Synthesis of libraries of thiazole, oxazole and imidazole-based cyclic peptides from azole-based amino acids. A new synthetic approach to bistratamides and didmolamides

Article abstract of DOI:10.1039/b701999h

Treatment of a 1: 1 mixture of the thiazole-based amino acids 8a and 8b with FDPP-i-Pr₂NEt in CH₃CN gave a mixture of the cyclic trimers 14, 15, 16 and 17 and the cyclic tetramers 19 and 23 in the ratio 2: 7: 5: 8: 1: 1 and in a comb

Full text of DOI:10.1039/b701999h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of libraries of thiazole, oxazole and imidazole-based cyclic peptides
from azole-based amino acids. A new synthetic approach to bistratamides and
didmolamides†
Anna Bertram, Nakia Maulucci, Olivia M. New, Siti Mariam Mohd Nor and Gerald Pattenden*
Received 8th February 2007, Accepted 19th March 2007
First published as an Advance Article on the web 16th April 2007
DOI: 10.1039/b701999h
Treatment of a 1 : 1 mixture of the thiazole-based amino acids 8a and 8b with FDPP–i-Pr2NEt in
CH3CN gave a mixture of the cyclic trimers 14, 15, 16 and 17 and the cyclic tetramers 19 and 23 in the
ratio 2 : 7 : 5 : 8 : 1 : 1 and in a combined yield of 70%. Separate coupling reactions between the
bisimidazole amino acid 45 and the thiazole/oxazole amino acids 43a and 42a in the presence of
FDPP–i-Pr2NEt led to the bisimidazole based cyclic trimers 55 and 57 respectively (54–57%) and to the
cyclic tetramer 56 (8–11%). Similar coupling reactions involving the bisthiazole and bisoxazole amino
acids 49 and 47 with the imidazole/oxazole/thiazole amino acids 41a, 42a and 43a gave rise to the
library of oxazole, thiazole and imidazole-based cyclic peptides 58, 59, 60, 61, 62, 63, 64 and 65. A
coupling reaction between the bisthiazole amino acid 49 and the oxazole amino acid 73 led to an
efficient (36% overall) synthesis of bistratamide H (67) found in the ascidian Lissoclinum bistratum.
Coupling reactions involving oxazolines with thiazole amino acids were less successful. Thus, a coupling
reaction between the phenylalanine-based oxazoline amino acid 71a and either the thiazole amino acid
8a or the bisthiazole amino acid 74 gave only a 2% yield of the cyclic hexapeptide didmolamide A (4)
found in the ascidian Didemnum molle. Didmolamide B (68) was obtained in 9% yield from a coupling
reaction between 74 and the phenylalanine threonine amino acid 72, using either FDPP or DPPA.
Introduction
The past decade has seen rapid progress in the isolation and
characterisation of a plethora of azole-based cyclic peptides
from marine organisms, fungi and algae.1 Furthermore, many
of these secondary metabolites show useful biological properties,
including antibacterial and antiviral activities and cytotoxicity.2
Prominent amongst these cyclic peptides are the “bistratamides”,
e.g. 1 and 2, which are oxazole, oxazoline, thiazole, thiazoline-
based hexapeptides, isolated from the Great Barrier Reef and
from the Philippine ascidian (“sea squirt”) Lissoclinum bistratum.3
The bistratamides are related to the C3-symmetric trisoxazoline
westiellamide 3 which is also found in L. bistratum,4 and to
the bisthiazole based “didmolamides”, e.g. 4, isolated more
recently from the ascidian Didemnum molle collected off the
coast of Madagascar.5 Structures similar to the bistratamides and
didmolamides, are the dendroamides and nostocyclamides, e.g. 5
and 6 respectively, which have been isolated from cyanobacteria.6
The interesting antitumor and antidrug resistance properties, in
particular, and their potential for acting as metal ion chelators,
have combined to make azole-based cyclic hexapeptides of the type
represented by structures 1–6 attractive targets for total synthesis
and biological evaluation.7
School of Chemistry, University of Nottingham, Nottingham, UK NG7 2RD.
E-mail: Gerald.Pattenden@nottingham.ac.uk; Fax: +44 (0)115 9513564;
Tel: +44 (0)115 9513530
† Electronic supplementary information (ESI) available: Experimental
data for selected compounds. See DOI: 10.1039/b701999h
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FDPP-i-Pr2NEt. Earlier, we had shown that when the thiazoles
8a and 8b are treated separately with FDPP–i-Pr2NEt at room
temperature under high dilution in CH3CN, they each led to the
cyclic trimers 9 and the cyclic tetramers 10, in ratios of 9 : 2
and 5 : 2 respectively, in very good overall yields.9 Only minute
amounts of higher cyclic oligomers could be detected by HPLC-
MS from these reactions. Treatment of a 1 : 1 mixture of 8a and 8b
with FPPP–i–Pr2NEt under the same reaction conditions a priori,
would be expected to lead to four possible cyclic trimers, i.e. 14, 15,
16, 17, and to six possible cyclic tetramers, i.e. 18, 19, 20, 21, 22,
23.
In reality, treatment of a solution of a 1 : 1 mixture of 8a and 8b
in CH3CN, with FDPP–i-Pr2NEt, produced all the cyclic trimers
14, 15, 16 and 17, but only two cyclic tetramers,i.e. 19 and 23, in
the ratio 2 : 7 : 5 : 8 : 1 : 1 and in a combined yield of 70%. The ratio
of the cyclic peptide products was determined by HPLC analysis
and comparison of retention time data with those of authentic
compounds prepared by more conventional linear routes starting
from the enantiopure thiazole amino acids 8a and 8b.
The symmetrical cyclic trimers 14 and 15 and cyclic tetramers 18
and 19 were enantiomers of compounds from our earlier studies.9
The cyclic trimers 16 and 17 were both elaborated from the same
bisthiazole 26a produced from a coupling reaction between the
thiazole amine 24a and the thiazole carboxylic acid 25, using
EDCI–HOBt–NMM (Scheme 1). Saponification of the ethyl ester
group in 26a next led to the bisthiazole carboxylic acid 27. A
second coupling reaction between 27 and 24a then gave the
tristhiazole 28 which, by sequential deprotection of the ethyl ester
and Boc groups gave the x-amino acid 29. Macrolactamisation
of 29, using FDPP–i-Pr2NEt, finally gave the cyclic peptide 16.
In a similar manner, the bisthiazole 27 was elaborated to the
tristhiazole 30, en route to the cyclic peptide 17 (Scheme 1).
The overwhelming majority of the published syntheses of azole-
based cyclic hexapeptides have used a straightforward strategy
involving the iterative coupling of enantiopure azole amino acids
to produce a linear hexapeptide, followed by macrolactamisation
of an appropriate x-amino acid intermediate.7 Several years ago,
Wipf and Miller8 demonstrated that the 18-membered cyclic
hexapeptide westiellamide 3 could be obtained in 20% yield by
cyclooligomerisation of the trans-oxazoline 7 in the presence of
the coupling agent DPPA. In later studies, our own research
group showed that similar cyclooligomerisations could be carried
out with thiazole-based amino acids, e.g. 8a and 8b, in the
presence of FDPP–i-Pr2NEt, leading to high yields (approx. 70%)
of the cyclic trimers 9 together with smaller amounts of the
corresponding cyclic tetramers 10.9 Somewhat remarkably, we also
showed that acceptable yields, i.e. approx. 22–26%, of the natural
products dendroamide A (5) and nostocyclamide 6, were produced
when mixtures of their constituent azole-based amino acids, i.e.
8a, 8b, 11, and 8b, 12, 13 respectively, were treated similarly
with FDPP–i-Pr2NEt.10 In continuation of these studies of the
assembly of cyclic peptides, we have now evaluated the scope for
the formation of other, mixed, azole-based structures, including
those from imidazoles and oxazolines. These studies are described
here, alongside an approach to bisthiazole oxazoline-based cyclic
hexapeptides, e.g. didmolamide A (4).
Mixed cyclooligomerisation of the alanine and valine-based
thiazole amino acids 8a and 8b
To gain some insight into the factors which might control the
selectivity of cyclooligomerisations of azole-based amino acids,
we first decided to study the outcome of treating a 1 : 1 mixture of
the alanine and valine-based thiazoles, 8a and 8b respectively, with
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Scheme 1 Reagents and conditions: i, EDCI (1.0 mole eq.), HOBt (1.0 mole eq.), NMM (1.0 mole eq.), CH2Cl2, DMF, ca. 70%; ii, NaOH (10 mole eq.),
THF–H2O 9 : 1, rt, 18 h; iii, 4 M HCl in dioxane, rt, 6 h; iv, FDPP (1.5 mole eq.), i-Pr2NEt (3 mole eq.), CH3CN, rt, 2 h, ca. 60%.
