(±)-cis-(6-Ethyl-tetrahydropyran-2-yl)-formic acid: A novel substance with antinociceptive properties

Article abstract of DOI:10.1016/j.bmcl.2003.12.075

We described in this paper the first synthesis to the (±) cis (6-ethyl-tetrahydropyran-2-yl) formic acid (1) using the very efficient Prins cyclization reaction as strategy to construction of its tetrahydropyran skeleton. This new compound presented a significant antinociceptive property by the tail-flick model.

Full text of DOI:10.1016/j.bmcl.2003.12.075

Bioorganic & Medicinal Chemistry Letters 14 (2004) 1573–1575
(Æ)-cis-(6-Ethyl-tetrahydropyran-2-yl)-formic acid: a novel
substance with antinociceptive properties
L. S. M. Miranda,a Bruno G. Marinho,c Suzana G. Leitao,b Maria Eline Matheus,c
Patrıcia D. Fernandesc and M. L. A. A. Vasconcellosa,*
aNu´cleo de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro-UFRJ, CCS, Bloco H, Ilha do Funda˜o, 21941-590,
Rio de Janeiro, Brazil
b
´
Departamento de Produtos Naturais e Alimentos, Faculdade de Farmacia, UFRJ, CCS, Bloco A, Rio de Janeiro, Brazil
c
´
Departamento de Farmacologia Basica e Clınica, UFRJ, CCS, Bloco J, Rio de Janeiro, Brazil
´
Received 7 August 2003; revised 13 December 2003; accepted 18 December 2003
Abstract—We described in this paper the first synthesis to the (Æ) cis (6-ethyl-tetrahydropyran-2-yl) formic acid (1) using the very
efficient Prins cyclization reaction as strategy to construction of its tetrahydropyran skeleton. This new compound presented a
significant antinociceptive property by the tail-flick model.
# 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Chemistry
In our continuing search for bioactive substances from
natural sources, we have detected a very active one,
from the barks of a Brazilian medicinal plant of the
genus Vitex, with analgesic properties by the tail-flick
model.1 Further, the substance responsible for the
major activity of this extract was isolated, and its struc-
ture was tentatively assigned as cis-(6-ethyl-tetra-
hydropyran-2-yl) formic acid, 1.2 In order to confirm its
structure, and also to provide large amounts of this
substance for further pharmacological assays, a fast and
efficient synthetic route was proposed. In this work, we
describe the first diastereoselective synthesis of 1, which
when compared with the spectroscopic data of the nat-
ural product proved to have a different, although very
similar, structure. However, pharmacological assays
with the synthetic product 1 showed that it is also an
analgesic, by the tail-flick model.
Preparation of 1, was based on the strategy of
construction of the tetrahydropyran ring through the
Prins cyclisation reaction.3 The Prins cyclisation is an
old reaction that is now emerging as an efficient and
high diastereoselective methodology for the preparation
of tetrahydropyran skeletons, leading to tetra-
hydropyrans 2,4,6 all cis substituted. It has already been
successfully used in the synthesis of natural products.4
The synthesis of 1 starts with the allylation of the
commercial aldehyde 2, with allyl bromide, under zinc
mediated Barbier protocol,5 leading to the formation of
homoallylic alcohol 3 in 72% yield, after 3 h at rt. The
racemic homoallylic alcohol 3 was then employed as the
substrate for the Prins cyclization reaction with Propa-
nal, mediated by aluminum chloride as the Lewis acid,6,7
to furnish 4 in 67% yield as the only diastereoisomer
(Scheme 1).
For the dechlorination reaction of C4 in compound 4
energetic conditions were necessary, using lithium alu-
minum hydride in refluxing THF for 6 h.8 This protocol
led to alcohol 5 in 75% yield (Scheme 2).9
Finally the alcohol 5 was oxidized by the Jones
reagent,10 furnishing the carboxylic acid 1 in 91% yield.
The relative cis configuration of the groups present in
*Corresponding author. Fax: +55-21-2270-22683; e-mail: mlaav@
nppn.ufrj.br
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.12.075

