Synthesis of the marine sponge derived β2-adrenoceptor agonist S1319

Article abstract of DOI:10.1021/ol0518840

(Chemical Equation Presented) The marine sponge derived β₂-adrenoceptor agonist S1319 has been synthesized following a six-step linear sequence. Central to the approach employed is the formation of a 7-lithiated-2,4-dialkoxybenzothiazole interm

Full text of DOI:10.1021/ol0518840

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4697-4700
Synthesis of the Marine Sponge Derived
2-Adrenoceptor Agonist S1319
â
Robin A. Fairhurst,* Diana Janus, and Annabel Lawrence
NoVartis Institutes for BioMedical Research, NoVartis Respiratory Research Centre,
Wimblehurst Road, Horsham, West Sussex, RH12 5AB, United Kingdom
robin.fairhurst@pharma.noVartis.com
Received August 5, 2005
ABSTRACT
The marine sponge derived â2-adrenoceptor agonist S1319 has been synthesized following a six-step linear sequence. Central to the approach
employed is the formation of a 7-lithiated-2,4-dialkoxybenzothiazole intermediate obtained via a directed-lithiation/benzyne-mediated cyclization
reaction. The incorporation of a tert-butyl ether residue into the cyclization precursor for the pivotal ring-closing step has been shown to
significantly increase the efficiency of the reaction by the suppression of a competing directed ortho-lithiation reaction.
Over the past century â2-adrenoceptor agonists have evolved
to become established as one of the front-line treatments for
the respiratory conditions asthma and chronic obstructive
pulmonary disease. Historically, the principal strategy for
refinement of this family of drugs has been achieved through
the rational manipulation of the endogenous ligand adrenaline
1.1 Following this approach has proven effective, and marked
improvements in stability, selectivity, and pharmacological
profile have been achieved. This has culminated in the
identification of the currently prescribed inhaled long-acting
â2-adrenoceptor agonists formoterol and salmeterol.2 Pres-
ently, the search to identify more effective â2-adrenoceptor
agonists continues with several groups striving to define the
next generation of drugs to advance this class.3 As an
alternative strategy, natural products have repeatedly pro-
vided the inspiration for new pharmaceuticals.4 Hence, the
disclosure by the Kirin Brewery of the natural product S1319
2, isolated from the marine sponge Dysidea sp., and described
as a â2-adrenoceptor agonist of equivalent potency to
formoterol attracted our attention as a potential new lead for
this therapeutic class.5 The structural relationship between
S1319 and adrenaline is shown in Figure 1. Noteworthy are
Figure 1. Structures of adrenaline 1 and S1319 2.
the common structural elements which indicate that both
compounds satisfy the same pharmacophore. The 5-hydroxy-
benzothiazolone group of 2 mimicks the oxidatively labile
catechol moiety of the native hormone.6 In this Letter we
describe our initial studies to define an efficient synthetic
route to 2.
(1) Waldeck, B. Eur. J. Pharmacol. 2002, 445, 1-12.
(2) Campbell, L. M. Int. J. Clin. Pract. 2002, 56, 783-790.
(3) (a) Anon Expert Opin. Ther. Pat. 2003, 13, 273-277. (b) Anon.
Expert Opin. Ther. Pat. 2004, 14, 1385-1388. (c) Cazzola, M.; Matera,
M. G.; Lo¨tvall, J. Expert Opin. InVest. Drugs 2005, 14, 775-783.
(4) Harvey, A. L. Trends Pharmacol. Sci. 1999, 20, 196-198. Drug
DiscoVery from Nature; Grabley, S., Thiericke, R., Eds.; Springer-Verlag:
Berlin: Germany, 1999.
(5) Suzki, H.; Shindo, K.; Ueno, A.; Miura, T.; Takei, M.; Sakakibara,
M.; Fukamachi, H.; Tanaka, J.; Higa, T. Bioorg. Med. Chem. Lett. 1999, 9,
1361-1364.
10.1021/ol0518840 CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/20/2005