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The bisthiazole carboxylic acid 27 was also used to prepare the
cyclic tetramer 22, following removal of the Boc-protection and
‘dimerisation’ of the resulting bisthiazole x-amino acid 32 in the
presence of FDPP–i-Pr2NEt (Scheme 2).
Scheme 2 Reagents and conditions: i, 4 M HCl in dioxane, rt, 6 h, 95%;
ii, FDPP (1.5 mole eq.), i-Pr2NEt (3 mole eq.), CH3CN, rt, 2 h, 50%.
The three remaining cyclic tetramers 20, 21, and 23 were each
synthesised in an iterative manner from appropriately substituted
and protected bisthiazole intermediates prepared from straight-
forward coupling reactions between appropriately functionalised
alanine and valine-based thiazoles. Thus, a coupling reaction
between 24a and the thiazole carboxylic acid 33 first gave the
bisthiazole 34 which was saponified to the carboxylic acid 35. A
coupling reaction between 35 and the free amine 26b produced
after Boc-deprotection of 26a, next led to the tetrathiazole
36. Removal of the protecting groups from 36, followed by
macrolactamisation of the resulting x-amino acid 37 finally gave
the cyclic tetramer 20 (Scheme 3).
In a similar straightforward manner, the unsymmetrical cyclic
tetramer 21 was prepared from a coupling reaction between the
bisthiazole carboxylic acid 35 and the bisthiazole amine 38b,
followed by sequential deprotection of the Boc and ethyl ester
groups in the product 39 and macrolactamisation of the resulting
x-amino acid (Scheme 4). A corresponding coupling reaction
between 38b and the bisthiazole carboxylic acid 27 led to the
tetrathiazole 40 which, using similar chemistry, was converted into
the cyclic tetramer 23.
Scheme 4 Reagents and conditions: i, EDCI (1.5 mole eq.), HOBt
(1.5 mole eq.), NMM (1.5 mole eq.), CH2Cl2, 0 ◦C, 75%; ii, NaOH
(10 mole eq.), THF–H2O 9 : 1, rt, 2.5 h; iii, 4 M HCl in dioxane, rt, 1 h,
57% (over 2 steps); iv, EDCI (1.5 mole eq.), HOBt (1.5 mole eq.), NMM
(1.5 mole eq.), CH2Cl2, 0 ◦C, 63%; v, NaOH (10 mole eq.), THF–H2O 9 :
1, rt, 3 h; vi, 4 M HCl in dioxane, rt, 1 h; vii, FDPP, i-Pr2NEt, CH3CN, rt,
23 ◦C; 53% (over 3 steps for 23), 57% (over 3 steps for 21).
The ease of formation of cyclic trimers, i.e. 14–17, over cyclic
tetramers during the cyclooligomerisation of a 1 : 1 mixture of
8a and 8b is consistent with the observations made earlier when
the same thiazoles were treated separately with FDPP–i-Pr2NEt.
Perhaps more surprising was the observation that the unsymmet-
rical cyclic trimers 16 and 17 were produced in amounts similar to
Scheme 3 Reagents and conditions: i, NaOH (10 mole eq.), THF–H2O 9 : 1, rt, 18 h, 86%; ii, 26b, EDCI (1.5 mole eq.), HOBt (1.5 mole eq.), NMM (3.0
mole eq.), CH2Cl2, DMF, 61%; iii, NaOH (10 mole eq.), THF–H2O 9 : 1, rt, 3.5 h; iv, 4 M HCl in dioxane, rt, 2 h; v, FDPP (1.0 mole eq.), i-Pr2NEt (1.0
mole eq.), CH3CN, rt, 24 h, 60%.
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15, and that relatively small amounts of the alanine-based cyclic
trimer 14 were obtained. Of course we have no information on
the order in which the thiazole amino acids 8a and 8b are coupled
to each other to form a linear tristhiazole, and hence the amide
bond which is formed last in the macrolactamisations. On the
basis of minimisation of transannular non-bonding interactions
between the alkyl side chains in the transition states during the
macrocyclisations, we might expect the bulkier isopropyl groups
to favour formation of the cyclic trimers 14 and 16 containing the
smaller methyl group substituents, but this is not the case. What
needs to be taken into account, however, is the greater solubility
of the valine-based thiazole 8b, and possibly any isopropyl-
substituted acylic intermediates, which may be responsible for the
increased formation of the cyclic trimers 15 and 17. It is perhaps
also significant that the only two cyclic tetramers produced in
the mixed cyclooligomerisation of 8a and 8b, i.e. 19 and 23, also
contain only (in the case of 19), or largely, isopropyl group side
chains.
elaborate the corresponding valine-based bisazole amino acids
45,13 47 and 49 (Scheme 5), in readiness for further coupling
reactions to elaborate mixed imidazole/oxazole/thiazole-based
cyclic peptides.
Our earlier studies haddemonstrated that cyclooligomerisations
of homogeneous, and even cyclisations of mixed, thiazole amino
acids favoured the formation of cyclic trimers and cyclic tetramers,
with only minute amounts of higher oligomers being produced
concurrently.9 In principle then, we would expect largely the
formation of only two cyclic trimers, i.e. 50 and 51, and three cyclic
tetramers i.e. 52, 53 and 54, from any cyclisation reaction involving
one of the bisazole amino acids 45, 47 and 49 with one of the mono-
azole amino acids 41a, 42a and 43a (Scheme 6). Furthermore,
bearing in mind the relative number of amide bond-forming
reactions involved, we would expect that the aforementioned
cyclisations would favour the production of the cyclic trimer 50
and the cyclic tetramer 52 where only two amide bond forming
reactions are involved.
As expected, therefore, a coupling reaction between the bisim-
idazole amino acid 4513 and the thiazole amino acid 43a, in
CH3CN, in the presence of FDPP–Pr2NEt at room temperature
for three days, produced only the expected cyclic trimer 55 and
the cyclic tetramer 56 which were obtained in the ratio 5 : 1 and
in a combined yield of 68%. A corresponding reaction between 45
and the oxazole amino acid 42a, led to a similar yield and similar
Synthesis of mixed imidazole, oxazole and thiazole-based cyclic
peptides
Imidazole-containing cyclic peptides have not yet been found in
nature, but there are a few alkaloids, e.g. pilocarpine,11 derived
from the imidazole ring-containing amino acid histidine that are
known, and imidazoles commonly act as ligands in several impor-
tant metalloenzymes.12 In view of their special properties, it was
decided to extend the scope of our synthetic studies and prepare a
range of imidazole ring-based cyclic peptides13 linked to oxazoles
and thiazoles for biological evaluation and possible exploitation
in asymmetric synthesis. We therefore prepared the enantiopure
valine-based imidazole,13 oxazole9 and thiazole9 amino acids,
41a, 42a and 43a respectively, and their various carboxylic acid
and amine derivatives, using methods which are well-precedented
in the literature.9,10,14 The mono-azole derivatives 41a/b, 42a/b
and 43a/b were then used in separate coupling reactions to
Scheme 5 Reagents and conditions: i, DPPA, DIPEA, DMF, 70%; ii, EDCI, HOBt, NMM, DCM, 85–97%; iii, LiOH, THF–MeOH–H2O 2 : 2 : 1, 0 ◦C;
iv, 4 M HCl in 1,4-dioxane; v, aq. NaOH, MeOH–1,4-dioxane.
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the symmetrical cyclic tetramer 11b (combined 50% yield), and 49
reacted with the imidazole amino acid 41a leading to a similar
4 : 1 mixture of the cyclic trimer 60 and the tetramer 9b in 50%
yield (Scheme 8). A small amount of the trisoxazole based cyclic
trimer 59 (3%) was also obtained from the former cyclisation and
the thiazole-imidazole based cyclic tetramer 61 was a significant
product (9%) produced in the cyclisation between 49 and 41a
(Scheme 8).
Cyclisations involving the bisoxazole amino acid 47 and the
azole amino acids 41a and 43a were less selective and resulted
in reduced yields of modified cyclic peptides due to the poorer
solubility of 47 in acetonitrile (Scheme 9). The bisoxazole-based
cyclic trimers 62 and 64 were the major products produced in each
of the reactions (23–30%), alongside smaller amounts, i.e. 8–12%,
of the corresponding bisoxazole based cyclic tetramers 63 and 65
respectively.
Synthesis of oxazoline-containing cyclic peptides; Didmolamides A
and B
As a corollary to our studies of the synthesis of mixed oxazole,
imidazole and thiazole-based cyclic peptides from the assembly of
azole amino acids, we also evaluated the scope for similar assem-
blies involving oxazoline amino acids which might, hopefully, lead
to oxazoline-based cyclic hexapeptides, e.g. bistratamide E (66)
and didmolamide A (4).
Bistratamide E (66) is the oxazoline analogue of bistratamide H
(67), and both metabolites were isolated in 2003 by Faulkner and
Perez15 from the ascidian L. bistratum collected in the southern
Philippines. The bistratamides show modest activity, i.e. IC50 1.7–
7.9 lg ml−1 against human colon tumour (HCT-116) cell lines.
