O);
[a]2D5¼þ23.7 (c 1.0, CHCl3); 1H NMR (360 MHz, CDCl3) d
8.09 (s, 1H), 8.06 (s, 2H), 8.04 (s, 1H), 7.98 (d, J¼9.0 Hz,
1H), 7.89 (d, J¼9.0 Hz, 1H), 7.85 (d, J¼9.0 Hz, 1H), 5.38–
5.30 (m, 3H), 5.14 (d, J¼7.8 Hz, 1H), 4.88 (d, J¼7.8 Hz,
1H), 4.42 (q, J¼7.1 Hz, 2H), 2.72–2.53 (m, 4H), 1.44 (br s,
9H), 1.39 (t, J¼7.1 Hz, 3H), 0.92–1.06 (d, J¼6.8 Hz, 24H);
13C NMR (90 MHz, CDCl3) d 173.7 (C), 172.0 (C), 171.9
(C), 171.8 (C), 161.2 (C), 160.9 (C), 160.8 (C), 160.7 (C),
155.4 (C), 149.4 (C), 149.3 (C), 147.4 (C), 127.0 (CH),
123.7 (CH), 123.6 (CH), 80.3 (C), 61.4 (CH2), 56.5 (CH),
56.3 (CH), 32.9 (CH), 28.2 (CH3), 19.7 (CH3), 19.5 (CH3),
19.2 (CH3), 18.9 (CH3), 17.9 (CH3), 17.8 (CH3), 17.4 (CH3),
17.3 (CH3), 8 signals obscured or overlapping; m/z (ES)
4.13.10. Bis-thiazole acid 17b. The ester 14b (0.20 g,
0.39 mmol) was treated according to general procedure 1
and gave the acid (0.15 g, 79%) as a colourless solid; mp
102–1068C (CH2Cl2/Et2O); [a]2D4¼226.8 (c 1.0, CHCl3);
1H NMR (360 MHz, CDCl3) d 8.20 (s, 1H), 8.08 (s, 1H),
7.94 (bs, 1H), 5.36–5.31 (m, 1H), 5.18 (bs, 1H), 4.90 (bs,
1H), 2.65–2.50 (m, 1H), 2.41–2.26 (m, 1H), 1.45 (s, 9H),
1.06–1.00 (m, 9H), 0.95 (d, J¼6.2 Hz, 3H), signal due to
carboxylic acid group proton not observed; m/z (ES)
505.1588 (C21H30N4O5S2Na requires 505.1555, [MþNa]þ).
4.13.11. Linear tris-thiazole 15. The amine 18c (0.87 g,
1.9 mmol) and the acid 5a (0.52 g, 1.7 mmol) were coupled
according to general procedure 3 and the crude product was
purified by column chromatography (silica; ethyl acetate/
petroleum ether; 2:3) to give the tristhiazole (1.0 g, 85%) as
a colourless foam; m.p. 104–1068C, [a]2D1¼þ7.3 (c 0.8,
CHCl3); 1H NMR (360 MHz, CDCl3) d 8.06 (s, 1H), 8.05 (s,
1H), 8.03 (s, 1H), 7.95 (d, J¼9.2 Hz, 1H), 7.84 (d,
J¼9.2 Hz, 1H), 5.35 (dd, J¼5.9, 9.2 Hz, 1H), 5.33 (dd,
J¼6.7, 9.2 Hz, 1H), 5.20 (d, J¼8.7 Hz, 1H), 4.89 (bs, 1H),
4.39 (q, J¼7.1 Hz, 2H), 2.66–2.53 (m, 2H), 2.41–2.30 (m,
897.2904,
[MþNa]þ).