A synthesis of 2 by the isolating group has previously been
described in the patent literature.7 This sequence is based
around an electrophilic closure to provide a 7-methylben-
zothiazole derivative as a key intermediate. The subsequent
manipulation of the 7-methyl residue, through an extended
sequence, delivered the required 7-N-methylethanolamine
functionality of 2 in 12 steps and 0.5% overall yield. More
recently a second synthetic approach has been described in
the patent literature based upon a Fries rearrangement of
4-bromoacetyloxy-benzothiazolone as the key step to install
the two-carbon unit at the 7-position of 2.8 We had sought
a more efficient route and reasoned that a requirement would
be the ability to introduce a more highly functionalized
7-substituent into the benzothiazolone nucleus at the ap-
propriate point in the synthesis. As a way to achieve this,
the intramolecular nucleophilic cyclizations of lithiated
benzyne thiocarbamates attracted our interest as reported by
Stanetty et al.9 Following such an approach would be
anticipated to provide an efficient route to 7-lithiated 2,4-
dialkoxybenzothiazole intermediates. The trapping of orga-
nometalic species of this type with suitably functionalized
electrophiles would provide the potential for direct access
to protected versions of the target 2. Such an approach is
outlined in the retrosynthetic analysis shown in Scheme 1.
precursor 3 was achieved in a single step by the addition of
2-propanol, as shown in Scheme 2. Exposure of 3 to the
Scheme 2. Preparation and Cyclization of 3
reported deprotonation/benzyne-mediated cyclization condi-
tions,9 followed by the addition of DMF produced the desired
7-formylated benzothiazole 4. Thus, this demonstrated the
formation of the desired 7-lithio-2,4-dialkoxybenzothiazole
intermediate, and the ability of this anion to react with a
model electrophile. However, in addition to the anticipated
product 4, the 3-formylated derivative 5 was also isolated,
along with the recovery of unreacted starting material 3. All
three of these components were present in the crude reaction
mixture to a similar extent. The byproduct 5 presumably is
derived from a competing lithiation ortho to the methoxy
group in 3, rather than the desired in-between deprotonation
at the 6-position. Observing such an effective competing
deprotonation of 3 was unanticipated based upon the reported
efficient cyclization of the equivalent carbamate analogues
to 7-lithio-4-methoxybenzoxazole intermediates which in-
dicates that in these doubly activated systems the thiocar-
bamate group is a less effective functionality for directing
ortho-metalation compared to the equivalent carbamate
moiety.10
Scheme 1. Retrosynthetic Analysis of 2
As a consequence, we considered ways for rationally
improving the selectivity in the above reaction in favor of
the 7-lithiated benzothiazole intermediate. To explore this
possibility, modifications of the reaction conditions to bias
the site of directed ortho-metalation away from the chelation
driven 3-position and in favor of both the inductively and
chelation driven 6-position were investigated as depicted in
Figure 2. In summary, variations of the solvent, base,
temperature profile, and the inclusion of anion modifiers were
all screened based upon precedents which had been shown
to favor either a halogen inductively driven ortho-deproto-
nation, a chelation assisted lithiated acyl aniline directed
ortho-lithiation, or anion equilibrating conditions at temper-
atures where elimination to the benzyne intermediate would
be anticipated to occur.11 The above modified conditions all
failed to either improve the selectivity ratio between 4 and
5 or increase the isolated yield of 4, compared with the
originally reported conditions.9 Complete consumption of the
starting material 3 could be achieved by increasing the
Our initial investigations toward the synthetic approach
proposed above started from the commercially available
5-chloro-2-methoxyphenylisothiocyanate. Conversion of this
starting material to the required thiocarbamate cyclization
(6) 4-Hydroxybenzothiazolones have previously been employed as
catechol mimics in a series of dopamine D2 agonists, and the dual dopamine
D2/â2-adrenoceptor agonist sibenadet, see: (a) Weinstock, J.; Gaitanopoulos,
D. E.; Stringer, O. D.; Franz, R. G.; Hieble, J. P.; Kinter, L. B.; Mann, W.
A.; Flaim, K. E.; Gessner, G. J. Med. Chem. 1987, 30, 1166-1176. (b)
Bonnert, R. V.; Brown, R. C.; Chapman, D.; Cheshire, D. R.; Dixon, J.;
Ince, F.; Kinchin, E. C.; Lyons, A. J.; Davis, A. M.; Hallam, C.; Harper, S.
T.; Unitt, J. F.; Dougall, I. G.; Jackson, D. M.; McKechnie, K.; Young, A.;
Simpson, W. T. J. Med. Chem. 1998, 41, 4915-4917.
(7) Suzki, H.; Shindo, K.; Ueno, A.; Miura, T.; Takei, M.; Fukamachi,
H.; Higa, T. PCT Int. Appl. WO 9909018, 1999.
(8) Okita, T.; Otsuka, N. Jpn. Kokai Tokkyo Koho JP 2005187357, 2005.
(9) Stanetty, P.; Krumpak, B. J. Org. Chem. 1996, 61, 5130-5133.
(10) Fisher, L. E.; Caroon, J. M. Synth. Commun. 1989, 19, 233-237.
Org. Lett., Vol. 7, No. 21, 2005
4698

