Chiral bicyclic tetramates as non-planar templates for chemical library synthesis

Article abstract of DOI:10.1111/cbdd.12110

Chemoselective Dieckmann cyclization reactions may be used on oxazolidine and thiazolidine templates derived from various aldehydes to access bicyclic tetramates, which have potential as templates for chemical library construction. Bioassay against Staphylococcus aureus and Escherichia coli showed that these systems have little or no intrinsic antibacterial bioactivity.

Full text of DOI:10.1111/cbdd.12110

Chem Biol Drug Des 2013; 81: 645–649
Research Article
Chiral Bicyclic Tetramates as Non-Planar Templates for
Chemical Library Synthesis
were obtained in good yield (Table 1) as stable oils and in
approximately equal ratio of inseparable diastereomers.
These products were readily purified by column chroma-
tography, but could be used directly in the next step if
desired. Coupling with monoethyl malonate using DCCI/
DMAP gave the product malonamides 6a–g also in good
yield (Table 1) and predominantly as the cis-isomer as
shown by Nuclear overhauser effect (NOE) analysis in sev-
eral casesa (Figure 1).a Cyclization under standard condi-
tions (reflux in presence of KOt-Bu) successfully gave the
desired tetramates 7a–e, g in very good yield (Table 1)
and as single diastereomers, with the ring stereochemistry
again readily established by NOE analysisb (Figure 1).b
Noteworthy was that in these systems, reaction proceeded
by initial epimerization of 6a–g to epi-6a–g followed by
ring closure from the malonyl a-carbon onto the C(4) ester
Muhammad Anwar and Mark G. Moloney*
Department of Chemistry, Chemistry Research Laboratory,
The University of Oxford, 12 Mansfield Road, Oxford, OX1
3TA, UK
*Corresponding author: Mark G. Moloney, mark.
moloney@chem.ox.ac.uk
Chemoselective Dieckmann cyclization reactions may
be used on oxazolidine and thiazolidine templates
derived from various aldehydes to access bicyclic
tetramates, which have potential as templates for
chemical library construction. Bioassay against Staph-
ylococcus aureus and Escherichia coli showed that
these systems have little or no intrinsic antibacterial
bioactivity.
of the thiazolidine ring to give products 7a–e,
g
Key words: chemical structure, cheminformatics, combinato-
(Scheme 3); this had been earlier found to be minor path-
way in the serine and threonine systems leading to tetra-
mates 3a, b (Scheme 1) (11), and we attribute this
difference both to the smaller aromatic substituent on the
thiazolidine ring and to the larger sulphur atom, which
makes the alternative C(4) enolate attack onto the terminal
ethyl ester less sterically favourable. This is borne out by
the fact that in the ring closure of thiazolidine 6 (R=t-Bu),
product 7 (R=t-Bu) was obtained only as the minor prod-
uct, with product 3c (X=S, R=H) formed as the major one,
as has been observed in the oxazolidine series (11).
Cheminformatic analysis (Table 1) indicated that several of
these compounds were indeed significantly more polar
than the t-butyl analogue 7 (R=t-Bu) (ClogP = 1.97, Polar
Surface Area [PSA] = 63.7, %PSA = 15.0), but all com-
pounds have very similar molecular volumes in the range
rial chemistry, drug design
Received 12 December 2012, revised 23 January and
accepted for publication 15 January 2013
We have been working on a programme aimed to develop
novel antibacterials modelled on natural products (1),
including equisetin (2), reutericyclin (3), kibdelomycin (4)
and streptolydigin (5), which all possess a core tetramate
unit (6). To this end, we have used our published
approach for the synthesis of highly substituted tetra-
mates, which relies upon Dieckmann cyclization of tem-
plates 2a,b derived from serine 1a (7) or threonine 1b (8).
However, this work was limited to the use of pivaldehyde
as the condensing species (Scheme 1) (9), which led to
very hydrophobic tetramate products 3a,b. We wished to
use polar aldehydes to improve molecular polarity and
aqueous solubility, so that the resulting templates were
more suitable for drug development, and embarked on a
study to expand the scope of this sequence, the results of
which are reported here.
ꢀ3
of 235–280 A . Of interest, however, is that although this
approach could be used to access the malonamide
derived from p-methoxybenzaldehyde, final ring closure
was not successful, and p-hydroxybenzaldehyde failed in
this sequence completely.
a-Methyl serine could also be reacted with 5-methylisoxa-
zole-3-carbaldehyde to give oxazolidine 8 which, on conden-
sation with malonate, gave cis- and trans-oxazolidines 9a, b
in 1:2 ratio (Scheme 4). Both oxazolidines were subjected to
standard cyclization conditions but only trans oxazolidine 9b
was successfully cyclized to give tetramate 10; the stereo-
chemistry of this product was readily established by NOE
analysis (Figure 1). Isomer 9a gave only the product from
We initially chose L-cysteine as the amino acid partner,
believing that the resulting N,S-acetal systems would be
more stable. We found that when L-cysteine methyl ester
4 was reacted with furfural, thiophene aldehyde, p-fluoro-
benzaldehyde, p-nitrobenzaldehyde, 2,3,5-trichlorbenzal-
dehyde and 5-methylisoxazole-3-carbaldehyde using the
reported conditions of reflux in petrol and triethylamine
(10), the corresponding thiazolidines 5a–g (Scheme 2)
ª 2013 John Wiley & Sons A/S. doi: 10.1111/cbdd.12110
645

