Access to the bicyclic core of isatisine, and an investigation of its antibacterial activity

Article abstract of DOI:10.1055/s-0030-1259330

A chemoselective Dieckmann ring closure using an oxazolidine derived from serine may be used to generate a tetramic acid, the further manipulation of which by reduction and ring closure leads to the bicyclic core of isatisine; depending on the nature of t

Full text of DOI:10.1055/s-0030-1259330

378
LETTER
Access to the Bicyclic Core of Isatisine, and an Investigation of Its
Antibacterial Activity
Bicyclic Core of
h
Department of Chemistry, Chemistry Research Laboratory, The University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
Fax +44(1865)285002; E-mail: mark.moloney@chem.ox.ac.uk
Received 15 November 2010
ly novel alkaloid shown to have moderate anti-HIV activ-
Abstract: A chemoselective Dieckmann ring closure using an ox-
ity (EC50 37.8 mM) and cytotoxicity against C8166 cells
azolidine derived from serine may be used to generate a tetramic ac-
id, the further manipulation of which by reduction and ring closure
leads to the bicyclic core of isatisine; depending on the nature of the
(CC50 302 mM).13 This compound was first isolated from
the leaves of the Chinese plant Isatis indigotica Fort. (cru-
ring closing electrophile, different diastereomers are obtained. ciferae) in 2007, and the roots and leaves of I. indigotica
None of the compounds from this sequence exhibited activity
against S. aureus but several showed activity against E. coli.
have been used in traditional Chinese medicine for the
treatment of bacterial and viral infections, and immuno-
regulatory and tumour diseases.14 The first total synthesis
Key words: heterocycles, natural products, cyclisation, antibiotics,
lactams
of (+)-isatisine A was completed earlier this year by Ka-
radeolian and Kerr in 14 steps with an overall yield of
5.8%.15
The discovery of new antibiotics has become imperative
Retrosynthetic analysis (Scheme 1) of isatisine 1 suggest-
ed that functional group simplification could give tricycle
2, which would in turn be readily generated from tetramic
acid 3 by reduction and cyclisation; such systems are
by reason of the emergence of bacterial strains resistant to
current clinically-effective drugs,1 and the urgency of the
task has recently been emphasised.2 However, since there
is a paucity of New Chemical Entities (NCE) entering the
available from oxazolidines 4 using our previously pub-
antibacterial pipeline,3 a number of new strategies for
lished approaches by aldol16 or Dieckman17 cyclisation.
more efficient drug development have been elaborated in
An initial investigation of this strategy (Scheme 2) using
oxazolidine 7a (prepared by acylation of oxazolidine 5
with the malonate half ester 6a) involved allylation using
cinnamyl bromide to give 7b, confirmation of the relative
recent years4 and re-examination of the function and
availability of natural products has been pivotal.5 In par-
ticular, it has recently become apparent that the physico-
chemical characteristics of antibacterial compounds differ
stereochemistry being readily achieved by single crystal
sufficiently from the property space of commonly avail-
X-ray analysis.18 Chemoselective Dieckmann cyclisation
able compound libraries that re-investigation of natural
gave tetramate 8a in 63% yield. Reduction by a well-
products to identify novel antibacterials is fully justified6
established19 procedure using NaBH4–AcOH gave
and that the structural information thus obtained will be
epimeric alcohols 10a and 11a in a ratio of 1:1.5 and mod-
est overall yield (relative stereochemistry assigned on the
basis of nOe data; see Supporting Information). This ste-
useful for the design of NCE suitable for fragment-based
drug design.7 Libraries based upon such natural product
leads have several key benefits which do not apply to
reochemical outcome resulted from epimerisation at the
combinatorially-derived systems: they will have benefited
acidic C(7) position, although fully diastereoselective
from the optimisation of bioactivity for a given receptor as
endo-hydride addition at C-6 was observed.20 Epoxidation
(MCPBA) of 10a and 11a proceeded without diastereo-
control to give 12 and 13, both in good yield, and ring clo-
sure of 12 under basic conditions gave the desired
tricyclic core 14 as a mixture of four inseparable diastere-
omers, as shown by NMR and MS analysis. As expected,
similar treatment of epimeric epoxide 13 returned unre-
acted starting material. This approach demonstrated that a
a result of natural selection; they will be expected to pro-
vide an enhanced rate of positive hits for a given library
size; they are more likely to provide novel structural
chemotypes not currently in use in existing therapeutic re-
gimes; they would not be immediately susceptible to re-
sistance-conferring genes in the bacterial and DNA pools
and they are likely to provide novel new target proteins
and receptors.8 Mindful of the long-standing application
strategy based upon cycloetherification was possible, but
of traditional Chinese medicine,9 and to develop further
that improvements in yield and diastereoselectivity would
the compound and bioactivity space encompassed by pyr-
be required.