Didmolamide A (4) together with didmolamide B (68) were also
isolated in 2003, but from the ascidian Didemnum mole collected
in Madagascar.5 These metabolites are also mildly toxic to several
cultured tumour cell lines, with IC50 values of 10–20 lg ml−1.
Both the bistratamide and the didmolamide families of cyclic
peptides have attracted a great deal of interest within the synthetic
chemistry community and several of their members have been
synthesised, including the metabolites 1, 2, 66, 67 and 68.7 All
Scheme 6
ratio of the analogous cyclic trimer 57 and the cyclic tetramer 56
(Scheme 7). Interestingly, when a 1 : 1 : 1 mixture of the azole amino
acids 42a, 43a and 45 was treated with FDPP–Pr2NEt only the two
cyclic trimers 55 and 57 were obtained, and in equal amounts in a
combined yield of 62%. Only minute amounts (<1%) of the cyclic
tetramer 56 could be detected by HPLC analysis.
In other investigations of cyclisations of mixtures of mono and
bisazole amino acids, the bisthiazole amino acid 49 and the oxazole
amino acid 42a produced a 4 : 1 mixture of the cyclic trimer 58 and
Scheme 7
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Scheme 8
Scheme 9
of these syntheses have used a conventional linear approach,
building up a linear azole-based peptide chain, followed by a
macrocyclisation mediated by pyBOP–DMAP.
that DPPA was the best coupling reagent for the synthesis of
cyclic peptides, and particularly for those compounds containing
oxazoline rings.16 Indeed, Wipf and Miller8 showed that the
cyclooligomerisation of the oxazoline amino acid 7, leading to
westiellamide 3, was best carried out in the presence of DPPA
◦
at 0–22 C over 4 days. We therefore examined both FDPP and
DPPA in our attempted assemblies of didmolamide A (4) and
bistratamide E (66) from the oxazoline-based amino acids 71a
and 71b respectively. The oxazolines 71a and 71b, were both
synthesised from the corresponding dipeptides 69 following: i)
cyclodehydration using Deoxo-Fluor, ii) careful saponification
of the resulting oxazoline esters 70, and iii) Boc-deprotection
(Scheme 10).17
When a solution of the phenylalanine-based oxazoline 71a and
the bisthiazole amino acid 74 produced after Boc-deprotection of
35 in CH3CN was treated with FDPP in DMF with added NMM
for 4 days at room temperature, work up and chromatography gave
didmolamide A (4) in a disappointing 2% yield. The structure and
In the majority of our cyclooligomerisation and assembly
studies leading to cyclic peptides from azole-based amino acids, we
had found that optimum yields were obtained using FDPP and i-
Pr2NEt as coupling agents in acetonitrile at room temperature for
3–5 days.9 Previously however, other researchers had concluded
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bisthiazole amino acid 49 in the presence of FDPP–i-Pr2NEt
and isolated bistratamide H (67)15 in a very agreeable 36% yield
(Scheme 12). A small amount (∼9%) of the cyclic tetramer 10b
was produced concurrently. Bistratamide H (67) could also be
produced in 25% yield when the oxazole amino acid 73 (1 eq.) was
reacted with 2 equivalents of the monothiazole amino acid 8b in
the presence of FDPP–i-Pr2NEt. Small amounts of the thiazole-
based cyclic trimer (9b, 8%) and tetramer (10b, 4%), together with
the bisoxazole-based cyclic trimer (75, 9%) and tetramer (76, 8%)
were also produced in the reaction. A comparison of this approach
to bistratamide H with that described by Kelly and You,7i showed
that our mixed azole amino acid approach involved 8 steps and
gave the target in 24% overall yield, whereas the linear approach
used 12 steps and led to bistratamide H in 13% overall yield.
Scheme 10 Reagents and conditions: i, Deoxo-Fluor, DCM, −20 ◦C; ii,
LiOH, H2O, MeOH, 78%; iii, TMSOTf, DCM, 0 ◦C, 85%; iv 4 M HCl,
1,4-dioxane, rt; v, BrCCl3, DBU, DCM, 0 ◦C to rt, 90% over 3 steps.
stereochemistry of 4 followed from comparison of its spectroscopic
and other data with those of an authentic sample prepared in a
linear fashion according to the method of Kelly and You.7g The
major product isolated from the reaction was the cyclic tetramer
10a (10–12%), accompanied by trace amounts of higher oligomers.
The same outcome was observed when the two substrates 71a
and 74 were reacted in the presence of DPPA, DMF, NMM
at 0–5 ◦C for 4.5 days. Likewise, when the oxazoline 71a was
reacted with two equivalents of the thiazole amino acid 8a, using
either FDPP or DPPA as coupling agents, didmolamide A (4) was
still only produced in 2% yield. In these instances however, the
major product was the cyclic trimer 9a (12%), accompanied by the
corresponding cyclic tetramer 10a (2%).
To our disappointment, the cyclic tetramer 10b was the only
product isolated when the valine-based oxazoline 71b and the
bisthiazole amino acid 49 were treated with FDPP–i-Pr2NEt, i.e.
no bistratamide E (66) could be detected in the crude reaction
product. More interesting perhaps, was the observation that when
a 1 : 1 mixture of the dipeptide amino acid 72 and the bisthiazole
amino acid 74 was exposed to DPPA or to FDPP (with added i-
Pr2NEt in DMF), didmolamide B (68) was produced in 7–9% yield
(Scheme 11), accompanied by the cyclic tetramer 10a (5–13%).
Scheme 12
Experimental
General details
Nuclear magnetic resonance spectra (NMR) were recorded on
1
Bruker DPX (270, 360 and 500 MHz for H, and 67.5, 90.5 and
125 MHz for 13C) spectrometers as dilute solutions in deuterated
solvents as specified. Deuterochloroform was deacidified over
anhydrous potassium carbonate. Chemical shifts (d) are quoted
in parts per million (ppm) downfield of tetramethylsilane (TMS)
or referenced to residual protonated solvent: chloroform (dH 7.27,
dC 77.0) or residual methanol (dH 3.31, dC 49.0), as internal
standard. Signal multiplicities are designated by the following
1
abbreviations: H spectra: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, app = apparent, br = broad. In 13C
spectra the multiplicities were determined using a DEPT sequence
with secondary pulses at 90◦ and 135◦ where appropriate. Signal
multiplicities are designated by: s = quaternary, d = tertiary
methine, t = secondary methylene, q = primary methyl. 19F
NMR spectra were recorded on a Bruker DPX 300 (282 MHz)
spectrometer and are referenced to residual protonated solvent, i.e.
chloroform. All coupling constants (J) are quoted to the nearest
0.1 Hz.
Scheme 11 Reagents and conditions: i, 4 M HCl, 1,4-dioxane, 25 ◦C, 4 h;
ii, FDPP, DMF, NMM, 25 ◦C or DPPA, DMF, NMM, 0–25 ◦C, 4.5 d.
Synthesis of bistratamide H and concluding remarks
To further demonstrate the scope and advantages of our one
step synthesis of azole-based cyclic hexapeptides from their azole-
constituent amino acids, we prepared the oxazole amino acid 73
from the corresponding oxazoline 70, and reacted it with the
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Ultraviolet spectra were recorded on a Phillips PU 8700
spectrophotometer as solutions in spectroscopic grade ethanol
and are given in nm, with e in dm3 mol−1 cm−1 in parentheses.
Infrared (IR) spectra were obtained using a Perkin Elmer 1600
series FT-IR or Avatar 320 FT-IR instrument as dilute solutions in
0.6 mmol) in anhydrous CH2Cl2 (3 ml) at 0 ◦C under a ni-
trogen atmosphere. 1-Hydroxybenzotriazole (82 mg, 0.6 mmol)
and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (116 mg, 0.6 mmol) were added consecutively in one portion.
The mixture was stirred at 0 ◦C for 40 minutes and then a precooled
solution of L-alanine thiazole amine 24a (128 mg, 0.6 mmol) and
4-methylmorpholine (60 lL, 0.6 mmol) in dichloromethane (3 ml)
was added dropwise over 1 min. The mixture was stirred at 0 ◦C
for 4 h and then allowed to warm to room temperature over 15 h.
Water (ca. 20 ml) was added and the aqueous layer was separated
and extracted with dichloromethane (3 × 20 ml). The combined
organic extracts were washed successively with saturated aqueous
NaHCO3 (3 × 20 ml), 10% aqueous citric acid (3 × 10 ml), and
brine (3 × 10 ml), then dried (MgSO4) and evaporated in vacuo.
The residue was purified by chromatography on silica gel, eluting
with pentane–ethyl acetate (1 : 1) to giv◦e the dipeptide (208 mg,
72%) as a colourless solid, mp 165–167 C (from petroleum 40–
spectroscopic grade solvents or as liquid films. Absorptions (mmax
are reported in wavenumbers (cm−1).