Anwar and Moloney
O
MeO2C
HN
MeO2C
R
R
CO2Me
OH
CO2Me
R
4
O
Cl–H3N+
EtO
N
O
O
2
N
R
X
O
O
t-Bu
t-Bu
t-Bu
1a R = H
1b R = Me
2a R = H
2b R = Me
3a X = O, R = H
3b X = O, R = Me
3b X = S, R = H
Scheme 1: Synthesis of Tetramates by Dieckmann ring closure.
EtO2C
O
S
MeO2C
CO2Me
MeO2C
4
(i)
(ii)
(iii)
SH
O
N
Cl–H3N+
HN
EtO
N
S
S
2
4
O
O
R
R
R
5a-g
6a-g
7a-g
(i) RCHO, petrol (40/60
-20h; (ii) DCCI, DMAP, EtO2CCH2CO2H, DCM, 4h; (iii) KOt-Bu, THF
Cl
Cl
Cl
R =
F
O2N
MeO
N
Me
O
S
O
a
c
e
g
b
d
f
Scheme 2: Synthesis of Core Templates derived from Cysteine.
Table 1: Yields and cheminformatic data for products in Scheme 1
Yield (%)
Cheminformatic dataa for products 7
Compound (R)
5
6
7
ClogP
PSA
80.0
66.8
66.8
112.7
66.8
–
MSA
%PSA
a (R=C4H3O)
b (R=C4H3S)
c (R=FC6H4)
d (R=O2NC6H4)
e (R=Cl3C6H4)
f (R=MeOC6H4)
g (R=C4H4NO)
71 (1:1)
76 (1:1)
73 (3:2)
58 (1:1)
73 (1:1)
65 (2:1)
52 (1:3)
74 (3:1)
61 (1:0)
68 (4:1)
72 (5:3)
78 (5:2)
61 (2:1)
64 (5:2)
59
62
57
63
68
–
0.85
1.7
1.9
1.7
3.6
–
364
371
398
432
438
–
22.0
18.0
16.8
26.1
15.2
–
49
0.22
92.9
388
23.9
aData compiled using Chemicalize.c
methyl ester hydrolysis. For the product 10, it was found that
ClogP 0.02 and %PSA 24.4 were consistent with a highly
polar template, as might be expected.
and suggests that these heterocyclic templates may pro-
vide useful skeletons for elaboration to biologically active
systems.
Antibacterial biossayd of these compounds with Staphylo-
coccus aureus and Escherichia coli showed that they were
inactive for all compounds at concentrations of 2 and
4 mg/mL, with the exception of tetramate 7c, which was
found to be weakly active against S. aureus and E. coli,
and compound 7b, which was weakly active against
E. coli, an outcome of interest because the two of them
have very similar ClogP and %PSA values. This general
lack of bioactivity is consistent with our earlier results,
which show that the intrinsic antibacterial activity of simple
pyroglutamates (12,13) and tetramates is low (14). On the
other hand, introduction of appropriate side chain substitu-
ents returns antibacterial activity very effectively (14,15),
Recently, there has been interest in the identification of
heterocyclic systems (16) with increased molecular
complexity suitable for ‘escaping from flatland’ in the pro-
cess of drug discovery (17,18). The systems reported
herein offer non-planar but stereochemically well-defined
skeletons, with several points of diversity, in as few as 3
synthetic steps from readily available starting materials and
with favourable values of MW, PSA, numbers of rotatable
bonds, H-bond acceptors and H-bond donors. Moreover,
they have ample scope for ADMET optimization using the
Lipinski parameters, for application in fragment-based drug
design (19), in which there is significant current interest
(20). They therefore offer promise for application as core
646
Chem Biol Drug Des 2013; 81: 645–649