rolidin(on)es as commonly occurring core structural com-
To develop this approach further, allylation of oxazolidine
7a proved to be possible, but the yield was only 36%, and
we found that the synthesis of the required allyl derivative
7c could be better achieved in 58% yield by acylation of
oxazolidine 5 with ethyl allylmalonate 6b directly (pre-
pared by partial hydrolysis of diethyl allylmalonate) using
ponents of natural products,10–12 we examined isatisine A
as an unusual lead structure. Isatisine A (1) is a structural-
SYNLETT 2011, No. 3, pp 0378–0382
x
x.
x
x.
2
0
1
1
Advanced online publication: 19.01.2011
DOI: 10.1055/s-0030-1259330; Art ID: D30410ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Bicyclic Core of Isatisine
379
OH
O
OH
O
H
HO
HO
MeO2C
R
N
O
CO2Me
H
O
EtO
N
CO2Me
O
O
O
N
N
O
N
O
O
t-Bu
O
O
t-Bu
t-Bu
2
3
4
isatisine A (1)
Scheme 1
DCCI–DMAP, conditions which we found to be superior ditions, since this would have led to a trans-fused bicyclic
to a similar recently reported coupling using MsCl– ring system.
Et3N.21 Dieckmann ring closure of oxazolidine 7c to give
allyl tetramate 8b proceeded smoothly and in excellent
yield (92%), but column chromatographic purification re-
quired the use of alumina, since silica gel led to epimeri-
sation at C(7); the relative stereochemistry was
determined by an NOE experiment (see Supporting Infor-
mation). Moreover, we found that variable quantities of 9
were also obtained from this cyclisation, presumably as a
result of adventitious water leading to ester hydrolysis and
decarboxylation, and this material could not be separated
from the major product 8b; careful exclusion of water suc-
cessfully prevented this side reaction, as has been noted
previously.17 Application of the above reduction proce-
dure using excess NaBH4–AcOH led to formation of alco-
hols 10b and 11b (ratio 2:1), along with significant
recovery of starting material 8b (18–41%). Alternative
conditions were investigated (2–15 equiv of NaBH4 with
addition of CeCl3 or CaCl2; use of LiBH4), but selective
formation of 10b could not be achieved. The relative ste-
reochemistries of 10b and 11b were readily established by
NOE experiments (see Supporting Information). Attempt-
ed conversion of 11b to 10b by deprotonation (LDA, –78
°C) and low temperature quench with ammonium chloride
Figure 1 Thermal ellipsoid plot of 15a with the heteroatoms label-
led and drawn at 50% probability
With the expectation that this route might be shortened by
one step, it was of interest to apply our recently published
protocol for plumbolactonisation,22 a modification of
which was found to be also suitable for plumboetherifica-
tion;23 we found that cyclisation of tetramate 10b using
lead tetrabenzoate or lead tetra(thiophene-2-carboxylate)
gave the desired products, but only as the unwanted dias-
tereomers 16d and 16e, respectively (yields of 21% and
gave a 49% recovery of 11b, along with some of the de-
sired alcohol 10b (13% isolated yield).