Scheme 3. Preparation and Cyclization of 6
Figure 2. Factors controlling the regioselectivity of deprotonation
for the cyclization precursor 3, and potential strategies for favoring
proton removal from the 6-position.
followed by the addition of DMF.9 This similarly resulted
in the isolation of a mixture of the formylated products 4
and 7, in addition to the recovery of the starting material 6.
The ratio of these three components in the crude reaction
mixture was equivalent to that observed with the 5-chloro
analogue 3. This indicated that the change in the nature of
the leaving group at the 5-position seemed to have little effect
on the reaction outcome. Hence, we switched our attention
to the possibility of steric blockade as a way to suppress the
competing proton removal from the 3-position as a more
efficient route to the desired 7-lithiated 2,4-dialkoxyben-
zothiazole intermediate.
An added benefit of the steric blocking approach at the
2-position was anticipated to be the scope for the inclusion
of more readily removable protecting groups for the phenolic
residue present in the target 2. To this end, increasing the
size of the 2-methoxy group present in 3 and 6 to the level
of the tert-butoxy analogue, in addition to impeding the
undesired reactivity, was additionally anticipated to provide
an acid labile functionality for the final phase of the synthesis.
To explore this possibility, preparation of the required
cyclization precursor was started from 2,5-difluoronitroben-
zene, as shown in Scheme 4. Displacement of the more
amount of tert-butyllithium beyond the 2.8 equiv described
for the original procedure. However, this also resulted in what
was rationalized as the further reaction of the desired product
4, involving the displacement of the 2-isopropxy benzothia-
zole moiety by the tert-butyl anion, to give the 2-tert-butyl
benzothiazole analogue. This resulted in no improvement in
the overall efficiency of the reaction, but only in a more
tedious chromatographic separation to isolate the products.
As a consequence of the above limitations we next turned
our attention to an investigation into modifications of the
cyclization precursor 3 as a way to enhance the efficiency
of the formation of the desired 7-lithiated benzothiazole
species.
Two strategies were considered for the modification of
the cyclization precursor 3, as outlined in Figure 2. First
switching the 5-chloro to a 5-fluoro substituent was antici-
pated to enhance the inductive contribution to favor the
desired removal of the proton from the 6-position.12 As a
second strategy, increasing the size of the 2-alkoxy residue
was reasoned to be a way to stericaly suppress the undesired
deprotonation at the 3-position.
To explore the first strategy, the 5-fluoro cyclization
precursor 6 was readily prepared in an analogous manner to
the equivalent chloro analogue 3, as shown in Scheme 3.
Starting from 4-fluoro-2-nitroanisole, manipulation of the
nitro residue by reduction to the aniline, followed by
conversion to the isothiocyanate and the addition of 2-pro-
panol gave the desired thiocarbamate cyclization precursor
6.13 With 6 in hand, exposure of this material to the reported
deprotonation/benzyne-mediated cyclization conditions was
Scheme 4. Preparation and Cyclization of 9
(11) For conditions favoring deprotonation ortho to a halo substituent,
or metalated acylated aniline, see: (a) Fuhrer, W.; Gschwend, H. W. J.
Org. Chem. 1979, 44, 1133-1136. (b) Schlosser, M.; Katsoulos, G.;
Takagishi, S. Synlett 1990, 747-748. (c) Katsoulos, G.; Takagishi, S.;
Schlosser, M. Synlett 1991, 731-732. (d) Takagishi, S.; Katsoulos, G.;
Schlosser, M. Synlett 1992, 360-362. (e) Maggi, R.; Schlosser, M. J. Org.
Chem. 1996, 61, 5430-5434. (f) Moro-oka, Y.; Iwakiri, S.; Fukuda, T.;
Iwao, M. Tetrahedron Lett. 2000, 41, 5225-5228. For examples of reaction
conditions controlling equilibration between anion species, see: (g) Ziegler,
F. E.; Fowler, K. W. J. Org. Chem. 1976, 41, 1564-1565. (h) Leonard, N.
J.; Bryant, J. D. J. Org. Chem. 1979, 44, 4612-4616.
activated fluoride from the 2-position of this material
occurred efficiently via an SNAr reaction with potassium tert-
butoxide to produce the aryl ether 8.14 Subsequent reduction
(12) Kessar, S. V. ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 4, Chapter 2.3.
(13) Hodgkins, J. E.; Reeves, W. P. J. Org. Chem. 1964, 29, 3098-
3099.
(14) Woiwode, T. F.; Rose, C.; Wandless, T. J. J. Org. Chem. 1998, 63,
9594-9596.
Org. Lett., Vol. 7, No. 21, 2005
4699