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L. S. M. Miranda et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1573–1575
Scheme 1.
Figure 1. Effect of 1, dipyrone and morphine on tail flick model.
Substances were administered by oral application at the doses of 1 mg/
kg for 1 (&), morphine (*), dipyrone (ꢁ). At different time the reac-
tion time was recorded as described in materials and methods. Results
are expressed as increase in baseline (in%) from 10 animals.
4. Pharmacology
4.1. Tail flick test
Scheme 2.
the C2 and C6 positions of 1 were determinated by 13C
NMR spectroscopy through the characteristic down
field shift of the C2, C6 carbons11,12 for cis substituted
tetrahydropyran skeletons. The acid 1 was prepared
from 2 in 33% global yield (Scheme 3).
Mice were tested according to Eddy and Leimback.13
The animals tail were placed on a water bath set at
55Æ1 ꢀC and the reaction time was recorded when the
animals withdraw their tail. The reaction time (s) was
measured 40 and 20 min before and 20, 40, 80, 100, and
120 min after oral treatment with 1 mg/kg of 1. In order
to compare with commercially avaiable analgesic drugs
groups were composed by animals that received oral
administration 1 mg/kg of morphine or dipyrone.
3. Sample of the Prins cyclization
3.1. Isobutiric acid (cis-4-chloro-cis-6-ethyl-tetrahydro-
pyran-2-yl) methyl ester (4)
Figure 1 shows the results obtained after oral adminis-
tration of 1 at the dose of 1 mg/kg. This substance
developed a maximal effect increasing the antino-
ciceptive activity in 40% after 1 h decreasing thereafter.
When 1 was compared with analgesic drugs dipyrone
and morphine at doses corresponding to its IC50 values
(in our model) we observed that the effects of 1 was
almost the same of dipyrone with curves with similar
patterns. When 1 was compared with morphine admi-
nistered orally the results showed that maximal effects
from morphine was reached only after 100 min and
maximal response was 55% increase in analgesic activ-
ity. Results indicates that substance 1 develops analgesic
activity similar to dipyrone and more rapidly than
morphine in this case in half of time necessary to
reached tmaximal effects.
In a typical procedure for the Prins cyclization reaction,
2.70 g of aluminum chloride (20.2 mmol) is added to a
flame-dried flask, where 10 mL of dichloromethane
(dried under calcium hydride), is added. To this flask, a
solution containing 3.5 g (20.2 mmol) of homoallylic
alcohol 3, 1.5 mL (20.2 mmol) of propanal, in 6 mL of
dichloromethane is slowly added at 0 ꢀC. The reaction
mixture is left stirring at this temperature for 2.5 h.
After this time, 5 mL of a saturated sodium bicarbonate
solution is slowly added until pH 7. The organic phase
is then separated washed with brine, dried with sodium
sulphate and the evaporated under reduced pressure.
This crude product is then submitted to column flash
chromatography, yielding a colorless liquid in 67%
1
yield (3.03 g). H NMR (CDCl3 200 MHz) d 4.0 (m,
3H), 3.6 (m, 1H), 3.2 (m, 1H), 2.6 (sp, 7.1 Hz, 1H), 2.1
(m, 2H), 1.55 (m, 5H), 1.18 (d, 7.1 Hz, 6H) 0.93 (t, 7.4
Hz, 3H). 13C NMR (CDCl3 50 MHz), d 176.4, 77.8,
74.1, 55.0, 41.6, 38.5, 33.6, 28.3, 18.6, 9.5. IR (neat,
cmÀ1) 2972, 2937, 1737, 1470, 1387, 1197, 1150, 757.
5. Conclusion
The present work showed the first preparation of 1. The
methodology employed was highly diastereoselective
through the Prins cyclization reaction for the construc-
tion of the tetrahydropyran ring. This compound
showed significative antinocioceptive properties in the
preliminary tests by the tail flick model.
Detailed pharmacological and toxicological essays are
under investigation.
Scheme 3.

L. S. M. Miranda et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1573–1575
1575
Acknowledgements
this unsuccess was due to steric or electronic effects is
under investigation.
8. The use of tributyl tin hydride showed good results in this
transformation, however the difficulties in purifying the
product from the excess of reagent and its by-products,
led us to exclude this reaction as the reaction of choice.
The use of alkali metal reductions and hydrogenolisis led
to poor yields in this transformation.
CNPq, CAPES, FUJB and FAPERJ.
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