With the desired allylpyroglutamate 10b in hand, investi-
99%) with no trace of the other stereoisomers 15d and
gation of electrophilic tetrahydrofuran ring closure was
15e; relative stereochemistry being again established by
NOE experiments (see Supporting Information). We have
observed that the thiophene-2-carboxylate system gives
better yields and is also much more reactive than other
investigated (Scheme 2). Treatment with I2–NaHCO3 re-
sulted in 5-exo-tet ring closure giving diastereomers 15a
and 16a in a ratio of 10:3 (61% yield). The two epimers
arylcarboxylates in these cyclisations22–24 and believe that
the change in stereochemical outcome in this case arises
because the reaction proceeds by initial co-ordination of
the C(6) hydroxy function rather than the alkene to the
lead(IV) followed by syn-oxyplumbylation.25 Deprotec-
tion of 16e using Corey–Reichard conditions26 gave the
bicyclic product 18a in excellent yield (75% yield) and
this material was readily converted to diester 18b by
DCC–DMAP coupling. Once again, epimeric alcohol 11b
did not ring close under these conditions, but of interest is
that tetramate 8b cyclised to give tricycle 19, whose struc-
ture was established by NMR analysis, although it was
formed in only 12% yield.
were inseparable by column chromatography, but careful
recrystallisation (CH2Cl2–n-heptane) provided access to
the pure major epimer 15a, whose structure was deter-
mined by an NOE experiment and single crystal X-ray
analysis (see Supporting Information and Figure 1).18 Re-
action of the 15a/16a mixture with potassium p-nitroben-
zoate and a catalytic amount of 18-crown-6 gave
inseparable benzoates 15b/16b in 31% overall yield, and
another separable by-product 17 (24%), presumably aris-
ing by elimination from 15b/16b followed by double bond
equilibration. Hydrolysis of the mixture of esters 15b/16b
proceeded smoothly under basic conditions and furnished
alcohols 15c/16c in quantitative yield. Unsurprisingly,
epimeric alcohol 11b did not ring close under these con-
Synlett 2011, No. 3, 378–382 © Thieme Stuttgart · New York

380
C. J. Matthews et al.
LETTER
R1
MeO2C
HN
t-Bu
(i)
O
O
O
O
MeO2C
R1
O
O
5
6
6
CO2Me
(ii)
+
O
O
EtO
N
O
EtO
OH
N
N
2
2
R1
O
O
O
t-Bu
t-Bu
t-Bu
6a R1 = H
7a R1 = H (70%)
8a R1 = Ph (63%)
8b R1 = H (92%)
9
6b R1 = CH2CH=CH2
7b R1 = CH2CH=CHPh (80%)
7c R1 = CH2CH=CH2 (58%)
(iii)
R1
R1
H
X
H
X
O
O
OH
OH
CO2Me
H
H
H
H
(vi), (ix),
or (x)
CO2Me
CO2Me
+
CO2Me
+
O
O
O
O
N
N
N
N
O
O
O
O
t-Bu
15a R1 = I (47%)
t-Bu
t-Bu
t-Bu
16a R1 = I (14%)
10a R1 = Ph (24%)
10b R1 = H (20%)
11a R1 = Ph (32%)
11b R1 = H (10%)
(vii)
(viii)
(vii)
(viii)
15b R1 = OC(O)C6H4p-NO2 (26%)
15c R1 = OH (87%)
16b R1 = OC(O)C6H4p-NO2 (5%)
16c R1 = OH (13%)
15d R1 = OC(O)C6H5 (0%)
15e R1 = OC(O)C4H3S (0%)
16d R1 = OC(O)C6H5 (21%)
16e R1 = OC(O)C4H3S (99%)
(iv)
Ph
(iv)
Ph
(xi)
O
OH
O
O
O
OH
CO2Me
CO2Me
H
CO2Me
O
N
H
O
O
N
S
O
O
N
O
t-Bu
O
H
H
O
CO2Me
t-Bu
t-Bu
12 (68%)
O
17 (24%)
N
H
13 (97%)
(v)
HO
O
X
(v)
18a R = H (75%)
18b R = C(O)C4H3S (69%)
(xii)
Ph
OH
O
O
S
O
CO2Me
H
H
O
N
CO2Me
O
O
N
t-Bu
O
19 (12%)
t-Bu
14
Scheme 2 Reagents and conditions: (i) EDAC or DCC, DMAP, 5; (ii) NaOMe, MeOH, r.t., 3 d; (iii) NaBH4 (15 equiv), AcOH (10%), CH2Cl2,
r.t.; (iv) MCPBA, CH2Cl2; (v) K2CO3, MeOH; (vi) I2, NaHCO3, MeCN; (vii) KO2CC6H4NO2, 18-C-6, MeCN; (viii) Na2CO3, H2O, EtOH; (ix)
(PhCO2)4Pb, F3CPh; (x) (C4H3SCO2)4Pb, F3CPh; (xi) HS(CH2)3SH, F3CCH2OH, r.t.; (xii) DCC, DMAP, C4H3SC(O)Cl.