of the nitro residue in 8 was followed by a sequence
analogous to that described above for the preparation of the
thiocarbamate 6. This sequence delivered the thiocarbamate
cyclization precursor 9 in 57% overall yield for the four steps.
As done previously, exposure of 9 to the reported deproto-
nation/benzyne-mediated cyclization conditions was followed
by quenching of the anion by the addition of DMF.9
Interestingly, in contrast to the 2-methoxy analogues of 9,
this modification now delivered the 7-formylated benzothia-
zolone 10 as the predominant product. 1H NMR analysis of
the crude reaction mixture showed no evidence for the
presence of significant quantities of the uncyclized 3-formy-
lated byproduct, equivalent to 5 and 7. Additionally, con-
sumption of the starting material 9 was essentially complete
in this reaction, with the aldehyde 10 being isolated in 78%
yield.
With an efficient route to the 7-lithiated 2,4-dialkoxyben-
zothiazole anion identified, we turned our attention to
reaction partners that would enable the introduction of the
required functionality into the 7-position of the natural
product 2. To achieve this, the readily prepared Boc-protected
sarcosine derived aldehyde 11 was anticipated to be suitable
for the introduction of a protected form of the desired
N-methylethanolamine residue directly.15 Thus, generation
of the 7-lithiated benzothiazole intermediate from 9, as
described above, was followed by addition of the electrophile
11. This reaction delivered the anticipated benzylic alcohol
12 in 74% isolated yield, as shown in Scheme 5. Finally,
global deprotection of 12 was then readily achieved upon
treatment with trifluoroacetic acid to give the target molecule
2.16
Scheme 5. Completion of the Synthesis of 2
In summary, the marine natural product 2 has been
prepared in racemic form following a six-step linear sequence
in 20% overall yield. The key step for this approach made
use of a directed-lithiation/benzyne-mediated cyclization,
which enabled the rapid introduction of a highly function-
alized substituent into the 7-position of the benzothiazolone
nucleus. To maximize the efficiency of this pivotal cycliza-
tion, the incorporation of a tert-butyl aryl ether residue was
used as a means to sterically suppress a competing directed
ortho-lithiation reaction. With an efficient synthetic route in-
hand, future studies will concentrate on exploring the
potential of the â2-adrenoceptor agonist 2 as a led for the
further advancement of this therapeutic class.
Acknowledgment. The authors thank Dr. Brian Everatt
and Dr. John Tyler for analytical support.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for the sequence leading to
2 and the model studies with 3, 6, and 9. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) Kato, S.; Harada, H.; Morie, T. J. Chem. Soc., Perkin Trans. 1 1997,
3219-3225.
(16) Comparison of the spectroscopic data obtained for 2, as the
trifluoroacetate salt, was consistent with that reported for the natural product
S1319 described in refs 5 and 7.
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