A hetero Diels-Alder approach to novel thiopyran analogues of aprikalim, a potassium channel activator

Article abstract of DOI:10.1016/S0040-4039(00)60834-1

α-Thioketo-ester (6) derived from Bunte salt (5) has been shown to undergo a hetero Diels-Alder reaction with a variety of dienes to form the basis of a concise synthesis of dihydrothiopyran analogues of the potassium channel activator aprikalim.

Full text of DOI:10.1016/S0040-4039(00)60834-1

Vol. 33. NO. 49. pp.
Britain
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A Hetero
A
To Novel Thiopyran Analogues Of
Potassium Channel Activator
Ivan L.
Derek R. Buckle,
K.
and David G. Smith
Great Burgh, Yew Tree Bottom
Surrey.
UK.
Key Words:
Channel Activator.
a
(6)
salt (5) has been shown to undergo a hetero
of a concise synthesis of dihydrothiopyran
reaction
of the potassium
with a variety of
the
channel activator aprikalim.
Potassium channel activators represent a new class of drug which appear to exert their smooth
muscle relaxant activity through the opening of ATP-sensitive potassium channels and consequent
Drugs
disorders including asthma, hypertension and angina pectoris. The
particular, has an immense impetus to delineate the structural
While the majority of synthetic effort has on cromakalim and its
has appeared on a structurally distinct but
activator.3 A versatile synthesis of such systems is described.
by this
hanism have potential in the treatment of a number of
of
in
required for
relatively little work
similar potassium channel
(1
In order to investigate the structural requirements for activity in aprikahm a flexible route for the
synthesis of was required and in particular one which addressed the problem of generating the
centre adjacent to the sulphoxide.
analysis (Scheme 1) suggested a possible
with suitably substituted dienes. Such an
fashion, with appropriate
approach via hetero Diels-Alder reactions of
approach would allow the construction of the thiopyran ring in a
SCHEME
1
7597

substituents derived
the diene component.
While thioketones of various types am readily available and are well documented as effective
constitute a little investigated class. This is possibly due to the of
synthesis
the thioketone in the
of the
the
developed by Kirby5 has allowed the
of the key intermediate (6) (Scheme 2) required to
investigate the hetero Diels-Alder approach. The
for ease of synthesis and has been shown to be an
substituent in (6) was chosen
replacement for the
group in
Br
NBS
90%
92%
SCHEME2
Thus, benxylic
of the
acetate (3) followed by displacement of
the bromide with sodium thiosulphate in aqueous ethanol yielded the Bunte salt
Initial attempts at isolating the key a-thioketoester (6) by treating this salt,
in 83% overall yield5.
with potassium t-butoxide
or triethylamine in the presence of calcium chloride led only to complex mixtures. suggesting that if (6) was
feasibility of trapping (6)
with a suitable diene in the hope that cycloaddition would compete favourably with the
it was prone to rapid decomposition under the conditions employed.
in
decomposition pathway was therefore investigated In this manner successful cycloaddition was shown to
proceed for a series of dienes (Table 1).
The conditions adopted in the
solvent. Under this regimen a modest yield of the dihydrothiopyran
dimethylbuta-1.3-d (Entry 1, Table 1). However, upon similar treatment cyclopentadiene failed to
When the
instance utiliscd potassium t-butoxide as the base and DMF as
was isolated on trapping with
provide any cycloaddition product, possibly due to the formation of the cyclopentadienyl anion.
base was
to triethylamine in ethanol and calcium chloride was added to precipitate the sulphite
These conditions
product5 a good yield of the
generally the most favourable
+
(9) was observed (Entry 3, Table 1).
and the
both
could be isolated
in good yields (Entries 2 and 4, Table 1). The Diels-Alder reactions of cyclopentadiene and
cyclohexadiene with (6) proceeded without any preference for the
over the exo isomer.
The only unsymmetrically substituted diene
diene. Under the usual conditions employed substantial cleavage of the silyl group was observed,
however, the Bunte salt (5) was, found to be soluble in most organic solvents and ether was a suitable
alternative to ethanol in this instance. In contrast to the observed with
ngioisomer (11) was the exclusive cycloaddition
observation is in accord with those reported by Vedejs for a series of
in which it was found that the of cycloaddition
with electron-rich dienes was reversed for Z ester, acyl, CN (electron withdrawing) compared with Z
with (6) was
dienes and carbonyl
the
isolated (Entry 5, Table 1).
reactions with thioaldehydes,

orbital
while
that when Z is strongly
enhance
enlargement of the
carbon atom.
of the
PRODUCT
SUBSTRATE
ENTRY
+
1
35%
2
65%
75%’
74%
I : I
39
ii)
TABLE
1

Table 1 contain the
minimal manipulation to convert the ester function into an amide. This is exemplified with the
(Scheme 3) hydrolysis of the ester (8) followed by conversion into
the N-methyl amide (14) via the acid chloride was achieved in good yield Finally, sodium
stereochemistry on the basis
of
only
to yield predominantly one isomer
of similar oxidations leading to
assigned the
2
1
A novel strategy for the synthesis of aprikalim
has been developed which should allow
rapid access to compounds having tetrahydrothiopyran rings. The aromatic ring substituents
can also be varied by
appropriate
in place of
so allowing a detailed
activity relationship profile to be built up.
REFERENCES
1.
V. A.; Buckingham, R. E.; Cassidy, F.; Evans, J. M.;
D. J.; Stemp, G.; Willcocks, K. Med.
Arch, J. R. S.; Buckle, D. R.; C.; Parr-Dobrxanski, H.;
E. A.; Hamilton, T. C.; Nash,
A.; Foster, K. A.;
Frydrych, C. S. V.; Pinto, I. L.; Smith, D. G.; Taylor, G. Med.
and
references therein.
J. C.;
Boger, D. L.; Weinreb, S. N.
Press: San Diego. pp
D.; James,
Mondot, S.;
Diels-Alder
I. Drugs
Future,
3.
4.
in
Academic
Kirby, G. W.; Lochead, A. W.;
Patent to May and Baker Ltd., U.S.
G. N. C.
1984,922.
and/or spectroscopic properties.
1990.
All new
exhibited satisfactory
All compounds with
Fleming, I.
centers
racemates of which one isomer is depicted.
Wiley: New York.
pp 140.
9.
Vedejs, E.; Perry,
A.; Houk, N.;
N. G. Ant.
10.
(Received in UK 17 August 1992)