Synthesis and antibacterial activity of bicyclic lactam-lactones

Article abstract of DOI:10.1055/s-0030-1261197

The synthesis of a lactam-lactone bicyclic system containing a pyroglutamate subunit proceeds to give the fused lactone system, which is favoured over the spirocyclic lactone alternative. These systems display no or weak antibacterial activity against the

Full text of DOI:10.1055/s-0030-1261197

LETTER
2181
Synthesis and Antibacterial Activity of Bicyclic Lactam–Lactones
S
ynthesis and
l
A
ntiba
a
c
terial Acti
m
c
e
tam–Lacton
n
e
s
Angelov,a Kallappa M. Hosamani,b Yong-chul Jeong,c Mark G. Moloney,*c Amber L. Thompson,c
Muhammad Yaqoobc
a
Department of Organic Chemistry, University of Plovdiv, 24 ‘Tsar Asen’ Str., 4000 Plovdiv, Bulgaria
Department of Studies in Chemistry, Karnatak University, Pavate Nagar, Dharwad 580003, India
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
b
c
Fax +44(1865)275002; E-mail: mark.moloney@chem.ox.ac.uk
Received 10 June 2011
sation.9 It was found that similar endo-phenylacetylide
delivery also generates the pyroglutaminol 3b in good
yield (92%), the stereochemistry of which was established
by NOE analysis (Figure 2) and confirmed by single crys-
tal X-ray analysis (Figure 3).10 Similar highly chemose-
lective acetylide additions have been reported.11
Deprotection of the oxazolidine ring of each of 3a,b using
Corey–Reichard conditions12 gave alcohols 4a,c in excel-
lent yields, and the stereochemistry of 4c was established
by single crystal X-ray crystallography (Figure 3).10 Ester
hydrolysis (LiOH, THF, H2O, MeOH) of 4a to give acid
4b, which could be easily isolated by acid-base extraction
in highly pure form, was followed by b-lactone formation
using tosyl chloride–pyridine conditions. Although two
possible modes of cyclisation were possible, only fused
bicyclic product 5a and not the alternative spirocyclic
product was obtained, although their calculated enthalpies
are similar at –115.1 kcal/mol and –118.4 kcal/mol, re-
spectively (Spartan), and after optimisation, yields were
up to 80%.13 That b-lactone formation had been achieved
was clearly indicated from IR and 13C NMR analysis (n =
1835 cm–1 and d = 167.5 ppm), but unequivocal assign-
ment of selectivity was possible only with successful
characterisation of lactone 5a by single crystal X-ray anal-
ysis (Figure 3).10 It was found that lactam 5a could be
readily acylated by reaction with acetyl chloride and tri-
ethylamine to give 5b in 75% yield or methylated using
neat methyl iodide and caesium carbonate to give the N-
methyl derivative 5c in quantitative yield, confirmed by
IR absorptions at 1810, 1716 and 1689 cm–1. The prefer-
ence for the formation of the fused b-lactone product in
this case is likely to be due to the conformational con-
straint which places the reacting carboxylic acid and alco-
hol functions in close proximity.
Abstract: The synthesis of a lactam–lactone bicyclic system con-
taining a pyroglutamate subunit proceeds to give the fused lactone
system, which is favoured over the spirocyclic lactone alternative.
These systems display no or weak antibacterial activity against the
test organisms S. aureus and E. coli.
Key words: heterocycles, natural products, cyclisation, antibiotics,
lactams
Spirocyclic and fused lactone–lactam systems 1 and 2
(Figure 1) have been of recent interest, both as a result of
their occurrence in the salinosporamide,1 cinnabarimide2
and oxazolomycin3 natural products, and of their confor-
mationally well-defined structures, providing useful tem-
plates for drug design (e.g. MI-219 which possesses
p53:MDM2 inhibitory activity4). Methodology is now
well established to access spirocyclic5 and fused b-lac-
tone–lactam systems,1,6 and given the ease with which it
is possible to prepare highly functionalised tetramates us-
ing some of our recently reported methodology,7 it was of
interest to examine the possibility of direct lactone forma-
tion in a highly functional pyroglutamate nucleus; we
have already made use of modified tetramates for the
preparation of mimics of oxazolomycin.8
O
O
N
O
H
2-oxa-5-azaspiro[3.4]octane-1,6-dione (1)
O
O
O
N
H
6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione (2):
Ph
Figure 1
HO
Me
Me
O
CO2Me
We recently reported that pyroglutamate 3a (Scheme 1) is
readily available by kinetically controlled endo-delivery
of a dithiane anion to the parent tetramate,7 and this out-
come is different from that obtained by direct aldol cycli-
H
H
N
O
t-Bu
H
3b
SYNLETT 2011, No. 15, pp 2181–2184
x
x
.x
x
.2
0
1
1
Advanced online publication: 24.08.2011
DOI: 10.1055/s-0030-1261197; Art ID: D18011ST
Figure 2
© Georg Thieme Verlag Stuttgart · New York