)
Mass spectra were recorded on either a VG Autospec, MM-
701CF or Micromass LCT spectrometer using electrospray (ES)
or fast atom bombardment (FAB) techniques. Due to the soft
nature of these techniques, little fragmentation of the compounds
occurred and hence nominal mass and fragmentation data have
not been included. High-resolution mass spectra are calculated to
4 decimal places from the molecular formula corresponding to the
observed signal using the most abundant isotopes of each element.
Microanalytical data were obtained on a Perkin-Elmer 240B el-
emental analyser, and melting points (which are uncorrected) were
recorded on a Stuart Scientific SMP3 melting point apparatus.
Optical rotations were measured on a JASCO DIPA-370
polarimeter, and solutions were prepared using spectroscopic
grade solvents, [a]D values are recorded in units of 10−1 deg cm2 g−1.
Flash chromatography was performed using Merck Kieselgel 60
(230–400 mesh) andthesolvents employed were either of analytical
grade or were distilled before use according to the technique of
Still et al.18
◦
60 C–diethyl ether); [a]2D3 −35.9 (c 1.0 in CHCl3); mMax (soln:
CHCl3)/cm−1 3442, 1719, 1602; dH (360 MHz, CDCl3) 1.05 (3H, d,
J 6.8, CHCH3CH3), 1.10 (3H, d, J 6.8, CHCH3CH3), 1.41 (3H, t,
J 6.8, OCH2CH3), 1.47 (9H, s, But), 1.81 (3H, d, J 6.8, CH3CH),
2.84 (1H, m, CHCH(CH3)2), 4.30 (2H, q, J 6.8, OCH2CH3), 5.32
(1H, m, NHBoc), 5.43 (1H, m, CHCH(CH3)2), 5.51 (1H, dq, J
6.8, 2.4, CHCH3), 7.88 (1H, d, J 6.8, NHCO), 8.03 (1H, s, CHS),
8.07 (1H, s, CHS); dC (90.5 MHz, CDCl3) 14.4 (q), 18.1 (q), 22.3
(q), 28.3 (q), 33.0 (d), 48.8 (d), 56.5 (t), 61.4 (d), 127.1 (d), 149.2
(s), 161.3 (s), 171.8 (s), 174.7 (s); m/z (FAB) found 505.1502 ([M
+ Na]+ C21H30N4NaO5S2 requires 505.1555).
All HPLC analyses were performed using either a Hewlett
Packard series 1100 system with a reverse phase Waters-Associates
R
440, or a Nova-Pakꢀ C18 column (3.9 × 300 mm internal diameter).
Simultaneous detections of the products were carried out at several
wavelengths using a Hewlett Packard 1100 Diode Array UV detec-
tor, and also using a refractometer detector. The solvent flow was
kept at 1 ml min−1, and 10 lL samples were injected. The solvent
mixture was varied depending on the compounds being analysed.
All reactions were monitored by thin layer chromatography
(TLC) using Merck Dc-Alufolien silica gel 60F254 0.2 mm pre-
coated aluminium plates. TLC plates were visualised by quenching
of UV fluorescence (kmax = 254 nm) light and were subsequently
developed using either acidic ninhydrin solution, acidic alcoholic
vanillin solution or a basic potassium permanganate solution as
appropriate.
Routinely, organic extracts were dried over anhydrous magne-
sium sulfate or sodium sulfate. Solvents were removed in vacuo
using a Bu¨chi rotary evaporator. Anhydrous organic solvents were
stored under an atmosphere of nitrogen and/or over sodium
wire. Other organic solvents were dried by distillation as follows:
THF and dimethyl ethylene glycol (sodium benzophenone ketyl),
dichloromethane and methanol (calcium hydride), acetonitrile
(K2CO3), under an inert atmosphere. Other organic solvents and
reagents were purified according to accepted literature procedures.
Where necessary, reactions requiring anhydrous conditions were
performed in flame or oven dried apparatus under a nitrogen
atmosphere.
(1ꢀS)-2-(1-{[2-(1ꢀ-tert-Butoxycarbonylamino-2ꢀ-methylpropyl)-
thiazole-4-carbonyl]-amino}-ethyl)-thiazole-4-carboxylic acid 27.
General Procedure B
Sodium hydroxide (40 mg, 0.9 mmol) was added to a stirred
solution of the thiazole ester 26a (60 mg, 0.12 mmol) in THF–H2O
(9 : 1) (1.5 ml) at room temperature, and the mixture was stirred
at room temperature for a further 3 h. The separated aqueous
layer was acidified to pH 4 with citric acid (ca. 50 mg) and then
extracted with ethyl acetate (3 × 5 ml). The combined organic
extracts were washed with water (3 × 15 ml) and brine (3 ×
10 ml), then dried (MgSO4) and evaporated in vacuo to leave
the thiazole acid (49 mg, 90%) which crystallis◦ed as a colourless
◦
solid, mp 172–173 C (from petroleum 40–60 C–diethyl ether);
[a]2D3 −22.9 (c 1.0 in CHCl3); mmax (soln: CHCl3)/cm−1 3433, 3244,
3090, 2961, 1715, 1513; dH (360 MHz, CDCl3) 0.99 (3H, d, J
6.8, CHCH3CH3), 1.05 (3H, d, J 6.8, CHCH3CH3), 1.40 (9H, s,
But), 1.58 (3H, d, J 6.7, CH3CH), 2.86 (1H, m, CHCH(CH3)2),
5.23 (1H, m, CHCH(CH3)2), 5.32 (1H, m, NHBoc), 5.58 (1H,
m, CHCH3), 7.75 (1H, d, J 7.4, NHCO), 8.10 (1H, s, CHS), 8.21
(1H, s, CHS); dC (90.5 MHz, CDCl3) 16.8 (q), 17.2 (q), 23.3 (q),
28.7 (q), 34.3 (d), 50.3 (d), 61.7 (d), 70.6 (s), 119.6 (d), 143.2 (s),
165.0 (s), 166.3 (s), 167.9 (s), 172.0 (s); m/z (FAB) found 455.1440
([M + H]+ C19H27N4O5S2 requires 455.1423).
(1ꢀS)-2-(1-{[2-(1ꢀ-tert-Butoxycarbonylamino-2ꢀ-methylpropyl)-
thiazole-4-carbonyl]-amino}-ethyl)-thiazole-4-carboxylic acid
ethyl ester 26a. General Procedure A
(1ꢀS)-2-(1ꢀS-{[2-(1-{[2-(1ꢀ-tert-Butoxycarbonylamino-2ꢀ-
methylpropyl)-thiazole-4-carbonyl]-amino}-ethyl)-thiazole-4-
carbonyl]-amino}-ethyl)-thiazole-4-carboxylic acid ethyl ester 28
4-Methylmorpholine (60 lL, 0.6 mmol) was added dropwise
to a stirred solution of the L-valine thiazole acid 25 (181 mg,
Using General Procedure A, the bisthiazole carboxylic acid 27
(88 mg, 0.24 lmol) was coupled to the thiazole hydrochloride
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salt 249b (50 mg, 0.24 mmol) to give the tripeptide (62 mg, 68%)
as a colourless solid, mp 236–238 ◦C (from petroleum 40–60 ◦C–
diethyl ether); [a]D23 −15.7 (c 0.1 in CHCl3); mmax (soln: CHCl3)/cm−1
3400, 2874, 1738, 1651; dH (360 MHz, CDCl3) 1.01 (3H, d, J 6.8,
CHCH3CH3), 1.05 (3H, d, J 6.8, CHCH3CH3), 1.40 (3H, t, J 7.1,
OCH2CH3), 1.45 (9H, s, But), 1.62 (3H, d, J 6.8, CH3CH), 1.80
(3H, d, J 6.9, CH3CH), 2.65 (1H, app quintet, J 6.8, CH(CH3)2),
4.42 (2H, q, J 7.1, OCH2CH3), 5.06–5.10 (1H, m, CHCH3), 5.10–
5.18 (1H, m, NHBoc), 5.34 (1H, dd, J 6.8, 9.2, CHCH(CH3)2),
5.59 (1H, dq, J 6.9, 6.9, CHCH3), 7.79 (1H, d, J 8.4, NHCO), 7.97
(1H, d, J 9.3, NHCO), 8.06 (1H, s, CHS), 8.07 (1H, s, CHS), 8.08
(1H, s, CHS); dC (90.5 MHz, CDCl3) 14.2 (q), 17.9 (q), 19.6 (q),
21.0 (q), 21.2 (q), 28.2 (q), 32.9 (d), 47.0 (d), 56.4 (d), 61.3 (t), 80.2
(s), 123.9 (d), 124.0 (d), 126.9 (d), 147.3 (s), 148.9 (s), 149.0 (s),
160.4 (s), 160.6 (s), 161.2 (s), 171.6 (s), 172.9 (s), 175.0 (s), 179.8 (s);
m/z (FAB) found 659.1722 ([M + Na]+ C27H36N6NaO6S3 requires
659.1756).