Chiral Bicyclic Tetramates as Non-Planar Templates
O
O
O
O
Me
H
H
H
O
O
O
O
O
N
H
S
O
N
H
S
O
N
H
O
O
N
H
S
O
O
O
O
O
O
H
O
O
H
H
N
N
O
O
F
OMe
5c
5g
9a
5f
EtO2C
O
OH
EtO2C
O
OH
EtO2C
OH
EtO2C
O
OH
H
H
H
H
H
H
H
H
H
O
N
N
S
N
N
H
H
H
Cl
S
S
S
S
H
H
H
H
Cl
H
H
H
F
O2N
Cl
7c
7e
7b
7d
EtO2C
OH
O
EtO2C
OH
Me
H
H
H
O
H
O
H
N
N
N
H
H
S
H
H
N
O
O
7g
10
Figure 1: NOE enhancements for key compounds.
EtO2C
O
O
O
S
MeO2C
MeO2C
CO2Me
4
2
4
O
EtO
N
EtO
N
S
S
2
N
X
N
S
O
O
O
O
R
R
R
R
6a-g
epi-6a-g
7a-e,g
3c
Scheme 3: Chemoselectivity in Dieckmann ring closure.
CHO
R1
R2
O
EtO2C
O
MeO2C
HN
Me
O
N
Me
O
Me
4
N
2
DCCI, DMAP,
EtO
Me
CO2Me
OH
O
N
Et3N, toluene
51%
EtO2CCH2CO2H
KOt-Bu
N
Cl–H3N+
O
O
O
THF
56%
62%
N
Me
O
N
O
O
Me
Me
9a R1 = CO2Me, R2 = Me
9b R1 = Me , R2 = CO2Me
10
8
Scheme 4: Synthesis of Core Templates derived from a Serine Template.
Chem Biol Drug Des 2013; 81: 645–649
647

Anwar and Moloney
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oxazolidine systems (1).
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Acknowledgments
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We are particularly grateful for valuable input by Drs Phil
Dudfield and John Lowther (Galapagos NV).
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Notes
aGeneral acylation method: To a stirred solution of thiazoli-
dine 5a–g and dicyclohexylcarbodiimide (DCCI) and DMAP in
DCM (20 mL) at 0°C was added a solution of ethyl hydrogen
malonate in DCM (3 mL). The mixture was stirred at 0°C for
15 min then at room temperature for 4–5 h. The reaction
mixture was filtered to remove dicyclohexyl urea, the residue
was washed with DCM (3 9 15 mL), and the combined
filtrates were evaporated in vacuo to give products 6a–g.
bGeneral cyclization method: To a solution of thiazolidine
6a–g (1.0 mmol) in dry THF (15 mL) was added KOtBu
(1.05 mmol) and solution was heated at reflux for 3 h,
cooled to room temperature and partitioned between ether
(15 mL) and water (2 9 15 mL). The aqueous layer was
648
Chem Biol Drug Des 2013; 81: 645–649

Chiral Bicyclic Tetramates as Non-Planar Templates
acidified with 2 M HCl and extracted with ethyl acetate
(3 9 15 mL). The combined ethyl acetate extracts were
washed with brine, dried over MgSO4 and evaporated in
vacuo. The residue was purified by flash column chroma-
tography (EtOAc:MeOH; 5:1) to give the products 7a–e, g.
cChemicalize.org was used for drawing, displaying and
characterizing chemical structures, substructures and
reactions (http://www.chemaxon.com).
prepared with cephalosporin C; this is expressed as zone
diameter per M, of the analyte relative to cephalosporin
C standard.
Supporting Information
d
Bioassay of products: (21–23) Microbiological assays
Additional Supporting Information may be found in the
online version of this article:
were performed by the hole-plate method with the test
organism Staphylococcus aureus N.C.T.C. 6571 or E. coli
X580. Solutions (100 lL) of the compounds to be tested
(4 mg/mL) were loaded into wells in bioassay plates, and
incubated overnight at 37°C. The diameters of the resul-
tant inhibition zones were measured (Æ1 mm), and rela-
tive potency estimated by reference to standards
Appendix S1. Electronic supporting information (Experi-
mental details).
Appendix S2. Electronic supporting information (NMR
spectra).
Chem Biol Drug Des 2013; 81: 645–649
649