2182
P. Angelov et al.
LETTER
R
CO2Me
HO
Me
O
N
Me
O
t-Bu
3a R = 1,3-dithian-2-yl
3b R = C≡CPh (92%)
F3CCH2OH, HCl
HS(CH2)3SH
Ph
Me
Me
R1
(i) LDA (2 equiv), THF
(ii) p-TsCl, THF
or Mitsunobu
HO
Me
R1
CO2R2
HO
Me
p-TsCl, Et3N, THF
Me
O
N
NH
H
O
Me
N
H
HO
HO
O
7 (40–50%)
6a R1 = 1,3-dithian-2-yl
6b R1 = phenylethynyl
4a R1 = 1,3-dithian-2-yl; R2 = Me (89%)
4b R1 = 1,3-dithian-2-yl; R2 = H (81%)
4c R1 = phenylethynyl; R2 = Me (89%)
4d R1 = phenylethynyl; R2 = H (92%)
LiOH, THF, MeOH,
H2O then HCl
LiOH, THF, MeOH,
H2O then HCl
(i) p-TsCl, py, CH2Cl2, r.t.
(ii) MeI, Cs2CO3, r.t., overnight
S
O
O
S
Me
OR1
NR2
Me
O
5a R1 = H; R2 = H (80%)
5b R1 = OAc; R2 = H (75%)
5c R1 = OAc; R2 = Me (95%)
Scheme 1
However, of interest was that application of this sequence out b-lactone formation. In an attempt to force the desired
to the corresponding phenylethynyl derivative 4c gave no cyclisation, double deprotonation of 4b and 4d with two
isolable lactone products; thus hydrolysis of ester 4c and equivalents of LDA followed by reaction with one equiv-
subjection of the product 4d to the tosyl chloride–pyridine alent of TsCl gave not the desired product, but the enam-
conditions gave only enyne 7 in yields of 40–50%, possi- ides 6a and 6b, respectively. An attempted cyclisation of
bly arising from transient formation of the desired fused 4b by intramolecular Mitsunobu reaction (Ph3P, DEAD or
b-lactone followed by collapse with loss of carbon diox- DIAD) gave alkene 6a; however, application of this se-
ide, although another route is by direct decarboxylation– quence to 4d gave only a complex mixture of products.
elimination of the expected tosyloxy intermediate, with- Neither 6a nor 6b were stable nor could they be isolated
Figure 3 Thermal ellipsoid plots (ORTEP-3) at 40% probability level for compounds 3b, 4c and 5a
Synlett 2011, No. 15, 2181–2184 © Thieme Stuttgart · New York