in CH3CN); kmax (CH3CN)/nm 231 (e/dm3 mol−1 cm−1 19 600);
mmax (soln: CHCl3)/cm−1 3698, 3404, 2927, 1665, 1601, 1543; dH
(500 MHz, CDCl3) 1.04 (3H, d, J 6.8, CHCH3CH3), 1.09 (3H, d,
J 6.8, CHCH3CH3), 1.75 (3H, d, J 6.8, CH3CH), 1.75 (3H, d, J
6.7, CH3CH), 2.26–2.35 (1H, m, CH(CH3)2), 5.46 (1H, dd, J 5.6,
9.1, (CHCH(CH3)2), 5.58–5.71 (2H, m, (CHCH3)2), 8.13 (2H, s,
(3 × CHS)), 8.17 (1H, s, CHS), 8.53 (1H, d, J 9.1, NHCO), 8.64
(2H, d, J 7.8, (2 × NHCO)); dC (125 MHz, CDCl3) 18.4 (q), 18.8
(q), 29.7 (q), 35.5 (q), 47.2 (d), 47.3 (d), 55.8 (d), 123.6 (d), 123.8
(d), 124.1 (d), 148.7 (s), 149.0 (s), 149.1 (s), 159.5 (s), 159.6 (s),
159.7 (s), 168.6 (s), 171.0 (s), 171.4 (s); m/z (FAB) found 513.0763
([M + Na]+ C20H22N6NaO3S3 requires 513.0813).
(1ꢀS)-2-(1-{[2-(1ꢀ-Amino-2ꢀ-methylpropyl)-thiazole-4-carbonyl]-
amino}-ethyl)-thiazole-4-carboxylic acid hydrochloride 32.
General Procedure D
A solution of hydrogen chloride in 1,4-dioxane (0.1 ml, 4 M)
was added to the Boc amine 27 (25 mg, 55 lmol), and the
mixture was stirred at room temperature for 6 h under a nitrogen
atmosphere. The dioxane was evaporated in vacuo, using toluene
(ca. 0.5 ml) as an azeotrope to leave the amine hydrochloride
(20◦mg, 97%) which crystallised as a hygroscopic solid, mp 83–
84 C (from dichloromethane); [a]2D1 −28.0 (c = 0.1, MeOH); dH
(360 MHz, CD3OD) 0.97 (3H, d, J 7.2, CHCH3CH3), 1.01 (3H,
d, J 7.2, CHCH3CH3), 1.58 (3H, d, J 7.4, CH3CH), 2.56 (1H,
m, CHCH(CH3)2), 3.89 (1H, m, CHCH(CH3)2), 5.05 (1H, m,
CHCH3), 7.91 (1H, s, CHS), 8.11 (1H, s, CHS); dC (90.5 MHz,
CD3OD) 16.4 (q), 16.8 (q), 23.3 (q), 36.8 (d), 50.3 (d), 63.1 (d),
119.8 (d), 144.5 (s), 166.4 (s), 167.9 (s), 172.0 (s); m/z (FAB) found:
355.0869 ([MH − Cl]+, C14H19N4O3S2 requires 355.0899).
(1ꢀS)–(1-{[2-(1-{[2-(1-Amino-2-methyl-propyl)-thiazole-4-
carbonyl]-amino}-ethyl)-thiazole-4-carbonyl]-amino}-ethyl)-
thiazole-4-carboxylic acid hydrochloride 29
Using General Procedure B, the tristhiazole ethyl ester 28 (50 mg,
79 lmol) was converted into the corresponding carboxylic acid,
which was obtained as a yellow oil. The thiazole carboxylic acid
was then stirred with a solution of hydrogen chloride in 1,4-
dioxane (1.6 ml, 4 M) at room temperature for 2 h under an
atmosphere of nitrogen. The solvent was removed in vacuo by
azeotroping with toluene to leave the carboxylic acid hydrochloride
23
(32 mg, 75%) as a viscous oil, [a]D −76.4 (c 0.1 in CH3CN); dH
(360 MHz, CD3OD) 1.01 (3H, d, J 6.7, CHCH3CH3), 1.13 (3H,
d, J 6.7, CHCH3CH3), 1.83 (3H, d, J 6.9, CH3CH), 1.84 (3H,
d, J 6.9, CH3CH), 2.50–2.60 (1H, m, CH(CH3)2), 4.99–5.13 (1H,
m, CHCH3), 5.28 (1H, d, J 8.0, CHCH(CH3)2), 5.62–5.65 (1H,
m, CHCH3), 8.25 (1H, s, CHS), 8.37 (1H, s, CHS), 8.43 (1H, s,
CHS); dC (90.5 MHz, CD3OD) 19.1 (q), 20.0 (q), 20.3 (q), 21.1 (q),
34.3 (d), 58.3 (d), 74.1 (d), 125.9 (d), 127.4 (d), 129.4 (d), 148.0 (s),
149.8 (s), 149.9 (s), 162.3 (s), 162.9 (s), 163.9 (s), 168.9 (s), 173.4
(s), 176.8 (s).
Cyclic-(S)-alaninethiazole-(S)-valinetetrathiazole 22 and
hexathiazole
Using General Procedure C, the thiazole amino acid hydrochloride
32 (30 mg, 77 lmol) was dimerised to give the cyclic tetramer
(eluted first) (13 mg, 50%) as a colourless powder, mp 272–275 ◦C
(CH3CN–diethyl ether); [a]2D3 −90.3 (c 0.1 in CH3CN); mmax (soln:
CHCl3)/cm−1 3441, 3396, 3123, 2965, 1759, 1709, 1673, 1539;
dH (360 MHz, CDCl3) 0.89 (6H, d, J 6.7, (2 × CHCH3CH3)),
0.92 (6H, d, J 6.7, (2 × CHCH3CH3)), 1.38 (6H, d, J 6.8, (2 ×
CHCH3)), 2.10 (2H, m, CHCH (2 × CH3)), 5.40 (2H, m, (2 ×
CHCHNH)), 5.67 (2H, m, (2 × CHCH3)), 7.89 (2H, s, (2 ×
CHS)), 7.91 (2H, s, (2 × CHS)), 8.16 (2H, d, J 8.4, (2 × NHCO)),
8.22 (2H, d, J 9.2, (2 × NHCO)); dC (90.5 MHz, CDCl3) 17.3
(q), 21.2 (q), 27.8 (d), 46.2 (d), 53.1 (d), 135.2 (d), 152.6 (d),
154.9 (d), 160.1 (s), 160.8 (s), 170.8 (s), 171.6 (s); m/z (FAB)
found 673.1536 ([M + H]+ C28H33N8O4S4 requires 673.1508). The
corresponding cyclic hexamer (3 mg, 12%) (eluted second) was also
produced as a colourless powder, [a]2D3 −212.8 (c 0.05 in CH3CN);
mmax (soln: CHCl3)/cm−1 3688, 3244, 3123, 3008, 2963, 2873, 1728,
1665, 1515, 1501; dH (270 MHz, CDCl3) 1.02 (9H, d, J 7.0, (3 ×
CHCH3CH3)), 1.21 (9H, d, J 7.0, (3 × CHCH3CH3)), 1.91 (9H,
d, J 6.8 CH (2 × CH3)), 2.45 (3H, m, (3 × CHCH(CH3)2)), 5.29
(3H, m, (3 × CHCHNH)), 5.32 (3H, m, (3 × CHCH3)), 8.05 (6H,
d, J 8.2, (6 × NHCO)), 8.06 (3H, s, (3 × CHS)), 8.08 (3H, s, (3 ×
CHS)); dC (67.5 MHz, CDCl3) 19.7 (q), 19.9 (q), 21.2 (q), 34.0 (d),
41.9 (d), 45.8 (d), 53.4 (d), 55.5 (d), 60.5 (d), 67.2 (d), 124.3 (d),
Cyclic-bis-(S)-alaninethiazole-(S)-valinetristhiazole 16. General
Procedure C9b,10b
N,N-Diisopropylethylamine (17 lL, 74 lmol) was added to
a stirred solution of the x-amino acid 29 (20 mg, 37 lmol)
in anhydrous acetonitrile (7 ml) at room temperature under a
nitrogen atmosphere. The mixture was stirred at room temperature
for 3 min, then pentaflurophenyldiphenylphosphinate (FDPP,
28 mg, 74 lmol) was added and the mixture was stirred at room
temperature for a further 30 h. The solvent was evaporated in vacuo
and the residue was partitioned between dichloromethane (15 ml)
and water (5 ml). The separated aqueous layer was extracted with
dichloromethane (3 × 10 ml) and the combined organic extracts
were then washed successively with saturated aqueous K2CO3
(3 × 5 ml) and brine (2 × 5 ml), dried (MgSO4) and evaporated
in vacuo. The residue was purified by chromatography on silica
gel, eluting with light petroleum 40–60 ◦C–ethyl acetate (1 : 1)
to give the cyclic peptide (11 mg, 59%) as a colourless powder,
◦
mp 263–264 C (from CH2Cl2–diethyl ether); [a]2D3 −28.3 (c 0.1
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125.1 (d), 148.3 (d), 148.8 (s), 160.2 (s), 160.3 (s), 169.8 (s); m/z
(FAB) found 1031.2020 ([M + Na]+ C42H48N12NaO6S6 requires
1031.2042).
evaporated in vacuo, using toluene (ca. 1 ml) as an azeotrope to
leave the x-amino acid. The residue was suspended in acetonitrile
(6 ml), and then N,N-diisopropylethylamine (11 lL, 64 lmol)
and pentaflurophenyldiphenylphosphinate (23 mg, 64 lmol) were
added at 23 ◦C under a nitrogen atmosphere. The solution was
stirred at room temperature for 30 h, and then the acetonitrile
was evaporated in vacuo. The residue was partitioned between
dichloromethane (5 ml) and water (0.5 ml), and the separated
aqueous layer was extracted with dichloromethane (3 × 5 ml).