In those reactions in which tetramate 9 was formed along former, but that several were active against the latter, typ-
with 8b (Scheme 2), reduction of the mixture permitted ically with a potency of about 0.05–0.07% of the cepha-
isolation of alcohol 20 (Scheme 3) and plumboetherifica- losporin standard; this outcome is of interest given that
tion gave tricycle 21 (59% yield). Assignment of the for- Gram-negative bacteria are intrinsically more resistant to
mation of the five-membered ring and the stereochemistry antibacterials as a result of a more impermeable outer cell
was made by comparison of the chemical shifts with those membrane, and particularly efficient efflux pumps.6 Bio-
of product 16e [C(8)H, the two C(9)H and the two C(12)H activity and chemical informatics28 analysis is of interest
have very similar chemical shifts in both compounds] and (see Table in Supplementary Information). Although ox-
deprotection to lactam 22 proceeded efficiently (72% azolidines 7c, tetramates 8a,8b, pyroglutamates 10a,b,
yield).
11a,b, 12, 13 and 18b are active against E. coli, tricycles
15a, 16a, 16d and 16e (which might be considered most
closely to mimic the core ring system of isatisine) are to-
tally inactive against both organisms. For the active mol-
Of interest is that bioassay27 against S. aureus and E. coli
indicated that no compounds were active against the
Synlett 2011, No. 3, 378–382 © Thieme Stuttgart · New York

LETTER
Bicyclic Core of Isatisine
381
H
H
OC(O)C4H3S
OC(O)C4H3S
O
O
OH
O
H
H
H
H
(i)
(iii)
(ii)
9
O
O
O
N
N
N
H
O
HO
t-Bu
t-Bu
20
21 (59%)
22 (72%)
Scheme 3 Reagents and conditions: (i) NaBH4, AcOH (10%), CH2Cl2, r.t.; (ii) (C4H3SCO2)4Pb, F3CPh; (iii) HS(CH2)3SH, F3CCH2OH, r.t.
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range 452–587 Å2,29 and the CMR value, which is a mea-
sure of the van der Waals attractive forces that act in drug-
receptor interactions30 is in the range 74–107; this is to be
expected from the common structural skeleton of these
compounds. The active molecules have ClogD, %PSA
and CMR average values of 2.5 0.76, 14.5 1.3 and
91.6 12.9, respectively. The polar surface area parameter
(PSA), which correlates the presence of polar atoms with
membrane permeability and therefore gives an indication
of drug transport properties,31 has been reported to have
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orally absorbable drug,32 and of interest is that the com-
pounds active against E. coli all lie at the lower end of this
range, with the exception of diester 18b. The use of this
approach, guided by bioactive natural product structures,
is likely to be valuable for the characterisation of chemical
space33 and may provide a useful start point for the iden-
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design, especially where target identity or structure is not
known.34
We have recently demonstrated the low intrinsic antibac-
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but that modest manipulation of the skeletal
functionality10,35 or homologation to longer chain side-
units36 can restore activity. It may be that similar adjust-
ment of the tricyclic skeletons synthesised in this work
will be required before antibacterial bioactivity is ob-
served; however, it is noted that no antibacterial activity
of isatisine 1 per se, as opposed to the plant extracts, has
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bacterial plant extract activity may not result from this
compound alone.
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