(C39H54N8O7S4Na
requires
897.2896,
4.13.14. Linear tetra-thiazole 16c. The amine 18b (0.15 g,
0.31 mmol) and the acid 17a (0.17 g, 0.31 mmol) were
coupled according to general procedure 3, and the crude

A. Bertram et al. / Tetrahedron 59 (2003) 6979–6990
6989
product was purified by column chromatography (ethyl
acetate/petroleum ether (7:3) to give the tetramer (0.15 g,
57%) as a colourless solid, mp 80–848C (CH2Cl2/Et2O);
[a]2D4¼þ31.7 (c 1.0, CHCl3); 1H NMR (360 MHz, CDCl3) d
8.03–8.09 (s, 4H), 7.80–7.96 (d J¼10.8 Hz, 4H), 5.29–
5.46 (m, 2H), 5.12 (d, J¼7.8 Hz, 1H), 4.88 (d, J¼7.8 Hz,
1H), 4.42 (q, J¼7.1 Hz, 2H), 2.53–2.67 (m, 4H), 1.44 (br s,
9H), 1.39 (t, J¼7.1 Hz, 3H), 0.92–1.09 (d, J¼6.8 Hz, 24H);
13C NMR (90 MHz, CDCl3) d 172.0 (C), 171.9 (C), 161.1
(C), 160.7 (C), 149.2 (C), 147.3 (C), 123.5 (CH), 80.3 (C),
61.3 (CH2), 61.2 (C), 60.2 (CH), 56.4 (CH), 56.2 (CH), 32.8
(CH), 28.1 (CH3), 20.7 (CH3), 19.5 (CH3), 19.3 (CH3), 19.1
(CH3), 17.6 (CH3), 17.5 (CH3), 17.3 (CH3), 14.2 (CH3), 14.0
(CH3), 13 signals obscured or overlapping; m/z (ES)
purified by column chromatography (silica; ethyl acetate) to
give 10 (6 mg, 68%) as a colourless solid, which was
identical, in all respects, to the product obtained upon
cyclooligomerisation of rac-6a.
4.17. Macrocyclisation of compound 16c
The tetrathiazole 16c (10 mg, 0.012 mmol) was treated
according to general procedure 5, and the crude product was
purified by column chromatography (silica; ethyl acetate) to
give 11 (5 mg, 58%) as a colourless solid, which was
identical, in all respects apart from optical rotation, to the
product obtained upon cyclooligomerisation of rac-6a,
[a]2D6¼þ63.2 (c 1.0, CHCl3).
897.2876
(C39H54N8O7S4Na
requires
897.2896,
[MþNa]þ); Found C, 51.0; H, 5.9; N, 12.3. C39H54N8O7-
4.18. Macrocyclisation of compound 16d
S4.2(H2O) requires: C, 51.4; H, 6.4; N, 12.3%).
The tetrathiazole 16d (10 mg, 0.012 mmol) was treated
according to general procedure 5, and the crude product was
purified by column chromatography (silica; ethyl acetate) to
give 12 (6 mg, 68%) as a colourless solid, which was
identical, in all respects, to the product obtained upon
cyclooligomerisation of rac-6a.
4.13.15. Linear tetra-thiazole 16d. The amine 18d (0.15 g,
0.31 mmol) and the acid 17a (0.17 g, 0.31 mmol) were
coupled according to general procedure 3, and the crude
product was purified by column chromatography (ethyl
acetate/petroleum ether (7:3) to give the tetramer (0.15 g,
57%) as a colourless solid, mp 94–968C (CH2Cl2/Et2O);
[a]2D6¼þ23.2 (c 1.0, CHCl3); 1H NMR (360 MHz, CDCl3) d
8.08 (s, 1H), 8.06 (s, 2H), 8.03 (s, 1H), 7.93 (d, J¼9.1 Hz,
1H), 7.88 (d, J¼9.3 Hz, 1H), 7.84 (d, J¼9.0 Hz, 1H), 5.39–
5.30 (m, 3H), 5.12 (d, J¼8.7 Hz, 1H), 4.88 (br s, 1H), 4.42
(q, J¼7.1 Hz, 2H), 2.72–2.52 (m, 4H), 1.45 (s, 9H), 1.39 (t,
J¼7.1 Hz, 3H), 1.08–0.90 (m, 24H); 13C NMR (90 MHz,
CDCl3) d 173.8 (C), 172.3 (C), 172.1 (C), 172.0 (C), 171.7
(C), 161.3 (C), 161.0 (C), 160.9 (C), 155.4 (C), 149.5 (C),
149.3 (C), 149.2 (C), 147.5 (C), 127.1 (CH), 123.8 (CH),
123.7 (CH), 123.6 (CH), 80.4 (C), 61.34 (CH2), 58.1 (CH),
56.6 (CH), 56.5 (CH), 56.4 (CH), 33.1 (CH), 33.0 (CH3),
32.9 (CH), 28.0 (CH3), 19.8 (CH3), 19.6 (CH3), 19.5 (CH3),
19.3 (CH3), 17.9 (CH3), 17.8 (CH3), 17.6 (CH3), 17.4 (CH3),
14.4 (CH3), 1 signal obscured or overlapping; m/z (ES)
897.2910 (C39H54N8O7S4Na requires 897.2896, [MþNa]þ).
Acknowledgements
We thank the EPSRC for a studentship (to JSH), and
AstraZeneca (Studentship to F. G-L. T), SmithKline
Beecham (CASE award to J. S. H.) and Pfizer Ltd for
their support of this work.
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¨
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