The combined organic extracts were washed successively with
saturated aqueous K2CO3 (3 × 10 ml) and brine (2 × 10 ml), then
dried over (Na2SO4) and evaporated in vacuo. The residue was
purified by chromatography on silica gel, eluting with pentane–
ethyl acetate (1 : 1) to give the cyclic peptide (11 mg, 57%) as
a colourless powder, [a]2D3 −35.4 (c 1.0 in CHCl3); mmax (soln:
CHCl3)/cm−1 3082, 2860, 1710, 1681; dH (500 MHz, CDCl3)
0.90 (6H, d, J 7.0, (CH3CH3CH)), 0.95 (6H, d, J 7.0, (2 ×
CH3CH3CH)), 1.68–170 (6H, d, J 6.8, (2 × CH3CH)), 2.66–2.68
(2H, m, (2 × CH(CH3)2), 5.38–5.42 (2H, m, (2 × CHCH(CH3)2),
5.35–5.49 (2H, br m, (2 × CHCH3)), 7.86 (2H, d, J 8.8, (2 ×
NHCO)), 7.92 (2H, d, J 8.5, (2 × NHCO)), 8.07 (2H, s, (2 ×
CHS)), 8.11 (2H, s, (2 × CHS)); dC (125 MHz, CDCl3) 17.7 (q),
17.9 (q), 27.2 (q), 27.9 (q), 33.5 (d), 56.4 (d), 68.3 (d), 123.8 (d),
126.9 (d), 147.4 (s), 149.3 (s), 160.8 (s), 161.2 (s), 171.6 (s), 171.7
(s); m/z (FAB) found 673.1515 ([M + H]+ C28H33N8O4S4 requires
673.1508).
Cyclic-tris-(S)-alaninethiazole-(S)-valinetetrathiazole 20
1 M sodium hydroxide solution (0.3 ml, 0.30 mmol) was slowly
added to a stirred solution of the tetrapeptide 36 (30 mg, 28 lmol)
in THF–H2O (9 : 1) (1.5 ml) at room temperature, and the mixture
was stirred for a further 3.5 h. The mixture was partitioned between
ethyl acetate (5 ml) and water (1 ml), and the separated aqueous
layer was then acidified to pH 4 with citric acid (ca. 40 mg) and
extracted with ethyl acetate (3 × 5 ml). The combined organic
extracts were washed with brine (3 × 10 ml), then dried (MgSO4)
and evaporated in vacuo to leave the corresponding carboxylic acid
as a colourless solid which was used immediately. The carboxylic
acid was stirred with a solution of hydrogen chloride in 1,4-
dioxane (80 lL, 4 M) at room temperature under an atmosphere
of nitrogen for 2 h. The dioxane was evaporated in vacuo, using
toluene (ca. 1 ml) as an azeotrope to leave the amine hydrochloride
37. The x-amino acid 37 was suspended in acetonitrile (8 ml),
and then N,N-diisopropylethylamine (15 lL, 87 lmol), and
pentaflurophenyldiphenylphosphinate (31 mg, 87 lmol) were
added at room temperature under a nitrogen atmosphere. The
solution was stirred at room temperature for 24 h, and then the
acetonitrile was evaporated in vacuo. The residue was partitioned
between dichloromethane (5 ml) and water (0.5 ml), and the
separated aqueous layer was extracted with dichloromethane (3 ×
5 ml). The combined organic extracts were washed successively
with saturated aqueous K2CO3 (3 × 10 ml) and brine (2 ×
10 ml), then dried over (Na2SO4) and evaporated in vacuo. The
residue was purified by chromatography on silica gel, eluting with
pentane–ethyl acetate (1 : 1) to give the cyclic peptide (10 mg,
60%) as a colourless powder, mp 251–252 ◦C (CH3CN–diethyl
ether), [a]2D3 −168 (c 0.1 in CH3CN); kmax (CH3CN)/nm 235, 237
(e/dm3 mol−1 cm−1 227 976, 228 500); dH (360 MHz, CDCl3) 1.10
(3H, d, J 6.8, CHCH3CH3), 1.19 (3H, d, J 6.8, CHCH3CH3),
1.79 (9H, d, J 7.2 (3 × CHCH3)), 2.57 (1H, m, CH(CH3)2), 5.18
(1H, m, CHCH(CH3)2), 5.65 (3H, m, (3 × CHCH3)), 8.07 (1H, s,
CHS), 8.19 (3H, s, (3 × CHS)), 8.68 (4H, m, (4 × NHCO)); dC
(90.5 MHz, CDCl3) 17.3 (q), 21.2 (q), 27.8 (d), 46.0 (d), 52.0 (d),
135.2 (d), 149.4 (d), 154.9 (d), 160.3 (s), 161.4 (s), 171.2 (s), 171.8
(s); m/z (FAB) found 645.1197 ([M + H]+ C26H29N8O4S4 requires
645.1195).
Cyclic-tris-(S)-valinethiazole-(S)-alaninetetrathiazole 23
1 M sodium hydroxide solution (0.2 ml, 0.20 mmol) was added
slowly to a stirred solution of the tetrapeptide 40 (20 mg, 24 lmol)
in THF–H2O (9 : 1) (1.0 ml) at room temperature, and the mixture
was stirred for a further 3 h. The mixture was partitioned between
ethyl acetate (5 ml) and water (0.5 ml), and the separated aqueous
layer was then acidified to pH 4 with citric acid (ca. 25 mg) and
extracted with ethyl acetate (3 × 5 ml). The combined organic
extracts were washed with brine (3 × 10 ml), then dried (MgSO4)
and evaporated in vacuo to leave the thiazole carboxylic acid, as
a colourless solid which was used immediately. The carboxylic
acid was stirred with a solution of hydrogen chloride in 1,4-
dioxane (50 lL, 4 M) at room temperature under an atmosphere
of nitrogen for 1 h. The dioxane was evaporated in vacuo, using
toluene (ca. 1 ml) as an azeotrope, to give the correspond-
ing x-amino acid. The residue was suspended in acetonitrile
(5 ml), and then N,N-diisopropylethylamine (9 lL, 55 lmol)
and pentaflurophenyldiphenylphosphinate (20 mg, 55 lmol) were
added at 23 ◦C under an atmosphere of nitrogen. The solution
was stirred at room temperature for 24 h, and then the acetonitrile
was evaporated in vacuo. The residue was partitioned between
dichloromethane (5 ml) and water (0.5 ml), and the separated
aqueous fraction was then extracted with dichloromethane (3 ×
5 ml). The combined organic extracts were washed successively
with saturated aqueous K2CO3 (3 × 10 ml) and brine (2 ×
10 ml), then dried over (Na2SO4) and evaporated in vacuo. The
residue was purified by chromatography on silica gel, eluting with
pentane–ethyl acetate (1 : 1) to give the cyclic peptide (8 mg, 53%)
as a colourless powder, [a]2D3 −83.2 (c 1.0 in CHCl3); mMax (soln:
CHCl3)/cm−1 3019, 1785, 1681; dH (500 MHz, CDCl3) 0.97 (9H,
d, J 7.2, (3 × CH3CH3CH)), 0.99 (9H, d, J 7.2, (3 × CH3CH3CH)),
Cyclic-bis-(S)-valinethiazolebis-(S)-alaninetetrathiazole 21
1 M sodium hydroxide solution (0.2 ml, 0.20 mmol) was added
slowly to a stirred solution of the tetrapeptide 39 (23 mg, 28 lmol)
in THF–H2O (9 : 1) (1.0 ml) at room temperature, and the mixture
was stirred for a further 2.5 h. The mixture was partitioned between
ethyl acetate (5 ml) and water (0.5 ml), and the separated aqueous
layer was then acidified to pH 4 with citric acid (ca. 25 mg) and
extracted with ethyl acetate (3 × 5 ml). The combined organic
extracts were washed with brine (3 × 10 ml), then dried (MgSO4)
and evaporated in vacuo to leave the thiazole carboxylic acid as a
colourless solid. The acid was used immediately and stirred with a
solution of hydrogen chloride in 1,4-dioxane (59 lL, 4 M) at room
temperature under a nitrogen atmosphere for 1 h. The dioxane was
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1.72 (3H, d, J 6.8, CH3CH), 2.58–2.63 (3H, br m, (3 × CH(CH3)2),
5.39–5.47 (3H, m, (3 × CHCH(CH3)2)), 5.52 (1H, m, CHCH3),
7.93 (3H, d, J 9.8, (3 × NHCO)), 7.97 (1H, br s, NHCO), 7.99
(3H, s, (3 × CHS)), 8.07 (1H, s, CHS); dC (125 MHz, CDCl3) 18.2
(q), 27.7 (q), 34.7 (d), 57.4 (d), 67.3 (d), 124.1 (d), 127.2 (d), 147.3
(s), 148.9 (s), 161.8 (s), 162.4 (s), 171.7 (s), 172.3 (s); m/z (FAB)
found 723.1610 ([M + Na]+ C30H36N8NaO4S4 requires 723.1640).