LETTER
Synthesis and Antibacterial Activity of Bicyclic Lactam–Lactones
2183
Table 1 Cheminformatic and Bioactivity Data for Selected Compounds
Compound cLogPa
PSAa
%PSAa
MSAa
CMRa
Polarisabilitya
Bioactivityb
S. aureus
E. coli
inactive
–
4a
4b
4c
4d
5a
5b
0.32
0.16
1.1
95.9
106.9
95.9
20.4
24.7
20.9
25.3
18.6
17.3
469.5
433.6
458.6
422.2
407.4
470.8
79.5
74.7
81.3
76.5
73.0
82.2
32.0
30.6
32.7
30.6
29.5
33.3
inactive
inactive
inactive
inactive
inactive
inactive
weakly active
–
0.9
106.9
75.6
0.85
1.31
weakly active
inactive
81.7
a cLogP, polar surface area parameter (PSA), calculated molecular refractivity (CMR) and molecular surface area (MSA) were calculated using
Marvin;15 %PSA = (PSA/MSA) × 100%.
b Inhibition by hole-plate bioassay using 100 mL of a 4 mg/mL solution (DMSO).
in pure form, and evidence for their formation came from glutamates,17,18 which we have also shown not to exhibit
NMR spectroscopic (methylene resonances in the region significant bioactivity.
d = 5.5–6.5 ppm) and mass spectrometric data.
Calculation of some cheminformatic parameters,14 includ-
ing polarisability, calculated molecular refractivity
(CMR), cLogP, polar surface area (PSA), molecular sur-
face area (MSA) and molecular volume, was made using
Marvin (www.chemaxon.org, accessed via chemical-
ize.org),15 and the relevant data are included in Table 1.
The cLogP values (0.32–1.3) confirm the hydrophilic
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by EPSRC (grant GR/T20380/01), by the
Korea Research Foundation Grant funded by the Korean Govern-
character of all compounds and the van der Waals molec- ment (MOEHRD; KRF-2006-352-C00044), and Professor K. M.
Hosamani is highly indebted to the British Commonwealth Schol-
ular surface area (MSA) is in the range of 405–470, as
arship Commission UK for the award of a Commonwealth Acade-
would be expected from their common structural skeleton.
mic Staff Fellowship – 2008/2009 (Ref. No. INCF-2008-68).
The CMR, polarisability and %PSA parameters are in the
Plamen Angelov gratefully acknowledges funding from EC (FP7/
range of 73–83, 30–34, and 17–25%, respectively, consis-
REGPOT-2009-1/BioSupport).
tent with a tightly defined library. No compounds exhibit-
ed activity against S. aureus, and only 4c and 5a were
References and Notes
weakly active against E. coli. We recently reported two
different tetramate libraries which exhibited activity
against E. coli possessing cLogP and %PSA values of 2.3
0.9 and 16.5 3.0, and –0.6 0.6 and 26.2 4.1 respec-
tively.16 Of interest is that the weakly active compounds
4c and 5a lie outside both of these ranges, and this may ac-
count for their low activity; noteworthy is the lack of ac-
tivity of 5b, and this suggests that the b-lactone itself is
insufficient for the introduction of antibacterial activity in
these systems. This observation is consistent with our re-
cently reported results in which we demonstrated that al-
though simple tetramates do not exhibit antibacterial
activity,8 larger conjugates do, probably since they pos-
sess better cell membrane permeability.
(1) Moore, B. S.; Gulder, T. A. M. Angew. Chem. Int. Ed. 2010,
49, 9346.
(2) Stadler, M.; Bitzer, J.; Mayer-Bartschmid, A.; Müller, H.;
Benet-Buchholz, J.; Gantner, F.; Tichy, H.-V.; Reinemer, P.;
Bacon, K. B. J. Nat. Prod. 2007, 70, 246.
(3) Moloney, M. G.; Trippier, P. C.; Yaqoob, M.; Wang, Z.
Curr. Drug Discovery Technol. 2004, 1, 181.
(4) Zinzalla, G.; Thurston, D. E. Future Med. Chem. 2009, 1, 65.
(5) (a) Mondal, D.; Bera, S. Synthesis 2010, 3301. (b) Yamada,
T.; Sakaguchi, K.; Shinada, T.; Ohfune, Y.; Soloshonok, V.
A. Tetrahedron: Asymmetry 2008, 19, 2789. (c) Donohoe,
T. J.; Chiu, J. Y. K.; Thomas, R. E. Org. Lett. 2007, 9, 421.
(d) Mohapatra, D. K.; Mondal, D.; Gonnade, R. G.;
Chorghade, M. S.; Gurjar, M. K. Tetrahedron Lett. 2006, 47,
6031. (e) Papillon, J. P. N.; Taylor, R. J. K. Org. Lett. 2000,
2, 1987.
(6) (a) Borissenko, L.; Groll, M. Chem. Rev. 2007, 107, 687.
(b) Nguyen, H.; Ma, G.; Gladysheva, T.; Fremgen, T.;
Romo, D. J. Org. Chem. 2011, 76, 2.
(7) Moloney, M. G.; Yaqoob, M. Tetrahedron Lett. 2008, 49,
6202.
(8) Bagwell, C. L.; Moloney, M. G.; Yaqoob, M. Bioorg. Med.
Chem. Lett. 2010, 20, 2090.
(9) Andrews, M. D.; Brewster, A. G.; Moloney, M. G. Synlett
1996, 612.
We have shown that the fused 6-oxa-2-azabicy-
clo[3.2.0]heptane-3,7-dione but not the alternative spiro-
cyclic system can be obtained by a selective lactonisation
process from a highly functional pyroglutamate precursor,
and that the cyclisation is dependent on the nature of the
lactam ring substituents. Moreover, such compounds are
not strongly antibacterial against the test organisms S. au-
reus and E. coli; this behaviour appears to be similar to
that of other simple tetramates16 and spirocyclic pyro-
Synlett 2011, No. 15, 2181–2184 © Thieme Stuttgart · New York

2184
P. Angelov et al.
LETTER
(10) Crystallographic data (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data
Centre (3b: CCDC 827286, 4c: CCDC 827287, 5a: CCDC
682703) and copies of these data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif.
(11) Cordero-Vargas, A.; Perez-Martin, I.; Quiclet-Sire, B.; Zard,
S. Z. Org. Biomol. Chem. 2004, 2, 3018.
(12) Corey, E. J.; Reichard, G. A. J. Am. Chem. Soc. 1992, 114,
10677.
(13) Calculated by using semi-empirical AM1 and PM3 at
ground state in Spartan 02.
(15) Marvin 5.2.1(2009) was used for drawing, displaying and
characterising chemical structures, substructures and
reactions. Calculator plugins were used for structure
property prediction and calculation, Marvin 5.2.5.1(2009)
by ChemAxon (http://www.chemaxon.com).
(16) Holloway, C. A.; Matthews, C. J.; Jeong, Y.-C.; Moloney,
M. G.; Roberts, C. F.; Yaqoob, M. Chem. Biol. Drug. Des.
2011, 78, 229.
(17) Jeong, Y.-C.; Moloney, M. G. Synlett 2009, 2487.
(18) Hill, T.; Kocis, P.; Moloney, M. G. Tetrahedron Lett. 2006,
47, 1461.
(14) Hann, M. M.; Leach, A. R.; Harper, G. J. Chem. Inf. Comput.
Sci. 2001, 41, 856.
Synlett 2011, No. 15, 2181–2184 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.