Didmolamide A (4)
N-Methylmorpholine (0.05 mL, 0.46 mmol) was added to a stirred
solution of the oxazoline 71a (19 mg, 0.077 mmol) and the
bisthiazole 74 (28 mg, 0.077 mmol) in dry DMF (3.85 ml) at room
temperature under a nitrogen atmosphere. The stirred mixture
was cooled to 0 ◦C and then DPPA (0.05 mL, 0.23 mmol) was
added. The yellow solution was stirred at 0 ◦C for 1 hour and then
allowed to warm to room temperature where it was stirred for
4.5 days. The mixture was evaporated in vacuo to leave a residue
which was dissolved in ethyl acetate (15 ml). The solution was
washed with H2O (2 × 10 ml) and the organic extract was then
dried (Na2SO4) and evaporated in vacuo. The residue was purified
by chromatography eluting with DCM–EA–MeOH (75 : 25 : 3)
to give i) didmolamide A (4) (0.85 mg, 2%) as a colourless solid,
[a]D29 −37.0 (c 1.0, MeOH) (lit.5 [a]D25 −35.7 (c 0.59, MeOH)); mmax
(soln, CHCl3) 3706, 2967, 1660 cm−1; dH (360 MHz, CDCl3) 1.39
(3H, d, J 10.5, CH3CHO), 1.44 (3H, d, J 6.8, CHCH3), 1.76 (3H,
d, J 6.8, CH3CH), 3.25 (1H, dd, J 14.0, 4.1, CH2Ph), 3.41 (1H,
dd, J 14.0, 4.1, CH2Ph), 4.65 (1H, dd, J 10.5, 2.3, CHCH(O)),
5.13–5.20 (1H, m, CH(O)), 5.20–5.29 (1H, m, CHCH2Ph), 5.38–
5.46 (1H, m, CHCH3), 5.46–5.60 (1H, m, CHCH3), 7.20–7.31
(5H, m, ArH), 7.69 (1H, app d, J 7.1, NH-ala), 8.10 (1H, s,
CHS), 8.17 (1H, s, CHS), 8.27 (1H, app d, J 7.7, NH-ala), 8.64
(1H, app d, J 6.5, NH-phe); dC (90.5 MHz, CDCl3) 16.5 (q), 24.2
(q), 25.0 (q), 37.4 (t), 46.2 (d), 48.0 (d), 48.1 (d), 70.4 (d), 80.8
(d), 123.8 (d), 123.9 (d), 127.3 (d), 128.2 (d), 130.0 (d), 135.6 (s),
148.4 (s), 149.1 (s), 159.4 (s), 159.8 (s), 167.7 (s), 168.3 (s), 170.8
(s), 171.2 (s); m/z (EI) 539.1535 ([M+ + H], C25H26O4N2S2 + H
requires 539.1530), and ii) the cyc◦lic tetramer 10a (5.6 mg, 12%) as
a colourless solid, mp 272–273 C (DCM–ethyl acetate–MeOH)
(lit.9 mp 270–271 ◦C (CH3CN–Et2O)); [a]D25 −148.0 (c 0.3, CHCl3)
(lit.9 [a]D23 −160.2 (c 1.0, CH3CN)); mmax (soln, CHCl3) 3696, 3370,
2962, 1666, 1602 cm−1; dH (360 MHz, CDCl3) 1.85 (12H, d, J 6.9,
(4 × CH3CH)), 5.60 (4H, app quintet, J 6.9, (4 × CHCH3)), 8.06
(4H, d, J 7.9, 4 × NHCO), 8.12 (4H, s, 4 × CHS); dC (90.6 MHz,
CDCl3) 170.9 (s), 160.0 (s), 148.4 (s), 124.9 (d), 46.1 (d), 21.3 (q).
Oxazole/bisimidazole-based cyclic trimer 57
Using General Procedure C, the bisimidazole 45 (83 mg,
0.183 mmol) was reacted with the oxazole 42a (40 mg, 0.18◦3 mmol)
to give i) the cyclic trimer (58 mg, 57%); mp 111–113 C; [a]D25
−90.2 (c 1, CHCl3); dH (360 MHz, CDCl3) 0.99–1.09 (9H, m,
(3 × –CH(CH3)(CH3)) overlapped), 0.99–1.09 (9H, m, (3 × –
CH(CH3)(CH3)) overlapped), 2.03–2.23 (2H, m, (2 × –CH(CH3)2)
overlapped), 2.27 (1H, m, –CH(CH3)2), 2.52 (3H, s, Imid-CH3),
2.53 (3H, s, Imid-CH3), 3.48 (3H, s, –NCH3), 3.50 (3H, s, –NCH3),
5.05 (1H, dd, J 8.4, 5.6 Hz, Het-CH), 5.08–5.18 (2H, m, 2 × Het-
CH), 8.12 (1H, s, Oxaz-H), 8.30 (1H, d, J 9.3 Hz, –C(O)NH), 8.36
(1H, d, J 8.7 Hz, –C(O)NH), 8.39 (1H, d, J 8.4 Hz, –C(O)NH); dC
(90 MHz, CDCl3) 9.7 (×2), 17.9, 18.2 (×2), 18.7, 19.4, 19.5, 30.3,
30.4, 33.9, 34.9, 35.0, 49.6, 50.6, 52.3, 129.5 (×2), 132.5, 132.8,
135.5, 140.8, 145.9, 147.1, 159.8, 163.2, 163.7, 164.5; HRMS [M
+ H]+ m/z 553.3261 (calcd for C28H41N8O4 553.3270), and ii) the
known cyclic tetramer 56 (8%).13
Imidazole/bisthiazole-based cyclic trimer 60
Using General Procedure C, the bisthiazole 49 (44.0 mg,
0.105 mmol) reacted with the imidazole 41a (26.0 mg, 0.105 mmol)
to give i) the cyclic trimer (24 mg, 41%): dH (360 MHz, CDCl3) 1.02–
1.09 (9H, m, (3 × –CH(CH3)(CH3)) overlapped), 1.02–1.09 (9H,
m, (3 × –CH(CH3)(CH3)) overlapped), 2.18 (1H, m, –CH(CH3)2),
2.21 (1H, m, –CH(CH3)2), 2.56 (3H, s, Imid-CH3), 2.58 (1H, m,
–CH(CH3)2), 3.53 (3H, s, –NCH3), 5.20 (1H, dd, J 9.5, 5.7 Hz,
Het-CH), 5.37 (1H, dd, J 9.4, 5.7 Hz, Het-CH), 5.42 (1H, dd,
J 9.5, 6.1 Hz, Het-CH), 8.05 (2H, s, 2 × Thiaz-H), 8.42 (1H,
d, J 9.4 Hz, –C(O)NH), 8.48 (2H, br d, J 9.5 Hz, –C(O)NH);
dC (90 MHz, CDCl3) 9.7, 17.9, 18.4, 18.5, 19.0, 19.1, 19.4, 29.8,
30.4, 34.9, 35.5, 50.4, 55.0, 55.5, 123.0, 123.3, 124.3, 146.2, 149.1,
149.5, 160.0, 160.4, 163.0, 168.5, 169.4, 169.6. HRMS [M + H]+
m/z 558.2314 (calcd for C26H36N7O3S2 558.2321), ii) the cyclic
tetramer 61 (6.9 mg, 9%): dH (360 MHz, CDCl3) 0.90–1.06 (12H,
m, (4 × –CH(CH3)(CH3)) overlapped), 0.90–1.06 (12H, m, (4 ×
–CH(CH3)(CH3)) overlapped), 2.44 (1H, m, –CH(CH3)2), 2.50
(3H, s, Imid-CH3), 2.51 (3H, s, Imid-CH3), 2.55 (2H, m, (2 × –
CH(CH3)2)), 2.63 (1H, m, –CH(CH3)2), 3.64 (6H, s, (2 × –NCH3)),
4.92 (1H, app t, J 10.2 Hz, Het-CH), 4.98 (1H, app t, J 9.6 Hz, Het-
CH), 5.13 (1H, m, Het-CH), 5.37 (1H, m, Het-CH), 7.98 (2H, s,
2 × Thiaz-H), 8.02–8.11 (4H, m, 4 × –C(O)NH overlapped); dC
(90 MHz, CDCl3) 9.8, 9.9, 17.8, 17.9, 18.1, 18.3 (×2), 18.5, 18.7,
18.8, 30.1, 31.3, 33.8, 34.2, 35.1, 35.4, 49.9, 50.3, 54.2, 55.0, 122.9,
123.4, 128.9, 130.0, 131.7, 133.0, 145.9, 146.3, 158.9, 159.3, 160.0,
160.2, 163.1, 163.4, 167.7, 168.2; HRMS [M + H]+ m/z 751.3462
(calcd for C36H51N10O4S2 751.3468), and iii) the cyclic tetramer 9b
(9%).
Didmolamide B (68)
a) Using General Procedure C, the phenylalanine threonine 72
(30 mg, 0.11 mmol) was coupled with the bisthiazole amino acid
74 (40 mg, 0.11 mmol) and the crude product was purified by
chromatography on silica eluting with DCM–EA–MeOH (75 :
25 : 2–5) to give i) didmolamide B (5.5 mg, 9%) as a colourless
foam: [a]2D5 −225.0 (c, 0.008, MeOH) (lit.5 [a]2D5 −216 (c, 0.11,
MeOH); mmax (soln, CHCl3), 3685, 2925, 1668 cm−1; dH (360 MHz,
CDCl3CD3OD) 0.85 (3H, d, J 6.5, CH3CHOH), 1.54 (3H, d, J
7.0, CH3CH-thz), 1.65 (3H, d, J 6.8, CH3CH-thz), 3.18 (1H, dd,
J 7.6, 14.2, CH2Ph), 3.31 (1H, dd, J 7.5, 10.7, CH2Ph), 4.01 (1H,
t, J 7.2, CHCHOH), 4.22–4.31 (1H, m, CHOH), 4.98–5.07 (1H,
m, CHCH2Ph), 5.30–5.39 (1H, m, CHCH3), 5.39–5.48 (1H, m,
CHCH3), 7.15–7.31 (5H, m, ArH), 7.50 (1H, d, J 6.9, NH-ala),
8.02 (1H, s, CHS), 8.03 (1H, s, CHS), 8.17 (1H, d, J 7.8, NH-
ala), 8.44 (1H, d, J 7.2, NH-thr), 8.57 (1H, d, J 8.5, NH-phe);
dC (90 MHz, CDCl3–CD3OD) 18.7 (q), 22.1 (q), 23.7 (q), 37.4
(t), 46.4 (d), 47.4 (d), 54.4 (d), 60.5 (d), 66.0 (d), 123.6 (d), 123.9
(d), 127.2 (d), 128.8 (d), 129.3 (d), 136.2 (s), 148.2 (s), 149.0 (s),
160.0 (s), 160.6 (s), 169.9 (s), 170.4 (s), 171.5 (s), 171.6 (s); HRMS:
1552 | Org. Biomol. Chem., 2007, 5, 1541–1553
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[M + H]+ m/z 557.1565 (calcd for C25H28N6O5S2 557.1642), and
ii) the cyclic tetramer 10a (5%).
b) A coupling reaction between 72 and 74, using DPPA–i-
Pr2NEt in DMF, gave didmolamide B (7%) and the cyclic tetramer
10a (12%).
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Bistratamide H (67)
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Using General Procedure C, the bisthiazole 49 (77.0 mg,
0.18 mmol) was coupled with the oxazole 73 (43.1 mg, 0.18 mmol)
to give the cyclic peptide (36 mg, 36%) as a solid: [a]2D5 −94.8 (c
1, MeOH); [lit19: −92.2 (c 1, MeOH)]; dH (360 MHz, DMSO-d6)
0.94 (3H, d, J 6.8 Hz, –CH(CH3)(CH3)), 0.96 (3H, d, J 6.8 Hz,
–CH(CH3)(CH3)), 0.98 (3H, d, J 6.8 Hz, –CH(CH3)(CH3)), 0.99
(3H, d, J 6.8 Hz, –CH(CH3)(CH3)), 1.01 (3H, d, J 6.8 Hz, –
CH(CH3)(CH3)), 1.03 (3H, d, J 6.8 Hz, –CH(CH3)(CH3)), 2.25
(3H, m, 3 × –CH(CH3)2 overlapped), 2.63 (3H, s, Oxaz-CH3), 5.10
(1H, dd, J 8.5, 5.2 Hz, Het-CH), 5.38 (1H, dd, J 8.5, 5.5 Hz, Het-
CH), 5.47 (1H, dd, J 9.7, 6.6 Hz, Het-CH), 8.37 (1H, s, Thiaz-H),
8.39 (1H, s, Thiaz-H), 8.40 (1H, d, J 10.5 Hz, –C(O)NH), 8.54
(1H, d, J 9.0 Hz, –C(O)NH), 8.56 (1H, d, J 11.0 Hz, –C(O)NH);
dC (90 MHz, DMSO-d6) 12.2, 18.9, 19.0, 19.1, 19.2, 19.5, 19.9,
33.7, 35.3, 35.5, 53.2, 55.5, 55.7, 125.7, 126.2, 128.7, 148.7, 149.2,
154.2, 159.9, 160.4, 160.7, 161.4, 169.4, 169.9; HRMS [M + Na]+
m/z 567.1777 (calcd for C25H32N6NaO4S2 567.1819).
575–577.
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2001, 66, 3459–3466; (e) S. V. Downing, E. Aguilar and A. I. Meyers,
J. Org. Chem., 1999, 64, 826–831; (f) S.-L. You and J. W. Kelly, Chem.–
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8 P. Wipf and C. P. Miller, Tetrahedron Lett., 1992, 33, 907–910.
9 (a) A. Bertram, A. J. Blake, J. S. Hannam, K. A. Jolliffe, F. Gonza´lez-
Lo´pez de Turiso and G. Pattenden, Synlett, 1999, 1723–1726; (b) A.
Bertram, A. J. Blake, F. Gonza´lez-Lo´pez de Turiso, J. S. Hannam,
K. A. Jolliffe, G. Pattenden and M. Skae, Tetrahedron, 2003, 59, 6979–
6990; (c) A. J. Blake, J. S. Hannam, K. A. Jolliffe and G. Pattenden,
Synlett, 2000, 1515–1518; see also; L. Dudin, G. Pattenden, M. S.
Viljoen and C. Wilson, Tetrahedron, 2005, 61, 1257–1267; N. Sokolenko,
G. Abbenante, M. J. Scanlon, A. Jones, L. R. Gahan, G. R. Hanson
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Abbreviations
Boc: N-tert-Butoxycarbonyl; BOP: (benzotriazol-1-yloxy)tris-
(dimethylamino)phosphonium hexafluorophosphate; DIPEA:
i-Pr2NEt (Hu¨nigs Base); DMF: HCON(CH3)2; DPPA: (PhO)2-
P(O)N3; EDCI: (dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride; FDPP: Ph2P(O)OC6F5; NMM: N-methylmorpholine; Py
BOP: benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluo-
rophosphate.
11 L. Maat and H. C. Bayerman, The Imidazole Alkaloids, in The
Alkaloids Chemistry and Pharmacology, ed. A. Brossi, Acad. Press,
San Diego, 1983, vol. 22, pp. 282–331.
12 F. K. Winkler, A. D’Arcy and W. Hunziker, Nature, 1990, 343, 771–774.
13 For earlier studies of the synthesis of imidazole-based cyclic peptides
see: G. Haberhauer and F. Rominger, Tetrahedron Lett., 2002, 43, 6335–
6338; G. Haberhauer and F. Rominger, Eur. J. Org. Chem., 2003, 3209–
3218.
Acknowledgements
14 (a) M. W. Bredekamp, C. W. Holzapfel and W. J. van Zyl, Synth.
Commun., 1990, 20, 2235–2249; (b) A. I. Meyers and X. F. Tavares,
J. Org. Chem., 1996, 23, 8203–8215; see also refs. 9 and 10.
15 L. J. Perez and D. J. Faulkner, J. Nat. Prod., 2003, 66, 247–250.
16 (a) Y. Hamada, S. Kato and T. Shiori, Tetrahedron Lett., 1985, 26,
3223–3226; (b) P. Wipf and Y. Uto, Tetrahedron Lett., 1999, 40, 5165–
5169.
We thank Putra University of Malaysia and the Malaysian
Governement for a scholarship (to SMMN), and AstraZeneca
for financial support.
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The Royal Society of Chemistry 2007
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